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Objective: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose-related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC)., Methods: Two-dose NGM282 (1 and 6 mg, subcutaneously daily), parallel-group, randomized, placebo-controlled, 14-day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4, and TGR5 (GPBAR1)., Statistical Analysis: overall ANCOVA at α = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (α = 0.008)., Results: Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose-related effects were seen with GC 24 h, but not with gastric emptying (GE) and GC 48 h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n = 0 with placebo, 2 with 1 mg, 9 with 6 mg), injection site reaction (n = 2 placebo, 4 with 1 mg, 8 with 6 mg), and diarrhea (n = 1 with 1 mg and 4 with 6 mg NGM282). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p = 0.056)., Conclusion: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.

Background: Functional dyspepsia (FD) is a highly prevalent functional bowel disorder. The effects of antidepressant therapy (ADTx) on gastric sensorimotor function in FD patients are poorly understood., Aims: Determine whether FD and subtypes with abnormalities in gastric function respond differently to ADTx compared to those with normal physiology., Methods: This multicenter, prospective trial randomized FD patients to 12 weeks of amitriptyline (AMI; 50 mg), escitalopram (ESC; 10 mg), or matching placebo. Demographics, symptoms, psychological distress, gastric emptying, and satiation were measured. Gastric accommodation (GA) using single-photon emission computed tomography imaging was performed in a subset of patients. An intent to treat analysis included all randomized subjects. The effect of treatment on gastric emptying was assessed using ANCOVA. A post hoc appraisal of the data was performed categorizing patients according to the Rome III subgrouping (PDS and EPS)., Results: In total, 292 subjects were randomized; mean age=44 yrs. 21% had delayed gastric emptying. Neither antidepressant altered gastric emptying, even in those with baseline delayed gastric emptying. GA increased with ADTx (P=0.02). Neither antidepressant affected the maximal-tolerated volume (MTV) of the nutrient drink test although aggregate symptom scores improved compared to placebo (P=0.04). Patients with the combined EPS-PDS subtype (48%) had a lower MTV on the nutrient drink test compared to the EPS group at baseline (P=0.02). Postprandial bloating improved with both AMI (P=0.03) and ESC (P=0.02)., Conclusions: Amitriptyline (50 mg) improves FD symptoms but does not delay gastric emptying, even in patients with baseline delayed gastric emptying. GA improved with low-dose ADTx; the precise mechanism of action is unknown warranting further study.

Objectives: The Functional Dyspepsia Treatment Trial reported that amitriptyline (AMI) was associated with adequate relief of functional dyspepsia (FD) symptoms, but the pharmacogenetics of antidepressant response in FD are not known. GNβ3 825C>T CC genotype has been previously linked to FD and TT genotype to antidepressant response in depression. The ss genotype of the 5-HTT LPR variant of the serotonin transporter gene (SLC6A4) has been linked to selective serotonin reuptake inhibitor (SSRI) response. We aimed to examine whether GNβ3 825C>T and 5-HTT LPR polymorphisms result in differential treatment effects in FD patients receiving antidepressant therapy., Methods: Participants were randomized to receive placebo, 50 mg AMI, or 10 mg escitalopram (ESC). The primary end point was adequate relief for ≥5 weeks of the last 10 weeks. Genotyping of GNβ3 825C>T and 5-HTT LPR was performed utilizing PCR-based methods., Results: GNβ3 825C>T and 5-HTT LPR genotype data were available for 256 (88%) and 246 (84%) patients, respectively. Both polymorphisms were in Hardy-Weinberg equilibrium. In tests for differential treatment, neither 5-HTT LPR nor GNβ3 825C>T genotype influenced response to therapy (P=0.89 and P=0.54, respectively). Although there was a tendency for a more favorable response to ESC in the SS/LS genotype compared to the LL genotype groups (40% vs. 31% reporting adequate relief of FD symptoms) among those in the ESC treatment arm, this was not significant (P=0.43)., Conclusions: GNβ3 825C>T and 5-HTT LPR genetic variants do not alter treatment response to tricyclic and SSRI antidepressants in FD.

Objectives: Rifaximin relieves irritable bowel syndrome (IBS) symptoms, bloating, abdominal pain, and loose or watery stools. Our objective was to investigate digestive functions in rifaximin-treated IBS patients., Methods: In a randomized, double-blind, placebo-controlled, parallel-group study, we compared the effects of rifaximin, 550 mg t.i.d., and placebo for 14 days in nonconstipated IBS and no evidence of small intestinal bacterial overgrowth (SIBO). All subjects completed baseline and on-treatment evaluation of colonic transit by scintigraphy, mucosal permeability by lactulose-mannitol excretion, and fecal microbiome, bile acids, and short chain fatty acids measured on random stool sample. Overall comparison of primary response measures between treatment groups was assessed using intention-to-treat analysis of covariance (ANCOVA, with baseline value as covariate)., Results: There were no significant effects of treatment on bowel symptoms, small bowel or colonic permeability, or colonic transit at 24 h. Rifaximin was associated with acceleration of ascending colon emptying (14.9±2.6 h placebo; 6.9±0.9 h rifaximin; P=0.033) and overall colonic transit at 48 h (geometric center 4.0±0.3 h placebo; 4.7±0.2 h rifaximin; P=0.046); however, rifaximin did not significantly alter total fecal bile acids per g of stool or proportion of individual bile acids or acetate, propionate, or butyrate in stool. Microbiome studies showed strong associations within subjects, modest associations with time across subjects, and a small but significant association of microbial richness with treatment arm (rifaximin vs. treatment)., Conclusions: In nonconstipated IBS without documented SIBO, rifaximin treatment is associated with acceleration of colonic transit and changes in microbial richness; the mechanism for reported symptomatic benefit requires further investigation.

Objectives: Data on the incidence and natural history of diverticulitis are largely hospital-based and exclude the majority of diverticulitis patients, who are treated in an outpatient setting for uncomplicated diverticulitis. We assessed temporal trends in the epidemiology of diverticulitis in the general population., Methods: Through the Rochester Epidemiology Project we reviewed the records of all individuals with a diagnosis of diverticulitis from 1980 to 2007 in Olmsted County, Minnesota, USA., Results: In 1980-1989, the incidence of diverticulitis was 115/100,000 person-years, which increased to 188/100,000 in 2000-2007 (P<0.001). Incidence increased with age (P<0.001); however, the temporal increase was greater in younger people (P<0.001). Ten years after the index and second diverticulitis episodes, 22% and 55% had a recurrence, respectively. This recurrence rate was greater in younger people (hazard ratio (HR) per decade 0.63; 95% confidence interval (CI), 0.59-0.66) and women (HR 0.68; 95% CI, 0.58-0.80). Complications were seen in 12%; this rate did not change over time. Recurrent diverticulitis was associated with a decreased risk of complications (P<0.001). Age was associated with increased risk of local (odds ratio (OR) 1.27 per decade; 95% CI, 1.04-1.57) and systemic (OR 1.83; 95% CI, 1.20-2.80) complications. Survival after diverticulitis was lower in older people (P<0.001) and men (P<0.001) and worsened over time (P<0.001). The incidence of surgery for diverticulitis did not change from 1980 to 2007., Conclusions: The incidence of diverticulitis has increased by 50% in 2000-2007 compared with 1990-1999, and more so in younger people. Complications are relatively uncommon. Recurrent diverticulitis is frequent but typically uncomplicated. Younger people with diverticulitis have less severe disease, more recurrence, and better survival.

