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1.  Dissecting GI Phenotype – Genotype Relationships in GERD and Dyspepsia: An SNP Here and an SNP There! 
It is known that the predisposition to human disease is a mixture of inherited susceptibility and acquired exposure to environmental factors. Understanding gastrointestinal disease has indicated that germline adenomatous polyposis coli mutations predispose with a 99% certainty to colorectal cancer, whereas squamous esophageal cancer is caused by a combination of environmental exposures (including alcohol consumption, cigarette smoke, ingestion of contaminated preserved food) and/or infection (specifically with human papilloma virus), in most cases. Until now, despite the reasonably strong evidence for genetic risk from monozygotic twin studies for gastroesophageal reflux disease (GERD), there have been no documented genetic targets in GERD. In this edition of the Journal, there is intriguing evidence that a common, single base-pair change in the secondary messenger gene GNβ3 (i.e., a single-nucleotide polymorphism) may be important, perhaps through promoting abnormal perception of visceral pain in the esophagus. Other works link this genetic factor to functional dyspepsia, and these exciting preliminary lines of evidence are reviewed.
PMCID: PMC3935284  PMID: 19174788
2.  Acid and non-acid reflux in patients refractory to proton pump inhibitor therapy: Is gastroparesis a factor? 
AIM: To determine whether an increased number and duration of non-acid reflux events as measured using the multichannel intraluminal impedance pH (MII-pH) is linked to gastroparesis (GP).
METHODS: A case control study was conducted in which 42 patients undergoing clinical evaluation for continued symptoms of gastroesophageal reflux disease (both typical and atypical symptoms) despite acid suppression therapy. MII-pH technology was used over 24 h to detect reflux episodes and record patients’ symptoms. Parameters evaluated in patients with documented GP and controls without GP by scintigraphy included total, upright, and supine number of acid and non-acid reflux episodes (pH < 4 and pH > 4, respectively), the duration of acid and non-acid reflux in a 24-h period, and the number of reflux episodes lasting longer than 5 min.
RESULTS: No statistical difference was seen between the patients with GP and controls with respect to the total number or duration of acid reflux events, total number and duration of non-acid reflux events or the duration of longest reflux episodes. The number of non-acid reflux episodes with a pH > 7 was higher in subjects with GP than in controls. In addition, acid reflux episodes were more prolonged (lasting longer than 5 min) in the GP patients than in controls; however, these values did not reach statistical significance. Thirty-five patients had recorded symptoms during the 24 h study and of the 35 subjects, only 9% (n = 3) had a positive symptom association probability (SAP) for acid/non-acid reflux and 91% had a negative SAP.
CONCLUSION: The evaluation of patients with a documented history of GP did not show an association between GP and more frequent episodes of non-acid reflux based on MII-pH testing.
PMCID: PMC3787349  PMID: 24115816
Gastroparesis; Non-acid gastroesophageal reflux; Acid gastroesophageal reflux; Multi-channel intraluminal impedance; Functional bowel disorder
3.  Irritable bowel syndrome and chronic pelvic pain: A population-based study 
Women with IBS frequently report chronic pelvic pain, however, it is still unanswered whether these are truly separate entities. IBS negatively impacts on quality of life, but the impact of IBS on sexual function is not clear.
We aimed to 1) describe the impact of IBS on sexual function, and 2) evaluate the association between pelvic pain and IBS, and in particular identify if there are unique characteristics of the overlap group.
The Talley Bowel Disease Questionnaire was mailed to an age-and gender-stratified random sample of 1,031 Olmsted County, Minnesota residents aged 30-64 years. Manning (at least 2 of 6 positive) and Rome criteria (Rome I and modified Rome III) were used to identify IBS. Pelvic pain was assessed by a single item. Somatization was assessed by the valid somatic symptom checklist.
