Background
Abrogating tolerance is a critical step in the pathogenesis of Crohn’s disease (CD). T cell-anergy is one of the main mechanisms of tolerance and is regulated by the gene related to anergy ...in lymphocytes (GRAIL). This study investigated the expressions and regulation of GRAIL in CD and murine colitis models.
Methods
Expressions of GRAIL mRNA and protein in CD4
+
T cells were investigated in the peripheral blood and mucosal tissues of patients with CD, mice with dextran sodium salt (DSS)-induced colitis, and
Il
-
10
-deficient mice. MicroRNAs responsible for the regulation of GRAIL were examined by miRNA microarray. GRAIL-overexpressing T cells were intravenously injected in mice with DSS-induced colitis.
Results
The GRAIL expression was higher in the lamina propria (LP) CD4
+
T cells of CD patients than of the control subjects, while it was lower in the peripheral blood CD4
+
T cells of the CD patients than of the control subjects. The GRAIL mRNA expression was lower, but the GRAIL protein expression was higher in the LP of colitic mice than that of non-colitic mice. The miRNA microarray identified miR-290-5p as an miRNA that inhibits expression of the GRAIL protein and that is highly expressed in the LP of non-colitic mice. GRAIL-expressing T cells expressed regulatory T cell markers and showed suppressive effects in murine DSS-induced colitis.
Conclusions
Our results show that expression of GRAIL is uniquely regulated by the specific miRNA in the intestinal mucosa, and suggest that GRAIL may associate with the pathophysiology of CD.
Agalactosyl immunoglobulin (Ig) G is increased in inflammatory bowel disease (IBD) similarly to rheumatoid arthritis (RA). The lectin complement pathway is shown to be activated through association ...of agalactosyl IgG with mannan-binding lectin (MBL) in RA. Functional changes of IgG agalactosylation in IBD, however, have not yet been clarified.
The ratio of the agalactosyl/non-agalactosyl fraction in fucosylated IgG oligosaccharides (G0F/G2F) and serum MBL levels were analyzed in 59 patients with Crohn's disease (CD), 64 ulcerative colitis (UC), and 39 healthy volunteers (HV). The MBL levels associated with serum IgG were analyzed by enzyme-linked immunosorbent assay. MBL expression in the intestinal mucosa was analyzed by immunohistochemistry. Phagocytosis of sheep red blood cells (SRBC) reacted with either an agalactosyl or non-agalactosyl SRBC-specific IgG antibody was determined by flow cytometry.
The serum MBL levels were not significantly different among CD, UC, or HV. In patients with CD, the serum MBL levels were negatively correlated with the Crohn's Disease Activity Index (CDAI). The levels of MBL associated with agalactosyl IgG were not different from those associated with non-agalactosyl IgG. Immunoreactivity to MBL was less in the inflamed mucosa compared with the noninflamed mucosa. Phagocytic activity of SRBC was significantly higher in the presence of agalactosyl IgG compared to non-agalactosyl IgG.
Agalactosyl IgG oligosaccharides enhanced antibody-dependent phagocytosis in vitro but did not activate the lectin complement pathway. Oligosaccharide alterations of IgG are not only a marker of IBD but also functionally modulate the immune function of IBD.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in patients with rheumatoid arthritis (RA) but have several side effects including mucosal damage in the small intestine. We aimed to ...evaluate whether the small bowel injury is ameliorated by switching from nonselective NSAIDs to celecoxib in patients with RA.
Sixteen patients with RA who were treated with nonselective NSAIDs were enrolled in this study. Nonselective NSAIDs were converted to celecoxib for 12 weeks. Capsule endoscopy was performed before and after treatment with celecoxib. Videos were screened by gastroenterologists blinded to the patients' treatment.
Before the administration of celecoxib, reddened folds, denuded areas, petechiae/red spots and mucosal breaks were observed in 63, 63, 88 and 69% of the patients, respectively. In the 14 patients who completed this study, conversion to celecoxib significantly reduced the number of petechiae/red spots, the number of mucosal breaks, and Lewis scores. RA activity and cytokine levels in the peripheral blood were not significantly different before and after treatment with celecoxib.
The incidence of small bowel injury by nonselective NSAIDs is high in patients with RA. Conversion from nonselective NSAIDs to celecoxib can be useful for protecting patients with RA from small bowel injury.
In the course of our screening program for anticancer agents from natural sources, five new angucyclines, JBIR-90 (1), -116 (2), -91 (3), -92 (4) and -93 (5), were isolated from the fermentation ...broth of Streptomyces sp. RI33. The structures of 1-5 were elucidated on the basis of 1D and 2D NMR spectroscopy and MS analyses. Compounds 2-4 showed cytotoxic activities against malignant pleural mesothelioma cells at IC(50) values of 20-50 μM.
Peyer's patches (PPs) play a major role in mucosal immunity. However, their roles in nonsteroidal anti-inflammatory drug-induced enteropathy are poorly understood.
