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An impedance-manometry based method for non-radiological detection of pharyngeal postswallow residue
Background Postswallow residue is indicative of impaired pharyngeal bolus clearance. The integrated nadir impedance to impedance ratio (iZn/Z) is a novel functional variable that can be derived using automated impedance manometry (AIM). In this study, the postswallow pharyngeal iZn/Z was evaluated as a potential correlated postswallow residue and therefore predictor of ineffective swallowing.Methods Optimal iZn/Z criteria were determine using a database of 50 randomly selected bolus swallows recorded with impedance, manometry, and videofluoroscopy. The iZn/Z was derived for a region of interest (ROI), spanning the mid-point of the pharyngeal stripping wave to the upper esophageal sphincter proximal margin, and from 0.25 to 1.25 s after the peak of the pharyngeal stripping wave. Videofluorscopy was scored by four experts using a six-point bolus residue scale (BRS) score. Optimized criteria for iZn/Z were then applied to a much larger database of 225 swallows scored for residue by one expert observer.Key Results Among individual database, swallows iZn/Z was significantly correlated with average expert BRS score (r = 0.748, P < 0.0001). An iZn/Z of ≥500 was optimally predictive of swallows with residue defined by a BRS score of 4 or more. Within the larger cohort, iZn/Z was higher in dysphagia patient swallows compared with controls [2 (1, 4) vs 1 (1, 3), P < 0.005] and swallows with an iZn/Z ≥ 500 had higher bolus residue scores [4 (1, 6) vs 2 (1, 4), P < 0.001].Conclusions & Inferences The AIM derived iZn/Z is an easily determined objective non-radiological marker of clinically relevant postswallow residue and therefore has potential diagnostic relevance as a predictor of ineffective swallowing.
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Voltage-gated potassium channel (Kv1) autoantibodies in patients with chagasic gut dysmotility and distribution of Kv1 channels in human enteric neuromusculature (autoantibodies in GI dysmotility)
Background Autoantibodies directed against specific neuronal antigens are found in a significant number of patients with gastrointestinal neuromuscular diseases (GINMDs) secondary to neoplasia. This study examined the presence of antineuronal antibodies in idiopathic GINMD and GINMD secondary to South American Trypanosomiasis. The GI distribution of voltage-gated potassium channels (VGKCs) was also investigated.Methods Seventy-three patients were included in the study with diagnoses of primary achalasia, enteric dysmotility, chronic intestinal pseudo-obstruction, esophageal or colonic dysmotility secondary to Chagas’ disease. Sera were screened for specific antibodies to glutamic acid decarboxylase, voltage-gated calcium channels (VGCCs; P/Q subtype), nicotinic acetylcholine receptors (nAChRs; α3 subtype), and voltage-gated potassium channels (VGKCs, KV1 subtype) using validated immunoprecipitation assays. The distribution of six VGKC subunits (KV1.1–1.6), including those known to be antigenic targets of anti-VGKC antibodies was immunohistochemically investigated in all main human GI tract regions.Key Results Three patients (14%) with chagasic GI dysmotility were found to have positive anti-VGKC antibody titers. No antibodies were detected in patients with idiopathic GINMD. The VGKCs were found in enteric neurons at every level of the gut in unique yet overlapping distributions. The VGKC expression in GI smooth muscle was found to be limited to the esophagus.Conclusions & Inferences A small proportion of patients with GI dysfunction secondary to Chagas’ disease have antibodies against VGKCs. The presence of these channels in the human enteric nervous system may have pathological relevance to the growing number of GINMDs with which anti-VGKC antibodies have been associated.
