Administration of cyclophosphamide to rats induces pica and potentiates 5-hydroxytryptamine synthesis in the intestine without causing severe intestinal injury.

The effects of cyclophosphamide on 5-hydroxytryptamine (5-HT) synthesis in the intestinal tissue of rats were investigated. Rats received 120 mg/kg cyclophosphamide intraperitoneally as a single administration, and kaolin and food intake was measured by an automatic monitoring apparatus. Ileal tissues were collected at either 24 or 72 h after administration. Cyclophosphamide caused a significant increase in kaolin intake at the acute and the delayed phases and was associated with a decrease in food intake, and body weight. Cyclophosphamide had no significant effect on intestinal mucosal morphology, or inducible nitric oxide synthase and cyclooxygenase-2 expression in the intestine. Cyclophosphamide significantly increased tryptophan hydroxylase 1 (TPH1) mRNA expression, number of anti-TPH antibody-positive cells, and 5-HT content in the intestine. Cyclophosphamide also significantly increased the expression of Tac1 mRNA, encoding preprotachykinin-1, which is a preprotein of substance P, and the number of anti-substance P antibody-positive cells in the intestine. Cyclophosphamide significantly increased Lgr5, Bmi1, and Atoh1 mRNA levels, which are markers for the proliferation and differentiation of stem cells. This study demonstrated that cyclophosphamide induced pica in rats, and potentiated 5-HT synthesis associated with hyperplasia of substance P-containing enterochromaffin cells without causing severe intestinal injury.

TLR2 Plays a Pivotal Role in Mediating Mucosal Serotonin Production in the Gut.

Serotonin (5-hydroxytryptamine [5-HT]) is a key enteric signaling molecule that mediates various physiological processes in the gut. Enterochromaffin (EC) cells in the mucosal layer of the gut are the main source of 5-HT in the body and are situated in close proximity to the gut microbiota. In this study, we identify a pivotal role of TLR2 in 5-HT production in the gut. Antibiotic treatment reduces EC cell numbers and 5-HT levels in naive C57BL/6 mice, which is associated with downregulation of TLR2 expression but not TLR1 or TLR4. TLR2-deficient (Tlr2 -/-) and Myd88 -/- mice express lower EC cell numbers and 5-HT levels, whereas treatment with TLR2/1 agonist upregulates 5-HT production in irradiated C57BL/6 mice, which are reconstituted with Tlr2 -/- bone marrow cells, and in germ-free mice. Human EC cell line (BON-1 cells) release higher 5-HT upon TLR2/1 agonist via NF-κB pathway. Tlr2 -/- mice and anti-TLR2 Ab-treated mice infected with enteric parasite, Trichuris muris, exhibited attenuated 5-HT production, compared with infected wild-type mice. Moreover, excretory-secretory products from T. muris induce higher 5-HT production in BON-1 cells via TLR2 in a dose-dependent manner, whereby the effect of excretory-secretory products is abrogated by TLR2 antagonist. These findings not only suggest an important role of TLR2 in mucosal 5-HT production in the gut by resident microbiota as well as by a nematode parasite but also provide, to our knowledge, novel information on the potential benefits of targeting TLR2 in various gut disorders that exhibit aberrant 5-HT signaling.

Role of an active reserve stem cell subset of enteroendocrine cells in intestinal stem cell dynamics and the genesis of small intestinal neuroendocrine tumors.

Small intestinal neuroendocrine tumors (SI-NET) are serotonin-secreting well-differentiated neuroendocrine tumors of putative enterochromaffin (EC) cell origin. Recent studies recognize a subset of EC cells that is label-retaining at the +4 position in the crypt and functions as a reserve intestinal stem cell. Importantly, this +4 reserve EC cell subset not only contributes to regeneration of the intestinal epithelium during injury and inflammation but also to basal crypt homeostasis at a constant rate. The latter function suggests that the +4 EC cell subset serves as an active reserve stem cell via a constant rate of dedifferentiation. Characterization of early tumor formation of SI-NET, observed as crypt-based EC cell clusters in many cases of familial SI-NETs, suggests that the +4 active reserve EC cell subset is the cell of origin. This newly discovered active reserve stem cell property of EC cells can account for unique biological mechanisms and processes associated with the genesis and development of SI-NETs. The recognition of this property of the +4 active reserve EC cell subset may provide novel opportunities to explore NETs in the gastrointestinal tract and other organs.

