Chronic stress is associated with gastrointestinal functional diseases. Although the pathophysiology seems to be associated with gastrointestinal motility, their mechanisms remain unclear. We investigated gastric emptying and chemical mediators under conditions of continuous stress, which were produced using 8-week-old male Wistar rats kept in a cage filled with water to 2 cm height for 5 days. We examined gastric emptying by the phenol red method and chemical mediators at 4, 8, and 24 h and 3 and 5 days after initiation of stress restraint. Plasma ACTH level was significantly higher in the stress throughout the period of measurement. Continuous stress delayed gastric emptying until 24 h: peak delay was observed at 8 h, whereas gastric emptying was accelerated on days 3 and 5. Plasma noradrenalin level was significantly elevated at every time point until 24 h. Guanethidine pretreatment eliminated the delay in gastric emptying at 8 h. Active ghrelin was significantly increased on days 3 and 5 after peak (at 24 h) plasma total and desacyl ghrelin in the stress group. Number of ghrelin-immunoreactive cells and level of preproghrelin mRNA expression in the gastric body increased in parallel with plasma active ghrelin level. Pretreatment with growth hormone secretagogue receptor antagonist at 5 days partially inhibited the stress-induced acceleration of gastric emptying. Delayed gastric emptying at acute phase of continuous stress was mediated via sympathetic pathway, while acceleration at chronic phase was mediated via increased active ghrelin release from the stomach.

Gastroesophageal reflux disease (GERD) is a common upper gastrointestinal disease. However, the role of exosomal microRNAs (miRNAs) and esophageal miRNAs in GERD has not been studied. A rat model of acid reflux esophagitis was used to establish a novel diagnosis marker for GERD and examine dynamics of miRNA expression in GERD. Rats were sacrificed 3 (acute phase), 7 (sub-acute phase) and 21 days (chronic phase) after induction of esophagitis. Exosomes were extracted from serum, and the expression patterns of serum miRNAs were analyzed. Four upregulated miRNAs (miR-29a-3p, 128-3p, 223-3p and 3473) were identified by microarray analysis. The expression levels of exosomal miR-29a-3p were significantly higher in the chronic phase of reflux esophagitis compared with controls, and increased expression of miR-29a-3p was specific to chronic reflux esophagitis. Esophageal miR-223-3p expression was higher compared with controls, and gradually decreased from acute to chronic phase in esophagitis. In conclusion, exosomal miR-29a-3p and esophageal miR-223-3p might play roles in GERD.

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.

Our previous report described the development of a self-administered questionnaire to screen patients for cervical myelopathy (SQC). For clinical application, the characteristics of the SQC should be verified.

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.

The purpose of this study was to compile the currently available evidence on the clinical characteristics of the locomotive syndrome (LS) categorised by the 25-question Geriatric Locomotive Function Scale (GLFS-25) and clarify its clinical usefulness for assessing mobility function.

Toll-like receptor 2 (TLR2) recognizes conserved molecular patterns associated with both gram-negative and gram-positive bacteria, and detects some endogenous ligands. Previous studies demonstrated that in ischemia-reperfusion (I/R) injury of the small intestine, the TLR2-dependent signaling exerted preventive effects on the damage in young mice, but did not have a significant effect in neonatal mice. We investigated the role of TLR2 in adult ischemia-reperfusion injury in the small intestine. Wild-type and TLR2 knockout mice at 16 weeks of age were subjected to intestinal I/R injury. Some wild-type mice received anti-Ly-6G antibodies to deplete circulating neutrophils. In wild-type mice, I/R induced severe small intestinal injury characterized by infiltration by inflammatory cells, disruption of the mucosal epithelium, and mucosal bleeding. Compared to wild-type mice, TLR2 knockout mice exhibited less severe mucosal injury induced by I/R, with a 35%, 33%, and 43% reduction in histological grading score and luminal concentration of hemoglobin, and the numbers of apoptotic epithelial cells, respectively. The I/R increased the activity of myeloperoxidase (MPO), a marker of neutrophil infiltration, and the levels of mRNA expression of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and cyclooxygenase-2 (COX-2) in the small intestine of the wild-type mice by 3.3-, 3.2-, and 13.0-fold, respectively. TLR2 deficiency significantly inhibited the I/R-induced increase in MPO activity and the expression of mRNAs for TNF-α and ICAM-1, but did not affect the expression of COX-2 mRNA. I/R also enhanced TLR2 mRNA expression by 2.9-fold. TLR2 proteins were found to be expressed in the epithelial cells, inflammatory cells, and endothelial cells. Neutrophil depletion prevented intestinal I/R injury in wild-type mice. These findings suggest that TLR2 may mediate I/R injury of the small intestine in adult mice via induction of inflammatory mediators such as TNF-α and ICAM-1.

