Diagnostic performance of deep-learning-based virtual chromoendoscopy in gastric neoplasms.

BACKGROUNDS: Cycle-consistent generative adversarial network (CycleGAN) is a deep neural network model that performs image-to-image translations. We generated virtual indigo carmine (IC) chromoendoscopy images of gastric neoplasms using CycleGAN and compared their diagnostic performance with that of white light endoscopy (WLE). METHODS: WLE and IC images of 176 patients with gastric neoplasms who underwent endoscopic resection were obtained. We used 1,633 images (911 WLE and 722 IC) of 146 cases in the training dataset to develop virtual IC images using CycleGAN. The remaining 30 WLE images were translated into 30 virtual IC images using the trained CycleGAN and used for validation. The lesion borders were evaluated by 118 endoscopists from 22 institutions using the 60 paired virtual IC and WLE images. The lesion area concordance rate and successful whole-lesion diagnosis were compared. RESULTS: The lesion area concordance rate based on the pathological diagnosis in virtual IC was lower than in WLE (44.1% vs. 48.5%, p < 0.01). The successful whole-lesion diagnosis was higher in the virtual IC than in WLE images; however, the difference was insignificant (28.2% vs. 26.4%, p = 0.11). Conversely, subgroup analyses revealed a significantly higher diagnosis in virtual IC than in WLE for depressed morphology (41.9% vs. 36.9%, p = 0.02), differentiated histology (27.6% vs. 24.8%, p = 0.02), smaller lesion size (42.3% vs. 38.3%, p = 0.01), and assessed by expert endoscopists (27.3% vs. 23.6%, p = 0.03). CONCLUSIONS: The diagnostic ability of virtual IC was higher for some lesions, but not completely superior to that of WLE. Adjustments are required to improve the imaging system's performance.

Lipoprotein Lipase Up-regulation in Hepatic Stellate Cells Exacerbates Liver Fibrosis in Nonalcoholic Steatohepatitis in Mice.

Lipoprotein lipase (LPL) plays a central role in incorporating plasma lipids into tissues and regulates lipid metabolism and energy balance in the human body. Conversely, LPL expression is almost absent in normal adult livers. Therefore, its physiological role in the liver remains unknown. We aimed to elucidate the role of LPL in the pathophysiology of nonalcoholic steatohepatitis (NASH), a hepatic manifestation of obesity. Hepatic stellate cell (HSC)-specific LPL-knockout (LplHSC-KO ) mice, LPL-floxed (Lplfl/fl ) mice, or double-mutant toll-like receptor 4-deficient (Tlr4-/- ) LplHSC-KO mice were fed a high-fat/high-cholesterol diet for 4 weeks to establish the nonalcoholic fatty liver model or an high-fat/high-cholesterol diet for 24 weeks to establish the NASH model. Human samples, derived from patients with nonalcoholic fatty liver disease, were also examined. In human and mouse NASH livers, serum obesity-related factors, such as free fatty acid, leptin, and interleukin-6, dramatically increased the expression of LPL, specifically in HSCs through signal transducer and activator of transcription 3 signaling, as opposed to that in hepatocytes or hepatic macrophages. In the NASH mouse model, liver fibrosis was significantly reduced in LplHSC-KO mice compared with that in Lplfl/fl mice. Nonenzymatic LPL-mediated cholesterol uptake from serum lipoproteins enhanced the accumulation of free cholesterol in HSCs, which amplified TLR4 signaling, resulting in the activation of HSCs and progression of hepatic fibrosis in NASH. Conclusion: The present study reveals the pathophysiological role of LPL in the liver, and furthermore, clarifies the pathophysiology in which obesity, as a background factor, exacerbates NASH. The LPL-mediated HSC activation pathway could be a promising therapeutic target for treating liver fibrosis in NASH.

Crohn's Disease Accompanied with Small Intestinal Extramedullary Plasmacytoma.