In August 2013, the National Institutes of Health sponsored a conference to address major gaps in our understanding of the epidemiology, pathophysiology, and management of fecal incontinence (FI) and to identify topics for future clinical research. This article is the first of a two-part summary of those proceedings. FI is a common symptom, with a prevalence that ranges from 7 to 15% in community-dwelling men and women, but it is often underreported, as providers seldom screen for FI and patients do not volunteer the symptom, even though the symptoms can have a devastating impact on the quality of life. Rough estimates suggest that FI is associated with a substantial economic burden, particularly in patients who require surgical therapy. Bowel disturbances, particularly diarrhea, the symptom of rectal urgency, and burden of chronic illness are the strongest independent risk factors for FI in the community. Smoking, obesity, and inappropriate cholecystectomy are emerging, potentially modifiable risk factors. Other risk factors for FI include advanced age, female gender, disease burden (comorbidity count, diabetes), anal sphincter trauma (obstetrical injury, prior surgery), and decreased physical activity. Neurological disorders, inflammatory bowel disease, and pelvic floor anatomical disturbances (rectal prolapse) are also associated with FI. The pathophysiological mechanisms responsible for FI include diarrhea, anal and pelvic floor weakness, reduced rectal compliance, and reduced or increased rectal sensation; many patients have multifaceted anorectal dysfunctions. The type (urge, passive or combined), etiology (anorectal disturbance, bowel symptoms, or both), and severity of FI provide the basis for classifying FI; these domains can be integrated to comprehensively characterize the symptom. Several validated scales for classifying symptom severity and its impact on the quality of life are available. Symptom severity scales should incorporate the frequency, volume, consistency, and nature (urge or passive) of stool leakage. Despite the basic understanding of FI, there are still major knowledge gaps in disease epidemiology and pathogenesis, necessitating future clinical research in FI.

Objectives: The objective of this study was to compare participation rates and clinical effectiveness of sedated esophagogastroduodenoscopy (sEGD) and unsedated transnasal endoscopy (uTNE) for esophageal assessment and Barrett's esophagus (BE) screening in a population-based cohort., Methods: This was a prospective, randomized, controlled trial in a community population. Subjects ≥50 years of age who previously completed validated gastrointestinal symptom questionnaires were randomized (stratified by age, sex, and reflux symptoms) to one of three screening techniques (either sEGD or uTNE in a mobile research van (muTNE) or uTNE in a hospital outpatient endoscopy suite (huTNE)) and invited to participate., Results: Of the 459 subjects, 209 (46%) agreed to participate (muTNE n=76, huTNE n=72, and sEGD n=61). Participation rates were numerically higher in the unsedated arms of muTNE (47.5%) and huTNE (45.7%) compared with the sEGD arm (40.7%), but were not statistically different (P=0.27). Complete evaluation of the esophagus was similar using muTNE (99%), huTNE (96%), and sEGD (100%) techniques (P=0.08). Mean recovery times (min) were longer for sEGD (67.3) compared with muTNE (15.5) and huTNE (18.5) (P<0.001). Approximately 80% of uTNE subjects were willing to undergo the procedure again in future. Respectively, 29% and 7.8% of participating subjects had esophagitis and BE., Conclusions: Mobile van and clinic uTNE screening had comparable clinical effectiveness with similar participation rates and safety profile to sEGD. Evaluation time with uTNE was significantly shorter. Prevalence of BE and esophagitis in community subjects ≥50 years of age was substantial. Mobile and outpatient unsedated techniques may provide an effective alternative strategy to sEGD for esophageal assessment and BE screening.

Objectives: Functional dyspepsia is predominantly attributed to gastric sensorimotor dysfunctions. The contribution of intestinal chemosensitivity to symptoms is not understood. We evaluated symptoms and plasma hormones during enteral nutrient infusion and the association with impaired glucose tolerance and quality-of-life (QOL) scores in patients with functional dyspepsia vs. healthy controls., Methods: Enteral hormonal responses and symptoms were measured during isocaloric and isovolumic dextrose and lipid infusions into the duodenum in 30 patients with functional dyspepsia (n=27) or nausea and vomiting (n=3) and 35 healthy controls. Infusions were administered in randomized order over 120 min each, with a 120-min washout. Cholecystokinin, glucose-dependent insulinotropic peptide, glucagon-like peptide 1 (GLP1), and peptide YY were measured during infusions., Results: Moderate or more severe symptoms during lipid (4 controls vs. 14 patients) and dextrose (1 control vs. 12 patients) infusions were more prevalent in patients than controls (P≤0.01), associated with higher dyspepsia symptom score (P=0.01), worse QOL (P=0.01), and greater plasma hormone concentrations (e.g., GLP1 during lipid infusion). Moderate or more severe symptoms during enteral infusion explained 18%, and depression score explained 21%, of interpatient variation in QOL. Eight patients had impaired glucose tolerance, associated with greater plasma GLP1 and peptide YY concentrations during dextrose and lipid infusions, respectively., Conclusions: Increased sensitivity to enteral dextrose and lipid infusions was associated with greater plasma enteral hormone concentrations, more severe daily symptoms, and worse QOL in functional dyspepsia. These observations are consistent with the hypothesis that enteral hormones mediate increased intestinal sensitivity to nutrients in functional dyspepsia.

Objectives: Approximately 25% of patients with irritable bowel syndrome-diarrhea (IBS-D) have increased total fecal bile acids (BA) and serum C4 (surrogate for BA synthesis). BA synthesis-related genes (KLB and FGFR4) are associated with colonic transit (CT) in IBS-D. Our aims were: (i) to compare phenotype and pathophysiology in IBS-D patients with increased or normal fecal excretion or synthesis of BA; and (ii) to explore association of variations in two candidate bile-acid synthesis genes (KLB and FGFR4) in these two subgroups of IBS-D., Methods: A total of 64 IBS-D patients underwent on one occasion: fasting serum C4 and FGF19, total fecal fat and BA excretion, CT, intestinal and colonic permeability, and candidate genotyping (rs17618244 (KLB), rs351855 (FGFR4)). Colonic sensation and tone were measured in 47 of the IBS-D patients. IBS-D subgroups were identified by fecal BA >2,337 mM per 48 h or by serum C4 >47.1 ng/ml., Results: IBS-D patients with fecal BA >2,337 mM per 48 h (19/54) had significantly greater body mass index, fecal fat, percent chenodeoxycholic acid (CDCA) in feces, and intestinal permeability, and borderline increased CT (P=0.13). Those IBS-D patients with serum C4 >47.1 ng/ml (13/54) had increased total fecal BA excretion and borderline increased colonic permeability. Variants in genes involved in feedback regulation of BA synthesis (KLB, P=0.06 and FGFR4, P=0.09) were potentially associated with the subgroup with elevated serum C4., Conclusions: IBS-D with increased BA excretion or synthesis is associated with significant pathophysiological changes relative to patients with normal BA profile. BA diarrhea is identified more effectively with total fecal BA than with serum C4.

Objectives: The prevalence of celiac disease (CD) varies greatly, potentially because of incomplete ascertainment of cases and small study samples with limited statistical power. Previous reports indicate that the incidence of CD is increasing. We examined the prevalence of CD in a well-defined US county., Methods: Population-based study in Olmsted County, Minnesota, USA. Using the infrastructure of the Rochester Epidemiology Project, medical, histopathology, and CD serology records were used to identify all new cases of CD in Olmsted County since 2000. Age- and sex-specific and adjusted (to the US white 2000 population) incidence rates for CD were estimated. Clinical presentation at diagnosis was also assessed., Results: Between 2000 and 2010, 249 individuals (157 female or 63%, median age 37.9 years) were diagnosed with CD in Olmsted County. The overall age- and sex-adjusted incidence of CD in the study period was 17.4 (95% confidence interval (CI)=15.2-19.6) per 100,000 person-years, increasing from 11.1 (95% CI=6.8-15.5) in 2000-2001 to 17.3 (95% CI=13.3-21.3) in 2008-2010. The temporal trend in incidence rates was modeled as a two-slope pattern, with the incidence leveling off after 2004. Based on the two classic CD symptoms of diarrhea and weight loss, the relative frequency of classical CD among incident cases decreased over time between 2000 and 2010 (P=0.044)., Conclusions: The incidence of CD has continued to increase in the past decade in a North-American population.

