Submucosal Plexus Research Articles

ESOPHAGEAL VARICEAL-PULMONARY VENOUS FISTULA: A RARE CAUSE OF RIGHT TO LEFT SHUNT

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Esophageal varices are dilated submucosal venous plexus in the lower esophagus due to increased pressure in the portal venous system. We present a patient with esophageal varices which fistularized with a left pulmonary vein, thus creating a right to left shunt. The complications of right to left shunt include predominantly hypoxia, cyanosis and sometimes paradoxical emboli in case of intracardiac shunts. CASE PRESENTATION: 64-year-old gentleman who had a liver transplant in 2013 for Hepatitis C virus and hepatocellular cancer (HCC) which was complicated by HCC recurrence with metastasis. On his routine surveillance imaging he was noted to have an incidental finding of a fistula between his esophageal varices and the left pulmonary vein. This created a right to left shunt. Patient denied any significant respiratory symptoms. He denied orthopnea, platypnea, hemoptysis or cough. The patient was offered referral to Interventional Radiology for possible treatment options; however, he declined interventions and wanted to pursue conservative approach. He was continued on maintenance therapy with regorafenib. DISCUSSION: Right to Left shunts occur due to anatomic or physiologic causes. Anatomic shunts occur when the alveoli are completely bypassed as in the case of intracardiac shunts, intrapulmonary arteriovenous malformations. Physiologic shunts occur due to wasted perfusion of non-ventilated alveoli creating a ventilation-perfusion mismatch. Pulmonary manifestations of liver disease include hepatopulmonary syndrome, porto-pulmonary hypertension and hepatic hydrothorax. Hepatopulmonary syndrome is the most common of these and is a special variant of a right to left shunt. It is associated with intrapulmonary vascular dilatations and arteriovenous connections which are more common in lung bases. These are postulated to be secondary to vasoactive mediators like nitric oxide and inability of the liver to clear pulmonary vasodilators resulting in dyspnea and hypoxia. Classically hepatopulmonary syndrome is associated with platypnea and orthodeoxia. This refers to increased dyspnea and drop in O2 tension respectively from supine to upright positions. Our patient did not have any clinical manifestations as a result of this detected fistula, likely due to the volume of blood shunted being minimal and inadequate to cause symptoms. Hence, he did not need any intervention. Hypothetically though, a variceo-pulmonary venous fistula could become significant in a patient with hepatopulmonary manifestations and may necessitate an intervention based upon symptoms. CONCLUSIONS: This case report brings to light a very rare imaging finding that was incidentally detected which to the best of our knowledge has not been reported before. In the right clinical setting the presence of such a fistula could have clinical relevance and require treatment as well. Reference #1: 1. Krowka MJ, Fallon MB, Kawut SM, et al. International Liver Transplant Society Practice Guidelines: Diagnosis and Management of Hepatopulmonary Syndrome and Portopulmonary Hypertension. Transplantation 2016; 100:1440. Reference #2: 2. Hopkins WE, Waggoner AD, Barzilai B. Frequency and significance of intrapulmonary right-to-left shunting in end-stage hepatic disease. Am J Cardiol 1992; 70:516. Reference #3: 3. Schenk P, Schöniger-Hekele M, Fuhrmann V, et al. Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis. Gastroenterology 2003; 125:1042 DISCLOSURES: No relevant relationships by Siddique Chaudhary, source=Web Response No relevant relationships by Neeraja Swaminathan, source=Web Response

Mucosectomy disrupting the enteric nervous system causes contraction and shrinkage of gastrointestinal flaps: potential implications for augmentation cystoplasty

Augmenting the bladder with a seromuscular gastrointestinal flap is a promising alternative approach aiming for a mucus-free bladder augmentation; however, the contraction (shrinkage) of the flaps remains a major concern. Enteric nervous system (ENS) abnormalities cause a failure of relaxation of the intestinal muscle layers in motility disorders such as Hirschsprung's disease and intestinal neuronal dysplasia. In mammals, the submucosal enteric nervous plexus contains nitrergic inhibitory motor neurons responsible for muscle relaxation. The authors hypothesize that mucosectomy disconnects the submucosal nervous plexus from the myenteric plexus resulting in flap shrinkage. After ethical approval, mucosectomy was performed on vascularized flaps from the ileum, colon, and stomach in five anesthetized pigs. In Group (I), only the mucosa was scraped off with forceps, creating a sero-musculo-submucosal flap, while in Group (II), the mucosa and submucosa were peeled off as one layer, leaving a seromuscular flap. Isolated and detubularized segments served as control. The width of each flap was measured before and after the mucosectomy. The ENS was assessed by neurofilament immunohistochemistry in conventional sections and by acetylcholinesterase and NADPH-diaphorase enzyme histochemistry in whole-mount preparations. The stomach contracted to a lesser extent of its original width, 92.82±7.86% in Group (I) and 82.24±6.96% in Group (II). The ileum contracted to 81.68±4.25% in Group (I) and to 72.675±5.36% in Group (II). The shrinkage was most noticeable in the colon: 83.89±15.73% in Group (I) and to 57.13±11.51% in Group (II). One-way equal variance test showed significant difference (P<0,05) between Group (I) and (II), comparing stomach with ileum and ileum with colon. The histochemistry revealed that the submucosal nervous plexus containing nitrergic inhibitory neurons was disconnected from the myenteric plexus in Group (II) of all specimens. Mucosectomy resulted in significant immediate shrinkage of the flaps. This was more expressed when also the submucosa was peeled off, thus fully disrupting the ENS. The shrinkage affected the stomach the least and the colon the greatest. This phenomenon should be taken into consideration when planning mucus-free bladder augmentation.