We herein present the case of an immunocompetent 63-year-old man who had previously undergone resection of Crohn's disease (CD)-related small intestinal obstruction more than 30 years ago. He had not been receiving any medication for many years, but had recently started to suffer from ileus. A stenosed site of ileo-cecal anastomosis was identified and therefore was surgically resected, which was diagnosed as CD with small intestinal extramedullary plasmacytoma (EMP). The subsequent progression of CD was successfully controlled by anti-TNFα agents without any recurrence of EMP for over 3 years, implying the clinical benefit and safety of the biological therapy. This was the first known case of a patient who received anti-TNFα agents after a resection of small intestinal EMP accompanied with CD.

Depression Promotes the Onset of Irritable Bowel Syndrome through Unique Dysbiosis in Rats.

Background/Aims: Although studies using conventional animal models have shown that specific stressors cause irritable bowel syndrome (IBS), it is unclear whether depression itself causes IBS. Our aim was to establish a rat model to determine if depression itself promotes the onset of IBS and to elucidate the role of gut microbiota in brain-gut axis pathogenesis during coincident depression and IBS. Methods: Rat models of depression were induced using our shuttle box method of learned helplessness. Visceral hypersensitivity was evaluated by colorectal distension (CRD) to diagnose IBS. Gut microbiota compositions were analyzed using high-throughput sequencing. In the subanalysis of rats without depression-like symptoms, rats with posttraumatic stress disorder (PTSD) were also examined. Results: The threshold value of CRD in depressed rats was significantly lower than that in control rats. Microbial community analysis of cecal microbiota showed that the relative abundance of Clostridiales incertae sedis, the most prevalent microbe, was significantly lower in depressed rats than in control rats. The distribution pattern of the microbiota clearly differed between depressed rats and control rats. Neither visceral hypersensitivity nor the composition of gut microbiota was altered in rats with PTSD-like phenotypes. Conclusions: Our rat model of depression is useful for clarifying the effect of depression on IBS and suggests that depression itself, rather than specific stressors, promotes the onset of IBS. Further, we provided evidence that various psychiatric diseases, viz., depression and PTSD, are associated with unique gut microbiota profiles, which could differentially affect the onset and progression of coincident IBS.

Atypical Clinical Presentation of Crohn's Disease with Superior Mesenteric Vein Obstruction and Protein-losing Enteropathy.

We herein report a 44-year-old man suffering from systemic edema due to protein-losing enteropathy (PLE) with superior mesenteric vein (SMV) obstruction and development of collateral veins, which subsequently proved to be a chronic result of thrombosis and a complication of Crohn's disease (CD). PLE was supposedly induced by both intestinal erosion and thrombosis-related lymphangiectasia, which was histologically proven in his surgically-resected ileal stenosis. Elemental diet and anti-TNFα agent improved his hypoalbuminemia after surgery. The rarity of the simultaneous coexistence of SMV obstruction and PLE and the precedence of these complications over typical abdominal symptoms of CD made the clinical course complex.

Nicotine treatment ameliorates DSS-induced colitis by suppressing MAdCAM-1 expression and leukocyte recruitment.

The enhanced recruitment of leukocytes to the inflamed colon is a key feature of ulcerative colitis (UC). The gut-specific adhesion molecules involved in leukocyte recruitment have emerged as recent therapeutic targets. Nicotine absorbed from smoking has been reported to work protectively in UC patients. Our hypothesis is that nicotine may suppress the aberrant leukocyte recruitment and colonic inflammation via the suppression of the overexpressed gut-specific adhesion molecules in the inflamed colon. To test this hypothesis, the severity of colitis and the degree of leukocyte recruitment induced by gut-specific adhesion molecules were assessed in dextran sulfate sodium (DSS) colitis mice (C57BL/6J mice treated with 3% DSS) with or without nicotine treatment. We also studied the in vitro changes in the expression of adhesion molecules by using a vascular endothelial cell line. DSS-induced colitis was accompanied by increases in disease activity index (DAI), histological score, recruitment of leukocytes, and the expression of adhesion molecules, mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1) and VCAM-1. Nicotine treatment significantly attenuated MAdCAM-1 expression, leukocyte recruitment, DAI, and histological score. The expression of ß7-integrin, the ligand for MAdCAM-1, on leukocytes was not affected by nicotine treatment. In vitro study, the TNF-α-enhanced mRNA expression of MAdCAM-1 was reduced by the coadministration of nicotine in a dose-dependent manner, possibly via nicotinic receptor activation. These results supported our hypothesis that nicotine treatment ameliorated colitis through the suppression of MAdCAM-1 expression on the microvessels in the inflamed colon. Further investigation is warranted on the role of nicotine in the treatment of UC.

