Interferon-α exerts proinflammatory properties in experimental radiation-induced esophagitis: Possible involvement of plasmacytoid dendritic cells.

AIMS: Radiation-induced esophagitis, experienced during radiation therapy for lung cancer and head and neck cancer, is a major dose-limiting side effect of the treatment. This study aimed to elucidate the role of interferon-α (IFN-α) in radiation-induced esophagitis. MAIN METHODS: C57BL/6 mice were exposed to 10 and 25Gy of single thoracic irradiation. Esophageal mucosal damage and inflammatory reactions were assessed for 5 days after irradiation. KEY FINDINGS: Irradiation induced esophagitis, characterized by reduction in the thickness of epithelial layer, upregulation of proinflammatory cytokines and chemokines, infiltration of inflammatory cells into the esophageal mucosa, and apoptosis of epithelial cells. Irradiation upregulated the level of gene expression for IFN-α in the esophageal tissue, and the neutralizing antibody against IFN-α ameliorated radiation-induced esophageal mucosal damage, while administration of IFN-α receptor agonist (RO8191) had an inverse effect. Depletion of plasmacytoid dendritic cells (pDCs) by anti-CD317 antibody or pharmacological inactivation with bortezomib suppressed radiation-induced mucosal inflammation and damage, accompanied by decrease in IFN-α expression level. SIGNIFICANCE: These findings suggest that IFN-α and pDCs exert proinflammatory properties in the pathophysiology of radiation-induced esophagitis.

Selective Recovery of Estrogenic Endocrine Disruptors from 48 Environmental Samples Using a Substrate for Activity-Specific Concentration.

hER-MIP is a molecularly imprinted polymer (MIP) that has been shown to selectively collect human estrogen receptor (hER) binding active substances. However, environmental samples contain various chemicals depending on the location and regional differences, and the hER binding activity depends on the sample type. Thus, the general applicability of hER-MIP to actual environmental samples must be elucidated. In this study, 48 environmental samples were collected and screened with hER-MIP, and a yeast assay was performed to evaluate the adsorption characteristics of the samples according to the adsorption and elution fractions. The results showed that hER-MIP collects hER binding active substances almost selectively but does not collect constitutive androstane receptor (CAR) binding active substances selectively. CAR binding activity was detected in the adsorbed fraction because several hER binding active substances also demonstrate CAR binding activity.

Eosinophilic esophagitis and asymptomatic esophageal eosinophilia display similar immunohistological profiles.

Patients with asymptomatic esophageal eosinophilia (aEE) do not exhibit clinical symptoms because of esophageal dysfunction, although they have endoscopic and histological findings similar to those of eosinophilic esophagitis (EoE). The cause of the symptoms and the differences between aEE and EoE are unclear. The aim of this study is to determine whether aEE and EoE are same disease entities by comparing immune-related tissue biomarkers using immunohistological staining. Esophageal biopsy specimens from 61 patients, including 18 with aEE and 43 with EoE, were analyzed. Immunofluorescence staining was performed to quantify the immune-related tissue biomarkers such as major basic protein, eosinophil-derived neurotoxin, eotaxin-3, and immunoglobulin G4. Data are presented as median (interquartile range). There were no significant differences in clinical, endoscopic, or histological features, between patients with aEE and EoE, with the exception of body mass index. There were no significant differences in all immune-related tissue biomarkers between both groups. In conclusions, EoE and aEE displayed similar immunohistological profiles. Hence, they may be similar disease entities with some common pathogenic mechanisms. Our findings suggest that patients with aEE also have histopathological esophageal inflammation.

Protective role of resolvin D1, a pro-resolving lipid mediator, in nonsteroidal anti-inflammatory drug-induced small intestinal damage.

