Search

While anal sphincter neurogenic injury documented by needle electromyography (EMG) has been implicated to cause fecal incontinence (FI), most studies have been uncontrolled. Normal values and the effects of age on anal sphincter motor unit potentials (MUP) are ill defined. The functional significance of anal sphincter neurogenic injury in FI is unclear. Anal pressures and EMG were assessed in 20 asymptomatic nulliparous women (age, 38 ± 5 yr; mean ± SE) and 20 women with FI (54 ± 3 yr). A computerized program quantified MUP duration and phases. These parameters and MUP recruitment were also semiquantitatively assessed by experienced electromyographers in real time. Increasing age was associated with longer and more polyphasic MUP in nulliparous women by quantitative analysis. A higher proportion of FI patients had prolonged (1 control, 7 patients, P = 0.04) and polyphasic MUP (2 controls, 9 patients, P = 0.03) at rest but not during squeeze. Semiquantitative analyses identified neurogenic or muscle injury in the anal sphincter (11 patients) and other lumbosacral muscles (4 patients). There was substantial agreement between quantitative and semiquantitative analyses (κ statistic 0.63 ± 95% CI: 0.32-0.96). Anal resting and squeeze pressures were lower (P ≤ 0.01) in FI than controls. Anal sphincter neurogenic or muscle injury assessed by needle EMG was associated (P = 0.01) with weaker squeeze pressures (83 ± 10 mmHg vs. 154 ± 30 mmHg) and explained 19% (P = 0.01) of the variation in squeeze pressure. Anal sphincter MUP are longer and more polyphasic in older than younger nulliparous women. Women with FI have more severe neurogenic or muscle anal sphincter injury, which is associated with lower squeeze pressures.

The glucagon-like peptide 1 (GLP-1) analog ROSE-010 reduced pain during acute exacerbations of irritable bowel syndrome (IBS). Our objective was to assess effects of ROSE-010 on several gastrointestinal (GI) motor and bowel functions in constipation-predominant IBS (IBS-C). In a single-center, randomized, parallel-group, double-blind, placebo-controlled, dose-response study, we evaluated safety, pharmacodynamics, and pharmacokinetics in female patients with IBS-C. ROSE-010 (30, 100, or 300 μg sc) or matching placebo was administered once daily for 3 consecutive days and on 1 day 2-10 days later. We measured GI and colonic transit by validated scintigraphy and gastric volumes by single-photon emission computed tomography. The primary end points were half time of gastric emptying of solids, colonic transit geometric center at 24 h, and gastric accommodation volume. Analysis included intent-to-treat principle, analysis of covariance (with body mass index as covariate), and Dunnett-Hsu test for multiple comparisons. Exposure to ROSE-010 was approximately dose-proportional across the dose range tested. Demographic data in four treatment groups of female IBS-C patients (total 46) were not different. Gastric emptying was significantly retarded by 100 and 300 μg of ROSE-010. There were no significant effects of ROSE-010 on gastric volumes, small bowel or colonic transit at 24 h, or bowel functions. The 30- and 100-μg doses accelerated colonic transit at 48 h. Adverse effects were nausea (P < 0.001 vs. placebo) and vomiting (P = 0.008 vs. placebo). Laboratory safety results were not clinically significant. In IBS-C, ROSE-010 delayed gastric emptying of solids but did not retard colonic transit or alter gastric accommodation; the accelerated colonic transit at 48 h with 30 and 100 μg of ROSE-010 suggests potential for relief of constipation in IBS-C.

Background: Colonic mechanosensory afferents 'in parallel' to circular muscle activate prevertebral ganglion reflexes; 'in series', afferents convey visceral sensation to the central nervous system; and pain receptors are activated with muscle distension. Our aim was to analyze the relationships of gas and pain sensations during graded distensions, and the association of sensations with colonic compliance in conscious humans., Methods: The data were acquired in a prior study performed on 60 healthy volunteers (aged 18-75 years) under baseline conditions. Colonic compliance was measured in response to 4 mmHg stepwise balloon distensions to estimate pressure at half-maximum volume (Pr(50%)). Sensation ratings for gas and pain were averaged over distensions at 16, 24, 30 and 36 mmHg above baseline operating pressure. Associations between mean gas and pain ratings, and colonic compliance were assessed with Pearson correlations., Key Results: Gas and pain sensations were significantly correlated at all levels of distension (all P < 0.001). Significant inverse correlations between Pr(50%) and sensations of gas and pain were observed, suggesting that lower compliance was associated with lower sensations. Up to 25% of the variance in sensation may be attributed to colonic compliance., Conclusions & Inferences: These data are consistent with the hypothesis that, if circumferential colonic receptors are stimulated by distension to mediate gas and pain in humans, they are, at least partly, arranged 'in parallel' to the muscle layer., (© 2012 Blackwell Publishing Ltd.)

Objectives: Current concepts based on referral center data suggest that pelvic floor injury from obstetric trauma is a major risk factor for fecal incontinence (FI) in women. In contrast, a majority of community women only develop FI decades after vaginal delivery, and obstetric events are not independent risk factors for FI. However, obstetric events are imperfect surrogates for anal and pelvic floor injury, which is often clinically occult. Hence, the objectives of this study were to evaluate the relationship between prior obstetric events, pelvic floor injury, and FI among community women., Methods: In this nested case-control study of 68 women with FI (cases; mean age 57 years) and 68 age-matched controls from a population-based cohort in Olmsted County, MN, pelvic floor anatomy and motion during voluntary contraction and defecation were assessed by magnetic resonance imaging. Obstetric events and bowel habits were recorded., Results: By multivariable analysis, internal sphincter injury (cases-28%, controls-6%; odds ratio (OR): 8.8; 95% confidence interval (CI): 2.3-34) and reduced perineal descent during defecation (cases-2.6 ± 0.2 cm, controls-3.1 ± 0.2 cm; OR: 1.7; 95% CI: 1.2-2.4) increased FI risk, but external sphincter injury (cases-25%, controls-4%; P<0.005) was not independently predictive. Puborectalis injury was associated (P<0.05) with impaired anorectal motion during squeeze, but was not independently associated with FI. Grades 3-4 episiotomy (OR: 3.9; 95% CI: 1.4-11) but not other obstetric events increased the risk for pelvic floor injury. Heavy smoking (≥ 20 pack-years) was associated (P=0.052) with external sphincter atrophy., Conclusions: State-of-the-art imaging techniques reveal pelvic floor injury or abnormal anorectal motion in a minority of community women with FI. Internal sphincter injury and reduced perineal descent during defecation are independent risk factors for FI. In addition to grades 3-4 episiotomy, smoking may be a potentially preventable, risk factor for pelvic floor injury.

Background: Tapentadol is a mu-opioid receptor agonist and norepinephrine reuptake inhibitor. In clinical trials, tapentadol provided somatic pain relief comparable to mu-opioids such as oxycodone, with significantly less gastrointestinal adverse effects. The acute effects of tapentadol on gastrointestinal and colonic transit are unclear., Aim: To compare acute effects of oral tapentadol and oxycodone on gastric, small bowel and colonic transit of solids in 38 healthy human subjects., Methods: In a randomised, parallel-group, double-blind, placebo-controlled study of the effects of identical-appearing tapentadol immediate release (IR), 75 mg t.d.s., or oxycodone IR, 5 mg t.d.s., for 48 h, we measured gastric (GE), small bowel (SBT measured as colonic filling at 6 h) and colonic transit by validated scintigraphy. Drug was commenced on the evening before the start of the transit test. The primary endpoints were overall colonic transit (geometric centre, GC) at 24 h and GE half-time (t1/2 ). ancova of transit data included gender or BMI as covariates. Adverse effects were summarised., Results: At the doses tested, oxycodone and tapentadol significantly delayed GE t1/2 and SBT, but not overall colonic transit, compared to placebo. Transit profiles in all regions were not significantly different between oxycodone and tapentadol at the doses tested. Both oxycodone and tapentadol were associated with nausea and central effects attributable to central opiate effects., Conclusions: Tapentadol significantly delayed gastric emptying t1/2 and small bowel transit, similar to oxycodone. These data suggest that acute administration of tapentadol may not have significant advantages over standard mu-opioids, in terms of the potential to avoid upper gastrointestinal motor dysfunction., (© 2012 Blackwell Publishing Ltd.)