Amelioration of colitis through blocking lymphocytes entry to Peyer's patches by sphingosine-1-phosphate lyase inhibitor.

BACKGROUND AND AIM: Sphingosine-1-phosphate (S1P) receptor 1, a therapeutic target of the S1P1 agonist FTY720, plays a crucial role in lymphocyte migration and is expressed in several cells including naïve T lymphocytes and endothelial cells. 2-Acetyl-4-tetrahydroxybutyl imidazole (THI), an inhibitor of S1P lyase, exhibits immunomodulatory activity through increasing the S1P concentration in the secondary lymphoid organs, but its effects on colitis remain unclear. This study aimed to clarify how THI affects colitis and migration of naïve T lymphocytes in Peyer's patches (PPs). METHODS: The effect of THI on gut immunity was investigated by analyzing the dextran sulfate sodium (DSS)-induced murine colitis model, lymphocyte components in thoracic duct lymphocytes (TDLs), and microscopic movement of TDLs in PPs. RESULTS: 2-Acetyl-4-tetrahydroxybutyl imidazole ameliorated DSS-induced colitis histologically by causing a significant decrease in colonic lymphocyte infiltration and expression of mucosal pro-inflammatory cytokines. THI suppressed the inflow of naïve T lymphocytes into the thoracic duct. Microscopic observation of PPs in control animals revealed that many TDLs egressed to the stroma and migrated to lymph capillaries after attaching to the high endothelial venules (HEVs). THI or FTY720 treatment in recipient animals blocked lymphocyte egression from the HEVs to the stroma. CONCLUSIONS: This is the first study to clarify the ameliorating effects of THI on DSS-induced colitis. Microscopic observations demonstrated the involvement of HEVs in the egression of S1P-dependent gut-tropic T lymphocytes to lymph capillaries. This S1P lyase inhibitor might become a novel immunosuppressant for inflammatory bowel disease therapy by blocking infiltration of lymphocytes through HEVs into the stroma in PPs.

Novel probiotics isolated from a Japanese traditional fermented food, Funazushi, attenuates DSS-induced colitis by increasing the induction of high integrin αv/ß8-expressing dendritic cells.

BACKGROUND: We isolated two novel probiotics strains (s193 and s292) from Funazushi, which is a traditional Japanese fermented food, and evaluated its effects on DSS-induced colitis to determine the possible underlying mechanisms. METHODS: A single colony from homogenized Funazushi was isolated by its ability to suppress TNF-α in RAW 264.7. Effect of probiotics on colonic inflammation induced by DSS was evaluated. Effect of probiotics on Treg induction by CD11c+ dendritic cells (DCs) of MLNs were analyzed. RESULTS: Two novel probiotics strains classified into the genus Lactobacillus were isolated (s193 and s292), and those strains showed stronger anti-inflammatory effects on DSS-induced colitis than those of L. gasseri isolated from the gut. mRNA expression ß8 integrin in CD11c+DCs of MLNs and the number of Tregs in the large intestine were significantly increased by s193 and s292 administration compared with L. gasseri administration. Bone marrow DCs treated with s193 and s292 highly increased ß8 integrin, and those cells strongly induced differentiation of CD4+ T cells into Tregs. Differentiation of Tregs was remarkably inhibited by anti-ß8 integrin antibody treatment. CONCLUSIONS: Strains s193 and s292 demonstrate strong anti-inflammatory effects on DSS-induced colitis through induction of ß8 integrin expression on DCs. Our results suggested that Japanese traditional fermented foods are valuable sources for probiotics that are effective for IBD therapy and treatment.

