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AbstractBackgroundThis study compared the effects of ondansetron and placebo in patients with diabetes mellitus and symptoms of dyspepsia (diabetic gastroenteropathy [DGE]).MethodsWe performed a randomized, double‐blinded, placebo‐controlled study of ondansetron tablets (8 mg) three times daily for 4 weeks in DGE patients. Symptoms were assessed with the Gastroparesis Cardinal Symptom Index daily diaries. Gastric emptying (GE) of solids (scintigraphy) and duodenal lipid infusions (300 kcal over 2 h) were each assessed twice, with placebo and ondansetron. Drug effects on GE, symptoms during the GE study and during lipid infusion, and daily symptoms were analyzed.Key ResultsOf 41 patients, 37 completed both GE studies and one completed 1; 31 completed both lipid infusions and four only placebo; and all 35 randomized patients completed 4 weeks of treatment. Compared to placebo, ondansetron reduced the severity of fullness (p = 0.02) and belching (p = 0.049) during lipid infusion but did not affect GE T1/2. Both ondansetron and placebo improved daily symptoms versus the baseline period (p < 0.05), but the differences were not significant. In the analysis of covariance of daily symptoms during the treatment period, the interaction term between treatment and the acute effect of ondansetron on symptoms during lipid challenge was significant (p = .024).Conclusions & InferencesOndansetron significantly reduced fullness during enteral lipid infusion in patients with DGE. Overall, ondansetron did not improve daily symptoms versus placebo. But patients in whom ondansetron improved symptoms during enteral lipid challenge were perhaps more likely to experience symptom relief during daily treatment.

AbstractBackgroundDiarrhea and rectal urgency are risk factors for fecal incontinence (FI). The effectiveness of bowel modifiers for improving FI is unclear.MethodsIn this double‐blind, parallel‐group, randomized trial, women with urge FI were randomly assigned in a 1:1 ratio to a combination of oral clonidine (0.1 mg twice daily) with colesevelam (1875 mg twice daily) or two inert tablets for 4 weeks. The primary outcome was a ≥50% decrease in number of weekly FI episodes.Key ResultsFifty‐six participants were randomly assigned to clonidine–colesevelam (n = 24) or placebo (n = 32); 51 (91%) completed 4 weeks of treatment. At baseline, participants had a mean (SD) of 7.5 (8.2) FI episodes weekly. The primary outcome was met for 13 of 24 participants (54%) treated with clonidine–colesevelam versus 17 of 32 (53%) treated with placebo (p = 0.85). The Bristol stool form score decreased significantly, reflecting more formed stools with clonidine–colesevelam treatment (mean [SD], 4.5 [1.5] to 3.2 [1.5]; p = 0.02) but not with placebo (4.2 [1.9] to 4.1 [1.9]; p = 0.47). The proportion of FI episodes for semiformed stools decreased significantly from a mean (SD) of 76% (8%) to 61% (10%) in the clonidine–colesevelam group (p = 0.007) but not the placebo group (61% [8%] to 67% [8%]; p = 0.76). However, these treatment effects did not differ significantly between groups. Overall, clonidine–colesevelam was well tolerated.Conclusions and InferencesCompared with placebo, clonidine–colesevelam did not significantly improve FI despite being associated with more formed stools and fewer FI episodes for semiformed stools.

