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Background Spermidine suppress oxidative stress and is involved in various disease pathogenesis including ulcerative colitis (UC). Arginase 2 (ARG2) plays a central role in the synthesis of spermidine. This study aimed to clarify the effect of endogenously produced spermidine on colitis. Methods The physiological role of ARG2 and spermidine was investigated using Arg2 -deficient mice with reduced spermidine. Immunohistochemical staining of the rectum was used to analyze ARG2 expression and spermidine levels in healthy controls and UC patients. Results In mice with dextran sulfate sodium-induced colitis, ARG2 and spermidine levels were increased in the rectal epithelium. Spermidine protects colonic epithelial cells from oxidative stress and Arg2 knockdown cells reduced antioxidant activity. Organoids cultured from the small intestine and colon of Arg2 -deficient mice both were more susceptible to oxidative stress. Colitis was exacerbated in Arg2 -deficient mice compared to wild-type mice. Supplementation with spermidine result in comparable severity of colitis in both wild-type and Arg2 -deficient mice. In the active phase of UC, rectal ARG2 expression and spermidine accumulation were increased compared to remission. ARG2 and spermidine levels were similar in healthy controls and UC remission patients. Conclusions ARG2 produces spermidine endogenously in the intestinal epithelium and has a palliative effect on ulcerative colitis. ARG2 and spermidine are potential novel therapeutic targets for UC.

Background The intestinal microbiome is involved in the pathogenesis of chronic kidney disease (CKD). Despite its importance, the microbiome of the small intestinal mucosa has been little studied due to sampling difficulties, and previous studies have mainly focused on fecal sources for microbiome studies. We aimed to characterize the small intestinal microbiome of CKD patients by studying the microbiome collected from duodenal and fecal samples of CKD patients and healthy controls. Methods Overall, 28 stage 5 CKD patients and 21 healthy participants were enrolled. Mucosal samples were collected from the deep duodenum during esophagogastroduodenoscopy and fecal samples were also collected. The 16S ribosomal RNA gene sequencing using Qiime2 was used to investigate and compare the microbial structure and metagenomic function of the duodenal and fecal microbiomes. Results The duodenal flora of CKD patients had decreased alpha diversity compared with the control group. On the basis of taxonomic composition, Veillonella and Prevotella were significantly reduced in the duodenal flora of CKD patients. The tyrosine and tryptophan metabolic pathways were enhanced in the urea toxin-related metabolic pathways based on the Kyoto Encyclopedia of Genes and Genomes database. Conclusion The small intestinal microbiome in CKD patients is significantly altered, indicating that increased intestinal permeability and production of uremic toxin may occur in the upper small intestine of CKD patients.

We herein describe a 49‐year‐old man with severe heart failure due to fulminant myocarditis who underwent left ventricular assist device implantation and received clopidogrel and warfarin as antithrombotic agents. The patient developed anemia secondary to chronic bleeding gastric hyperplastic polyps, necessitating endoscopic mucosal resection. Despite attempts to manage post‐endoscopic mucosal resection bleeding from a gastric ulcer by endoscopic hemostasis using hemostatic forceps, local hemostatic agents, and polyglycolic acid sheets, the bleeding persisted. Hemostasis of the refractory bleeding was finally achieved by endoscopic hand‐suturing of the ulcer. One month later, the ulcer was almost completely scarred. This case has important clinical value in that it demonstrates the efficacy of endoscopic hand‐suturing even in challenging cases such as refractory bleeding gastric ulcers in patients with left ventricular assist devices.

Background There are several options for the treatment of gastrointestinal stricture, including endoscopic stent placement and bypass surgery. However, a benign stricture is difficult to manage in a reconstructed gastric tube in the thoracic cavity owing to the technical difficulty of bypass surgery, and the possibility of stent migration. Case presentation A 78-year-old woman was admitted to our hospital for treatment for her inability to eat. She had undergone video-assisted subtotal esophagectomy with retromediastinal gastric tube reconstruction 7 years earlier. At the current admission, there was a severely dilated gastric tube in the thoracic cavity with a soft stricture immediately anterior to the spine. Conservative therapy was ineffective; therefore, endoscopic stenting was performed. However, the stent migrated to the upper side of the stricture because the stricture was mild, and the stent was not fixed in the gastric tube. Next, endoscopic stent placement followed by laparoscopic stent fixation was performed. The stent was patent and worked well, and the patient’s body weight increased. However, the stent collapsed 2 years later, with recurrence of symptoms. Stent-in-stent placement with an over-the-scope clip was performed, and the second stent was also patent and worked well. Conclusions Laparoscopic stent fixation with endoscopic stent placement could be an effective option for patients with a benign stricture in the reconstructed gastric tube.