Resolvin D1, a specialized pro-resolving lipid mediator produced from docosahexaenoic acid by 15- and 5-lipoxygenase, exerts anti-inflammatory effects driving to the resolution of inflammation. The present study aimed to elucidate its role in small intestinal damage induced by nonsteroidal anti-inflammatory drug (NSAID). Indomethacin was administered orally to C57BL/6J male mice, which were sacrificed 24 h later to collect small intestine specimens. Before administration of indomethacin, mice were subjected to intraperitoneal treatment with resolvin D1 or oral administration of baicalein, a 15-lipoxygenase inhibitor. Small intestinal damage induced by indomethacin was attenuated by pretreatment with resolvin D1. Furthermore, resolvin D1 reduced the gene expression levels of interleukin-1ß, tumor necrosis factor-α, and CXCL1/keratinocyte chemoattractant. Conversely, the inhibition of 15-lipoxygenase activity by baicalein increased the expression of genes coding for these inflammatory cytokines and chemokine, leading to exacerbated small intestinal damage, and reduced the concentration of resolvin D1 in the small intestinal tissue. Exogenous treatment with resolvin D1 negated the deleterious effect of baicalein. 15-lipoxygenase was mainly expressed in the epithelium and inflammatory cells of the small intestine, and its gene and protein expression was not affected by the administration of indomethacin. Inhibition of the resolvin D1 receptor, lipoxin A4 receptor /formyl peptide receptor 2, by its specific inhibitors Boc-1 and WRW4 aggravated indomethacin-induced small intestinal damage. Collectively, these results indicate that resolvin D1 produced by 15-lipoxygenase contributes to mucoprotection against NSAID-induced small intestinal damage through its anti-inflammatory effect.

Gastrointestinal endoscopic practice during COVID-19 pandemic: a multi-institutional survey.

Introduction. An on-going coronavirus disease 2019 (COVID-19) has become a challenge all over the world. Since an endoscopy unit and its staff are at potentially high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we conducted a survey for the management of the gastrointestinal endoscopic practice, personal protective equipment (PPE), and risk assessment for COVID-19 during the pandemic at multiple facilities.Methods. The 11-item survey questionnaire was sent to representative respondent of Department of Gastroenterology, Osaka City University Hospital, and its 19 related facilities.Results. A total of 18 facilities submitted valid responses and a total of 373 health care professionals (HCPs) participated. All facilities (18/18: 100%) were screening patients at risk for SARS-CoV-2 infection before endoscopy. During the pandemic, we found that the total volume of endoscopic procedures decreased by 44%. Eleven facilities (11/18: 61%) followed recommendations of the Japan Gastroenterological Endoscopy Society (JGES); consequently, about 35%-50% of esophagogastroduodenoscopy and colonoscopy were canceled. Mask (surgical mask or N95 mask), face shield/goggle, gloves (one or two sets), and gown (with long or short sleeves) were being used by endoscopists, nurses, endoscopy technicians, and endoscope cleaning staff in all the facilities (18/18: 100%). SARS-CoV-2 infection risk assessment of HCPs was conducted daily in all the facilities (18/18: 100%), resulting in no subsequent SARS-CoV-2 infection in HCPs.Conclusion. COVID-19 has had a dramatic impact on the gastrointestinal endoscopic practice. The recommendations of the JGES were appropriate as preventive measures for the SARSCoV-2 infection in the endoscopy unit and its staff.

Successful Eradication of Helicobacter pylori Could Prevent Metachronous Gastric Cancer: A Propensity Matching Analysis.

BACKGROUND AND AIM: Helicobacter pylori is the leading cause of gastric cancer, but it is still uncertain whether eradicating H. pylori in early gastric cancer (EGC) patients who underwent endoscopic resection can prevent metachronous gastric cancer (MGC). This study aimed to investigate the effect of H. pylori eradication to prevent MGC after endoscopic submucosal dissection (ESD). METHODS: In this propensity-matched retrospective observational study, 770 patients with EGC who received ESD were enrolled. The outcome was the incidence of MGC; this was compared between the persistent and eradicated groups. RESULTS: MGC was detected in 27 patients (7.8%) during a median period of 39.0 months (range 26.0-64.0). After propensity matching, 126 pairs of patients in each group were analyzed. The 5-year cumulative incidence rates of MGC were 13.2 and 3.9% in the persistent and eradicated groups, respectively (p= 0.021, log-rank test). On multivariate analysis, H. pylori eradication prevented MGC significantly (hazard ratio [HR] 0.32; p = 0.029). The results remained robust after inverse probability of treatment weighting analysis (HR 0.30; p = 0.020). CONCLUSIONS: Successful H. pylori eradication could prevent MGC after ESD for EGC.

