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Background/aims No screening test for esophageal motility disorder (EMD) has been established, the objective of this study is to examine the potential usefulness of our newly developed "Onigiri esophagography" combined with an obstruction level (OL) classification system in screening for EMD. Methods A total of 102 patients with suspected EMDs who underwent both high-resolution manometry (HRM) and Onigiri esophagography between April 2017 and January 2019 were examined. The EMD diagnosis was performed based on the Chicago classification version 3.0 by HRM. Onigiri esophagography was performed using a liquid medium (barium sulfate) followed by a solid medium, which consisted of an Onigiri (a Japanese rice ball) with barium powder. The extent of medium obstruction was assessed by the OL classification, which was defined in a stepwise fashion from OL0 (no obstruction) to OL4 (severe obstruction). Results Thirty-two percent of the patients with OL0 (32.3%), OL1 (50.0%), OL2 (88.0%), OL3 (100.0%), and OL4 (100.0%) were diagnosed EMDs by HRM. The area under the curve, as determined by a receiver operating characteristic analysis, for the OL classification was 0.86. Using the cutoff value of OL1, the sensitivity and specificity were 87.3% and 61.3%, respectively, while using a cutoff value of OL2, the sensitivity and specificity were 73.2% and 90.3%, respectively. Conclusion In conclusion, Onigiri esophagography combined with the OL classification system can be used as a screening test for EMDs with a cutoff value of OL1.

Ulcerative colitis (UC) has been considered a Th2- and Th17-related disease. However, anti-IL-12/23 p40 antibody, which blocks Th1 and Th17 cell induction and maintenance, has shown efficacy in treating UC, suggesting that UC might not be a prototypical Th2 and Th17 cell-mediated autoimmune disease. To verify how the immune responses in UC patients interact with each other, we analyzed the cytokine expression and transcription factors involved in the Th1, Th2, and Th17 responses. The mucosal expression of 19 cytokines and transcription factors related to Th1, Th2, and Th17 cells, as well as Tregs, were measured by quantitative polymerase chain reaction using endoscopic biopsy specimens from inflamed colons of UC patients. A correlation analysis between the cytokines and transcription factors was conducted. The characteristic cytokine profile in UC patients has two immune response clusters: Th17-related responses and Th1-/Th2-related responses. IL-23 showed a weaker association with Th17 cell-related cytokines and transcription factor RORC and a much stronger correlation with T-bet and GATA3. In the high-IL-23-expression group, the rate of chronic continuous type was higher and the remission rate lower than in the low-IL-23-expression group. IL-23 may be a very important cytokine for evaluating the UC disease condition, as the expression of IL-23 is associated with certain clinical characteristics of UC patients. A unique association between IL-23 and T-bet/GATA3 might play a key role in the pathogenesis of UC.

Introduction: The newly developed vonoprazan (a potassium-competitive acid blocker) has a greater ability to suppress gastric acid production than convention proton pump inhibitors (PPIs). The objective of the present study was to determine how vonoprazan influences the pathogenesis of refractory gastroesophageal reflux disease (GERD) in clinical practice. Methods: Between March 2013 and November 2018, a total of 73 refractory GERD patients (34 in the conventional PPI group versus 39 in the vonoprazan group) were enrolled in this retrospective study. We then compared the underlying disease conditions between the 2 groups, examined by high-resolution manometry and multichannel intraluminal impedance/pH (MII-pH) monitoring. Results: There was a significant difference in the proportion of underlying disease conditions, including erosive esophagitis, non-erosive reflux disease, reflux hypersensitivity, functional heartburn and oesophageal motility disorder (EMD), between the conventional PPI (6, 14, 23, 40 and 17% respectively) and vonoprazan groups (0, 0, 10, 49, and 41% respectively; p < 0.01). No cases of acid-related GERD were observed in the vonoprazan group. When the EMD patients were excluded, the lower oesophageal acid exposure time of the vonoprazan group (0.1% [0.0–0.5%], n = 23) was significantly lower than that of the conventional PPI group (0.35% [0.1–3.9%], n = 28; p < 0.05), and the gastric pH p < 0.01). Conclusions: Vonoprazan serves as a diagnostic tool to exclude acid-related GERD.

Background and aim The prevalence of ulcerative colitis (UC) is increasing in Japan. Validated claims-based definitions are required to investigate the epidemiology of UC and its treatment and disease course in clinical practice. This study aimed to develop a claims-based algorithm for UC in Japan. Methods A committee of epidemiologists, gastroenterologists, and internal medicine physicians developed a claims-based definition for UC, based on diagnostic codes and claims for UC treatments, procedures (cytapheresis), or surgery (post-operative claims). Claims data and medical records for a random sample of 200 cases per site at two large tertiary care academic centers in Japan were used to calculate the positive predictive value (PPV) of the algorithm for three gold standards of diagnosis, defined as physician diagnosis in the medical records, adjudicated cases, or registration in the Japanese Intractable Disease Registry (IDR). Results Overall, 1139 claims-defined UC cases were identified. Among 393 randomly sampled cases (mean age 44; 48% female), 94% had received ≥1 systemic treatment (immunosuppressants, tumor necrosis factor inhibitors, corticosteroids, or antidiarrheals), 4% had cytapheresis, and 2% had post-operative claims. When physician diagnosis was used as a gold standard, PPV was 90.6% (95% confidence interval [CI]: 87.7-93.5). PPV with expert adjudication was also 90.6% (95% CI: 87.7-93.5). PPVs with enrollment in the IDR as gold standard were lower at 41.5% (95% CI: 36.6-46.3) due to incomplete case registration. Conclusions The claims-based algorithm developed for use in Japan is likely to identify UC cases with high PPV for clinical studies using administrative claims databases.