Background: Functional dyspepsia (FD) is a common problem affecting up to 10-25% of individuals. FD accounts for significant health care costs and affects quality of life but has no definitive treatment., Objectives: The Functional Dyspepsia Treatment Trial (FDTT) aims to test whether treatment with an antidepressant (amitriptyline or escitalopram) leads to improvement of symptoms in patients with moderate to severe FD., Design: The FDTT is an international multicenter, parallel group, randomized, double-blind, placebo-controlled trial to evaluate whether 12 weeks of treatment with escitalopram or amitriptyline improves FD symptoms compared to treatment with placebo. Secondly, it is hypothesized that acceleration of solid gastric emptying, reduction of postprandial satiation, and enhanced gastric volume change with a meal will be significant positive predictors of short- and long-term outcomes for those on antidepressants vs. placebo. The third aim is to examine whether polymorphisms of GNβ3 and serotonin reuptake transporter influence treatment outcomes in FD patients receiving a tricyclic antidepressant, selective serotonin reuptake inhibitor therapy, or placebo., Methods: The FDTT enrollment began in 2006 and is scheduled to randomize 400 patients by the end of 2012 to receive an antidepressant or placebo for 12 weeks, with a 6-month post-treatment follow-up. The study incorporates multiple validated questionnaires, physiological testing, and specific genetic evaluations. The protocol was approved by participating centers' Institutional Review Boards and an independent Data Safety Monitoring Board was established for monitoring to ensure patient safety and a single interim review of the data in December 2010 (ClinicalTrials.gov number NCT00248651)., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background & Aims: The prevalence of chronic constipation (CC) has been reported to be as high as 20% in the general population, but little is known about its natural history. We estimated the natural history of CC and characterized features of persistent CC and nonpersistent CC, compared with individuals without constipation., Methods: In a prospective cohort study, we analyzed data collected from multiple, validated surveys (minimum of 2) of 2853 randomly selected subjects, over a 20-year period (median, 11.6 years). Based on responses, subjects were characterized as having persistent CC, nonpersistent CC, or no constipation. We assessed the association between constipation status and potential risk factors using logistic regression models, adjusting for age and sex., Results: Of the respondents, 84 had persistent CC (3%), 605 had nonpersistent CC (21%), and 2164 had no symptoms of constipation (76%). High scores from the somatic symptom checklist (odds ratio [OR] = 2.1; 95% confidence interval [CI], 1.3-3.4) and frequent doctor visits (OR = 2.0; 95% CI, 1.0-3.8) were significantly associated with persistent CC, compared with subjects with no constipation symptoms. The only factor that differed was increased use of laxatives or fiber among subjects with persistent CC (OR = 3.0; 95% CI, 1.9-4.9)., Conclusions: The prevalence of constipation might be exaggerated-the proportion of the population with persistent CC is low (3%). Patients with persistent and nonpersistent CC have similar clinical characteristics, although individuals with persistent CC use more laxatives or fiber. CC therefore appears and disappears among certain patients, but we do not have enough information to identify these individuals in advance., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The mechanisms by which common genetic variation predisposes to type 2 diabetes remain unclear. The disease-associated variants in TCF7L2 (rs7903146) and WFS1 (rs10010131) have been shown to affect response to exogenous glucagon-like peptide 1 (GLP-1), while variants in KCNQ1 (rs151290, rs2237892, and rs2237895) alter endogenous GLP-1 secretion. We set out to validate these observations using a model of GLP-1-induced insulin secretion. We studied healthy individuals using a hyperglycemic clamp and GLP-1 infusion. In addition, we measured active and total GLP-1 in response to an oral challenge in nondiabetic subjects. After genotyping the relevant single nucleotide polymorphisms, generalized linear regression models and repeated-measures ANCOVA models incorporating potential confounders, such as age and BMI, were used to assess the associations, if any, of response with genotype. These variants did not alter GLP-1 concentrations in response to oral intake. No effects on β-cell responsiveness to hyperglycemia and GLP-1 infusion were apparent. Diabetes-associated variation (T allele at rs7903146) in TCF7L2 may impair the ability of hyperglycemia to suppress glucagon (45 ± 2 vs. 47 ± 2 vs. 60 ± 5 ng/L for CC, CT, and TT, respectively, P = 0.02). In nondiabetic subjects, diabetes-associated genetic variation does not alter GLP-1 concentrations after an oral challenge or its effect on insulin secretion.

Background: Protein products of klothoβ (KLB) and fibroblast growth factor receptor 4 (FGFR4) impact fibroblast growth factor 19-mediated feedback inhibition of hepatic bile acid (BA) synthesis. Variants of KLB and FGFR4 influence colonic transit (CT) in diarrhea-predominant irritable bowel syndrome (IBS-D)., Aim: The purpose of this study was to test the hypothesis that colesevelam's slowing effects on CT in IBS-D patients is influenced by genetic variants in KLB and FGFR4., Methods: We examined pharmacogenetic effects of KLB and FGFR4 coding variants (SNPs) on scintigraphic CT response to the BA sequestrant, colesevelam 1.875 g b.i.d. versus placebo (PLA) for 14 days in 24 female IBS-D patients., Results: FGFR4 rs351855 and KLB rs497501 were associated with differential colesevelam effects on ascending colon (AC) half-emptying time (t(1/2), P = 0.046 and P = 0.085 respectively) and on overall CT at 24 h (geometric center, GC24: P = 0.073 and P = 0.042, respectively), with slower transit for rs351855 GA/AA (but not for GG) and rs497501 CA/AA (but not CC) genotypes., Conclusion: FGFR4 rs351855 and KLB rs4975017 SNPs may identify a subset of IBS-D patients with beneficial response to colesevelam.

The current health-care environment is demanding evidence-based medicine that relies on clinical trials as the basis for decisions. Clinician investigators are more often finding that they are personally responsible for coordinating large, multisite trials. We present strategies for successful implementation and management of multisite clinical trials and knowledge gained through an international, multisite randomized clinical trial. Topics include team composition, regulatory requirements, study organization and governance, communication strategies, recruitment and retention efforts, budget, technology transfer, and publication.

Background: Genetic variation in endocannabinoid metabolism is associated with colonic transit in irritable bowel syndrome (IBS) with diarrhea (IBS-D). The nonselective cannabinoid (CB) receptor agonist, dronabinol (DRO), reduced fasting colonic motility in nonconstipated IBS. FAAH and CNR1 variants influenced DRO's effects on colonic motility. Our aims were: (i) to compare dose-related effects of DRO to placebo (PLA) on gut transit in IBS-D, and (ii) to examine influence of genetic variations in CB mechanisms on DRO’s transit effects., Methods: Thirty-six IBS-D volunteers were randomized (double-blind, concealed allocation) to twice per day PLA (n = 13), DRO 2.5 mg (n = 10), or DRO 5 mg (n = 13) for 2 days. We assessed gastric, small bowel, and colonic transit by validated radioscintigraphy and genotyped the single nucleotide polymorphisms CNR1 rs806378 and FAAH rs324420. Data analysis utilized a dominant genetic model., Key Results: Overall treatment effects of DRO on gastric, small bowel, or colonic transit were not detected. CNR1 rs806378 CT/TT was associated with a modest delay in colonic transit at 24 h compared with CC (P = 0.13 for differential treatment effects on postminus pretreatment changes in colonic transit by genotype). No significant interaction of treatment with FAAH rs324420 was detected., Conclusions & Inferences: Overall, DRO 2.5 or 5 mg twice per day for 2 days had no effect on gut transit in IBS-D. There appears to be a treatment-by-genotype effect, whereby DRO preferentially delays colonic transit in those with the CNR1 rs806378 CT/TT genotypes. Further study of CB pharmacogenetics may help identify a subset of IBS-D patients most likely to benefit from CB agonist therapy., (© 2012 Blackwell Publishing Ltd.)

Background: While bowel and bladder dysfunction are recognized consequences of a radical hysterectomy, the effects of a simple hysterectomy on anorectal sensorimotor functions, particularly rectal sensation, vary among studies and the effects on rectal compliance remain unknown. Our aims were to prospectively evaluate anorectal sensorimotor functions before and after a hysterectomy., Methods: Anal pressures, rectal compliance, capacity, sensation, and bowel symptoms were assessed before, at 2 months, and at 1 year after a simple vaginal hysterectomy for benign indications in 19 patients. Rectal staircase (0-44 mmHg, 4-mmHg steps), ramp (0-200 mL at 50, 200 and 600 mL min(-1)) and phasic distentions (8, 16, and 24 mmHg above operating pressure) were performed., Key Results: Anal resting (63 ± 4 before, 56 ± 4 mmHg after) and squeeze pressures (124 ± 12 before, 124 ± 12 mmHg after), rectal compliance and capacity (285 ± 12 before, 290 ± 11 mL 1 year after), and perception of phasic distentions were not different before vs after a hysterectomy. Sensory thresholds for first sensation and the desire to defecate were also not different, but pressure and volume thresholds for urgency were somewhat greater (Hazard ratio = 0.7, 95% CI [0.5, 1.0]) 1 year after (vs before) a hysterectomy. Rectal pressures were higher (P < 0.0001) during fast compared with slow ramp distention; this rate effect was greater at 1 year after a hysterectomy, particularly at 100 mL (P = 0.04)., Conclusions & Inferences: A simple vaginal hysterectomy has relatively modest effects (i.e., somewhat reduced rectal urgency and increased stiffness during rapid distention) on rectal sensorimotor functions., (© 2011 Blackwell Publishing Ltd.)

Background: The overlap of dyspepsia and gastroesophageal reflux (GER) is known to be frequent, but whether the overlap group is a distinct entity or not remains unclear. The aims of the study was to evaluate whether the overlap of dyspepsia and GER (dyspepsia-GER overlap) occurs more than expected due to chance alone, and evaluate the risk factors for dyspepsia-GER overlap., Methods: In 2008 and 2009, a validated Bowel Disease Questionnaire was mailed to a total of 8006 community sample from Olmsted County, MN. Overall, 3831 of the 8006 subjects returned surveys (response rate 48%). Dyspepsia was defined by symptom criteria of Rome III; GER was defined by weekly or more frequent heartburn and/or acid regurgitation., Key Results: Dyspepsia and GER occurred together more commonly than expected by chance. The somatic symptom checklist score was significantly associated with dyspepsia-GER overlap vs GER alone or dyspepsia alone [OR = 1.9 (1.4, 2.5), and 1.6 (1.2, 2.1), respectively]. Insomnia was also significantly associated with dyspepsia-GER overlap vs. GER alone or dyspepsia alone [OR = 1.4 (1.1, 1.7), OR = 1.3 (1.1, 1.6), respectively]. Moreover, proton pump inhibitor use was significantly associated with dyspepsia-GER overlap vs dyspepsia alone [OR = 2.4 (1.5, 3.8)]., Conclusions & Inferences: Dyspepsia-GER overlap is common in the population and is greater than expected by chance., (© 2011 Blackwell Publishing Ltd.)

