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BackgroundThe etiology of several common gastric motility diseases remains largely unknown. Gastric wall biopsy specimens that include the muscularis propria to evaluate the enteric nervous system, interstitial cells of Cajal, and related cells are essential to promote our understanding of the pathophysiologic mechanisms. On the basis of our previous work, a double EMR technique provided sufficient tissue to identify myenteric ganglia. A serious limitation to the technique was the resultant gastric wall perforation after tissue resection. The optimal procedure would seal the gastric wall defect before tissue resection, eliminating the risk of peritonitis.ObjectivesThe aims of this study were to (1) determine the technical feasibility and reproducibility of a full-thickness gastric biopsy by use of a novel double EMR technique without creating a perforation ('no hole') and to (2) determine safety of the procedure.Design and InterventionsPreclinical study of 6 pigs. Each animal underwent a 'no hole' double EMR survival procedure. To prevent perforation, detachable endoloops and prototype T-tag tissue anchors were placed before resection. At 2 weeks repeat endoscopy was performed followed by necropsy.Main Outcome MeasurementsHematoxylin-eosin staining was used to determine which muscle layers were included in the resected specimen, and an antibody to neuronal nitric oxide synthase was used to visualize myenteric ganglia in the sample. Technical feasibility, reproducibility, and safety of the procedure were evaluated.ResultsFull-thickness gastric biopsy specimens were obtained from all animals without overt perforation. There were no procedural complications. Histologic examination showed muscularis propria with all layers of muscle present, and immunochemical studies demonstrated myenteric ganglia in all tissue samples. Four animals had an uneventful clinical course, and repeat endoscopy at week 2 showed ulceration with stellate fibrosis. Necropsy showed mild localized adhesions. Two animals were killed at days 3 and 6, respectively, because of suspected peritonitis. At necropsy, delayed perforations at the resection sites were noted with displaced endoloops and tissue anchors.ConclusionThis study explored the concept of obtaining deep muscle wall biopsy specimens with use of a unique approach of resection without perforation. The novel 'no hole' double EMR technique was technically feasible and reproducible with sufficient tissue obtained to identify myenteric ganglia. However, there was a high delayed perforation rate associated with displaced endoloops and tissue anchors. On the basis of this early experience, improved safety data may be anticipated with future studies using improved tissue closure devices. [ABSTRACT FROM AUTHOR]