NOD-Like Receptor Family Pyrin Domain-Containing 3 Inflammasome Activation Exacerbates 5-Fluorouracil-Induced Small Intestinal Mucositis via Interleukin-1ß Activation.

BACKGROUND AND AIM: 5-Fluorouracil (5-FU) is an anticancer agent that induces intestinal mucositis, which causes diarrhea and dehydration. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is responsible for inflammatory response activation via caspase-1 cleavage and subsequent interleukin-1ß (IL-1ß) and IL-18 activation and secretion. The objective of this study was to determine the role of the NLRP3 inflammasome in 5-FU-induced small intestinal mucositis. METHODS: Small intestinal mucositis was induced in wild-type, NLRP3-/-, and caspase-1-/- mice by intraperitoneal injection of 5-FU. Some mice received intraperitoneal injection of a caspase-1 inhibitor, recombinant IL-1ß or IL-18, or neutralizing antibody against IL-1ß. RESULTS: Mice treated with 5-FU developed small intestinal mucositis with diarrhea and body weight loss, characterized by a decrease in villus height and the villus height-to-crypt depth ratio. These histological changes peaked on day 3 and were accompanied by an increase in mRNA expression of NLRP3 and IL-1ß and protein expression of cleaved caspase-1 and mature IL-1ß. Mature IL-18 protein expression was not affected by 5-FU administration. NLRP3-/- mice exhibited less severe 5-FU-induced mucositis, and this phenotype was mimicked by genetic depletion or pharmacological inhibition of caspase-1. Small intestinal mucositis was aggravated by exogenous IL-1ß and neutralized by IL-1ß antibody treatment. Administration of exogenous IL-18 or anti-IL-18 antibody did not affect any parameters associated with mucositis. NLRP3, cleaved caspase-1, and IL-1ß were expressed by inflammatory cells (mainly macrophages) in the lamina propria and damaged epithelial cells. CONCLUSIONS: NLRP3 inflammasome activation may exacerbate 5-FU-induced small intestinal mucositis via IL-1ß maturation.

Vonoprazan shows efficacy similar to that of proton pump inhibitors with respect to symptomatic, endoscopic, and histological responses in patients with eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic allergic disease with esophageal symptoms and intraepithelial eosinophil infiltration. Effects of potassium-competitive acid blockers (P-CABs) on EoE have not been elucidated. We aimed to examine and compare the effects of P-CABs and PPIs on symptomatic, endoscopic, and histological responses of patients with EoE. METHODS: We analyzed 118 EoE patients who received PPI or P-CAB therapy with rabeprazole 10 mg (RPZ10, N = 22), rabeprazole 20 mg (RPZ20, N = 34), esomeprazole 20 mg (EPZ20, N = 25), or vonoprazan 20 mg (VPZ20, N = 33). We evaluated symptomatic responses by classifying the patients into three groups: complete relief, partial relief, and no change. Endoscopic responses were evaluated using the endoscopic reference score (EREFS) following PPI or P-CAB therapy. Histological responses were evaluated by determining eosinophil counts in esophageal biopsy samples and classifying the patients into two groups: complete remission [0/1 eosinophil/high-power field (eos/HPF)] and remission (< 15 eos/HPF). RESULTS: There were no differences among the therapy groups in terms of clinical characteristics, endoscopic findings, and histological findings of the patients before treatment. The rate of complete relief in clinical symptoms was 54.5% in the RPZ10 group, 64.7% in the RPZ20 group, 72.0% in the EPZ20 group, and 75.7% in the VPZ20 group. There were no significant differences in the therapeutic effect among the therapy groups. Similarly, endoscopic and histological complete remission rates were not significantly different among the therapy groups. CONCLUSIONS: Vonoprazan showed similar efficacy to PPIs in EoE.

