Bharucha, Adil E.

INTRODUCTION: Uncontrolled results suggest that diaphragmatic breathing (DB) is effective in gastroesophageal reflux disease (GERD) but the mechanism of action and rigor of proof is lacking. This study aimed to determine the effects of DB on reflux, lower esophageal sphincter (LES), and gastric pressures in patients with upright GERD and controls. METHODS: Adult patients with pH proven upright GERD were studied. During a high-resolution impedance manometry, study patients received a standardized pH neutral refluxogenic meal followed by LES challenge maneuvers (Valsalva and abdominal hollowing) while randomized to DB or sham. After that, patients underwent 48 hours of pH-impedance monitoring, with 50% randomization to postprandial DB during the second day. RESULTS: On examining 23 patients and 10 controls, postprandial gastric pressure was found to be significantly higher in patients compared with that in controls (12 vs 7 mm Hg, P = 0.018). Valsalva maneuver produced reflux in 65.2% of patients compared with 44.4% of controls ( P = 0.035). LES increased during the inspiratory portion of DB (42.2 vs 23.1 mm Hg, P < 0.001) in patients and healthy persons. Postprandial DB reduced the number of postprandial reflux events in patients (0.36 vs 2.60, P < 0.001) and healthy subjects (0.00 vs 1.75, P < 0.001) compared with observation. During 48-hour ambulatory study, DB reduced the reflux episodes on day 2 compared with observation on day 1 in both the patient and control groups ( P = 0.049). In patients, comparing DB with sham, total acid exposure on day 2 was not different (10.2 ± 7.9 vs 9.4 ± 6.2, P = 0.804). In patients randomized to DB, esophageal acid exposure in a 2-hour window after the standardized meal on day 1 vs day 2 reduced from 11.8% ±6.4 to 5.2% ± 5.1, P = 0.015. DISCUSSION: In patients with upright GERD, DB reduces the number of postprandial reflux events pressure by increasing the difference between LES and gastric pressure. These data further encourage studying DB as therapy for GERD.

AbstractObjectivesDefecation requires relaxation of the internal and external anal sphincters. High anal resting pressure is associated with painful constipation, defecatory disorders, and increased healthcare utilization in constipated patients; the mechanisms are unclear. Perhaps patients with a high anal resting pressure have a less distensible canal, which impedes defecation.MethodsIn 50 of 64 participants (33 healthy and 17 constipated women), anal pressures and distensibility were measured, respectively, with manometry and balloon distention combined with magnetic resonance imaging; rectal balloon expulsion time (BET) was also studied.ResultsThe BET (P = .006) was longer, and the mean (SD) rectoanal pressure gradient (−58[40] vs −34[26] mm Hg,P = .03) was more negative in constipated than healthy women; anal resting pressure was not different. During anal distention, the balloon expanded rapidly at an opening pressure of 49 (18) mm Hg, which was lower (P < .0001) than resting pressure (90 [25] mm Hg). The resting pressure was correlated with the opening pressure (r = 0.57,P < .0001) and inversely (r = −0.38,P = .007) with maximum volume but not with anal distensibility (volume‐pressure slope). In healthy women, the difference (opening‐resting pressure) was correlated with anal relaxation during evacuation (r = 0.35,P = .04). Anal distensibility and sensory thresholds were not different between constipated and healthy women.ConclusionsAmong healthy and constipated women, a greater anal resting pressure is correlated with greater opening pressure and lower maximum volume during distention, and, hence, provides a surrogate marker of anal distensibility. The difference (opening‐resting pressure), which reflects anal relaxation during distention, is correlated with anal relaxation during evacuation. Anal resting pressure and distensibility were comparable in healthy and constipated women.

Abstract Background There is increased recognition of duodenal disturbances (inflammation, altered mucosal protein expression, and chemosensitivity) in functional dyspepsia (FD). Besides sensorimotor functions, enteric submucosal neurons also regulate epithelial ion transport. We hypothesized that duodenal mucosal ion transport and expression of associated genes are altered in FD. Methods Duodenal mucosal ion transport (basal and acetylcholine‐ and glucose‐evoked changes in short‐circuit current [Isc]) and expression of associated genes and regulatory miRNAs were evaluated in 40 FD patients and 24 healthy controls. Results Basal Isc (FD: 88.2 [52.6] μA/cm 2 vs healthy: 20.3 [50.2] μA/cm 2 ; P ≤ .0001), acetylcholine‐evoked Isc (FD: Emax 50.4 [35.8] μA/cm 2 vs healthy: 16.6 [15] μA/cm 2 ; P ≤ .001), and glucose‐evoked Isc responses (FD: E max 69.8 [42.1] μA/cm 2 vs healthy: 40.3 [24.6] μA/cm 2 ; P = .02) were greater in FD than in controls. The Emax for glucose was greater in FD patients on selective serotonin reuptake inhibitors. In FD, the mRNA expression of SLC4A7 and SLC4A4 , which transport bicarbonate into cells at the basolateral surface, and the apical anion exchanger SLC26A3 were reduced (false discovery rate <0.05), the serotonin receptor HTR4 was increased, and the serotonin transporter SLC6A4 was decreased. Selected miRNAs (hsa‐miR‐590‐3p, hsa‐miR‐32‐5p) that target genes associated with ionic transport were upregulated in FD. Conclusions Compared to controls, FD patients had greater baseline and agonist‐evoked duodenal mucosal secretory responses. These findings may be explained by reduced gene expression, which would be anticipated to reduce luminal bicarbonate secretion. The upregulated miRNAs may partly explain the downregulation of these genes in FD.

