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OBJECTS Ultrashort-segment Barrett's esophagus (USSBE; length of

Introduction The bleeding source of hematochezia is unknown without performing colonoscopy. We sought to identify whether colonoscopy is a risk-stratifying tool to identify etiology and predict outcomes and whether presenting symptoms can differentiate the etiologies in patients with hematochezia. Methods This multicenter retrospective cohort study conducted at 49 hospitals across Japan analyzed 10,342 patients admitted for outpatient-onset acute hematochezia. Results Patients were mostly elderly population, and 29.5% had hemodynamic instability. Computed tomography was performed in 69.1% and colonoscopy in 87.7%. Diagnostic yield of colonoscopy reached 94.9%, most frequently diverticular bleeding. Thirty-day rebleeding rates were significantly higher with diverticulosis and small bowel bleeding than with other etiologies. In-hospital mortality was significantly higher with angioectasia, malignancy, rectal ulcer, and upper gastrointestinal bleeding. Colonoscopic treatment rates were significantly higher with diverticulosis, radiation colitis, angioectasia, rectal ulcer, and postendoscopy bleeding. More interventional radiology procedures were needed for diverticulosis and small bowel bleeding. Etiologies with favorable outcomes and low procedure rates were ischemic colitis and infectious colitis. Higher rates of painless hematochezia at presentation were significantly associated with multiple diseases, such as rectal ulcer, hemorrhoids, angioectasia, radiation colitis, and diverticulosis. The same was true in cases of hematochezia with diarrhea, fever, and hemodynamic instability. Discussion This nationwide data set of acute hematochezia highlights the importance of colonoscopy in accurately detecting bleeding etiologies that stratify patients at high or low risk of adverse outcomes and those who will likely require more procedures. Predicting different bleeding etiologies based on initial presentation would be challenging.

No prediction scores for the mortality of both inpatients and outpatients who developed nonvariceal upper gastrointestinal bleeding (UGIB) without endoscopic findings have been established. We aimed to derive and validate a novel prediction score for in-hospital mortality. We conducted a three-stage, multicenter retrospective study. In the derivation stage, patients with nonvariceal UGIB at six institutions were enrolled to derive the prediction score by logistic regression analysis. External validation of the score was performed to analyze discrimination by patients at six other institutions. Then the performance of this score was compared with that of four existing scores. We enrolled 1380 and 825 patients in the derivation and validation cohorts, respectively. A prediction score (CHAMPS-R Score) comprising seven variables (Charlson Comorbidity Index ≥ 2, in-hospital onset, albumin

Inflammatory myofibroblastic tumor is a rare intermediate-grade tumor. We herein report the case of an 81-year-old man with rectal ulceration and abnormal retroperitoneal soft tissue with a high serum level of IgG4. The administration of prednisolone reduced the retroperitoneal lesion; however, the rectal ulceration expanded. Surgical resection was performed. A histopathological examination revealed proliferating spindle cells accompanied by inflammatory cells and plasma cells. Liver metastasis emerged two months after surgical resection, and the histology of the proliferating spindle cells sampled by a fine-needle biopsy was similar to that of the rectal tissue. The patient ultimately died of inflammatory myofibroblastic tumor.

Background: Gastrointestinal bleeding (GIB) is one of the most common medical emergencies. We investigated the overall mortality after GIB in our institute and analyzed the prognostic factors in upper GIB (UGIB) and lower GIB (LGIB) separately. Summary: Between January 2010 and December 2018, 190 patients diagnosed with GIB in our hospital were retrospectively enrolled. Clinical records and biological data were collected. Risks for rebleeding and in-hospital mortality were assessed by a logistic regression analysis. Overall, the rebleeding rate and in-hospital mortality were 22.6 and 7.6%, respectively. GIB itself was not the direct cause of death in any cases. While older age (>65 years) was a significant risk factor for rebleeding in UGIB with an OR of 6.1 and 95% CI of 1.3–29.1, a poorer performance status (PS; ≥3) was a strong risk factor for rebleeding in LGIB, with an OR of 11.8 and 95% CI of 1.7–83.8. Poor PS and tachycardia (>100/min) were significantly associated with mortality in both UGIB and LGIB. In contrast, hypoalbuminemia (Key Messages: There were considerable differences in the risk factors for rebleeding and in-hospital mortality between UGIB and LGIB. The overall in-hospital mortality was 7.9% after GIB, including that a substantial portion of patients with GIB died from systemic complications after successful endoscopic hemostasis. Physicians need to diligently perform systematic treatment for GIB, which may be particularly important in societies of advancing aging, like Japan.

