Recent PubMed Articles on Gut Motility

Neuronal Nitric Oxide Mediates the Anti-Inflammatory Effects of Intestinal Ischemic Preconditioning.

Neuronal Nitric Oxide Mediates the Anti-Inflammatory Effects of Intestinal Ischemic Preconditioning.

J Surg Res. 2019 Jul 10;244:241-250

Authors: Varga S, Juhász L, Gál P, Bogáts G, Boros M, Palásthy Z, Szabó A, Kaszaki J

Abstract
BACKGROUND: Ischemic preconditioning (IPC) can provide a defense against ischemia-reperfusion (IR)-induced acute inflammation and barrier dysfunction in many organs. Because nitric oxide (NO) has been implicated as a trigger or mediator in the IPC mechanism and because neuronal NO synthase (nNOS) is a dominant isoform of NOS in the gastrointestinal tract, our aim was to investigate the role of nNOS in IPC-induced protection after mesenteric IR.
MATERIALS AND METHODS: Intestinal IR was induced in sodium pentobarbital-anesthetized dogs by clamping the superior mesenteric artery for 60 min followed by 2 h of reperfusion (IR group; n = 7). In further groups, IPC was used (three cycles of 5-min ischemia/5-min reperfusion periods) before IR in the presence or absence of selective inhibition of nNOS with 7-nitroindazole (5 mg/kg, intravenously, in a bolus 15 min before IPC, n = 6 each). Changes in mesenteric vascular resistance, intramucosal pH (pHi), and small bowel motility were monitored. Plasma nitrite/nitrate levels, intestinal NO synthase activity, leukocyte accumulation, mast cell degranulation, and histologic injury were also determined.
RESULTS: Ischemia significantly decreased mesenteric vascular resistance and pHi, whereas IR induced a temporary bowel hypermotility and acute inflammatory reaction. IPC facilitated pHi recovery, attenuated motility dysfunction, elevated NOS-dependent NO production, and reduced leukocyte accumulation, mast cell degranulation, and mucosal injury. Pretreatment with 7-nitroindazole halted the IPC-induced increase in NO availability, pHi recovery, and the anti-inflammatory and morphologic effects.
CONCLUSIONS: Our data demonstrate that NO generated by intestinal nNOS plays a pivotal role in IPC-linked tissue protection by inhibiting an IR-related acute inflammatory response.

PMID: 31301480 [PubMed - as supplied by publisher]

Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A.

Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A.

FASEB J. 2019 Jul 12;:fj201900858R

Authors: Cil O, Anderson MO, Yen R, Kelleher B, Huynh TL, Seo Y, Nilsen SP, Turner JR, Verkman AS

Abstract
Interstitial cells of Cajal, which express the calcium-activated chloride channel transmembrane member 16A (TMEM16A), are an important determinant of gastrointestinal (GI) motility. We previously identified the acylaminocycloalkylthiophene class of TMEM16A inhibitors, which, following medicinal chemistry, gave analog 2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxylic acid o-tolylamide (TMinh-23) with 30 nM half-maximal inhibitory concentration. Here, we tested the efficacy of TMinh-23 for inhibition of GI motility in mice. In isolated murine gastric antrum, TMinh-23 strongly inhibited spontaneous and carbachol-stimulated rhythmic contractions. Pharmacokinetic analysis showed predicted therapeutic concentrations of TMinh-23 for at least 4 h following a single oral or intraperitoneal dose at 10 mg/kg. Gastric emptying, as assessed following an oral bolus of phenol red or independently by [99mTc]-diethylenetriamine pentaacetic acid scintigraphy, was reduced by TMinh-23 by ∼60% at 20 min. Interestingly, there was little effect of TMinh-23 on baseline whole-gut transit time or time to diarrhea induced by castor oil. Consequent to the delay in gastric emptying, TMinh-23 administration significantly reduced the elevation in blood sugar in mice following an oral but not intraperitoneal glucose load. These results provide pharmacological evidence for involvement of TMEM16A in gastric emptying and suggest the utility of TMEM16A inhibition in disorders of accelerated gastric emptying, such as dumping syndrome, and potentially for improving glucose tolerance in diabetes mellitus/metabolic syndrome and enhancing satiety in obesity.-Cil, O., Anderson, M. O., Yen, R., Kelleher, B., Huynh, T. L., Seo, Y., Nilsen, S. P., Turner, J. R., Verkman, A. S. Slowed gastric emptying and improved oral glucose tolerance produced by a nanomolar-potency inhibitor of calcium-activated chloride channel TMEM16A.