This longitudinal study was designed to elucidate whether gut microbiota is associated with relapse and treatment response in ulcerative colitis (UC) patients. Fifty-one patients with UC were enrolled between 2012 and 2017, and followed up through 2020. Colon mucosal biopsy were obtained at enrollment, and 16S ribosomal RNA sequencing was performed using extracted RNA. Of the 51 patients, 24 were in remission and 27 had active UC at enrollment. Of the 24 patients in remission, 17 maintained remission and 7 developed relapse during follow-up. The 7 patients with relapse showed lower diversity, with a lower proportion of Clostridiales (p = 0.0043), and a higher proportion of Bacteroides (p = 0.047) at enrollment than those without relapse. The 27 patients with active UC were classified into response (n = 6), refractory (n = 13), and non-response (n = 8) groups according to their treatment response in 6 months. The refractory and non-response groups showed lower diversity with a lower proportion of Prevotella (p = 0.048 and 0.043) at enrollment than the response group. This study is the first demonstration that reduced diversity and particular microbes are associated with the later clinical course of relapse events and treatment response in UC.

Biologics against tumor necrosis factor-α (TNF) and the p40 subunit of interleukin (IL)-12 and IL-23 are increasingly used in inflammatory bowel disease (IBD) treatment. However, information on response prediction to these agents is limited. Thus, we aimed to identify factors for IBD treatment response prediction. We conducted a retrospective study in 33 IBD subjects for anti-TNF and a prospective study of 23 IBD and 11 non-IBD subjects for ustekinumab (UST). Mucosal biopsy specimens were obtained before treatment with biologics. The expression of 18 immune-related genes encoding representative cytokines and transcription factors was analyzed by quantitative polymerase chain reaction. There was no difference between the treatment-resistant and -sensitive groups with regard to clinical characteristics. A higher expression of oncostatin M (OSM) and its receptor OSMR in the intestinal mucosa was most strongly associated with anti-TNF resistance, whereas lower IL23A expression was most strongly associated with UST resistance. In addition to the absolute expression levels of genes, concordant or discordant expression patterns of particular gene sets were associated with treatment sensitivity and resistance. The association of anti-TNF resistance and mucosal OSM and OSMR expression was consistent with the results of a previous study in a European cohort. Our observation that IBD subjects with higher mucosal IL23A expression were more likely to achieve remission by UST has not been previously reported. The response to biologics may thus be predicted in IBD patients through the analysis of mucosal gene expression levels and patterns.

The preparatory accommodation response of lower esophageal sphincter (LES) before swallowing is one of the mechanisms involved in LES relaxation during wet swallows, however, the physiological and/or pathological roles of LES accommodation remain to be determined in humans. To address this problem, we conducted a prospective observational study of 38 patients with normal high-resolution manometry (HRM) and 23 patients with idiopathic esophagogastric junction outflow obstruction (EGJOO) to assess dry and wet swallows. The LES accommodation measurement was proposed for practical use in evaluating the LES accommodation response. Although swallow-induced LES relaxation was observed in both dry and wet swallows, LES accommodation (6.4, 3.1–11.1 mmHg) was only observed in wet swallows. The extent of LES accommodation was impaired in idiopathic EGJOO (0.6, − 0.6–6 mmHg), and the LES accommodation measurement of patients with idiopathic EGJOO (36.8, 29.5–44.3 mmHg) was significantly higher in comparison to those with normal HRM (23.8, 18–28.6 mmHg). Successful LES relaxation in wet swallowing can be achieved by LES accommodation in combination with swallow-induced LES relaxation. Impaired LES accommodation is characteristic of idiopathic EGJOO. In addition to the IRP value, the LES accommodation measurement may be useful for evaluating the LES relaxation function in clinical practice.