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Rectal hypersensitivity as hallmark for irritable bowel syndrome: defining the optimal cutoff
Background Visceral hypersensitivity is a frequently observed hallmark of irritable bowel syndrome (IBS). Studies have reported differently about the presence of visceral hypersensitivity in IBS resulting from lack of standardization of the barostat procedure and due to different criteria used to assess hypersensitivity. We aimed to calculate the optimal cutoff to detect visceral hypersensitivity in IBS.Methods A total of 126 IBS patients and 30 healthy controls (HC) were included for assessment of visceroperception by barostat. Pain perception was assessed on a visual analogue scale (VAS). ROC-curves were used to calculate optimal discriminative cutoff (pressure and VAS-score) between IBS patients and HC to define hypersensitivity. Furthermore, pain perception to distension sequences below the pressure threshold for hypersensitivity was defined as allodynia.Key Results Irritable bowel syndrome patients showed increased visceroperception compared to HC. Thresholds for first sensation and first pain were lower in IBS patients VS HC (P < 0.01). ROC-curves showed optimal discrimination between IBS patients and HC at 26 mmHg with a VAS cutoff ≥20 mm. Using this criterion, hypersensitivity percentages were 63.5% and 6.6% in IBS patients and HC, respectively. No significant differences were observed between IBS subtypes. Allodynia was found in a small number of patients (11%).Conclusions & Inferences Optimal cutoff for visceral hypersensitivity was found at pressure 26 mmHg with a VAS ≥20 mm, resulting in 63.5% of IBS patients being hypersensitive and 11% being allodynic. Standardization of barostat procedures and defining optimal cutoff values for hypersensitivity is warranted when employing rectal barostat measurements for research or clinical purposes.
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The Places to be for Neurogastroenterologists
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Intestinal barrier function in health and gastrointestinal disease
Defects in intestinal barrier function are associated with diseases of the gastrointestinal (GI) tract. There is growing evidence that increases in intestinal permeability plays a pathogenic role in diseases, such as inflammatory bowel disease (IBD) and celiac disease, and functional bowel disorders, such as irritable bowel syndrome (IBS). This review takes a unique translational approach to discuss the physiological and pathophysiological mechanisms involved in the regulation of intestinal barrier function in IBS. The review summarizes the components of the intestinal barrier including the tight junction complex within the epithelium, and the methods used to assess gut permeability both in vitro and in vivo. Throughout the review, the authors have attempted to critically review the latest research from both experimental animal models and human studies to appraise whether intestinal barrier dysfunction is a primary cause of functional GI disorders, such as IBS.…
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A comparison of the organization of longitudinal and circular contractions during pendular and segmental activity in the duodenum of the rat and guinea pig
Background Little is known of the spatiotemporal organization of pendular duodenal contractions.Methods We used longitudinal and radial spatiotemporal mapping to examine and compare pendular and segmental contractile activity in the proximal duodenum of the rat and guinea pig when the lumen was perfused with saline or micellar decanoic acid.Key Results Isolated phasic longitudinal contractions occurred along the rat duodenum with a frequency of 36 ± 2 cpm and strain rate amplitude of 26.8 ± 8.0% s−1. These contractions occurred at fixed locations along the duodenum forming columns on the longitudinal strain rate map. The strain rate activity had local maxima at 4–6 points spaced at 7.7 ± 4.0 mm intervals along the duodenum and were uncoordinated between neighboring domains. Similarly disposed, less distinct, longitudinal contractions occurred in the guinea pig duodenum at a frequency of 25.2 ± 6.6 cpm with amplitude 6.8 ± 3.6% s−1 but these were generally accompanied by numerous circular contractions that were distributed over 4–5 fixed locations and occurred with a frequency of 9 ± 3 cpm. Isolated static circular muscle contractions also occurred but at a lower rate in the rat than the guinea pig. Both types of contractions propagated after dosage with tetrodotoxin, lidocaine, atropine, or apamin.Conclusions & Inferences Localized contractions during segmental and pendular activity had some features of the spike patches that are normally associated with slow wave propagation. However, the commencement of propagation following administration of neural blocking agents and cholinergic inhibitors indicates their localization is maintained by inhibitory elements of the enteric nervous system.
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Gastroesophageal and laryngopharyngeal reflux profiles in patients with obstructive sleep apnea/hypopnea syndrome as determined by combined multichannel intraluminal impedance–pH monitoring
Background The profiles of gastroesophageal reflux (GER) and laryngopharyngeal reflux (LPR) in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) have never been explored. The aim of the study was to investigate the reflux profile in OSAHS patients.Methods Consecutive snoring out-patients suspected with having OSAHS and 20 healthy volunteers were included. All subjects underwent simultaneous 24-h combined multichannel intraluminal impedance–pH (MII–pH) monitoring and polysomnography. Obstructive sleep apnea/hypopnea syndrome was defined when the apnea/hypopnea index was over 5. Stepwise multiple logistic regression analysis was performed to determine the predictor for OSAHS.Key Results Fifty-three patients were included, 37 with and 16 without OSAHS. The prevalence of reflux symptoms was similar between OSAHS (35.1%) and non-OSHAS (37.5%) patients. More OSAHS patients, compared with non-OSAHS patients and healthy volunteers, had pathologic acid GER, nocturnal acid GER, and prolonged acid clearance (P < 0.001). However, no difference in non-acid reflux episodes was observed among the three groups. Laryngopharyngeal reflux was detected in 51.4%, 43.8%, and 35.0% of OSAHS, non-OSAHS, and healthy volunteers, respectively (P = 0.034). In OSAHS patients, there was no difference in the sleep parameters between patients with and without LPR. Body mass index was the only predictor of OSAHS in the regression analysis.Conclusions & Inferences OSAHS patients have more pathologic acid GER and prolonged acid clearance than non-OSAHS patients whereas non-acid reflux was similar between the two groups. However, BMI, not GER, is the only independent predictor for OSAHS. Laryngopharyngeal reflux occurs in more than half of OSAHS patients despite no significant association with OSAHS.