Mayo endoscopic subscore is a simple and validated endoscopic score for ulcerative colitis but the range of inflammation was not considered for scoring. There were few reports analyzing the range of inflammation for clinical relapse using Mayo endoscopic subscore (MES). The aim of this study is to investigate the relapsing potential of limited mucosal inflammation on endoscopic remission equivalent to MES of 0.For this retrospective observational study, ulcerative colitis patients underwent total colonoscopy were enrolled. Small mucosal lesion (SML) was defined as limited inflammation of range less than 3 cm. Clinical relapse was analyzed using the Kaplan-Meier curve with log-rank test, and factors associated with clinical relapse was analyzed using the cox proportional hazard regression model.A total of 102 periods with mucosal healing or modified MES of 0 with SML were analyzed. In 12-months observation periods, clinical relapse occurred more frequently in MES of 1 than in MES of 0 or modified MES of 0 with SML, but it was comparable between MES of 0 and modified MES of 0 with SML. When compared to patients with modified MES of 0 with SML, the hazard ratio in patients with MES of 1 (6.55;Small mucosal inflammation in UC does not affect the clinical relapse if most of the mucosa achieved a score similar to MES of 0.

Outcomes of acute lower gastrointestinal bleeding have not been compared according to hospital capacity. We aimed to perform a propensity score-matched cohort study with path and mediation analyses for acute hematochezia patients. Hospitals were divided into high- versus low-volume hospitals for emergency medical services. Rebleeding and death within 30 days were compared. Computed tomography, early colonoscopy (colonoscopy performed within 24 h), and endoscopic therapies were included as mediators. A total of 2644 matched pairs were yielded. The rebleeding rate within 30 days was not significant between high- and low-volume hospitals (16% vs. 17%, P = 0.44). The mortality rate within 30 days was significantly higher in the high-volume cohort than in the low-volume cohort (1.7% vs. 0.8%, P = 0.003). Treatment at high-volume hospitals was not a significant factor for rebleeding (odds ratio [OR] = 0.91; 95% confidence interval [CI], 0.79–1.06; P = 0.23), but was significant for death within 30 days (OR = 2.03; 95% CI, 1.17–3.52; P = 0.012) on multivariate logistic regression after adjusting for patients’ characteristics. Mediation effects were not observed, except for rebleeding within 30 days in high-volume hospitals through early colonoscopy. However, the direct effect of high-volume hospitals on rebleeding was not significant. High-volume hospitals did not improve the outcomes of acute hematochezia patients.

BackgroundThe value of endoscopy for acute lower GI bleeding (ALGIB) remains unclear, given few large cohort studies. We aim to provide detailed clinical data for ALGIB management and to identify patients at risk for adverse outcomes based on endoscopic diagnosis.MethodsWe conducted a multicenter, retrospective cohort study, named CODE BLUE J-Study, in 49 hospitals throughout Japan and studied 10,342 cases admitted for outpatient-onset of acute hematochezia.ResultsCases were mostly elderly, with 29.5% hemodynamic instability and 60.1% comorbidity. 69.1% and 87.7 % of cases underwent CT and colonoscopy, respectively. Diagnostic yield of colonoscopy reached 94.9%, revealing 48 etiologies, most frequently diverticular bleeding. During hospitalization, the endoscopic therapy rate was 32.7%, mostly using clipping and band ligation. IVR and surgery were infrequently performed, for 2.1% and 1.4%. In-hospital rebleeding and death occurred in 15.2% and 0.9%. Diverticular bleeding cases had higher rates of hemodynamic instability, rebleeding, endoscopic therapy, IVR, and transfusion, but lower rates of death and surgery than other etiologies. Small bowel bleeding cases had significantly higher rates of surgery, IVR, and transfusion than other etiologies. Malignancy or upper GIB cases had significantly higher rates of thromboembolism and death than other etiologies. Etiologies that have favorable outcomes were ischemic colitis, infectious colitis, and post-endoscopy bleeding.ConclusionsLarge-scale data of patients with acute hematochezia revealed high proportions of colonoscopy and CT, resulting in high endoscopic therapy rates. We highlight the importance of colonoscopy in detecting accurate bleeding etiologies that stratify patients at high or low risk of adverse outcomes.