Intestinal Neuronal Dysplasia Type B: Timely Diagnosis and Management

Abstract A 23-year-old female presented to the emergency department with abdominal pain and constipation. She reported an extensive history of constipation. Imaging showed distended bowel without an obstruction. During laparotomy, no obvious mechanical cause was found and a total colectomy was performed. Gross examination of the colectomy specimen showed cobblestoning in a 10-cm portion of the colon. Microscopic examination demonstrated hypoganglionosis of the myenteric plexus, hyperganglionosis of Auerbach’s plexus, and “giant ganglia.” This case met the 2006 Meier-Ruge criteria and diagnosis of intestinal neuronal dysplasia (IND) was established. IND was first described in 1971. The frequency of IND varies widely due to lack of consensus of diagnostic criteria and has a geographic distribution with the highest rates in Europe, which correlates to published research in this region. Diagnostic criteria are controversial and require standardization. Meier-Ruge suggests a quantitative analysis of the number of ganglion cells in the submucosal plexuses and the identification of at least 20% giant ganglia with at least 8 neurons each, in 25 analyzed ganglia. More recent diagnostic criteria are conservative with differences, including (1) elimination of increased AChE-positive nerve fibers around submucosal blood vessels, (2) stipulation that a giant ganglion contains more than 8 ganglion cells, (3) the requirement that more than 20% of at least 25 ganglia be giant ganglia, and (4) diagnostic exclusion of patients &lt;1 year. Clinical management is also controversial. Schimpl et al reported satisfactory results in 80% of 105 patients treated with dietary changes, cisapride, and laxatives with a median 7.2 years follow-up. Since colonic peristalsis is impaired by dysganglionosis, subtotal colectomy procedures have been widely successful. Clinicians should be mindful of IND in patients with a history of chronic constipation with abdominal pain and nonspecific imaging, as timely diagnosis can spare the patient from total colectomy and improve quality of life.

Opioid-Induced Foregut Dysfunction.

The impact of opioid use on the lower gastrointestinal tract is well described, but recent opioid crisis has caused increased awareness of the detrimental effects of these drugs on esophageal and gastroduodenal motility. Opioid use has been associated with increased incidence of spastic esophageal motility disorders and gastroduodenal dysfunction. Opioid receptors are present with high abundance in the myenteric and submucosal plexus of the enteric nervous system. Activation of these receptors leads to suppressed excitability of the inhibitory musculomotor neurons and unchecked tonic contraction of the autogenic musculature (such as the lower esophageal sphincter and the pylorus).

A study of residual lesions in horses that recovered from clinical signs of chronic equine dysautonomia.

BackgroundEquine dysautonomia (ED) causes degeneration and loss of autonomic neurons. Approximately 50% of chronic cases recover, but it is unclear how they survive neuronal loss.ObjectivesTo assess lesions, autonomic neuron numbers, interstitial cells of Cajal (ICC), and neurodegeneration in recovered cases.AnimalsThirteen cases (group ED), euthanized 10.3 ± 5.2 (1–16) years from diagnosis and 6 age‐matched controls (group C).MethodsProspective, case control; routine post mortem examination, neuron counts in peripheral and enteric ganglia and immunohistochemical assessment of neural networks (Protein gene product [PGP] 9.5), ICC (c‐kit), and neurodegeneration (beta‐amyloid precursor protein and ubiquitin) in intestine.ResultsPostmortem findings in group ED were small intestinal dilation (4/12, 33%) and muscular hypertrophy (4/12, 33%), and gastric mucosal hypertrophy (3/11, 27%) and ulceration (4/11, 36%). Neuron density was lower in group ED (mean 39% lower for cranial cervical ganglion [P < .001], median 44% lower in celiacomesenteric ganglion [P = .01]). In intestine, neuronal depletion was worst in ileum (median 100% lower in submucosal plexus [P < .001], 91% lower in myenteric plexus [P = .004]). Group ED had less PGP 9.5 staining in ileal myenteric plexus (mean 66% lower [P = .04]) and circular muscle (median 75% lower [P = .006]). In ileum, there was less c‐kit staining in myenteric plexus (median 57% lower [P = .02]) but not muscularis externa. Beta‐amyloid precursor protein and ubiquitin results were not indicitive of neurodegeneration.Conclusions and Clinical ImportanceIntact ICC in muscularis externa might help maintain motility after neuronal loss. Treatment supporting ICC function warrants investigation.

