Search

Familial Mediterranean fever (FMF) is an autosomal recessive hereditary disease commonly observed around the Mediterranean basin presenting as recurrent febrile episodes. We herein describe a Japanese case of genetically-confirmed FMF, in which fever was lacking during attacks. An otherwise healthy 34-year-old man presented with frequent episodes of abdominal pain, which resolved spontaneously. During the attacks, the patient was afebrile, but the inflammatory marker levels in his blood were increased. Abdominal CT demonstrated enhancement of the jejunal membrane. After the initiation of colchicine therapy, the patient experienced no attacks for more than one year. The diagnosis of FMF was confirmed by a genetic analysis.

We conducted a questionnaire survey on voluntary inoculation of hepatitis B (HB) vaccine to children at 79 pediatric clinics. The voluntary vaccination rate was 65.2%, the desired vaccination target was "all infants" at 84.8% of clinics, the recommended method was "only when the patient wishes" at a rate of 80.0%, and "actively recommended" at 20.0%. If there was a request, 71.7% of clinics answered that they would like to recommend it in the future, and 38.9% said that it was difficult to recommend it because of the voluntary nature of vaccination. The requests were "expansion of the scope of regular vaccination" at 60.9% of clinics and "enlightenment activities and information provision" at 54.3%. Since it was suggested that voluntary vaccination is difficult to recommend, it is necessary to proactively provide information and public relations activities regarding its necessity to medical personnel and parents.

We conducted a questionnaire survey on the status of implementation of hepatitis B vaccination and HBs antibody testing. It involved medical personnel covering 484 regional medical institutions in the Osaka Province. Results showed that the recognition rate was 30.1%, the hepatitis B vaccination implementation rate was 38.9%, and that of HBs antibody testing was 38.9%. Although 42.5% of the medical institutions had experienced needle-stick injuries, some medical institutions did not respond properly. The low implementation rate of hepatitis B vaccination and HBs antibody test could be explained by lack of recognition for hepatitis B infection control guidelines. Therefore, we can achieve a possible improvement in the control of infection in the Province, if sensitization programs on hepatitis B infection control are organized in the various regional medical institutions in order to provide adequate information and raise awareness on the importance of respecting these guidelines.

Gastroenterologists working in hospitals that have adopted the chief physician system are often required to work overtime during the night and on holidays treating critically ill patients and ordering emergency tests. To help alleviate the attending physician's duties, our hospital initiated an on-call system in October 2019 to replace the existing system. Changes in overtime hours worked and business stress before and after the introduction of the on-call system were verified. After the introduction of the on-call system, both overtime hours and the number of holidays worked decreased and work stress was reduced. We report that the on-call system is a suitable alternative to the attending physician system because it increases the work efficiency and satisfaction of attending physicians.

Background and Aim Few studies have shown the associations between colonic diverticula and endoscopic findings such as location, inflammation, number of diverticula, sigmoid colon rigidity, and bowel habits. Methods Japanese subjects who underwent total colonoscopies at six centers in Japan from November 2015 to October 2016 were analyzed. Bowel habits were evaluated using the Gastrointestinal Symptom Rating Scale. Location and number of diverticula, inflammation, and sigmoid colon rigidity were evaluated from endoscopy results. Results A total of 762 subjects (486 men and 276 women [ratio, 1.76:1]) whose mean age was 65.5 ± 11.4 years were evaluated. In multivariate analysis, presence of constipation was associated with a significantly lower likelihood of left-sided colonic diverticula (odds ratio = 0.40, 95% confidence interval 0.20–0.82, P = 0.012), whereas right-sided and bilateral-sided colonic diverticula, multiple colonic diverticula, inflammation findings, and sigmoid colon rigidity were not related to bowel habits. Conclusions Among endoscopic findings related to colonic diverticula and bowel habits, only left-sided colonic diverticula were inversely associated with constipation, whereas inflammation findings, multiple diverticula, and sigmoid colon rigidity were not related to bowel habits. However, the association of inflammation findings with colonic diverticula and bowel habits should be further studied. Investigation of changes in left-sided colonic diverticula may lead to new treatments for constipation.

Peripheral neuropathy reportedly develops after a long period of metronidazole administration. Here, we report a case of amoebic colitis in which peripheral neuropathy occurred approximately 24 hours after administering metronidazole. A 76-year-old man presented with mucous and bloody stool. Initially, lower gastrointestinal endoscopy and stool analysis confirmed the occurrence of amoebic colitis, and metronidazole was then intravenously administered. The following day, however, the patient experienced a diminished sensation in a glove-and-stocking distribution in his extremities, followed by bilateral burning foot pain. After the withdrawal of metronidazole, the symptoms improved and finally disappeared 3 months later.

We report a rare case of hepatic cholangiolocellular carcinoma (CoCC) with long-term observation. A 73-year-old woman was found to have a solitary hepatic tumor with a diameter of 10mm on dynamic computed tomography (CT), which showed peripheral enhancement in the arterial phase and enhancement retention in the delayed phase. Although it was initially diagnosed as hepatic hemangioma, the follow up examination conducted 16 months later revealed that the tumor had grown to 18mm. Doubling time of the tumor was calculated to be 177 days. Because magnetic resonance imaging results were not typical for hepatic hemangioma, hepatocellular carcinoma was suspected and partial hepatectomy was performed. Histologically, the tumor was comprised dense proliferation of small irregular tubules with fibrous stroma. Immunohistochemistry revealed that the carcinoma cells were positive for cytokeratin (CK) 7, CK19, and neurnal cell adhesion molecule. Cells were negative for hepatocyte paraffin 1. Periodic acid-Schiff and Alcian blue staining showed an absence of mucin in the tumor cells, and epithelial membrane antigen was strongly positive on the luminal surface of tubules. These findings were typical of CoCC;therefore, CoCC should be ruled out when dynamic CT images suggest hepatic hemangioma.