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Intragastric pressure as a determinant of food intake
Background Different studies indicated a correlation between intragastric pressure (IGP) and satiation. Our aim was to investigate this correlation while artificially increasing the IGP.Methods In 12 fasted healthy volunteers an infusion catheter and a manometry probe were positioned intragastrically. Intragastric pressure was increased using a custom-made belt before or progressively during intragastric nutrient infusion. Nutrient drink (1.5 kcal mL−1) was intragastrically infused at 60 mL min−1. The subjects scored satiation using a 6-point Likert scale until maximum, when the infusion ended and the belt was released. Results are presented as mean ± S.E.M. and compared using a paired t-test.Key Results When the belt was tightened before the nutrient infusion, fasting IGP was significantly increased (13.6 ± 1.3 vs 9.6 ± 0.9 mmHg; P < 0.05) but no differences in satiation could be observed. When progressively tightening the belt during nutrient infusion the IGP increased with 0.43 ± 0.04 mmHg per minute while in control experiments this was 0.28 ± 0.05 mmHg per minute (P < 0.01). During the latter experiment satiation linearly increased with 0.35 ± 0.03 and 0.29 ± 0.02 units per minute until maximal satiation (P < 0.01) while maximum volume consumed was 926 ± 66 and 1095 ± 82 mL when progressively increasing the IGP vs control respectively (P < 0.01).Conclusions & Inferences These findings indicate that IGP per se does not affect satiation but that a gradual IGP increase during food intake is associated with decreased food intake, indicating that gastric accommodation is an important determinant of food intake.
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Esophageal impedance baselines in infants before and after placebo and proton pump inhibitor therapy
Background Esophageal impedance monitoring records changes in conductivity. During esophageal rest, impedance baseline values may represent mucosal integrity. The aim of this study was to assess the influence of acid suppression on impedance baselines in a placebo-controlled setting.Methods Impedance recordings from 40 infants (0–6 months) enrolled in randomized placebo-controlled trials of proton pump inhibitor (PPI) were retrospectively analyzed. Infants underwent 24 h pH-impedance monitoring prior to and after 2 weeks of double blind therapy with placebo or a PPI. Typical clinical signs of gastro-esophageal reflux (GER) were recorded and I-GERQ-R questionnaire was completed.Key Results Median (IQR) impedance baseline increased on PPI treatment (from 1217 (826–1514) to 1903 (1560–2194) Ω, P < 0.001) but not with placebo (from 1445 (1033–1791) to 1650 (1292–1983) Ω, P = 0.13). Baselines before treatment inversely correlate with the number of GER, acid GER, weakly acid GER, acid exposure, and symptoms. The change in baseline on treatment inversely correlates with acid exposure and acid GER. Patients with initial low baselines have no improved symptomatic response to treatment.Conclusions & Inferences Impedance baselines are influenced by GER and increase significantly more with PPI therapy than with placebo. Clinical impact of this observation remains undefined as targeting therapy at infants with low baselines does not improve symptomatic response to treatment.