Objectives: We sought to estimate the need for surgery in an American population-based cohort of Crohn's disease., Methods: The medical records of 310 incident cases of Crohn's disease from Olmsted County, Minnesota, diagnosed between 1970 and 2004, were reviewed through March 2009. 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 and expressed as hazards ratios (HRs) with 95% confidence intervals., Results: Median follow-up per patient was 12 years. One hundred and fifty-two patients underwent at least 1 major abdominal surgery, 65 had at least 2 surgeries, and 32 had at least 3 surgeries. The cumulative probability of major abdominal surgery was 38, 48, and 58% at 5, 10, and 20 years after diagnosis, respectively. Baseline factors significantly associated with time to major abdominal surgery were: ileocolonic (HR, 3.3), small bowel (HR, 3.4), and upper gastrointestinal (HR, 4.0) extent, relative to colonic alone; current cigarette smoking (HR, 1.7), male gender (HR, 1.6), penetrating disease behavior (HR, 2.7), and early corticosteroid use (HR=1.6). Major abdominal surgery rates remained stable, with 5-year cumulative probabilities in 1970-1974 and 2000-2004 of 37.5 and 35.1%, respectively., Conclusions: The cumulative probability of major abdominal surgery in this population-based cohort of Crohn's disease approached 60% after 20 years of disease, and many patients required second or third surgeries. Non-colonic disease extent, current smoking, male gender, penetrating disease behavior, and early steroid use were significantly associated with major abdominal surgery.

Objectives: High-resolution manometry (HRM) is used to measure anal pressures in clinical practice but normal values have not been available. Although rectal evacuation is assessed by the rectoanal gradient during simulated evacuation, there is substantial overlap between healthy people and defecatory disorders, and the effects of age are unknown. We evaluated the effects of age on anorectal pressures and rectal balloon expulsion in healthy women., Methods: Anorectal pressures (HRM), rectal sensation, and balloon expulsion time (BET) were evaluated in 62 asymptomatic women ranging in age from 21 to 80 years (median age 44 years) without risk factors for anorectal trauma. In total, 30 women were aged <50 years., Results: Age is associated with lower (r=-0.47, P<0.01) anal resting (63 (5) (≥50 years), 88 (3) (<50 years), mean (s.e.m.)) but not squeeze pressures; higher rectal pressure and rectoanal gradient during simulated evacuation (r=0.3, P<0.05); and a shorter (r=-0.4, P<0.01) rectal BET (17 (9) s (≥50 years) vs. 31 (10) s (<50 years)). Only 5 women had a prolonged (>60 s) rectal BET but 52 had higher anal than rectal pressures (i.e., negative gradient) during simulated evacuation. The gradient was more negative in younger (-41 (6) mm Hg) than older (-12 (6) mm Hg) women and negatively (r=-0.51, P<0.0001) correlated with rectal BET but only explained 16% of the variation in rectal BET., Conclusions: These observations provide normal values for anorectal pressures by HRM. Increasing age is associated with lower anal resting pressure, a more positive rectoanal gradient during simulated evacuation, and a shorter BET in asymptomatic women. Although the rectoanal gradient is negatively correlated with rectal BET, this gradient is negative even in a majority of asymptomatic women, undermining the utility of a negative gradient for diagnosing defecatory disorders by HRM.

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.

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.

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.

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.

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.

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.

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.

Objectives: Functional gastrointestinal disorders (FGIDs) comprise a constellation of symptoms that have no identifiable structural or biochemical abnormality. In view of the lack of data from large-scale population-based studies evaluating the effects of these disorders on survival, we aimed to examine whether FGIDs are associated with impaired survival., Methods: Between 1988 and 1993, valid self-report questionnaires that recorded gastrointestinal symptoms required for the diagnosis of irritable bowel syndrome (IBS), chronic constipation, chronic diarrhea, dyspepsia, and abdominal pain were mailed to randomly selected cohorts of Olmsted County, Minnesota residents. Minnesota administrative death records were used to identify which of the survey respondents had died over the follow-up period (through April 2008). The association between survival and each FGID was assessed using proportional hazards regression models with univariate and adjusted hazard ratios (HRs, 95% confidence intervals (CIs)), adjusting for age at time of survey, gender, smoking, alcohol, marital status, and Charlson Comorbidity Index (CCI)., Results: Of the 5,262 randomly selected eligible subjects who received a questionnaire, a total of 4,176 responded to the surveys (overall response rate 79%). From these respondents, 243 subjects were excluded because of lack of research authorization (or were registered solely at a different medical institution in Olmsted County, MN), resulting in 3,933 eligible subjects for analysis (eligible response rate 75%); 10% reported symptoms of IBS; 16% chronic constipation; 18% chronic diarrhea; 2% dyspepsia; and 15% abdominal pain. At baseline, the mean (s.d.) age was 54 (18) years, and 52% were female. No association with overall survival was detected for IBS (HR=1.06 (95% CI: 0.86-1.32)), chronic diarrhea (HR=1.03 (95% CI: 0.90-1.19)), abdominal pain (HR=1.09 (95% CI: 0.92-1.30)), or dyspepsia (HR=1.08 (95% CI: 0.58-2.02)). Reporting symptoms of chronic constipation was associated with poorer survival (HR=1.23 (95% CI: 1.07-1.42)). This association remained significant after adjusting for the CCI (HR=1.19 (95% CI: 1.03-1.37))., Conclusions: In this large population-based cohort study with over 30,000 person-years of follow-up, no significant association was observed between survival and IBS, chronic diarrhea, dyspepsia, or abdominal pain. Furthermore, no association was found between increasing burden of FGIDs and survival. However, in contrast to these other FGIDs, subjects with symptoms of chronic constipation were found to be at increased risk of poorer survival. Further investigation is required to determine the cause of this observed association.

Objectives: A subset of patients with colonic diverticular disease have chronic gastrointestinal symptoms, and some have a clinical diagnosis of irritable bowel syndrome (IBS), but whether IBS and diverticular disease are linked is uncertain. We aimed to evaluate this association in the community., Methods: A population-based, cross-sectional survey was conducted by mailing a valid symptom questionnaire to the eligible residents of Olmsted County, MN, aged 30-95 years. Colonic diverticular disease (diverticulosis and diverticulitis) was ascertained through a review of the complete medical history of all responders. Subjects with at least one relevant test (colonoscopy, computed tomography (CT) scan, CT colonography, or barium enema) were included. IBS was defined using Rome II criteria., Results: Among 2,267 eligible respondents, there were 1,712 subjects who had undergone colon testing (76%): 919 women (54%); mean (+/-s.d.) age 65 (+/-11 years). Colonic diverticular disease was identified in 44.4% (95% confidence interval (CI) 42.1-46.8) of the subject. IBS was reported by 8.8% (95% CI 6.9-11.0) of men and 17.0% (95% CI 14.6-19.6) of women. After adjusting for age and gender, the presence of IBS was associated with an increased odds for diverticulosis (odds ratio (OR) =1.8, 95% CI 1.3-2.4) but not diverticulitis (OR=1.7, 95% CI 0.9-3.2). In those 65 years of age or older, the presence of IBS was associated with a ninefold higher odds for diverticulosis (OR=9.4, 95% CI 5.8-15.1). Relative to the non-IBS subgroup, diarrhea-predominant IBS and mixed IBS were significantly associated with an increased odds for diverticular disease (OR=1.9, 95% CI 1.1-3.2; OR=2.6, 95% CI 1.0-6.4, respectively)., Conclusions: There is a significantly increased odds for colonic diverticulosis in subjects with IBS (relative to those without IBS). These results suggest that IBS and colonic diverticular disease may be connected.

Objectives: The natural history of fecal incontinence (FI) in community subjects is uncertain and the onset rate is unknown. The aim of the study is to estimate the prevalence, new-onset rate, and risk factors for FI in community subjects., Methods: A random sample of 2,400 community subjects aged > or =50 years was surveyed in 1993, using a validated questionnaire. Responders were recontacted in 2003. FI was defined as self-reported problems with leakage of stool. Onset rate was calculated as the proportion of subjects without FI who became new cases. Logistic regression models were constructed to identify predictive factors for developing FI and changes in bowel habit associated with the onset of FI., Results: Overall, 1,540 (64%) subjects responded to the initial survey, and 674 (44%) of them responded to the second survey a median of 9 (8.8-9.5) years later. The prevalence of FI in the first survey was 15.3% (13.4-17.3%). In the second survey, 37 reported incident FI; thus, the onset rate of FI was 7.0% (5.0-9.6) per 10 years. Predictive factors at baseline for the onset of FI were self-reported diarrhea (odds ratio (OR)=3.8 (1.5, 9.4)), incomplete evacuation (OR=3.4 (1.2, 9.8)), and pelvic radiation (OR=5.1 (1.01, 25.9)). Development of urgency was the primary predictor among the set of predictors reflecting changes in bowel symptoms that were associated with the onset of FI (OR=24.9 (10.6, 58.4))., Conclusions: The onset rate of FI is approximately 7% per 10 years in community subjects aged > or =50 years. Prevention may be possible if bowel habit is appropriately managed in high-risk individuals.