An 80-year-old man had a medical history of chronic hepatitis C and pancreatoduodenectomy. We detected recurrence of hepatocellular carcinoma, and performed transcatheter arterial chemoembolization, instead of radiofrequency ablation or surgery, because of the patient's medical history of bile duct reconstruction and liver dysfunction. On the second day, he was diagnosed with a gas-forming liver abscess and underwent liver abscess drainage. Clostridium perfringens and sordellii were detected by aspiration and the blood culture. Meropenem and Clindamycin were administered intravenously. He was treated shortly after the occurrence before the involvement of severe hemolysis and recovered from the acute phase.

Few studies have shown the associations between colonic diverticula and endoscopic findings such as location, inflammation, number of diverticula, sigmoid colon rigidity, and bowel habits.Japanese subjects who underwent total colonoscopies at six centers in Japan from November 2015 to October 2016 were analyzed. Bowel habits were evaluated using the Gastrointestinal Symptom Rating Scale. Location and number of diverticula, inflammation, and sigmoid colon rigidity were evaluated from endoscopy results.A total of 762 subjects (486 men and 276 women [ratio, 1.76:1]) whose mean age was 65.5 ± 11.4 years were evaluated. In multivariate analysis, presence of constipation was associated with a significantly lower likelihood of left-sided colonic diverticula (odds ratio = 0.40, 95% confidence interval 0.20-0.82, P = 0.012), whereas right-sided and bilateral-sided colonic diverticula, multiple colonic diverticula, inflammation findings, and sigmoid colon rigidity were not related to bowel habits.Among endoscopic findings related to colonic diverticula and bowel habits, only left-sided colonic diverticula were inversely associated with constipation, whereas inflammation findings, multiple diverticula, and sigmoid colon rigidity were not related to bowel habits. However, the association of inflammation findings with colonic diverticula and bowel habits should be further studied. Investigation of changes in left-sided colonic diverticula may lead to new treatments for constipation.

A 50-year-old female became aware of skin yellowing and consulted another hospital where she was diagnosed intraoperatively with duodenal cancer because of lymph node metastases around the aorta. Endoscopy revealed type IIa + IIc cancer distal to the duodenal papilla, and biopsy allowed a diagnosis of well-differentiated adenocarcinoma. Computed tomography revealed a large number of lymph node metastases around the aorta and in the left supraclavicular cavity. The patient was given many regimens of chemotherapy, mainly containing S-1, and multidisciplinary treatment, and achieved long-term survival for 6 years and 1 month. This is a valuable case suggesting the usefulness of this therapeutic approach. In view of the fact that duodenal cancer is a relatively rare disease and the possibility that the incidence of this disease may increase in the future, it seems essential to collect additional data from multicenter prospective studies towards the goal of establishing a standard method of treatment for this disease.

Background and Aims: MicroRNA (miRNA) are endogenous, approximately 22-nucleotide non-coding RNA that suppress gene expression at post-transcriptional levels by binding to the 3′-untranslated region of specific mRNA targets through base-pairing. It has been recently reported that miRNA have critical functions in key biological processes such as cell proliferation and cell death in various cancer cells. However, the relationship between intestinal inflammation and miRNA expression remains unclear. In the present study, we used microarray technology to identify miRNA induced in the colonic mucosa of patients with active ulcerative colitis (UC). Methods: Two colonic biopsy specimens from patients with active stage (>Matts grade 2) of UC under colonoscopy and two colonic biopsy specimens from healthy volunteers were obtained for gene expression profiles. Total RNA was extracted, and miRNA expression profiles were investigated using miRNA Microarray. Subsequently, to confirm the result of the Microarray investigation, we checked the expression of several selected miRNA using real-time polymerase chain reaction (PCR) in 12 colonic biopsy specimens from patients with active UC under colonoscopy and 12 specimens from the healthy volunteers. Results: In the microarray study, the expression of several miRNA was upregulated in the colonic mucosa of patients with active UC. Furthermore, two miRNA (miR-21, miR-155) were selected in the study using real-time PCR. Conclusion: Upregulated miRNA may be responsible for the development of intestinal inflammation in UC.

Gemcitabine (GEM) has improved both overall survival and tumor-related symptoms in patients with advanced pancreatic cancer when compared to 5-FU, and is a widely accepted treatment for such patients. However, pancreatic cancers remain extremely resistant to chemotherapy. Empiric chemotherapy based on GEM has had no major successes in treating patients with advanced disease. The objective of this study was to evaluate the response rate, survival, and toxicity of the sequential combination of GEM and hyperthermia. Between November 2005 and November 2007, 7 patients with unresectable pancreatic cancer received sequential combination therapy with GEM and hyperthermia at the Matsushita Memorial Hospital. Data were then compared with 7 historical controls treated with GEM alone at the same institution. There were no significant differences in age, performance status or UICC stage between the GEM plus hyperthermia and GEM monotherapy groups. The disease control rate (CR+PR+SD) was 14.3% for patients treated GEM alone and 57.1% for patients treated with GEM plus hyperthermia. The median survival time was 198 days for patients treated with GEM alone, and 327 days for patients treated with GEM plus hyperthermia. Combination therapy with GEM and hyperthermia thus improves overall survival when compared with GEM monotherapy (p=0.0275). The sequential combination of GEM plus hyperthermia showed a potential therapeutic effect, and was at least as effective as GEM monotherapy. To clarify the effects of this combination therapy, a larger prospective clinical trial is required.

