Exploring associations between lower urinary tract symptoms (LUTS) and gastrointestinal (GI) problems in women: a study in women with urological and GI problems vs a control population.

OBJECTIVES: To study the prevalence of self-reported lower urinary tract symptoms (LUTS) in women consulting a Gastroenterology clinic with complaints of functional constipation (FC), fecal incontinence (FI) or both, compared with a female control population. Also, to study the influence of FC, FI, or both on self-reported LUTS in women attending a Urology clinic. PATIENTS AND METHODS: We present a retrospective study of data collected through a validated self-administered bladder and bowel symptom questionnaire in a tertiary referral hospital from three different female populations: 104 controls, 159 gastroenterological patients and 410 urological patients. Based on the reported bowel symptoms, patients were classified as having FC, FI, a combination of both, or, no FC or FI. LUTS were compared between the control population and the gastroenterological patients, and between urological patients with and without concomitant gastroenterological complaints. Results were corrected for possible confounders through logistic regression analysis. RESULTS: The prevalence of LUTS in the control population was similar to large population-based studies. Nocturia was significantly more prevalent in gastroenterological patients with FI compared with the control population [odds ratio (OR) 9.1]. Female gastroenterological patients with FC more often reported straining to void (OR 10.3), intermittency (OR 5.5), need to immediately re-void (OR 3.7) and feeling of incomplete emptying (OR 10.5) compared with the control population. In urological patients, urgency (94%) and urgency urinary incontinence (UUI, 54% of UI) were reported more often by patients with FI than by patients without gastroenterological complaints (58% and 30% of UI respectively), whereas intermittency (OR 3.6), need to immediately re-void (OR 2.2) and feeling of incomplete emptying (OR 2.2) were reported more often by patients with FC than by patients without gastroenterological complaints. CONCLUSION: As LUTS are reported significantly more often by female gastroenterological patients than by a control population, and as there is a difference in self-reported LUTS between female urological patients with different concomitant gastroenterological complaints, we suggest that general practitioners, gastroenterologists and urologists should always include the assessment of symptoms of the other pelvic organ system in their patient evaluation. The clinical correlations between bowel symptoms and LUTS may be explained by underlying neurological mechanisms.

Histamine H4 and H1 receptors contribute to postinflammatory visceral hypersensitivity.

OBJECTIVES: Substantial evidence implicates mast cells and their main constituent histamine in the pathogenesis of visceral hypersensitivity. We explored the specific contribution of histamine H4 (H4R) and H1 (H1R) receptors to visceral hypersensitivity in a postinflammatory rat model. DESIGN: Trinitrobenzenesulfonic acid (TNBS)-colitis was monitored individually by colonoscopy: first on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Experiments were performed 3 days after endoscopic resolution of colitis. Visceral sensitivity was assessed by quantifying visceromotor responses (VMRs) to colorectal distension. Colonic mast cell numbers, histamine release and H4R and H1R mRNA expression were quantified. JNJ7777120 (H4R antagonist) and/or levocetirizine (H1R antagonist) were administered 30 min prior to VMR assessment or histamine release assay. RESULTS: Postcolitis rats displayed a higher number of colonic mast cells, excessive histamine release and significantly enhanced VMRs. Heightened VMRs were dose-dependently reduced by JNJ7777120 and levocetirizine; combined administration of JNJ7777120 and levocetirizine potentiated the antinociceptive effect. In the colon, both H4R and H1R mRNA were present; in the dorsal root ganglia, only H1R mRNA was found. Only colonic H4R mRNA expression was increased in postcolitis rats. Excessive histamine release in postcolitis rats was attenuated by the highest dose of JNJ7777120. CONCLUSIONS: H4R and H1R antagonists dose-dependently reduce and even normalise postinflammatory visceral hypersensitivity via different underlying mechanisms but with a synergistic effect. Both receptor subtypes represent promising targets for the treatment of postinflammatory visceral hypersensitivity.