Context: There has been much speculation as to whether defects in glucagon-like peptide-1 (GLP-1) secretion play a role in the pathogenesis of type 2 diabetes and the progression from normal glucose tolerance to prediabetes and diabetes., Objective: Our objective was to determine whether fasting and postchallenge concentrations of active and total GLP-1 decrease as glucose tolerance and insulin secretion worsen across the spectrum of prediabetes., Design: This was a cross-sectional study., Setting: The study was performed in the clinical research unit of an academic medical center., Participants: Participants included 165 subjects with a fasting glucose below 7.0 mmol/liter and not taking medications known to affect gastrointestinal motility or glucose metabolism., Intervention: Intervention included a 2-h, 75-g oral glucose tolerance test with insulin, C-peptide, glucagon, and GLP-1 measurements at seven time points., Main Outcome Measure: We evaluated the association of integrated, incremental active, and total GLP-1 concentrations with integrated, incremental glucose response to 75 g oral glucose., Results: After accounting for covariates, there was no evidence of a relationship of incremental glucose concentrations after oral glucose tolerance test with active and total GLP-1 (r(s) = -0.16 and P = 0.14, and r(s) = 0.00 and P > 0.9, respectively). There also was no association of GLP-1 concentrations with insulin secretion and action., Conclusions: The lack of association of GLP-1 concentrations with glucose tolerance status and with insulin secretion and action in a cohort encompassing the full spectrum of prediabetes strongly argues against a significant contribution of defects in GLP-1 secretion to the pathogenesis of prediabetes.

Aims/hypothesis: Individuals with impaired fasting glucose (IFG) are at increased risk of developing diabetes over the subsequent decade. However, there is uncertainty as to the mechanisms contributing to the development of diabetes. We sought to quantitate insulin secretion and action across the prediabetic range of fasting glucose., Methods: We studied a cohort of 173 individuals with a fasting glucose concentration <7·0 mM after an overnight fast using a 75-g oral glucose tolerance test (OGTT). Insulin action (S(i)) was estimated using the oral glucose minimal model, and β-cell responsivity indices (φ) were estimated using the oral C-peptide minimal model. The disposition index (DI) for each individual was calculated. The relationship of DI, φ and S(i) with fasting and postchallenge glucose, as well as other covariates, was explored using a generalized linear regression model., Results: In this cross-sectional study, S(i) and DI were inversely related to fasting glucose concentrations. On the other hand, φ was unrelated to fasting glucose concentrations. S(i), φ and DI were all inversely related to area above basal glucose concentrations after glucose challenge. Multiple parameters including body composition and gender contributed to the variability of S(i) and DI at a given fasting or postchallenge glucose concentration., Conclusions/interpretation: Defects in insulin secretion and action interact with body composition and gender to influence postchallenge glucose concentrations. There is considerable heterogeneity of insulin secretion and action for a given fasting glucose likely because of patient subsets with isolated IFG and normal glucose tolerance., (© 2011 Blackwell Publishing Ltd.)

Background: Ulcerative colitis (UC) patients are at increased risk of colorectal dysplasia and cancer. Few studies have examined the clinical outcomes of dysplastic polyps resembling sporadic adenomas that are removed with endoscopic polypectomy., Methods: A centralized diagnostic index identified patients evaluated between 1994 and 2004 with UC and polypoid dysplasia who were followed from the time of polypectomy until the most recent colonoscopy. They were stratified into two groups by polyp occurrence, either within (adenoma-like dysplasia) or outside (sporadic adenoma) the most proximal endoscopic or histologic extent of colitis. The endpoints of interest were the development of subsequent colorectal neoplasia, flat dysplasia, or cancer. The cumulative probabilities of these endpoints were estimated using the Kaplan-Meier method, and the association with clinical factors assessed using Cox proportional hazards regression., Results: Ninety-five patients were found to have polypoid dysplasia; of these, 77 underwent polypectomy. The cumulative probability of subsequent colorectal neoplasia in polypectomy patients was 18% at 1 year and 69% at 5 years. After polypectomy, cumulative incidence of cancer or flat dysplasia was 2% at 1 year and 13% at 5 years. The proportional hazards models indicated that these outcomes were not significantly associated with polyp type, primary sclerosing cholangitis, family history of colorectal cancer, 5-aminosalicylate use, extent of colitis, or duration of disease., Conclusions: While polypectomy may be safe for the management of adenomas occurring in most UC patients, the 5-year cumulative incidence of a combined endpoint (cancer or flat dysplasia) was 13%. Such patients should be followed closely., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Objectives: Nonadherence is an issue in the management of inflammatory bowel disease (IBD), and no validated screening tool is available. We aimed to determine whether scores from a self-reported adherence survey correlated with pharmacy refill data as a reliable measure of medication adherence., Methods: We used the eight item, self-reported Morisky Medication Adherence Scale. Each question is worth a point, with a maximum score of 8. Pharmacies were contacted for refill information for the previous 3 months, then 3 and 6 months from enrollment. Refill data were recorded for each time interval as the medication possession ratio (MPR); adherence was defined as >80%. Analysis of variance was used to determine the relationship between survey scores and MPR by drug class., Results: One hundred fifty outpatients were enrolled, of whom 94 had Crohn's disease and 56 had ulcerative colitis; 89 were female. At baseline, 47% of patients were on 5-aminosalicylic acid (5-ASA), 54% an immunomodulator, 15% infliximab, 8% an injectable biologic, and 6% budesonide. The median adherence score was 7. Fifty-two percent stated they "rarely" missed a dose of medication. The median adherence score, as defined by refill data, ranged from 0% (injectable biologic) to 75% (infliximab) by drug class. Only those on an immunomodulator had a survey score that positively correlated with adherence., Conclusions: Only those on a thiopurine were likely to have a score predicting adherence behavior. Adherence to therapy for IBD is complex and cannot be predicted reliably by a self-reported survey tool validated for other chronic conditions.

Background/aims: The prevalence of diagnosed gastroparesis is 24.2/100,000 inhabitants, but a large group of people with gastroparesis-like symptoms have never had a gastric emptying (GE) test. Some of them may have undiagnosed gastroparesis. Our aim was to estimate the prevalence of hidden gastroparesis in the community., Methods: The study was conducted in 2 parts: (1) Patients referred for a scintigraphic GE test completed a validated questionnaire (Bowel Disease Questionnaire). Multiple linear regression models to predict 2 hours and 4 hours GE rates were developed. (2) A revised Bowel Disease Questionnaire was mailed to a random sample of 4,194 Olmsted County residents. GE rates were estimated with the models for each subject and delayed GE was considered when they were lower than normal values. Hidden gastroparesis was defined in community subjects with predicted delayed GE that had not been diagnosed with gastroparesis prior to the survey., Results: The regression models for GE rates were constructed using data from 450 patients. In addition to age and gender, the symptoms found significant were nausea/vomiting, early satiety, upper abdominal pain, bloating, loss of appetite and weight loss more than 7 pounds. 2,298 (55%) community subjects returned a questionnaire. Five subjects were excluded due to a prior diagnosis of gastroparesis. When models were applied to the community survey data, 42 (1.8%) subjects were estimated to have delayed GE., Conclusions: Delayed GE was estimated to occur in 1.8% of community subjects. Since the prevalence of diagnosed gastroparesis is low (0.02%), many subjects with gastroparesis may remain undiagnosed.

Objectives: In patients with diabetes mellitus (DM) and upper gastrointestinal symptoms, a diagnosis of diabetic gastroparesis is often considered, but population-based data on the epidemiology of diabetic gastroparesis are lacking. We aimed to estimate the frequency of and risk factors for gastroparesis among community subjects with DM., Methods: In this population-based, historical cohort study, the medical records linkage system of the Rochester Epidemiology Project was used to identify 227 Olmsted County, MN residents with type 1 DM in 1995, a random sample of 360 residents with type 2 DM, and an age- and sex-stratified random sample of 639 nondiabetic residents. Using defined diagnostic criteria, we estimated the subsequent risk of developing gastroparesis in each group through 2006. The risk in DM, compared with frequency-matched community controls, was assessed by Cox proportional hazards modeling., Results: The cumulative proportions developing gastroparesis over a 10-year time period were 5.2% in type 1 DM, 1.0% in type 2 DM, and 0.2% in controls. The age- and gender-adjusted hazard ratios (HRs) for gastroparesis (relative to controls) was 33 (95% confidence interval (CI): 4.0, 274) in type 1 DM and 7.5 (95% CI: 0.8, 68) in type 2 DM. The risk of gastroparesis in type 1 DM was significantly greater than in type 2 DM (HR: 4.4 (1.1, 17)). Heartburn (HR: 6.6 (1.7, 25)) at baseline was associated with diabetic gastroparesis in type 1 DM., Conclusions: Gastroparesis is relatively uncommon in patients with DM, although an increased risk for gastroparesis was observed in type 1 DM.