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Altered brain activation to colorectal distention in visceral hypersensitive maternal-separated rats
Background Early life trauma can predispose to increased visceral pain perception. Human neuroimaging studies emphasize that altered brain processing may contribute to increased visceral sensitivity. The aim of our study was to evaluate brain responses to painful visceral stimuli in maternal-separated rats before and after acute stress exposure in vivo.Methods H215O microPET scanning was performed during colorectal distention in maternal-separated rats before and after water avoidance stress. Brain images were anatomically normalized to Paxinos space and analyzed by voxel-based statistical parametric mapping (SPM2). Colorectal induced visceral pain was assessed by recording of the visceromotor response using abdominal muscle electromyography.Key Results Colorectal distention (1.0–2.0 mL) evoked a volume-dependent increase in visceromotor response in maternal-separated rats. Stress [water avoidance (WA)] induced an increased visceromotor response to colorectal distention in awake and anesthetized rats. In pre-WA rats, colorectal distention evoked significant increases in regional blood flow in the cerebellum and periaquaductal gray (PAG). Colorectal distention post-WA revealed activation clusters covering the PAG as well as somatosensory cortex and hippocampus. At maximal colorectal distention, the frontal cortex was significantly deactivated.Conclusions & Inferences WA stress induced increased pain perception as well as activation of the somatosensory cortex, PAG, and hippocampus in maternal-separated rats. These findings are in line with human studies and provide indirect evidence that the maternal separation model mimics the cerebral response to visceral hypersensitivity in humans.
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Is symptom relief associated with reduction in gastric retention after gastric electrical stimulation treatment in patients with gastroparesis? A sensitivity analysis with logistic regression models
Background Enterra gastric electrical stimulation (GES) is an alternative treatment for gastroparesis (GP) when standard medical therapy fails. The aims of this study were to evaluate the association between total symptom score (TSS) and reduction in gastric retention (GR) after GES by GP etiology and to examine the sensitivity of the association to varying cutpoints used to define GR and TSS improvement.Methods Gastric retention assessed with a standardized 99mTc radio-labeled egg meal and TSS measured by a five-point Likert scale in 221 GP patients treated with Enterra GES therapy for at least 1 year were analyzed. Bivariate chi-square test and multivariable logistic regression with all possible cutpoints were used to assess the consistency of association and quantitate the relationship across three GP etiologies.Key Results Symptom relief in diabetic GP was more likely attributable to GR reduction as indicated by the consistently significant odds ratios (P < 0.01) across all cutpoints. The association in idiopathic GP was inconclusive because odds ratios were sensitive to cutpoints with P-values ranging from 0.01 to 0.47. No association was found for patients with post surgical gastroparesis (P > 0.1 for all cutpoints). Patient age, gender, baseline TSS and baseline GR had no significant effect at 5% level on clinical improvement regardless of cutpoints for GR.Conclusions & Inferences Association between clinical improvements and GR reduction following GES treatment depends on patient etiology and was able to be demonstrated in diabetic GP. The association for idiopathic GP was inconclusive and no such association was found for post surgical GP across all possible cutpoint combinations.
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Mechano-transcription of COX-2 is a common response to lumen dilation of the rat gastrointestinal tract
Background In obstructive bowel disorders (OBDs) such as achalasia, pyloric stenosis, and bowel obstruction, the lumen of the affected segments is markedly dilated and the motility function is significantly impaired. We tested the hypothesis that mechanical stress in lumen dilation leads to induction of cyclooxygenase-2 (COX-2) in smooth muscle throughout the gastrointestinal (GI) tract, contributing to motility dysfunction.Methods Lumen dilation was induced in vivo with obstruction bands (12 × 3 mm) applied over the lower esophageal sphincter (LES), the pyloric sphincter, and the ileum in rats for 48 h. Mechanical stretch in vivo was also emulated by balloon distension of the distal colon. Direct stretch of muscle strips from the esophagus, gastric fundus, and ileum was mimicked in an in vitro tissue culture system.Key Results Partial obstruction in the LES, pylorus, and ileum significantly increased the expression of COX-2 mRNA and protein in the muscularis externae of the dilated segment oral to the occlusions, but not in the aboral segment. Direct stretch of the lumen in vivo or of muscle strips in vitro markedly induced COX-2 expression. The smooth muscle contractility was significantly suppressed in the balloon-distended segments. However, treatment with COX-2 inhibitor NS-398 restored the contractility. Furthermore, in vivo administration of NS-398 in gastric outlet obstruction significantly improved gastric emptying.Conclusions & Inferences Mechanical dilation of the gut lumen by occlusion or direct distension induces gene expression of COX-2 throughout the GI tract. Mechanical stress-induced COX-2 contributes to motility dysfunction in conditions with lumen dilation.