AbstractBackgroundWe compared the utility of existing and modified versions of high‐resolution manometry for diagnosing defecatory disorders (DD).MethodsIn 64 healthy and 136 constipated women, we compared left lateral (LL) and seated manometry, and analyzed with existing (ManoView™) and new methods, for discriminating between constipated patients with normal and prolonged rectal balloon expulsion time (BET). In both positions, the rectoanal gradient (RAG) and, for the new analysis, the pressure topography pattern during evacuation were used to discriminate between constipated patients without and with DD.Key ResultsThe BET was prolonged, suggestive of a DD, in 52 patients (38%). During evacuation, rectoanal pressures and the RAG were greater in the seated than the LL position (P≤.001). The new analysis identified 4 rectoanal pressure patterns. In the seated position, the BET was associated with the pattern (P=.0001), being prolonged in, respectively, 45%, 15%, 53%, and 0% of patients with minimal change, anal relaxation, paradoxical contraction, and transmission. Within each pattern, the RAG was greater (ie, less negative, P<.0001) in patients with a normal than a prolonged BET. Compared to the ManoView™ RAG in the LL position, the integrated analysis (ie, pattern and new RAG) in the LL position (P<.01) and the seated ManoView™ gradient (P=.02) were more effective for discriminating between constipated patients without and with DD.Conclusions & InferencesAnorectal HRM ideally should be performed in the more physiological seated position and analyzed by a two‐tier approach, which incorporates the overall pattern followed by the rectoanal gradient. These findings reinforce the utility of manometry for diagnosing DD.

INTRODUCTION: Epigenetic modifications have been implicated to mediate several complications of diabetes mellitus (DM), especially nephropathy and retinopathy. Our aim was to ascertain whether epigenetic alterations in whole blood discriminate among patients with DM with normal, delayed, and rapid gastric emptying (GE). METHODS: Using the ChIP-seq (chromatin immunoprecipitation combined with next-generation sequencing) assays, we compared the genome-wide enrichment of 3 histone modifications (i.e., H3K4me3, H3K9ac, and H3K27ac) in buffy coats from 20 diabetic patients with gastrointestinal symptoms and normal (n = 6), delayed (n = 8), or rapid (n = 6) GE. RESULTS: Between patients with DM with delayed vs normal GE, there were 108 and 54 genes that were differentially bound (false discovery rate < 0.05) with H3K27ac and H3K9ac, respectively; 100 genes were differentially bound with H3K9ac in patients with rapid vs normal GE. The differentially bound genes with H3K27ac were functionally linked to the type 2 immune response, particularly Th2 cell activation and function (e.g., CCR3 , CRLF2 , CXCR4 , IL5RA , and IL1RL1 ) and glucose homeostasis ( FBP-1 , PDE4A , and CMKLR1 ). For H3K9ac, the differentially occupied genes were related to T-cell development and function (e.g., ICOS and CCR3 ) and innate immunity ( RELB , CD300LB , and CLEC2D ). Compared with normal GE, rapid GE had differential H3K9ac peaks at the promoter site of diverse immunity-related genes (e.g., TNFRSF25 and CXCR4 ) and genes related to insulin resistance and glucose metabolism. Motif analysis disclosed enrichment of binding sites for transcription factors relevant to the pathogenesis and complications of DM. DISCUSSION: GE disturbances in DM are associated with epigenetic alterations that pertain to dysimmunity, glucose metabolism, and other complications of DM.