Background: The cumulative incidence of and risk factors for perianal Crohn's disease (CD) for findings other than fistulas are unknown., Methods: The medical records of 310 incident cases of CD from Olmsted County, Minnesota, diagnosed between 1970 and 2004, were reviewed for evidence of perianal disease findings other than fistulas. Cumulative incidence was estimated using the Kaplan-Meier method, and associations between baseline factors and time to first event were assessed using proportional hazards regression. Four types of lesions were studied: anorectal strictures, deep anal canal ulcers, anal fissures, and perianal skin tags., Results: The 10-year cumulative probability from time of diagnosis was 5.8% (95% confidence interval [CI], 2.6%-8.8%) for anorectal strictures, 6.6% (3.6%-9.6%) for deep anal canal ulcers, 10.5% (6.8%-14.1%) for anal fissures, and 18.7% (13.9%-23.3%) for perianal skin tags. The cumulative probability for any perianal lesion other than fistulas was 21.3% (16.5%-25.8%) at 5 years and 29.2% (23.5%-34.5%) at 10 years. Baseline factors associated with time to first perianal lesion other than fistulas were age (hazard ratio [HR] per 10 years, 0.9; 95% CI, 0.8-0.98; P = 0.026), female gender (HR, 1.7; 95% CI, 1.1-2.7; P = 0.013), and presence of extraintestinal manifestations (HR, 1.7; 95% CI, 1.03-2.8; P = 0.038)., Conclusions: Perianal lesions other than fistulas occurred frequently during the clinical course of CD. Female gender and extraintestinal manifestations were associated with increased risks for perianal lesions other than fistulas, while older age at diagnosis was associated with a slightly decreased risk., (Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.)

Objectives: Clostridium difficile infection (CDI) is a common hospital-acquired infection with increasing incidence, severity, recurrence, and associated morbidity and mortality. There are emerging data on the occurrence of CDI in nonhospitalized patients. However, there is a relative lack of community-based CDI studies, as most of the existing studies are hospital based, potentially influencing the results by referral or hospitalization bias by missing cases of community-acquired CDI., Methods: To better understand the epidemiology of community-acquired C. difficile infection, a population-based study was conducted in Olmsted County, Minnesota, using the resources of the Rochester Epidemiology Project. Data regarding severity, treatment response, and outcomes were compared in community-acquired vs. hospital-acquired cohorts, and changes in these parameters, as well as in incidence, were assessed over the study period., Results: Community-acquired CDI cases accounted for 41% of 385 definite CDI cases. The incidence of both community-acquired and hospital-acquired CDI increased significantly over the study period. Compared with those with hospital-acquired infection, patients with community-acquired infection were younger (median age 50 years compared with 72 years), more likely to be female (76% vs. 60%), had lower comorbidity scores, and were less likely to have severe infection (20% vs. 31%) or have been exposed to antibiotics (78% vs. 94%). There were no differences in the rates of complicated or recurrent infection in patients with community-acquired compared with hospital-acquired infection., Conclusions: In this population-based cohort, a significant proportion of cases of CDI occurred in the community. These patients were younger and had less severe infection than those with hospital-acquired infection. Thus, reports of CDI in hospitalized patients likely underestimate the burden of disease and overestimate severity.

Background: Cyclic vomiting syndrome (CVS) is characterized by stereotypical episodes of vomiting separated by symptom-free intervals. However, the difficulty encountered in the management of patients with CVS may be a reflection of a deficiency in our understanding of the disorder. We aimed to evaluate whether clinical or gastric emptying (GE) data discriminate patients labeled as having CVS from functional vomiting (FV) or irritable bowel syndrome (IBS)., Methods: The medical records of patients diagnosed with any vomiting (including CVS, FV) over a 13-year period (1993-2006) at our institution were carefully reviewed. Disease controls were age and gender matched subjects with IBS. Gastric emptying was performed by scintigraphy (99mTc-egg meal). The associations of clinical factors and GE data with patient status (CVS vs FV or IBS) were analyzed., Key Results: A total of 82 patients with CVS and 62 FV patients were identified. Younger age [per 10 years, OR = 0.7 (0.5, 0.9)], male gender [OR = 0.4 (0.2, 0.9)], and cannabinoid use [OR = 2.9 (1.2, 7.2)] were significantly associated with CVS compared with FV. However, there were no significant associations between patient status (CVS vs FV) and age, BMI, smoking, alcohol use, gastrointestinal symptoms, or GE. The proportion of cannabinoid users was significantly higher in patients with CVS compared with patients with IBS, whereas proportions for headaches and psychiatric disease were higher in subjects with IBS., Conclusions & Inferences: Cyclic vomiting syndrome (vs FV) was not associated with clinical factors, but was associated with younger age, male gender and cannabinoid use. A larger proportion of CVS (vs IBS) patients had used cannabinoids., (© 2011 Blackwell Publishing Ltd.)

Objectives: Delivery of bile acid (BA) to the colon stimulates propulsive motility and fluid secretion. The objective of this study was to examine gastrointestinal (GI) transit effects of A3309, a small molecule inhibitor of the ileal BA transporter, in patients with functional constipation (FC)., Methods: In a double-blind, placebo-controlled study of 36 female FC patients randomized to placebo, 15 mg A3309, or 20 mg A3309 administered orally once daily for 14 consecutive days, we assessed GI and colonic transit, stool characteristics, symptoms of constipation, fasting serum C4 (7α-hydroxy-4-cholesten-3-one) (surrogate of BA synthesis and malabsorption), and fasting serum total and low-density lipoprotein (LDL) cholesterol (surrogates of inhibition of BA absorption). Following the intention-to-treat paradigm, we used analysis of covariance to assess the overall treatment effects and Dunnett's test for pairwise comparisons., Results: Overall colonic transit (geometric center at 24 h) was significantly accelerated with 20 mg A3309 compared with placebo (overall effect, P=0.059; A3309 15 mg, P=0.18; and A3309 20 mg, P=0.04). Colonic transit at 48 h was significantly accelerated with both A3309 dosages (overall effect, P<0.001; A3309 15 mg, P=0.002; and A3309 20 mg, P<0.001). Significantly looser stool consistency was noted with both A3309 dosages compared with placebo (P<0.005). Significant effects of A3309 on constipation rating, ease of stool passage, and reduction of straining were also detected. The most common side effect was lower abdominal cramping/pain. A3309 treatment significantly and reversibly increased fasting C4 (A3309 15 mg, P=0.05; A3309 20 mg, P<0.01) but did not affect fasting total and LDL cholesterol., Conclusions: A3309 accelerates colonic transit and loosens stool consistency in FC patients.

Background: Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder, affecting more than 10% of the general population worldwide. Although a genetic component is suspected, unambiguous susceptibility genes have so far not been identified. This study tested the hypothesis that genes contributing to epithelial barrier integrity, control of mucosal immune responses and interactions with bacteria in the gut are associated with IBS., Methods: Single nucleotide polymorphisms (SNPs) corresponding to top signals of association with Crohn's disease at 30 known susceptibility loci were tested for their effect on IBS risk in 1992 individuals from two independent case-control cohorts from Sweden and the USA. Association tests included a conservative Bonferroni correction for multiple comparisons, and were also performed on specific subgroups of patients characterised by constipation (IBS-C), diarrhoea (IBS-D) or alternating constipation and diarrhoea (IBS-A)., Results: The Crohn's disease risk allele rs4263839 G in the TNFSF15 gene was significantly associated with an increased risk of both IBS (p=2.2×10(-5); OR 1.37) and more pronouncedly, IBS-C (p=8.7×10(-7); OR 1.79) in the entire sample. Similar associations and risk effects of the same magnitude were observed in the two cohorts analysed separately. A correlation between rs4263839 genotype and TNFSF15 mRNA expression was detected both in peripheral blood and in rectal mucosal biopsies from healthy individuals (combined p=0.0033)., Conclusions: TNFSF15 is a susceptibility gene for IBS and IBS constipation. As TL1A, the protein encoded by TNFSF15, contributes to the modulation of inflammatory responses, the results support a role of immune activation in IBS.

Objective: To assess the feasibility of unsedated transnasal endoscopy (uTNE) and video capsule endoscopy (VCE) as alternatives to sedated endoscopy (sEGD) as screening tools for Barrett esophagus (BE) and to obtain preliminary estimates of participation rates for sEGD, uTNE, and VCE when used for community BE screening in a population cohort., Patients and Methods: From February 1, 2009, to May 31, 2010, patients from Olmsted County, Minnesota, who were older than 50 years and had no history of known BE were randomized (stratified by age, sex, reflux symptoms noted in a validated questionnaire) into 3 groups for esophageal evaluation with sEGD, uTNE, or VCE. Participation rates and safety profiles were estimated., Results: We contacted 127 patients to recruit 20 for each procedure arm (60 total). The probability of participation was 38% (95% confidence interval [CI], 26%-51%) for sEGD, 50% (95% CI, 35%-65%) for uTNE, and 59% (95% CI, 42%-74%) for VCE. Both uTNE and VCE were well tolerated without adverse effects. BE was identified in 3 patients and esophagitis in 8., Conclusion: Unsedated techniques may be acceptable, feasible, and safe alternatives to sEGD to screen for BE in the community., Trial Registration: clinicaltrials.gov identifier: NCT00943280.

Background: The membrane bound bile acid (BA) receptor, TGR5, is located on myenteric, cholinergic and nitrergic neurons in colon and proximal small intestine. Our aim was to assess the association of genetic variation in TGR5 and small bowel transit (SBT) and colonic transit., Methods: In 230 healthy controls and 414 patients with lower functional GI disorders [FGID: irritable bowel syndrome (IBS)-alternators (Alt) 84, IBS-constipation (IBS-C) 157, IBS-diarrhea (IBS-D) 173], we tested the association between TGR5 SNP rs11554825 (minor allele frequency 41%) with symptom phenotype (total cohort) and intermediate phenotype (SBT or colonic transit by radioscintigraphy) which was available in 213 people in this cohort. The association with symptom phenotype was assessed using logistic regression, while the association with colonic filling at 6 h (CF6), and colonic transit [geometric center (GC) at 24 h] was assessed using ancova, in each instance assuming a dominant genetic model., Key Results: There was no significant association with symptom phenotype. We observed a potential association of SNP rs11554825 with overall transit: CF6 (P = 0.061) and GC24 (P = 0.083). The association of the SNP with CF6 in the IBS-D subgroup (P = 0.017) indicated the TC/CC subgroup had an average 50% faster SBT compared with the TT subgroup. In IBS-D patients, GC24 was not significantly associated with rs11554825 (TC/CC vs TT)., Conclusions & Inferences: Variation in TGR5 may contribute to altered SBT and colonic transit in lower FGID. Further studies are required to characterize the potential role of BA receptor, TGR5, in the mechanism and treatment of bowel dysfunction in lower FGID., (© 2011 Blackwell Publishing Ltd.)