Safety of Endoscopic Mucosal Resection Using a Bipolar Snare for Superficial Nonampullary Duodenal Epithelial Tumors and the Predictive Factors of Piecemeal Resection.

INTRODUCTION: Endoscopic mucosal resection for small superficial nonampullary duodenal epithelial tumors is a noninvasive treatment; however, perforations can occur. Bipolar snares can reduce the risk of perforation due to small tissue damage. Currently, only few studies have reported endoscopic mucosal resection for small superficial nonampullary duodenal epithelial tumors using a bipolar snare and the effect of preoperative findings. OBJECTIVE: To investigate (1) resectability and adverse events of endoscopic mucosal resection using a bipolar snare for small superficial nonampullary duodenal epithelial tumors and (2) the predictions of piecemeal resection. METHODS: Between 2007 and 2017, 89 patients with 107 lesions underwent endoscopic mucosal resection using a bipolar snare. Among them, 88 lesions of 77 patients were evaluated. The primary outcome was the incidence of en bloc resection and R0 resection and adverse events. Risk factors associated with piecemeal resection, including preoperative lesion findings, were also examined. RESULTS: The incidence rates of en bloc and R0 resections were 85.2 and 48.9%, respectively. Neither intraoperative or delayed perforations nor procedure-related mortality was noted. The nonlifting sign after submucosal injection was associated with an increase in piecemeal resection (odds ratio: 20.3, 95% confidence interval: 2.53-162; p = 0.005). CONCLUSION: Endoscopic resection for small superficial nonampullary duodenal epithelial tumors can cause perforation; however, endoscopic mucosal resection using a bipolar snare can be a safe treatment option as it does not cause perforations. The nonlifting sign after submucosal injection is a predictive factor for piecemeal resection.

Predictive factors for difficult endoscopic submucosal dissection for esophageal neoplasia including failure of en bloc resection or perforation.

BACKGROUND: Endoscopic submucosal dissection (ESD) is accepted as the standard treatment for early-stage esophageal neoplasia. However, esophageal perforation may occur, leading to mediastinitis and pneumothorax, which occasionally require emergency surgery. Moreover, failure of en bloc resection causes local recurrence. However, studies on the predictors of such difficulties during ESD are limited. Hence, we evaluated the predictors associated with the difficulty of ESD for esophageal neoplasia including failure of en bloc resection or perforation. METHODS: Data of 549 consecutive patients who were treated with ESD between May 2004 and March 2016 at a single institution were retrospectively studied. Exclusion criteria were the presence of metachronous esophageal neoplasia or missing data. The primary outcome was determining the predictors associated with the difficulty of ESD for esophageal neoplasia including failure of en bloc resection or perforation. RESULTS: Altogether, 543 patients with 736 lesions were evaluated. Failure of en bloc resection occurred in 6 patients (1.1%) with 6 lesions, and perforation occurred in 11 patients (2.0%) with 11 lesions (1.5%). Multivariate logistic regression analysis showed that large lesion diameter (odds ratio [OR] 1.49; 95% confidence interval [CI] 1.21-1.84; p < 0.001) and previous chemoradiotherapy (OR 5.24; 95% CI 1.52-18.06; p = 0.009) were independent predictive factors. CONCLUSIONS: Larger lesions and previous chemoradiotherapy for esophageal cancer increased the risk for failure of en bloc resection or perforation in patients who underwent esophageal ESD.

Long-term persistence of gastric dysbiosis after eradication of Helicobacter pylori in patients who underwent endoscopic submucosal dissection for early gastric cancer.