Background The pathological conditions of UC and CD involved in inflammatory bowel disease-unclassified (IBD-U), UC with primary sclerosing cholangitis (PSC-UC), and UC with autoimmune pancreatitis type 2 (AIP-UC) remain unclear. Therefore, it is difficult to decide the appropriate treatments for these subtypes of UC. Our aim was to examine whether the discriminant equation using the mucosally expressed mediators designed as our previous study for IBD, could characterize IBD-U, PSC-UC, or AIP-UC. Methods A total of 56 patients including UC (n = 24), CD (n = 15), IBD-U (n = 10), PSC-UC (n = 4), and AIP-UC (n = 3), along with 9 control patients were enrolled in this study. Mucosally expressed inflammatory mediators related to Th1, Th2, Th17, and Treg were measured using quantitative PCR in endoscopic biopsies from the inflamed intestines of the patients. The IBD-U, PSC-UC or AIP-UC were characterized using discriminant analysis and principle component analysis. Results Through discriminant analyses, combinations of 3 to 7 inflammatory mediators were used to discriminate between UC and CD. Moreover, the identified 3 markers could diagnose patients with IBD-U as UC or CD with high accuracy. The distribution graph of inflammatory mediators using the principal component analysis revealed that PSC-UC and AIP-UC exhibited CD-like and UC-like features, respectively. Conclusions The discriminant equation using mucosally expressed mediators of IL-13, IL-21 and T-bet can be used as a universal diagnostic tool not only for IBD-U but also to assess pathological conditions in PSC-UC and AIP-UC.

Background/Aim: Currently, there are no established biomarkers to differentiate between glucocorticoid (GC)-resistant and GC-sensitive ulcerative colitis (UC); however, interleukin (IL)-1β could be one such candidate biomarker. The aim of this study was to investigate whether mucosally expressed IL-1β could predict the response to GC in patients with UC. Methods: A total of 27 mucosal tissue samples from 10 patients with GC-resistant UC (GC-resistant group), 9 patients with GC-sensitive UC (GC-sensitive group), and 8 control patients (control group) were analyzed by qRT-PCR for the expression of IL-1β, GC receptor α (GRα), GRβ, and other inflammatory mediators. Rachmilewitz endoscopic index (REI) between the GC-resistant and GC-sensitive groups was matched to avoid any potential influence of inflammation. Results: The REI did not significantly differ between the GC-resistant and GC-sensitive groups. Mucosally expressed IL-1β levels in the GC-resistant group were significantly higher than those in the GC-sensitive group. However, there were no significant differences in the expression levels of GRα, GRβ, and other inflammatory mediators between the 2 groups. We could distinguish between the GC-resistant and GC-sensitive groups with a sensitivity of 90.0% and specificity of 77.8% based on mucosally expressed IL-1β. Conclusions: Mucosally expressed IL-1β can be used as a predictor of GC response in patients with UC.

Background and Aim: Although basic research has shown that certain cytokines affect gastrointestinal motility, the clinical evidence is lacking. The objective of this study was to explore the association between mucosally expressed cytokines and the esophageal motility function in humans. Methods: We enrolled a total of 57 patients with suspected esophageal motility disorders (EMDs) who underwent high-resolution manometry. Results: The diagnoses of the patients were as follows: normal esophageal motility (n = 25), ineffective esophageal motility (n = 5), esophagogastric junction outflow obstruction (EGJOO; n = 10), distal esophageal spasm (n = 5), achalasia (n = 10), absent contractility (n = 1), and jackhammer esophagus (n = 1). The expression of tumor necrosis factor (TNF)-α in the esophagogastric junction (EGJ) was significantly higher in EGJOO (14.6, 14.0–15.8, n = 10) than in normal esophageal motility (13.3, 12.8–14.1, n = 25); however, there was no difference in the expression of TNF-α between achalasia (13.4, 13.0–14.1, n = 10) and normal esophageal motility (13.3, 12.8–14.1, n = 25). EGJOO was discriminated from achalasia/normal by a linear discriminant analysis (AUC = 0.917). A multivariable regression analysis revealed that interleukin (IL)-13 and IL-23A were predictive of the distal contractile integral, whereas TNF-α and IL-6 were predictive of the basal EGJ pressure. Conclusions: The esophageal motility was associated with mucosally expressed cytokines in humans; these cytokines could be useful targets for the diagnosis and treatment of EMDs.

T helper (Th) and regulatory T (Treg) cell-related cytokines are implicated in inflammatory bowel diseases, including ulcerative colitis (UC). While these cytokines are generally upregulated in inflamed mucosae, the key cytokine profile explaining disease severity has not been determined. The Rachmilewitz endoscopic index (REI) was assessed in 61 UC patients undergoing colonoscopy. Biopsies obtained from inflamed (REI 3–12) and noninflamed (REI 0–2) areas were analyzed by quantitative PCR for expression of mRNAs encoding cytokines and transcription factors related to Th1 (TNF-α, IFN-γ, IL-12p35, IL-12p40, and T-bet), Th2 (IL-4, IL-13, IL-33, and GATA3), Th17 (IL-17A, IL-17F, IL-21, IL-22, IL-23p19, IL-6, and RORC), Th9 (IL-9, IRF4, and PU.1), and Treg (TGF-β and Foxp3). Expression patterns associated with higher REI were determined by univariate and multivariate analyses. Despite general upregulation, none of these mRNAs showed univariate correlation with REI in inflamed samples. Multiple regression analysis, however, found that joint expression of IL-17A, IL-17F, IL-21, RORC, and TGF-β was significantly predictive of REI (P