AbstractBackgroundThe optimal methods for measuring and analyzing anal resting and squeeze pressure with high‐resolution manometry (HRM) are unclear.MethodsAnal resting and squeeze pressures were measured with HRM in 90 healthy women, 35 women with defecatory disorders (DD), and 85 with fecal incontinence (FI). Pressures were analyzed with Manoview™ software and a customized approach. Resting pressures measured for 20, 60, and 300 s were compared. During the squeeze period, (3 maneuvers, 20 s each), the squeeze increment, which was averaged over 5, 10, 15, and 20 s, and squeeze duration were evaluated.ResultsCompared to healthy women, the anal resting pressure, squeeze pressure increment, and squeeze duration were lower in FI (p ≤ 0.04) but not in DD. The 20, 60, and 300 s resting pressures were strongly correlated (concordance correlation coefficients = 0.96–0.99) in healthy and DD women. The 5 s squeeze increment was the greatest; 10, 15, and 20 s values were progressively lower (p < 0.001). The squeeze pressure increment and duration differed (p < 0.01) among the three maneuvers in healthy and DD women but not in FI women. The upper 95th percentile limit for squeeze duration was 19.5 s in controls, 19.9 s in DD, and 19.3 s in FI. Adjusted for age, resting pressure, and squeeze duration, a greater squeeze increment was associated with a lower risk of FI versus health (OR, 0.96; 95% CI, 0.94–0.97).ConclusionsThese findings suggest that anal resting and squeeze pressures can be accurately measured over 20 s. In most patients, one squeeze maneuver is probably sufficient.

AbstractBackgroundIt is suggested that patients with defecation disorders (DD) strain excessively or do a Valsalva maneuver (VM) during evacuation, resulting in rectoanal discoordination, which hinders rectal evacuation. However, definitive data are lacking.MethodsRectoanal pressures during evacuation and a VM were measured with seated high‐resolution manometry (HRM) in 64 healthy and 136 constipated women with a normal (84 women, C‐normal) or prolonged (52 women, C‐abnormal) balloon expulsion time (BET). The number of abnormal rectoanal parameters during evacuation and the joint distribution of pressures during evacuation and a VM were used to discriminate between controls and C‐abnormal BET patients.Key ResultsThe peak anal pressure (5 s) during a VM accounted for 0%, 26%, and 49% of the variance in anal pressure during evacuation in healthy women, C‐normal BET, and C‐abnormal BET. The association between anal pressure during a VM and evacuation was stronger in C‐abnormal BET than in healthy women and C‐normal BET (p for interaction <0.001). Fifty‐eight of 64 controls and 33 of 52 C‐abnormal BET patients had no or one abnormal parameter during evacuation; hence, the probability of C‐abnormal BET was 33/91 (36%). In patients with no or one abnormal parameter during evacuation, a logistic model based on anal pressures during evacuation and a VM discriminated between controls and patients with C‐abnormal BET with a sensitivity and a specificity of 67% and 75%.ConclusionsAssessment of rectoanal pressures during evacuation and a VM uncovers rectaoanal discoordination and facilitates the diagnosis of DD in selected patients.

AbstractObjectivesDefecation requires relaxation of the internal and external anal sphincters. High anal resting pressure is associated with painful constipation, defecatory disorders, and increased healthcare utilization in constipated patients; the mechanisms are unclear. Perhaps patients with a high anal resting pressure have a less distensible canal, which impedes defecation.MethodsIn 50 of 64 participants (33 healthy and 17 constipated women), anal pressures and distensibility were measured, respectively, with manometry and balloon distention combined with magnetic resonance imaging; rectal balloon expulsion time (BET) was also studied.ResultsThe BET (P = .006) was longer, and the mean (SD) rectoanal pressure gradient (−58[40] vs −34[26] mm Hg,P = .03) was more negative in constipated than healthy women; anal resting pressure was not different. During anal distention, the balloon expanded rapidly at an opening pressure of 49 (18) mm Hg, which was lower (P < .0001) than resting pressure (90 [25] mm Hg). The resting pressure was correlated with the opening pressure (r = 0.57,P < .0001) and inversely (r = −0.38,P = .007) with maximum volume but not with anal distensibility (volume‐pressure slope). In healthy women, the difference (opening‐resting pressure) was correlated with anal relaxation during evacuation (r = 0.35,P = .04). Anal distensibility and sensory thresholds were not different between constipated and healthy women.ConclusionsAmong healthy and constipated women, a greater anal resting pressure is correlated with greater opening pressure and lower maximum volume during distention, and, hence, provides a surrogate marker of anal distensibility. The difference (opening‐resting pressure), which reflects anal relaxation during distention, is correlated with anal relaxation during evacuation. Anal resting pressure and distensibility were comparable in healthy and constipated women.