Background & Aims: Cannabinoid receptors are located on cholinergic neurons. Genetic variants that affect endocannabinoid metabolism are associated with colonic transit in patients with irritable bowel syndrome (IBS) with diarrhea. We compared the effects of dronabinol, a nonselective agonist of the cannabinoid receptor, with those of placebo on colonic motility and sensation in patients with IBS, and examined the effects of IBS subtype and specific genetic variants in cannabinoid mechanisms., Methods: Seventy-five individuals with IBS (35 with IBS with constipation, 35 with IBS with diarrhea, and with 5 IBS alternating) were randomly assigned to groups that were given 1 dose of placebo or 2.5 mg or 5.0 mg dronabinol. We assessed left colonic compliance, motility index (MI), tone, and sensation during fasting and after a meal. We analyzed the single nucleotide polymorphisms CNR1 rs806378, fatty acid amide hydrolase (FAAH) rs324420, and MGLL rs4881., Results: In all patients, dronabinol decreased fasting proximal left colonic MI compared with placebo (overall P = .05; for 5 mg dronabinol, P = .046), decreased fasting distal left colonic MI (overall P = .08; for 5 mg, P = .13), and increased colonic compliance (P = .058). The effects of dronabinol were greatest in patients with IBS with diarrhea or IBS alternating (proximal colonic MI, overall P = .022; compliance, overall P = .03). Dronabinol did not alter sensation or tone. CNR1 rs806378 (CC vs CT/TT) appeared to affect fasting proximal MI in all patients with IBS (P = .075). Dronabinol affected fasting distal MI in patients, regardless of FAAH rs324420 variant (CA/AA vs CC) (P = .046); the greatest effects were observed among IBS with constipation patients with the FAAH CC variant (P = .045). Dronabinol affected fasting proximal MI in patients with IBS with diarrhea or alternating with the variant FAAH CA/AA (P = .013)., Conclusions: In patients with IBS with diarrhea or alternating, dronabinol reduces fasting colonic motility; FAAH and CNR1 variants could influence the effects of this drug on colonic motility., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Mucosal barrier dysfunction contributes to gastrointestinal diseases. Our aims were to validate urine sugar excretion as an in vivo test of small bowel (SB) and colonic permeability and to compare permeability in patients with irritable bowel syndrome-diarrhea (IBS-D) to positive and negative controls. Oral lactulose (L) and mannitol (M) were administered with (99m)Tc-oral solution, (111)In-oral delayed-release capsule, or directly into the ascending colon (only in healthy controls). We compared L and M excretion in urine collections at specific times in 12 patients with IBS-D, 12 healthy controls, and 10 patients with inactive or treated ulcerative or microscopic colitis (UC/MC). Sugars were measured by high-performance liquid chromatography-tandem mass spectrometry. Primary endpoints were cumulative 0-2-h, 2-8-h, and 8-24-h urinary sugars. Radioisotopes in the colon at 2 h and 8 h were measured by scintigraphy. Kruskal-Wallis and Wilcoxon tests were used to assess the overall and pairwise associations, respectively, between group and urinary sugars. The liquid in the colon at 2 h and 8 h was as follows: health, 62 ± 9% and 89 ± 3%; IBS-D, 56 ± 11% and 90 ± 3%; and UC/MC, 35 ± 8% and 78 ± 6%, respectively. Liquid formulation was associated with higher M excretion compared with capsule formulation at 0-2 h (health P = 0.049; IBS-D P < 0.001) but not during 8-24 h. UC/MC was associated with increased urine L and M excretion compared with health (but not to IBS-D) at 8-24 h, not at 0-2 h. There were significant differences between IBS-D and health in urine M excretion at 0-2 h and 2-8 h and L excretion at 8-24 h. Urine sugars at 0-2 h and 8-24 h reflect SB and colonic permeability, respectively. IBS-D is associated with increased SB and colonic mucosal permeability.

Background & Aims: Upper abdominal pain (UAP) in patients with gallstones is often treated by cholecystectomy but it frequently persists. We aimed to identify symptoms associated with relief., Methods: We followed 1008 patients who received cholecystectomy for gallstones and UAP at the Mayo Clinic (Rochester, Minnesota) or Kaiser Permanente (San Diego, California) for 12 months. A validated, self-completed biliary symptoms questionnaire identified features of UAP, gastroesophageal reflux disease (GERD), and irritable bowel syndrome (IBS); the questionnaire was given initially and 3 and 12 months after cholecystectomy, to identify features that predicted sustained relief of UAP., Results: Five hundred ninety-four patients (59%) reported relief from UAP. Factors associated univariately (P < .05) with relief included frequency of UAP ≤1 per month, onset ≤1 year preoperatively, usual duration (30 minutes to 24 hours, most often in the evening or night), and severity >5/10. Compared to no features, multiple predictive features of UAP (frequency, onset, duration, or timing) were associated with increasing odds ratios (95% confidence interval) for relief: 1, 2, or 3 features (4.2 [1.1-16]; P = .03) and 4 features (6.3 [1.6-25]; P = .008). Negative univariate associations included lower abdominal pain (LAP), usual bowel pattern, nausea ≥1 per week, often feeling bloated or burpy, GERD, and/or IBS. There was an inverse association between relief and somatization; relief was not associated with postprandial UAP. Multivariable logistic regression analysis revealed independent associations (P < .05) with UAP frequency, onset, and nocturnal awakening, but inverse associations with lower abdominal pain, abnormal bowel pattern, and frequent bloated or burpy feelings., Conclusions: UAP features and concomitant GERD, IBS, and somatization determine the odds for relief from UAP after cholecystectomy., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) coexist in some patients. We observed an association between Crohn's disease (CD) candidate gene TNFSF15 and IBS symptom phenotype. Three genes (TLR9, IL6, and CDH1) have been associated with postinfectious (PI)-IBS. Our aim was to preliminarily assess association between 30 susceptibility loci for CD, three genes associated with PI-IBS, and PARM1, with colonic transit in lower functional gastrointestinal disorders (FGID)., Methods: A cohort of 665 persons was assembled in previous studies. TaqMan assay was used for all single nucleotide polymorphisms (SNPs) associated with the loci of interest. Data were analyzed for univariate associations with symptoms phenotype and colonic transit (nominal P values, uncorrected) using dominant and co-dominant genetic models., Key Results: Carriers of the rs5743836 risk allele had increased odds for IBS-D (vs control, P = 0.02, uncorrected). Among the CD risk loci, rs7927894 (P = 0.007), rs7746082 (P=0.011), rs2872507 (P = 0.014), together with rs5743836 (P = 0.010) were univariately associated with colonic transit at 24 or 48 h. Specific tests for genetic interactions between loci revealed potential association of genes that influence neural, barrier, or mast cell function with colonic transit., Conclusions & Inferences: Genetic variations that may influence local mucosal immune functions are univariately associated with altered colonic transit in lower FGID., (© 2011 Blackwell Publishing Ltd.)

Objectives: Population-based data on the epidemiology and outcomes of subjects with intestinal metaplasia of the gastroesophageal junction (IMGEJ) and Barrett's esophagus (BE) are limited. The objectives of this study were to (i) estimate the incidence of IMGEJ and BE diagnosed from clinically indicated endoscopy in Olmsted County, MN, over three decades (1976-2006) and prevalence as of 1 January 2007, (ii) compare baseline characteristics of subjects with IMGEJ and BE, and (iii) study the natural history and survival of both cohorts., Methods: This was a population-based cohort study. The study setting was Olmsted County, MN. Patients with BE (columnar segment >1 cm with intestinal metaplasia) and IMGEJ (intestinal metaplasia in biopsies from the gastroesophageal junction) from 1976 to 2006 in Olmsted County, MN, were identified using Rochester Epidemiology Project resources. Demographic and clinical data were abstracted from medical records and pathology confirmed by gastrointestinal pathologists. The association of baseline characteristics with overall and progression-free survival was assessed using proportional hazards regression models. Outcome measures were baseline characteristics and overall survival of subjects with IMGEJ compared to those with BE., Results: In all, 487 patients (401 with BE and 86 with IMGEJ) were identified and followed for a median interval of 7 (BE subjects) to 8 (IMGEJ subjects) years. Subjects with BE were older, heavier, reported reflux symptoms more often, and had higher prevalence of advanced neoplasia than those with IMGEJ. No patient with IMGEJ progressed to esophageal adenocarcinoma (EAC) in contrast to BE subjects who had a cumulative risk of progression of 7% at 10 years and increased risk of death from EAC (standardized mortality ratio 9.62). The overall survival of subjects with BE and IMGEJ did not differ from that expected in similar age- and sex-distributed white Minnesota populations., Conclusions: Subjects with IMGEJ appear to have distinct clinical characteristics and substantially lower cancer progression risk compared to those with BE.