PMID: 31299174 [PubMed - as supplied by publisher]

First translational consensus on terminology and definitions of colonic motility in animals and humans studied by manometric and other techniques.

First translational consensus on terminology and definitions of colonic motility in animals and humans studied by manometric and other techniques.

Nat Rev Gastroenterol Hepatol. 2019 Jul 11;:

Authors: Corsetti M, Costa M, Bassotti G, Bharucha AE, Borrelli O, Dinning P, Di Lorenzo C, Huizinga JD, Jimenez M, Rao S, Spiller R, Spencer NJ, Lentle R, Pannemans J, Thys A, Benninga M, Tack J

Abstract
Alterations in colonic motility are implicated in the pathophysiology of bowel disorders, but high-resolution manometry of human colonic motor function has revealed that our knowledge of normal motor patterns is limited. Furthermore, various terminologies and definitions have been used to describe colonic motor patterns in children, adults and animals. An example is the distinction between the high-amplitude propagating contractions in humans and giant contractions in animals. Harmonized terminology and definitions are required that are applicable to the study of colonic motility performed by basic scientists and clinicians, as well as adult and paediatric gastroenterologists. As clinical studies increasingly require adequate animal models to develop and test new therapies, there is a need for rational use of terminology to describe those motor patterns that are equivalent between animals and humans. This Consensus Statement provides the first harmonized interpretation of commonly used terminology to describe colonic motor function and delineates possible similarities between motor patterns observed in animal models and humans in vitro (ex vivo) and in vivo. The consolidated terminology can be an impetus for new research that will considerably improve our understanding of colonic motor function and will facilitate the development and testing of new therapies for colonic motility disorders.

PMID: 31296967 [PubMed - as supplied by publisher]

The role of mast cells in pediatric gastrointestinal disease.

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The role of mast cells in pediatric gastrointestinal disease.

Ann Gastroenterol. 2019 Jul-Aug;32(4):338-345

Authors: Ravanbakhsh N, Kesavan A

Abstract
Mast cells are granulocytes derived from CD34+ pluripotent progenitor cells that demonstrate plasticity in their development, leaving the bone marrow and differentiating in the tissue where they ultimately reside. They are best known for their role in the allergic response, but also play a prominent immunoregulatory role in other processes, including immune tolerance, the innate immune response, angiogenesis, wound healing and tissue remodeling. Mast cells are found throughout the gastrointestinal tract; their metabolic products influence and regulate intestinal epithelial and endothelial function, gastrointestinal secretion, intestinal motility and absorption, and contribute to host defense. They also play an important role in the development of visceral hypersensitivity through bidirectional interaction with the enteric nervous system. Mast cells have been found to have an increasingly important role in the pathophysiology of a number of pediatric gastrointestinal diseases. This review summarizes the current understanding of the role that mast cells play in the development of pediatric gastrointestinal disorders, including eosinophilic esophagitis, functional dyspepsia, irritable bowel syndrome, celiac disease, inflammatory bowel disease, histologically negative appendicitis, Hirschsprung's disease, intestinal neuronal dysplasia, and food protein-induced enterocolitis syndrome.

PMID: 31263355 [PubMed]

Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms.

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Ursodeoxycholic acid protects against intestinal barrier breakdown by promoting enterocyte migration via EGFR- and COX-2-dependent mechanisms.