Background T helper (Th)- and regulatory T (Treg) cell-related immune molecules are implicated in ulcerative colitis (UC). However, the association between their mucosal expression during remission and the subsequent clinical course of UC is unknown. Methods The expression of cytokines and transcription factors related to Th1, Th2, Th17, and Treg in endoscopic mucosal biopsy specimens from 40 UC patients in clinical remission and 9 controls was measured by quantitative polymerase chain reaction. The relationship between their expression patterns, as stratified by Mayo Endoscopic Subscore (MES), and any future relapse was evaluated by univariate and multivariate analyses. Results Six of 40 patients (baseline MES 0/1/2, 22/14/4) experienced a relapse during the study period (median, 37 months). At baseline, even in the MES0 patients, the interleukin (IL)-17A of the patients was significantly upregulated in comparison with controls (P = 0.0351). Future relapse was associated with a higher baseline expression of IL-17A, IL-17F, and IL-21 in MES0/1, and the upregulation of IL-17F and IL-21 remained statistically significant when limited to MES0 patients. Kaplan-Meier analysis revealed that as a single marker, a higher IL-21 level best grouped patients with an increased risk of relapse (P = 0.0042). Furthermore, a multivariate model that consisted of IL-21 and T-bet showed an even greater value (P = 0.0001). Conclusions The profiles of Th/Treg-related gene expression in the colonic mucosa are altered, even during clinical and endoscopic remission of UC, with a detectable Th17-predominant profile predicting future relapse. This association might represent latent immune dysregulation during disease quiescence and has the potential to be utilized to improve patient care.

Daikenchuto, a traditional Japanese herbal medicine, suppresses bacterial translocation by improvement of gastrointestinal motility and blood flow. As Daikenchuto reportedly reduces gastrointestinal inflammatory activity by these mechanisms, we analyzed whether Daikenchuto suppresses experimental colitis and reduces inflammatory cytokine expression in a mouse model.Colitis was induced by transfer of naive CD4(+) T cells of BALB/c mice into SCID mice, and mice were given either control or 2.7 % Daikenchuto-containing feed. We investigated body weight, clinical symptoms, histological changes, and Th1- and Th17-cytokine expression. Cytokine mRNA expression was analyzed using real-time RT-PCR. The ratio of IL-17(+) and IFN-γ(+) CD4(+) T cells were analyzed by flow cytometry.Daikenchuto delayed the development of colitis and significantly reduced the histological inflammation scores. Analyses of cytokine mRNA revealed that Th17 cytokines were significantly decreased in colons of mice that received Daikenchuto. Absolute numbers of IL-17(+) or IFN-γ(+) CD4(+) T cells per colon were less in mice receiving Daikenchuto than in mice that received control feed, as both groups received naive CD4(+) T cells to induce colitis.We demonstrated that feeding administration of Daikenchuto suppresses colitis induced by naive CD4(+) T cell transfer into SCID mice. Daikenchuto may show clinical benefit in the treatment of human inflammatory bowel disease and further studies are warranted.

Inflammatory bowel disease (IBD) is frequently associated with extraintestinal manifestations such as hepatopancreatobiliary manifestations (HPBMs), which include primary sclerosing cholangitis (PSC), pancreatitis, and cholelithiasis. PSC is correlated with IBD, particularly ulcerative colitis (UC); 70-80% of PSC patients in Western countries and 20-30% in Japan have comorbid UC. Therefore, patients diagnosed with PSC should be screened for UC by total colonoscopy. While symptoms of PSC-associated UC are usually milder than PSC-negative UC, these patients have a higher risk of colorectal cancer, particularly in the proximal colon. Therefore, regular colonoscopy surveillance is required regardless of UC symptoms. Administration of 5-aminosalicylic acid or ursodeoxycholic acid may prevent colorectal cancer and cholangiocarcinoma. While PSC is diagnosed by diffuse multifocal strictures on cholangiography, it must be carefully differentiated from immunoglobulin G4 (IgG4)-associated cholangitis, which shows a similar cholangiogram but requires different treatment. When PSC is suspected despite a normal cholangiogram, the patient may have small-duct PSC, which requires a liver biopsy. IBD patients have a high incidence of acute and chronic pancreatitis. Most cases are induced by cholelithiasis or medication, although some patients may have autoimmune pancreatitis (AIP), most commonly type 2 without elevation of serum IgG4. AIP should be accurately identified based on characteristic image findings, because AIP responds well to corticosteroids. Crohn's disease is frequently associated with gallstones, and several risk factors are indicated. HPBMs may influence the management of IBD, therefore, accurate diagnosis and an appropriate therapeutic strategy are important, as treatment depends upon the type of HPBM.