Age-associated changes of the intrinsic nervous system in relation with interstitial cells in the pre-weaning goat rumen.

In this study, we investigated the neural changes and their relationships with interstitial cells (ICs) in the rumen of pre-weaning goats by transmission electron microscopy, western blot and immunofluorescence (antibody: general neuronal marker-Protein Gene Product (PGP9.5)/ IC marker-vimentin). The immunofluorescence results showed that PGP9.5-positive reaction was widely distributed in neuronal soma (NS) and nerve fibre (NF). The NSs were observed in the ganglia of the myenteric plexus (MP) but not in the submucosal plexus. The mean optical density (MOD) of the whole of PGP9.5-positive nerves and the protein expression level of PGP.5 in the rumen wall both decreased significantly with age. However an obvious increase MOD of PGP.5-positive NFs within the rumen epithelium were observed. In the MP, the nerves and ICs were interwoven to form two complex networks that gradually tightened with age. Furthermore, NSs and nerve trunks were surrounded by a ring-boundary layer consisting of several ICs that became physically closer with aging. Moreover, ICs were located nearby NFs within the ML, forming connections between ICs, smooth muscle cells and axons. This study describes the pattern of neural distribution and its association with ICs in the developing rumen which shed light on the postpartum development of ruminants.

Alterations in Galanin-Like Immunoreactivity in the Enteric Nervous System of the Porcine Stomach Following Acrylamide Supplementation.

In recent years, a significant increase in the consumption of products containing large amounts of acrylamide (e.g., chips, fries, coffee), especially among young people has been noted. The present study was created to establish the impact of acrylamide supplementation, in tolerable daily intake (TDI) dose and a dose ten times higher than TDI, on the population of galanin-like immunoreactive (GAL-LI) stomach neurons in pigs. Additionally, in the present study, the possible functional co-operation of GAL with other neuroactive substances and their role in acrylamide intoxication was investigated. Using double-labelling immunohistochemistry, alterations in the expression of GAL were examined in the porcine stomach enteric neurons after low and high doses of acrylamide supplementation. Generally, upregulation in GAL-LI immunoreactivity in both myenteric and submucous plexuses was noted in all stomach fragments studied. Additionally, the proportion of GAL-expressing cell bodies simultaneously immunoreactive to vasoactive intestinal peptide (VIP), neuronal nitric oxide synthase (nNOS) and cocaine- and amphetamine- regulated transcript peptide (CART) also increased. The results suggest neurotrophic or/and neuroprotective properties of GAL and possible co-operation of GAL with VIP, nNOS, CART in the recovery processes in the stomach enteric nervous system (ENS) neurons following acrylamide intoxication.

Persistent Increased Enteric Glial Expression of S100β is Associated With Low-grade Inflammation in Patients With Diverticular Disease.

Diverticular disease (DD) is a common gastrointestinal inflammatory disorder associated with an enteric neuropathy. Although enteric glial cells (EGCs) are essential regulators of intestinal inflammation and motility functions, their contribution to the pathophysiology of DD remains unclear. Therefore, we analyzed the expression of specific EGC markers in patients with DD. Expression of the glial markers S100β, GFAP, Sox10, and Connexin 43 was analyzed by real-time quantitative PCR in colonic specimens of patients with DD and in that of controls. Protein expression levels of S100β, GFAP, and Connexin 43 were further analyzed using immunohistochemistry in the submucosal and myenteric plexus of patients with DD and in that of controls. Expression of the inflammatory cytokines tumor necrosis factor-α and interleukin-6 was quantified using qPCR, and infiltration of CD3+ lymphocytes was determined using immunohistochemistry. Expression of S100β was increased in the submucosal and myenteric plexus of patients with DD compared with that in controls, whereas expression of other glial factors remained unchanged. This increased expression of S100β was correlated to CD3+ lymphocytic infiltrates in patients with DD, whereas no correlation was observed in controls. DD is associated with limited but significant alterations of the enteric glial network. The increased expression of S100β is associated with a persistent low-grade inflammation reported in patients with DD, further emphasizing the role of EGCs in intestinal inflammation.