Aspirin and nonsteroidal anti-inflammatory agents are known to induce gastroduodenal complications such as ulcer, bleeding, and dyspepsia. In this study, we examined the prophylactic effect of rebamipide, an anti-ulcer agent with free-radical scavenging and antiinflammatory effect, on acidified aspirin-induced gastric mucosal injury in rats. In addition, we investigated the mucosal barrier functions disrupted by aspirin. Oral administration of acidified aspirin resulted in linear hemorrhagic erosions with increasing myeloperoxidase activity and thiobarbituric acid-reactive substance concentrations in the gastric mucosa. Rebamipide suppressed these acidified aspirin-induced gastric lesions and inflammatory changes significantly, and its protective effect was more potent in the case of repeated (twice daily for 3 days) treatment than single treatment before aspirin administration. Immunostaining of zonula occludens (ZO)-1, one of the tight junctional proteins, was strengthened in rat gastric mucosa after repeated administration of rebamipide. In addition, aspirin induced the increasing transport of fluorescine isothiocyanate-labeled dextrans with localized disruption and decreased expression of ZO-1 protein on rat gastric mucosal cell line RGM-1. Rebamipide effectively prevented aspirin-induced permeability changes and disruption of ZO-1 distribution. These results suggest that rebamipide protects against aspirin-induced gastric mucosal lesions by preserving gastric epithelial cell-to cell integrity in addition to the anti-inflammatory effects. Keywords:: aspirin, gastric mucosal injury, tight junction, zonula occludens (ZO)-1, rebamipide

A woman in her 70s presented with dehydration and malnutrition due to watery diarrhea. She was examined and diagnosed with gastrointestinal amyloidosis accompanied by a protein-losing gastroenteropathy secondary to rheumatoid arthritis. She first underwent treatment with an anti-tumor necrosis factor alpha (TNF-α) antibody for secondary amyloidosis, but due to lack of adequate response, she was switched to an anti-interleukin (IL)-6 receptor antibody. Her clinical symptoms subsequently improved, and endoscopy revealed a marked decrease of amyloid protein deposits in the digestive tract. She was followed up for 3 years while continuing to receive the anti-IL-6 receptor antibody, with no recurrence. Although secondary amyloidosis is a fatal disease associated with chronic inflammatory diseases, clinical symptoms and prognosis have recently been improved by intervention with biological therapies. In particular, anti-IL-6 receptor antibodies have been reported to be superior to anti-TNF-α antibodies in the treatment of secondary amyloidosis and are expected to play a central role in treating secondary amyloidosis in the future.

Ménétrier's disease has been reported to be associated with Helicobacter pylori infection. The aim of this study was to investigate the genetic characteristics of various virulence factors and cytokine expression profiles in Helicobacter pylori isolated from patients with Ménétrier's disease. The genotyping of virulence factors was accomplished by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Induction of various cytokines in MKN45 cells or gastric fibroblasts by Helicobacter pylori stimulus was measured by real-time reverse transcription-PCR. We found that the Helicobacter pylori strain isolated from a patient with Ménétrier's disease was different from other strains in the MseI-RFLP pattern of the ureC gene. Helicobacter pylori isolated from a patient with Ménétrier's disease showed the highest hepatocyte growth factor (HGF) and TNF-alpha mRNA expressions from gastric fibroblasts, and the highest TNF-alpha expression from MKN45 cells. The results in this study suggest that the difference in cytokine production, depending on the difference in bacteria components, plays an important role in the development of Ménétrier's disease.

Summary A number of studies have shown that activated mast cells are involved in the pathogenesis of inflammatory and allergic diseases. Tryptase is one of the serine proteases that stored almost exclusively in the secretory granules of mast cells. It acts to induce microvascular leakage, the chemotaxis of inflammatory cells, and stimulates the release of inflammatory cytokines through the mitogen-activated protein kinase /activator protein-1 pathway and protease-activated receptor (PAR) nuclear factor-κB pathway. Recent studies have strongly indicated that tryptase and PAR are implicated in the pathogenesis of inflammatory bowel disease and experimental colitis. The effect of anti-tryptase therapy on human inflammatory bowel disease and experimental colitis has been demonstrated. The result of a pilot study has revealed that systemic administration of a specific tryptase inhibitor is safe and there is evidence of activity in the treatment of ulcerative colitis. Recently, we found that nafamostat mesilate, which selectively inhibits tryptase activity at low concentration, could reduce intestinal inflammation in rats. In addition, nafamostat mesilate enema improved clinical and endoscopic findings in ulcerative colitis patients, resistant to conventional therapy such as corticosteroids and sulfasalazine/5-aminosalicylic acid. These studies suggest that anti-tryptase therapy may represent a new therapeutic strategy for human inflammatory bowel disease.

Summary Background Recent studies in models of inflammatory bowel disease have demonstrated that heme oxygenase-1 (HO-1) induction, or its by-products in this process such as carbon monoxide (CO), plays an important role in the intestinal inflammation. However, the distribution of HO-1 in intestinal mucosa and the concentration of intestinal luminal CO in humans have not yet been investigated. Aim To detect the HO-immunopositive cells in the intestine of normal subjects and in patients with ulcerative colitis (UC) and to measure intestinal luminal CO gas contents using gas chromatography. Materials and Methods The expression of HO-1 in the intestine was determined using immunohistochemistry. Human colonic gas was collected using colonoscopy from healthy volunteers and patients with UC. Analysis of intestinal luminal gas was performed using a newly developed portable gas chromatograph. Results Immunopositive staining for HO-1 was localized in the inflammatory cells, mainly mononuclear cells, and the number of cells that accepted stain was greater in patients with UC. CO level in the intestinal lumen significantly increased in patients in the active stage of UC. Conclusion These findings indicate that the HO-CO system is induced in UC.