Introduction: An association has been found between human-gut microbiota and various diseases (e.g., metabolic disease) by analyzing fecal or colonic microbiota. Despite the importance of the small intestinal microbiota, sampling difficulties prevent its full analysis. We investigated the composition and metagenomic functions of microbiota along the small intestine and compared them with the microbiota from feces and from other gastrointestinal (GI) sites. Methods: Mucosal samples from the six GI sites (stomach, duodenum, distal jejunum, proximal ileum, terminal ileum, and rectum) were collected under balloon-assisted enteroscopy. Fecal samples were collected from all participants. The microbial structures and metagenomic functions of the small intestinal mucosal microbiota were compared with those from feces and other GI sites using 16S ribosomal RNA gene sequencing. Results: We analyzed 133 samples from 29 participants. Microbial beta diversity analysis showed that the jejunum and ileum differed significantly from the lower GI tract and the feces (p < 0.001). Jejunal and duodenal microbiotas formed similar clusters. Wide clusters spanning the upper and lower GI tracts were observed with the ileal microbiota, which differed significantly from the jejunal microbiota (p < 0.001). Veillonella and Streptococcus were abundant in the jejunum but less so in the lower GI tract and feces. The metagenomic functions associated with nutrient metabolism differed significantly between the small intestine and the feces. Conclusions: The fact that the compositional structures of small intestinal microbiota differed from those of fecal and other GI microbiotas reveals that analyzing the small intestinal microbiota is necessary for association studies on metabolic diseases and gut microbiota.

Background/Aims:Helicobacter pylori infection and the use of nonsteroidal anti-inflammatory drugs (NSAIDs) are the main causes of peptic ulcers. The purpose of the present study was to elucidate the time trends of the impact of H. pylori infection and use of NSAIDs and/or antithrombotic agents on peptic ulcer bleeding (PUB) in Japanese patients. Methods: We retrospectively reviewed 719 patients who had received endoscopic hemostasis for PUB between 2002 and 2013. Subjects were divided into either the first-half group (2002-2007, n = 363) or the second-half group (2008-2013, n = 356). The clinical characteristics of the patients, including the prevalence of H. pylori infection and use of NSAIDs and antithrombotic agents, were compared between the two groups. Results: Compared to the first-half group, patients in the second-half group were characterized by older age (proportion of the patients above 60 years old, 63.9 vs. 76.7%, p = 0.0002), less frequent H. pylori infection (71.6 vs. 57.9%, p < 0.001) and more frequent NSAID intake (39.9 vs. 48.6%, p = 0.02). No significant difference was observed regarding the use of antithrombotic agents between the two groups (18.6 vs. 23.3%, p = 0.13). The prevalence of H. pylori infection and proportion of patients above 60 years old were significantly different between the two groups in a multivariate analysis. Conclusion: The main cause of PUB has clearly shifted from H. pylori infection to the use of NSAIDs over the last decade.

Abstract BACKGROUND AND AIM Serum Leucine-rich alpha-2 glycoprotein (LRG) was identified as a novel biomarker for rheumatoid arthritis and IBD by using a proteomics approach. Several studies have suggested that serum LRG levels and fecal calprotectin (fCal) were correlated with clinical activities in patients with ulcerative colitis (UC). We compared utility of these biomarkers for monitoring disease activity in UC. METHODS A single-center observational study was conducted at Kyushu University Hospital. A total of 101 patients who underwent colonoscopy during the period from February to December 2021 were enrolled. The associations between endoscopic and histological activity and biomarkers were investigated. Endoscopic activity was defined as Mayo endoscopic score (MES) of 1 or less for mucosal healing and 0 for complete mucosal healing. For histological activity (n=90), Geboes score of 2 or less was defined as histological remission. RESULTS Subjects ranged in age from 16 to 80 years (35 males and 66 females). There were 63 cases of total colitistype, 32 cases of left-sided colitis type, and 6 cases of proctitis type. The MES at enrollment were as follows: MES 0 in 41 cases, MES 1 in 33 cases, MES 2 in 19 cases, and MES 3 in 8 cases. In comparison between the mucosal healing and non-mucosal healing groups, LRG was significantly lower in the mucosal healing group (p<0.0001). The correlation coefficient of LRG with MES was r=0.614 (p<0.0001), which was higher than that of fCal, r=0.414 (p<0.0001). In ROC analysis with mucosal healing as the outcome, the AUC and cut-off value of LRG were 0.781 and 17.9 μg/ml, respectively, and for fCal were 0.850 and 396 μg/g, respectively. In the ROC analysis with complete mucosal healing as the outcome, the AUC for LRG was 0.690, which was lower than the AUC of 0.846 for fCal . When compared by histological remission, LRG was lower in the histological remission group (p<0.001). In the ROC analysis with histological remission as the outcome, the AUC for LRG was 0.722 (cutoff value 14.2 μg/ml) and for fCal was 0.837 (cutoff value 119 μg/g). CONCLUSION Both LRG and fCal are valuable biomarkers reflecting disease activity in UC.