Pregabalin, an α2δ ligand, is used clinically to treat somatic pain. A prior study suggested that pregabalin reduces distension-induced pain while increasing rectal compliance. We aimed to quantify effects of pregabalin on colonic sensory and motor functions and assess relationships between sensory effects and colonic compliance. We conducted a randomized, double-blind, placebo-controlled, parallel-group study of a single oral administration of 75 or 200 mg of pregabalin in 62 healthy adults (aged 18-75 yr). Subjects underwent left colon intubation. We assessed "stress-arousal symptoms", compliance, sensation thresholds, sensation ratings averaged over four levels of distension, fasting and postprandial colonic tone, and phasic motility index (MI). Analysis of covariance (adjusted for age, sex, body mass index, and corresponding predrug response) and proportional hazard models were used. There were no clinically important differences among treatment groups for demographics, predrug compliance, tone, MI, and sensation. Treatment was associated with reduced energy and increased drowsiness but no change in tension or relaxation. Sensation ratings averaged over the four distension levels were lower for gas sensation [overall effect P = 0.14, P = 0.05 (pregabalin 200 mg vs. placebo)] and for pain sensation [overall effect P = 0.12, P = 0.04 (pregabalin 200 mg vs. placebo)]. The magnitude of the effect of 200 mg of pregabalin relative to placebo is on average a 25% reduction of both gas and pain sensation ratings. Pregabalin did not significantly affect colonic compliance, sensation thresholds, colonic fasting tone, and MI. Thus 200 mg of pregabalin reduces gas and pain sensation and should be tested in patients with colonic pain.

Background: The endocannabinoid system is associated with food intake. We hypothesized that genes regulating cannabinoids are associated with obesity. Genetic variations in fatty acid amide hydroxylase (FAAH) and cannabinoid receptor 1 (CNR1) are associated with satiation and gastric motor function., Methods: In 62 overweight or obese adults of European ancestry, single nucleotide polymorphisms of rs806378 (nearest gene CNR1) and rs324420 (nearest gene FAAH) were genotyped and the associations with gastric emptying (GE) of solids and liquids, gastric volume (GV), and satiation [maximum tolerated volume (MTV) and symptoms after Ensure(®) nutrient drink test] were explored using a dominant genetic model, with gender and BMI as covariates., Key Results: rs806378 CC genotype was associated with reduced fasting GV (210.2±11.0mL for CC group compared to 242.5±11.3mL for CT/TT group, P=0.031) and a modest, non-significant association with GE of solids (P=0.17). rs324420 genotype was not associated with alterations in gastric motor functions; however, there was a difference in the Ensure(®) MTV (1174.6±37.2mL for CC group compared to 1395.0±123.1mL for CA/AA group, P=0.046) suggesting higher satiation with CC genotype., Conclusions & Inferences: Our data suggest that CNR1 and FAAH are associated with altered gastric functions or satiation that may predispose to obesity., (© 2011 Blackwell Publishing Ltd.)

The mechanisms of increased rectal stiffness in women with fecal incontinence (FI) and rectal urgency are not understood. Our hypothesis was that distention-induced activation of mechanosensitive L-type calcium channels in smooth muscle contributes to increased rectal stiffness in FI. Anal pressures, rectal distensibility (compliance, capacity, and contractile response to sinusoidal oscillation), and rectal sensation were assessed before and after oral nifedipine (30 + 10 mg) or placebo in 16 women with FI and 16 asymptomatic women. At baseline, FI patients had a lower anal pressure increment during squeeze (health, 66.9 ± 7.6: FI, 28.6 ± 5.9, mean ± SE, P ≤ 0.01), lower rectal capacity (P = 0.052), and higher rectal pressures during sinusoidal oscillation (health, 13.7 ± 3.2: FI, 21.7 ± 1.4, mean ± SE, P = 0.02) than the healthy women, which suggests an exaggerated rectal contractile response to distention. Nifedipine decreased mean BP, increased heart rate (P = 0.01 vs. placebo), and reduced anal resting pressure (P ≤ 0.01) but did not significantly modify rectal distensibility in health or FI. Plasma nifedipine concentrations (health, 103 ± 21 ng/ml: FI, 162 ± 34 ng/ml) were correlated with increased rectal compliance (r = 0.6, P = 0.02) in all study participants and, in healthy subjects, with decreased rectal pressures during sinusoidal oscillation (r = 0.86, P = 0.01), indicative of reduced stiffness. No consistent effects on rectal perception were observed. These observations confirm that FI is associated with anal weakness and increased rectal stiffness. At therapeutic plasma concentrations, nifedipine reduced anal resting pressure but did not improve rectal distensibility in FI, outcomes that argue against a predominant contribution of myogenic L-type calcium channels to reduced rectal distensibility in FI.

Background: The mechanisms of 'idiopathic' rapid gastric emptying, which are associated with functional dyspepsia and functional diarrhea, are not understood. Our hypotheses were that increased gastric motility and reduced postprandial gastric accommodation contribute to rapid gastric emptying., Methods: Fasting and postprandial (300kcal nutrient meal) gastric volumes were measured by magnetic resonance imaging (MRI) in 20 healthy people and 17 with functional dyspepsia; seven had normal and 10 had rapid gastric emptying. In 17 healthy people and patients, contractility was analyzed by spectral analysis of a time-series of gastric cross-sectional areas. Logistic regression models analyzed whether contractile parameters, fasting volume, and postprandial volume change could discriminate between health and patients with normal or rapid gastric emptying., Key Results: While upper gastrointestinal symptoms were comparable, patients with rapid emptying had a higher (P=0.002) body mass index than normal gastric emptying. MRI visualized propagating contractions at ∼3cpm in healthy people and patients. Compared with controls (0.32±0.04, Mean±SEM), the amplitude of gastric contractions in the entire stomach was higher (OR 4.1, 95% CI 1.2-14.0) in patients with rapid (0.48±0.06), but not normal gastric emptying (0.20±0.06). Similar differences were observed in the distal stomach. However, the propagation velocity, fasting gastric volume, and the postprandial volume change were not significantly different between patients and controls., Conclusions & Inferences: MRI provides a non-invasive and refined assessment of gastric volumes and contractility in humans. Increased gastric contractility may contribute to rapid gastric emptying in functional dyspepsia., (© 2011 Blackwell Publishing Ltd.)

Background: Colonic transit (CT) is accelerated in 46% of patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Improvement in IBS-D with gluten withdrawal is associated with human leukocyte antigen (HLA)-DQ2 positivity; the mechanism of improvement is unclear., Objective: To determine if HLA-DQ2-positive or HLA-DQ8-positive patients with IBS-D have faster small bowel (SB) or CT than HLA-DQ2-negative and HLA-DQ8-negative patients., Materials and Methods: Among 94 patients with IBS-D, who previously provided DNA samples, 64 had undergone validated measurements of CT [geometric center at 24 h (GC24)]; 50 of the patients also had measurement of gastric emptying (GE) and 54 of SB transit (colonic filling at 6 h). HLA-DQ status was determined by tag single nucleotide polymorphism approach. Associations of colonic filling at 6 h and GC24 with HLA-DQ2 and HLA-DQ8 status were assessed using analysis of covariance, adjusting for BMI., Results: Mean age was 40.8±1.6 years; 98.5% were females. In 60 of the 64 patients, celiac disease was excluded by serology or histology. There were no significant differences in age or BMI among the different HLA-DQ groups. Independently, patients positive for HLA-DQ2 had numerically greater colonic filling at 6 h compared with HLA-DQ2-negative (P=0.065), and those positive for HLA-DQ8 had greater colonic filling at 6 h compared with HLA-DQ8-negative patients (P=0.021). Gastric emptying was not associated with HLA-DQ2 and HLA-DQ8 status. Patients positive for both HLA-DQ2 and HLA-DQ8 had greater colonic filling at 6 h (P=0.013) and numerically higher, but not significant, GC24 (P=0.38) compared with HLA-DQ2-negative and HLA-DQ8-negative patients., Conclusion: Patients with IBS-D positive for HLA-DQ8 or for both HLA-DQ2 and HLA-DQ8 have faster SB transit. The mechanism of the accelerated SB transit and the effect of gluten withdrawal on SB function in IBS-D deserve further investigation.

Objective: Genetic variation in transcription factor 7-like 2 (TCF7L2), a regulator of proglucagon processing, is reproducibly associated with type 2 diabetes. GLP-1 alters gastric function and increases satiation., Hypothesis: Genetic variation in TCF7L2 is associated with satiation, gastric motor function, and GLP-1 concentrations., Methods: In 62 adults, a single nucleotide polymorphism (SNP) of TCF7L2 (rs7903146) was genotyped and associations with gastric emptying (GE) of solids and liquids, gastric volume (GV), and satiation (maximum tolerated volume and symptoms after nutrient drink test) were explored using a dominant genetic model, with gender and BMI as covariates. In 50 of the participants, we also measured plasma GLP-1 during fasting and after ingestion of a nutrient drink., Results: Presence of the T allele compared to CC genotype in rs7903146 SNP of the TCF7L2 gene was associated with reduced fasting GV (246.3 ± 11.4 mL for CC group, compared to 215.7 ± 11.4 mL for CT/TT group, p= 0.05) and accelerated GE t(1/2) of liquids (26.3 ± 2.0 minutes for CC compared to 17.7 ± 1.4 for CT/TT, p < 0.005). There was no significant association of rs7903146 SNP with GE of solids, gastric accommodation, satiation, fasting, or postprandial GLP-1., Conclusion: Our data suggest TCF7L2 is associated with altered gastric functions that may predispose to obesity., (© 2011 Wiley Periodicals, Inc.)