The effect of chemically induced colitis, psychological stress and their combination on visceral pain in female Wistar rats.

Visceral sensitivity is of pathophysiological importance in abdominal pain disorders and can be modulated by inflammation and stress. However, it is unclear whether inflammation and stress alter visceral perception independently of each other or in conjunction through neuroendocrine interactions. Therefore, we compared the short- and long-term effects of experimental colitis and water avoidance stress (WAS), alone or in combination, on visceral sensitivity in female Wistar rats. Colitis was induced by trinitrobenzene sulfonic acid (TNBS) and colonoscopically confirmed. During WAS, rats were placed on a platform surrounded by water for 1 h. Visceral sensitivity was assessed by quantifying the visceromotor responses (VMRs) to colorectal distension. Activation of the hypothalamic-pituitary-adrenal axis was determined by measuring serum corticosterone in a separate protocol. TNBS instillation resulted in overt colitis, associated with significant visceral hypersensitivity during the acute inflammatory phase (3 days post-TNBS; n = 8/group); after colitis had subsided (28 days post-TNBS), hypersensitivity was resolved (n = 4-8/group). Single WAS was associated with increased VMRs of a magnitude comparable to acute TNBS-induced hypersensitivity (n = 8/group). However, after repetitive WAS no significant hypersensitivity was present (n = 8/group). No additive effect of colitis and stress was seen on visceral pain perception (n = 6-8/group). Corticosterone levels were only increased in acute TNBS-colitis, acute WAS and their combination. To conclude, both colitis and stress successfully induced short-term visceral hypersensitivity and activated the hypothalamic-pituitary-adrenal axis, but long-term effects were absent. In addition, our current findings do not support an additive effect of colitis and stress on visceral sensitivity in female Wistar rats.

Mechanisms of pelvic organ crosstalk: 1. Peripheral modulation of bladder inhibition by colorectal distention in rats.

PURPOSE: Bladder activity can be inhibited by afferent input from the colorectum (inhibitory rectovesical reflex). We evaluated the functional response of the rat bladder to nonnoxious and noxious colorectal distention, and investigated the mechanical and pharmacological peripheral modulation of this response. MATERIALS AND METHODS: In 70 female Sprague-Dawley® rats we evaluated the effect of nonnoxious (20 mm Hg) and noxious (40 and 60 mm Hg) colorectal distention on the micturition volume threshold and on bladder activity in a filled bladder. We also studied the effect of rectal balloon size (1.5 vs 3.5 cm long), and rectal administration of 2% lidocaine jelly or 1 mM allyl isothiocyanate solution on the inhibitory rectovesical reflex. RESULTS: Colorectal distention at 60 mm Hg increased the micturition volume threshold (mean ± SE 0.640 ± 0.056 vs 0.448 ± 0.035 ml in controls, p <0.001). Bladder contraction frequency was significantly decreased by 40 and 60 mm Hg colorectal distention vs controls (mean 0.62 ± 0.06 and 0.33 ± 0.05 per minute, respectively, vs 0.77 ± 0.03, each p <0.001). These effects were reversible and pressure dependent (p <0.001), and more pronounced using a large rectal balloon (mean 40 vs 60 mm Hg colorectal distention 0.35 ± 0.12 vs 0.07 ± 0.04 per minute, p = 0.004). We noted no significant graded inhibition of bladder contraction amplitude or duration. The inhibitory rectovesical reflex was reversibly abolished by intrarectal lidocaine administration. Intrarectal allyl isothiocyanate administration significantly increased the effect of noxious colorectal distention on bladder contraction frequency. CONCLUSIONS: Only noxious levels of colorectal distention initiated the inhibitory rectovesical reflex. The effect increased with rectal balloon size and with intrarectal administration of allyl isothiocyanate. It was reversibly abolished by lidocaine. Results suggest that spinal interneurons are the mechanism behind the inhibitory rectovesical reflex.

Renewed attention for overtube-assisted colonoscopy to prevent incomplete endoscopic examination of the colon.