Overall 648 (69%) of 935 eligible subjects responded (mean age 52 years, 52% female). Self-reported sexual dysfunction was rare (0.9%; 95% CI 0.3-2.0%). Among women, 20% (95% CI 16-24%) reported pain in the pelvic region; 40% of those with pelvic pain met IBS by Manning, or Rome criteria. IBS and pelvic pain occurred together more commonly than expected by chance (p<0.01). The overall somatization score (and specifically the depression and dizziness item scores) predicted IBS-pelvic pain overlap vs. either IBS alone or pelvic pain alone.
In a subset with pelvic pain, there is likely to be a common underlying psychological process (somatization) that explains the link to IBS.
PMCID: PMC3935283  PMID: 20375730
IBS; pelvic pain; sexual dysfunction
4.  Genetics of Irritable Bowel Syndrome 
Irritable bowel syndrome (IBS) is one of the most common diagnoses made by gastroenterologists and primary care providers alike, and yet the underlying mechanism remains poorly understood. Family and twin studies suggest that IBS may have a genetic basis. Several candidate gene association studies have been performed, but thus far, they have failed to clearly identify an “IBS gene.” Epidemiological studies are needed to facilitate phenotype definition and identify relevant environment risk factors that will need to factor in gene and environment interactions in all future genetic studies. As genetic research in IBS is relatively nascent, much opportunity, as well as many challenges, exists in identifying the genes responsible for IBS.
PMCID: PMC3935287  PMID: 18684190
5.  Challenges and Lessons Learned in Conducting Comparative-Effectiveness Trials 
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.
PMCID: PMC3935288  PMID: 22552235
6.  The role of 5-HTT LPR and GNβ3 825C>T polymorphisms and gene-environment interactions in irritable bowel syndrome (IBS) 
Digestive diseases and sciences  2012;57(10):2650-2657.
Smaller studies have evaluated SLC6A4 5-HTTLPR and GNβ3 825C>T polymorphisms in IBS, and interactions between 5-HTT LPR with life events have been reported in the psychiatric literature, but gene-environment studies in IBS are lacking.
To assess the association of two polymorphisms with IBS and age of onset; and to assess whether there are gene-environment interactions with IBS.
Outpatients with IBS and controls completed a validated questionnaire and provided blood for DNA. Comparisons of genotype/allele frequencies between cases and controls were performed with logistic regression. Linear regression was used to evaluate the association between the variants and age of onset. Environmental variables tested included abuse, parental alcohol abuse, parental psychiatric disorders, and gastrointestinal infections.
Genotyping was performed in 385 cases and 262 controls with median age of 50 yrs (range: 18.0–70.0) and 498 (77%) females. The IBS subtype distribution among cases was: 102 (26%) D-IBS, 40 (10%) C-IBS, 125 (32%) M-IBS, 118 (31%) other. No association was observed between IBS or age of onset and both variants. Significant interactions were observed between GI infection and the GNβ3 825T allele. For those reporting gastrointestinal infection, the OR for IBS was 3.9 (95%CI: 1.2–12.7) whereas the OR was 0.86 (95% CI: 0.65–1.13) for those without prior infection.
There was a significant interaction between the GNβ3 polymorphism and infection in the development of IBS, suggesting that its etiology is the result of a combination of specific genetic and environmental risk factors.
PMCID: PMC3912694  PMID: 22855291
Irritable bowel syndrome; genes; genetics; infection
7.  Gastric antral injections of botulinum toxin delay gastric emptying but do not reduce body weight 
Background & Aims
Gastric injections of botulinum toxin A (BTA) have been reported to delay gastric emptying, increase satiation, and reduce body weight, but there are few data from randomized, placebo-controlled studies.
We enrolled 60 obese participants in a 24-week, double-blind, randomized, placebo-controlled, concealed allocation trial to compare the effects of gastric antral injections of BTA (100 U, 300 U, or 500 U) and saline placebo. The study was conducted at an outpatient clinical research unit. Participants were given one set of injections of BTA or placebo into the gastric antral muscularis propria, using endoscopic ultrasound guidance. Gastric emptying of solids (GES) was measured by scintigraphy; we also measured body weight, satiation (maximum tolerated volume in a caloric liquid drink test), calorie intake (by food frequency questionnaire), gastrointestinal symptoms, and psychologic aspects of eating behavior (by rating scale).