Mast cell tryptase has been proposed to be involved in the pathogenesis of human inflammatory bowel disease (IBD). Recently, it was reported that a low dose of nafamostat mesilate (NM), a serine protease inhibitor that is widely used to treat disseminated intravascular coagulation (DIC) and acute pancreatitis, can selectively inhibit human tryptase activity. The aim of this study was to investigate the anti-inflammatory effects of NM on experimental colitis in rats.Colitis was induced in male Wistar rats using an enema of trinitrobenzene sulfonic acid (TNBS) dissolved in 50% ethanol. NM or 5-aminosalicylic acid (5-ASA), foundation therapy for mild-to-moderate IBD, was administered via the anus once a day on each of the 6 days after administration of TNBS. Colonic inflammation was assessed 1 week after TNBS administration.Intracolonic administration of TNBS resulted in the infiltration of numerous tryptase-positive cells in the colonic mucosa. The colonic mucosal injury induced by TNBS was significantly decreased by treatment with NM or 5-ASA. The increases in thiobarbituric acid-reactive substances (TBA-RS), myeloperoxidase (MPO) activity, tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractants-1 (CINC-1) in the colonic mucosa were inhibited in the NM group and the 5-ASA group, without significant differences between them.These results indicate that a low dose of NM can inhibit the colonic mucosal inflammation induced by TNBS in rats, which suggests that anti-tryptase therapy using low doses of NM has excellent potential to become a new therapeutic strategy for IBD.

The aim of the present study was to explore whether heme oxygenase-1 (HO-1) is involved in the hyperthermia-provided protection of the small intestine from ischemia/reperfusion injury in rats.Intestinal damage was induced in male Sprague-Dawley rats by clamping both the superior mesenteric artery and the celiac trunk for 30 min, followed by reperfusion. Whole-body hyperthermia was induced in anesthetized rats by placement in a temperature-controlled water bath. Whole-body hyperthermia to a core temperature of 42-43 degrees C for 15 min was followed by passive cooling. We started the hyperthermic treatment 6 h before the vascular clamping. The severity of the mucosal injury was evaluated by several biochemical markers and histological findings. Hyperthermia-induced heat-shock proteins were detected by Western blotting. We also investigated the effect of zinc protoporphyrin IX (an HO-1 inhibitor) on the protective effect of hyperthermia.The rats, which were killed after ischemia/reperfusion, had severe intestinal inflammation. Hyperthermia significantly induced the production of Hsp70 and HO-1 in intestinal mucosa and significantly reduced ischemia/reperfusion-induced mucosal injury. The combination of zinc protoporphyrin IX with hyperthermia extinguished the protective effects of hyperthermia on ischemia/reperfusion injury.Hyperthermia protects against ischemia/reperfusion injury in rat small intestine through the expression of heat-shock proteins, especially HO-1.

Proinflammatory factors, including neutrophil-derived oxygen free radicals and inflammatory cytokines, have recently been implicated in the pathogenesis of reflux esophagitis. Rebamipide has been widely used as an anti-ulcer agent. The aim of the present study was to assess the protective effect of rebamipide against acute reflux esophagitis in rats. Esophagitis was induced in rats by ligation at the limiting ridge and the lower portion of the duodenum. Vehicle or rebamipide were given as a single dose intraduodenally. Lesion index (LI), thiobarbituric acid-reactive substances (TBA-RS), myeloperoxidase (MPO) activity, mRNA and protein of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC)-1 in the esophageal mucosa were markedly increased; pretreatment with rebamipide, however, significantly reduced both macroscopic and microscopic injuries and increases in inflammatory mediators. The results of this study indicate that rebamipide protects against the occurrence of esophagitis and has highly promising potential as a new therapeutic agent for reflux esophagitis.

In ischemia-reperfusion (I/R)-induced tissue injury, oxygen radicals can be generated by several mechanisms. One of the important sources of oxygen radicals is thought to be mitochondrial respiration. The aim of this study was to investigate the antioxidative defense effect of the mitochondrial electron transport inhibitor, rotenone using the I/R-induced rat intestinal mucosal injury model in vivo. Intestinal ischemia was induced for 30 min by applying a small clamp to the superior mesenteric artery in rats. Rotenone at a dose of 100 mg/kg was given to rats orally 2 h before the ischemia. Intraluminal hemoglobin and protein levels, the mucosal content of thiobarbituric acid-reactive substances (TBARS), the mucosal myeloperoxidase activity, and the content of inflammatory cytokines (CINC-1, TNF-alpha) were all significantly increased from mean basal levels after 60 min of reperfusion. These increases after I/R were inhibited by treatment with rotenone at a dose of 100 mg/kg. Co-administration with succinate (100 mg/kg), a substrate of the mitochondrial electron transport system, cancelled significant reduction of intraluminal hemoglobin and mucosal TBARS treated with rotenone alone. The results of the present study indicate that rotenone inhibited lipid peroxidation and reduced development of the intestinal mucosal inflammation induced by I/R in rats. This investigation suggests that rotenone has potential as a new therapeutic agent for reperfusion injury.