Ultrastructural changes of the human enteric nervous system and interstitial cells of Cajal in diverticular disease.

In spite of numerous advances in understanding diverticular disease, its pathogenesis remains one of the main problems to be solved. We aimed to investigate the ultrastructural changes of the enteric nervous system in unaffected individuals, in asymptomatic patients with diverticulosis and in patients with diverticular disease. Transmission electron microscopy was used to analyse samples of the myenteric, outer submucosal and inner submucosal plexuses from patients without diverticula (n=9), asymptomatic patients with diverticulosis (n=7) and in patients with complicated diverticular disease (n=9). We described the structure of ganglia, interstitial cells of Cajal and enteric nerves, as well as their relationship with each other. The distribution and size of nerve processes were analysed quantitatively. In complicated diverticular disease, neurons exhibited larger lipofuscin-like inclusions, their membranous organelles had larger cisterns and the nucleus showed deeper indentations. Nerve remodeling occurred in every plexus, characterised by an increased percentage of swollen and fine neurites. Interstitial cells of Cajal had looser contacts with the surrounding cells and showed cytoplasmic depletion and proliferation of the rough endoplasmic reticulum. In asymptomatic patients with diverticulosis, alterations of enteric nerves and ICC were less pronounced. In conclusion, the present findings suggest that most ultrastructural changes of the enteric nervous system occur in complicated diverticular disease. The changes are compatible with damage to the enteric nervous system and reactive remodeling of enteric ganglia, nerves and interstitial cells of Cajal. Disrupted architecture of enteric plexuses might explain clinical and pathophysiological changes associated with diverticular disease.

Down syndrome mouse models have an abnormal enteric nervous system.

Children with trisomy 21 (Down syndrome [DS]) have a 130-fold increased incidence of Hirschsprung Disease (HSCR), a developmental defect where the enteric nervous system (ENS) is missing from distal bowel (i.e., distal bowel is aganglionic). Treatment for HSCR is surgical resection of aganglionic bowel, but many children have bowel problems after surgery. Post-surgical problems like enterocolitis and soiling are especially common in children with DS. To determine how trisomy 21 affects ENS development, we evaluated the ENS in two DS mouse models, Ts65Dn and Tc1. These mice are trisomic for many chromosome 21 homologous genes, including Dscam and Dyrk1a, which are hypothesized to contribute to HSCR risk. Ts65Dn and Tc1 mice have normal ENS precursor migration at E12.5 and almost normal myenteric plexus structure as adults. However, Ts65Dn and Tc1 mice have markedly reduced submucosal plexus neuron density throughout the bowel. Surprisingly, the submucosal neuron defect in Ts65Dn mice is not due to excess Dscam or Dyrk1a, since normalizing copy number for these genes does not rescue the defect. These findings suggest the possibility that the high frequency of bowel problems in children with DS and HSCR may occur because of additional unrecognized problems with ENS structure.

1131-P: Endoscopic Duodenal Submucosal Laser Ablation for the Treatment of Type 2 Diabetes Mellitus: Results of First-in-Human Pilot Study

The duodenum has recently emerged as a key regulator in glucose metabolism via modulation of a complex network of neural and hormonal signals in response to ingested food. DiaGone™ is an endoscopic device which utilizes precisely controlled laser technology to target the duodenal submucosal neural plexi with the aim of improving glucose control by modulating the gastrointestinal neurohumoral axis. Nine subjects (5 males) with obesity (BMI 34.0 ± 4.6 kg/m2) and type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin were included in this first-in-human trial in order to assess the efficacy and safety of DiaGone™. Subjects were instructed to continue with regular diet 24h after the procedure and metformin dose was not changed during the study period. Biochemical and anthropometric parameters were assessed at baseline and 3 and 6 months after the procedure and continuous glucose monitoring (CGM) and a standard liquid meal test were performed at baseline and 3 months after the procedure. DiaGone™ significantly decreased HbA1C from 78.3 ± 13.3 mmol/mol at baseline to 64.9 ± 6.4 mmol/mol and 64.8 ± 7.1 mmol/mol at 3 and 6 months, respectively (p&amp;lt;0.01). Similarly, a decrease in fasting glucose levels was noted (12.4 ± 3.5 vs. 9.5 ± 2.0 vs. 9.7 ± 2.7 mmol/l, p&amp;lt;0.01) with no significant changes in fasting insulin levels. Glucose AUC during the 150 min meal test 3 months after the procedure showed a reduction of 20% from baseline (43,435 vs. 34,096, p&amp;lt;0.01). No significant changes were observed in AUC for insulin. No adverse events related to the procedure or significant changes in weight were reported throughout the 6-month period. In conclusion, these pilot results suggest that endoscopic duodenal submucosal laser ablation using the DiaGone™ device is associated with improvements in both baseline and postprandial glycemia as well as HbA1C with no significant changes in insulin levels or body weight while having a favorable safety and tolerability profile. Disclosure M. Mraz: None. I. Marcovitch: Employee; Self; Digma Medical. I. Lankova: None. H. Kratochvilova: None. A. Cinkajzlova: None. M. Benes: None. J. Korner: Board Member; Self; Digma Medical. Stock/Shareholder; Self; Digma Medical. Z. Vlasakova: None. J. Spicak: None. T. Pelikanova: None. M. Haluzik: None. Funding MH CZ - DRO; Institute for Clinical and Experimental Medicine (IN00023001); RVO (VFN64165)