BACKGROUND: Colonoscopy is the standard examination to detect mucosal pathology in the colon. However, failure to complete colonoscopy may reach more than 10% in population-based endoscopy practices. The reasons for incomplete conventional colonoscopy are diverse and result in missed diagnosis of colonic polyps and carcinoma. OBJECTIVE: Recent endoscopic developments have shown that the use of specialized overtubes may help to reach the cecum in the case of a difficult colonoscopy, even with less discomfort. Several types of overtubes are currently available, whereas other types are being developed and clinically evaluated. The current review highlights the development of overtubes for colonoscopy and the available clinical data on overtube-assisted colonoscopy in the case of incomplete conventional colonoscopy. DATA SOURCES: Data were derived from a PubMed search through November 2012. STUDY SELECTION: Available clinical literature data on recent developments in overtube-assisted colonoscopy were studied. INTERVENTION: A descriptive comparison was made of currently available endoscopy systems used for overtube-assisted colonoscopy. MAIN OUTCOME MEASURES: The primary outcomes measured were the feasibility and safety of different endoscopy systems to perform overtube-assisted colonoscopy. RESULTS: Several overtube-assisted colonoscopy systems have recently been developed to complete colonoscopy in the case of difficult conventional colonoscopy. Literature data show excellent feasibility to reach the cecum with very low complication rates and good patient tolerance for the different overtube systems. LIMITATIONS: The majority of available studies are uncontrolled case series describing 7 to 110 patients undergoing overtube-assisted colonoscopy with only 1 direct comparison between 2 overtube systems. CONCLUSIONS: Overtube-assisted colonoscopy has been shown to be useful in performing colonoscopy by increasing the cecal intubation rate and patient tolerance and by decreasing the need for sedation. There is no standardized superior overtube system at this moment.

Safety of pull-type and introducer percutaneous endoscopic gastrostomy tubes in oncology patients: a retrospective analysis.

BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) allows long-term tube feeding. Safety of pull-type and introducer PEG placement in oncology patients with head/neck or oesophageal malignancies is unknown. METHODS: Retrospective analysis of 299 patients undergoing PEG tube placement between January 2006 and December 2008 revealed 57 oncology patients. All patients with head/neck or oesophageal malignancy were treated with chemo- and radiotherapy. In case of high-grade stenosis introducer Freka® Pexact PEG tube was placed (n = 24) and in all other patients (n = 33) conventional pull-type PEG tube. Short-term complications and mortality rates were compared. RESULTS: Patients' characteristics and clinical status were comparable in both groups. Short-term complications were encountered in 11/24 (48%) introducer PEG patients as compared to only 4/33 (12%) pull-type PEG patients (P < 0.05). Accidental removal of the introducer PEG tube occurred in 4/24 (17%) with need for surgical intervention in 1 vs. 0/33 (0%, P < 0.05). Wound infection occurred in 3/24 (12%) leading to septic shock and admission to intensive care unit (ICU) in 1 vs. 3/33 (9%, NS). Finally, 3/24 gastrointestinal perforations (12%) resulted from a difficult placement procedure vs. 1/33 (3%), leading to urgent surgical intervention and admission to ICU. Two introducer PEG patients died at ICU, resulting in an overall mortality rate of 8% vs. 0% (P = 0.091). CONCLUSION: The introducer Freka® Pexact PEG procedure for long-term tube feeding may lead to significantly higher complication and mortality rates in patients with head/neck or oesophageal malignancies treated with chemo- and radiotherapy. It is suggested to use the conventional pull-type PEG tube placement in this group of patients, if possible.

Cecal intubation rate with the double-balloon endoscope after incomplete conventional colonoscopy: a study in 45 patients.