The overproduction of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) may contribute to the pathophysiology of intestinal injury induced by ischemia–reperfusion. The aim of the present study was to examine the effect of selective iNOS inhibition by a cyclic amidine analogue, ONO-1714, on reperfusion-induced small intestinal injury and inflammation in rats. Intestinal damage was induced in male Sprague–Dawley rats by clamping both the superior mesenteric artery and the celiac trunk for 30 min, followed by reperfusion. The luminal nitrite concentration in the small intestine was measured by Griess reaction and the iNOS mRNA expression by RT-PCR. The severity of the intestinal mucosal injury and inflammation were evaluated by several biochemical markers and by the histological findings. The rats which were killed after ischemia–reperfusion had increased luminal concentrations of nitrite and iNOS mRNA expression, in addition to severe intestinal inflammation characterized by significant increases in myeloperoxidase activity, a marker of neutrophil infiltration, and by the mucosal content of CINC-1 cytokine, a neutrophil chemotactic cytokine. Administration with ONO-1714 significantly inhibited the luminal NO production. Reperfusion after 30-min ischemia resulted in an increase in luminal protein and hemoglobin concentrations, with levels reaching a maximum after 60 min of reperfusion. In contrast, pre-treatment with ONO-1714 2 h before the ischemia inhibited the increases in luminal protein and hemoglobin concentration in a dose-dependent manner (0.001–0.1 mg/kg). The contents of the thiobarbituric acid-reactive substances (a marker of oxidative lipid peroxidation) were significantly increased by ischemia–reperfusion, and this increase was reduced by ONO-1714. After reperfusion, the increase in tissue-associated myeloperoxidase activity, an index of neutrophil infiltration, was significantly inhibited by pre-treatment with ONO-1714. ONO-1714 also inhibited increases in intestinal CINC-1 protein and mRNA expression, as determined by ELISA and RT-PCR, respectively. In conclusion, the improvement of reperfusion-induced intestinal injury by ONO-1714 suggested that an excess of NO, produced by iNOS, may have contributed to the initiation/amplification of intestinal inflammatory injury by various mechanisms, including nitrosative and oxidative damage as well as the enhancement of inflammatory cytokine release.

Sclerosing mesenteritis is a rare, benign disorder characterized by non-specific and chronic inflammation of the mesenteric adipose tissue. The disease usually presents with gastrointestinal symptoms and abdominal masses. The long-term prognosis is favorable, but it often becomes severe. In the present report we describe a 77-year-old man who presented with diarrhea, massive ascites and an abdominal mass. The rapid deterioration of the general condition of the patient limited invasive examinations and left the primary disease unclear. Despite symptomatic therapy, malnutrition and hypovolemia were prolonged, and he died. The definitive diagnosis of sclerosing mesenteritis and the cause of the fatal outcome were disclosed at autopsy. This case indicates that sclerosing mesenteritis is a potentially-fatal disease and the need for aggressive treatment should be discussed.

Aim. Chronic gastritis was assessed serologically, endoscopically and histologically to identify correlations between these methods.Methods. Subjects comprised 319 patients who had provided informed consent. Serological assessment of chronic gastritis was based on the pepsinogen test method. Endoscopic gastritis and histological gastritis were assessed and scored according to the Kimura-Takemoto classification system and the updated Sydney classification system respectively, and correlations between these three methods were studied.Results. Pepsinogen I/II ratio showed a significant correlation to the extent of mononuclear cell infiltration of the gastric corpus. When histological gastritis was divided, on the basis of the distribution of mononuclear cell infiltration, into gastritis limited to the antrum and corpus gastritis, these types were distinguished with high accuracy using a pepsinogen I/II ratio of 3 as the cutoff. A good correlation was also seen between pepsinogen I/II ratio and development of atrophy in endoscopic gastritis, where groups with and without advanced atrophy were also distinguished with high accuracy using a cutoff value of 3.Conclusion. Significant correlations exist between serum pepsinogen levels, endoscopic gastritis, and histological gastritis. Pepsinogen I/II ratio allows prediction of the existence of endoscopic gastritis and histological gastritis, or the extent of their development, with high accuracy.

Protease-activated receptors (PARs) are widely recognized for their modulatory properties during inflammation. The aim of the present study was to examine the role of PAR-2 on ischemia/reperfusion-induced small intestinal injury in rats. Intestinal damage was induced in male Wistar rats by clamping both the superior mesenteric artery and the celiac trunk for 30 min, followed by reperfusion for 60 min. Expression of PAR-2 in the intestinal mucosa was estimated by Western blot analysis and real-time PCR. Anti-rat PAR-2 cleavage site (PCS) antibody was intraperitoneally administered to the rats 1 h before the vascular clamping. The intestinal mucosal injury and inflammation were evaluated by biochemical markers and histological findings. Thiobarbituric acid (TBA) reactive substances and tissue-associated myeloperoxidase (MPO) activity were measured in the intestinal mucosa as indices of lipid peroxidation and neutrophil infiltration, respectively. Expression of cytokine-induced neutrophil chemoattractant-1 (CINC-1) in intestinal mucosa was measured by enzyme-linked immunosorbent assay. Expression of PAR-2 mRNA and protein in the intestinal mucosa was increased after reperfusion following ischemia. Reperfusion after ischemia resulted in an increase in luminal protein concentrations, hemoglobin concentrations, TBA reactive substances, MPO activity and CINC-1 protein. Pre-treatment with anti-rat PCS antibody significantly inhibited the increases in these parameters. These results suggest that PAR-2 plays an important role in the pathogenesis of ischemia/reperfusion-induced intestinal injury.

MicroRNA (miRNA) are endogenous, approximately 22-nucleotide non-coding RNA that suppress gene expression at post-transcriptional levels by binding to the 3'-untranslated region of specific mRNA targets through base-pairing. It has been recently reported that miRNA have critical functions in key biological processes such as cell proliferation and cell death in various cancer cells. However, the relationship between intestinal inflammation and miRNA expression remains unclear. In the present study, we used microarray technology to identify miRNA induced in the colonic mucosa of patients with active ulcerative colitis (UC).Two colonic biopsy specimens from patients with active stage (Matts grade 2) of UC under colonoscopy and two colonic biopsy specimens from healthy volunteers were obtained for gene expression profiles. Total RNA was extracted, and miRNA expression profiles were investigated using miRNA Microarray. Subsequently, to confirm the result of the Microarray investigation, we checked the expression of several selected miRNA using real-time polymerase chain reaction (PCR) in 12 colonic biopsy specimens from patients with active UC under colonoscopy and 12 specimens from the healthy volunteers.In the microarray study, the expression of several miRNA was upregulated in the colonic mucosa of patients with active UC. Furthermore, two miRNA (miR-21, miR-155) were selected in the study using real-time PCR.Upregulated miRNA may be responsible for the development of intestinal inflammation in UC.