Compared with baseline values, 2 weeks after injections, the mean t1/2 for GES increased by 0.8, 14, 24, and 14 minutes among subjects given placebo, 100 U, 300 U, or 500 U of BTA, respectively (P=.24 overall, P=.04 for the group given 300 U vs placebo); 16 weeks after the injections, mean body weights were reduced by 2.2, 0.2, 2.3, and 3.0 kg in these groups, respectively. There were no statistically significant differences in mean body weight change, satiation volume, caloric intake, gastrointestinal symptoms, or psychological aspects of eating behavior among groups.
Gastric antral injections of BTA may delay gastric emptying at a dose of 300 U, but do not cause early satiety, altered eating behaviors, or loss of body weight. Clinicaltrials. gov identifier: NCT00976443
PMCID: PMC3552074  PMID: 23063681
obesity; therapy; endoscopy; motility
8.  Metabolic Syndrome as a Risk Factor for Barrett’s Esophagus: A Population Based Case Control Study 
To assess the association between Barrett’s esophagus (BE) and the Metabolic Syndrome in subjects with and without reflux symptoms and to determine if this association is reflux independent and metabolically driven.
Patients and Methods
BE cases and controls were residents of Olmsted County, MN (1999–2006). Two control groups (one with and one without symptoms of gastroesophageal reflux) were identified from a cohort of subjects who had responded to a validated GI 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 multiple variable conditional logistic regression separately for each control group.
309 subjects were included (103 BE cases, 103 controls with reflux symptoms and 103 controls without reflux symptoms). 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 twofold increased risk of BE relative to subjects with (OR=2.00 (1.10, 3.65) p=0.02) and without (OR=1.90 (1.03, 3.60), p=0.04) reflux symptoms. This association was independent of smoking, alcohol consumption and BMI and remained robust with sensitivity analysis.
The Metabolic Syndrome is associated with BE independent of reflux symptoms. This may reflect a reflux independent pathway of BE pathogenesis.
Subjects with the Metabolic syndrome may be at higher risk for BE and esophageal adenocarcinoma.
PMCID: PMC3771537  PMID: 23374619
arrett’s Esophagus; Metabolic syndrome; Obesity; Visceral fat; Screening; Esophageal Adenocarcinoma
9.  Endoscopic Ultrasound-Guided Gastric Botulinum Toxin Injections in Obese Subjects: A Pilot Study 
Obesity surgery  2008;18(4):401-407.
Gastric injections of botulinum toxin A (BTA) may induce changes in gastric emptying and body weight, but results vary. BTA dose and depth of injection may affect efficacy. This study assessed changes in gastric emptying, satiation, symptoms, and body weight after endoscopic ultrasound (EUS)-guided injection of 100 or 300 U BTA into gastric antral muscularis propria of obese subjects.
Open label study of ten healthy, obese adults (age=29–49 years, body mass index=31–54 kg/m2) who received 100 U (n=4) or 300 U (n=6) BTA and were followed for 16 weeks. Measures included gastric emptying of solids (by scintigraphy), satiation (by maximum tolerated volume [MTV] during nutrient drink test), gastrointestinal symptoms (by the Gastrointestinal Symptom Rating Scale), caloric intake (by food frequency questionnaire), and body weight.
For the entire cohort, MTV decreased from 1,380 cc (range: 474–2,014) at baseline to 620 cc (range: 256–1,180) 2 weeks after BTA injection; decreases were statistically significant in the subjects receiving 300 U BTA (p=0.03). Average body weight loss was 4.9 (±6.3) kg after 16 weeks. Gastric emptying T1/2 was prolonged in the 300 U BTA group, but not significantly different from baseline (p=0.17). BTA injections were well tolerated without significant adverse effects.