BACKGROUND AND AIM: Conventional colonoscopy is the gold standard for colorectal cancer screening. However, a failure rate to complete conventional colonoscopy of more than 10% is reported in the literature. We evaluated whether the therapeutic Fujinon double-balloon endoscope EN-450T5/20 is a valuable tool to intubate the cecum and to carry out all conventional endoscopic procedures after incomplete conventional colonoscopy. METHODS: Forty-five consecutive patients with prior incomplete conventional colonoscopy were prospectively enrolled. All but three procedures were carried out under conscious sedation with the patient in the left lateral decubitus position without fluoroscopic guidance. RESULTS: The cecum was reached in 42 of 45 patients (93%) and in 62% additional therapeutic interventions were carried out. Double-balloon colonoscopy required less conscious sedation compared to conventional colonoscopy. No external abdominal compression nor fluoroscopic control was used. The insertion depth of the double-balloon endoscope did not exceed the working length of a conventional colonoscope. CONCLUSIONS: The present study illustrates that the concept of double-balloon endoscopy is a valuable alternative to reach the cecum after prior incomplete conventional colonoscopy, especially due to redundant colon and colonic loop formation. The procedure requires less conscious sedation and no fluoroscopic control, but allows all conventional endoscopic interventions.

Effect of genetic SSTR4 ablation on inflammatory peptide and receptor expression in the non-inflamed and inflamed murine intestine.

The recently suggested pivotal role of somatostatin (SOM) receptor 4 (SSTR4) in inflammation and nociception in several non-intestinal organs and in gastrointestinal (GI) physiology, necessitates exploration of the role of SSTR4 in GI pathophysiology. Therefore, the role of SSTR4 in GI activity was explored by investigating the effects of SSTR4 deficiency on intestinal motility, smooth muscle contractility and on the expression of SSTRs and neuropeptides in the healthy and Schistosoma mansoni-infected murine small intestine. Functional experiments revealed no differences in intestinal motility or smooth muscle cell contractility between wild-type and SSTR4 knockout (SSTR4(-/-)) mice in physiological conditions. As revealed by multiple immunofluorescent labellings, RT-PCR and quantitative real time RT-PCR (qPCR), genetic deficiency of SSTR4 considerably altered the expression of SOM and SSTRs in non-inflamed and inflamed conditions, affecting both extrinsic and intrinsic components of the intestinal innervation, along with SSTR expression in several non-neuronal cell types. Moreover, substance P and calcitonin gene-related peptide expression were significantly elevated in SSTR4(-/-) mice, confirming the modulatory role of SSTR4 on intestinal pro-inflammatory neuropeptide expression. These data suggest that SSTR4 plays a previously unexpected modulatory role in the regulation of intestinal SSTR expression. Moreover, in addition to the recently described inhibitory effects of SSTR4 on the neuronal release of pro-inflammatory peptides, SSTR4 appears also to be involved in the neuronal expression of both pro- and anti-inflammatory peptides in the murine small intestine.

Diagnostic and therapeutic double-balloon enteroscopy after small bowel Roux-en-Y reconstructive surgery.

BACKGROUND: Roux-en-Y reconstruction excludes the afferent limb and the biliopancreatic system from conventional endoscopic access. Postoperative problems in these excluded gastrointestinal systems are therefore often dealt with surgically. We investigated the usefulness of the therapeutic double-balloon enteroscope to perform interventional endoscopic procedures in the excluded segment of the gastrointestinal tract after Roux-en-Y reconstruction. METHODS: 30 procedures were performed in 22 patients with Roux-en-Y reconstruction after enterobiliary anastomosis, gastrectomy or bariatric gastric bypass. All procedures were performed with the therapeutic double-balloon enteroscope, under general anesthesia and with fluoroscopic control. RESULTS: ERCP at the enterobiliary anastomosis was successful in 90% (n = 10) of the procedures. ERCP at the intact papilla was successful in 60% (n = 5). Enterocutaneous fistula closure after (sub)total gastrectomy was performed in 2 procedures. Successful diagnostic procedures encompassed intubation of the excluded stomach after bariatric gastric bypass (89%, n = 9) or the afferent limb after Roux-en-Y reconstruction (75%, n = 4). The overall success rate in accessing the aimed excluded segment with the double-balloon enteroscope was 87%. Interventional procedures were able to avoid surgery in 65%. One retroperitoneal perforation occurred during ERCP which was conservatively treated. CONCLUSIONS: Excluded gastrointestinal segments after Roux-en-Y reconstruction can be accessed with a substantial success rate using double-balloon enteroscopy. Therapeutic interventions like ERCP can prevent surgery in the majority of patients.