AbstractBackgroundWe compared the utility of existing and modified versions of high‐resolution manometry for diagnosing defecatory disorders (DD).MethodsIn 64 healthy and 136 constipated women, we compared left lateral (LL) and seated manometry, and analyzed with existing (ManoView™) and new methods, for discriminating between constipated patients with normal and prolonged rectal balloon expulsion time (BET). In both positions, the rectoanal gradient (RAG) and, for the new analysis, the pressure topography pattern during evacuation were used to discriminate between constipated patients without and with DD.Key ResultsThe BET was prolonged, suggestive of a DD, in 52 patients (38%). During evacuation, rectoanal pressures and the RAG were greater in the seated than the LL position (P≤.001). The new analysis identified 4 rectoanal pressure patterns. In the seated position, the BET was associated with the pattern (P=.0001), being prolonged in, respectively, 45%, 15%, 53%, and 0% of patients with minimal change, anal relaxation, paradoxical contraction, and transmission. Within each pattern, the RAG was greater (ie, less negative, P<.0001) in patients with a normal than a prolonged BET. Compared to the ManoView™ RAG in the LL position, the integrated analysis (ie, pattern and new RAG) in the LL position (P<.01) and the seated ManoView™ gradient (P=.02) were more effective for discriminating between constipated patients without and with DD.Conclusions & InferencesAnorectal HRM ideally should be performed in the more physiological seated position and analyzed by a two‐tier approach, which incorporates the overall pattern followed by the rectoanal gradient. These findings reinforce the utility of manometry for diagnosing DD.

AbstractBackgroundNutrient‐mediated release of cholecystokinin and glucagon‐like peptide‐1 (GLP‐1) regulates gastric emptying (GE) via duodenogastric feedback mechanisms; GLP‐1 also regulates postprandial insulin secretion. Some patients with functional upper gastrointestinal symptoms have impaired glucose tolerance during enteral dextrose infusion. Our hypothesis was that variants in CCK, GLP‐1, and TCF7L2 (transcription factor 7‐like 2 locus), which is associated with greatest genetic risk for development of type 2 diabetes mellitus, are associated with GE and independently with glucose tolerance. Our aims were to evaluate the associations between these GE, glucose tolerance, and these single nucleotide polymorphisms (SNPs).MethodsGenetic variants, scintigraphic GE of solids, plasma glucose, insulin, and GLP‐1 during enteral dextrose infusion (75gm over 2 hours) were measured. GE and enteral dextrose infusion were, respectively, evaluated in 44 (27 controls and 17 patients with functional dyspepsia or nausea) and 42 (28 controls, 14 patients) participants; of these, 51 participants consented to assessment of SNPs. Four functional SNPs were studied: rs6923761 and rs1042044 at GLP‐1 receptor, rs7903146 (TCF7L2), and rs1800857 (CCK receptor).Key ResultsGastric emptying was normal in 38, rapid in 4, and delayed in two participants; 38 had normal, and four had impaired glucose tolerance. The T allele at rs7903146 (TCF7L2) was non‐significantly associated (P = .14) with faster GE. The associations between SNPs and demographic variables, GE thalf, glucose tolerance and plasma GLP1 levels were not significant.Conclusions & InferencesThere is a trend toward an association between faster GE and the diabetes‐associated allele at rs7903146 in TCF7L2. However, these SNPs were not associated with plasma glucose or GLP1 concentrations during enteral dextrose infusion.