Ulcerative colitis (UC) is a chronic lifelong condition characterized by alternating flare-ups and remission. There is no single known unifying cause, and the pathogenesis is multifactorial, with genetics, environmental factors, microbiota, and the immune system all playing roles. Current treatment modalities for UC include 5-aminosalicylates, corticosteroids, immunosuppressants (including purine antimetabolites, cyclosporine, and tacrolimus), and surgery. Therapeutic goals for UC are evolving. Medical treatment aims to induce remission and prevent relapse of disease activity. Infliximab, an anti-tumor necrosis factor (TNF)-α monoclonal antibody, is the first biological agent for the treatment of UC. Over the last decade, infliximab and adalimumab (anti-TNF-α agents) have been used for moderate to severe UC, and have been shown to be effective in inducing and maintaining remission. Recent studies have indicated that golimumab (another anti-TNF-α agent), tofacitinib (a Janus kinase inhibitor), and vedolizumab and etrolizumab (integrin antagonists), achieved good clinical remission and response rates in UC. Recently, golimumab and vedolizumab have been approved for UC by the United States Food and Drug Administration. Vedolizumab may be used as a first-line alternative to anti-TNF-α therapy in patients with an inadequate response to corticosteroids and/or immunosuppressants. Here, we provide updated information on various biological agents in the treatment of UC.

To provide rapid immunosuppression without side effects, we analyzed whether rapamycin alone, and regulatory T cells (Tregs) expanded ex vivo by rapamycin, suppressed colitis in a mouse model.Severe combined immunodeficiency (SCID) mice reconstituted with naive CD4(+) T cells were treated with or without intraperitoneal rapamycin. Body weight was evaluated. CD4(+) T cells were cultured in the presence of rapamycin for three 7-day rounds of stimulation. The ratio of Tregs to CD4(+) T cells was analyzed by flow cytometry. Naive CD4(+) T cells were transferred into SCID mice with CD4(+) T cells expanded in the presence or absence of rapamycin. Clinical symptoms of colitis, histological changes, and cytokine expression were investigated.Systemic rapamycin partially prevented the development of colonic inflammation in a transfer model of colitis, but decreased body weight in control mice. With rapamycin, stimulated CD4(+) T cells expanded eightfold in 3 weeks in vitro, and the proportion of Tregs increased to about 40%. Without rapamycin, CD4(+) T cells expanded 20-fold in 3 weeks, but the proportion of Tregs remained at about 15%. CD4(+) T cells expanded with rapamycin prevented the development of colitis in a naïve CD4(+) T-cell transfer model, in association with the downregulation of Th1 and Th17 responses.We demonstrated, for the first time, that CD4(+) T cells expanded with rapamycin in vitro suppressed colitis. Therefore, rapamycin-expanded Treg transfer therapy is expected to be efficacious for inflammatory bowel disease.

Treatment with infliximab, a chimeric anti-tumor necrosis factor (TNF)-α antibody, is highly efficient in patients with inflammatory bowel disease (IBD). It neutralizes soluble TNF-α and induces the apoptosis of transmembrane TNF-α-positive macrophages and T cells in the gut. Recently, T helper (Th)17, as well as Th1, responses have been implicated in the pathogenesis of IBD.To clarify the effects of infliximab on Th1 and Th17 responses in vitro.Naive CD4(+) T cells isolated from the peripheral blood of healthy volunteers were stimulated under Th1- or Th17-inducing conditions in the presence of 10 μg/ml of infliximab or control immunoglobulin (Ig)G1. The concentrations of interferon (IFN)-γ, interleukin (IL)-17, and TNF-α in the culture supernatants were determined by enzyme-linked immunosorbent assay (ELISA). Th1 and Th17 cells were immunostained with infliximab or control IgG1 and transmembrane TNF-α-positive cells were analyzed by flow cytometry. Annexin V staining and terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) assays were conducted in order to analyze the percentage of apoptotic cells.Both Th1 and Th17 cells expressed soluble and transmembrane TNF-α abundantly. Although infliximab suppressed IFN-γ secretion by Th1 cells and IL-17 secretion by Th17 cells, the level of the former was more profound than the latter. Infliximab increased annexin V- and TUNEL-positive apoptotic cells under Th1-inducing conditions, but not under Th17-inducing conditions.Infliximab suppressed Th1 and Th17 differentiation in vitro; however, IFN-γ production by Th1 cells was more profoundly suppressed than IL-17 secretion by Th17 cells. Th1 responses were more susceptible to infliximab-mediated apoptosis than Th17 responses. Our results clarify a new mechanism of action of infliximab.

Background: Mainstream therapy for early gastric cancer in Japan has now shifted from endoscopic mucosal resection (EMR) to endoscopic submucosal dissection (ESD). Although bacteremia is reported as being infrequent and transient in gastric EMR, there are no reports of it being investigated in gastric ESD. This study aimed to determine the frequency of bacteremia in gastric ESD. Patients and Methods: A prospective study, in 46 consecutive patients who underwent gastric ESD, investigated the frequency of bacteremia before and after the procedure. Results: The median time for the total ESD procedure was 105 min (range 30–400). The median volume of the submucosal injection was 80 ml (range 20–260). The mean size of the resected specimen was 40 ± 9.7 mm. Blood cultures obtained before ESD were positive in 4.4% (2/45) of cases. Bacillus subtilis and Bacillus spp. were the isolated microorganisms. Blood cultures obtained 10 min after ESD were positive in 4.3% (2/46) of cases; with the same microorganisms being isolated. Blood cultures obtained 3 h after ESD were all negative. No signs of sepsis were seen in the two patients with a positive blood culture 10 min after ESD. Conclusions: The frequency of bacteremia after gastric ESD was low and transient. ESD for gastric lesions is thought to have a low risk of infectious complications; therefore, prophylactic administration of antibiotics may not be warranted.