A 24-year-old man presented complaining of epigastralgia and tenderness in the epigastric region. An abdominal computed tomography revealed a low density tumor, extending between the anterior wall of the stomach and the abdominal wall. Because the tumor was found to enlarge, an operation was performed to remove the tumor. During the operation, it was revealed that the tumor was connected with the lesser omentum, which suggested that it had originated from the lesser omentum. We diagnosed an inflammatory myofibroblastic tumor based on the pathological examination, which revealed infiltration of inflammatory cells, sparse proliferation of spindle cells and limited proliferation of collagen fibers, characterized by an irregular arrangement.

It has been reported that polymorphisms of human leukocyte antigen (HLA) genes and several cytokine genes are associated with an increased risk of developing gastric cancer (GC). However, the results of studies from different geographic regions, ethnic groups and study groups are inconsistent. The aim of this study was to evaluate the influence of H. pylori infection and host genetic factors on GC susceptibility in Japanese patients with GC. We analyzed genotypes for HLA class I and II, tumor necrosis factor alpha, interleukin (IL)-1beta, IL-1 receptor, IL-4, IL-4Ralpha and IL-10 in 330 H. pylori-infected noncardia patients with GC and 190 H. pylori-infected nonulcer dyspeptic controls. Haplotype analyses indicated that the frequencies of the HLA DRB1*0405 and DQB1*0401 alleles were increased in the patients with intestinal-type GC when compared with controls (both DRB1*0405 and DQB1*0401: p = 0.015, OR = 1.57, 95% CI = 1.09-2.26), but the changes were not statistically significant after correction for multiple comparisons. None of the cytokine gene polymorphisms were associated with GC susceptibility, whether patients with GC were analyzed as a group according to the histological subtype. Of interest was the comparison of controls and patients with intestinal-type GC. The frequency of an IL-10-592AA homozygote showing concomitant carriage of the HLA DRB1*0405-DQB1*0401 haplotype was significantly higher in patients with intestinal-type GC (chi(2) = 6.369, p = 0.0116, p(c) = 0.0464, OR = 2.43, 95% CI = 1.21-4.48). Our results suggest that the HLA class II and IL-10-592A/C polymorphisms synergistically affect the susceptibility to GC development of H. pylori-infected individuals in the Japanese population.

A 31-year-old woman suffering from stomach pain was admitted to our hospital, and diagnosed with unresectable advanced gastric cancer. She was initially treated with combination therapy of S-1 and CDDP, and a partial response was achieved. After two courses of the chemotherapy, however, she complained of dyspnea, and pulmonary carcinomatous lymphangitis was confirmed by computed tomography. As second-line chemo-therapy, we attempted combination therapy with docetaxel, CDDP and S-1(DCS). After one course of the combination therapy, a remarkable response in the pulmonary carcinomatous lymphangitis was achieved. Treatment of patients with advanced gastric cancer associated with pulmonary carcinomatous lymphangitis is quite difficult and there is no scientific evidence to select anti-cancer drugs for these patients. We concluded that DCF could be a useful regimen for patients with gastric cancer associated with pulmonary carcinomatous lymphangitis.

128 Background: Irinotecan is a key drug in second- or further-line chemotherapy for patients with advanced gastric cancer. Continuous administration of trastuzumab beyond first progression is expected to contribute to the benefit of chemotherapy for HER2-positive gastric cancer. We assessed the efficacy and safety of combination chemotherapy with trastuzumab and irinotecan in Japanese patients with advanced HER2-positive chemo-refractory gastric cancer. Methods: Intravenous infusion of irinotecan every 2 weeks at a dose of 150 mg/m2; intravenous infusion of trastuzumab at a dose of 8 mg/kg on day 1 of the first cycle, followed by 6 mg/kg every 3 weeks. Administration of irinotecan and trastuzumab were repeated in independent schedules. The primary endpoint was disease control rate. The secondary endpoints were adverse events, response rate, time-to-treatment failure, progression-free survival, overall survival, and response rate stratified by prior trastuzumab use. This study was conducted by the Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG). Results: From October 2012 to Augst 2014, 30 patients were enrolled and one patient withdrew before study treatment. Accordingly, 29 patients were assessable for efficacy and safety. The disease control rate was 65.5% [95% C.I. 45.7 - 82.1%], and the response rate was 20.7% [95% C.I. 8.0 - 39.7%]. The median progression free survival and the median overall survival were 3.7 and 7.5 months, respectively. The major grade 3/4 toxic effects were neutropenia (24%); anemia (24%); leucopenia (21%); anorexia (11%); fatigue (14%); hypoalbuminemia (24%); and hypokalemia (14%). One death (NOS) was considered to be related to the study. Conclusions: The results of combination Trastuzumab with irinotecan showed feasible and promising efficacy against advanced HER2-positive chemo-refractory gastric cancer. These findings indicated that trastuzumab continuation use might be beneficial. Clinical trial information: 000008626.