EUS-guided injection of BTA into gastric muscularis propria can be performed safely with minimal adverse effects. A dose of 300 U BTA significantly enhances satiation, is associated with weight loss, and may slow gastric emptying. Further study of higher dose BTA in obese subjects is warranted.
PMCID: PMC3899096  PMID: 18286347
Obesity; Endoscopic ultrasound; Botulinum toxin; Gastric emptying; Satiation
10.  Effects of Amitriptyline on Gastric Sensorimotor Function and Postprandial Symptoms in Healthy Individuals: A Randomized, Double-Blind, Placebo-Controlled Trial 
Low-dose tricyclic antidepressants have been used to treat chronic somatic and gastrointestinal pain disorders, including refractory functional dyspepsia. However, there are only limited data on the effects of these drugs on upper gastrointestinal function.
To compare the effects of two doses of amitriptyline (AMT) and placebo on gastric accommodation, emptying, satiation, and postprandial symptoms in healthy volunteers.
Using a parallel-group, double-blind, placebo-controlled design, 41 healthy volunteers were randomized to AMT 25 mg, AMT 50 mg, or placebo for 2 wk. During the final 3 days of therapy, the following end points were assessed: fasting and postprandial gastric volumes, 2- and 4-h gastric emptying, time and volume to maximum satiation using a nutrient drink test, and postprandial symptoms 30 min later using 10-cm visual analog scales. AMT and metabolite levels were measured.
AMT slowed gastric emptying at 2 h (median 75% for placebo, 57% for AMT 25 mg, 67% for AMT 50 mg; P = 0.037) and 4 h (median 98% for placebo, 96% for AMT 25 mg, 92% for AMT 50 mg; P = 0.003). AMT did not affect gastric volumes or satiation volume, but it did reduce nausea scores at 30 min in a dose-dependent manner (median 2.1 for placebo, 0.9 for AMT 25 mg, and 0.0 for AMT 50 mg; P = 0.009).
In healthy volunteers, AMT slows gastric emptying of solids, but it does not significantly affect gastric volumes or satiation. AMT reduces nausea after challenge with a high calorie liquid load.
PMCID: PMC3897125  PMID: 18803000
11.  Predictors of Response Rates to a Long Term Follow-Up Mail out Survey 
PLoS ONE  2013;8(11):e79179.
Very little is known about predictors of response rates to long-term follow-up mail-out surveys, including whether the timing of an incentive affects response rates. We aimed to determine whether the timing of the incentive affects response rates and what baseline demographic and psychological factors predict response rates to a 12 year follow-up survey.
Study design and setting: Participants were 450 randomly selected people from the Penrith population, Australia who had previously participated in a mail-out survey 12 years earlier. By random allocation, 150 people received no incentive, 150 received a lottery ticket inducement with the follow-up survey and 150 received a lottery ticket inducement on the return of a completed survey.
The overall response rate for the study was 63%. There were no significant differences in terms of response rates between the no incentive (58.8%;95%CI 49.8%,67.3%), incentive with survey (65.1%;95%CI 56.2%,73.3%) and promised incentive (65.3%;95%CI 56.1%,73.7%) groups. Independent predictors of responding to the 12 year survey were being older (OR=1.02, 95%CI 1.01,1.05,P=0.001) and being less neurotic as reported on the first survey 12 years earlier (OR=0.92, 95%CI 0.86,0.98, P=0.010).
Psychological factors may play a role in determining who responds to long-term follow-up surveys although timing of incentives does not.
PMCID: PMC3817035  PMID: 24223902
12.  So you aspire to be a Professor? 
PMCID: PMC2785069  PMID: 20037627
13.  Psychosocial Distress and Somatic Symptoms in Community Subjects With Irritable Bowel Syndrome: A Psychological Component Is the Rule 
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.
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.
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.
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.