BACKGROUND: Relative to men, women are diagnosed more frequently with functional gastrointestinal (GI) disorders. With increased awareness of basic gender differences in perception and treatment of visceral pain, there has been new interest in research on gender disparity in the care of people with functional GI disorders. Past attention has focused on irritable bowel syndrome, whereas gender differences in other disorders are less well described. OBJECTIVE: Our aim was to systematically review studies that have examined gender-related differences among patients with dyspepsia. METHODS: MEDLINE, HealthSTAR, and PsycINFO databases were searched for English-language articles on dyspepsia published between 1966 and August 2001. Epidemiologic studies, clinical trials, review articles, and conceptual articles from peer-reviewed journals were included for review. Findings were summarized and discussed within a framework of biological and psychosocial factors. Statistical analysis of combined data was inappropriate because of the inconsistent definition of dyspepsia among different studies and wide variation in the types of articles reviewed. RESULTS: Studies that examine gender-related differences in patients with dyspepsia have focused their investigations on the clinical epidemiology and pathophysiology of dyspepsia. In most epidemiologic studies, no gender analysis was performed beyond a description of sample demographics, and when statistical significance was tested, few consistent gender differences were found. Overall, it appears that men and women with dyspepsia possibly differ with respect to pattern of symptoms, pain perception or modulation, and antinociceptive mechanisms, but these observations have not been confirmed. No study evaluated the clinical implications of these possible differences. CONCLUSIONS: Future efforts should be directed to not only examine gender-related differences in the clinical epidemiology of dyspepsia, but also understand their clinical significance. Therefore, well-designed population-based studies using a consistent definition of dyspepsia are needed to investigate the prevalence of dyspepsia symptoms and patterns of dyspepsia management among men and women. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether unexplained gastrointestinal (GI) symptoms are more common in people with self-reported sleep disturbance. PARTICIPANTS AND METHODS: From November 1988 to June 1994, valid self-report questionnaires were mailed to age- and sex-stratified random samples of Olmsted County, Minnesota, residents aged 20 to 95 years. RESULTS: Of 2269 study participants (74% response rate), 52% were women (mean age, 45.0 years). The overall age- and sex-adjusted prevalence of sleep disturbance per 100 population was 13.5% (95% confidence interval [CI], 11.7%-15.3%). Among study participants with sleep disturbance, the prevalence of irritable bowel syndrome (IBS) was 33.3% (95% CI, 26.0%-40.5%) and the prevalence of frequent dyspepsia (FD) was 21.3% (95% CI, 14.4%-28.2%). After adjusting for age, sex, and somatization score, IBS was significantly more common in those with sleep disturbance (odds ratio, 1.6; 95% CI, 1.1-2.2), but the univariate association with FD was no longer statistically significant (odds ratio, 1.3; 95% CI, 0.9-1.9). CONCLUSIONS: Both IBS and FD are prevalent in those with self-reported sleep disturbance. Sleep disturbance was independently associated with IBS but not FD in the general population. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether undiagnosed celiac disease is associated with irritable bowel syndrome (IBS) or dyspepsia in the community. SUBJECTS AND METHODS: A self-report bowel disease questionnaire was mailed to a random sample of Olmsted County, Minnesota, residents aged 20 to 50 years. All respondents who reported symptoms of dyspepsia or IBS (cases) and all respondents without notable gastrointestinal symptoms (controls) were invited to participate (260 eligible subjects; 150 [58%] were studied). Each respondent was examined by a physician, and the medical records of each were reviewed (3 subjects did not meet the criteria for dyspepsia or IBS at the time of the physician interview). Serum was obtained to measure antiendomysial antibodies and tissue transglutaminase (TTg) IgA antibodies using validated assays. RESULTS: A total of 34 subjects had dyspepsia (20 had ulcerlike dyspepsia), 50 had IBS (19 had diarrhea-predominant IBS), and 15 met criteria for both dyspepsia and IBS; 78 were asymptomatic healthy controls. The overall prevalence of positive TTg serology was 4% (95% confidence interval [CI], 1.5%-8.5%). The number of subjects who were seropositive for TTg was 2 of 34 (5.9%) with dyspepsia (95% CI, 0.7%-19.7%), 2 of 50 (4.0%) with IBS (95% CI, 0.5%-13.7%), and 2 of 78 (2.6%) of asymptomatic controls (95% CI, 03%-9.0%) (P = .64 IBS vs controls; P = .58 dyspepsia vs controls). No subjects had positive antiendomysial antibodies. CONCLUSION: In this community, celiac disease did not explain the presence of either IBS or dyspepsia. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the triggers and maintenance of atrial fibrillation (AF) are not fully understood. One potential unproved mechanism is that gastroesophageal reflux disease (GERD), in which acid reflux induces local and systemic inflammation, may increase triggered activity in the myocardium and pulmonary veins and increase AF risk. A self-report questionnaire was mailed to a random sample of 5,288 residents of Olmsted County, Minnesota, aged 25 to 74 years to assess the presence and frequency of GERD from 1988 to 1994. The long-term risk for AF over a period of 11.4 +/- 5.0 years was determined through review of clinical evaluations and the electrocardiographic database in those without previous AF. The average age was 53 +/- 17 years, and 2,571 subjects (49%) were man. Of these patients, 741 developed AF (cumulative probability of AF at 18 years 20%, 95% confidence interval [CI] 17% to 22%). Age (hazard ratio [HR] 1.09, 95% CI 1.08 to 1.10, p <0.001), male gender (HR 1.81, 95% CI 1.53 to 2.14, p <0.001), hypertension (HR 1.36, 95% CI 1.14 to 1.61, p = 0.0006), and heart failure (HR 1.74, 95% CI 1.16 to 2.60, p = 0.007) were independently associated with the risk of AF. The presence of any GERD was not associated with risk for AF (HR 0.81, 95% CI 0.68 to 0.96, p = 0.014) after adjustment for other risk factors. The frequency of GERD did not significantly affect the risk for AF, although patients with more frequent GERD had a slightly higher AF risk. Esophagitis increased the risk for AF (HR 1.94, 95% CI 1.35 to 2.78, p <0.001), but the association did not persist when accounting for other risk factors (p = 0.72). In conclusion, in this large population-based study of patients surveyed for GERD, no association was found with the presence or frequency of symptoms and AF. Patients with esophagitis were more likely to develop AF, although this association requires further study. [ABSTRACT FROM AUTHOR]