Am J Physiol Gastrointest Liver Physiol. 2018 08 01;315(2):G259-G271

Authors: Golden JM, Escobar OH, Nguyen MVL, Mallicote MU, Kavarian P, Frey MR, Gayer CP

Abstract
The intestinal barrier is often disrupted in disease states, and intestinal barrier failure leads to sepsis. Ursodeoxycholic acid (UDCA) is a bile acid that may protect the intestinal barrier. We hypothesized that UDCA would protect the intestinal epithelium in injury models. To test this hypothesis, we utilized an in vitro wound-healing assay and a mouse model of intestinal barrier injury. We found that UDCA stimulates intestinal epithelial cell migration in vitro, and this migration was blocked by inhibition of cyclooxygenase 2 (COX-2), epidermal growth factor receptor (EGFR), or ERK. Furthermore, UDCA stimulated both COX-2 induction and EGFR phosphorylation. In vivo UDCA protected the intestinal barrier from LPS-induced injury as measured by FITC dextran leakage into the serum. Using 5-bromo-2'-deoxyuridine and 5-ethynyl-2'-deoxyuridine injections, we found that UDCA stimulated intestinal epithelial cell migration in these animals. These effects were blocked with either administration of Rofecoxib, a COX-2 inhibitor, or in EGFR-dominant negative Velvet mice, wherein UDCA had no effect on LPS-induced injury. Finally, we found increased COX-2 and phosphorylated ERK levels in LPS animals also treated with UDCA. Taken together, these data suggest that UDCA can stimulate intestinal epithelial cell migration and protect against acute intestinal injury via an EGFR- and COX-2-dependent mechanism. UDCA may be an effective treatment to prevent the early onset of gut-origin sepsis. NEW & NOTEWORTHY In this study, we show that the secondary bile acid ursodeoxycholic acid stimulates intestinal epithelial cell migration after cellular injury and also protects the intestinal barrier in an acute rodent injury model, neither of which has been previously reported. These effects are dependent on epidermal growth factor receptor activation and downstream cyclooxygenase 2 upregulation in the small intestine. This provides a potential treatment for acute, gut-origin sepsis as seen in diseases such as necrotizing enterocolitis.

PMID: 29672156 [PubMed - indexed for MEDLINE]

The recruitment of extra-intestinal cells to the injured mucosa promotes healing in radiation enteritis and chemical colitis in a mouse parabiosis model.

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The recruitment of extra-intestinal cells to the injured mucosa promotes healing in radiation enteritis and chemical colitis in a mouse parabiosis model.

Mucosal Immunol. 2019 03;12(2):503-517

Authors: Sung J, Sodhi CP, Voltaggio L, Hou X, Jia H, Zhou Q, Čiháková D, Hackam DJ

Abstract
Mucosal healing occurs through migration and proliferation of cells within injured epithelium, yet these processes may be inadequate for mucosal healing after significant injury where the mucosa is denuded. We hypothesize that extra-intestinal cells can contribute to mucosal healing after injury to the small and large intestine. We generated parabiotic pairs between wild-type and tdTomato mice, which were then subjected to radiation-induced enteritis and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis. We now show that as compared with singleton mice, mice with a parabiotic partner were protected against intestinal damage as revealed by significantly reduced weight loss, reduced expression of pro-inflammatory cytokines, reduced enterocyte apoptosis, and improved crypt proliferation. Donor cells expressed CD45-, Sca-1+, c-kit+, and CXCR4+ and accumulated around the injured crypts but did not transdifferentiate into epithelia, suggesting that extra-intestinal cells play a paracrine role in the healing response, while parabiotic pairings with Rag1-/- mice showed improved healing, indicating that adaptive immune cells were dispensable for mucosal healing. Strikingly, ablation of the bone marrow of the donor parabionts removed the protective effects. These findings reveal that the recruitment of extra-intestinal, bone marrow-derived cells into the injured intestinal mucosa can promote mucosal healing, suggesting novel therapeutic approaches for severe intestinal disease.

PMID: 30617302 [PubMed - indexed for MEDLINE]

IL-10 signaling prevents gluten-dependent intraepithelial CD4+ cytotoxic T lymphocyte infiltration and epithelial damage in the small intestine.