Worms and the treatment of inflammatory bowel disease: are molecules the answer?

The lack of exposure to helminth infections, as a result of improved living standards and medical conditions, may have contributed to the increased incidence of IBD in the developed world. Epidemiological, experimental, and clinical data sustain the idea that helminths could provide protection against IBD. Studies investigating the underlying mechanisms by which helminths might induce such protection have revealed the importance of regulatory pathways, for example, regulatory T-cells. Further investigation on how helminths influence both innate and adaptive immune reactions will shed more light on the complex pathways used by helminths to regulate the hosts immune system. Although therapy with living helminths appears to be effective in several immunological diseases, the disadvantages of a treatment based on living parasites are explicit. Therefore, the identification and characterization of helminth-derived immunomodulatory molecules that contribute to the protective effect could lead to new therapeutic approaches in IBD and other immune diseases.

The role of tachykinins in circular muscle contractility of the murine ileum: a functional investigation.

We investigated the participation of different tachykinin receptors in contractility of circular muscle strips of the mouse ileum using selective NK receptor agonists and antagonists. The NK1 receptor agonist septide (1-100 nM) induced dose-dependent contractions which were reduced by atropine and augmented by L-NNA. L-NNA increased and TTX consecutively reduced contractions to the NK2 receptor agonist beta-A-NKA (1-100 nM). Senktide, agonist of NK3 receptors, failed to induce contractions. NANC contractions to EFS were decreased after NK1 receptor blockade with RP67580. This inhibitory effect was more pronounced after additional blockade of NK2 and NK3 receptors. NK3 receptor antagonism alone reduced contractions at higher frequencies of stimulation. When the duration of the EFS stimulus was increased, the participation of all NK receptor subtypes became more evident. Our results suggest that excitatory NANC transmission in the circular muscle layer of the mouse ileum is mediated by tachykinins acting principally on NK1 receptors on cholinergic nerves and smooth muscle cells. Also NK2 receptors, located on smooth muscle cells and nitrergic neurons, and NK3 receptors on enteric neurons are involved.

Gastrointestinal parasites: potential therapy for refractory inflammatory bowel diseases.

Crohn's disease and ulcerative colitis are chronic relapsing inflammatory bowel diseases (IBDs). Different pharmacological agents are currently used in several combinations to control the inflammatory process. Recently, antibodies against the proinflammatory cytokine tumor necrosis factor-alpha appeared to be very effective in treating patients with Crohn's disease. However, due to the fact that the pathogen causing IBD is still unknown, no causative treatment is currently available that is able to make the disease disappear. Recently, the hygiene hypothesis of the development of immunological diseases was proposed, stating that raising children in extremely hygienic environments with less exposure to parasite infections may negatively affect the development of the immune system, predisposing them to immunologic diseases such as IBD. This hypothesis is supported by experimental data showing that helminthic parasites protect against T helper (TH) type 1 cell-mediated gastrointestinal inflammations like Crohn's disease. Both TH-2 cells and regulatory T cells may be involved in this immunomodulatory mechanism. Here, we review the experimental and clinical studies in favor of the hygiene hypothesis, opening perspectives on new therapies for IBD.

Functional characterisation of tachykinin receptors in the circular muscle layer of the mouse ileum.