Goals: To evaluate agreement of MCM6-13910 with self-report of dairy sensitivity (DS) and lactose hydrogen methane breath test (LHMBT) results in subjects with irritable bowel syndrome (IBS)., Background: IBS is a functional gastrointestinal disorder with symptoms including abdominal pain, variable bowel habits, and bloating. Adult patients with lactose malabsorption may present with similar symptoms. Patients with lactose malabsorption have a lactase nonpersistent (LNP) phenotype. Recent studies found 2 single nucleotide polymorphisms associated with LNP: G/A-22018 and C/T-13910., Study: Genotyping the MCM6-13910 variant of LNP in 538 IBS patients and 317 controls (without IBS). Subjects completed questionnaires pertaining to gastrointestinal problems and dietary consumption, with charts abstracted., Results: Self-reported DS was higher in IBS (45%) than controls (9.8%, odds ratio=6.46, P<0.001). The C/C-13910 genotype was similar in IBS cases and controls, 81 (15.1%) and 47 (14.8%). Among subjects reporting DS, 49 (18.0%) had the C/C genotype. Overall agreement between genotype and self-reported DS was 0.06 in IBS and 0.07 in controls. There were 20 subjects with LHMBT results; 3 had positive results, 17 were negative. LNP genotypes were found in all 3 of positive LHMBT results; 16 had negative LHMBT among the 17 who were lactase persistent. Agreement between C/C-13910 genotype and LHMBT was excellent with κ-statistic of 0.83 (0.50-1.00)., Conclusions: In IBS patients, self-report of lactose intolerance are highly prevalent but are a poor indicator of underlying C/C-13910 genotype. LHMBT had excellent agreement with C/C-13910 genotype.

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.

Background: Defecatory disorders (DD) are defined by clinical and objective features of impaired rectal evacuation. The epidemiology of DD in the population is unknown, partly because many constipated patients do not undergo anorectal tests. Our objectives were to estimate the incidence rate and clinical features of DD in the community., Methods: We reviewed the medical records of all patients older than 16 years in Olmsted County, MN, who had constipation and underwent anorectal manometry from 1999 through 2008. Criteria for diagnosing DD were constipation for 6 months or longer and one of the following: (i) abnormal rectal balloon expulsion test; (ii) reduced or increased perineal descent; or (iii) two or more abnormal features with defecography or surface electromyography., Key Results: Of 11 112 constipated patients, 516 had undergone anorectal tests; 245 of these (209 women, 36 men) had a DD. The mean (±SD) age at diagnosis was 44 years (±18) among women and 49 years (±19) among men. The overall age- and sex-adjusted incidence rate per 100 000 person-years was 19.3 (95% CI: 16.8-21.8). The age-adjusted incidence per 100 000 person-years was greater (p < 0.0001) in women (31.8, 95% CI: 27.4-36.1) than in men (6.6, 95% CI: 4.4-8.9). Prior to the diagnosis of DD, nearly 30% of patients had irritable bowel syndrome (IBS), 48% had a psychiatric diagnosis, 18% had a history of abuse, and 21% reported urinary and/or fecal incontinence., Conclusions & Inferences: Among constipated patients, DD are fourfold more common in women than men and often associated with IBS and psychiatric diagnoses., (© 2016 John Wiley & Sons Ltd.)

Background: Early life events have been found to be associated with irritable bowel syndrome (IBS) suggesting a role in development of functional disorders. The study aim was to identify potential perinatal risk factors for adult IBS., Methods: Utilizing a population-based nested case-control design, cases who met modified Rome III criteria for IBS and age- and-gender matched controls were identified using responses from prior mailed surveys to a random sample of Olmsted County residents. Medical records of eligible respondents were reviewed for perinatal events of interest. The association of early life events with subsequent case status was assessed using conditional logistic regression., Key Results: Of 3 417 respondents, 513 were born in Olmsted County and 108 met criteria for IBS. Due to missing records, 89 pairs were included in the final analyses. Logistic regression revealed only birth weight as a predictor of IBS. Lower birth weight increased the odds for IBS (OR = 1.54 [95% CI = (1.12, 2.08), p = 0.008]). Median birth weight was 3.35 kg (range: 1.96-5.24) and 3.57 kg (range: 2.18-4.59) for cases and controls, respectively. Maternal age, delivery method, and antibiotic exposure were not associated with IBS status but this study was only powered to detect large odds ratios., Conclusions and Inferences: Lower birth weight was observed as a risk factor for IBS. It is not clear if in utero developmental delays directly lead to IBS or if low birth weight is a prospective marker for subsequent early life problems leading to IBS., (© 2016 John Wiley & Sons Ltd.)