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IL-10 signaling prevents gluten-dependent intraepithelial CD4+ cytotoxic T lymphocyte infiltration and epithelial damage in the small intestine.

Mucosal Immunol. 2019 03;12(2):479-490

Authors: Costes LMM, Lindenbergh-Kortleve DJ, van Berkel LA, Veenbergen S, Raatgeep HRC, Simons-Oosterhuis Y, van Haaften DH, Karrich JJ, Escher JC, Groeneweg M, Clausen BE, Cupedo T, Samsom JN

Abstract
Breach of tolerance to gluten leads to the chronic small intestinal enteropathy celiac disease. A key event in celiac disease development is gluten-dependent infiltration of activated cytotoxic intraepithelial lymphocytes (IELs), which cytolyze epithelial cells causing crypt hyperplasia and villous atrophy. The mechanisms leading to gluten-dependent small intestinal IEL infiltration and activation remain elusive. We have demonstrated that under homeostatic conditions in mice, gluten drives the differentiation of anti-inflammatory T cells producing large amounts of the immunosuppressive cytokine interleukin-10 (IL-10). Here we addressed whether this dominant IL-10 axis prevents gluten-dependent infiltration of activated cytotoxic IEL and subsequent small intestinal enteropathy. We demonstrate that IL-10 regulation prevents gluten-induced cytotoxic inflammatory IEL infiltration. In particular, IL-10 suppresses gluten-induced accumulation of a specialized population of cytotoxic CD4+CD8αα+ IEL (CD4+ CTL) expressing Tbx21, Ifng, and Il21, and a disparate non-cytolytic CD4+CD8α- IEL population expressing Il17a, Il21, and Il10. Concomitantly, IL-10 suppresses gluten-dependent small intestinal epithelial hyperproliferation and upregulation of stress-induced molecules on epithelial cells. Remarkably, frequencies of granzyme B+CD4+CD8α+ IEL are increased in pediatric celiac disease patient biopsies. These findings demonstrate that IL-10 is pivotal to prevent gluten-induced small intestinal inflammation and epithelial damage, and imply that CD4+ CTL are potential new players into these processes.

PMID: 30542112 [PubMed - indexed for MEDLINE]

Tyrosine kinase Pyk2 is involved in colonic smooth muscle contraction via the RhoA/ROCK pathway.

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Tyrosine kinase Pyk2 is involved in colonic smooth muscle contraction via the RhoA/ROCK pathway.

Physiol Res. 2019 03 06;68(1):89-98

Authors: Tong L, Ao JP, Lu HL, Huang X, Zang JY, Liu SH, Song NN, Huang SQ, Lu C, Chen J, Xu WX

Abstract
The contraction of gastrointestinal (GI) smooth muscles is regulated by both Ca(2+)-dependent and Ca(2+) sensitization mechanisms. Proline-rich tyrosine kinase 2 (Pyk2) is involved in the depolarization-induced contraction of vascular smooth muscle via a Ca(2+) sensitization pathway. However, the role of Pyk2 in GI smooth muscle contraction is unclear. The spontaneous contraction of colonic smooth muscle was measured by using isometric force transducers. Protein and phosphorylation levels were determined by using western blotting. Pyk2 protein was expressed in colonic tissue, and spontaneous colonic contractions were inhibited by PF-431396, a Pyk2 inhibitor, in the presence of tetrodotoxin (TTX). In cultured colonic smooth muscle cells (CSMCs), PF-431396 decreased the levels of myosin light chain (MLC20) phosphorylated at Ser19 and ROCK2 protein expression, but myosin light chain kinase (MLCK) expression was not altered. However, Y-27632, a Rho kinase inhibitor, increased phosphorylation of Pyk2 at Tyr402 and concomitantly decreased ROCK2 levels; the expression of MLCK in CSMCs did not change. The expression of P(Tyr402)-Pyk2 and ROCK2 was increased when CSMCs were treated with Ach. Pyk2 is involved in the process of colonic smooth muscle contraction through the RhoA/ROCK pathway. These pathways may provide very important targets for investigating GI motility disorders.