Background: Optimal timing of colonoscopy for acute lower gastrointestinal bleeding is controversial, and it is unclear which patients benefit from early colonoscopy. The reported proportion of hemodynamically unstable patients is lower in randomized controlled trials than in observational studies. Methods: We studied 6,311 patients admitted for acute hematochezia in 49 Japanese hospitals, named the CODE-BLUE J Study. One propensity score-matched cohort comprised patients who underwent early (

OBJECTS Although anti-thrombotic use is recognized as a risk factor for upper gastrointestinal bleeding (UGIB), there has been no clear evidence that it worsens the outcomes after the bleeding. The aim of this study is to investigate the effects of anti-thrombotic agents on in-hospital mortality following UGIB. METHODS Information on clinical parameters, including usage of anti-thrombotic agents, was retrospectively collected from consecutive patients with UGIB at 12 high-volume centers in Japan between 2011 and 2018. The all-cause in-hospital mortality rate was evaluated according to the usage of anti-thrombotic agents. RESULTS Clinical data were collected from 2205 patients with endoscopically confirmed UGIB. Six hundred and forty-five (29.3%) patients used anti-thrombotic agents. The all-cause in-hospital mortality rate was 5.7% (125 deaths). After excluding 29 cases in which death occurred due to end-stage malignancy, 96 deaths (bleeding-related, n = 22 ; non-bleeding-related, n = 74) were considered "preventable." Overall, the "preventable" mortality rate in anti-thrombotic users was significantly higher than that in non-users (6.0% vs. 3.7%, P

Introduction Proton pump inhibitors (PPIs) are associated with the onset of Clostridioides difficile infection (CDI). Although a new potassium-competitive acid blocker, vonoprazan, consistently shows a more potent acid inhibitory effect in comparison to PPIs, the risk of CDI in vonoprazan-treated patients relative to those treated with PPIs is unknown. In this retrospective case-control study, using a nationwide hospital-based administrative database in Japan, we investigated the association of the onset of CDI in patients treated with vonoprazan. Methods A CDI case was defined as a case in which a patient was diagnosed and treated for CDI. For each CDI case, 3 non-CDI patients were extracted as controls. Information on the usage of acid suppressants in the 2 months before the onset of CDI and other confounding factors was collected. Relative associations of gastric acid suppressants with the onset of CDI were estimated. Results A total of 4,466 CDI cases and 13,220 of non-CDI controls were extracted. A multivariate conditional regression analysis revealed that PPI or vonoprazan use was modestly, but significantly associated with CDI (odds ratio [95% confidence interval]: PPI, 1.3 [1.2-1.4]; vonoprazan, 1.4 [1.2-1.7]). With PPI users as a reference, vonoprazan did not show a stronger association with CDI (odds ratio [95% confidence interval]: 1.07 [0.91-1.26]). Discussion We found a significant positive association between vonoprazan use and CDI; however, the magnitude of the association was not beyond that in PPI users. This is the first report on any potential adverse effects of vonoprazan.

Background/Aims: 5-Aminosalicylic acid (5-ASA) is a basic drug for inducing and maintaining remission for ulcerative colitis. One of its formulations has a coating with a pH-dependent degradation that ensures the release 5-ASA at the terminal ileum. No evidence has been shown concerning the effects of proton pump inhibitors (PPIs) or H2 receptor antagonists (H2RAs) on the clinical course of ulcerative colitis patients in remission. The present study assessed the effect of PPIs or H2RAs on the relapse of ulcerative colitis patients in clinical remission maintained by pH-dependent released 5-ASA.Methods: Ulcerative colitis patients who had been prescribed time- or pH-dependent-released 5-ASA between January 2015 and December 2018 were enrolled in this multicenter retrospective study. The period of remission until relapse occurred was analyzed among the patients taking time-dependent-released 5-ASA or pH-dependent-released 5-ASA with/without PPIs or H2RAs.Results: One hundred and nineteen patients were analyzed in this study. In the primary endpoint, the relapse rate was higher in patients taking pH-dependent-released 5-ASA and PPIs or H2RAs than in those taking the pH-dependent-released 5-ASA without PPIs or H2RAs, while the relapse rate was similar in patients taking the time-dependent-released 5-ASA with or without PPIs or H2RAs concomitantly. Patients with a short duration of disease and middle-aged patients more frequently showed relapse with PPIs or H2RAs than the other patients.Conclusions: The coadministration of PPIs or H2RAs affects the clinical course of ulcerative colitis in remission maintained by pH-dependent-released 5-ASA.