Background: Abdominal wall pain (AWP) is an important cause of chronic abdominal pain. History and physical examination are critical to the diagnosis of AWP. Trigger point injection (TPI) using either a steroid or a local anesthetic or a combination of both is often used to treat AWP., Aim: To determine the efficacy of ultrasound-guided TPI and to determine the predictors of a successful response., Methods: Patients who received ultrasound-guided TPI between July 2010 and June 2011 were surveyed. The primary outcome was determined using the Treatment Efficacy Questionnaire (TEQ). Electronic medical records were reviewed to determine patient, pain and TPI characteristics. Linear regression was used to determine the predictors of a successful response on the TEQ., Results: Right upper quadrant was the most common site of AWP, and the median pain duration was 12 months. Pain was rated as >8 (1-10 scale) by 57 % and 30 % described it as an ache. Narcotic use was reported in 38 %, and 73 % had a history of at least one abdominal surgery. Forty-four of the 120 (37 %) patients met the criteria for responder on the TEQ. Compared to before treatment, 36 % reported being "significantly better" and 22 % "slightly better." Multiple linear regression analysis showed that higher somatization negatively predicted response. None of the other historical, examination or TPI characteristics were associated with response to the TPI., Conclusion: TPI can provide significant, long-term symptom relief in a third of patients with chronic abdominal pain attributed to AWP. Somatization was inversely related to the treatment success.

Background: Gastrointestinal infections are risk factors for irritable bowel syndrome (IBS) and functional dyspepsia (FD). We investigated whether non-enteric infections and antibiotic exposure are also associated with the development of functional gastrointestinal disorders (FGIDs)., Methods: In a nested case-control study, random samples of Olmsted County, MN, were mailed valid self-report questionnaires from 1988 through 1994, and then follow-up questionnaires from 1995 through 2003. Survey responders who did not report any FGID symptoms at baseline, but then reported such symptoms in at least one subsequent survey, were classified as new-onset cases. Age-matched controls were individuals who did not have symptoms at either the initial or subsequent surveys., Key Results: The overall response rate was 78% to the initial survey and 52% to the follow-up survey. Based on the responses, 316 participants had a new onset of an FGID (43 IBS constipation, 95 IBS diarrhea, 25 IBS mixed, and 153 other FGIDs, including FD) and 250 did not (controls). Around 76% (241/316) of cases reported a non-enteric infection vs 66% (166/250) of the controls. The frequency of enteric infections was similar between the two groups. Of the new FGID cases, 83% had a non-enteric infection that was treated with antibiotic. In a logistic regression model, treatment with antibiotics for a non-gastrointestinal infection was associated with the development of an FGID (odds ratio = 1.90; 95% CI: 1.21-2.98; p = 0.005), after adjusting for age and sex., Conclusions & Inferences: Based on a case-control study, treatment of a non-gastrointestinal infection with antibiotics appears to be a risk factor for development of an FGID., (© 2015 John Wiley & Sons Ltd.)

Background & Aims: Celiac disease has been linked to irritable bowel syndrome (IBS)-like symptoms in outpatient clinics. Guidelines recommend that all patients with IBS-like symptoms undergo serologic testing for celiac disease, but there is controversy over whether celiac disease is more prevalent in populations with IBS-like symptoms. We aimed to determine whether positive results from serologic tests for celiac disease are associated with IBS and other functional gastrointestinal disorders (FGIDs) in a large U.S. white population., Methods: Validated, self-report bowel disease questionnaires (BDQs) were sent to randomly selected cohorts of Olmsted County, Minnesota residents. In separate protocols, serum samples were collected from more than 47,000 Olmsted County residents without a prior diagnosis of celiac disease; we performed serologic tests for celiac disease on stored serum samples from residents who completed the BDQ. Logistic regression was used to test for the association between serologic markers of celiac disease (positive vs negative) and individual FGIDs., Results: A total of 3202 subjects completed the BDQ and had serum available for testing. IBS was identified in 13.6% of these subjects (95% confidence interval [CI], 12.4%-14.8%), and any gastrointestinal symptom occurred in 55.2% (95% CI, 53.5%-56.9%). The prevalence of celiac disease on the basis of serologic markers was 1.0% (95% CI, 0.7%-1.4%). IBS was less prevalent in patients with celiac disease (3%) than patients without celiac disease (14%), although the difference was not statistically significant (odds ratio, 0.2; 95% CI, 0.03-1.5). Abdominal pain, constipation, weight loss, and dyspepsia were the most frequent symptom groups in subjects who were seropositive for celiac disease, but none of the gastrointestinal symptoms or disorders were significantly associated with celiac disease serology., Conclusions: Symptoms indicative of FGIDs and seropositive celiac disease are relatively common in a U.S. white community. Testing for celiac disease in patients with IBS in the community may not have a significantly increased yield over population-based screening in the United States., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the usefulness of a community-based mailed survey to identify participants with functional dyspepsia (FD) for a clinical trial., Material and Methods: In 2008, a valid self-report questionnaire of gastrointestinal symptoms required for diagnosis of FD was mailed to randomly selected cohorts of Olmsted County, Minnesota, residents. From survey responses (54%), FD cases and controls were identified. Phone calls were completed in 2010 and 2011 to 54% of respondents offering participation to those meeting criteria., Results: Of 937 people identified from the survey, 189 cases and 265 controls were contacted by phone using four questions similar to the written survey resulting in a moderate level of agreement (Kappa 0.43, 95% CI: 0.35- 0.51; p = 0.11). The proportion reporting FD symptoms by survey was 42%, while the proportion by phone was 38%. Comparing classification of cases and controls, 118 (62%) survey cases had dyspepsia symptoms on phone screening while 53 (20%) of the survey controls reported FD symptoms. Of 171 who had symptoms, 60 (35%) declined, 33 (19%) were over study age limit, 24 (14%) had inadequate symptom levels and 36 (21%) had comorbidities. Of survey respondents contacted, six (3%) people were enrolled with two screen fails resulting in four (1%) randomized., Conclusion: Agreement between survey and phone questions was modest. Classifications between case and control changed. People eligible and willing to participate were a fraction of people reporting symptoms. People participating in clinical trials do not broadly represent those in the population.