BACKGROUND: Gastric microbiome, other than Helicobacter pylori, plays a role in the tumorigenesis of gastric cancer (GC). Patients who undergo endoscopic submucosal dissection for early GC have a high risk of developing metachronous GC even after successful eradication of H. pylori. Thus, we investigated the microbial profiles and associated changes in such patients after the eradication of H. pylori. METHODS: A total of 19 H. pylori-infected patients with early GC who were or to be treated by endoscopic resection, with paired biopsy samples at pre- and post-eradication therapy, were retrospectively enrolled. Ten H. pylori-negative patients were enrolled as controls. Biopsy samples were analyzed using 16S rRNA sequencing. RESULTS: H. pylori-positive patients exhibited low richness and evenness of bacteria with the deletion of several genera, including Blautia, Ralstonia, Faecalibacterium, Methylobacterium, and Megamonas. H. pylori eradication partially restored microbial diversity, as assessed during a median follow-up at 13 months after eradication therapy. However, post-eradication patients had less diversity than that in the controls and possessed a lower abundance of the five genera mentioned above. The eradication of H. pylori also altered the bacterial composition, but not to the same extent as that in controls. The microbial communities could be clustered into three separate groups: H. pylori-negative, pre-eradication, and post-eradication. CONCLUSION: Changes in dysbiosis may persist long after the eradication of H. pylori in patients with a history of GC. Dysbiosis may be involved in the development of both primary and metachronous GC after the eradication of H. pylori in such patients.

Endoscopic findings of gastric lesions in patients with eosinophilic gastrointestinal disorders.

Background and study aims Eosinophilic gastrointestinal disorders are classified into eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, and eosinophilic colitis according to the site of eosinophilic infiltration. Although well established in eosinophilic esophagitis, endoscopic findings in eosinophilic gastritis and eosinophilic gastroenteritis with regard to gastric lesions have not been clearly described. The aim of this study was to identify endoscopic findings of gastric lesions associated with eosinophilic gastrointestinal disorders. Patients and methods Out of 278 patients with eosinophilic gastrointestinal disorders, 18 had eosinophilic gastritis or eosinophilic gastroenteritis confirmed by biopsy; their endoscopic images were analyzed retrospectively. The association between endoscopic findings and number of eosinophils in the gastric mucosa was investigated. Results Erythema was most frequently observed (72 %), followed by ulcers (39 %), discoloration (33 %), erosions (28 %), nodularity (28 %), and polyps (28 %). There were several unique endoscopic findings such as submucosal tumor-like deep large ulcers in three patients, antral Penthorum -like appearances (small nodules radially lined toward the pyloric ring) in three patients, "muskmelon-like appearances" (discolored mucosa-composed mesh pattern) in three patients, multiple white granular elevations in two patients, cracks (appearance of furrows similar to those in eosinophilic esophagitis) in five patients, and antral rings in one patient. No significant association was observed between endoscopic findings and number of gastric eosinophils. Conclusions Several unique endoscopic findings of gastric lesions were observed in patients with eosinophilic gastritis or eosinophilic gastroenteritis. Submucosal tumor-like ulcers, antral Penthorum -like appearances, muskmelon-like appearances, and cracks might be associated with eosinophilic gastrointestinal disorders.

Repeated Endoscopic Submucosal Dissection for Esophageal Neoplasia Located Close to a Previous Endoscopic Submucosal Dissection Scar.