Enteric Neurogenesis During Life Span Under Physiological and Pathophysiological Conditions.

The enteric nervous system (ENS) controls gastrointestinal key functions and is mainly characterized by two ganglionated plexus located in the gut wall: the myenteric plexus and the submucous plexus. The ENS harbors a high number and diversity of enteric neurons and glial cells, which generate neuronal circuitry to regulate intestinal physiology. In the past few years, the pivotal role of enteric neurons in the underlying mechanism of several intestinal diseases was revealed. Intestinal diseases are associated with neuronal death that could in turn compromise intestinal functionality. Enteric neurogenesis and regeneration is therefore a crucial aspect within the ENS and could be revealed not only during embryogenesis and early postnatal periods, but also in the adulthood. Enteric glia and/or enteric neural precursor/progenitor cells differentiate into enteric neurons, both under homeostatic and pathologic conditions beyond the perinatal period. The unique role of the intestinal microbiota and serotonin signaling in postnatal and adult neurogenesis has been shown by several studies in health and disease. In this review article, we will mainly focus on different recent studies, which advanced the concept of postnatal and adult ENS neurogenesis. Moreover, we will discuss the key factors and underlying mechanisms, which promote enteric neurogenesis. Finally, we will shortly describe neurogenesis of transplanted enteric neural progenitor cells. Anat Rec, 302:1345-1353, 2019. © 2019 Wiley Periodicals, Inc.

Effects of Serotonin and Slow-Release 5-Hydroxytryptophan on Gastrointestinal Motility in a Mouse Model of Depression.

Mood disorders and constipation are often comorbid, yet their shared etiologies have rarely been explored. The neurotransmitter serotonin (5-HT) regulates central nervous system and enteric nervous system (ENS) development and long-term functions, including gastrointestinal (GI) motility and mood. Therefore, defects in neuron production of 5-HT might result in brain and intestinal dysfunction. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT biosynthesis. A variant of TPH2 that encodes the R441H substitution (TPH2-R441H) was identified in individuals with severe depression. We studied mice with an analogous mutation (TPH2-R439H), which results in a 60%-80% decrease in levels of 5-HT in the central nervous system and behaviors associated with depression in humans. Feeding chow that contains 5-HTP slow release (5-HTP SR) to TPH2-R439H mice restores levels of 5-HT in the central nervous system and reduces depressive-like behaviors. We compared the effects of feeding chow, with or without 5-HTP SR, to mice with the TPH2-R439H mutation and without this mutation (control mice). Myenteric and submucosal plexuses were isolated from all 4 groups of mice, and immunocytochemistry was used to quantify total enteric neurons, serotonergic neurons, and 5-HT-dependent subsets of neurons. We performed calcium imaging experiments to evaluate responses of enteric neurons to tryptamine-evoked release of endogenous 5-HT. In live mice, we measured total GI transit, gastric emptying, small intestinal transit, and propulsive colorectal motility. To measure colonic migrating motor complexes (CMMCs), we isolated colons and constructed spatiotemporal maps along the proximodistal length to quantify the frequency, velocity, and length of CMMCs. We measured villus height, crypt perimeter, and relative densities of enterochromaffin and enteroendocrine cells in small intestinal tissue. Levels of 5-HT were significantly lower in enteric neurons from TPH2-R439H mice than from control mice. TPH2-R439H mice had abnormalities in ENS development and ENS-mediated GI functions, including reduced motility and intestinal epithelial growth. Total GI transit and propulsive colorectal motility were slower in TPH2-R439H mice than controls, and CMMCs were slower and less frequent. Villus height and crypt perimeter were significantly decreased in colon tissues from TPH2-R439H mice compared with controls. Administration of 5-HTP SR to adult TPH2-R439H mice restored 5-HT to enteric neurons and reversed these abnormalities. Adult TPH2-R439H mice given oral 5-HTP SR had normalized numbers of enteric neurons, total GI transit, and colonic motility. Intestinal tissue from these mice had normal measures of CMMCs and enteric epithelial growth CONCLUSIONS: In studies of TPH2-R439H mice, we found evidence for reduced release of 5-HT from enteric neurons that results in defects in ENS development and GI motility. Our findings indicate that neuron production of 5-HT links constipation with mood dysfunction. Administration of 5-HTP SR to mice restored 5-HT to the ENS and normalized GI motility and growth of the enteric epithelium. 5-HTP SR might be used to treat patients with intestinal dysfunction associated with low levels of 5-HT.