Human intestinal spirochetosis mimicking ulcerative colitis.

Human intestinal spirochetosis (HIS) is a colorectal infection caused by the Brachyspira species of intestinal spirochetes, whose pathogenicity in humans remains unclear owing to the lack of or mild symptoms. We monitored the 5-year clinical course of a woman diagnosed with HIS in whom ulcerative colitis (UC) had been suspected. Following a positive fecal occult blood test, she underwent a colonoscopic examination at a local clinic where she was diagnosed with "right-sided" UC concomitant with incidentally detected HIS, and was referred to our hospital. Colonoscopic, histopathological, and cytological examination revealed localized erosive colitis in the ascending and the right transverse colon concomitant with HIS resembling skip lesions of UC. Initially, we chose the wait-and-watch approach; however, she gradually developed bloody diarrhea. Metronidazole improved her abdominal symptoms, as well as her colonoscopic and histopathological findings, suggesting that HIS was responsible for her colorectal inflammation. This case reveals (1) a possible pro-inflammatory role of HIS, (2) difficulties in diagnosing HIS in chronic proctocolitis, and (3) a possible inclusion of some HIS cases in "UC". HIS could mimic UC and might be included in differential diagnoses for UC. Antibiotic administration is necessary following the detection of HIS, particularly in patients demonstrating an atypical presentation of UC.

Evaluation by MR Enterocolonography of Lansoprazole-induced Collagenous Colitis Accompanied with Protein-losing Enteropathy.

We herein describe a 69-year-old man suffering from chronic diarrhea caused by lansoprazole (LPZ)-induced collagenous colitis (CC) accompanied with protein-losing enteropathy (PLE), diagnosed by increased fecal alpha-1 antitrypsin clearance and the findings of leakage from the descending colon to the sigmoid colon on scintigraphy. MR enterocolonography (MREC) was also performed for differentiating digestive diseases, and inflamed findings were observed around the same portion as those on scintigraphy, suggesting that this region was responsible for protein loss in this case. The MREC findings improved after the cessation of LPZ, and hypoalbuminemia also improved simultaneously. This case suggests that MREC may be a new and useful diagnostic tool for CC with PLE.

Vitamin A-coupled liposome system targeting free cholesterol accumulation in hepatic stellate cells offers a beneficial therapeutic strategy for liver fibrosis.

AIM: Liver fibrosis is a life-threatening disorder for which no approved therapy is available. Recently, we reported that mouse hepatic stellate cell (HSC) activation increased free cholesterol (FC) accumulation, partly by enhancing signaling through sterol regulatory element-binding protein 2 (SREBP2) and microRNA-33a (miR-33a), which resulted in HSC sensitization to transforming growth factor-ß (TGFß)-induced activation in a "vicious cycle" of liver fibrosis. METHODS: Human HSCs were isolated from surgical liver specimens from control patients and patients with liver fibrosis. C57BL/6 mice were treated with carbon tetrachloride for 4 weeks and concurrently given SREBP2-siRNA- or anti-miR-33a-bearing vitamin A-coupled liposomes. RESULTS: In human activated HSCs obtained from patients with liver fibrosis, FC accumulation was enhanced independently of serum cholesterol levels through increased signaling by both SREBP2 and miR-33a. This increased FC accumulation enhanced Toll-like receptor 4 (TLR4) protein levels and lowered the TGFß-pseudoreceptor Bambi (bone morphogenetic protein and activin membrane-bound inhibitor) mRNA levels in HSCs. Notably, in a mouse liver fibrosis model, reduction of FC accumulation, specifically in activated HSCs by suppression of SREBP2 or miR-33a expression using SREBP2-siRNA- or anti-miR-33a-bearing vitamin A-coupled liposomes, downregulated TLR4 signaling, increased Bambi expression, and consequently ameliorated liver fibrosis. CONCLUSIONS: Our results suggest that FC accumulation in HSCs, as an intracellular mediator promoting HSC activation, contributes to a vicious cycle of HSC activation in human and mouse liver fibrosis independent of serum cholesterol levels. Targeting FC accumulation-related molecules in HSCs through a vitamin A-coupled liposomal system represents a favorable therapeutic strategy for liver fibrosis.