PMCID: PMC3772628  PMID: 19491833
14.  Novel associations with dyspepsia: A community based study of familial aggregation, sleep dysfunction and somatization 
Dyspepsia is common and the majority of patients have functional dyspepsia; however, potential risk factors are unclear with conflicting results in the literature. Although several risk factors have been evaluated previously, this knowledge has not lead to more effective management.
To assess potential novel risk factors for dyspepsia in both a cross sectional and a nested case control study among a randomly selected community based cohort.
A valid questionnaire was mailed to a random sample of Olmsted County, MN residents (n=659 responders; 133 had dyspepsia). In a nested case-control study, dyspeptic patients (n=52) and healthy controls (n=40) identified among community respondents completed further questionnaires on diet.
Independent risk factors for dyspepsia adjusted for age, sex, body mass index and anti-secretory therapy were a positive family history of abdominal pain (OR=4.7, 95% CI 1.5, 14.9, p=0.008) and indigestion (OR=3.4., 95% CI 1.0, 11.5, p=0.04) difficulty falling asleep (OR=8.2, 95% CI (2.2–31.5, p=0.002), poor sleep associated with worsening symptoms (OR=15.9, 95% CI (2.0–124.9, p=0.009) and a high somatic symptom checklist score (OR=5.6, 95% CI (1.5–20.7, p=0.01). Diet including total calories (kcalories/day) and total protein, carbohydrate and fat intake (grams/day) was not significantly associated with dyspepsia
Familial aggregation raises the possibility of a genetic component although shared environmental factors need to be considered. Sleep dysfunction and somatization suggests a primary psychological component.
PMCID: PMC3748718  PMID: 19496951
15.  Biliary events and an increased risk of new onset irritable bowel syndrome: A population-based cohort study 
Prospective data are lacking to determine if IBS a risk factor for cholecystectomy, or if biliary disease and cholecystectomy predisposes to the development of IBS.
Validated symptom surveys sent to cohorts of Olmsted County, MN, (1988–1994) with follow-up in 2003. Medical histories were reviewed to determine any “biliary events” (defined by gallstones or cholecystectomy). Analyses examined: 1) time to a biliary event post initial survey and separately, 2) risk of IBS (Rome II) in those with vs. without a prior biliary event.
1908 eligible subjects mailed a follow-up survey. For aim 1) of the 726 without IBS at initial survey, 44 (6.1%) had biliary events during follow up, in contrast to 5 of 93 (5.4%) with IBS at initial survey (HR 0.8, 95% CI 0.3-2.1). For aim 2) of the 59 subjects with a biliary event at initial survey, 10 (17%) reported new IBS on the follow-up survey, while in 682 without a biliary event up to 1.5 years prior to the second survey, 58 (8.5%) reported IBS on follow-up (OR=2.2, 95% CI 1.1-4.6, p=0.03).
There is an increased risk of new IBS in community subjects who have been diagnosed as having a biliary event.
PMCID: PMC3335764  PMID: 19086237
16.  Increased Incidence and Impact of Upper and Lower Gastrointestinal Events in Patients with Rheumatoid Arthritis in Olmsted County, Minnesota: A Longitudinal Population-based Study 
The Journal of Rheumatology  2012;39(7):1355-1362.
To assess the incidence and mortality impact of upper and lower gastrointestinal (GI) events in rheumatoid arthritis (RA) compared to non-RA subjects.
We identified incident upper and lower GI events and estimated their incidence rates using person-year methods in a population-based incident RA cohort of residents of Olmsted County, Minnesota, USA (1987 American College of Rheumatology criteria first fulfilled between January 1, 1980, and January 1, 2008) and non-RA subjects from the same population.