Immunohistochemical and ultrastructural analysis of the maturing larval zebrafish enteric nervous system reveals the formation of a neuropil pattern

The gastrointestinal tract is constructed with an intrinsic series of interconnected ganglia that span its entire length, called the enteric nervous system (ENS). The ENS exerts critical local reflex control over many essential gut functions; including peristalsis, water balance, hormone secretions and intestinal barrier homeostasis. ENS ganglia exist as a collection of neurons and glia that are arranged in a series of plexuses throughout the gut: the myenteric plexus and submucosal plexus. While it is known that enteric ganglia are derived from a stem cell population called the neural crest, mechanisms that dictate final neuropil plexus organization remain obscure. Recently, the vertebrate animal, zebrafish, has emerged as a useful model to understand ENS development, however knowledge of its developing myenteric plexus architecture was unknown. Here, we examine myenteric plexus of the maturing zebrafish larval fish histologically over time and find that it consists of a series of tight axon layers and long glial cell processes that wrap the circumference of the gut tube to completely encapsulate it, along all levels of the gut. By late larval stages, complexity of the myenteric plexus increases such that a layer of axons is juxtaposed to concentric layers of glial cells. Ultrastructurally, glial cells contain glial filaments and make intimate contacts with one another in long, thread-like projections. Conserved indicators of vesicular axon profiles are readily abundant throughout the larval plexus neuropil. Together, these data extend our understanding of myenteric plexus architecture in maturing zebrafish, thereby enabling functional studies of its formation in the future.

A Case Report of a Gastric Schwannoma on the Lesser Curvature of the Stomach Presenting with Upper Gastrointestinal Bleeding

Introduction: Gastric schwannomas are extremely rare mesenchymal tumors that represent only 0.2% of all gastric neoplasms. These tumors arise from the Auerbach or Meissner’s plexus and are most commonly found incidentally. Of those presenting with a gastric schwannoma only 12.8% of patients will present with upper gastrointestinal bleeding. Case Presentation: In this report, we present the case of a 51 year old female with signs and symptoms of upper gastrointestinal bleeding from a gastric schwannoma. The patient’s computed tomography revealed a 6.4 x 5.7 cm mass on the lesser curvature of the stomach near the pylorus. She subsequently underwent esophagogastroduodenoscopy with endoscopic ultrasound and fine needle aspiration revealing SMMS-1, Pankeratin, CD34, DOG-1, and CD117 negative immunohistochemical stains, which suggested a spindle cell neoplasm. The patient’s tumor was surgically resected two weeks later via laparoscopic distal gastrectomy with gastrojejunostomy. On immunohistochemistry, the tumor stained positive for S100, suggesting a gastric schwannoma. The patient’s postoperative course was complicated by possible early dumping syndrome which resolved in one week with dietary changes. She is tolerating regular food on follow-up and doing well. Discussion: With only a handful of reported cases, the need for inclusion of gastric schwannomas to the differential diagnosis of a bleeding gastric mass is essential. From these figures the likelihood of a patient with a gastric mass and upper gastrointestinal bleeding being caused by a gastric schwannoma is 0.026%. This points to the fact that this patient presentation is extremely rare but that gastric schwannomas do occur and need to be on the differential diagnosis of a patient with a gastric mass and signs of upper gastrointestinal bleeding.

Xenin-25 induces anion secretion by activating noncholinergic secretomotor neurons in the rat ileum.