Impairment of gastric emptying is well recognized in patients with diabetes mellitus (DM), especially long-standing insulin-dependent diabetes mellitus (IDDM). The aim of this study was to evaluate the cause of delayed gastric emptying in DM patients. In 16 controls, 16 non-insulin-dependent diabetes mellitus (NIDDM) patients and 23 IDDM patients, gastric emptying was studied using the 13C octanoic acid breath test. Breath samples were taken before a test meal labeled with 100 mg of 13C octanoic acid, and at 15-min intervals over a 300-min period postprandially. In all DM patients, the gastric emptying coefficient was lower than that in the controls (P < 0.05), and lag time and half-emptying time were significantly longer (P < 0.05). Both NIDDM and IDDM patients showed delayed 13CO2 excretion compared with the controls, but IDDM patients showed more delayed gastric emptying than NIDDM patients (P < 0.05). There were no significant differences in sex, HbA1c level, or the rate of neuropathy between the two groups. IDDM patients showed delayed gastric emptying compared with NIDDM patients, and the 13C octanoic acid breath test is useful for evaluating DM patients with delayed gastric emptying.

Tocilizumab is a monoclonal antibody against human interleukin-6 receptor which blocks the binding of interleukin-6 to its receptor. Tocilizumab is effective for the treatment of inflammatory disorders including rheumatoid arthritis. We report a case of multiple ulcers in the small and large intestines, which occurred during tocilizumab therapy. A 57-year-old woman started to use tocilizumab for rheumatoid arthritis. Three months later, she complained of hematochezia. Double-balloon endoscopy revealed multiple small aphthoid ulcers in the small and large intestines. One month after the woman had recovered, she was given tocilizumab again. The woman had hematochezia and abdominal pain again 2 weeks later. Colonoscopy revealed multiple round, discrete punched-out ulcers in the terminal ileum, and vast deep ulcers from the cecum to the descending colon. Bioptic histopathology and cultivation showed non-specific findings. Six weeks after discontinuation of tocilizumab, ulcers in the small and large intestine dramatically improved, leaving ulcer scars. This disease course and the results of examination made us strongly suspect that tocilizumab induced multiple ulcers in the small and large intestines. Interleukin-6 is a pleiotropic cytokine and involved in intestinal mucosal wound healing as well as in inflammatory processes. It is possible that tocilizumab inhibited tissue repair of the intestine and caused intestinal ulcers.

Aerodigestive cancer, like esophageal cancer or head and neck cancer, is well known to have a poor prognosis. It is often diagnosed in the late stages, with dysphagia being the major symptom. Insufficient nutrition and lack of stimulation of the intestinal mucosa may worsen immune compromise due to toxic side effects. A poor nutritional status is a significant prognostic factor for increased mortality. Therefore, it is most important to optimize enteral nutrition in patients with aerodigestive cancer before and during treatment, as well as during palliative treatment. Percutaneous endoscopic gastrostomy (PEG) may be useful for nutritional support. However, PEG tube placement is limited by digestive tract stenosis and is an invasive endoscopic procedure with a risk of complications. There are three PEG techniques. The pull/push and introducer methods have been established as standard techniques for PEG tube placement. The modified introducer method, namely the direct method, allows for direct placement of a larger button-bumper-type catheter device. PEG tube placement using the introducer method or the direct method may be a much safer alternative than the pull/push method. PEG may be recommended in patients with aerodigestive cancer because of the improved complication rate.

BACKGROUND/AIMS Antithrombotic/nonsteroidal antiinflammatory drug (NSAID) therapies increase the incidence of upper gastrointestinal bleeding. The features of hemorrhagic peptic ulcer disease in patients receiving antithrombotic/NSAID therapies were investigated. METHODS We investigated the medical records of 485 consecutive patients who underwent esophagogastroduodenoscopy and were diagnosed with hemorrhagic gastroduodenal ulcers. The patients treated with antithrombotic agents/NSAIDs were categorized as the antithrombotic therapy (AT) group (n=213). The patients who were not treated with antithrombotics/NSAIDs were categorized as the control (C) group (n=263). The clinical characteristics were compared between the groups. RESULTS The patients in the AT group were significantly older than those in the C group (p

