The central pathophysiological mechanisms underlying irritable bowel syndrome (IBS), a female-predominant gastrointestinal disorder characterized by abdominal pain and abnormal bowel habits, remain poorly understood. IBS patients often report that chronic stress exacerbates their symptoms. Brain imaging studies have revealed that the amygdala, a stress-responsive brain region, of IBS patients is overactive when compared to healthy controls. Previously, we demonstrated that downregulation of the glucocorticoid receptor (GR) in the central nucleus of the amygdala (CeA) underlies stress-induced visceral hypersensitivity in female rats. In the current study, we aimed to evaluate in the CeA of female rats whether chronic water avoidance stress (WAS) alters DNA methylation of the GR exon 17 promoter region, a region homologous to the human GR promoter. As histone deacetylase (HDAC) inhibitors are able to change DNA methylation, we also evaluated whether administration of the HDAC inhibitor trichostatin A (TSA) directly into the CeA prevented WAS-induced increases in DNA methylation of the GR exon 17 promoter. We found that WAS increased overall and specific CpG methylation of the GR promoter in the CeA of female rats, which persisted for up to 28 days. Administration of the TSA directly into the CeA prevented these stress-induced changes of DNA methylation at the GR promoter. Our results suggest that, in females, changes in DNA methylation are involved in the regulation of GR expression in the CeA. These changes in DNA methylation may contribute to the central mechanisms responsible for stress-induced visceral hypersensitivity.
Background: Diagnosing anal incontinence (AI) based on manometry results is challenging due to the variation of the normal values and overlap between patients with and without AI. This study aimed to perform a systematic review on the difference in sphincter fatigability between patients with and without AI.
Methods: MEDLINE, EMBASE, SCOPUS, and Google Scholar were searched. Studies were included if they included adult patients and assessed anal sphincter fatigability between using manometry. The effect size was estimated as the standardized mean difference (SMD) with 95% confidence intervals. A random-effects model was used.
Results: The database searches identified 125 unique articles, and five additional articles were identified from the reference list of articles. One hundred thirteen were excluded through title and abstract review. Nine articles were included in the final analysis. There was no statistically significant difference in the resting pressure between the two groups. Patients with AI had significantly lower squeeze pressure. There was no statistically significant difference between the groups in the fatigue rate. The FRI was significantly lower in patients with AI (SMD 1.636, p = 0.001). Approximately a third of the patients in one study were able to maintain a contraction for 20s without reducing pressure. There was significant heterogeneity in the studies. The data available were inadequate for more robust calculations.
Conclusions: Sphincter fatigability, measured by the Fatigability Rate Index, has good discriminating power for anal incontinence. A standardized protocol needs to be followed by future researchers. Graphical Abstract The analysis used six studies with 413 patients to compare Fatigue Rate Index between patients with AI and controls. All studies reported a lower FRI in patients with incontinence and the FRI was significantly lower in patients with AI (standardized mean difference [SMD] 1.636, p= 0.001). Conflicting results were reported on the correlation between FRI and AI symptom scores.
Background: Pediatric Rome IV criteria are used to diagnose childhood functional gastrointestinal disorders (FGIDs). This study of pediatric gastroenterology physicians measured their agreement in (1) Making a pediatric Rome IV FGID diagnosis; and (2) Diagnostic testing for patients with FGIDs.
Methods: Pediatric gastroenterologists and pediatric gastroenterology fellows at two medical centers completed a survey containing clinical FGID vignettes. For each vignette, raters identified the most likely Rome IV diagnosis(es) and selected which diagnostic test(s) (if any) they typically would obtain. The survey was re-administered within 3 months. Inter-rater and intra-rater weighted percent agreement was determined. Linear mixed modeling identified sources of variability in diagnostic testing.
Key results: Thirty-four raters completed the initial survey of whom thirty-one (91%) completed the repeat survey. Overall inter-rater agreement on Rome IV diagnoses was 68% for initial and repeat surveys whereas intra-rater agreement was 76%. In contrast, overall inter-rater agreement on diagnostic testing was <30% for both initial and repeat surveys and intra-rater agreement was only 57%. Between-physician differences accounted for 43% of the variability in the number of tests selected. Rater identified use of Rome criteria in clinical practice was associated with 1.1 fewer diagnostic tests on average (95% CI 0.2-2.0, p = 0.015). Higher intra-rater agreement was noted for diagnostic testing in faculty when compared to fellows (p = 0.009).
Conclusions & inferences: In a multicenter evaluation among pediatric gastroenterology physicians, pediatric Rome IV diagnostic agreement was higher than that reported for previous Rome versions, and higher than agreement on diagnostic testing.
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