Background & Aims: Antidepressants are frequently prescribed to treat functional dyspepsia (FD), a common disorder characterized by upper abdominal symptoms, including discomfort or postprandial fullness. However, there is little evidence of the efficacy of these drugs in patients with FD. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effects of antidepressant therapy on symptoms, gastric emptying (GE), and meal-induced satiety in patients with FD., Methods: We performed a study at 8 North American sites of patients who met the Rome II criteria for FD and did not have depression or use antidepressants. Patients (n = 292; 44 ± 15 years old, 75% were female, 70% with dysmotility-like FD, and 30% with ulcer-like FD) were randomly assigned to groups given placebo, 50 mg amitriptyline, or 10 mg escitalopram for 10 weeks. The primary end point was adequate relief of FD symptoms for ≥5 weeks of the last 10 weeks (of 12). Secondary end points included GE time, maximum tolerated volume in Nutrient Drink Test, and FD-related quality of life., Results: An adequate relief response was reported by 39 subjects given placebo (40%), 51 given amitriptyline (53%), and 37 given escitalopram (38%) (P = .05, after treatment, adjusted for baseline balancing factors including all subjects). Subjects with ulcer-like FD given amitriptyline were >3-fold more likely to report adequate relief than those given placebo (odds ratio = 3.1; 95% confidence interval: 1.1-9.0). Neither amitriptyline nor escitalopram appeared to affect GE or meal-induced satiety after the 10-week period in any group. Subjects with delayed GE were less likely to report adequate relief than subjects with normal GE (odds ratio = 0.4; 95% confidence interval: 0.2-0.8). Both antidepressants improved overall quality of life., Conclusions: Amitriptyline, but not escitalopram, appears to benefit some patients with FD, particularly those with ulcer-like (painful) FD. Patients with delayed GE do not respond to these drugs. ClinicalTrials.gov ID: NCT00248651., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Irritable bowel syndrome (IBS) is common with prevalence reported between 10 and 20 %. IBS clusters in families but it is unknown whether this is explained by a common environment, genes, or both. If early-life factors are important, IBS might be expected to demonstrate a birth cohort phenomenon., Aim: To investigate whether there is a birth cohort phenomenon for subjects with IBS., Methods: Validated questionnaires were sent to a random sample of Olmsted County, Minnesota, residents who recorded gastrointestinal symptoms; IBS diagnosis was based on the modified Rome criteria. Birth cohorts were chosen a priori based on historical national trends in birth weights using 10-year increments. Logistic regression was used to develop odds ratios to assess the association of IBS with calendar period, birth cohort, age, gender, and somatic symptom score., Results: A total of 4,893 surveys were completed with an overall survey response rate of 58 %. The survey responders were between 25 and 94 years of age and 53 % were female. The overall prevalence of IBS was 16.2 % (95 % CI 15.3-17.4). The univariate association of IBS with birth cohort was significant (p < 0.001) as was the association adjusted for age and gender. The prevalence of IBS was highest for the birth cohort 1963-1972 with an odds ratio of 2.6 (95 % CI 0.97-7.0, p = 0.058)., Conclusions: Population-based data support a possible birth cohort phenomenon in IBS. If correct, early-life risk factors likely play a key role in the development of IBS.