The study included 813 patients with RA and 813 non-RA subjects (mean followup 10.3 and 10.8 yrs, respectively); 68% women; mean age 55.9 yrs in both cohorts. The rate of upper GI events/100 person-years was 2.9 in RA versus 1.7 in the non-RA cohort (rate ratio 1.7, 95% CI 1.4, 2.2); for lower GI events, the rates were 2.1 in RA versus 1.4 in the non-RA cohort (rate ratio 1.5, 95% CI 1.1, 1.9). The incidence of upper GI bleed, perforation, ulcer, obstruction, and any upper GI event in RA declined over calendar time; the incidence of lower GI events remained unchanged. Exposure to glucocorticoids, prior upper GI disease, abdominal surgery, and smoking were associated with lower GI events in RA. Both upper and lower GI events were associated with increased mortality risk in RA.
There is increased risk of serious upper and lower GI events in RA compared to non-RA subjects, and increased GI-related mortality in RA. Prominent declines in incidence of upper, but not lower GI events in RA highlight the need for studies investigating lower GI disease in patients with RA.
PMCID: PMC3389143  PMID: 22467929
17.  Opioid Bowel Dysfunction and Narcotic Bowel Syndrome: A Population-Based Study 
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.
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.
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.
NBS may be relatively uncommon. Those on narcotics report additional GI symptoms (abdominal pain and stool frequency) and use more laxatives.
PMCID: PMC3209714  PMID: 19367263
18.  Factors Associated with Persistant and Non-Persistant Chronic Constipation, Over 20 Years 
Background & Aims
The prevalence of chronic constipation (CC) has been reported to be as high as 20% in the general population, but little is known about its natural history. We estimated the natural history of CC and characterized features of persistent CC and non-persistent CC, compared to individuals without constipation.
In a prospective cohort study, we analyzed data collected from multiple, validated surveys (minimum of 2) of 2853 randomly selected subjects, over a 20-year period (median, 11.6 years). Based on responses, subjects were characterized as having persistent CC, non-persistent CC, or no constipation. We assessed the association between constipation status and potential risk factors using logistic regression models, adjusting for age and sex.
Of the respondents, 84 had persistent CC (3%), 605 had non-persistent CC (21%), and 2164 had no symptoms of constipation (76%). High scores from the somatic symptom checklist (odds ratio [OR] =2.1; 95% confidence interval [CI], 1.3–3.4) and frequent doctor visits (OR=2.0; 95% CI, 1.0–3.8) were significantly associated with persistent CC, compared to subjects with no constipation symptoms. The only factor that differed was increased use of laxatives or fiber among subjects with persistent CC (OR=3.0; 95% CI, 1.9–4.9).
The prevalence of constipation might be exaggerated—the proportion of the population with persistent CC is low (3%). Patients with persistent and non-persistent CC have similar clinical characteristics, although individuals with persistent CC use more laxatives or fiber. CC therefore appears and disappears among certain patients, but we do not have enough information to identify these individuals in advance.
PMCID: PMC3589972  PMID: 22289877
SSC; epidemiology; determinants; diagnosis
19.  AJG Series: Molecular Biology for Clinicians Pharmacogenetics and Genomics for Clinicians 
Pharmacogenetics is an evolving field that provides the link between an individual's genetic code and drug metabolism and drug response. This field offers the great promise of individualized medication selection and optimized dosage to maximize treatment response and to minimize adverse side effects. As our understanding of the role of the effects of genetic variants on drug metabolism and body drug processing grows, so does our ability to educate and inform our patients about expected treatment response to the medications being prescribed to them. This brief review will provide an overview of genetics, pharmacogenetics, and current and future examples of genetic variants predicting drug response in gastrointestinal disease, and the limitations and the promise of this exciting and developing field.
PMCID: PMC2901906  PMID: 19550416
20.  Overlap of dyspepsia and gastroesophageal reflux in the general population: one disease or distinct entities? 
The overlap of dyspepsia and gastroesophageal reflux (GER) is known to be frequent but whether the overlap group is a distinct entity or not remains unclear.
To evaluate whether the overlap of dyspepsia and GER (dyspepsia-GER overlap) occurs more than expected due to chance alone, and evaluate the risk factors for dyspepsia-GER overlap.