OBJECTIVES: Tachykinins are important mediators in neuromuscular signalling but have not been thoroughly characterised in the mouse gut. We investigated the participation of tachykinin receptors in contractility of circular muscle strips of the mouse ileum. RESULTS: Electrical field stimulation (EFS) of excitatory nonadrenergic noncholinergic (NANC) nerves induced frequency-dependent contractions which were mimicked by substance P (SP). Desensitisation of SP and NK(1), NK(2) or NK(3) receptors significantly reduced contractions to EFS. The NK(1) receptor blocker RP67580 significantly inhibited NANC contractions to EFS. The NK(2) and NK(3) receptor blockers nepadutant and SR142801 did not affect NANC contractions per se but increased the RP67580-induced inhibition of NANC contractions to EFS. Contractions to SP were significantly reduced by RP67580 but not affected by nepadutant or SR142801. The NK(1) and NK(2) receptor agonists, septide and [beta-ala(8)]-NKA 4-10 (beta-A-NKA), respectively, but not the NK(3) receptor agonist senktide-induced dose-dependent contractions. Atropine inhibited and l-NNA augmented contractions to septide. Contractions to beta-A-NKA were insensitive to atropine but augmented by l-NNA. CONCLUSIONS: Tachykinins mediate NANC contractions to EFS in the mouse small intestine. Endogenously released tachykinins activate mainly NK(1) receptors, located on cholinergic nerves and smooth muscle cells and, to a lesser degree, NK(2) and NK(3) receptors, most likely located presynaptically.

Delayed gastric emptying and gastric autoimmunity in type 1 diabetes.

OBJECTIVE: Delayed gastric emptying and/or gastrointestinal symptoms occur in 30-50% of diabetic patients. Known contributing factors are autonomic neuropathy and acute hyperglycemia, but the role of gastric autoimmunity has never been investigated, although 15-20% of type 1 diabetic patients exhibit parietal cell antibodies (PCAs). We studied gastric motility in diabetes in relation to PCA status, autonomic nerve function, HbA(1c), thyroid-stimulating hormone (TSH), Helicobacter pylori (HP), acid production, and gastric histology. RESEARCH DESIGN AND METHODS: Gastric emptying of solids and liquids (measured by (13)C-octanoic acid and (13)C-glycine breath tests, respectively) was tested in euglycemic conditions in 42 type 1 diabetic patients (male/female: 29/13; 15 PCA+; mean age 40 +/- 15 years; mean HbA(1c) 7.8 +/- 0.9%). Gastrointestinal symptoms, autonomic nerve function (Ewing tests), PCA status (indirect immunofluorescence), gastric histology, and acid secretion (pentagastrin) were assessed. RESULTS: Solid gastric emptying was delayed in 40% and liquid emptying in 36% of patients. Gastric motility did not correlate with symptoms. PCA status, gastric morphology, and acid secretion were similar in those with and without gastroparesis. HbA(1c) level (beta = 1.34, P = 0.011) was the only risk factor for delayed solid emptying in a logistic regression model testing HbA(1c), autonomic nerve function, PCA, HP status, age, sex, diabetes duration, and TSH. Half-emptying time for liquids correlated with TSH level (r = 0.83, P < 0.0001) and autonomic neuropathy score (r = -0.79, P = 0.001). CONCLUSIONS: We found that approximately 50% of type 1 diabetic patients studied had delayed gastric emptying that did not correlate with symptoms. Gastric autoimmunity did not contribute to diabetic gastroparesis. Metabolic control was worse in patients with delayed solid emptying.

Autoimmune gastropathy in type 1 diabetic patients with parietal cell antibodies: histological and clinical findings.