PMID: 30433799 [PubMed - indexed for MEDLINE]

Roles of esophageal manometry study in children with refractory gastroesophageal reflux symptoms.

Roles of esophageal manometry study in children with refractory gastroesophageal reflux symptoms.

Pediatr Int. 2019 Jun 20;:

Authors: Hsing TY, Tsai IJ, Hsu CT, Wu JF

Abstract
BACKGROUND: We investigated the prevalence of psychiatric referral, the frequency of repeat upper gastrointestinal (UGI) contrast studies, and esophagogastroduodenoscopy (EGD) in patients with ineffective esophageal motility (IEM) before diagnosis.
METHODS: A total of 19 patients (9 males and 10 females; mean 13.80 ± 5.10 years of age) with refractory symptoms of gastroesophageal reflux who underwent high-resolution esophageal impedance manometry (HRIM) were enrolled in this retrospective study. Refractory gastroesophageal reflux symptoms was defined as subjects with persist symptoms even under acid-suppression therapy for 8 weeks in this study. Clinical data including age, sex, time from symptom onset to diagnosis, and number of UGI contrast studies and EGD examination before diagnosis were obtained. HRM parameters and the prevalence of psychiatric referral were also analyzed.
RESULTS: A significant proportion of IEM patients were misdiagnosed with psychological problems rather than gastroesophageal reflux disease (GERD) patients (78.57% vs. 20.00%, P = 0.04). Three IEM subjects (21.43%) received antipsychotic and antidepressant agents before diagnosis of IEM, and all of them discontinued these medications after diagnosis. These patients underwent a greater number of UGI contrast studies (1.07 ± 0.92 vs. 0.20 ± 0.45-examinations; P = 0.02) and EGD (2.36 ± 2.50 vs. 0.60 ± 0.55 examinations; P = 0.03) before HRM than GERD patients.
CONCLUSIONS: HRIM for the diagnosis of IEM should be considered in pediatric subjects with refractory gastroesophageal reflux symptoms to acid-suppression therapy for 8 weeks to avoid repeat UGI contrast studies, EGD tests, and psychological therapy. This article is protected by copyright. All rights reserved.

PMID: 31220381 [PubMed - as supplied by publisher]

Long-Chain Fatty Acid Receptors Mediate Relaxation of the Porcine Lower Esophageal Sphincter.

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Long-Chain Fatty Acid Receptors Mediate Relaxation of the Porcine Lower Esophageal Sphincter.

Front Physiol. 2019;10:676

Authors: Tsai CC, Li YC, Chang LC, Tey SL, Lin KJ, Huang SC

Abstract
Long-chain fatty acids activate the free fatty acid receptor 1 (FFA1) and FFA4. In the gastrointestinal system, FFA1 and FFA4 have been found in the pancreas and intestine. Fatty food and decreased lower esophageal sphincter (LES) motility are associated with gastroesophageal reflux disease. The effect of long-chain fatty acids on the esophageal motility is unknown. The purpose of this study is to investigate the effects of long-chain fatty acids on the porcine LES motility ex vivo using isometric transducers. In endothelin 1-precontracted porcine LES strips, the FFA1 selective agonists, fasiglifam, TUG424, and GW9508, caused marked relaxations in a concentration-dependent manner. The relative efficacies to elicit relaxation were GW9508 > TUG424 > fasiglifam in both clasp and sling strips. In contrast, the FFA4 specific agonists, TUG891 and GSK137647, produced mild relaxations. In addition, the endogenous FFA1 agonist DHA caused a mild relaxation whereas GW1100, an FFA1 antagonist, inhibited GW9508 induced relaxation of the porcine LES clasp and sling muscle. Both real-time PCR and immunohistochemistry revealed that FFA1 and FFA4 were expressed in the porcine LES. Real-time PCR analysis showed that the FFA4 expression was much lower than FFA1. Taken together, long-chain fatty acid receptor agonists elicit relaxation of the porcine LES. FFA1 might influence LES motility.