In 2008 and 2009, a validated Bowel Disease Questionnaire was mailed to a total of 8006 community sample from Olmsted County, MN. Overall, 3831 of the 8006 subjects returned surveys (response rate 48%). Dyspepsia was defined by symptom criteria of Rome III; GER was defined by weekly or more frequent heartburn and/or acid regurgitation.
Dyspepsia and GER occurred together more commonly than expected by chance. The somatic symptom checklist score was significantly associated with dyspepsia-GER overlap vs. GER alone or dyspepsia alone (OR=1.9 [1.4, 2.5), and 1.6 [1.2, 2.1), respectively). Insomnia was also significantly associated with dyspepsia-GER overlap vs. GER alone or dyspepsia alone (OR=1.4 [1.1, 1.7], OR=1.3 [1.1, 1.6], respectively). Moreover, proton pump inhibitor use was significantly associated with dyspepsia-GER overlap vs. dyspepsia alone (OR=2.4 [1.5, 3.8]).
Dyspepsia-GER overlap is common in the population and is greater than expected by chance.
PMCID: PMC3589973  PMID: 22150874
Population-based study; dyspepsia; gastroesophageal reflux
22.  Prevalence of oesophageal eosinophils and eosinophilic oesophagitis in adults: the population‐based Kalixanda study 
Gut  2006;56(5):615-620.
Eosinophilic oesophagitis may be increasing but the prevalence in the general population remains unknown. Our aim was to assess this and the presence of eosinophils in the distal oesophageal epithelium in the community.
Oesophagogastroduodenoscopy was performed in a random sample (n = 1000) of the adult Swedish population (mean age 54 years, 49% men). Oesophageal biopsy samples were obtained from 2 cm above, and at, the Z‐line. Any eosinophil infiltration of the epithelium was defined as “eosinophils present”. Definite eosinophilic oesophagitis was defined as ⩾20, probable as 15–19, and possible as 5–14 eosinophils/high‐power field (HPF, at magnification ×40) in oesophageal biopsy specimens.
Eosinophils were present in 48 subjects (4.8%, 95% CI 3.5 to 6.1%, mean age 54 years, 63% men), in 54% without troublesome reflux symptoms. Definite eosinophilic oesophagitis was present in four subjects (0.4%, 95% CI 0.01 to 0.8%, mean age 51 years, 75% men) and probable eosinophilic oesophagitis in seven subjects (0.7%, 95% CI 0.2 to 1.2%, mean age 58 years, 43% men). Erosive oesophagitis (OR = 2.99, 95% CI 1.58 to 5.66) and absence of dyspepsia (OR = 0.23, 95% CI 0.07 to 0.75) and Helicobacter pylori infection (OR = 0.41, 95% CI 0.19 to 0.92) were independent predictors for “eosinophils present”. Definite eosinophilic oesophagitis was associated with dysphagia (2/66 vs 2/926, p = 0.025), and probable eosinophilic oesophagitis with narrowing of the oesophageal lumen (2/15 vs 5/978, p = 0.005).
Oesophageal eosinophils were present in nearly 5% of the general population; approximately 1% had definite or probable eosinophilic oesophagitis. Oesophageal eosinophils may be a manifestation of reflux disease in adults, but the condition is as likely to be asymptomatic and go unrecognised.
PMCID: PMC1942149  PMID: 17135307
eosinophilic oesophagitis; epidemiology; gastro‐oesophageal reflux disease; population‐based
23.  Gastroesophageal Reflux Disease and Sleep Disorders: Evidence for a Causal Link and Therapeutic Implications 
Gastroesophageal reflux disease (GERD) and sleep disturbances are both common health problems. There is a significant association between disturbed sleep and GERD, and this may be bidirectional. Sleep disorders may induce gastrointestinal (GI) disturbances, while GI symptoms also may provoke or worsen sleep derangements. Reflux of gastric acid is a less frequent event during sleep, however, acid clearance mechanisms (including swallowing, salivation and primary esophageal motility) are impaired during sleep resulting in prolongation of acid contact time. Nighttime reflux can lead to sleep disturbance and sleep disturbance may further aggravate GERD by prolonged acid contact time and heightened sensory perception. This may facilitate the occurrence of complicated GERD and decreased quality of life. However, the interplay between sleep problems and GERD is complex, and there are still relatively limited data on this issue. Further investigation of sleep-related GERD may identify common pathophysiological themes and new therapeutic targets.