INTRODUCTION: Endoscopic submucosal dissection (ESD) could become a standard treatment for early stage esophageal neoplasia. Recurrence sometimes develops close to a previous ESD scar. These lesions are predictably difficult to treat with ESD because of severe fibrosis. We evaluated the clinical outcomes of ESD for esophageal neoplasia located close to a previous ESD scar. METHODS: This was a retrospective observational study in a single institution. A total of 549 consecutive patients with 927 esophageal lesions were treated with ESD. The primary outcomes were resectability and adverse events of esophageal neoplasia located close to previous ESD scars (ESD scar group) than in primary esophageal ESD (primary group). Furthermore, predictive factors of perforation were examined. RESULTS: A total of 545 primary and 29 ESD scars in consecutive patients were evaluated. En bloc and complete (R0) resection rates in the ESD scar group were lower than those in the primary group (79.3% vs 98.3%, P < 0.01 and 75.9% vs 93.4%, P < 0.01). Perforations occurred more frequently in the ESD scar group (10.3% vs 2.0%, P = 0.03). The ESD scar group was a predictive factor for perforation (odds ratio = 10.37, 95% confidence interval: 2.15-49.94, P = 0.004). There were similar results for inverse probability of treatment weighting methods (odds ratio = 6.78, 95% confidence interval: 1.40-32.98, P = 0.018). DISCUSSION: ESD for esophageal neoplasia located close to a previous ESD scar was difficult to completely resect and increased the likelihood of perforation but could be a treatment option.

The usefulness of serial pancreatic juice aspiration cytological examination for pancreatic cancer not diagnosed by EUS-FNAB.

Endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) is safe and useful for the diagnosis of pancreatic cancer. However, sometimes a diagnosis cannot be established by EUS-FNAB. The efficacy of serial pancreatic juice aspiration cytological examination (SPACE) for pancreatic cancer was reported. SPACE may be useful in cases in which diagnosis by EUS-FNAB is difficult; however, this has not been reported previously. We herein report two cases of pancreatic cancer diagnosed by SPACE when diagnosis by EUS-FNAB was difficult. Case 1 was a 77-year-old female. She was suspected of pancreatic cancer because of new-onset diabetes. We performed EUS-FNAB to the lesion in the pancreatic body; however, diagnosis failed. We performed SPACE and diagnosed pancreatic cancer finally. Case 2 was 72 years old female. She was suspected of having pancreatic cancer because of the dilatation of the pancreatic duct. We performed EUS-FNAB twice to the lesion in the pancreatic head, however, diagnosis failed. Therefore, we performed SPACE and got final diagnosis as pancreatic cancer. From our experience, we suggest that SPACE is a useful diagnostic method for patients with pancreatic cancer that are difficult to diagnose.

Endoscopic closure of refractory esophageal fistula after esophagectomy using polyglycolic acid sheets: a pilot study.

Background and study aims Esophageal fistulas after esophagectomy are associated with high mortality and poor quality of life. They are sometimes intractable to conservative management and surgery that increases mortality. Few studies have assessed use of polyglycolic acid (PGA) sheets with fibrin glue for esophageal fistulas. We investigated the safety of using PGA sheets with fibrin glue for esophageal fistulas after esophagectomy. Patients and methods This was a single-center prospective pilot study. Patients who had refractory esophageal fistulas after esophagectomy were included. PGA sheets were filled in the fistula using biopsy forceps. Fibrin glue was applied to the PGA sheets. We repeated the procedure 1 week later. The outcome measures were the incidence of adverse events (AEs) and closure of the fistula. Results Five patients were assessed. No adverse events were observed. The esophageal fistula was closed with the application of PGA sheets four times in 40 % (2/5) of the cases. Conclusions PGA sheets with fibrin glue were safe for esophageal fistula closure after esophagectomy and do not involve the risk of AEs.

Slco2a1 deficiency exacerbates experimental colitis via inflammasome activation in macrophages: a possible mechanism of chronic enteropathy associated with SLCO2A1 gene.