After the recent discovery of Th17 cells, it was proposed that Th17 responses are involved in the pathogenesis of inflammatory bowel diseases (IBD). CD4(+)CD25(+) regulatory T cells (Treg) are considered to be an attractive tool for the treatment of IBD. Here, we investigated whether Treg are capable of suppressing Th17-mediated colitis.Naive CD4(+) T cells were transferred into SCID mice with or without Treg. In some experiments, Treg were transferred into recipient mice with established colitis. Mice treated with Treg were injected with an anti-transforming growth factor (TGF)-β mAb or control IgG. Clinical symptoms of colitis, histological changes and cytokine expressions were investigated.SCID mice transferred with naive CD4(+) T cells developed chronic colitis with significant increases in Th1 and Th17 cytokine expressions in the colon. When Treg were co-transferred with naive CD4(+) T cells, development of colitis was prevented, and Th17 cytokine expressions were markedly reduced. Similarly, when Treg were transferred into mice with established colitis, the colitis was significantly ameliorated in association with dramatic reductions in Th17 cytokine expressions. Injection of anti-TGF-β mAb abolished the Treg-mediated suppression with significant elevations in Th17 cytokine productions.This adoptive transfer model of colitis was associated with augmented Th1 and Th17 responses, and Treg were capable of suppressing colonic inflammation by downregulating Th17 responses as well as Th1 responses via TGF-β. Consequently, Treg transfer therapy is expected to be efficacious for IBD even if Th17 is involved in the pathogenesis.

In recent years, primary gastrointestinal follicular lymphoma has been increasingly detected in the duodenum on esophagogastroduodenoscopy (EGD). Primary gastrointestinal follicular lymphomas are frequently distributed to multiple sites in the gastrointestinal tract. Therefore, investigation into the spread of follicular lymphomas in the small bowel is important in order to determine the most appropriate treatment strategy. The performance of double-balloon endoscopy (DBE) in the diagnosis of jejunoileal follicular lymphoma lesions has not been fully evaluated. We aimed to investigate the value of DBE in addition to computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) in the diagnosis of jejunoileal follicular lymphoma. DBE with biopsy was performed in seven patients with primary duodenal follicular lymphoma diagnosed by EGD, in order to investigate jejunoileal involvement. Jejunoileal follicular lymphoma lesions were detected by DBE in six out of the seven patients (three in the jejunum and three in the jejunum and ileum), whereas CT and (18)F-FDG-PET failed to detect the existence of these lesions. Endoscopic findings of the jejunoileal lesions revealed multiple white nodules and white villi, which were similar to those of duodenal lesions. DBE was more useful for the diagnosis of jejunoileal involvement in primary intestinal follicular lymphoma than CT and (18)F-FDG-PET. The use of DBE will become important for determining the most appropriate treatment for gastrointestinal follicular lymphoma.

A 35-year-old man was admitted due to bloody stool and anemia. The bleeding source could not be detected by esophagogastroduodenoscopy or colonoscopy. Double balloon endoscopy (DBE) revealed a diverticulum-like hole in which coagula stuck in the ileum at 1 meter on the oral side from the ileocecal valve. The adjacent mucosa just to the oral side of the hole was elevated like a submucosal tumor. The lesion was considered the source of bleeding and removed surgically. It was determined to be a cyst with an ileal structure on the mesenteric aspect accompanying gastric mucosa. The diagnosis was a duplication cyst of the ileum, which is a rare entity that can cause gastrointestinal bleeding. In the present case, DBE was used to find the hemorrhagic duplication cyst in the ileum.

We report a case of an esophageal ulcer that mimicked advanced esophageal cancer in a patient who was on alendronate sodium treatment. A 56-year-old woman presented with progressively worsening pain on swallowing. For the past 6 months she had been taking 5 mg/day alendronate sodium (Bonalon) for the treatment of postmenopausal osteoporosis. Upper gastrointestinal endoscopic examination revealed an ulcerative lesion in the lower esophagus that resembled an advanced esophageal cancer (Figure 1 ). The ulcers mucosa was normal, but the ulcer bed was uneven and would not stain with Lugol dye. Biopsy specimens of the ulcer bed showed a marked infiltration of neutrophils and eosinophils in the subepithelial space, but no signs of malignancy (Figure 2). We stopped the alendronate sodium and prescribed a proton-pump inhibitor. Endoscopic examination 2 months later showed marked improvement in the ulcer, with no esophageal stricture.

Objective The standard therapy for recurrent esophageal cancer is systemic chemotherapy. However, in cases in which the recurrent lesion is confined to the area where radiotherapy is applied, chemoradiotherapy will be able to provide better local control and prognosis. Method A retrospective study was carried out on 14 patients with local recurrent esophageal cancer but no other metastasis who underwent chemoradiotherapy (FP-RT: 5FU 700 mg/m2 on days 1–4, CDDP 70 mg/m2 on day 1, 4 weeks for one course × 2, RT: 60–66 Gy/30–33 Fr) at Toyama Prefectural Central Hospital between April 2008 and February 2012. Result The subjects included 13 men and 1 woman. The median age was 64 years (PS0/1/2 = 3/9/2). The histology was classified into squamous cell carcinoma in 13 subjects and carcinosarcoma in one subject. The site of the radiation therapy was recurrence in the lymph nodes in 10 patients, anastomotic recurrence in 3 patients and recurrence in pleural nodes in 1 patient. Regarding the tumor reduction effect, the lesions of 12 patients were evaluable by RECIST, and the response rate was 66.6%. The median of progression-free survival (PFS) was 251 days (8.4 months) and the median of overall survival was 475 days (15.8 months). Exacerbation of the irradiated lesions was observed in four patients (31%), whereas new lesions at other sites were observed in seven patients (55%). G3 or more adverse events were hematologic toxicity (23%) and non-hematologic toxicity (23%), such as anorexia and nausea. Discussion and conclusion This study showed that chemoradiotherapy for local recurrent esophageal cancer provides the excellent local control. The severity of adverse reactions caused by the therapy was relatively mild, and OS was good. In the future, the relationship between transient local control and survival time should be studied in a prospective setting.