AbstractAimsSome patients with upper gastrointestinal symptoms have rapid gastric emptying (GE). We aimed to compare patients with normal and rapid GE and to identify phenotypes among patients with rapid GE.MethodsAmong 2798 patients who underwent GE scintigraphy, we compared patients with normal and rapid GE and separately, patients with rapid GE at 1 hour (GE1), 2 hours (GE2), or both (GE12).ResultsIn 2798 patients, GE was normal (74%), delayed (18%), or rapid (8%). Among 211 patients with rapid GE, patterns were rapid GE1 (48%), 2 hours (17%), or 1 and 2 hours (35%); 42 (20%) had diseases that explain rapid GE. A combination of upper and lower gastrointestinal symptoms (54%) was more common that isolated upper (17%) or lower (28%) gastrointestinal symptoms (P < .001). Constipation was more prevalent in patients with rapid GE 2 (72%) than rapid GE 1 (47%) or rapid GE12 hours (67%) (P < .05). Among 179 diabetes mellitus (DM) patients, 15% had rapid GE, which was not associated with the DM phenotype. By multivariable analysis, insulin therapy (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.15‐0.88), and weight loss (OR, 0.10; 95% CI, 0.01‐0.78) were associated with a lower risk of rapid than normal GE in DM.ConclusionsEight percent of patients undergoing scintigraphy had rapid GE, which is most frequently associated with upper and lower gastrointestinal symptoms; constipation is common. Insulin therapy and weight loss were associated with a lower risk of rapid than normal GE in DM patients.

AbstractBackgroundNutrient‐mediated release of cholecystokinin and glucagon‐like peptide‐1 (GLP‐1) regulates gastric emptying (GE) via duodenogastric feedback mechanisms; GLP‐1 also regulates postprandial insulin secretion. Some patients with functional upper gastrointestinal symptoms have impaired glucose tolerance during enteral dextrose infusion. Our hypothesis was that variants in CCK, GLP‐1, and TCF7L2 (transcription factor 7‐like 2 locus), which is associated with greatest genetic risk for development of type 2 diabetes mellitus, are associated with GE and independently with glucose tolerance. Our aims were to evaluate the associations between these GE, glucose tolerance, and these single nucleotide polymorphisms (SNPs).MethodsGenetic variants, scintigraphic GE of solids, plasma glucose, insulin, and GLP‐1 during enteral dextrose infusion (75gm over 2 hours) were measured. GE and enteral dextrose infusion were, respectively, evaluated in 44 (27 controls and 17 patients with functional dyspepsia or nausea) and 42 (28 controls, 14 patients) participants; of these, 51 participants consented to assessment of SNPs. Four functional SNPs were studied: rs6923761 and rs1042044 at GLP‐1 receptor, rs7903146 (TCF7L2), and rs1800857 (CCK receptor).Key ResultsGastric emptying was normal in 38, rapid in 4, and delayed in two participants; 38 had normal, and four had impaired glucose tolerance. The T allele at rs7903146 (TCF7L2) was non‐significantly associated (P = .14) with faster GE. The associations between SNPs and demographic variables, GE thalf, glucose tolerance and plasma GLP1 levels were not significant.Conclusions & InferencesThere is a trend toward an association between faster GE and the diabetes‐associated allele at rs7903146 in TCF7L2. However, these SNPs were not associated with plasma glucose or GLP1 concentrations during enteral dextrose infusion.

AbstractBackgroundThe relationship between cardiovascular and gastrointestinal (ie, plasma pancreatic polypeptide [PP] response to modified sham feeding [MSF]) indices of vagal function is unclear. Hyperglycemia inhibits PP secretion via vagally mediated mechanisms. Our aims were to (a) compare the PP response, (b) its relationship with glycemia, and (c) the relationship between PP response to MSF, gastric emptying (GE) of solids, and symptoms during GE study in healthy controls, patients with diabetic gastroenteropathy (DM), and non‐ulcer dyspepsia (NUD).MethodsIn 24 healthy controls, 40 DM, and 40 NUD patients, we measured plasma PP concentrations during MSF, cardiovagal functions, GE, and symptoms during a GE study.Key ResultsBaseline PP concentrations were higher in DM than in controls and NUD (P = .01), and in type 2 than in type 1 DM patients (P < .01). The PP increment during MSF was normal (≥20 pg/mL) in 70% of controls, 54% of DM, and 47% of NUD patients. Overall, the PP response and cardiovagal tests were concordant (P = .01). Among patients with a reduced PP increment with MSF, 7/10 of T1DM and 1/7 of T2DM patients had moderate or severe cardiovagal dysfunctions (P < .05). The PP response to MSF was not associated with GE.Conclusions & InferencesUp to 30% of healthy controls have a reduced PP increment during MSF, limiting the utility of this test to detect vagal injury. The PP response is more useful when it is normal than abnormal. A reduced PP response is more likely to be associated with cardiovagal dysfunctions in T1DM than in T2DM.