Objectives: St John's wort (SJW) is known to effectively treat patients with mild-to-moderate depression. Antidepressants are frequently used to treat irritable bowel syndrome (IBS). To date, no study that examines the efficacy of SJW in IBS has been carried out. The aim of this study was to evaluate the efficacy of SJW in IBS after 12 weeks., Methods: In this randomized, double-blind, placebo-controlled trial, 70 participants with an established diagnosis of IBS were randomized and assigned by concealed allocation to either SJW or placebo. Both treatment arms were balanced on symptom subtype. The primary end point was self-reported overall bowel symptom score (BSS) at 12 weeks. Secondary end points were individual BSS for diarrhea (D-BSS), constipation (C-BSS), pain or discomfort, and bloating; adequate relief (AR) of IBS on at least 50% of the last 4 weeks of therapy; and IBS quality-of-life score at 12 weeks., Results: In all, 86% of the participants were women, and the median age was 42 years. Overall, 29% had C-IBS, 37% D-IBS, and 31% had mixed IBS. Both groups reported decreases in overall BSS from baseline, with the placebo arm having significantly lower scores at 12 weeks (P=0.03) compared with SJW. These patterns of improvement were mirrored in the secondary end points with the placebo group faring better than the SJW-treated group, with significant differences observed at week 12 for D-BSS (P=0.03) and percent with AR (P=0.02). A similar proportion of subjects in each treatment group (SJW: 51% vs. placebo: 54%) believed that the study drug they received decreased IBS life interferences (P=0.79)., Conclusions: SJW was a less effective treatment for IBS than placebo.

Objectives: Psychosocial factors may drive people with irritable bowel syndrome (IBS) to seek health care, but whether psychological factors are causally linked to IBS is controversial. One hypothesis is that IBS is a heterogeneous syndrome comprising two distinct conditions, one psychological and the other biological. However, it is unclear how many people with IBS in the community have little somatization and minimal psychosocial distress. The aim of our study was to estimate the proportion of people with IBS in a representative US community, who have low levels of somatic and psychological symptoms., Methods: The cohort comprised subjects from three randomly selected population studies from Olmsted County, Minnesota. All of them filled out a validated gastrointestinal (GI) symptom questionnaire, the Symptom Checklist-90-R (SCL-90-R), and the Somatic Symptom Checklist (SSC) comprising 11 somatic complaint items. Logistic regression models were used to evaluate the associations between somatic symptoms/psychosocial factors and IBS, adjusting for age and gender., Results: Of the 501 eligible subjects, 461 (92%) provided complete data (mean age=56 years, 49% female). IBS (Rome II criteria) was associated with both higher SSC and Global Severity Index (GSI of SCL-90-R) scores. Among subjects with high (75th percentile) SSC scores, 43% reported IBS vs. 10% of those with low (<25th percentile) SSC scores. Among those with high (60) GSI scores, 23% reported IBS vs. 6% with low (<40) GSI scores. Specifically, none of the IBS subjects had both low SSC and low GSI scores., Conclusions: Psychological factors and somatization are strongly associated with IBS in the community. However, IBS may not be related to low psychological distress and/or somatization.

Objectives: Opioid prescription use is increasing. Narcotic bowel syndrome (NBS) refers to chronic abdominal pain aggravated by narcotic use. Despite increasing narcotic use, NBS may be under-recognized. The aim of this study was to assess whether gastrointestinal (GI) symptoms in the community are associated with chronic narcotic use and estimate the likely prevalence of NBS., Methods: Validated self-report GI symptom questionnaires were mailed to 4,898 randomly selected people in the community. The medical charts of all respondents were reviewed to identify participants who had used narcotics and to determine whether they were taking an opioid for > 5 weeks for the treatment of chronic pain (malignant or nonmalignant). NBS was defined as abdominal pain developing in those taking chronic narcotics. The associations between GI symptoms and chronic narcotics use were assessed using logistic regression analysis., Results: A total of 2,913 respondents returned a completed questionnaire (overall response rate 59%, mean age 62, 52% female); 117 participants (4.1%, 95% confidence interval (CI): 3.3, 4.5) were taking narcotics. Five participants (0.17%; 95% CI: 0.06, 0.40%) met the criteria for NBS. Participants using narcotics had an increased use of laxatives (17 vs. 8% in those not using narcotics, P < 0.05). GI symptom reporting was more common in participants on narcotics, although the adjusted (for age, gender, somatic symptom complaints, and use of laxatives) odds ratios (ORs) were significantly increased only for frequent abdominal pain and stool frequency., Conclusions: NBS may be relatively uncommon. Those on narcotics report additional GI symptoms (abdominal pain and stool frequency) and use more laxatives.

Background: Though most women with fecal incontinence (FI) have anorectal dysfunctions, a majority have intermittent symptoms. Variations in bowel habits and daily routine may partly explain this., Aim: To compare bowel habits and daily routine between controls and FI, and between continent and incontinent stools among women with FI., Method: Using a mailed questionnaire, we identified 507 women with FI among 5,300 women in Olmsted County, MN. Bowel habits were compared among 127 randomly selected controls and 154 women with self-reported FI, who did ("active" FI, N = 106) or did not ("inactive" FI, N = 48) have an incontinent episode during a 2-wk bowel diary period., Results: Independent risk factors for FI were: rectal urgency (odds ratio [OR] for inactive FI vs controls 5.6, 95% confidence interval [CI] 2.3-13.3; and OR for active FI vs inactive FI 2.0, 95% CI 0.9-4.3) and a sense of incomplete evacuation (OR for inactive FI vs controls 3.5, 95% CI 1.4-8.8; and OR for active FI vs inactive FI 2.2, 95% CI 1.1-4.9). Similar results were found for stool frequency and form. Among incontinent women, incontinent stools (versus continent stools) were less formed, more likely to occur at work, and to be preceded by rectal urgency., Conclusions: Bowel patterns, rectal urgency, and daily routine influence the occurrence of FI. Stool characteristics explained 46% of the likelihood for incontinence episodes, emphasizing that anorectal sensorimotor dysfunctions must also contribute to FI in women.

Background: While symptom questionnaires provide a snapshot of bowel habits, they may not reflect day-to-day variations or the relationship between bowel symptoms and stool form., Aim: To assess bowel habits by daily diaries in women with and without functional bowel disorders., Method: From a community-based survey among Olmsted County, MN, women, 278 randomly selected subjects were interviewed by a gastroenterologist, who completed a bowel symptom questionnaire. Subjects also maintained bowel diaries for 2 wk., Results: Among 278 subjects, questionnaires revealed diarrhea (26%), constipation (21%), or neither (53%). Asymptomatic subjects reported bowel symptoms (e.g., urgency) infrequently (i.e., <25% of the time) and generally for hard or loose stools. Urgency for soft, formed stools (i.e., Bristol form = 4) was more prevalent in subjects with diarrhea (31%) and constipation (27%) than in normals (16%). Stool form, straining to begin (odds ratio [OR] 4.1, 95% confidence interval [CI] 1.7-10.2) and end (OR 4.7, 95% CI 1.6-15.2) defecation increased the odds for constipation. Straining to end defecation (OR 3.7, 95% CI 1.2-12.0), increased stool frequency (OR 1.9, 95% CI 1.02-3.7), incomplete evacuation (OR 2.2, 95% CI 1.04-4.6), and rectal urgency (OR 3.1, 95% CI 1.4-6.6) increased the odds for diarrhea. In contrast, variations in stool frequency and form were not useful for discriminating between health and disease., Conclusions: Bowel symptoms occur in association with, but are only partly explained by, stool form disturbances. These observations support a role for other pathophysiological mechanisms in functional bowel disorders.