Loss-of-function mutations in the solute carrier organic anion transporter family, member 2a1 gene (SLCO2A1), which encodes a prostaglandin (PG) transporter, have been identified as causes of chronic nonspecific multiple ulcers in the small intestine; however, the underlying mechanisms have not been revealed. We, therefore, evaluated the effects of systemic knockout of Slco2a1 (Slco2a1-/-) and conditional knockout in intestinal epithelial cells (Slco2a1ΔIEC) and macrophages (Slco2a1ΔMP) in mice with dextran sodium sulphate (DSS)-induced acute colitis. Slco2a-/- mice were more susceptible to DSS-induced colitis than wild-type (WT) mice, but did not spontaneously develop enteritis or colitis. The nucleotide-binding domain, leucine-rich repeats containing family, pyrin domain-containing-3 (NLRP3) inflammasome was more strongly upregulated in colon tissues of Slco2a-/- mice administered DSS and in macrophages isolated from Slco2a1-/- mice than in the WT counterparts. Slco2a1ΔMP, but not Slco2a1ΔIEC mice, were more susceptible to DSS-induced colitis than WT mice, partly phenocopying Slco2a-/- mice. Concentrations of PGE2 in colon tissues and macrophages from Slco2a1-/- mice were significantly higher than those of WT mice. Blockade of inflammasome activation suppressed the exacerbation of colitis. These results indicated that Slco2a1-deficiency increases the PGE2 concentration, resulting in NLRP3 inflammasome activation in macrophages, thus exacerbating intestinal inflammation.

Exosomal hsa-miR-933 in Gastric Juice as a Potential Biomarker for Functional Dyspepsia.

BACKGROUND: MicroRNAs (miRNAs) in exosomes represent disease-specific profiles and are applied as biomarkers in oncology. However, in functional dyspepsia (FD), the role of exosomal miRNAs has not been fully elucidated. AIMS: To investigate exosomal miRNAs as potential biomarkers of FD using liquid biopsy. METHODS: This retrospective cohort study included 11 subjects with FD and 11 age- and sex-matched healthy controls (HCs). We collected gastric juice and isolated exosomal miRNAs. In a discovery cohort, expression levels of 2565 miRNAs were evaluated by 3D-Gene® microarray. miRNA expression profiles from exosomes of subjects with FD and HCs were compared by two normalization methods: (1) global normalization and (2) normalization by internal control. Subsequently, in a validation cohort, the expression levels of miRNAs were validated by quantitative reverse transcription PCR (RT-qPCR). RESULTS: Through microarray analysis using the two methods, we identified 39 miRNAs that were consistently and significantly downregulated in FD cases compared with those in HCs. Of these, 12 miRNAs (hsa-miR-933, hsa-miR-345-5p, hsa-miR-708-5p, hsa-miR-203a-3p, hsa-miR-619-5p, hsa-miR-4294, hsa-miR-4481, hsa-miR-196a-5p, hsa-miR-3918, hsa-miR-372-3p, hsa-miR-658, and hsa-miR-3654) were further validated by RT-qPCR. Our results indicated that hsa-miR-933 was significantly downregulated in FD compared with HCs (0.317 ± 0.205-fold, P = 0.0317). Furthermore, the expression level of hsa-miR-933 was negatively associated with dyspepsia score and the frequency of epigastric pain and/or burning (P < 0.01, r = - 0.835; P = 0.0280, r = - 0.688, respectively). CONCLUSIONS: Exosomal hsa-miR-933 in gastric juice could be a candidate biomarker for FD.

Effect of EP1 Receptor Antagonist on Transient Lower Esophageal Sphincter Relaxations in Humans.

BACKGROUND/AIMS: Transient lower esophageal sphincter relaxations (TLESRs) are the major cause of gastroesophageal reflux. Recently, an EP1 receptor antagonist, ONO-8539, showed the reduction of TLESRs in monkeys. However, its effect on TLESRs in humans remains unclear. This study investigated the effect of ONO-8539 on postprandial TLESRs in healthy male subjects. METHODS: Twenty-seven subjects participated in this placebo-controlled, cross-over study. The subjects received either placebo or ONO-8539 (450 mg) after a standardized breakfast. A 30-min basal recording was performed 4 h after drug administration. Subsequently, TLESR recordings were performed after a high-fat test meal for 3 h. The examination was repeated at least 7 days from the first evaluation for washout. RESULTS: Thirteen patients were ultimately analyzed. The basal lower esophageal sphincter pressure was not different between the 2 groups (16.3 and 18.0 mm Hg for placebo and ONO-8539, respectively; p = 0.88). ONO-8539 significantly reduced the number of TLESRs from 15.0 to 12.0 for 3 h (p < 0.05). The proportion of terminating events of TLESRs was significantly different between the 2 groups (p < 0.05). No events and swallowing terminated more TLESRs with ONO-8539 than with placebo. CONCLUSIONS: ONO-8539 suppressed TLESRs mildly. EP1 receptor may be involved with the mechanism of human TLESRs.