Interaction of Human Enterochromaffin Cells with Human Enteric Adenovirus 41 Leads to Serotonin Release and Subsequent Activation of Enteric Glia Cells.

Human adenovirus 41 (HAdV-41) causes acute gastroenteritis in young children. The main characteristics of HAdV-41 infection are diarrhea and vomiting. Nevertheless, the precise mechanism of HAdV-41-induced diarrhea is unknown, as a suitable small-animal model has not been described. In this study, we used the human midgut carcinoid cell line GOT1 to investigate the effect of HAdV-41 infection and the individual HAdV-41 capsid proteins on serotonin release by enterochromaffin cells and on enteric glia cell (EGC) activation. We first determined that HAdV-41 could infect the enterochromaffin cells. Immunofluorescence staining revealed that the cells expressed HAdV-41-specific coxsackievirus and adenovirus receptor (CAR); flow cytometry analysis supported these findings. HAdV-41 infection of the enterochromaffin cells induced serotonin secretion dose dependently. In contrast, control infection with HAdV-5 did not induce serotonin secretion in the cells. Confocal microscopy studies of enterochromaffin cells infected with HAdV-41 revealed decreased serotonin immunofluorescence compared to that in uninfected cells. Incubation of the enterochromaffin cells with purified HAdV-41 short fiber knob and hexon proteins increased the serotonin levels in the harvested cell supernatant significantly. HAdV-41 infection could also activate EGCs, as shown in the significantly altered expression of glia fibrillary acidic protein (GFAP) in EGCs incubated with HAdV-41. The EGCs were also activated by serotonin alone, as shown in the significantly increased GFAP staining intensity. Likewise, EGCs were activated by the cell supernatant of HAdV-41-infected enterochromaffin cells.IMPORTANCE The nonenveloped human adenovirus 41 causes diarrhea, vomiting, dehydration, and low-grade fever mainly in children under 2 years of age. Even though acute gastroenteritis is well described, how human adenovirus 41 causes diarrhea is unknown. In our study, we analyzed the effect of human adenovirus 41 infection on human enterochromaffin cells and found it stimulates serotonin secretion in the cells, which is involved in regulation of intestinal secretion and gut motility and can also activate enteric glia cells, which are found in close proximity to enterochromaffin cells in vivo This disruption of gut barrier homeostasis as maintained by these cells following human adenovirus 41 infection might be a mechanism in enteric adenovirus pathogenesis in humans and could indicate a possible serotonin-dependent cross talk between human adenovirus 41, enterochromaffin cells, and enteric glia cells.

Nitric oxide plays a critical role in methotrexate-induced hyperplasia of enterochromaffin cells containing 5-hydroxytryptamine in rat small intestine.

The role of nitric oxide (NO) in the changes in enterochromaffin cells and ileal 5-hydroxytryptamine (5-HT) content induced by a single i.p. administration of methotrexate was investigated in rats. Methotrexate significantly increased inducible NO synthase (iNOS) mRNA and protein expressions in the intestinal tissue at 96 h. Methotrexate also significantly caused hyperplasia of the enterochromaffin cells at 96 h; this was associated with a significant increase in 5-HT content. The methotrexate-induced hyperplasia of enterochromaffin cells and increase in 5-HT content were, however, completely suppressed by daily treatment with dexamethasone, and with NG-nitro-l-arginine methyl ester (l-NAME); this was not observed when meloxicam was administered. Histological examination showed slight but not pronounced mucosal injury, at 96 h after methotrexate administration. The methotrexate-induced decrease in body weight did not fully recover to the control level up to 96 h; however, the methotrexate-induced decrease in food/water intake slightly returned to the control level up to 96 h. l-NAME had no significant effect on methotrexate-induced body weight loss and anorexia. To conclude, the present study suggests that NO derived from methotrexate-induced iNOS plays a critical role in the mechanism of hyperplasia of enterochromaffin cells containing 5-HT in the intestinal tissue of rats.

Problems Associated with Deprescribing of Proton Pump Inhibitors.