Background: Concerns have been raised regarding the risks associated with gastroesophageal reflux (GER). We examined the association of gastroesophageal reflux with survival., Methods: Between 1988 and 1993, valid symptom surveys were mailed to population-based cohorts. Respondents were classified into 4 GER symptom categories: daily, at least weekly (not daily), infrequent (less than weekly), and none. Administrative records were used to identify deaths during the follow-up (through June 2006). Association between survival and GER subgroups was assessed using proportional hazards regression to compute hazard ratios (HRs, 95% confidence intervals), adjusting for age, gender, education level, Charlson Comorbidity Index, alcohol, and tobacco., Results: At baseline, 5,288 eligible subjects (mean age 53 yr, 51% female) responded (response rates over 70%); 2% reported daily heartburn, 13% weekly (not daily) heartburn, 40% infrequent heartburn, and 35% no heartburn. At 10 yr, 83% (95% CI 81-84%) of the no heartburn group was alive. An overall association between heartburn category and survival was detected (P < 0.001). Compared to no heartburn, daily heartburn was not associated with an increased risk of death (HR 1.16, 95% CI 0.82-1.65), but better survival was observed for weekly (HR 0.67, 95% CI 0.55-0.83) and infrequent (HR 0.80, 95% CI 0.70-0.92) heartburn. Increasing age, male gender, greater Charlson index, and tobacco use all predicted worse survival., Conclusions: In this population-based study with over 50,000 person-years of follow-up, reflux symptoms were not associated with worse survival. The vast majority of heartburn sufferers can be reassured of the benign nature of their condition.

Background: The heterogeneity of the dyspepsia symptom complex is well known. Several attempts to classify dyspepsia into subgroups have been proposed as a basis for diagnosis and therapy, but data are conflicting. We postulated that dyspepsia comprises three distinct subsets, characterized by pain, early satiety, or nausea/vomiting. We aimed to identify these subsets of dyspepsia: "frequent upper abdominal pain (UAP),""early satiety (ES)," and "nausea/vomiting (NV).", Methods: A population-based, cross-sectional survey study was conducted by mailing a valid questionnaire to an age- and gender-stratified random sample of residents of Olmsted County, MN, aged 20-94 yr (response rate 55%). Dyspepsia and irritable bowel syndrome (IBS) prevalence were estimated by Rome II criteria; gastroesophageal reflux (GERD) by weekly or more frequent heartburn or acid regurgitation. Dyspepsia subgroups were categorized based on a priori defined symptoms., Results: The prevalence (95% CI) of dyspepsia was 15% (14, 17). Of 351 dyspeptic subjects, 51% (46, 56) reported UAP, 21% (16, 25) NV, and 47% (42, 52) ES. The overlap of the subgroups was significantly less than expected by chance. Among the three groups, the subjects were similar in age, educational level, IBS status, and overall symptom severity. A high somatic symptom checklist score and those with GERD were associated with greater odds for reporting combination symptoms compared with the upper abdominal pain subgroup of dyspepsia or the early satiety subgroup of dyspepsia, respectively., Conclusion: Distinct subgroups of uninvestigated dyspepsia do exist in the general population, suggesting that separate evaluation and treatment strategies are needed.

Background: The incidence rates of adenocarcinoma involving specific gastric and esophageal subsites are changing significantly, but the risk factors associated with those subsite changes remain controversial. We aimed to describe the site-specific risk factors associated with adenocarcinoma of the stomach and esophagus., Methods: Using the Rochester Epidemiology Project, all cases of gastric and esophageal adenocarcinoma among Olmsted County, Minnesota, residents first diagnosed between 1971 and 2000 were identified. Complete inpatient and outpatient records were reviewed and specific subsites defined. Risk factors were assessed in cases, and age- and sex-matched controls., Results: A total of 186 incident cases of gastric or esophageal adenocarcinoma were identified between 1971 and 2000, in Olmsted County. Gastroesophageal reflux disease (GERD) was a significant risk factor for both esophageal (OR 5.5, 95% CI 1.2-25) and esophagogastric junction adenocarcinoma (OR 13.0, 95% CI 1.7-99), but not for either proximal or distal gastric cancer. Smoking (OR 2.8, 95% CI 1.0-7.8) was associated with distal gastric cancer. Proton pump inhibitor (PPI) exposure was limited and was not a significant risk factor at any subsite., Conclusions: This identification of distinct risk factors by subsite supports the concept that esophageal and gastric adenocarcinomas are two different diseases. Adenocarcinoma of the junction is probably a form of esophageal cancer and should not be coded with gastric neoplasms.

Objectives: Population-based data on risk factors and protective factors for colorectal dysplasia and cancer in patients with inflammatory bowel disease (IBD) are sparse. We conducted a nested case-control study of such factors in two well-described IBD cohorts from Copenhagen County, Denmark and Olmsted County, Minnesota., Methods: Forty-three neoplasia cases were matched on six criteria to 1-3 controls (N = 102). Medical records were scrutinized for demographic and clinical data. For each variable, the odds of neoplasia were estimated using conditional logistic regression., Results: Primary sclerosing cholangitis (PSC) (odds ratio [OR] 6.9, 95% confidence interval [CI] 1.2-40), percentage of disease course with clinically active disease (OR [per 5% increase] 1.2, 95% CI 0.996-1.4), and >or=1 yr of continuous symptoms (OR 3.2, 95% CI 1.2-8.6) were associated with neoplasia, whereas a borderline association with median number of small-bowel x-rays (OR 1.3, 95% CI 0.96-1.6) was observed. We did not observe a protective effect of frequency of physician visits (OR 1.4, 95% CI 0.96-2.0), number of colonoscopies (OR 1.4, 95% CI 1.0-2.1), cumulative dose of sulfasalazine (OR [per 1,000 g] 1.1, 95% CI 1.0-1.3) and mesalamine (OR [per 1,000 g] 1.3, 95% CI 0.9-1.9), or partial intestinal resections (OR 1.5, 95% CI 0.3-7.1)., Conclusions: Subgroups of IBD patients-those with PSC, severe long-standing disease, and exposure to x-ray-were at greater risk of colorectal neoplasia. The protective effect of close follow-up, colonoscopy, and treatment with 5-aminosalicylates was questionable.

Background: In women with "idiopathic" fecal incontinence (FI), consensus guidelines recommend anal sphincter imaging and surgical repair, when feasible, of anal sphincter defects believed to cause FI. However, the relative contributions of obstetric trauma and bowel symptoms to FI in the community are unknown., Methods: To assess risk factors for FI during the past year, a previously validated questionnaire was mailed to an age-stratified random sample of 5,300 women residing in Olmsted County, Minnesota., Results: Altogether, 2,800 women (53%) responded. The risk of fecal incontinence increased with age (odds ratio [OR] per decade 1.3, 95% CI 1.2-1.4). The risk of fecal incontinence was higher among women with rectal urgency (OR 8.3, 95% CI 4.8-14.3) whether or not they also had other bowel disturbances (i.e., constipation, diarrhea, or abdominal pain) or had a vaginal delivery with forceps or stitches (OR 9.0, 95% CI 5.6-14.4). Among women with FI, rectal urgency and age were also risk factors for symptom severity. In contrast, obstetric risk factors for anorectal trauma did not increase the risk for FI. The risk for FI was not significantly different among women with cesarean section, vaginal delivery with or without forceps or stitches, or anorectal surgery, compared with nulliparous women without any of these risk factors., Conclusions: Rectal urgency rather than obstetric injury is the main risk factor for FI in women. These observations reinforce the importance of behavioral, dietary, and pharmacological measures to ameliorate bowel disturbances before anal imaging in women with "idiopathic" FI.