Xenin-25 is a neurotensin-like peptide that is secreted by enteroendocrine cells in the small intestine. Xenin-8 is reported to augment duodenal anion secretion by activating afferent neural pathways. The intrinsic neuronal circuits mediating the xenin-25-induced anion secretion were characterized using the Ussing-chambered, mucosa-submucosa preparation from the rat ileum. Serosal application of xenin-25 increased the short-circuit current in a concentration-dependent manner. The responses were abolished by the combination of Cl--free and -free solutions. The responses were almost completely blocked by TTX (10-6 M) but not by atropine (10-5 M) or hexamethonium (10-4 M). The selective antagonists for neurotensin receptor 1 (NTSR1), neurokinin 1 (NK1), vasoactive intestinal polypeptide (VIP) receptors 1 and 2 (VPAC1 and VPAC2, respectively), and capsaicin, but not 5-hydroxyltryptamine receptors 3 and 4 (5-HT3 and 5-HT4), NTSR2, and A803467, inhibited the responses to xenin-25. The expression of VIP receptors (Vipr) in rat ileum was examined using RT-PCR. The Vipr1 PCR products were detected in the submucosal plexus and mucosa. Immunohistochemical staining showed the colocalization of NTSR1 and NK1 with substance P (SP)- and calbindin-immunoreactive neurons in the submucosal plexus, respectively. In addition, NK1 was colocalized with noncholinergic VIP secretomotor neurons. Based on the results from the present study, xenin-25-induced Cl-/ secretion is involved in NTSR1 activation on intrinsic and extrinsic afferent neurons, followed by the release of SP and subsequent activation of NK1 expressed on noncholinergic VIP secretomotor neurons. Finally, the secreted VIP may activate VPAC1 on epithelial cells to induce Cl-/ secretion in the rat ileum. Activation of noncholinergic VIP secretomotor neurons by intrinsic primary afferent neurons and extrinsic afferent neurons by postprandially released xenin-25 may account for most of the neurogenic secretory response induced by xenin-25. NEW & NOTEWORTHY This study is the first to investigate the intrinsic neuronal circuit responsible for xenin-25-induced anion secretion in the rat small intestine. We have found that nutrient-stimulated xenin-25 release may activate noncholinergic vasoactive intestinal polypeptide (VIP) secretomotor neurons to promote Cl-/ secretion through the activation of VIP receptor 1 on epithelial cells. Moreover, the xenin-25-induced secretory responses are mainly linked with intrinsic primary afferent neurons, which are involved in the activation of neurotensin receptor 1 and neurokinin 1 receptor.

Can Sertraline and Nortriptyline Protect the Neurons in Submucosal and Myenteric Plexuses of Rat's Colon Against Stress?

The colon is partly controlled by myenteric and submucosal plexuses, which respond to stress and lead to some gastrointestinal disorders. These plexuses play roles in irritable bowel syndrome. Patients suffering from this syndrome can be treated with some antidepressants, including sertraline and nortriptyline. The primary aim of study was to compare the effect of a sertraline and a nortriptyline on the structural changes of the enteric neurons after stress exposure in both sexes. The secondary objectives were to evaluate the effects of stress on the submucosal and myenteric plexuses. Male and female Sprague-Dawley rats were assigned to four subgroups. The first subgroup received no stress. The other three subgroups received chronic variable stress (CVS) and were given phosphate buffer, sertraline (10mg/kg/day), or nortriptyline (10mg/kg/day). After 45days, the neuron number in their colon plexuses was estimated using the stereologic method. The number of neurons increased by 40-51% in the submucosal plexus and by 57-69% in the myenteric plexus in the CVS group compared with the control group (p < 0.002) without any sex preference. The increment was significantly higher in the myenteric plexus than in the submucosal plexus (p < 0.05). Moreover, co-treatment of stressed rats with sertraline and nortriptyline could prevent the cellular hyperplasia of the plexuses, with more effective action for sertraline (p < 0.02). Stress exposure for 45days induced hyperplasia of the colon's enteric plexuses in both sexes. However, these drugs could prevent the changes, with a more effective action for sertraline.

Irinotecan-Induced Mucositis Is Associated with Goblet Cell Dysregulation and Neural Cell Damage in a Tumour Bearing DA Rat Model.