Background & Aims: Low grade gastrointestinal inflammation is a potent etiologic factor for developing irritable bowel syndrome. We have shown that Th1 and Th2 cytokines have opposing effect on intestinal muscle contraction via 5-HT signaling in the nematode infection and T cell-mediated enteropathy. In this study, we evaluated the gastrointestinal transit In Vivo and compared to the contraction study In Vitro, and investigated the effect of Th1/Th2 cytokines on smooth muscle cells (SMCs) in T cell-mediated persistent gut motor dysfunction model. In addition, we investigated the cytokine-induced intracellular signaling mechanism toward the gut motor dysfunction. Further, the improvement of hyper-contractility by a Japanese traditional medicine daikenchuto (DKT) (Kono T et al., Surgery 146:837-4

Background Inflammatory bowel disease (IBD) patients in remission often experience irritable bowel syndrome (IBS)-like symptoms. We investigated the mechanism for intestinal muscle hypercontractility seen in T-cell-induced enteropathy in recovery phase. Methods BALB/c mice were treated with an anti-CD3 antibody (100 μg per mouse) and euthanized at varying days post-treatment to investigate the histological changes, longitudinal smooth muscle cell contraction, cytokines (Th1, Th2 cytokines, TNF-α) and serotonin (5-HT)-expressing enterochromaffin cell numbers in the small intestine. The role of 5-HT in anti-CD3 antibody-induced intestinal muscle function in recovery phase was assessed by inhibiting 5-HT synthesis using 4-chloro-DL-phenylalanine (PCPA). Key Results Small intestinal tissue damage was observed from 24 h after the anti-CD3 antibody injection, but had resolved by day 5. Carbachol-induced smooth muscle cell contractility was significantly increased from 4 h after injection, and this muscle hypercontractility was evident in recovery phase (at day 7). Th2 cytokines (IL-4, IL-13) were significantly increased from 4 h to day 7. 5-HT-expressing cells in the intestine were increased from day 1 to day 7. The 5-HT synthesis inhibitor PCPA decreased the anti-CD3 antibody-induced muscle hypercontractility in recovery phase. Conclusions & Inferences Intestinal muscle hypercontractility in remission is maintained at the smooth muscle cell level. Th2 cytokines and 5-HT in the small intestine contribute to the maintenance of the altered muscle function in recovery phase.

Background & Aim: In the enteric-infection-induced model of inflammation, Th1 and Th2 cytokines have opposing effect on intestinal muscle function and 5-HT signaling (Motomura et al. Gut 2008; Gastroenterology 128;Suppl A 626,2005), but the role of Th1 and Th2 dominant environments for non-infective post-inflammatory (PI) gut dysfunction remains to be determined. Here we investigated the mechanism for gut dysfunction that persists after acute inflammation in Th1 and Th2 dominant environments utilizing mouse model of T cell-induced enteropathy. Methods: BALB/c (Th2 dominant response) and AKR (Th1 dominant response) mice were treated with an anti-CD3 antibody (100 μg), and sacrificed at days 0, 1, 3, 7, and 14 post-treatment to investigate the histological changes, longitudinal smooth muscle cell contraction, various cytokines (Th1, Th2, Th17 cytokines), chemokines, and mediators mRNA /protein expressions and 5-HT-expressing enterochromaffin (EC) cells numbers in the small intestine. Results: In BALB/c mice small intestinal tissue damage was observed from 24 hours after the anti-CD3 antibody injection, but had resolved by day 5. Carbachol-induced smooth muscle cell contractility was significantly increased (p

G A A b st ra ct s was determined in amultiplex immunoassay. Results: Prdx6 protein expression was decreased by acute and chronic colitis in wildtype as well as in Prdx6 overexpressing animals. No differences in the development of acute colitis could be observed between wildtype and Prdx6 overexpressing animals but Prdx6 knockout animals displayed lower histological scores in acute as well as in chronic DSS colitis. Prdx6 overexpressing animals on the other hand showed a higher histological score in the proximal colon after induction of chronic DSS colitis. In the chronic colitis model increased secretion of proinflammatory (e.g. TNFα, IL-6) as well as antiinflammatory (e.g. IL-10, IL-2, IL-4, IL-5) cytokines by mesenterial lymph node cells could be observed in Prdx6 knockout animals in comparison to wildtype animals whereas lower levels of these cytokines were secreted by mesenterial lymph node cells isolated from Prdx6 overexpressing animals. Conclusion: Our data suggest that effective defense against bacterial translocation by reactive oxygen species might ameliorate the course of DSS-colitis as Prdx6 knockout animals, in which less neutralization of ROS occurs, displayed lower histological scores in acute as well as in chronic colitis