Background: Despite strong evidence supporting a genetic and gene-environment interaction in the irritable bowel syndrome (IBS), the role of genes and early life in another common functional bowel disorder, chronic constipation (CC), have been little studied., Aim: To determine whether familial aggregation occurs in CC and whether risk factors differed in those with family members., Methods: A randomly selected population-based cohort from Olmsted County, MN, was surveyed (n = 8,006); 3,831 completed questionnaires (response rate 48 %). Cases were identified based upon their responses to a validated questionnaire and meeting Rome criteria for CC. Controls were matched one to one by age and gender. IBS (by Rome II criteria) was excluded. Recruitment of case and control probands occurred in 2010-2011 by mailing a family information form; then, first-degree relatives (FDR) were mailed a questionnaire. All potential proband participants were not informed of CC status., Results: Overall 1,185 cases who met criteria for CC without symptoms of IBS and 1,185 controls were surveyed; 309 case and 336 control probands provided data. The proportion of family members having CC was not associated with case status, and the constipation status of FDR was not significantly associated with case-controls status of the respective probands. Symptom burden in FDR was associated with gender and SSC score, but not age or proband status., Conclusions: No evidence of familial aggregation was observed in adults from the community with CC (excluding IBS). Our data suggest environmental factors in later life more likely account for adult CC.

Objective: We have observed that many patients with IBS drink very little alcohol and postulated that this may reflect membership in families affected by alcoholism and mental illness. We aimed to evaluate whether a family history of substance or alcohol abuse, or psychiatric illness, is associated with IBS., Methods: A valid GI questionnaire was mailed to a randomly selected population-based cohort to identify IBS and healthy controls. The electronic medical record was reviewed to record the subjects' self-reported personal and family health histories., Results: A total of 2300 subjects responded (response rate 55%; IBS 13%, n=287); 230 subjects with IBS and 318 controls were eligible. Family history of alcohol/substance abuse was reported by 33% of cases and 25% of controls (OR=1.4, 95% CI=1.0-2.1, p=0.06). Family history of psychiatric illness was reported by 37% of cases and 22% of controls (OR=2.0, 95% CI=1.3-2.9, p<0.001). In the absence of a personal history of alcohol use, a family history of alcohol/substance abuse was predictive of IBS status (OR adjusted for age and gender=1.5, 95% CI=1.0-2.3, p=0.05). In the absence of a personal history of alcohol use, reporting both a family history of alcohol/substance abuse and anxiety/depression/mental illness was clearly predictive of IBS status (OR=2.5, 95% CI=1.4-4.5; p<0.005). Substance abuse as a child was associated with an increased risk of IBS (OR=2.3, 95% CI=1.1-4.8; p<0.03)., Conclusion: IBS is independently associated with a family history of psychiatric illness and may be linked to a family history of alcohol/substance abuse., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Dysphagia is considered an alarm symptom but detailed population-based data on dysphagia are lacking. We aimed to estimate in a representative USA Caucasian population, the prevalence of dysphagia and potential risk factors., Methods: A modified version of the previously validated Bowel Disease Questionnaire was mailed to a population-based cohort (n = 7640) of Olmsted County, MN. Dysphagia was measured by one validated question 'In the last year, how often have you had difficulty swallowing (a feeling that food sticks in your throat or chest)?' The medical records were reviewed for organic causes of dysphagia. The associations of reported frequency of dysphagia with potential risk factors were assessed using logistic regression models., Key Results: The sex-specific, age-adjusted (US White 2000) prevalence for dysphagia experienced at least weekly was 3.0% (95% CI: 2.2, 3.7) in females and 3.0% (95% CI: 2.0, 4.0) in males. Those with frequent heartburn (OR = 5.9 [4.0, 8.6]) and acid regurgitation (OR = 10.6 [6.8, 16.6]) were significantly more likely to report frequent dysphagia. Proton pump inhibitor (PPI) use was significantly associated with frequent (3.1, 95% CI 2.2, 4.4) and infrequent dysphagia (1.5, 955 CI 1.3, 1.8). Gastro-esophageal reflux disease (GERD) was the most common diagnosis in those reporting dysphagia on the medical record; other organic explanations were rare and only found in the frequent dysphagia group., Conclusions & Inferences: Frequent dysphagia is not rare in the community (3%), occurs in both women and men across all adult age groups, and is most likely to indicate underlying GERD., (© 2014 John Wiley & Sons Ltd.)

Background: Screening for Barrett's esophagus (BE) and adenocarcinoma (EAC) is controversial, but interest remains in finding the optimal method. Attitudes on screening within the community are unknown. We aimed to assess these attitudes via a survey., Study: A mixed-mode survey was conducted in adults >50 years to assess awareness regarding BE, willingness to participate in screening, and preferences regarding method of screening. Methods evaluated were sedated endoscopy (sEGD), unsedated transnasal endoscopy (uTNE) and video capsule (VCE)., Results: A total of 136 from 413 (33%) adults responded [47% males, mean (SD) age 63 (10.2) years], and 26% of responders knew of BE at baseline. After reading the information on BE, 72% were interested in screening. A history of undergoing screening tests and GI symptoms were predictive of interest. Unsedated techniques were preferred by 64% (VCE: 56% and uTNE: 8%) versus sEGD (36%)., Conclusions: The majority of adults were willing to undergo screening for BE/EAC, with a preference for unsedated techniques.