Objectives: Recently, two ion channels associated with congenital long QT syndrome, the SCN5A-encoded Nav1.5 sodium channel and the KCNH2-encoded HERG potassium channel (IKr), have been found on gastrointestinal smooth muscle and interstitial cells of Cajal. The aim of this study was to determine if the cardiac channelopathy-associated mutations in SCN5A or KCNH2 are associated with GI symptom complexes., Methods: Mayo Clinic's Sudden Death Genomics Laboratory performed comprehensive mutational analysis on index patients referred for long QT syndrome genetic testing and their family members thus establishing a cohort of families for which the genotype status for SCN5A or KCNH2 is known. A valid GI symptom questionnaire was mailed to all family members (both genotype positive and genotype negative) in this cohort. The association between cardiac channel genotype and GI symptoms was assessed by logistic regression adjusted for age and sex., Results: Two hundred and nineteen (43% of 529) subjects returned the questionnaire. Fifty percent of the subjects with an SCN5A mutation reported abdominal pain compared to only 13% of controls (OR 5.7; 95% CI 1.3-24.4). Over 65% of subjects with an SCN5A mutation reported a GI symptom complex compared to 28% of controls (OR 5.2; 95% CI 1.5-18.3). No associations with KCNH2 genotype status were detected., Conclusions: This study is the first to suggest an association between a well-defined cardiac channelopathy and GI symptoms. The role of sodium channelopathies in the pathogenesis of digestive diseases merits exploration.

Background: The role of genetic predisposition to the development of dyspepsia is unclear. Recently, a significant association was reported with CC genotype of GNbeta3., Aim: To explore the association of candidate genotypes altering adrenergic, serotonergic, CCKergic, and G protein functions, and dyspepsia in a sample from a U.S. community., Methods: Dyspeptics and healthy controls were identified among community respondents who had been randomly selected to complete validated questionnaires. Other diseases were excluded by face-to-face history and physical examination. Polymorphisms of candidate genes for alpha(2A), alpha(2C), 5-HT(1A), 5-HT(2A), 5-HT(2C), CCK-1 receptors and CCK promoter, GNbeta3 protein, and SERT-promoter (SERT-P) were studied. The association between polymorphisms and meal-related or meal-unrelated dyspepsia, high somatic symptom scores, and somatization were evaluated using Fisher's exact test., Results: DNA was available from 41 dyspeptics and 47 healthy controls from Olmsted County. Community dyspepsia unrelated to meals was associated with both homozygous GNbeta3 protein 825T and C alleles. There were no significant associations with meal-related dyspepsia. Using Rome II subgroups, the same genotype was associated with dysmotility-like and other dyspepsia. Higher somatization scores were not significantly associated with any of the candidate genes when considered as single factors., Conclusion: Meal-unrelated dyspepsia in a U.S. community study is associated with the homozygous 825T or C alleles of GNbeta3 protein. Candidate genes controlling adrenergic, serotonergic, and CCKergic functions do not appear to be associated with dyspepsia.

Background: In the Rome II criteria, patients with both constipation and abdominal pain (AP) (i.e., "painful constipation" (PC)), who do not satisfy criteria for irritable bowel syndrome (IBS) are included in the same functional constipation (FC) category as patients with constipation without AP (i.e., "painless constipation" (PLC)). What differences, if any, exist between FC without (i.e., PLC) and with AP (i.e., PC) are unclear., Methods: To compare clinical features among PLC, PC, constipation-predominant IBS (C-IBS), and non-C-IBS, a validated questionnaire was mailed (with telephone follow-up of nonresponders) to an age-stratified random sample of 5,200 adult women in Olmsted County, Minnesota., Results: Altogether, 2,800 women (53%) responded. The age-adjusted prevalence of PLC (7.1 per 100; 95% confidence interval (95% CI), 6.2-8.0) was higher compared to PC (0.9 per 100; 95% CI, 0.6-1.2). Compared to PLC, patients with PC reported worse general health (i.e., excellent or very good = 37.5% vs 51.2%), more somatic symptoms (mean score = 1.3 vs 0.9), and urinary urgency (% often = 58% vs 32%), and had a higher prevalence of hysterectomy. Bowel symptoms significantly impacted > or =1 domain of quality of life (QOL) in 18% of PC versus 9% of PLC. In a logistic discriminant model, age, general health, impact of bowel symptoms on QOL, somatic symptoms, and urinary urgency independently discriminated between bowel subtypes., Conclusions: Patients with PC more closely resemble those with C-IBS than PLC. Consideration should be given to separating PC from PLC in the Rome criteria and in therapeutic trials.

Background: Diet has been implicated to play a role in functional gastrointestinal disorders (FGID) in clinic-based studies. No population-based data comparing food and nutrient consumption between individuals with FGID and without gastrointestinal symptoms are available., Objectives: The purpose of this study was to compare the dietary consumption of specific food items and nutrients between individuals with FGID and without symptoms in a population-based sample., Methods: A validated self-report Bowel Disease Questionnaire was mailed to an age- and gender-stratified random sample of participants aged 20-50 yr from Olmsted County, Minnesota. All patients who reported either FGID symptoms (irritable bowel or dyspepsia) or no gastrointestinal symptoms were invited to undergo a blinded physician interview and physical exam and to complete a validated Harvard Food Frequency Questionnaire. Wilcoxon rank sum tests and logistic regression were used for statistical analysis., Results: In total, 222 of the 260 eligible (85%) subjects participated and 218 provided diet data: 99 were FGID cases and 119 were healthy controls. Cases and controls consumed similar number of servings per week of wheat-containing foods, lactose-containing foods, caffeinated drinks, and fructose-sweetened beverages. Cases were slightly more likely to consume >or=7 servings per week of norepinephrine- and epinephrine-containing foods (57%vs 45%, p= 0.10), but not serotonin- or tryptophan-containing foods. No differences were observed for amount of intake of calories, fiber, protein, iron, calcium, niacin, and vitamins C, D, E, niacin, B(1), B(2), B(6), and B(12). Cases reported consuming more fat (median, 33%vs 31%) and less carbohydrates (median, 49%vs 52%) than controls., Conclusions: No differences were seen in the consumption of frequently suspected "culprit" foods between community residents with and without FGID symptoms. While symptoms may be due to food sensitivity rather than altered diet composition, the role of fat and perhaps norepinephrine and epinephrine in foods in gut symptoms needs to be studied further.

Background and Aims: The aim of the study was to examine whether endoscopic intralesional corticosteroid injection into recalcitrant peptic esophageal strictures reduces the need for repeat stricture dilation., Methods: Patients with a peptic esophageal stricture and recurrent dysphagia having had at least one dilation in the preceding 18 months were enrolled in a prospective randomized, double-blind study comparing steroid and sham injection. After endoscopic confirmation of recurrent stricture, patients were randomized to receive either 0.5 cc/quadrant triamcinolone (40 mg/cc) or sham injection into the stricture followed by balloon dilation of the stricture. Patients were stratified by the number of dilations required in the preceding 18 months, severity of dysphagia, the presence of esophagitis, stricture severity, and prior therapy with a proton-pump inhibitor. Patients and their physicians were blinded to the type of intervention received. Baseline dysphagia questionnaires were completed. Post-procedurally all patients were placed on a standardized proton-pump inhibitor regimen and standardized telephone follow-up questionnaires were completed at 1 wk and at 1, 3, 6, 9, and 12 months. The original sample-size calculation of 60 patients could not be met in a timely fashion because of a low incidence of recalcitrant peptic stricture patients., Results: A total of 30 patients were enrolled, 15 in the steroid group (10 men, mean age 66 yr) and 15 in the sham group (11 M, mean age 67 yr). Patients were followed for 1 yr, unless they underwent an antireflux operation or died. Two patients, one per group, died of non-esophageal causes at 1 and 12 months. Four patients had fundoplication, two in each group, unrelated to stricture or dysphagia. Two patients in the steroid group (13%) and nine in the sham group (60%) required repeat dilation (p= 0.011)., Conclusions: In patients with recalcitrant peptic esophageal stricture, steroid injection into the stricture combined with acid suppression significantly diminishes both the need for repeat dilation and the average time to repeat dilation compared to sham injection and acid suppression alone.