Helicobacter pylori-induced immune responses are skewed toward a T helper (Th) 1 phenotype. IL-17-producing Th17 cells have recently been discovered, and we examined the role of IL-17A in H. pylori-induced gastritis. Six months after inoculation with H. pylori, the mice received an intraperitoneal injection of recombinant IL-17A, anti-IL-17A antibody or irrelevant IgG(2a) for 3days. H. pylori infection markedly increased mRNA for IL-17A. Double immunofluorescence studies showed that IL-17A proteins were expressed on CD4(+) T cells, macrophages, and dendritic cells. H. pylori infection elevated mRNAs for IL-12, IFN-gamma, and TNF-alpha with increase in myeloperoxidase activity, whereas it did not affect mRNAs for IL-4 and IL-5. Neutralization of IL-17A elevated mRNAs for IFN-gamma and TNF-alpha, and myeloperoxidase activity, whereas recombinant IL-17A had a tendency to reduce these parameters. In conclusion, IL-17A exerts anti-inflammatory effects on H. pylori-induced gastritis through suppression of Th1 differentiation.

Proton pump inhibitors (PPIs) alter the composition of the intestinal microbiome, exacerbating indomethacin (IND)-induced small intestinal damage. Vonoprazan fumarate inhibits gastric acid secretion using a different mechanism from PPIs. We investigated the effects of both drugs on the intestinal microbiome and IND-induced small intestinal damage. We sought to clarify whether PPI-induced dysbiosis and worsening of the damage were due to a specific drug class effect of PPIs. Rabeprazole administration increased operational taxonomic unit numbers in the small intestines of C57BL/6 J mice, whereas the difference was not significant in the vonoprazan-treated group but exhibited a trend. Permutational multivariate analysis of variance of the unweighted UniFrac distances showed significant differences between vehicle- and vonoprazan- or rabeprazole-treated groups. L. johnsonii was the predominant microbial species, and the population ratio decreased after vonoprazan and rabeprazole administration. The vonoprazan- and rabeprazole-treated groups showed increased IND-induced damage. This high sensitivity to IND-induced damage was evaluated by transplantation with contents from the small intestine of mice treated with either vonoprazan or rabeprazole. Supplementation of L. johnsonii orally in mice treated with rabeprazole and vonoprazan prevented the increase in IND-induced small intestinal damage. In conclusion, both rabeprazole and vonoprazan aggravated NSAID-induced small intestinal injury by reducing the population of L. johnsonii in the small intestine via suppressing gastric acid secretion.

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.

Advanced techniques have been developed to overcome difficult cannulation cases in endoscopic retrograde cholangiopancreatography (ERCP). Pancreatic duct guidewire placement method (PGW) is performed in difficult cannulation cases; it is possible that it places patients at risk of post-ERCP pancreatitis (PEP). The mechanism of PEP is still unclear, but pancreatic duct pressure and injury of pancreatic duct are known causes of PEP. Therefore, we hypothesized a relationship between pancreatic duct diameter and PEP and predicted that PGW would increase the risk of PEP in patients with non-dilated pancreatic ducts. This study aimed to investigate whether PGW increased the risk of PEP in patients with pancreatic duct diameter ≤ 3 mm.