Irinotecan-induced mucositis is a major oncological problem. Goblet cells secrete mucus, protecting the intestinal mucosa, with secretion altered during mucositis. The enteric nervous system is involved in regulating gut motility and secretion. The aim of this study was to determine whether enteric neural cells and goblet cells are altered following irinotecan treatment. Tumour-bearing Dark Agouti rats were administered a single dose of 175mg/kg of irinotecan intraperitoneally and 0.01mg/kg atropine subcutaneously. Experimental and untreated control rats were killed at times 6, 24, 48, 72, 96 and 120h after treatment. Jejunum and colon samples were formalin fixed. Haematoxylin and eosin staining, Alcian Blue-PAS staining, and immunohistochemistry with S-100 antibody (neural cell marker) were carried out. Statistical analyses were carried out using Kruskal-Wallis test with Dunns post test, Mann Whitney U test and nonlinear regression. Total goblet cells decreased at 72h compared with controls in the colon (p < 0.05). The percentage of cavitated goblet cells decreased compared to all other time points at 120h in the colon. The number of S-100 positive cells in the submucosal plexus decreased in the colon (p = 0.0046) and in the myenteric plexus of the jejunum and colon (p = 0.0058 and p = 0.0022, respectively), when comparing treated with control. Enteric ganglia in the myenteric plexus of the jejunum decreased at 24h and 96h. Irinotecan-induced mucositis is associated with increases in mucus secretion, and enteric neural cell change. These changes may contribute to the pathophysiology of mucositis through the dysregulation of neural signalling.

Congenital intestinal stenosis and Hirschsprung\u2019s disease: two extremely rare pathologies in a newborn puppy

BackgroundHirschsprung’s disease (HSCR) is a common congenital malformation of the enteric nervous system (ENS). During fetal development, ganglion cells of the ENS are derived from neural crest cells that migrate to the bowel. These cells reside principally in two ganglionated plexus: 1) The myenteric plexus, extending from the esophagus to the anus, and 2) submucous plexus, extending from the duodenum to the anus. In large animal species, there is a third plexus called Henle’s or Schabadasch’s plexus.ENS ganglion cells play a key role in normal gastrointestinal motility, respond to sensory stimuli and regulate blood flow. Both plexus show a high degree of independence from the central nervous system. Alterations in the embryonic development of the ENS can induce multiple pathologies in animal models and humans.Case presentationThe present case was a female the fifth born in a litter of 5 puppies. At about 2–3 weeks of age, she suffered from abdominal distension, pain, and constipation. At approximately 8–10 weeks of age, the puppy started to vomit abundantly, and the regurgitated food appeared undigested. Progressive abdominal distention was observed, with quite visible peristaltic movements and more frequent vomiting episodes. The abdominal radiographs, based on AP and side projections, revealed an enlargement of the abdominal diameter and an increased width in the epigastric region. At 12 weeks of age, exploratory surgery revealed a stenotic segment in the jejunum, followed by a small transition zone and then a significantly reduced diameter. Immunohistochemical examinations were performed using antibodies against calretinin, S-100 protein, CD56, neuron specific enolase (NSE) and synaptophysin, which are the biological markers for diagnosing HSCR.ConclusionA reduced number of ganglion cells (1–3 cells per ganglion) were found. There was no specific staining pattern for many of these; while for others, the pattern was compatible with HSCR. Surgical intervention to remove the stenotic section prolonged the life of the puppy for 13 years. Extremely rare pathologies such as that discussed herein should be studied to understand the pathophysiology and be able to diagnose small species in veterinary medicine in a timely fashion. To our knowledge, this is the first report of congenital intestinal stenosis and Hirschprung’s disease in a newborn puppy.

Irinotecan induces enterocyte cell death and changes to muc2 and muc4 composition during mucositis in a tumour-bearing DA rat model.

Irinotecan-induced mucositis is a major oncological problem. Goblet cells secrete mucus, protecting the intestinal mucosa, with secretion altered during mucositis. The enteric nervous system is involved in regulating gut motility and secretion. The aim of this study was to determine whether enteric neural cells and goblet cells are altered following irinotecan treatment. Tumour-bearing Dark Agouti rats were administered a single dose of 175mg/kg of irinotecan intraperitoneally and 0.01mg/kg atropine subcutaneously. Experimental and untreated control rats were killed at times 6, 24, 48, 72, 96 and 120h after treatment. Jejunum and colon samples were formalin fixed. Haematoxylin and eosin staining, Alcian Blue-PAS staining, and immunohistochemistry with S-100 antibody (neural cell marker) were carried out. Statistical analyses were carried out using Kruskal-Wallis test with Dunns post test, Mann Whitney U test, and nonlinear regression. Total goblet cells decreased at 72h compared with controls in the colon (p < 0.05). The percentage of cavitated goblet cells decreased compared to all other time points at 120h in the colon. The number of S-100-positive cells in the submucosal plexus decreased in the colon (p = 0.0046) and in the myenteric plexus of the jejunum and colon (p = 0.0058 and p = 0.0022, respectively), on comparing treated with control. Enteric ganglia in the myenteric plexus of the jejunum decreased at 24h and 96h. Irinotecan-induced mucositis is associated with increases in mucus secretion and enteric neural cell change. These changes may contribute to the pathophysiology of mucositis through the dysregulation of neural signalling.