PMCID: PMC2879818  PMID: 20535322
Sleep; Gastroesophageal reflux disease
24.  Cyclic vomiting syndrome and functional vomiting in adults: association with cannabinoid use in males 
Cyclic vomiting syndrome (CVS) is characterized by stereotypical episodes of vomiting separated by symptom-free intervals. However, the difficulty encountered in the management of patients with CVS may be a reflection of a deficiency in our understanding of the disorder. We aimed to evaluate whether clinical or gastric emptying (GE) data discriminate patients labeled as having CVS from functional vomiting (FV) or IBS.
The medical records of patients diagnosed with any vomiting (including CVS, FV) over a 13-year period (1993–2006) at our institution were carefully reviewed. Disease controls were age and gender matched subjects with IBS. GE was performed by scintigraphy (99mTc-egg meal). The associations of clinical factors and gastric emptying data with patient status (CVS vs. FV or IBS) were analyzed.
Key Results
A total of 82 patients with CVS and 62 FV patients were identified. Younger age (per 10 years, OR=0.7 [0.5, 0.9]), male gender (OR=0.4 [0.2, 0.9]), and cannabinoid use (OR=2.9 [1.2, 7.2]) were significantly associated with CVS compared to FV. However, there were no significant associations between patient status (CVS vs. FV) and age, BMI, smoking, alcohol use, gastrointestinal symptoms, or GE. The proportion of cannabinoid users was significantly higher in subjects with CVS compared to subjects with IBS, while proportions for headaches and psychiatric disease were higher in subjects with IBS.
CVS (vs. FV) was not associated with clinical factors, but was associated with younger age, male gender and cannabinoid use. A larger proportion of CVS (vs. IBS) patients had used cannabinoids.
PMCID: PMC3375678  PMID: 21951771
cyclic vomiting syndrome; functional vomiting; male cannabinoid user
25.  Gluten-Free Diet and Steroid Treatment Are Effective Therapy for Most Patients With Collagenous Sprue 
Collagenous sprue (CS) is characterized by the presence of a distinctive band of subepithelial collagen deposition in the small bowel. We evaluated the clinical characteristics, treatments, and outcomes of patients with CS.
Thirty patients with CS were identified at the 3 Mayo Clinic sites between 1993 and 2009. Clinical data from medical records were reviewed.
The study cohort was 70% female (age range, 53–91 years). Most patients had severe diarrhea and weight loss. Hospitalization to treat dehydration was necessary in 16 (53%) patients. Associated immune-mediated diseases were noted in 70% of the patients; celiac disease was the most frequent. Other associated diseases were microscopic colitis, hypothyroidism, and autoimmune enteropathy. The median thickness of the layer of subepithelial collagen deposition in the small bowel was 29 μm (20 –56.5 μm). Subepithelial collagen deposition in the colon or stomach was noted in 8 patients. A clinical response was observed in 24 (80%) patients after treatment with a combination of a gluten-free diet and immunosuppressive drugs. Histologic improvement was confirmed in 9 patients, with complete remission in 5. Two patients died (1 of complications of CS and 1 of another illness).
Most patients with CS are treated effectively with a combination of gluten-free diet and steroids. CS is often associated with collagen deposition or chronic inflammation in other segments of the gastrointestinal tract as well as other immune-mediated disorders.
PMCID: PMC3493150  PMID: 20060071
Sprue; Microscopic Colitis; Celiac Disease; Duodenum; Collagen; Fibrosis

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