PMID: 31214048 [PubMed]

Irritable Bowel Syndrome: Is it Rare in Children?

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Irritable Bowel Syndrome: Is it Rare in Children?

Mymensingh Med J. 2018 Jan;27(1):216-221

Authors: Rukunuzzaman M, Karim AB, Nurullah M, Mazumder MW, Sultana K, Hussain F, Sultana F

Abstract
Irritable bowel syndrome (IBS) is one of the most common and best studied disorders among the group of functional gastrointestinal disorders. It is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit. Visceral hypersensitivity and increased GIT motility are the main patho-physiological mechanism for developing IBS. IBS present with diarrhea and constipation or both. Investigation is least needed for diagnosis of IBS rather done to exclude differential diagnosis. Diagnosis is done on the basis of Rome-III criteria. Proper counseling, dietary management, anti-spasmotic and antidepressant are the mainstay of treatment.

PMID: 29459618 [PubMed - indexed for MEDLINE]

It's Ok to be Negative!

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It's Ok to be Negative!

J Pediatr Gastroenterol Nutr. 2019 Jun 17;:

Authors: Di Lorenzo C, Nurko S

PMID: 31211765 [PubMed - as supplied by publisher]

Influence of Growth Factors on the Development of Necrotizing Enterocolitis.

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Influence of Growth Factors on the Development of Necrotizing Enterocolitis.

Clin Perinatol. 2019 03;46(1):51-64

Authors: Shelby RD, Cromeens B, Rager TM, Besner GE

Abstract
Growth factors have important roles in gastrointestinal tract development, maintenance, and response to injury. Various experiments have been used to demonstrate growth factor influence in multiple disease processes. These studies demonstrated enhancement of mucosal proliferation, intestinal motility, immune modulation, and many other beneficial effects. Select growth factors, including epidermal growth factor and heparin-binding epidermal growth factor like growth factor, demonstrate some beneficial effects in experimental and clinical intestinal injury demonstrated in necrotizing enterocolitis. The roles of glucagon-like peptide 2, insulin-like growth factor 1, erythropoietin, growth hormone, and hepatocyte growth factor in necrotizing enterocolitis are summarized in this article.

PMID: 30771819 [PubMed - indexed for MEDLINE]

Loss of Tbx3 in murine neural crest reduces enteric glia and causes cleft palate, but does not influence heart development or bowel transit.

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Loss of Tbx3 in murine neural crest reduces enteric glia and causes cleft palate, but does not influence heart development or bowel transit.

Dev Biol. 2018 12 01;444 Suppl 1:S337-S351

Authors: López SH, Avetisyan M, Wright CM, Mesbah K, Kelly RG, Moon AM, Heuckeroth RO

Abstract
Transcription factors that coordinate migration, differentiation or proliferation of enteric nervous system (ENS) precursors are not well defined. To identify novel transcriptional regulators of ENS development, we performed microarray analysis at embryonic day (E) 17.5 and identified many genes that were enriched in the ENS compared to other bowel cells. We decided to investigate the T-box transcription factor Tbx3, which is prominently expressed in developing and mature ENS. Haploinsufficiency for TBX3 causes ulnar-mammary syndrome (UMS) in humans, a multi-organ system disorder. TBX3 also regulates several genes known to be important for ENS development. To test the hypothesis that Tbx3 is important for ENS development or function, we inactivated Tbx3 in all neural crest derivatives, including ENS progenitors using Wnt1-Cre and a floxed Tbx3 allele. Tbx3 fl/fl; Wnt1-Cre conditional mutant mice die shortly after birth with cleft palate and difficulty feeding. The ENS of mutants was well-organized with a normal density of enteric neurons and nerve fiber bundles, but small bowel glial cell density was reduced. Despite this, bowel motility appeared normal. Furthermore, although Tbx3 is expressed in cardiac neural crest, Tbx3 fl/fl; Wnt1-Cre mice had structurally normal hearts. Thus, loss of Tbx3 within neural crest has selective effects on Tbx3-expressing neural crest derivatives.