Hyperthermia is known to protect against cellular injury through the expression of heat shock proteins. In this study, the therapeutic effects of hyperthermia on experimental colitis in the rat were evaluated.Male Wistar rats were given a single intracolonic injection of 2,4,6-trinitrobenzene sulphonic acid (TNBS). Hyperthermia was induced in anesthetized rats by placing them in a temperature-controlled water bath. We started the hyperthermic treatment on the day after the enema. The severity of colitis was evaluated pathologically, and the activities of tissue myeloperoxidase were measured 6 days after the induction of colitis. Furthermore, cytokines, and hyperthermia-induced heat shock proteins in colonic mucosa were detected by enzyme-linked immunosorbent assay and Western blotting. We also investigated the effects of geranylgeranylacetone and zinc protoporphyrin IX on the therapeutic effect of hyperthermia.Hyperthermia significantly improved the macroscopic scores of colitis. The TNBS-induced increases in the activities of myeloperoxidase in the colonic tissue were blunted significantly in hyperthermia-treated animals. Furthermore, hyperthermia attenuated increases in cytokine-induced neutrophil chemoattractants-1 and tumor necrosis factor-alpha in the colon. Furthermore, hyperthermia induced the production of heat shock proteins in rat colonic mucosa, and the combination of geranylgeranylacetone with hyperthermia further induced the heat shock protein HSP70, which resulted in further improvement of TNBS-induced colitis. On the other hand, the combination of zinc protoporphyrin IX with hyperthermia attenuated the therapeutic effect of hyperthermia.Hyperthermia ameliorates TNBS-induced colitis in rats through the expression of HSP70 and HO-1. It is postulated that hyperthermia may be useful for the treatment of inflammatory bowel diseases.

Irinotecan is a key drug in second- or further-line chemotherapy for patients with advanced gastric cancer. Continuous administration of trastuzumab beyond first progression is expected to contribute to the benefit of chemotherapy for human epidermal growth factor receptor 2-positive gastric cancer. The aim of this trial is to evaluate the efficacy and safety of combination chemotherapy with trastuzumab and irinotecan in Japanese patients with advanced human epidermal growth factor receptor 2-positive chemo-refractory gastric cancer. The primary endpoint is the disease control rate. The secondary endpoints are adverse events, overall response rate, time to treatment failure, progression-free survival, overall survival and response rate stratified by prior trastuzumab use. A total of 30 patients will be enrolled in this Osaka Gastrointestinal Cancer Chemotherapy Study Group trial.

The aim of the present study was to elucidate the beneficial effects of rosuvastatin, a new HMG-CoA reductase inhibitor, on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium (DSS) colitis model. Acute colitis was induced using 8% DSS in female BALB/c mice. Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. Mucosal protein contents and mRNA levels of tumor necrosis factor (TNF)-alpha were determined by immunoassay and real time-PCR. The mRNA levels of endothelial nitric oxide synthase (eNOS) were determined by real-time PCR. Disease activity scores in DSS-induced colitis model mice, as determined by weight loss, stool consistency, and blood in stool, were significantly lower in the rosuvastatin-treated mice than in control mice. Shortening of the colon was significantly reversed by rosuvastatin. Increases in tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin. Rosuvastatin also inhibited increases in intestinal TNF-alpha protein and mRNA expression after DSS administration, respectively. The mucosal mRNA levels of eNOS were decreased after DSS administration, but preserved in mice treated with rosuvastatin. These results suggest that rosuvastatin prevents the development of DSS-induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of eNOS transcription.

Oxygen radical-mediated lipid peroxidation and neutrophil activation may be involved in the development of gastric mucosal injury induced by non-steroidal anti-inflammatory drugs (NSAIDs). Vitamin E is one of the lipid-soluble antioxidants and is generally considered to protect against lipid peroxidation of the cell membrane and to scavenge singlet oxygen and superoxide anion radicals. Our object was to investigate the antioxidative effects of water-soluble vitamin E derivative, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetra-methylchroman-6-ol (TMG), on aspirin-induced gastric mucosal injury in rats. Gastric injury was induced by intragastric administration of aspirin and 0.15 N HCl in male Sprague-Dawley rats. TMG dissolved in physiological saline was injected intraperitoneally 0.5 h before the aspirin administration. The intragastric administration of acidified aspirin induced hyperemia and hemorragic erosions in rat stomach. The increase in total area of gastric erosions was reduced by pretreatment with TMG in a dose-dependent manner. The increases of thiobarbituric acid-reactive substances (TBA-RS) and myeloperoxidase (MPO) activity 3 h after aspirin administration were significantly inhibited by pretreatment with TMG. The gastric concentration of cytokine-induced neutrophil chemoattractants-1 (CINC-1) increased after aspirin administration, and the increase was also inhibited by pretreatment with TMG. These results suggest that TMG is effective for the treatment of aspirin-induced gastric injury. This anti-inflammatory effect of TMG seems to be related to impairment of lipid peroxidation, neutrophil function and cytokine production in gastric mucosa.

Background Angiotensin II has been implicated in the pathogenesis of vascular inflammation in various organs. The aim of the present study was to examine the effect of angiotensin II type I receptor antagonist, CV-11974, on reperfusion-induced small intestinal injury in rats. Methods Intestinal damage was induced by clamping both the superior mesenteric artery and the celiac trunk for 30 min followed by reperfusion for 60 min in male Wistar rats. CV-11974 was given to the rats by intravenous injection 1 h before the vascular clamping. The intestinal mucosal injury and inflammation were evaluated by biochemical markers and histological findings. Thiobarbituric acid reactive substances and tissue-associated myeloperoxidase (MPO) activity were measured in the gastric mucosa as indices of lipid peroxidation and neutrophil infiltration. The expressions of pro-inflammatory cytokines (CINC-1) in intestinal mucosa were measured by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-PCR (RT-PCR). In additional experiments with an in vitro flow system, human neutrophils were perfused on human umbilical vein endothelial cells (HUVEC) pretreated with anoxia–reoxygenation with or without CV-11974 and then the adhesive neutrophils were counted. Results Reperfusion after ischemia resulted in an increase in luminal protein concentrations, hemoglobin concentrations, thiobarbituric acid reactive substances, and MPO activity. Pretreatment with CV-11974 significantly inhibited the increases in these parameters. CV-11974 also inhibited increases in intestinal CINC-1 protein and mRNA expression induced by ischemia–reperfusion. Moreover, in an in vitro study, CV-11974 significantly inhibited the adherence of neutrophils to HUVEC exposed to reoxygenation after anoxia. Conclusions These results suggest that the blockade of angiotensin II type I receptor by treatment with CV-11974 remarkably reduced the reperfusion-induced intestinal injury.