Abstract BACKGROUND Indigo naturalis (IN) is one of the herbal medicines in Chinese medicine. Recent reports have demonstrated a strong remission induction efficacy of oral IN in induction therapy for ulcerative colitis (UC), but the efficacy of IN in maintenance therapy for UC is unknown. OBJECTIVES We aimed to clarify the maintenance effect of IN. METHODS A single-center, open-label, randomized, controlled trial was conducted from August 2017 to August 2020. Patients with UC who received induction therapy with IN and maintenance therapy with IN for at least 1 year were enrolled. Patients with endoscopically confirmed mucosal healing (Mayo endoscopic subscore 0 or 1) were randomized. Patients were randomized to continue or discontinue IN. The primary endpoint was the remission rate at 52 weeks after discontinuation. Patients who relapsed during the observation period were given additional therapy, and remission rates were examined for patients who received an increased dose of IN or resumed oral therapy. The study was registered in the University Hospital Medical Information Network Center Trials registry, UMIN000028574. RESULTS A total of 20 patients participated in this study, 10 in the IN-continued group and 10 in the IN-discontinued group. The median age was 32.5 years and 33.5 years in the IN-continued group and IN-discontinued group, respectively, and 6 and 5 patients were male. Two patients in the IN-continued group and three patients in the IN-discontinued group were treated with azathioprine. One patient in the IN-continued group and three patients in the IN-discontinued group were treated with anti-tumor necrosis factor therapy. The remission rates at 52 weeks were 90% (9/10) of patients in the IN-continued group and 20% (2/10) in the IN-discontinued group. The remission rate was significantly higher in the IN-continued group (p = 0.0055). Of the 9 patients who relapsed, 7 were treated with increased or resumed oral IN, and all patients were induced remission again. No serious adverse events were observed during the observation period. CONCLUSIONS IN appears to be very effective in maintaining remission; the high efficacy of reintroduction in patients who relapsed after discontinuation of IN suggests that discontinuation of IN in cases of remission may be an option.

Abstract BACKGROUND Spermidine which is a type of polyamine, shows elevated levels in patients with ulcerative colitis and is implicated in the pathogenesis of ulcerative colitis (UC). Arginase 2 (ARG2) plays a critical role in spermidine production. This study aimed to determine the role and mechanism of endogenous spermidine by using ARG2-deficient mice. METHODS The protective role of spermidine against oxidative stress was examined by intracellular reactive oxygen species levels and cell viability. The physiological role of spermidine was investigated using Arg2 knockdown cells with reduced spermidine. The importance of ARG2 in inflammation was examined in the dextran sulfate sodium-induced colitis model. Protein expression levels of ARG2 and accumulation of spermidine in patients with UC were evaluated by immunohistochemistry of the rectum. RESULTS ARG2 protein expression and the accumulation of spermidine were upregulated in the rectum of mice with dextran sulfate sodium colitis. Spermidine upregulated antioxidant genes in the cells. Arg2 knockdown cells showed reduced antioxidant activity. Dextran sulfate sodium colitis was more severe in Arg2-deficient mice, and organoids derived from Arg2-deficient mice showed diminished tolerance to oxidative stress. Furthermore, in the rectum of patients with UC, ARG2 and spermidine expression levels were higher in the active phase than in the remission phase. CONCLUSIONS Endogenous spermidine in the intestinal epithelium induced by ARG2 has a protective role in colitis. Spermidine may be a promising new therapeutic target for inflammatory bowel disease.

Small bowel capsule endoscopy (CE) produces lengthy videos that are time-consuming to review and susceptible to missed lesions. We evaluated whether an open-source, pretrained artificial intelligence (AI) model (SEE-AI) could improve diagnostic performance and interpretation efficiency compared with conventional reading. We retrospectively analyzed 249 PillCam SB3 examinations performed between 2007 and 2022 at six hospitals, using a two-reader crossover design. SEE-AI (confidence threshold 0.1) generated annotated videos with bounding boxes for eight lesion categories. The primary endpoints were sensitivity for lesion detection on a per-lesion and per-patient basis. Secondary endpoints included specificity, predictive values, overall accuracy, and reading time. A prespecified subgroup analysis evaluated cases of suspected small-bowel bleeding (SSBB), focusing on Saurin P1+P2 hemorrhagic lesions. Across 1550 adjudicated lesions, AI-assisted reading demonstrated higher sensitivity than conventional reading (per-lesion: 98.8% [1532/1550] vs. 86.4% [1339/1550]; per-patient: 99.1% [464/468] vs. 80.3% [376/468]; both < 0.0001). The mean reading time decreased from 17.9 to 13.7 min ( < 0.0001). In SSBB cases ( = 131), sensitivity for P1+P2 lesions improved on both a per-lesion basis (98.2% [439/447] vs. 82.8% [370/447]) and per-patient basis (98.6% [145/147] vs. 73.5% [108/147]), with a shorter reading time (14.1 vs. 18.0 min; all < 0.0001). In this multicenter evaluation, SEE-AI significantly improved lesion detection and reduced reading time for CE interpretation, including SSBB cases, while maintaining openness and reproducibility. AI-assisted reading may reduce clinicians' workload and support the adoption of SEE-AI as a practical tool - and a potential future standard of care - for small bowel CE. N/A.