Magnetic resonance imaging (MRI) is widely used to evaluate intervertebral disc degeneration. Recently, various evaluations of cervical disc degeneration using MRI have been conducted, but there is no gold standard. The purpose of this study was to compare the reproducibilities of previously reported classifications for evaluating cervical disc degeneration by MRI and their associations with clinical symptoms.

The effects of psychological stress on eosinophilic gastrointestinal disorders have not been elucidated. This study investigated the effects of psychological stress in a mouse model of eosinophilic enteritis (EoN). BALB/c mice were treated with ovalbumin (OVA) to create an EoN model and subjected to either water avoidance stress (WAS) or sham stress (SS). Microscopic inflammation, eosinophil and mast cell counts, mRNA expression, and protein levels of type 2 helper T cell (Th2) cytokines in the ileum were compared between groups. We evaluated ex vivo intestinal permeability using an Ussing chamber. A corticotropin-releasing hormone type 1 receptor (CRH-R1) antagonist was administered before WAS, and its effects were analyzed. WAS significantly increased diarrhea occurrence and, eosinophil and mast cell counts, and decreased the villus/crypt ratio compared to those in the SS group. The mRNA expression of CRH, interleukin IL-4, IL-5, IL-13, eotaxin-1, and mast cell tryptase β2 significantly increased, and the protein levels of IL-5, IL-13, and OVA-specific immunoglobulin E (IgE) also significantly increased in the WAS group. Moreover, WAS significantly increased the intestinal permeability. The CRH-R1 antagonist significantly inhibited all changes induced by WAS. Psychological stress exacerbated ileal inflammation via the CRH-mast cell axis in an EoN mouse model.

Accurate estimation of mortality and time to death at admission for COVID-19 patients is important and several deep learning models have been created for this task. However, there are currently no prognostic models which use end-to-end deep learning to predict time to event for admitted COVID-19 patients using chest radiographs and clinical data. We retrospectively implemented a new artificial intelligence model combining DeepSurv (a multiple-perceptron implementation of the Cox proportional hazards model) and a convolutional neural network (CNN) using 1356 COVID-19 inpatients. For comparison, we also prepared DeepSurv only with clinical data, DeepSurv only with images (CNNSurv), and Cox proportional hazards models. Clinical data and chest radiographs at admission were used to estimate patient outcome (death or discharge) and duration to the outcome. The Harrel's concordance index (c-index) of the DeepSurv with CNN model was 0.82 (0.75-0.88) and this was significantly higher than the DeepSurv only with clinical data model (c-index = 0.77 (0.69-0.84), p = 0.011), CNNSurv (c-index = 0.70 (0.63-0.79), p = 0.001), and the Cox proportional hazards model (c-index = 0.71 (0.63-0.79), p = 0.001). These results suggest that the time-to-event prognosis model became more accurate when chest radiographs and clinical data were used together.

Prostaglandin E(2) plays an important role in the maintenance of gastric mucosal integrity. The level of biologically active prostaglandin E(2) in the tissue is regulated by the balanced expression of its synthetic enzymes, such as cyclooxygenase, and its catabolic enzyme, 15-hydroxyprostaglandin dehydrogenase. We examined the effect of rebamipide, a mucoprotective drug, on prostaglandin E(2) production and metabolism in the gastric tissue and its effect on indomethacin-induced gastric mucosal injury in mice. Rebamipide suppressed indomethacin-induced gastric mucosal injury. Suppressive effect of rebamipide on indomethacin-induced gastric mucosal injury was also observed in cyclooxygenase-2-knockout mice. The mice that were treated with rebamipide showed a 2-fold increase in cyclooxygenase-2 mRNA expression in the gastric tissue, whereas 15-hydroxyprostaglandin dehydrogenase mRNA expression markedly decreased as compared to vehicle-treated control mice. Rebamipide did not affect the expression of cyclooxygenase-1 in the gastric tissue. Rebamipide did not increase prostaglandin E(2) production in the gastric tissue; however, it induced a 1.4-fold increase in the concentration of prostaglandin E(2) in the gastric tissue as compared to vehicle-treated control mice. These results suggest that the suppressive effect of rebamipide on non-steroidal anti-inflammatory drugs-induced gastric mucosal injury can be attributed to reduced 15-hydroxyprostaglandin dehydrogenase expression, which increases the prostaglandin E(2) concentration in the gastric tissue.