Background: Endoscopic evaluation plays a pivotal role in the assessment of treatment response in ulcerative colitis (UC). This study aimed to determine the interobserver agreement (IOA) for assessment of mucosal lesions, and to determine lesions predictive of global assessment of endoscopic severity (GAES)., Methods: Fifty-one UC patients had digital videorecording of their colonoscopic examinations, edited into videoclips representative of five colonic segments (rectum, sigmoid, descending, transverse, ascending/cecum). Seven gastroenterologists specializing in inflammatory bowel disease (IBD) independently and blindly rated individual lesions and endoscopic severity for each segment and globally. Edema, erythema, stricture, loss of haustral folds, rigidity, and pseudopolyps were scored as absent or present while vascular pattern, granularity, ulceration, and bleeding-friability were scored using a predefined severity scale. The GAES was based on a 4-point scale and a 10-cm visual analog scale (VAS). The IOA among raters was estimated using Lin's concordance correlation coefficient (CCC). Strength of agreement was categorized as excellent (0.81-1.00), good (0.61-0.80), moderate (0.41-0.60), and fair (0.21-0.40). Linear regression analysis was used to identify lesions predictive of overall endoscopic severity and develop a scoring system for clinical use., Results: Granularity, vascular pattern, ulceration, bleeding/friability, and pseudopolyps had good IOA in most segments. There was excellent agreement for VAS and good agreement for GAES and the VAS was significantly associated with GAES (P < 0.001). Granularity, vascular pattern, ulceration, and bleeding-friability were significant predictors of overall endoscopic severity., Conclusions: Granularity, vascular pattern, ulceration, and bleeding-friability demonstrated good reproducibility and were predictors of the GAES in UC patients., (Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.)

Background & Aims: Bile acid (BA) malabsorption of moderate severity is reported in 32% of patients with chronic unexplained diarrhea, including diarrhea-predominant irritable bowel syndrome (IBS-D). We hypothesized that variants of genes regulating hepatic BA synthesis play a role in IBS-D., Methods: In 435 IBS and 279 healthy subjects, we tested individual associations of 15 common single nucleotide polymorphisms (SNPs) from 7 genes critical to BA homeostasis with symptom-based subgroups using dominant genetic models. In a subset of 238 participants, we tested association with colonic transit. SNP-SNP interactions were investigated based on known protein interactions in BA homeostasis. The function of SNP rs17618244 in Klothoβ (KLB) was evaluated using a protein stability assay in HEK293 cells., Results: SNP rs17618244 (Arg728Gln in KLB) is associated with colonic transit at 24 hours. G allele (Arg728) compared with A allele (Gln728) is associated with accelerated colonic transit (P=.0007) in the overall cohort; this association was restricted to IBS-D (P=.0018). Interaction tests of KLB rs17618244 with 3 nonsynonymous SNPs of fibroblast growth factor receptor 4 (FGFR4) revealed that rs1966265 (Val10Ile) and rs351855 (Gly388Arg) modulate rs1768244's association with colonic transit in IBS-D (P=.0025 and P=.0023, respectively). KLB Arg728 significantly reduced protein stability compared with KLB Gln728, demonstrating KLB rs17618244's functional significance. No significant associations with symptom-based subgroups of IBS were detected., Conclusions: A functional KLB gene variant mediating protein stability associates with colonic transit in IBS-D. This association is modulated by 2 genetic variants in FGFR4. The FGF19-FGFR4-KLB pathway links regulation of BA synthesis to colonic transit in IBS-D., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: There has been increasing interest in small intestinal bacterial overgrowth (SIBO) after reports of a link with irritable bowel syndrome (IBS), yet our understanding of this entity is limited., Aim: Our aim was to estimate the yield of patients undergoing duodenal aspirate culture, and to identify symptoms and features that predict SIBO., Methods: A medical chart review of patients who had undergone duodenal aspirate culture at an academic medical centre in 2003 was performed to record clinical characteristics and culture results. The associations between aspirate results and symptoms, medical diagnoses and medication use were assessed using logistic regression., Results: A total of 675 patients had available aspirate results. Mean age of the sample was 53 (s.d. 17) and 443 (66%) were female patients. Overall, 8% of aspirates were positive for SIBO; 2% of IBS patients had SIBO. Older age, steatorrhoea and narcotic use were associated with SIBO (P < 0.05). PPI use was not associated with SIBO, but was associated with bacterial growth not meeting criteria for SIBO (P < 0.05). Inflammatory bowel disease (IBD), small bowel diverticula and pancreatitis were positively associated with an abnormal duodenal aspirate (P < 0.05), but other conditions including IBS were not associated with SIBO., Conclusion: Older age, steatorrhoea, narcotic use, IBD, small bowel diverticula and pancreatitis were associated with small intestinal bacterial overgrowth based on abnormal duodenal aspirate culture results. However, no clear associations of true small intestinal bacterial overgrowth with IBS or PPI use were detected, in contrast to recent speculation., (© 2011 Blackwell Publishing Ltd.)

Background: A non-invasive single photon emission computed tomography (SPECT) method was developed and validated to measure gastric volumes (GV). The natural variation in gastric volume responses and performance characteristics of SPECT imaging are unclear., Methods: The primary aim of this study was to assess the performance characteristics of SPECT imaging by estimating the inter-individual coefficients of variation (COV) in fasting and postprandial GV in 433 participants in prior research studies over the last decade, and the intra-individual COV in all volunteers who had undergone at least two studies. The secondary aim was to assess the relationship of gender, BMI and age on GV., Key Results: The COV(INTER) for all subjects in the study (n = 433) was 32.6% fasting, 16.0% fed, and 19.0%Δ fed - fasting. The COV(INTRA) for 47 subjects with repeat estimates of gastric volume was 37.0% fasting, 17.6% fed, and 22.0%Δ fed - fasting. COV(INTRA) was stable over time interval from 2 to 60 months. There were no significant differences by gender or subgroups. Mean fed and gastric accommodation volumes were associated with age and BMI but the magnitude of variation attributable was <5%., Conclusions & Inferences: COV(INTRA) and COV(INTER) of GV by SPECT are very similar, and there is a small effect of age and BMI. These data are important for planning future studies of GV and further validate SPECT for studies of gastric motility disorders and obesity., (© 2011 Blackwell Publishing Ltd.)

Aim: To describe the dietary recommendations of experienced endoscopists for patients who have undergone endoscopic retrograde cholangiopancreatography (ERCP) and the factors that influence these recommendations., Methods: Selected U.S. endoscopists with ERCP experience were surveyed by e-mail. A questionnaire with three hypothetical ERCP cases of patients at low, medium and high risk for development of post-ERCP pancreatitis (PEP) was shown. For each scenario, respondents were asked to recommend a post-procedure diet and time to first oral intake. Respondents were also asked about the effect of various clinical factors on their recommendations, including risk of PEP., Results: 97/187 selected ASGE members (51.9%) responded. When risk of PEP was either low, medium or high, 53%, 88% and 96% recommended a diet of clear liquids/NPO respectively, and 2%, 5% and 18% recommended delaying first oral intake until the following day. About 88% of respondents gave the same type of diet to patients at high as those with moderate-risk of PEP (P = 0.04). However, 37% and 43% of respondents gave different types of diet to patients at low vs moderate-risk and low-risk vs high-risk of PEP respectively (P < 0.001). No statistically significant associations were found regarding the effect of other clinical factors or respondent demographics., Conclusion: Most experienced endoscopists limit diet to NPO/clear liquids after ERCP for patients at high or moderate risk of post-ERCP pancreatitis. About half allow a low-fat or regular diet in patients at low risk.