Proton pump inhibitors (PPIs) are recommended as a first-line treatment for gastroesophageal reflux disease (GERD) and other acid related disorders. In recent years, concerns have been raised about the increasing prevalence of patients on long-term PPI therapy and inappropriate PPI use. It is well known that short-term PPI therapy is generally well tolerated and safe; however, their extensive long-term use is a major global issue. One of these long-standing concerns is PPI-induced gastrin elevation secondary to hypoacidity. Hypergastrinemia is believed to play a role in rebound hyperacidity when PPIs are discontinued resulting in induced dyspeptic symptoms that might result in the reinstitution of therapy. Gastrin exerts tropic effects in the stomach, especially on enterochromaffin-like (ECL) cells, and concerns have also been raised regarding the potential progression to dysplasia or tumor formation following long-term therapy. It is well known that a substantial number of patients on long-term PPI therapy can discontinue PPIs without recurrence of symptoms in deprescribing trials. What is unknown is how sustainable deprescribing should be undertaken in practice and how effective it is in terms of reducing long-term outcomes like adverse drug events, morbidity and mortality. Moreover, there is no clear consensus on when and how deprescribing strategies should be attempted in practice. This review sought to summarize the harms and benefits of long-term PPI therapy with special focus on gastrin elevation and its relation to deprescribing studies and future interventions that may improve PPI use.

Idiopathic Colitis in Rhesus Macaques Is Associated With Dysbiosis, Abundant Enterochromaffin Cells and Altered T-Cell Cytokine Expression.

Idiopathic chronic diarrhea (ICD) is a common ailment affecting captive rhesus macaques ( Macaca mulatta). ICD cases are characterized by diarrhea in the absence of commonly identified diarrheal pathogens and multiple recurrences even after supportive therapy. Histologically, the disease is characterized by lymphoplasmacytic colitis. We identified 35 rhesus macaques euthanized for ICD during a 7-month period and described demographic, clinical, histologic, and immunologic commonalities. We found a trend of historic Campylobacter spp. and trichomonad infections. Furthermore, rhesus macaques with ICD demonstrated loss of normal colonic adherent bacterium, identified in this study as Helicobacter macacae; increased abundance of Pentatrichomonas hominis; and increased frequency of colonic serotonin-positive enterochromaffin cells. Interestingly, colonic and ileal T-helper cells of animals with ICD manifested decreased capacity for expression of certain cytokines, in particular interleukin (IL)-4 and IL-13. These data further describe a common ailment and suggest new avenues to identify complex interactions involved in the etiology of recurring diarrhea in young rhesus macaques.

Autoimmune gastritis: relationships with anemia and Helicobacter pylori status.

BACKGROUND: Autoimmune gastritis (AIG) is a gastric pathologic condition affecting the mucosa of the fundus and the body and eventually leading to hypo-achlorhydria. AIMS: We report our clinical and pathological experience with AIG. METHODS: Data from patients with a diagnosis of AIG seen in the period January 2002-December 2012 were retrieved. Only patients with complete sets of biopsies were analyzed. RESULTS: Data from 138 patients were available for analysis. Pernicious anemia was present in 25% of patients, iron deficiency anemia was found in 29.7% of patients, hypothyroidism in 23% of patients, type 1 diabetes in 7.9% of patients, and vitiligo in 2.8% of patients. Parietal cell antibodies were positive in 65% of patients, and no patient had serology positive for celiac disease. All gastric biopsies showed glandular atrophy associated with enterochromaffin-like (ECL)-cells hyperplasia, features limited to the mucosa of the fundus and body, and focal glandular intestinal metaplasia. Helicobacter pylori was negative in all cases. CONCLUSIONS: AIG was strongly associated with anemia; atrophy, intestinal metaplasia and ECL hyperplasia in the gastric fundus and body are hallmarks of this condition.

Methotrexate causes acute hyperplasia of enterochromaffin cells containing substance P in the intestinal mucosa of rats.

This study aimed to investigate the acute and chronic effect of methotrexate on the intestinal substance P metabolism after a single administration to rats. Methotrexate caused a significant increase in the number of substance P-containing cells in the ileal mucosa both at 24 and 96 h. Most of enterochromaffin cells expressing l-tryptophan hydroxylase contained substance P. The expression of Tac1 mRNA was increased by methotrexate at 24 h, but not at 96 h. Thus, methotrexate causes acute hyperplasia of enterochromaffin cells in the intestinal mucosa of rats with a transient increase in the production of substance P.

Distinct cellular origins for serotonin-expressing and enterochromaffin-like cells in the gastric corpus.