Evaluation of an e-learning system for diagnosis of gastric lesions using magnifying narrow-band imaging: a multicenter randomized controlled study.

Background and study aim Magnifying narrow-band imaging (M-NBI) is useful for the accurate diagnosis of early gastric cancer (EGC). However, acquiring skill at M-NBI diagnosis takes substantial effort. An Internet-based e-learning system to teach endoscopic diagnosis of EGC using M-NBI has been developed. This study evaluated its effectiveness. Participants and methods This study was designed as a multicenter randomized controlled trial. We recruited endoscopists as participants from all over Japan. After completing Test 1, which consisted of M-NBI images of 40 gastric lesions, participants were randomly assigned to the e-learning or non-e-learning groups. Only the e-learning group was allowed to access the e-learning system. After the e-learning period, both groups received Test 2. The analysis set was participants who scored < 80 % accuracy on Test 1. The primary end point was the difference in accuracy between Test 1 and Test 2 for the two groups. Results A total of 395 participants from 77 institutions completed Test 1 (198 in the e-learning group and 197 in the non-e-learning group). After the e-learning period, all 395 completed Test 2. The analysis sets were e-learning group: n = 184; and non-e-learning group: n = 184. The mean Test 1 score was 59.9 % for the e-learning group and 61.7 % for the non-e-learning group. The change in accuracy in Test 2 was significantly higher in the e-learning group than in the non-e-learning group (7.4 points vs. 0.14 points, respectively; P < 0.001). Conclusion This study clearly demonstrated the efficacy of the e-learning system in improving practitioners' capabilities to diagnose EGC using M-NBI.Trial registered at University Hospital Medical Information Network Clinical Trials Registry (UMIN000008569).

Uric acid ameliorates indomethacin-induced enteropathy in mice through its antioxidant activity.

BACKGROUND AND AIM: Uric acid is excreted from blood into the intestinal lumen, yet the roles of uric acid in intestinal diseases remain to be elucidated. The study aimed to determine whether uric acid could reduce end points associated with nonsteroidal anti-inflammatory drug (NSAID)-induced enteropathy. METHODS: A mouse model of NSAID-induced enteropathy was generated by administering indomethacin intraperitoneally to 8-week-old male C57BL/6 mice, and then vehicle or uric acid was administered orally. A group of mice treated with indomethacin was also concurrently administered inosinic acid, a uric acid precursor, and potassium oxonate, an inhibitor of uric acid metabolism, intraperitoneally. For in vitro analysis, Caco-2 cells treated with indomethacin were incubated in the presence or absence of uric acid. RESULTS: Oral administration of uric acid ameliorated NSAID-induced enteropathy in mice even though serum uric acid levels did not increase. Intraperitoneal administration of inosinic acid and potassium oxonate significantly elevated serum uric acid levels and ameliorated NSAID-induced enteropathy in mice. Both oral uric acid treatment and intraperitoneal treatment with inosinic acid and potassium oxonate significantly decreased lipid peroxidation in the ileum of mice with NSAID-induced enteropathy. Treatment with uric acid protected Caco-2 cells from indomethacin-induced oxidative stress, lipid peroxidation, and cytotoxicity. CONCLUSIONS: Uric acid within the intestinal lumen and in serum had a protective effect against NSAID-induced enteropathy in mice, through its antioxidant activity. Uric acid could be a promising therapeutic target for NSAID-induced enteropathy.