Background: Epidemiological studies have confirmed that gastroesophageal symptoms are highly prevalent. However, studies linking epidemiology with clinical or chart data are scarce. We aimed to determine the frequency of endoscopy and endoscopic findings, as well as predictors of health-care utilization, among people with reflux symptoms in the community., Methods: A previous survey of 2,118 Olmsted County, MN, residents in 1993 identified 242 subjects with frequent reflux symptoms (at least weekly) who received care at a medical center in the county. Data were abstracted from Mayo Clinic records between 1988 and 1998., Results: Overall, 130 of the 242 (54%, 95% CI 47-60%) had sought care for reflux. Twenty-five patients (10%) had visited a gastroenterologist; 47 (19%) had an upper endoscopy (EGD), 64 (26%) had an upper GI X-ray, and one had an ambulatory 24-h esophageal pH study. Long segment Barrett's esophagus was detected in 4 (9%) of those having an EGD and adenocarcinoma was found in one patient with Barrett's. Three patients had surgery for gastroesophageal reflux disease. Thirteen patients (5%) died, but no deaths were due to esophageal reflux or adenocarcinoma. Age, higher education, frequent heartburn, and dysphagia were all significant, independent predictors of consulting., Conclusions: Although many people in the community have frequent reflux symptoms, few have investigations, and deaths were unrelated to reflux disease or its complications. Data from referral clinic or endoscopy series should not be extrapolated to the large numbers of people in the community with symptoms of reflux.

Background: Cholecystokinin (CCK) is involved in gastrointestinal motor response to meals. The potential role of CCK receptor antagonists in functional gastrointestinal disorders is unclear., Aims: To evaluate the effects of dexloxiglumide, a CCK-1 receptor antagonist, on gastrointestinal transit (GIT) and symptoms in patients with constipation-predominant IBS (C-IBS); and to explore the influence of CCK-1 receptor polymorphisms on gut transit and the pharmacodynamic response to therapy., Methods: A total of 36 patients with C-IBS and normal to slow baseline colonic transit (CT) were randomized (double-blind, parallel design) to 7 days of dexloxiglumide 200 mg or placebo t.i.d. Daily bowel habits diaries and weekly relief of IBS symptoms were recorded. At the end of treatment, GIT and CT were measured. Peripheral blood DNA was examined for polymorphisms in genes controlling CCK: four related to CCK-1, one to the CCK gene promoter, and one related to CCK-2. The distributions of allelic variants and association with gastric emptying in response to dexloxiglumide and placebo were assessed., Results: Dexloxiglumide was associated with accelerated gastric emptying t(1/2) (p= 0.004), and slower ascending colon emptying t(1/2) (p < 0.01), with no significant effect on overall CT or satisfactory relief of IBS. There was an association between CCK 779T > C polymorphism and slower rate of gastric emptying (p= 0.04)., Conclusions: Dexloxiglumide accelerates gastric emptying and delays proximal but not overall CT in patients with C-IBS. Dexloxiglumide does not accelerate transit in C-IBS. The role of CCK-1 gene polymorphisms in delaying gastric emptying and in determining response to therapy deserves further study.

Objectives: Perception of sensations arising from the gastrointestinal tract may be diminished in obese subjects and thus facilitate overeating. Alternatively, excess food intake may cause gastrointestinal (GI) symptoms in obese patients. We evaluated the relationship between body mass index (BMI) and specific GI symptoms in the community., Methods: Residents of Olmsted County, MN were selected at random to receive by mail one of two validated questionnaires. The association of reported GI symptoms with BMI (kg/m(2)) was assessed using a logistic regression analysis adjusting for age, gender, psychosomatic symptom score, and alcohol and tobacco use., Results: Response rate was 74% (1,963 of 2,660). The prevalence of obesity (BMI > or = 30 kg/m(2)) was 23%. There was a positive relationship between BMI and frequent vomiting (p= 0.02), upper abdominal pain (p= 0.03), bloating (p= 0.002), and diarrhea (p= 0.01). The prevalence of frequent lower abdominal pain, nausea, and constipation was increased among obese (BMI > or = 30 kg/m(2)) compared to normal weight participants, however, no significant association was found between BMI and these symptoms., Conclusions: In the community, increasing BMI is associated with increased upper GI symptoms, bloating, and diarrhea. Clarification of the cause-and-effect relationships and the mechanisms of these associations require further investigation.

Objective: Bleeding from esophagogastric varices is a major complication of portal hypertension. Despite recent practice guidelines for the management of bleeding esophageal or gastric varices, the widespread application of these measures by gastroenterologists has not been evaluated. The purpose of this study was to continue the concept of membership-based research within diverse practice settings by expanding the American College of Gastroenterology (ACG) GI Bleeding Registry to assess the management and outcome of acute variceal bleeding., Methods: All ACG members (domestic and foreign) were invited to participate during the 1997 Annual Fall meeting and by mail. Data were collected over 12 months. Information obtained included physician training, practice demographics, patient demographics, disease etiology and severity, clinical presentation, medications, transfusion needs, therapy, complications, and rebleeding within 2 wk., Results: A total of 93 physicians/centers (79.6% domestic, 26.9% university and affiliated, 3.2% Veterans Affairs) participated. Complete demographic data were available for 725 of the 741 patients enrolled with index bleeding. The median age of these 725 patients was 52 yr and 73.3% were male. The most common single etiology for portal hypertension was cirrhosis (94.3%). The most common causes of cirrhosis were alcohol (56.7%), hepatitis C virus (30.3%), and hepatitis B virus (10.0%). Hemodynamic instability was noted in 60.7% of the patients (22.3% tachycardic, 9.7% orthostatic, 28.7% hypotensive). Index interventions included banding (40.8%; median five bands), sclerotherapy (36.3%), combination banding/sclerotherapy (6.2%), octreotide (52.6%; median 3 days), balloon tamponade (5.5%), transjugular intrahepatic portosystemic shunt (TIPS) (6.6%), liver transplantation (1.1%), surgical shunt (0.7%), and embolization (0.1%). Transfusion of packed red blood cells, fresh frozen plasma, and platelets was given in 83.4%, 44.7%, and 24.6% of the patients with index bleeding, respectively. Median transfusion was four units of packed red blood cells, three units of fresh frozen plasma, and 1.5 units of platelets. Rebleeding occurred in 92 of the 741 patients (12.6%) at a median of 7 days (mean 11 days) and was treated by banding (18.5%; median six bands), sclerotherapy (30.4%), octreotide (63%; median 2 days), balloon tamponade (17.4%), TIPS (15.2%), and surgical shunt (3.3%). Complications from the index bleeding and rebleeding within 2 wk included ulceration (2.6%, 2.2%), aspiration (2.4%, 3.3%), medication side effects (0.8%, 0%), dysphagia (2.3%, 0%), odynophagia (2.2%,0%), encephalopathy (13%,17.4%), and hepatorenal syndrome (2.4%, 2.2%), respectively. After the index bleeding, 46.2% of patients were treated with beta-blockers and 8.2% with nitrates. The majority of patients with index bleeding had Child's B cirrhosis (61.5%). Patients presenting with recurrent bleeding had mostly Child's B (46.7%) or Child's C cirrhosis (44.6%). The overall short-term mortality after index bleeding was 12.9%., Conclusions: Acute variceal hemorrhage occurs more often in patients with Child's B and C cirrhosis. Endoscopic banding is the most common single endoscopic intervention. Adjunctive pharmacotherapy is prevalent acutely and after stabilization. Both morbidity and mortality may be lower than reported in previous studies.