Omeprazole is mainly metabolized in the liver by CYP2C19, a genetically determined enzyme, while rabeprazole is mainly nonenzymatically degraded with a minor involvement by CYP2C19. We investigated the gastric ulcer healing effect of omeprazole versus rabeprazole evaluated endoscopically with reference to the different CYP2C19 genotypes. Eighty patients with active gastric ulcer were treated with a daily dose of 20 mg of omeprazole or 10 mg of rabeprazole. The endoscopic evaluation was performed at the baseline and 2- and 8-week posttreatment periods. The endoscopic improvement of gastric ulcer size and ulcer healing rates using a thin rubber disc with a diameter of 6 mm, were evaluated in relation to the CYP2C19 genotypic status. The mean 2-week posttreatment ulcer size value by rabeprazole did not significantly differ among the different CYP2C19 genotypes, whereas the mean value in the homozygous extensive metabolizer patients treated with omeprazole was significantly (P = 0.0057) greater than in those with rabeprazole. However, after the 8-week treatment, omeprazole and rabeprazole showed the similarly high healing rates of 87.8% (31/37) and 88.9% (32/36), respectively. Although both omeprazole and rabeprazole showed a high healing rate of gastric ulcer after the 8-week treatment period, the healing effect of rabeprazole appears to be relatively independent of the CYP2C19 status, resulting in an earlier repair of gastric mucosal damage evaluated endoscopically compared to that of omeprazole.

Although edaravone (3-methyl-1-phenyl-pyrazolin-5-one), a newly developed radical scavenging agent, has been widely used for protection against ischemia-reperfusion (I-R) injury in patients with cerebral infarction, its effects on gastrointestinal I-R injury have not been evaluated. In the present study, we examined the effects of edaravone on experimental intestinal I-R damage in rats. In male Wistar rats with and without edaravone treatment, intestinal damage was induced by clamping the superior mesenteric artery for 30 min, followed by reperfusion. Edaravone was administered via intravenous infusion at 5 min before reperfusion was achieved by removal of the clamp. The rats were sacrificed after 60 min of reperfusion. Luminal protein and hemoglobin concentrations were measured as an index of mucosal injury and histological examination of hematoxylin and eosin-stained sections was performed. Thiobarbituric acid (TBA)-reactive substances and tissue-associated myeloperoxidase (MPO) activity were measured in the mucosa as indicators of lipid peroxidation and neutrophil infiltration, respectively. The mucosal concentration of cytokine-induced neutrophil chemoattractant (CINC)-1 (a member of the IL-8 family) was determined by enzyme-linked immunosorbent assay (ELISA). Additionally, CINC-1 messenger RNA (mRNA) was measured by the reverse-transcription polymerase chain reaction (RT-PCR). As a result, the levels of luminal protein and hemoglobin, TBA-reactive substances, and MPO activity were all increased significantly by I-R injury, and these increases were significantly inhibited by treatment with edaravone. Multiple erosions and bleeding were observed macroscopically after the small intestine was exposed to I-R injury, and these changes were inhibited by administration of edaravone. Microscopic I-R damage was also reduced by treatment with edaravone. CINC-1 protein and CINC-1 mRNA were both increased by I-R injury, while edaravone markedly reduced the levels of both protein and mRNA. In summary, these results suggest that edaravone can protect the small intestine against I-R injury by scavenging oxygen-derived free radicals.

AIM: To investigate the protective effect of lansoprazole on ischemia and reperfusion (I/R)-induced rat intestinal mucosal injury in vivo. METHODS: Intestinal damage was induced by clamping both the superior mesenteric artery and the celiac trunk for 30 min followed by reperfusion in male Sprague-Dawley rats. Lansoprazole was given to rats intraperitoneally 1 h before vascular clamping. RESULTS: Both the intraluminal hemoglobin and protein levels, as indices of mucosal damage, significantly increased in I/R-groups comparion with those of sham-operation groups. These increases in intraluminal hemoglobin and protein levels were significantly inhibited by the treatment with lansoprazole at a dose of 1 mg/kg. Small intestine exposed to I/R resulted in mucosal inflammation that was characterized by significant increases in thiobarbituric acid-reactive substances (TBARS), tissue-associated myeloperoxidase activity (MPO), and mucosal content of rat cytokine-induced neutrophil chemoattractant-1 (CINC-1). These increases in TBARS, MPO activities and CINC-1 content in the intestinal mucosa after I/R were all inhibited by pretreatment with lansoprazole at a dose of 1 mg/kg. Furthermore, the CINC-1 mRNA expression was increased during intestinal I/R, and this increase in mRNA expression was inhibited by treatment with lansoprazole. CONCLUSION: Lansoprazole inhibits lipid peroxidation and reduces development of intestinal mucosal inflammation induced by I/R in rats, suggesting that lansoprazole may have a therapeutic potential for I/R injury.