Positive correlation between pancreatic volume and post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND AND AIM: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains the most common and serious adverse event associated with ERCP. Risk factors for PEP have been described in various reports. However, risk factors have not been quantified to date. The aim of this study was to investigate the risk factors for PEP by quantification of pancreatic volume using pre-ERCP images. METHODS: Overall, 800 patients were recruited from April 2012 to February 2015 for this study. There were 168 patients who satisfied the inclusion criteria. Measurement of pancreatic volume was achieved using the volume analyzer SYNAPSE VINCENT in all cases and was used to evaluate the risk factors for PEP. RESULTS: According to the criteria established by the consensus guidelines (Cotton classification), 17 patients (10.1%) were classified as having mild disease, 4 (2.4%) as having moderate disease, and 5 (3.0%) as having severe disease. Multivariate model analysis showed that a large pancreatic volume was a significant risk factor for PEP (odds ratio [OR] 1.10, 95% confidence interval [CI] 1.06-1.13; P < 0.001). In addition, the association between the pancreatic volume and the severity of PEP was positively correlated (the effect of volume [per 1 mL]; OR 1.09, 95% CI 1.07-1.12; P < 0.001, the effect of volume [per 10 mL]; OR 2.27, 95% CI 1.72-3.00; P < 0.001). A larger pancreatic volume was significantly associated with a higher incidence of PEP. CONCLUSIONS: A large pancreatic volume was identified as a risk factor for PEP. The results of this study suggest that pre-ERCP images might be useful for predicting PEP.

Obesity and hiatal hernia may be non-allergic risk factors for esophageal eosinophilia in Japanese adults.

BACKGROUND: Esophageal eosinophilia (EE) is a basal condition of eosinophilic esophageal disorders including eosinophilic esophagitis (EoE) and asymptomatic EE. EoE is considered as an allergic disorder, while it is unclear whether other non-allergic conditions are involved in the pathophysiology of EE. The aim of this study is to investigate the non-allergic risk factors for EE. METHODS: This cross-sectional study included subjects who underwent esophagogastroduodenoscopy on a medical health check-up. We compared clinical characteristics between subjects with EE (n = 27) and those without EE (n = 5937). RESULTS: The detection rate of EE was 0.45% (27/5964 persons). Of 27 subjects with EE, 20 subjects were symptomatic and 7 were asymptomatic. On univariate analysis, subjects with EE significantly had higher body mass index (BMI) compared to those without EE; 23.4 (4.4) vs 22.3 (4.5) kg/m2, median (interquartile range), p = 0.005. Endoscopic findings revealed that subjects with EE had significantly higher proportion of hiatal hernia (29.6% vs 14.7%; p = 0.049). Subjects with EE were significantly younger and had higher proportion of bronchial asthma; 45 (11.5) vs 51 (18) years, p = 0.013; 25.9% vs 5.2%, p < 0.001, respectively. Multivariate analysis showed that subjects with EE were positively associated with BMI [odds ratio (OR) 1.11; 95% confidence interval (CI) 1.03-1.20; p = 0.010) and hiatal hernia (OR 2.63; 95% CI 1.12-6.18; p = 0.026) compared to those without EE. On trend test, advanced BMI classification had significant trend for increased prevalence of EE (p = 0.002). CONCLUSIONS: Obesity and hiatal hernia may be non-allergic risk factors for EE in Japanese adults.