Objectives: Urgent colonoscopy has been proposed for the diagnosis and management of acute colonic diverticular bleeding. Identification of active bleeding and nonbleeding stigmata facilitates diagnosis and endoscopic therapy, but it is unclear whether urgent colonoscopy after presentation increases the diagnostic yield. This study evaluated the association between timing of colonoscopy and diagnostic yield in patients admitted with acute colonic diverticular bleeding., Methods: Patients admitted for hematochezia and receiving a diagnosis of diverticular hemorrhage were identified using the Mayo Clinic GI Bleeding Team and Emergency Room Admissions Databases for the years 1998-2000. Timing of colonoscopy was determined from the time of admission. Logistic regression analysis was used to assess whether the timing of colonoscopy was associated with an endoscopic finding of active bleeding or nonbleeding stigmata (or both)., Results: A diagnosis of definitive or presumptive diverticular bleeding was made in 78 patients (39 men and 39 women, mean age 78 yr, range 49-96 yr). Twelve patients (15%) had active bleeding or stigmata. Colonoscopies were performed a mean of 18 +/- 11 h after admission. The association between a definitive diagnosis of acute diverticular bleeding and the timing of colonoscopy was not significant (p > 0.46)., Conclusions: No significant association is apparent between the timing of colonoscopy after admission and encountering active bleeding or nonbleeding stigmata. Based on these observations, urgent colonoscopy for these patients does not seem advantageous.

Objectives: Gallstone disease is common and causes high health care costs, but a measure of symptomatic biliary disease for outcome studies is lacking. We aimed to develop a reproducible, valid, discriminative, disease-specific measure of biliary symptoms., Methods: We created the self-report Biliary Symptoms Questionnaire (BSQ) by combining possible biliary symptoms with validated items for gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), and other disorders. We developed the final version through an iterative process and assessed reproducibility by the test-retest method, concurrent validity by comparing BSQ responses with symptoms obtained by structured interview, and discriminative validity by comparing BSQ-based diagnoses of biliary symptoms, GERD, and IBS with patients' final diagnoses. A shortened version (sBSQ) also underwent reproducibility testing., Results: A total of 245 outpatients (mean age, 55.2 yr; 61% female) participated. Median completion times for the BSQ and sBSQ were 36 and 10 min, respectively. For the BSQ, median kappa values were 0.65 (range -0.03 to 0.95) for reproducibility and 0.61 (range 0.15-0.95) for concurrent validity. Using BSQ responses, investigators distinguished IBS and GERD 79-90% of the time. For the sBSQ, the median kappa value for reproducibility was 0.72 (range 0.32-0.86)., Conclusions: The BSQ is reproducible and has good concurrent and discriminative validity for biliary symptoms. The abridged sBSQ has good reproducibility. These instruments may be useful in future outcome studies.

Objectives: The aim of this study was to identify temporal trends in the rate of Helicobacter pylori (H. pylori) testing, prevalence, and treatment among patients with peptic ulcer disease in Olmsted County, MN, from 1984 through 1997., Methods: All 3317 Olmsted County residents with a clinical diagnosis of peptic ulcer disease at the Mayo Clinic from 1984 through 1997 were identified. The complete medical records of an age-, sex-, and calendar year-stratified random sample were reviewed (n = 720); 298 patients (41%) had confirmed peptic ulcer disease. Changes in proportions of H. pylori testing, infection, and treatment over time were analyzed by logistic regression., Results: Of the 298 patients with confirmed peptic ulcer disease, 32% were tested for H. pylori; 36% were positive for infection, of whom 66% received antibiotic therapy. The rate of testing for H. pylori increased from 0% in 1984 to 96% in 1997, but the prevalence of infection did not change (36.4% vs 36.5%). The rate of treatment of those infected increased from 0% to 95%. By logistic regression, calendar year was associated with H. pylori testing and treatment but not infection. Recent use of nonsteroidal anti-inflammatory drugs was reported by 58% of patients, and 44% presented with GI bleeding., Conclusions: Physicians' practice of testing and treating for H. pylori in patients with confirmed peptic ulcer disease has steadily increased over the past 14 yr. However, in our study, only 36% of these patients were infected with H. pylori, whereas the majority used nonsteroidal anti-inflammatory drugs (NSAIDs). Therefore, testing seems to be more appropriate than empiric treatment in patients with peptic ulcer disease.

Objectives: 5-Aminosalicylate is metabolized in colonic mucosa by N-acetyltransferase 1 (NAT1), and sulfapyridine is metabolized in the liver by N-acetyltransferase 2 (NAT2). Common genetic polymorphisms in these enzymes result in rapid and slow acetylation. We determined the association between NAT1 genotype and response to mesalamine and sulfasalazine, as well as between NAT2 genotype and toxicity to sulfasalazine, in a population-based cohort of patients with ulcerative colitis., Methods: DNA was obtained from 77 white patients with ulcerative colitis from Olmsted County, MN. NAT1 and NAT2 genotyping was performed using microelectronic array devices. Phenotypes were deduced from previously published genotype/phenotype correlations. Clinical response to mesalamine and sulfasalazine, and toxicity to sulfasalazine, were determined by medical record review and associated with NAT1 and NAT2 genotypes., Results: The clinical response rates among 52 patients treated with mesalamine were 67% (31 of 46) for rapid acetylators and 83% (five of six) for slow acetylators (odds ratio = 0.4, 95% CI = < 0.1-3.9, p = 0.65). Similarly, the clinical response rates among 64 patients treated with sulfasalazine were 74% (43 of 58) for rapid acetylators and 67% (four of six) for slow acetylators (odds ratio = 1.4, 95% CI = 0.2-8.6, p = 0.65). The toxicity rates among the 64 patients treated with sulfasalazine were 34% (12 of 35) for slow acetylators and 45% (13 of 29) for rapid acetylators (odds ratio = 0.6, 95% CI = 0.2-1.8, p = 0.65)., Conclusions: NAT1 and NAT2 genotypes did not predict response to mesalamine or sulfasalazine, or toxicity to sulfasalazine.

Objective: Environmental factors other than gliadin exposure and certain HLA haplotypes may play a role in the pathogenesis of celiac disease. Previous studies have suggested a strong inverse relationship between cigarette smoking and celiac disease. We sought to determine the relationship between celiac disease and cigarette smoking in our patient population., Methods: All newly diagnosed adults with biopsy-proven celiac disease evaluated at Mayo Clinic Rochester between January 1, 1993, and June 30, 1998, were identified. Three clinic patients who were matched to each case on geographical area of residence, age, gender, and calendar year of visit served as controls. Smoking information was obtained from a standard medical questionnaire that was completed by all clinic patients at the time of registration. The adjusted odds ratio for celiac disease in current and former smokers relative to nonsmokers was estimated with a matched three-to-one conditional logistic regression model., Results: A total of 82 adults with biopsy-proven celiac disease were identified. At the time of diagnosis, the proportion of current smokers was 10% in cases and 10% in controls, yielding an adjusted odds ratio of 1.5 (95% CI = 0.5-4.3). In all, 34% of cases were former smokers versus 28% of controls, yielding an odds ratio of 1.6 (95% CI = 0.8-3.2)., Conclusion: This case-control study was unable to detect an association between cigarette smoking and celiac disease.

Objectives: Practice guidelines should improve care, but they are not routinely followed, in part because of lack of proven benefit. We evaluated the effect of introducing guidelines for inflammatory bowel disease (IBD) on practice variation and the IBD Quality of Life (IBDQ) score., Methods: This was a prospective, controlled, cohort study. A total of 65 patients were matched according to month of visit, diagnosis, and disease activity with control subjects seen 1 yr earlier. Physicians were educated throughout the study regarding the guidelines. Variation was measured by the Mayo Practice Guideline Score (MPGS), a 15-point assessment of documentation of diagnosis, nutrition, social support, education, functional status, and treatment. The IBDQ was measured at baseline and at 1 yr in the intervention group and after 1 yr in the control group., Results: The MPGS was significantly higher in the intervention group compared to the controls (p = 0.002), with median values of 12 versus 11. The IBDQ median score increased significantly in the intervention group (p < 0.001), baseline median of 133 versus 15-month median of 184. However, the final IBDQ was not significantly higher in the intervention group than in the controls (p = 0.33)., Conclusions: Practice guidelines for IBD reduce practice variation. The quality of life improved significantly compared to baseline with practice guidelines, but not compared to controls, perhaps because of the small sample size and homogenous practice setting. The MPGS is a tool that can be used in day-to-day management of IBD patients.