AbstractBackgroundOur aim is to explain the lack of clarity in the ways in which anxiety and depression, which are common in defecatory disorders (DD), may contribute to the disorder. In this study, we evaluate the effects of mental stress and relaxation on anal pressures and the mechanisms thereof.MethodsIn 38 healthy women and 36 DD patients, rectoanal pressures were assessed at rest and during mental stressors (ie, word‐color conflict [Stroop] and mental arithmetic tests) and mental relaxation, before and after randomization to placebo or the adrenergic α1‐antagonist alfuzosin.Key ResultsDuring the baseline Stroop test, the anal pressure increased by 6 ± 13 mm Hg (mean ± SD, P = 0.004) in healthy women and 9 ± 10 mm Hg (P = 0.0001) in constipated women. During mental arithmetic, the anal pressure increased in healthy (4 ± 8 mm Hg, P = 0.002) and constipated women (5 ± 9 mm Hg, P = 0.004). After relaxation, anal pressure declined (P = 0.0004) by 3 ± 4 mm Hg in DD patients but not in controls. Alfuzosin reduced (P = 0.0001) anal resting pressure (by 31 ± 19 mm Hg) vs placebo (16 ± 18 mm Hg). However, during the postdrug Stroop test, anal pressure increased (P = 0.0001) in participants who received alfuzosin but not placebo.Conclusions & InferencesIn healthy controls and DD patients, mental stressors likely increased anal pressure by contracting the internal anal sphincter; relaxation reduced anal pressure in DD patients. Alfuzosin reduced anal resting pressure but did not block the Stroop‐mediated contractile response, which suggests that this response is not entirely mediated by adrenergic α1 receptors.

AbstractBackgroundHigh‐resolution manometry (HRM) is used to measure rectoanal pressures in defecatory disorders and fecal incontinence. This study sought to define normal values for rectoanal HRM, ascertain the effects of age and BMI on rectoanal pressures, and compare pressures in asymptomatic women with normal and prolonged balloon expulsion time (BET).MethodsHigh‐resolution manometry pressures and BET were measured in 163 asymptomatic healthy participants. Women (96) and men (47) with normal BET were used to estimate normal values and the effects of age/BMI on pressures using a Medtronic 4.2‐mm‐diameter rectoanal catheter.Key ResultsAge is associated with lower resting pressure, higher rectal pressure during evacuation, and a higher rectoanal gradient during evacuation in women and men. In women, the BET is also inversely correlated with age while the BMI is correlated with a higher threshold volume for discomfort and a longer BET. The anal squeeze pressure increment, squeeze duration, and HPZ length are higher in men than women. The rectoanal gradient during evacuation is also lower (ie, more negative) in asymptomatic women with an abnormal than a normal BET.Conclusions & InferencesThese findings provide an expanded database of normal values for anorectal HRM in men and women. Age and sex affect anal resting and squeeze pressures, respectively; rectal pressure during evacuation is also higher in older people. Less than 15% of asymptomatic people have BET >60 seconds, which is associated with manometry features of impaired evacuation.

AbstractBackgroundIn order to understand the pathophysiology of rectal sensorimotor dysfunctions in women with fecal incontinence (FI) and rectal urgency, we evaluated the effects of a muscarinic antagonist and an adrenergic α2 agonist on these parameters.MethodsFirstly, rectal distensibility and sensation were evaluated with a barostat and sinusoidal oscillation at baseline and after randomization to intravenous saline or atropine in 16 healthy controls and 44 FI patients. Thereafter, FI patients were randomized to placebo or clonidine for 4 wk; rectal compliance and sensation were revaluated thereafter. The effect of atropine and clonidine on rectal functions and the relationship between them were evaluated.ResultsAt baseline, compared to controls, rectal capacity was lower (P = .03) while the mean pressure (P = .02) and elastance (P = .01) during sinusoidal oscillation were greater, signifying reduced distensibility, in FI. Compared to placebo, atropine increased (P ≤ .02) the heart rate in controls and FI and reduced (P = .03) the variability in rectal pressures during sinusoidal oscillation in controls. Clonidine increased rectal compliance (P = .04) and reduced rectal capacity (P = .03) in FI. The effects of atropine and clonidine on compliance (r = .44, P = .003), capacity (r = .34, P = .02), pressures during sinusoidal oscillation (r = .3, P = .057), pressure (r = .6, P < .0001), and volume sensory thresholds (r = .48, P = .003) were correlated.ConclusionsThe effects of atropine and clonidine on rectal distensibility and sensation were significantly correlated. A preserved response to atropine suggests that reduced rectal distensibility is partly reversible, mediated by cholinergic mechanisms, and may predict the response to clonidine, providing a pharmacological challenge.