Background: There is symptom overlap between gastro-esophageal reflux disease (GERD) and functional dyspepsia (FD). We aimed to test the hypothesis that FD cases are now more likely mislabeled as GERD., Methods: In subjects from Olmsted County, MN seen at Mayo Clinic: (i) Investigation of GERD and FD diagnosis rates between 1985 and 2009. (ii) Assessment of survey-based upper gastrointestinal symptoms between 1988 and 2009. (iii) Analysis of patients reporting GERD and/or FD symptoms and subsequently receiving a consistent diagnosis of GERD and/or FD during a medical encounter. (iv) Assess the association between PPI use and GERD and/or FD symptoms and between actual diagnoses received., Key Results: (i) Yearly GERD diagnosis rates rose between 1985 and 2009 (325-1866 per 100 000). FD diagnosis rates rose from 45 in 1985, to 964 in 1999 but decreased to 452 per 100 000 in 2009. (ii) Reported GERD symptoms did not significantly change between three survey waves in the years 1988-2009 (p = 0.052), whereas FD symptoms slightly increased (p = 0.01). (iii) 62.9% of subjects reporting GERD symptoms received a GERD diagnosis, however only 12.5% of subjects reporting FD symptoms received a FD diagnosis. (iv) PPI use was associated with documented GERD diagnosis (p < 0.001), however there was no significant association between GERD symptoms and PPI use (p = 0.078)., Conclusions & Inferences: We have found evidence supporting a systematic bias away from diagnosing FD, favoring a GERD diagnosis., (© 2014 John Wiley & Sons Ltd.)

Background & Aims: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5., Methods: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls., Results: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS., Conclusions: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The population ≥65 years is rapidly increasing, but remarkably little is known about the natural history of abdominal pain with ageing., Aim: To prospectively evaluate the natural history of abdominal pain (severity and frequency) in a US population, and evaluate potential risk factors (including somatisation) for the onset and disappearance of abdominal pain with increasing age., Methods: Between 1988 and 2004, valid self-report questionnaires that recorded gastrointestinal symptoms including severity and frequency of abdominal pain were mailed to randomly selected cohorts of community residents followed over time. This study identified all respondents who answered abdominal pain questions at an initial and follow-up survey., Results: One thousand nine hundred and thirteen subjects were included (mean age in years at first survey: 48 ± 12 (SD), mean age at second survey: 59 ± 13 (SD); 53% female). The onset and disappearance rate of abdominal pain over the follow-up were 18% (95% CI, 16, 20) and 47% (43, 50) respectively. The rates of increasing vs. decreasing abdominal pain score were 18% (16, 20) vs. 21% (20, 23) respectively. While younger age at initial survey was associated with the onset of abdominal pain {vs. subjects without abdominal pain, [OR 0.9 (0.7, 1.0)]}, older age at initial survey and times between surveys were associated with the disappearance of abdominal pain {vs. subjects with abdominal pain, [OR 1.2 (1.0, 1.5)]}. Female gender (OR 1.4 [1.0, 2.1]), higher somatisation scores (OR 5.3 [3.2, 8.7]) and larger changes in somatisation score (OR 2.1 [1.4, 3.2]) were positively associated with the onset of abdominal pain., Conclusion: Increasing age is associated with the disappearance of abdominal pain in the community., (© 2013 John Wiley & Sons Ltd.)

Background: Low basal lower esophageal sphincter (LES) pressure and transient LES relaxations are major causes of gastroesophageal reflux disease (GERD). Pumosetrag, a novel selective partial 5HT3 receptor agonist, showed a promising effect on reducing reflux events in health. We aimed to evaluate the effect of pumosetrag on changes in reflux episodes, lower esophageal sphincter pressure (LESP), and specific symptoms in patients with GERD receiving a refluxogenic meal., Methods: Patients with GERD, who developed heartburn and/or regurgitation after ingestion of a refluxogenic meal, were randomized to 1 of 3 dose levels of pumosetrag (0.2, 0.5, or 0.8 mg) or placebo. Before and after 7 days of treatment, patients underwent manometry, intraesophageal multichannel, intraluminal impedance and pH after a standard refluxogenic meal., Key Results: A total of 223 patients with GERD [125 (56%) women, mean (SD) age = 36 (12) years] were enrolled. No overall treatment effects were detected for the total number of reflux episodes (acidic and weakly acidic) (p > 0.5); however, significant treatment effects (p < 0.05) on the number of acid reflux episodes were observed with lower values on pumosetrag 0.2 mg (10.8 ± 1.1), 0.5 mg (9.5 ± 1.1), and 0.8 mg (9.9 ± 1.1) compared with placebo (13.3 ± 1.1). Significant treatment effects (p < 0.05) were also observed for the percentage of time pH was <4, with less time for pumosetrag at 0.5 mg (10%) and 0.8 mg (10%) compared with placebo (16%)., Conclusions & Inferences: In GERD, the partial 5HT3 agonist pumosetrag significantly reduced the rate of acid reflux events but did not result in a significant change in LESP or symptomatic improvement over a 1-week treatment period., (© 2013 John Wiley & Sons Ltd.)