Psychological stress exacerbates NSAID-induced small bowel injury by inducing changes in intestinal microbiota and permeability via glucocorticoid receptor signaling.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are popular painkillers, but they have serious side effects, not only in the upper gastrointestinal tract but also in the small intestine. It is well known that psychological stress may exacerbate various gastrointestinal diseases. The aim of this study was to determine whether psychological stress exacerbates NSAID enteropathy and to determine the possible underlying mechanisms for this. METHODS: Experiment 1: mice were exposed to water avoidance stress (WAS) or sham stress for 1 h per day for 8 consecutive days, and then enteropathy was induced by indomethacin. Experiment 2: cecal contents from stress (-) or (+) mice were transplanted into mice that had received antibiotics and in which NSAID enteropathy had been induced without WAS. Experiment 3: mifepristone, a glucocorticoid receptor antagonist, was injected before WAS for 8 days. Small intestinal injury, mRNA expression of TNFα, intestinal permeability, and the microbial community were assessed. RESULTS: Psychological stress exacerbated NSAID enteropathy and increased intestinal permeability. Psychological stress induced changes in the ileal microbiota that were characterized by increases in the total number of bacteria and the proportion of Gram-negative bacteria. The increased susceptibility to NSAIDs and intestinal permeability due to WAS was transferable via cecal microbiota transplantation. The increased permeability and aggravation of NSAID enteropathy caused by WAS were blocked by the administration of mifepristone. CONCLUSIONS: This study demonstrated a relationship between NSAID enteropathy and psychological stress, and showed the utility of studying the intestinal microbiota in order to elucidate the pathophysiology of NSAID enteropathy. It also showed the impact of stress on the intestinal microbiota and the mucosal barrier in gastrointestinal diseases.

Platelet interaction with lymphatics aggravates intestinal inflammation by suppressing lymphangiogenesis.

Lymphatic failure is a histopathological feature of inflammatory bowel disease (IBD). Recent studies show that interaction between platelets and podoplanin on lymphatic endothelial cells (LECs) suppresses lymphangiogenesis. We aimed to investigate the role of platelets in the inflammatory process of colitis, which is likely to be through modulation of lymphangiogenesis. Lymphangiogenesis in colonic mucosal specimens from patients with IBD was investigated by studying mRNA expression of lymphangiogenic factors and histologically by examining lymphatic vessel (LV) densities. Involvement of lymphangiogenesis in intestinal inflammation was studied by administering VEGF-receptor 3 (VEGF-R3) inhibitors to the mouse model of colitis using dextran sulfate sodium and evaluating platelet migration to LVs. The inhibitory effect of platelets on lymphangiogenesis was investigated in vivo by administering antiplatelet antibody to the colitis mouse model and in vitro by coculturing platelets with lymphatic endothelial cells. Although mRNA expressions of lymphangiogenic factors such as VEGF-R3 and podoplanin were significantly increased in the inflamed mucosa of patients with IBD compared with those with quiescent mucosa, there was no difference in LV density between them. In the colitis model, VEGF-R3 inhibition resulted in aggravated colitis, decreased lymphatic density, and increased platelet migration to LVs. Administration of an antiplatelet antibody increased LV densities and significantly ameliorated colitis. Coculture with platelets inhibited proliferation of LECs in vitro. Our data suggest that despite elevated lymphangiogenic factors during colonic inflammation, platelet migration to LVs resulted in suppressed lymphangiogenesis, leading to aggravation of colitis by blocking the clearance of inflammatory cells. Modulating the interaction between platelets and LVs could be a new therapeutic means for treating IBD.

Recombinant Thrombomodulin Modulates Murine Colitis Possibly via High-Mobility Group Box 1 Protein Inhibition.