Gastroesophageal reflux disease (GERD) is strongly associated with sleep disturbances. Proton pump inhibitor (PPI) therapy improves subjective but not objective sleep parameters in patients with GERD. This study aimed to investigate the association between GERD and sleep, and the effect of PPI on sleep by using a rat model of chronic acid reflux esophagitis.

Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)-25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)-24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2-25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2-25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.

The inflammasome is a large, multiprotein complex that consists of a nucleotide-binding oligomerization domain-like receptor (NLR), an apoptosis-associated speck-like protein containing a caspase recruitment domain, and pro-caspase-1. Activation of the inflammasome results in cleavage of pro-caspase-1 into cleaved caspase-1, which promotes the processing of pro-interleukin (IL)-1β into mature IL-1β. We investigated the effects of colchicine on non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal injury and activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. Colchicine treatment inhibited indomethacin-induced small intestinal injury by 86% (1 mg/kg) and 94% (3 mg/kg) as indicated by the lesion index 24 h after indomethacin administration. Colchicine inhibited the protein expression of cleaved caspase-1 and mature IL-1β, without affecting the mRNA expression of NLRP3 and IL-1β. Although treatment with recombinant IL-1β (0.1 μg/kg) did not change the severity of small intestinal damage, the preventive effects of colchicine were abolished by supplementation with the same dose of recombinant IL-1β. Indomethacin-induced small intestinal damage was reduced by 77%, as determined by the lesion index in NLRP3(-/-) mice, and colchicine treatment failed to inhibit small intestinal damage in NLRP3(-/-) mice. These results demonstrate that colchicine prevents NSAID-induced small intestinal injury by inhibiting activation of the NLRP3 inflammasome.

The inflammasomes induce maturation of pro-interleukin-1β (IL-1β) and pro-IL-18. We investigated roles of the NLRP3 inflammasome in the pathogenesis of ulcerative colitis (UC). After induction of oxazolone-induced colitis, a mouse UC model, colonic tissues were assayed for inflammatory mediators. Histological studies were performed on inflamed colonic tissue from mice and UC patients. Histological severity of murine colitis peaked on day 1, accompanied by an increase in the expression of Th2 cytokines including IL-4 and IL-13. Oxazolone treatment stimulated maturation of pro-caspase-1 and pro-IL-1β, while it reduced IL-18 expression. Either exogenous IL-1β or IL-18 ameliorated the colitis with or without reduction in Th2 cytokine expression, respectively. Induction of colitis decreased MUC2 expression, which was reversed by administration of IL-18, but not IL-1β. Compared to wild-type mice, NLRP3-/- mice exhibited higher sensitivity to oxazolone treatment with enhancement of Th2 cytokine expression and reduction of mature IL-1β and IL-18 production; this phenotype was rescued by exogenous IL-1β or IL-18. Immunofluorescent studies revealed positive correlation of NLRP3 expression with disease severity in UC patients, and localization of the inflammasome-associated molecules in macrophages. The NLRP3 inflammasome-derived IL-1β and IL-18 may play a protective role against UC through different mechanisms.

To examine the association between overactive bladder (OAB) symptom severity and falls and the contribution of OAB symptoms to falls in a community-dwelling population.