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Role of interleukin-6 in hemopoietic and non-hemopoietic synergy mediating TLR4-triggered late murine ileus and endotoxic shock1
Background Early murine endotoxin-induced ileus at 6 h is exclusively mediated by non-hemopoietic TLR4/MyD88 signaling despite molecular activation of hemopoietic cells which included a significant IL-6 mRNA induction. Our objective was to define the role of hemopoietic cells in LPS/TLR4-triggered ileus and inflammation over time, and identify mechanisms of ileus.Methods CSF-1−/−, TLR4 non-chimera and TLR4 chimera mice were single-shot intraperitoneal injected with ultrapure lipopolysaccharide (UP-LPS) and studied up to 4 days. Subgroups of TLR4WT mice were additionally intravenously injected with exogenous recombinant IL-6 (rmIL-6) or murine soluble IL-6 receptor blocking antibody (anti-sIL-6R mAB).Key Results Hemopoietic TLR4 signaling independently mediated UP-LPS-induced ileus at 24 h, but chemotactic muscularis neutrophil extravasation was not causatively involved and mice lacking CSF-1-dependent macrophages died prematurely. Synergy of hemopoietic and non-hemopoietic cells determined ileus severity and mortality which correlated with synergistic cell lineage specific transcription of inflammatory mediators like IL-6 within the intestinal muscularis. Circulating IL-6 levels were LPS dose dependent, but exogenous rmIL-6 did not spark off a self-perpetuating inflammatory response triggering ileus. Sustained therapeutic inhibition of functional IL-6 signaling efficiently ameliorated late ileus while preemptive antibody-mediated IL-6R blockade was marginally effective in mitigating ileus. However, IL-6R blockade did not prevent endotoxin-associated mortality nor did it alter circulating IL-6 levels.Conclusions & Inferences A time-delayed bone marrow-driven mechanism of murine endotoxin-induced ileus exists, and hemopoietic cells synergize with non-hemopoietic cells thereby prolonging ileus and fueling intestinal inflammation. Importantly, IL-6 signaling via IL-6R/gp130 drives late ileus, yet it did not regulate mortality in endotoxic shock.
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Anticipation of public speaking and sleep and the hypothalamic-pituitary-adrenal axis in women with irritable bowel syndrome
Background Evidence suggests that subgroups of patients with irritable bowel syndrome (IBS) are hyper-responsive to a variety of laboratory stress conditions.Methods This study compared sleep quality and night time plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels in response to anticipation of public speaking between 43 women with IBS and 24 healthy control women. In addition, comparisons were made between subgroups within the IBS sample based on predominant stool patterns, 22 IBS-constipation and 21 IBS-diarrhea. Subjects slept three nights in a sleep laboratory, and on the third night serial blood samples were drawn every 20 min from 08:00 PM until awakening. As the subjects had different sleep onsets, each subject’s results were synchronized to the first onset of stage 2 sleep.Key Results Compared the healthy control group, women with IBS had significantly worse sleep efficiency, and higher cortisol but not ACTH levels over the night. However, there were no IBS bowel pattern subgroup differences. Among IBS subjects, cortisol levels early in the night were higher than found in our previous study with a similar protocol but without the threat of public speaking. These results suggest that a social stressor, such as public speaking prior to bedtime, increases cortisol but not ACTH levels suggesting HPA dysregulation in women with IBS.Conclusions & Inferences This response to a social stressor contributes to our understanding of the relationship of stress to symptom expression in IBS.
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Measuring the interaction of meal and gastric secretion: a combined quantitative magnetic resonance imaging and pharmacokinetic modeling approach
Background The stimulation and intragastric accumulation of gastric secretion has been recognized as an important factor in gastroesophageal reflux disease. However, the interaction of gastric secretion and meal emptying has not been fully understood. Current methods to assess gastric secretion are either invasive or unable to provide information on its volume, distribution and dynamics. The aim of this study was to quantify the interaction between meal emptying and meal induced gastric secretion by using quantitative magnetic resonance imaging (MRI) and pharmacokinetic analysis.Methods A chocolate test meal was developed which is secretion stimulating and MRI compatible. Meal emptying and gastric secretion were assessed in fourteen healthy volunteers using a validated quantitative MRI technique. A population based pharmacokinetic model was developed and applied to the extracted volume data, assessing the meal emptying rate, rate of secretion and their interaction.Key Results The test meal continuously induced gastric secretion in all subjects, which partly accumulated at the meal–air interface, forming a ‘secretion layer’ in the proximal stomach. Traditional fitting detected a significant correlation between meal emptying rate and rate of secretion. The pharmacokinetic model quantified this interaction and estimated a 2.3 ± 1 fold higher effect of meal on secretion than vice versa. The efficacy of the emptied meal to produce gastric secretion was 61%.Conclusions & Inferences The combined quantitative MRI and pharmacokinetic model approach allows for the quantification of gastric secretion volume and its interaction on meal emptying. The observed secretion layer might explain previous findings postulating the presence of an intragastric ‘acid pocket’.