BACKGROUND & AIMS: The alimentary tract contains a diffuse endocrine system comprising enteroendocrine cells that secrete peptides or biogenic amines to regulate digestion, insulin secretion, food intake, and energy homeostasis. Lineage analysis in the stomach revealed that a significant fraction of endocrine cells in the gastric corpus did not arise from Neurogenin3 (Neurog3)-expressing cells, unlike enteroendocrine cells elsewhere in the digestive tract. We aimed to isolate enriched serotonin-secreting and enterochromaffin-like (ECL) cells from the stomach and to clarify their cellular origin. METHODS: We used Neurogenic differentiation 1 (NeuroD1) and Neurog3 lineage analysis and examined the differentiation of serotonin-producing and ECL cells in stomach tissues of NeuroD1-cre;ROSA(tdTom), tryptophan hydroxylase 1 (Tph1)-cyan fluorescent protein (CFP), c-Kit(wsh/wsh), and Neurog3Cre;ROSA(tdTom) mice by immunohistochemistry. We used fluorescence-activated cell sorting to isolate each cell type for gene expression analysis. We also performed RNA sequencing analysis of ECL cells. RESULTS: Neither serotonin-secreting nor ECL cells of the corpus arose from cells expressing NeuroD1. Serotonin-secreting cells expressed a number of mast cell genes but not genes associated with endocrine differentiation; they did not develop in c-Kit(wsh/wsh) mice and were labeled with transplanted bone marrow cells. RNA sequencing analysis of ECL cells revealed high expression levels of many genes common to endocrine cells, including transcription factors, hormones, ion channels, and solute transporters but not markers of bone marrow cells. CONCLUSIONS: Serotonin-expressing cells of the gastric corpus of mice appear to be bone marrow-derived mucosal mast cells. Gene expression analysis of ECL cells indicated that they are endocrine cells of epithelial origin that do not express the same transcription factors as their intestinal enteroendocrine cell counterparts.

[Neuroendocrine neoplasms of the distal jejunum and ileum]. / Neuroendokrine Neoplasien des distalen Jejunums und Ileums.

Neuroendocrine neoplasms (NEN) of the distal jejunum and ileum derive from serotonin-producing enterochromaffin (EC) cells. Due to their low proliferation rate and their infiltrative growth, they are often discovered at an advanced disease stage when metastasis has already occurred. The biology of these tumours is different from other NEN of the digestive tract. In order to standardise and improve diagnosis and therapy, the guidelines for the diagnosis and clinical management of jejuno-ileal NEN as well as for the management of patients with liver and other distant metastases from NEN were revised by the European Neuroendocrine Tumour Society (ENETS) in 2012. This review focuses on aspects relevant for surgical pathology.

Case 200: Gastric enterochromaffinlike cell tumors in a patient with type 1 multiple endocrine neoplasia.

History A 55-year-old man presented with chronic epigastric pain lasting for about 1 year and without fever or vomiting. The abdomen was soft and tender at physical examination. Laboratory tests revealed unremarkable liver function, normal hemoglobin level, and normal amylase level. White blood cell count was normal, and there was no inflammatory syndrome. The patient's medical history included pancreatic gastrinoma resected by means of left pancreatectomy 31 years before, hyperparathyroidism treated with subtotal parathyroidectomy 24 years before, and a slowly growing lung mass known for 9 years. Esophagogastroduodenoscopy was performed because of a suspected gastroduodenal ulcer. The results showed numerous small (<10 mm) gastric and duodenal ulcers and multiple 10-15-mm polypoid gastric masses. Contrast material-enhanced dual-phase multidetector row computed tomography (CT) of the chest and abdomen was performed with a 64-section CT scanner (LightSpeed VCT; GE Healthcare, Milwaukee, Wis). Technical parameters for CT were as follows: pitch, 0.98; section thickness and reconstruction interval, 1.25 mm; 120 kVp; and variable milliamperage determined by x-, y-, and z-axis dose modulation. After an unenhanced abdominal scan, iobitridol, a nonionic iodinated contrast agent containing 350 mg of iodine per milliliter (Xenetix 350; Guerbet, Aulnay-sousbois, France), was administered intravenously through a 16-18-gauge catheter. A 120-mL dose of the contrast agent was injected via an antecubital vein at a rate of 4 mL/sec. No oral contrast medium was administered. After preliminary unenhanced abdominal scanning, arterial and portal venous phase acquisitions were obtained 45 and 80 seconds after initiation of contrast medium injection.

Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting.

Rotavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT) by enterochromaffin (EC) cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves connected to nucleus of the solitary tract (NTS) and area postrema in the brain stem, structures associated with nausea and vomiting. Our experiments revealed that RV can infect and replicate in human EC tumor cells ex vivo and in vitro and are localized to both EC cells and infected enterocytes in the close vicinity of EC cells in the jejunum of infected mice. Purified NSP4, but not purified virus particles, evoked release of 5-HT within 60 minutes and increased the intracellular Ca²âº concentration in a human midgut carcinoid EC cell line (GOT1) and ex vivo in human primary carcinoid EC cells concomitant with the release of 5-HT. Furthermore, NSP4 stimulated a modest production of inositol 1,4,5-triphosphate (IP3), but not of cAMP. RV infection in mice induced Fos expression in the NTS, as seen in animals which vomit after administration of chemotherapeutic drugs. The demonstration that RV can stimulate EC cells leads us to propose that RV disease includes participation of 5-HT, EC cells, the enteric nervous system and activation of vagal afferent nerves to brain structures associated with nausea and vomiting. This hypothesis is supported by treating vomiting in children with acute gastroenteritis with 5-HT3 receptor antagonists.

Glucose sensing by gut endocrine cells and activation of the vagal afferent pathway is impaired in a rodent model of type 2 diabetes mellitus.

Glucose in the gut lumen activates gut endocrine cells to release 5-HT, glucagon-like peptide 1/2 (GLP-1/2), and glucose-dependent insulinotropic polypeptide (GIP), which act to change gastrointestinal function and regulate postprandial plasma glucose. There is evidence that both release and action of incretin hormones is reduced in type 2 diabetes (T2D). We measured cellular activation of enteroendocrine and enterochromaffin cells, enteric neurons, and vagal afferent neurons in response to intestinal glucose in a model of type 2 diabetes mellitus, the UCD-T2DM rat. Prediabetic (PD), recent-diabetic (RD, 2 wk postonset), and 3-mo diabetic (3MD) fasted UCD-T2DM rats were given an orogastric gavage of vehicle (water, 0.5 ml /100 g body wt) or glucose (330 µmol/100 g body wt); after 6 min tissue was removed and cellular activation was determined by immunohistochemistry for phosphorylated calcium calmodulin-dependent kinase II (pCaMKII). In PD rats, pCaMKII immunoreactivity was increased in duodenal 5-HT (P < 0.001), K (P < 0.01) and L (P < 0.01) cells in response to glucose; glucose-induced activation of all three cell types was significantly reduced in RD and 3MD compared with PD rats. Immunoreactivity for GLP-1, but not GIP, was significantly reduced in RD and 3MD compared with PD rats (P < 0.01). Administration of glucose significantly increased pCaMKII in enteric and vagal afferent neurons in PD rats; glucose-induced pCaMKII immunoreactivity was attenuated in enteric and vagal afferent neurons (P < 0.01, P < 0.001, respectively) in RD and 3MD. These data suggest that glucose sensing in enteroendocrine and enterochromaffin cells and activation of neural pathways is markedly impaired in UCD-T2DM rats.

A clinicopathological study of serotonin of sigmoid colon mucosa in association with chronic symptoms in uncomplicated diverticulosis.

INTRODUCTION: Neurotransmitter imbalance is hypothesised as a pathogenetic mechanism in several bowel conditions. We previously reported increased 5-HT in the sigmoid mucosa of colon resected for complicated diverticular disease (DD). We aimed to identify if abnormal 5-HT expression is associated with symptoms of uncomplicated DD. METHODS: This was a prospective, comparative study and follow-up survey of symptoms. We examined the differences in 5-HT between DD patients and controls, as well as the presence of bowel symptoms at time of endoscopy and also 2 years later. Sigmoid biopsies were collected at colonoscopy. Immunohistochemical staining for 5-HT cells was performed. RESULTS: Eighty-seven patients were recruited, 37 (42.5 %) DD and 50 (57.5 %) controls. No patients underwent surgery. There was no significant difference in total mean number of 5-HT-positive cells in DD compared to controls or between patients and controls with abdominal symptoms. Forty-one patients (47.1 %) responded to questionnaires at median 57.8 months from biopsy. Eighteen (43.9 %) were DD and 23(56.1 %) controls. 5-HT counts showed no significant association to symptom persistence. DISCUSSION: Although 5-HT expression has previously been found to be increased in complicated DD in whole bowel-resected specimens, the same is not confirmed on colonic mucosal biopsies. This raises the suggestion that 5-HT may be involved in the development of acute complications but may not be involved in the pathogenesis of chronic symptoms.

Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome.

OBJECTIVES: Serotonin (5-hydroxytryptamine, 5-HT) metabolism may be altered in gut disorders, including in the irritable bowel syndrome (IBS). We assessed in patients with IBS vs. healthy controls (HCs) the number of colonic 5-HT-positive cells; the amount of mucosal 5-HT release; their correlation with mast cell counts and mediator release, as well as IBS symptoms; and the effects of mucosal 5-HT on electrophysiological responses in vitro. METHODS: We enrolled 25 Rome II IBS patients and 12 HCs. IBS symptom severity and frequency were graded 0-4. 5-HT-positive enterochromaffin cells and tryptase-positive mast cells were assessed with quantitative immunohistochemistry on colonic biopsies. Mucosal 5-HT and mast cell mediators were assessed by high-performance liquid chromatography or immunoenzymatic assay, respectively. The impact of mucosal 5-HT on electrophysiological activity of rat mesenteric afferent nerves was evaluated in vitro. RESULTS: Compared with HCs, patients with IBS showed a significant increase in 5-HT-positive cell counts (0.37 ± 0.16% vs. 0.56 ± 0.26%; P=0.039), which was significantly greater in patients with diarrhea-predominant IBS vs. constipation-predominant IBS (P=0.035). Compared with HCs, 5-HT release in patients with IBS was 10-fold significantly increased (P < 0.001), irrespective of bowel habit, and was correlated with mast cell counts. A significant correlation was found between the mucosal 5-HT release and the severity of abdominal pain (r(s)=0.582, P=0.047). The area under the curve, but not peak sensory afferent discharge evoked by IBS samples in rat jejunum, was significantly inhibited by the 5-HT3 receptor antagonist granisetron (P<0.005). CONCLUSIONS: In patients with IBS, 5-HT spontaneous release was significantly increased irrespective of bowel habit and correlated with mast cell counts and the severity of abdominal pain. Our results suggest that increased 5-HT release contributes to development of abdominal pain in IBS, probably through mucosal immune activation.

Mechanism of acid hypersecretion post curative gastrinoma resection.

BACKGROUND: Some patients with Zollinger-Ellison syndrome post curative gastrinoma resection continue to show gastric acid hypersecretion; however, the mechanism is unknown. AIM: The aim of this study was to prospectively study acid secretion following curative gastrinoma resection and analyze factors contributing in patients with Zollinger-Ellison syndrome. METHODS: Fifty patients cured post gastrinoma resection were studied with serial assessments of acid secretory status, cure status and ECL-cell status/activity (with serial biopsies, CgA, urinary N-MIAA). Correlative analysis was performed to determine predictive factors. RESULTS: Hypersecretion occurred in 31 patients (62%) and 14 had extreme-hypersecretion. There was an initial decline (3-6 months) in BAO/MAO, which then remained stable for eight years. Preoperative BAO correlated with the postoperative secretion, but not other clinical, tumoral, laboratory variables, the degree of postoperative acid suppression or type of antisecretory drug needed. Hypersecretors had greater postoperative ECL changes (P=0.005), serum CGA (P=0.009) and 24-h urinary N-MIAA (P=0.0038). CONCLUSIONS: Post curative resection, gastric hypersecretion persists long term (mean 8 years) in 62% of patients and in 28% it is extreme, despite normogastrinemia. No preoperative variable except BAO correlates with postresection hypersecretion. The persistent increased ECL-cell extent post curative resection suggests prolonged hypergastrinemia can lead to changes in ECL-cells that are either irreversible in humans or sustained by unknown mechanisms not involving fasting hypergastrinemia and which can result in hypersecretion, in a proportion of which it can be extreme. Whether similar findings may occur in patients with idiopathic GERD treated for prolonged periods (>10 years) with PPIs, at present, is unknown.

Review of the pathogenesis, diagnosis, and management of type I gastric carcinoid tumor.

Gastric carcinoid tumors comprise 7% of all gastrointestinal carcinoids and have significantly increased in incidence over the past few decades. Seventy to 80% of gastric carcinoids are type I, which usually are clinically asymptomatic and found incidentally at endoscopic evaluation for abdominal pain or anemia. In this review, advances in understanding the pathophysiology of type I gastric carcinoid are highlighted. In addition, various current diagnostic and treatment options are discussed. Although type I carcinoids generally hold a benign course, rigorous investigation is needed to ensure accurate diagnosis and optimal treatment. This includes appropriate diagnostic procedures and imaging and accurate staging of tumor. Tumor size, depth of invasion, presence of metastasis, and the tumor's gastrin dependency dictate treatment options. Appropriate treatments can consist of endoscopic resection, antrectomy, medical management, or frequent follow-up. This article provides a systematic method of evaluating and treating type I gastric carcinoid.