BACKGROUND AND AIM: Thrombomodulin (TM) is an anticoagulant cofactor protein. We hypothesized that its recombinant soluble TM (rhTM) form, widely used to treat disseminated intravascular coagulation, might have anti-inflammatory action in inflammatory bowel disease (IBD), possibly through its inhibition of high-mobility group box 1 protein (HMGB1). METHODS: We investigated inflammatory effects of HMGB1 and anti-inflammatory effect of rhTM in dextran sulfate sodium (DSS)-treated mice, some cell lines and ulcerative colitis (UC) patients, particularly focusing on changes of vascular endothelial adhesion molecules. RESULTS: Treatments with rhTM significantly attenuated DSS-treated mice clinically and histologically. The mRNA levels of proinflammatory cytokines and adhesion molecules were decreased by rhTM. Increased inflammatory cells in the colonic mucosa strongly expressed HMGB1 in the cytoplasm in the DSS-treated mice and UC patients' colonic mucosa, which were significantly decreased by rhTM in mice. In in vitro experiments, rhTM significantly decreased the mRNA levels of tumor necrosis factor-alpha (TNF-α) and adhesion molecules increased by endotoxin exposures in RAW 264.7 (macrophage cell line) and bEND.3 cells (endothelial cell line), suggesting the proinflammatory role of HMGB1 in TNF-α production from macrophages. CONCLUSIONS: These findings suggest that rhTM may be useful for the treatment of IBD by attenuating inflammatory cytokine production and adhesion molecule expression, partly because of its inhibition of HMGB1.

Lethal hemorrhage from duodenal ulcer due to small pancreatic cancer.

Gastrointestinal massive arterial hemorrhage is difficult to stop endoscopically, especially from a duodenal ulcer (DU), because of the anatomically narrow lumen. Here we report a rare case of small pancreatic cancer-induced lethal hemorrhagic DU. The 69-year-old patient was transferred due to massive hematemesis, hypotension and loss of consciousness. Emergency upper endoscopy revealed a DU with active bleeding from an unclear hemorrhagic spot, which stopped transiently by itself. Subsequently he began to vomit blood again and angiography showed extravasation from the gastroduodenal artery (GDA). Hemostasis by transcatheter arterial embolization (TAE) was achieved but the patient unfortunately died soon after because of hemorrhagic shock (10 h after his first hematemesis). The autopsy revealed a small pancreatic cancer (poorly differentiated adenocarcinoma, 10 × 25 mm in size) infiltrating into one-half of the penetrating DU with a nearby ruptured GDA wall, suggesting that the DU was caused by the pancreatic cancer. Our 7-year analysis of emergency endoscopies in our department for upper gastrointestinal bleeding revealed that TAE was performed in more cases of duodenal hemorrhage (5.7 %) than stomach hemorrhage (1.8 %), showing the difficulty in stopping hemorrhage from DU endoscopically. This case raises the possibility that intractable lethal hemorrhagic DU could be caused by a very small pancreatic tumor.

Toll-like receptor (TLR) 2 agonists ameliorate indomethacin-induced murine ileitis by suppressing the TLR4 signaling.

BACKGROUND AND AIM: Few drugs have been found satisfactory in the treatment of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy. Toll-like receptor (TLR) 4 and aberrant leukocyte migration to the intestinal mucosa are reported to be involved in the pathology of intestinal enteropathy and TLR2 agonists have been found to evoke hyposensitivity to TLR4 stimulation in vitro. In this study, we investigated whether and how lipoarabinomannan (LAM) or lipoteichoic acid (LTA), TLR2 agonists, attenuated indomethacin (IND)-induced intestinal damage. METHODS: LAM (0.5 mg/kg) or LTA (15 mg/kg) was administered intraperitoneally to mice before IND (10 mg/kg) administration. Disease activity was evaluated macroscopically and histologically. In the migration analysis, fluorescence-labeled leukocyte movement in the intestinal microvessels was observed by intravital microscopy. Expression of P-selectin, MAdCAM-1, TLR2, TLR4, and F4/80 was observed immunohistochemically. In the in vitro analysis, RAW264.7 macrophage cells were preincubated with LAM and stimulated with lipopolysaccharide (LPS), and the mRNA expression levels of TLR4, tumor necrosis factor-α, and interleukin-12p40 were measured. RESULTS: Pretreatment with LAM or LTA significantly decreased IND-induced injury as well as decreased leukocyte infiltration. Pretreatment with LAM decreased IND-induced TLR4 expression on F4/80(+) macrophages, the level of P-selectin expression, and leukocyte migration in the small intestinal vessels. In the in vitro study, a single administration of LAM decreased TLR4 mRNA expression and inhibited the increase in mRNA expression of inflammatory cytokines by LPS in a dose-dependent manner. CONCLUSION: TLR2 agonists attenuated IND-induced small intestinal lesions and leukocyte infiltration probably by suppressing the TLR4 signaling pathway in tissue macrophages.