This paper presents commentaries on how endoluminal antireflux procedures compare to laparoscopic fundoplication; new endoscopic procedures being studied to treat refractory gastroesophageal reflux disease (GERD); the new Stretta; the relationship between obesity and proton pump inhibitor (PPI) resistance; data concerning acid hypersensitivity and sensory receptors (vallinoid, TRPV1) causing refractory GERD; whether microscopic esophagitis is relevant in determining symptoms of non-erosive reflux disease (NERD); how concomitant functional gastrointestinal disorders affect the PPI response in NERD; the evidence that a functional esophagus is associated with inflammatory bowel syndrome (IBS); the role of GABA agonists in the treatment of refractory GERD; the role of biofeedback and antidepressants in refractory GERD; and endoluminal fundoplication using the EsophyX device., (© 2013 New York Academy of Sciences.)

Background: Functional GI syndromes are known to be very prevalent, but this may be linked to unrecognized medications use. We aimed to estimate the prevalence of PPI, antidepressant, and narcotic use in the general population, and to evaluate the association between each medication and functional GI syndromes adjusting for potential confounders., Methods: In 2008 and 2009, newly revised versions of a validated bowel disease questionnaire were mailed to a community-based cohort (total mailed = 8006) of Olmsted County, MN residents; 3831 returned the questionnaire (response rate = 48.0%). Medication usage, specifically PPIs, narcotics, and antidepressants in the last year, was elicited via three separate questions on the questionnaire. The association between each medication and GI symptom complexes was assessed using multiple variable logistic regression models., Key Results: A total of 3515 of the respondents (92%) had complete data (mean age: 61 ± 15; 54% female). The overall proportion reporting PPI use was 20% (95% CI: 19, 22), narcotic use 12% (95% CI: 11, 13), and antidepressant use 15% (95% CI: 14, 16). PPI use was significantly associated with IBS status (OR = 1.4, 95% CI 1.1, 1.7) as well as with GERD (OR = 3.5, 95% CI 2.7, 4.4) and dyspepsia (OR = 2.0, 95% CI 1.5, 2.7). The association of PPI use with IBS was not explained by coexistent GERD or dyspepsia. Antidepressant use was significantly associated only with bloating (OR = 1.6, 1.1, 2.2)., Conclusions & Inferences: Some medications that may alter intestinal transit or bowel flora are commonly utilized by the general population, and PPI use appears to be linked to IBS., (© 2013 Blackwell Publishing Ltd.)

Objectives: To assess the association between Barrett esophagus (BE) and the metabolic syndrome in patients with and without reflux symptoms and to determine whether this association is reflux independent and metabolically driven., Patients and Methods: Case patients with BE and controls were residents of Olmsted County, Minnesota (1999-2006). Two control groups (one with and one without symptoms of gastroesophageal reflux) were identified from a cohort of patients who had responded to a validated gastrointestinal symptom questionnaire. Cases and controls were individually matched by age, sex, and duration of follow-up. Controls did not have a known diagnosis of BE. The association of the metabolic syndrome and its individual components with BE was assessed using univariate and multivariate conditional logistic regression separately for each control group., Results: A total of 309 patients were included (103 BE cases, 103 controls with reflux symptoms, and 103 controls without reflux symptoms). A total of 64% of cases, 47% of controls with reflux symptoms, and 50% of controls without reflux symptoms had the metabolic syndrome. The metabolic syndrome was associated with a 2-fold increased risk of BE relative to those with (odds ratio, 2.00; 95% CI, 1.10-3.65; P=.02) and without (odds ratio, 1.90; 95% CI, 1.03-3.60; P=.04) reflux symptoms. This association was independent of smoking, alcohol consumption, and body mass index and remained robust with sensitivity analysis., Conclusion: The metabolic syndrome is associated with BE independent of reflux symptoms, which may reflect a reflux-independent pathway of BE pathogenesis., (Copyright © 2013 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)