Background & Aims: Sodium chenodeoxycholate (CDC) accelerates colonic transit in health. Our aim was to examine pharmacodynamics (colonic transit, bowel function) and pharmacogenetics of CDC in constipation-predominant irritable bowel syndrome (IBS-C)., Methods: In a double-blind placebo-controlled study, 36 female patients with IBS-C were randomized to treatment with delayed-release oral formulations of placebo, 500 mg CDC, or 1000 mg CDC for 4 days. We assessed gastrointestinal and colonic transit, stool characteristics, and associations of transit with fasting serum 7αC4 (surrogate of bile acid synthesis) and FGF19 (negative regulator of bile acid synthesis) levels. Candidate genetic polymorphisms involved in regulation of bile acid synthesis were analyzed in the 36 patients with IBS-C and 57 healthy volunteers to assess genetic influence on effects of CDC on transit., Results: Overall colonic transit and ascending colon emptying (AC t(½)) were significantly accelerated in the CDC group compared with placebo (P = .005 and P = .028, respectively). Looser stool consistency (P = .003), increased stool frequency (P = .018), and greater ease of passage (P = .024) were noted with CDC compared with placebo. The most common side effect was lower abdominal cramping/pain (P = .01). Fasting serum 7αC4 (but not FGF19) was positively associated with colonic transit (r(s) = 0.749, P = .003, placebo group). Genetic variation in FGFR4 was associated with AC t(½) in response to CDC (uncorrected P = .015); αKlothoβ variant showed a gene-by-treatment interaction based on patient subgroup (uncorrected P = .0088)., Conclusions: CDC accelerates colonic transit and improves bowel function in female patients with IBS-C. The rate of bile acid synthesis influences colonic transit. Genetic variation in negative feedback inhibition of bile acid synthesis may affect CDC-mediated acceleration of colonic transit., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Age, diarrhea, and certain chronic illnesses are risk factors for fecal incontinence (FI). However, the contribution of obstetric injury to the development of FI later in life is unclear. We sought to better understand the risk factors for FI., Methods: Through the Rochester Epidemiology Project, a nested case-control study of 176 randomly selected women with FI (cases; mean age, 58 years) and 176 age-matched community controls was conducted in a population-based cohort from Olmsted County, Minnesota. Risk factors for FI were evaluated by reviewing inpatient and outpatient medical (including original obstetric) records. Analyses focused on conditions that preceded the index date (incidence date of FI for case in each matched pair)., Results: In 88% of cases, FI began at age ≥40 years; severity was mild (37%), moderate (58%), or severe (5%). By multivariable analysis, current smoking (odds ratio [OR], 4.7; 95% confidence interval [CI], 1.4-15), body mass index (OR per unit, 1.1; 95% CI, 1.004-1.1), diarrhea (OR, 53; 95% CI, 6.1-471), irritable bowel syndrome (OR, 4.8; 95% CI, 1.6-14), cholecystectomy (OR, 4.2; 95% CI, 1.2-15), rectocele (OR, 4.9; 95% CI, 1.3-19), and stress urinary incontinence (OR, 3.1; 95% CI, 1.4-6.5), but not obstetric events, were independent risk factors for FI., Conclusions: Bowel disturbances rather than prior obstetric injury are the main risk factors for FI. Measures to ameliorate bowel disturbances and other potentially reversible risk factors should be implemented before anal imaging is performed on women with FI., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: We sought to assess the effectiveness and safety of adalimumab for the treatment of Crohn's disease (CD) in clinical practice., Methods: Demographic, clinical, and treatment data were abstracted from the medical record. The primary outcome was clinical response to induction therapy with adalimumab for CD (complete, partial, or nonresponse)., Results: In all, 118 patients were prescribed adalimumab for CD between January 2003 and June 2007. All but five subjects (96%) had received prior infliximab and 50 were on systemic corticosteroids at the time of initial adalimumab dose (44%). A complete response was achieved in 53 patients and 20 patients had no response. The cumulative probability of any response (complete or partial) was 81.3% at 1 year. Dose escalation was required in 59 patients (1-year cumulative probability, 54.0%). Among patients with complete response, 18 lost response during follow-up (1-year cumulative probability, 21.4%). Among 50 patients on corticosteroids at baseline the median daily dose was 20 mg, which decreased to a median of 0 mg during treatment. Sixty-four patients (54%) experienced a total of 117 adverse events. Thirteen patients (11%) experienced 15 serious adverse events. Sixteen patients (14%) discontinued adalimumab due to an adverse event., Conclusions: Adalimumab was both effective and well tolerated for the treatment of CD in this tertiary practice with a high prevalence of past infliximab exposure. This experience largely predates FDA approval of adalimumab for CD.

Background: The short-term effects of methylnaltrexone (MNTX), a peripherally acting mu-opioid receptor antagonist, on gastrointestinal and colonic transit remain unclear., Aim: To compare the effects of placebo, codeine, subcutaneous (s.c.) MNTX and codeine with s.c. MNTX on gastrointestinal and colonic transit of solids in healthy humans., Methods: In a randomized, parallel-group, double-blind, placebo-controlled trial of 48 healthy volunteers, effects of 6 consecutive days of placebo [s.c. and p.o. (orally), n = 8], codeine (p.o. 30 mg q.d.s., n = 8), MNTX (s.c. 0.30 mg/kg, n = 16) and combined MNTX and codeine (same doses and routes, n = 16) on gastrointestinal and colonic transit were assessed. A validated scintigraphic method was used to measure transit during the last 48 h of treatment. Bowel function was estimated during treatment as well as 1 week preceding treatment using standard diaries. Analysis of covariance was used to assess treatment effects., Results: Codeine delayed colonic transit [geometric centre at 24 h (P = 0.04) and ascending colon t(1/2) (P = 0.02)] and reduced stool frequency (P = 0.002), but had no effect on stool form. MNTX did not affect transit, stool frequency or stool form, either alone or with codeine (P > 0.3). No drug interaction effects were detected (P > 0.15)., Conclusion: Methylnaltrexone does not alter gastrointestinal or colonic transit and does not reverse acute codeine-associated delayed gut transit in health.

Background and Aims: We sought to assess the evolution of Crohn's disease behavior in an American population-based cohort., Methods: Medical records of all Olmsted County, Minnesota residents who were diagnosed with Crohn's disease from 1970 to 2004 were evaluated for their initial clinical phenotype, based on the Montreal Classification. The cumulative probabilities of developing structuring and/or penetrating complications were estimated using the Kaplan-Meier method. Proportional hazards regression was used to assess associations between baseline risk factors and changes in behavior., Results: Among 306 patients, 56.2% were diagnosed between the ages of 17 and 40 years. Disease extent was ileal in 45.1%, colonic in 32.0%, and ileocolonic in 18.6%. At baseline, 81.4% had nonstricturing nonpenetrating disease, 4.6% had stricturing disease, and 14.0% had penetrating disease. The cumulative risk of developing either complication was 18.6% at 90 days, 22.0% at 1 year, 33.7% at 5 years, and 50.8% at 20 years after diagnosis. Among 249 patients with nonstricturing, nonpenetrating disease at baseline, 66 changed their behavior after the first 90 days from diagnosis. Relative to colonic extent, ileal, ileocolonic, and upper GI extent were significantly associated with changes in behavior, whereas the association with perianal disease was barely significant., Conclusions: In a population-based cohort study, 18.6% of patients with Crohn's disease experienced penetrating or stricturing complications within 90 days after diagnosis; 50% experienced intestinal complications 20 years after diagnosis. Factors associated with development of complications were the presence of ileal involvement and perianal disease., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Women with faecal incontinence and rectal urgency have increased rectal stiffness and sensation., Aim: To evaluate the effects of clonidine, an alpha(2) -adrenergic agonist, in faecal incontinence., Methods: In this open-label uncontrolled study, bowel symptoms and anorectal functions (anal pressures, rectal compliance, and sensation) were assessed before and during treatment with transdermal clonidine (0.2 mg daily, 4 weeks) in 12 women with urge-predominant faecal incontinence., Results: Clonidine reduced the frequency (17.8 +/- 3.1 before vs. 8.8 +/- 3.9 after, P = 0.03) and number of days with faecal incontinence (11.8 +/- 1.6 before vs. 6.1 +/- 1.8 after, P = 0.02), faecal incontinence symptom severity score (max = 13, 8.3 +/- 0.7 vs. 5.6 +/- 0.9, P < 0.01), and allowed patients to defer defecation for a longer duration (P = 0.03). Although overall effects on anorectal functions were not significant, the treatment-associated reduction in faecal incontinence episodes was associated with increased rectal compliance (r = -0.58, P < 0.05) and reduced rectal sensation. (r = -0.73, P = 0.007 vs. desire to defecate pressure threshold)., Conclusions: Clonidine improves symptoms in women with faecal incontinence; this improvement is associated with increased rectal compliance and reduced rectal sensitivity. A controlled study is necessary to confirm these observations., (2010 Mayo Foundation for Medical Education and Research.)

The aim of this study was to develop the Mayo Dysphagia Questionnaire-30 Day (MDQ-30), a tool to measure esophageal dysphagia, by adapting items from validated instruments for use in clinical trials, and assess its feasibility, reproducibility, and concurrent validity. Outpatients referred to endoscopy for dysphagia or seen in a specialty clinic were recruited. Feasibility testing was done to identify problematic items. Reproducibility was measured by test-retest format. Concurrent validity reflects agreement between information gathered in a structured interview versus the patients' written responses. The MDQ-30, a 28-item instrument, took 10 min (range = 5-30 min) to complete. Four hundred thirty-one outpatients [210 (49%) men; mean age = 61 years] participated. Overall, most concurrent validity kappa values for dysphagia were very good to excellent with a median of 0.78 (min 0.28, max 0.95). The majority of reproducibility kappa values for dysphagia were moderate to excellent with a median kappa value of 0.66 (min 0.07, max 1.0). Overall, concurrent validity and reproducibility kappa values for gastroesophageal reflux disease (GERD) symptoms were 0.81 (95% CI = 0.72, 0.91) and 0.66 (95% CI = 0.55, 0.77), respectively. Individual item percent agreement was generally very good to excellent. Internal consistency was excellent. We conclude that the MDQ-30 is an easy-to-complete tool to evaluate reliably dysphagia symptoms over the last 30 days.

Background & Aims: Outcomes of undiagnosed celiac disease (CD) are unclear. We evaluated the morbidity and mortality of undiagnosed CD in a population-based sample of individuals 50 years of age and older., Methods: Stored sera from a population-based sample of 16,886 Olmsted County, Minnesota, residents 50 years of age and older were tested for CD based on analysis of tissue transglutaminase and endomysial antibodies. A nested case-control study compared serologically defined subjects with CD with age- and sex-matched, seronegative controls. Medical records were reviewed for comorbid conditions., Results: We identified 129 (0.8%) subjects with undiagnosed CD in a cohort of 16,847 older adults. A total of 127 undiagnosed cases (49% men; median age, 63.0 y) and 254 matched controls were included in a systematic evaluation for more than 100 potentially coexisting conditions. Subjects with undiagnosed CD had increased rates of osteoporosis and hypothyroidism, as well as lower body mass index and levels of cholesterol and ferritin. Overall survival was not associated with CD status. During a median follow-up period of 10.3 years after serum samples were collected, 20 cases but no controls were diagnosed with CD (15.2% Kaplan-Meier estimate at 10 years)., Conclusions: With the exception of reduced bone health, older adults with undiagnosed CD had limited comorbidity and no increase in mortality compared with controls. Some subjects were diagnosed with CD within a decade of serum collection, indicating that although most cases of undiagnosed CD are clinically silent, some result in symptoms. Undiagnosed CD can confer benefits and liabilities to older individuals., (Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)