Analysis of real-time serotonin (5-HT) availability during experimental colitis in mouse.

Serotonin (5-HT)-containing enterochromaffin (EC) cells of the intestine transduce chemical and mechanical stimuli from the intestinal lumen by releasing 5-HT on to afferent nerve terminals. Dysfunctional mucosal 5-HT signaling has been implicated in heightened visceral sensitivity and altered motility in patients with inflammatory bowel disease and in animal models. Our aim was to characterize the release and uptake of 5-HT in the mouse dextran sulfate sodium (DSS; 5% wt/vol) model of colitis. We made electrochemical recordings and used an ELISA assay to determine mucosal 5-HT release and uptake in untreated mice and mice with DSS-induced colitis. Peak and steady-state 5-HT concentrations were measured before and during blockade of the serotonin reuptake transporter (SERT) with 1 microM fluoxetine. Electrochemical recordings showed that colons from DSS-treated mice had roughly twice the steady-state levels of extracellular 5-HT and compression-evoked 5-HT release compared with untreated mice. Fluoxetine doubled the compression-evoked and steady-state 5-HT levels in control and DSS mice. These data were supported by ELISA assays, which showed enhanced 5-HT release during colitis, by immunohistochemical analyses, which showed increases in EC cell numbers, and by real-time PCR, which identified a decrease in SERT mRNA expression in the mucosa during colitis. These data are the first to demonstrate 5-HT release close to its release site and near its site of action during DSS-colitis. We conclude that DSS-colitis increases 5-HT availability primarily by an increase in the numbers of EC cells and/or of content of 5-HT in these EC cells.

The study on the role of inflammatory cells and mediators in post-infectious functional dyspepsia.

OBJECTIVE: Functional dyspepsia is a common gastrointestinal disorder. The pathogenesis of functional dyspepsia remains unclear. Functional dyspepsia may begin after a bout of gastroenteritis (post-infectious functional dyspepsia) or de novo (nonspecific functional dyspepsia). The aim of this study was to investigate the prevalence and probable mechanisms of post-infectious functional dyspepsia. MATERIAL AND METHODS: Functional dyspepsia patients with a history of unsanitary food intake and acute gastroenteritis 6-12 months ago were enrolled. (13)C-UBT confirmed absence of H. pylori infection. Controls consisted of healthy nondyspeptic volunteers and patients with nonspecific functional dyspepsia. Gastric biopsies were used for routine histology, immunohistochemistry, electron microscopy, ELISA, HPLC assays and Western blot examination. RESULTS: Eighty-five subjects were entered including 35 with post-infectious functional dyspepsia, 30 with nonspecific functional dyspepsia, and 20 healthy controls. The number of mast cells in post-infectious functional dyspepsia and nonspecific functional dyspepsia were significantly greater than that in healthy controls. The number of enterochromaffin cells (ECs) in post-infectious functional dyspepsia was significantly higher than those in nonspecific functional dyspepsia or in healthy controls. The number of mast cells and ECs increased with the density of chronic inflammatory cells. The release of histamine and 5-hydroxytryptamine from gastric mucosa of post-infectious functional dyspepsia patients was significantly greater than those from nonspecific functional dyspepsia or healthy controls. Tryptase protein expression was higher in post-infectious functional dyspepsia and nonspecific functional dyspepsia than in healthy controls. The histological score of chronic gastric inflammation was greater in post-infectious functional dyspepsia versus patients with nonspecific functional dyspepsia or healthy controls. Electron microscopy showed secreting granules in the cytoplasm of both mast cells and ECs. The number of activated mast cells and Ecs at a distance of < 5 microm of nerve fibers were significantly greater in post-infectious functional dyspepsia versus nonspecific functional dyspepsia or controls. CONCLUSIONS: Dyspepsia may occur after an acute onset of gastroenteritis in a part of patients. Potent chemicals derived from mast cells and ECs, including histamine, tryptase and 5-hydroxytryptamine may be involved in the pathogenesis of post-infectious functional dyspepsia.