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Effects of aging on cholinergic neuromuscular transmission in isolated small intestine of ad libitum fed and calorically-restricted rats
Background Age-associated losses of enteric neurons have been described. In rat ileum, myenteric neurons lost during aging have been reported to be predominantly cholinergic, and caloric restriction (CR) has been shown to protect against these losses. Cholinergic myenteric neurons include excitatory motor neurons, so the aim of this work was to determine whether neuronal loss in ad libitum (AL)-fed animals is reflected in dysfunctional cholinergic neuromuscular transmission, and if CR reduces any such dysfunction.Methods Effects of electrical field stimulation (EFS) and applied acetylcholine (ACh) were examined in the longitudinal muscle of isolated ileal segments from 6-month-old rats and from 13- and 24-month-old rats fed either AL or CR diets.Key Results Contractile responses to EFS were abolished by atropine and potentiated by the acetylcholinesterase inhibitor, eserine. Frequency-response relationships were not significantly different amongst the three age-groups. Sensitivity to applied ACh, however, was three-fold lower in the oldest animals (P < 0.05). Eserine potentiated responses to ACh; there were no statistically significant differences amongst the sensitivities to ACh in its presence. No significant differences between AL- and CR-fed animals were measured, although variability was less in CR-fed than in AL-fed groups.Conclusions & Inferences The cholinergic system supplying the rat ileum longitudinal muscle did not appear to be impaired in old age. Decreased sensitivity to applied ACh in old tissues may have been due to increased acetylcholinesterase activity. Caloric restriction had no significant effect on responses to EFS or applied ACh. The implications of these results are discussed.
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Serotonin transporter gene promoter region polymorphisms and serotonin transporter expression in the colonic mucosa of irritable bowel syndrome patients
Background The role of serotonin transporter (SERT) gene polymorphism in irritable bowel syndrome (IBS) has been demonstrated. However, the expression of SERT mRNA and proteins in the colonic mucosa with different 5-HTT gene-linked polymorphic region (5-HTTLPR) genotypes remains unknown. We examined SERT mRNA and protein levels in colon biopsies from patients with different 5-HTTLPR genotypes and evaluated the links between the polymorphism and the expression levels.Methods Two hundred and fifty-four patients with IBS and 120 healthy subjects were studied. DNA samples were extracted from peripheral blood and genotyped by polymerase chain reaction (PCR). SERT mRNA and protein levels were evaluated by quantitative real time PCR and western blotting. The promoter efficiency of the serotonin transporter promoter (SERT-P) was evaluated with luciferase reporter system.Key Results The frequency of the L/L genotype in C-IBS group was significantly higher than that in the control and D-IBS. However, the S/S genotype in D-IBS was significantly higher than that in C-IBS. The transcriptional efficiency of the L/L genotype was significantly higher than that in the L/S and S/S genotype. Patients with the L/L genotype demonstrated increased production of the SERT protein when compared with L/S and S/S patients. The l variant increased SERT promoter activity by 2.43-fold when compared with the s variant.Conclusions & Inferences Polymorphism in the promoter region of the SERT gene can influence the expression of SERT mRNA and the levels of the SERT protein in the colonic mucosa, thereby playing a key role in motility-related symptoms of IBS patients.