Wild-type (WT) and PP-null mice ...were injected with indomethacin. Twenty-four hours later, the cellular profiles and cytokine levels in the PPs, mesenteric lymph nodes (MLNs), and lamina propria (LP) of the small intestine were measured. WT and PP-null mice were given antibiotics before indomethacin treatment to evaluate enteropathy. Naive CD4 T cells were co-cultured with CD103 or CD103 dendritic cells (DCs) to analyze the interleukin (IL)-10 expression levels. Finally, WT mice adoptively transferred with CD103 or CD103 DCs were injected with indomethacin.
The proportion of CD103 DCs in PPs and MLNs and IL-10-expressing CD4 T cells of PPs and the LP increased after indomethacin treatment. The PP-null mice showed greater indomethacin-induced enteropathy, fewer CD103 DCs in their MLNs, and lower proportion of IL-10-expressing CD4 T cells of their LP than WT mice, regardless of commensal bacteria. Naive splenic CD4 T cells co-cultured with CD103 DCs isolated from the MLNs of indomethacin-injected WT mice produced a higher amount of IL-10 compared with those co-cultured with CD103 DCs. Moreover, WT mice that received CD103 DCs showed milder enteropathy than those that received CD103 DCs.
PPs play a protective role in nonsteroidal anti-inflammatory drug-induced enteropathy, and this protection is associated with an increase in CD103 DCs and IL-10-producing CD4 T cells in the intestine, independent of the commensal bacteria.
Abstract
Background and study aims
An increasing number of patients have been using anticoagulants including anti-vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs); however, in ...patients using anticoagulants, limited data are available with regard to the risks of gastrointestinal bleeding and thromboembolic events during the peri-endoscopic period. We aimed to evaluate the peri-endoscopic bleeding and thrombotic risks in patients administered VKAs or DOACs.
Patients and methods
Consecutive patients using anticoagulants who underwent endoscopic biopsy, mucosal resection, or submucosal dissection were prospectively enrolled across 11 hospitals. The primary outcome assessed was difference in incidence of post-procedural gastrointestinal bleeding in patients using VKAs and DOACs. Duration of hospitalization and peri-procedural thromboembolic events were also compared.
Results
We enrolled 174 patients using VKAs and 37 using DOACs. In total, 16 patients using VKA were excluded from the analysis because of cancellation of endoscopic procedures and contraindications to the use of DOACs; 128 (81 %) patients using VKAs and 17 (46 %) using DOACs received heparin-bridging therapy (HB). The rate of post-procedural gastrointestinal bleeding in DOAC users was similar to that in VKA users (16.2 % vs. 16.4 %,
P
= 1.000). Duration of hospitalization was significantly longer in patients using VKAs than in those using DOACs (median 15 vs. 7 days,
P
< 0.0001). Myocardial infarction occurred during pre-endoscopic HB in one patient using VKAs.
Conclusion
DOAC administration showed similar post-procedural gastrointestinal bleeding risk to VKA administration in patients undergoing endoscopic procedures, but it shortened the hospital stay.
Transthoracic oesophagectomy is associated with major morbidity and mortality, which may be reduced by goal-directed therapy (GDT). The aim of this multicentre, RCT was to evaluate the impact of ...intraoperative GDT on major morbidity and mortality in patients undergoing transthoracic oesophagectomy.
Adult patients undergoing transthoracic oesophagectomy were randomised to receive either minimally invasive intraoperative GDT (stroke volume variation <8%, plus systolic BP maintained >90 mm Hg by pressors as necessary) or haemodynamic management left to the discretion of attending senior anaesthetists (control group; systolic BP >90 mm Hg alone). The primary outcome was the incidence of death or major complications (reoperation for bleeding, anastomotic leakage, pneumonia, reintubation, >48 h ventilation). A Cox proportional hazard model was used to examine whether the effects of GDT on morbidity and mortality were independent of other potential confounders.
A total of 232 patients (80.6% male; age range: 36–83 yr) were randomised to either GDT (n=115) or to the control group (n=117). After surgery, major morbidity and mortality were less frequent in 22/115 (19.1%) subjects randomised to GDT, compared with 41/117 (35.0%) subjects assigned to the control group {absolute risk reduction: 15.9% (95% confidence interval CI: 4.7–27.2%); P=0.006}. GDT was also associated with fewer episodes of atrial fibrillation (odds ratio OR: 0.18 95% CI: 0.05–0.65), respiratory failure (OR: 0.27 95% CI: 0.09–0.83), use of mini-tracheotomy (OR: 0.29 95% CI: 0.10–0.81), and readmission to ICU (OR: 0.09 95% CI: 0.01–0.67). GDT was independently associated with morbidity and mortality (hazard ratio: 0.51 95% CI: 0.30–0.87; P=0.013).
Intraoperative GDT may reduce major morbidity and mortality, and shorten hospital stay, after transthoracic oesophagectomy.
UMIN000018705
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