PMID: 30292786 [PubMed - indexed for MEDLINE]

Enteric nervous system manifestations of neurodegenerative disease.

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Enteric nervous system manifestations of neurodegenerative disease.

Brain Res. 2018 08 15;1693(Pt B):207-213

Authors: Chalazonitis A, Rao M

Abstract
Neurological disorders cause gastrointestinal (GI) symptoms that are debilitating and markedly diminish quality of life in patients. The enteric nervous system (ENS), the intrinsic nervous system of the GI tract that is often referred to as "the second brain", shares many features with the central nervous system. The ENS plays an essential role in regulating many GI functions including motility and fluid secretion. Enteric neuronal degeneration could therefore be responsible for the GI symptoms commonly observed in neurological conditions. Here we describe the organization and functions of the ENS and then review the evidence for ENS involvement in two common neurodegenerative disorders, Parkinson's disease (PD) and Alzheimer's disease (AD). Data from patients as well as animal models suggest that PD affects distinct subsets of neurons and glia in the ENS, and that the ENS may participate in the pathogenesis of this disorder. While there has been great enthusiasm for the possibility of sampling the ENS for diagnosis or therapeutic monitoring of PD, further work is needed to determine which enteric neurons are most affected and how ENS function could be modulated to ameliorate GI symptoms in patients. Although AD is far more common than PD and AD patients also experience GI symptoms, understanding of ENS dysfunction in AD is in its infancy. Much work remains to be done in both of these fields to determine how the ENS contributes to and/or is altered by these disorders, and how to target the ENS for more effective treatment of GI comorbidities.

PMID: 29360466 [PubMed - indexed for MEDLINE]

Integrative Approach to Pediatric Nausea.

Integrative Approach to Pediatric Nausea.

Pediatr Ann. 2019 Jun 01;48(6):e236-e242

Authors: Arruda J, Yeh AM

Abstract
Nausea is a bothersome symptom that is commonly seen in the pediatric population. The pathophysiology of nausea is complex and involves the central nervous system, the enteric nervous system, gastrointestinal tract motility, and psychologic influences. Pharmacologic and nonpharmacologic therapies are available for treating nausea. Mind-body interventions (hypnosis, biofeedback), botanicals and supplements (ginger, enteric-coated peppermint oil), aromatherapy, and acupuncture have emerging evidence for effectively treating pediatric nausea. [Pediatr Ann. 2019;48(6):e236-e242.].

PMID: 31185115 [PubMed - in process]

Sexual dimorphism in upper gastrointestinal motility is dependent on duration of fast, time of day, age, and strain of mice.

Sexual dimorphism in upper gastrointestinal motility is dependent on duration of fast, time of day, age, and strain of mice.

Neurogastroenterol Motil. 2019 Jun 03;:e13654

Authors: Soni KG, Halder T, Conner ME, Preidis GA

Abstract
BACKGROUND: An important limitation of gastrointestinal motility testing is high variability. Conditions that could contribute to variability, including the duration of pretest fasting and time of day, are rarely reported and have not been examined systematically. This study aimed to explore whether these conditions, as well as age, sex, and strain of mice, affect the results of a standard laboratory test of upper gastrointestinal motility.
METHODS: Male and female 8-week-old C57BL/6J mice received a gastric gavage of fluorescein isothiocyanate (FITC)-conjugated dextran. FITC-dextran distribution was measured 30 minutes later. Mean geometric centers (MGCs) were calculated to determine the effects of short versus prolonged fasting and morning versus afternoon testing. The influence of age was assessed in 2- to 10-week-old animals, and the influence of strain was determined in C57BL/6J, BALB/c, and CD-1 mice.
KEY RESULTS: Motility was sexually dimorphic. MGC progressed 19% further in 8-week-old C57BL/6J males versus females when tested in the morning after a short fast. Similar patterns were observed in morning or afternoon testing after overnight fasting. In males, motility was unaffected by time of day; however, MGC progressed 31% further in females tested in the afternoon versus morning after a short fast. Sex differences also were present in CD-1 but not BALB/c mice. Testing in neonates revealed strikingly low variability and no sex differences.
CONCLUSIONS & INFERENCES: Fasting duration, time of day, age, sex, and strain of mice all influence upper gastrointestinal motility testing. Sex differences are not present in neonatal pups, but develop soon after weaning.