OBJECTIVE: Approximately 15-20% of type 1 diabetic patients exhibit parietal cell antibodies (PCAs) targeting gastric H+/K+ATPase. We examined whether iron deficiency anemia, pernicious anemia, and autoimmune gastritis, which may predispose to gastric tumors, were more frequent in PCA+ than in PCA- patients. RESEARCH DESIGN AND METHODS: Gastric biopsies from 88 consecutively recruited type 1 diabetic patients (51 men and 37 women, 47 PCA+ and 41 PCA-, aged 42 +/- 13 years) were evaluated using the updated Sydney system. Immunostaining was done for parietal cells, B- and T-cells, enterochromaffin-like (ECL) cells, and Helicobacter pylori (HP). PCAs were assayed by indirect immunofluorescence, H+/K+ATPase antibodies by enzyme immunoassay, and HP by serology, urea breath test, and histology. Pentagastrin tests were performed in 42 subjects. RESULTS: Autoimmune gastritis (AG) was present in 57% of PCA+ and 10% of PCA- cases (OR 12.5, P < 0.0001). PCA positivity (beta = 1.44; P = 0.04) and hypergastrinemia (beta = 0.01; P = 0.026), but not HP, age, diabetes duration, sex, and HLA-DQ type were risk factors for AG. Iron deficiency anemia (OR 3.9, P = 0.015), pernicious anemia (OR = 4.6, P = 0.022), and hypochlorhydria (OR = 20.0, P = 0.0002) were more frequent in AG+ individuals. HP infection was present in 47 patients but did not influence corpus histology or gastrinemia. (Pre)malignant lesions were found in 26% of PCA+ subjects: ECL cell hyperplasia in 7 AG+ patients, comprising 1 with a gastric carcinoid tumor, and corpus intestinal metaplasia in 11 AG+ patients, including 1 with linitis plastica. CONCLUSIONS: PCA+ type 1 diabetic patients should be screened for autoimmune gastritis, iron deficiency, and pernicious anemia. Particularly hypergastrinemic PCA+ patients with autoimmune gastritis are at increased risk for (pre)malignant gastric lesions.

Neuroendocrine tumor markers and enterochromaffin-like cell hyper/dysplasia in type 1 diabetes.

OBJECTIVE: Parietal cell antibodies (PCAs) are found in 20% of type 1 diabetic patients, denoting autoimmune gastritis and pernicious anemia, which may predispose to enterochromaffin-like (ECL) cell hyper/dysplasia and gastric carcinoid tumors. We evaluated whether chromogranin A (CgA), 5-hydroxyindole acetic acid (5-HIAA), and neuron-specific enolase (NSE) contribute to screening for ECL cell hyper/dysplasia. RESEARCH DESIGN AND METHODS: Sera from 93 type 1 diabetic patients (53 men and 40 women, 31 PCA(+) and 62 PCA(-), aged 45 +/- 13 years) were analyzed for PCAs by indirect immunofluorescence and for CgA, NSE, and gastrin by radioimmunoassay. Urinary 5-HIAA was tested by high-performance liquid chromatography. Corpus atrophy and ECL cell proliferation were assessed in gastric biopsies. RESULTS: PCA(+) patients had higher gastrin (P < 0.0001) and CgA levels (P = 0.003) and were more prone to autoimmune gastritis (odds ratio [OR] 17, P < 0.0001) and ECL cell hyper/dysplasia (OR = 23, P = 0.005) than PCA(-) subjects. ECL cell hyper/dysplasia was present in seven PCA(+) patients who showed higher CgA levels (P < 0.0001) than subjects without ECL cell hyper/dysplasia, but NSE and 5-HIAA levels were similar. CgA levels correlated with gastrinemia (r = 0.50, P < 0.0001), PCA titer (r = 0.42, P = 0.001), and 5-HIAA levels (r = 0.38, P = 0.012). Logistic regression identified the CgA level (beta = 0.01, P = 0.027) as an independent risk factor for ECL cell hyper/dysplasia when PCA, CgA, 5-HIAA, NSE, gastrin, sex, and age were tested. Multivariate linear regression demonstrated that CgA level was determined by ECL cell density (r = 0.59, P < 0.0001) and gastrin level (r = 0.67, P = 0.02). One PCA(+) patient with elevated gastrin, CgA, and 5-HIAA levels had a gastric carcinoid tumor. CONCLUSIONS: PCA(+) patients, particularly those with high gastrin and CgA levels, risk developing ECL cell hyper/dysplasia. The determination of CgA, but not NSE and 5-HIAA, may complement histology in evaluating ECL cell mass.