Beneficial effect of an omega-6 PUFA-rich diet in non-steroidal anti-inflammatory drug-induced mucosal damage in the murine small intestine.

AIM: To investigate the effect of a fat rich diet on non-steroidal anti-inflammatory drug (NSAID)-induced mucosal damage in the murine small intestine. METHODS: C57BL6 mice were fed 4 types of diets with or without indomethacin. One group was fed standard laboratory chow. The other groups were fed a fat diet consisting of 8% w/w fat, beef tallow (rich in SFA), fish oil, (rich in omega-3 PUFA), or safflower oil (rich in omega-6 PUFA). Indomethacin (3 mg/kg) was injected intraperitoneally from day 8 to day 10. On day 11, intestines and adhesions to submucosal microvessels were examined. RESULTS: In the indomethacin-treated groups, mucosal damage was exacerbated by diets containing beef tallow and fish oil, and was accompanied by leukocyte infiltration (P < 0.05). The mucosal damage induced by indomethacin was significantly lower in mice fed the safflower oil diet than in mice fed the beef tallow or fish oil diet (P < 0.05). Indomethacin increased monocyte and platelet migration to the intestinal mucosa, whereas safflower oil significantly decreased monocyte and platelet recruitment (P < 0.05). CONCLUSION: A diet rich in SFA and omega-3 PUFA exacerbated NSAID-induced small intestinal damage via increased leukocyte infiltration. Importantly, a diet rich in omega-6-PUFA did not aggravate inflammation as monocyte migration was blocked.

Magnetic resonance enterocolonography in detecting erosion and redness in intestinal mucosa of patients with Crohn's disease.

BACKGROUND AND AIM: In Crohn's disease (CD), assessment of disease activity and extension is important for clinical management. Endoscopy is the most reliable tool for evaluating disease activity in these patients and it distinguishes between lesions based on ulcer, erosion, and redness. Magnetic resonance imaging (MRI) is less invasive than endoscopy; however, the sensitivity of MRI in detecting lesions is believed to be lower, and whether MRI can detect milder lesions has not been studied. The aim of this study was to compare the detection ability of magnetic resonance enterocolonography (MREC) with ileocolonic endoscopy in patients with CD. METHODS: A total of 27 patients with CD underwent both MREC and ileocolonoscopy. There were 55 lesions (18 ileum and 37 colon) endoscopically detected, and the findings of MREC were compared with each ileocolonoscopic finding to determine sensitivity and specificity. RESULTS: For a positive lesion defined as having at least one of the following: wall thickness, edema, diffusion-weighted imaging (DWI) high intensity and relative contrast enhancement (RCE) on MREC, the sensitivities were 100% for ulcer, 84.6% for erosion, and 52.9% for redness, suggesting an ability to detect milder lesions such as erosion or redness. Moreover, RCE values were well correlated with the severity of endoscopically identified active lesions. CONCLUSION: MREC findings may be useful not only for evaluation of ulcers, but also for detection of endoscopically identified milder lesions in CD, suggesting a clinical usefulness of MREC for disease detection and monitoring.