PMID: 31157504 [PubMed - as supplied by publisher]

Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature.

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Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature.

Am J Med Genet A. 2018 06;176(6):1455-1462

Authors: Lorenzo M, Stolte-Dijkstra I, van Rheenen P, Smith RG, Scheers T, Walia JS

Abstract
KIAA2022 is an X-linked intellectual disability (XLID) syndrome affecting males more severely than females. Few males with KIAA2022 variants and XLID have been reported. We present a clinical report of two unrelated males, with two nonsense KIAA2022 pathogenic variants, with profound intellectual disabilities, limited language development, strikingly similar autistic behavior, delay in motor milestones, and postnatal growth restriction. Patient 1, 19-years-old, has long ears, deeply set eyes with keratoconus, strabismus, a narrow forehead, anteverted nares, café-au-lait spots, macroglossia, thick vermilion of the upper and lower lips, and prognathism. He has gastroesophageal reflux, constipation with delayed rectosigmoid colonic transit time, difficulty regulating temperature, several musculoskeletal issues, and a history of one grand mal seizure. Patient 2, 10-years-old, has mild dysmorphic features, therapy resistant vomiting with diminished motility of the stomach, mild constipation, cortical visual impairment with intermittent strabismus, axial hypotonia, difficulty regulating temperature, and cutaneous mastocytosis. Genetic testing identified KIAA2022 variant c.652C > T(p.Arg218*) in Patient 1, and a novel nonsense de novo variant c.2707G > T(p.Glu903*) in Patient 2. We also summarized features of all reported males with KIAA2022 variants to date. This report not only adds knowledge of a novel pathogenic variant to the KIAA2022 variant database, but also likely extends the spectrum by describing novel dysmorphic features and medical conditions including macroglossia, café-au-lait spots, keratoconus, severe cutaneous mastocytosis, and motility problems of the GI tract, which may help physicians involved in the care of patients with this syndrome. Lastly, we describe the power of social media in bringing families with rare medical conditions together.

PMID: 29693785 [PubMed - indexed for MEDLINE]

Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans.

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Mutations in Vps15 perturb neuronal migration in mice and are associated with neurodevelopmental disease in humans.

Nat Neurosci. 2018 02;21(2):207-217

Authors: Gstrein T, Edwards A, Přistoupilová A, Leca I, Breuss M, Pilat-Carotta S, Hansen AH, Tripathy R, Traunbauer AK, Hochstoeger T, Rosoklija G, Repic M, Landler L, Stránecký V, Dürnberger G, Keane TM, Zuber J, Adams DJ, Flint J, Honzik T, Gut M, Beltran S, Mechtler K, Sherr E, Kmoch S, Gut I, Keays DA

Abstract
The formation of the vertebrate brain requires the generation, migration, differentiation and survival of neurons. Genetic mutations that perturb these critical cellular events can result in malformations of the telencephalon, providing a molecular window into brain development. Here we report the identification of an N-ethyl-N-nitrosourea-induced mouse mutant characterized by a fractured hippocampal pyramidal cell layer, attributable to defects in neuronal migration. We show that this is caused by a hypomorphic mutation in Vps15 that perturbs endosomal-lysosomal trafficking and autophagy, resulting in an upregulation of Nischarin, which inhibits Pak1 signaling. The complete ablation of Vps15 results in the accumulation of autophagic substrates, the induction of apoptosis and severe cortical atrophy. Finally, we report that mutations in VPS15 are associated with cortical atrophy and epilepsy in humans. These data highlight the importance of the Vps15-Vps34 complex and the Nischarin-Pak1 signaling hub in the development of the telencephalon.

PMID: 29311744 [PubMed - indexed for MEDLINE]

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