Treatment with egg antigens of Schistosoma mansoni ameliorates experimental colitis in mice through a colonic T-cell-dependent mechanism.

BACKGROUND: Helminth-derived molecules are being identified as a new therapeutic approach for immune-mediated diseases. We investigated the anti-inflammatory effect and the immunological mechanisms of Schistosoma mansoni soluble egg antigens (SmSEA) in a mouse model of chronic colitis. METHODS: Colitis was induced in immunocompromised severe combined immunodeficiency mice by the adoptive transfer of CD4CD25CD62L T cells. Two weeks post-transfer, SmSEA treatments were started (study 1: 1 × 20 µg SmSEA per week 5 times; study 2: 2 × 20 µg SmSEA per week 3 times). From the start of the treatment (week 2), the clinical outcome and colonic inflammation were assessed at different time points by a clinical disease score and colonoscopy, respectively. At the end of the studies, the colons were harvested for macroscopic examination, and colonic lamina propria mononuclear cells were isolated for flow cytometric T-cell characterization. RESULTS: In both studies, administration of SmSEA in colitis mice improved all the inflammatory parameters studied. However in study 1, this beneficial effect on inflammation diminished with time, and the T-cell characterization of the lamina propria mononuclear cells, performed at week 6, revealed no immunological effects of the SmSEA treatment. In study 2, mice were killed earlier (week 4) and at that time point, we found a significant downregulation of the number of interleukin-17A-producing T cells and a significant upregulation of the number of interleukin-4-producing T cells in the colon of the SmSEA-treated colitis mice. CONCLUSIONS: Our results demonstrated that the administration of SmSEA reduces the severity of colitis in the adoptive transfer mouse model characterized by an increased Th2 response and a suppressed Th17 response in the colon.

P2X3 receptors mediate visceral hypersensitivity during acute chemically-induced colitis and in the post-inflammatory phase via different mechanisms of sensitization.

OBJECTIVES: Experiments using P2X3 knock-out mice or more general P2X receptor antagonists suggest that P2X3 receptors contribute to visceral hypersensitivity. We aimed to investigate the effect of the selective P2X3 antagonist A-317491 on visceral sensitivity under physiological conditions, during acute colitis and in the post-inflammatory phase of colitis. METHODS: Trinitrobenzene sulphonic-acid colitis was monitored by colonoscopy: on day 3 to confirm the presence of colitis and then every 4 days, starting from day 10, to monitor convalescence and determine the exact timepoint of endoscopic healing in each rat. Visceral sensitivity was assessed by quantifying visceromotor responses to colorectal distension in controls, rats with acute colitis and post-colitis rats. A-317491 was administered 30 min prior to visceral sensitivity testing. Expression of P2X3 receptors (RT-PCR and immunohistochemistry) and the intracellular signalling molecules cdk5, csk and CASK (RT-PCR) were quantified in colonic tissue and dorsal root ganglia. ATP release in response to colorectal distension was measured by luminiscence. RESULTS: Rats with acute TNBS-colitis displayed significant visceral hypersensitivity that was dose-dependently, but not fully, reversed by A-317491. Hypersenstivity was accompanied by an increased colonic release of ATP. Post-colitis rats also displayed visceral hypersensitivity that was dose-dependently reduced and fully normalized by A-317491 without increased release of ATP. A-317491 did not modify visceral sensitivity in controls. P2X3 mRNA and protein expression in the colon and dorsal root ganglia were similar in control, acute colitis and post-colitis groups, while colonic mRNA expression of cdk5, csk and CASK was increased in the post-colitis group only. CONCLUSIONS: These findings indicate that P2X3 receptors are not involved in sensory signaling under physiological conditions whereas they modulate visceral hypersensitivity during acute TNBS-colitis and even more so in the post-inflammatory phase, albeit via different mechanisms of sensitization, validating P2X3 receptors as potential new targets in the treatment of abdominal pain syndromes.