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Acotiamide, a new orally active acetylcholinesterase inhibitor, stimulates gastrointestinal motor activity in conscious dogs
Background Acotiamide hydrochloride (acotiamide), a novel selective acetylcholinesterase (AChE) inhibitor, has proven significantly effective in treating functional dyspepsia (FD) in clinical trials, particularly in alleviating meal-related symptoms. In the present study, we examined the gastrointestinal prokinetic effects of acotiamide administered orally or intraduodenally in conscious dogs and investigated in vivo and ex vivo anti-AChE activity of acotiamide to clarify its mechanism of prokinetic action.Methods Gastrointestinal motility was measured in conscious dogs with chronically implanted force transducers.Key Results Oral administration of acotiamide stimulated postprandial gastroduodenal and colonic motor activities. Measurement of gastrointestinal motility showed that acotiamide, like itopride and mosapride, enhanced gastric antral motility. Further, acotiamide markedly improved clonidine (an α2-adrenoceptor agonist)-induced hypomotility in a dog model of gastric motor dysfunction. The postprandial gastric antral motility enhanced by acotiamide was completely abolished on treatment with the muscarinic receptor antagonist atropine. Results of an in vivo experiment on anti-AChE activity showed clearly increased acetylcholine-induced gastric motility on intraduodenal administration of acotiamide, just as observed with the AChE inhibitor neostigmine. Further, in ex vivo experiment, intraduodenal administration of acotiamide significantly inhibited AChE activity in canine gastric antrum.Conclusions & Inferences Our findings revealed that acotiamide administered through the alimentary tract exerts gastroprokinetic action via cholinergic pathways by inhibiting AChE activity. These results may also confirm the mechanism of action in clinical efficacy of acotiamide on FD.
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The Rome II and Rome III criteria identify the same subtype-populations in irritable bowel syndrome: agreement depends on the method used for symptom report
Background For comparing trials using different classifications for irritable bowel syndrome (IBS) subtypes, it is important to know whether these identify the same sub-populations. Our aim was to determine the agreement between Rome II and Rome III subtypes, and to explore whether agreement depends on the symptom reporting method.Methods Rome II IBS patients from two identical, randomized placebo-controlled trials of probiotics were included. Retrospective subtypes were based on the Rome II questionnaire. Prospective subtypes were based on diary cards for 2 weeks of run-in. Agreement was determined between: (i) retrospective Rome II and Rome III, (ii) prospective Rome II and Rome III, (iii) retrospective Rome II and prospectively Rome III, (iv) retrospective and prospective Rome II, and (v) retrospective and prospective Rome III.Key Results A total of 126 patients, 72% women, mean age 46 ± 15 years, were included. The agreement between subtypes using the same symptom reporting method was: (i) 90.3% (κ = 0.85) for retrospective subtypes, and (ii) 84% (κ = 0.76) for prospective subtypes. The agreement between subtypes using different symptom reporting methods was, (iii) 49% (κ = 0.23) for retrospective Rome II and prospective Rome III, (iv) 51% (κ = 0.26) for Rome II subtypes, and (v) 41% (κ = 0.25) for Rome III subtypes.Conclusions & Inferences Agreement between Rome II and Rome III subtypes is good to very good when using the same symptom reporting method. When mixing methods, agreement is only fair even within the same classification. This has implications for comparison of trials using different symptom reporting methods for subtyping.
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Colonic inflammation up-regulates voltage-gated sodium channels in bladder sensory neurons via activation of peripheral transient potential vanilloid 1 receptors
Background Primary sensory neurons express several types of ion channels including transient receptor potential vanilloid 1 (TRPV1) and voltage-gated Na+ channels. Our previous studies showed an increased excitability of bladder primary sensory and spinal neurons triggered by inflammation in the distal colon as a result of pelvic organ cross-sensitization. The goal of this work was to determine the effects of TRPV1 receptor activation by potent agonists and/or colonic inflammation on voltage-gated Na+ channels expressed in bladder sensory neurons.Methods Sprague–Dawley rats were treated with intracolonic saline (control), resiniferatoxin (RTX, 10−7 mol L−1), TNBS (colonic irritant) or double treatment (RTX followed by TNBS).Key Results TNBS-induced colitis increased the amplitude of total Na+ current by two-fold and of tetrodotoxin resistant (TTX-R) Na+ current by 78% (P ≤ 0.05 to control) in lumbosacral bladder neurons during acute phase (3 days post-TNBS). Instillation of RTX in the distal colon caused an enhancement in the amplitude of total Na+ current at −20 mV from −112.1 ± 18.7 pA/pF (control) to −183.6 ± 27.8 pA/pF (3 days post-RTX, P ≤ 0.05) without changes in TTX resistant component. The amplitude of net Na+ current was also increased by 119% at day 3 in the group with double treatment (RTX followed by TNBS, P ≤ 0.05 to control) which was significantly higher than in either group with a single treatment.Conclusions & Inferences These results provide evidence that colonic inflammation activates TRPV1 receptors at the peripheral sensory terminals leading to an up-regulation of voltage gated Na+ channels on the cell soma of bladder sensory neurons. This mechanism may underlie the occurrence of peripheral cross-sensitization in the pelvis and functional chronic pelvic pain.
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