Phlegmonous gastritis is a rare but often fatal acute pyogenic infection of the stomach. We herein report three cases of phlegmonous gastritis with different causes: the long-term placement of a nasogastric feeding tube, bacteremia associated with cellulitis in a diabetic patient, and an adverse reaction to paclitaxel/carboplatin chemotherapy for cancer of unknown primary cause, which were classified as primary, secondary, and idiopathic types, respectively. Coping with the increasing morbidity rate associated with the diverse background of such patients requires a thorough understanding of the clinical features and image findings associated with this entity.

With the decreasing global trend in the Helicobacter pylori infection rate, compositional changes in the gastric cancer subsites have occurred worldwide. However, the compositional changes in Asian countries, including Japan, remain to be clarified. The aim of this study is to investigate the latest chronological changes in the gastric cancer subsite using a hospital-based registration system in Akita prefecture in Japan. From 2007-2015, subsites of gastric cancers were coded according to the International Classification of Diseases for Oncology (ICD-03). The nine-year registration period was divided into the three 3-year periods: 2007-2009, 2010-2012, and 2013-2015. A total of 10,804 cases of gastric cancer were registered. The proportion of cardiac cancer among total gastric cancer slightly but significantly declined from 12.1% in 2007-2009 to 9.2% in 2013-2015 (P < 0.01). Among non-cardia cancer, the proportion of corpus cancer significantly increased from 41.3% to 50.2% during the study period (P < 0.01), while that of antropylorus cancer significantly decreased from 37.6% to 34.3% (P < 0.05). Such compositional changes in the gastric cancer subsite were observed largely in men, regardless of the histologic subtype of cancer. With the decreasing H. pylori infection rate, compositional changes in the gastric cancer subsite are occurring in Japan. While the proportion of cardia and antropylorus cancer is declining, that of corpus cancer is increasing, indicating diverse etiology of gastric carcinogenesis depending on the subsites. Identifying the most common sites of occurrence, may help to improve the efficiency of screening for gastric cancer.

A 60-year-old man presented with odynophagia after bronchial artery infusion chemotherapy for pulmonary metastasis of hepatocellular carcinoma. Esophagogastroduodenoscopy (EGD) revealed an esophageal ulcer in the middle thoracic esophagus. An esophageal biopsy demonstrated no malignancy. However, the symptoms had not improved after a month. EGD was performed again and showed a white cord lump at the bottom of the same esophageal ulcer identified before, showing no improving tendency. A repeated biopsy of the lump revealed actinomycosis, and the symptoms were improved by the oral administration of ampicillin. We herein report a case in which esophageal actinomycosis with a unique morphology of refractory esophageal ulcer was rapidly improved by the administration of antibiotics.

Primary enterolith is a rare condition that can induce ileus and intestinal perforation. We report the first case of a true primary enterolith treated by balloon-assisted enteroscopy. The patient presented with a small intestinal ileus. After its improvement following the insertion of an ileus tube, radiography with amidotrizoate sodium meglumine detected a round, movable defect in the ileum measuring 42 mm diameter. The patient was diagnosed with a primary enterolith based on her past history. The enterolith was fractured and removed using balloon-assisted enteroscopy. This case suggests that balloon-assisted enteroscopy may be an effective non-invasive treatment option for enteroliths.

It has been reported that the stomach is a source of leptin, which is the product of the obese (ob) gene. In the present study, the effect of alcohol on leptin level in serum, gastric mucosa, and adipose tissue was studied to understand the relationship between appetite and alcohol consumption. Male Sprague-Dawley rats were administered 1 ml of 25% ethanol perorally. Leptin levels in the serum, gastric mucosa, and adipose tissue were measured. The serum leptin level was significantly decreased 3 and 6 hr after ethanol administration, although the gastric leptin level was not affected. The leptin level in the adipose tissue was significantly increased 3 hr after administration. We conclude that the decreased serum leptin level after ethanol administration might be due to suppression of leptin secretion from adipose tissue to the systemic circulation. These findings might be important for understanding the relationship between alcohol consumption and appetite.

Behҫet's disease (BD) is a chronic disorder involving multiple organ systems including the small and large intestines. A 46-year-old female diagnosed with intestinal BD presented with ileocecal perforation and diffuse peritonitis and subsequently underwent ileocolic resection with ileostomy. After surgery, she suffered from refractory para-ileostomal ulceration associated with BD. Most importantly, however, treatment with infliximab was significantly effective in healing the ulceration. This is the first report of para-ileostomal ulceration associated with BD successfully treated with infliximab, suggesting the possible use of infliximab as a therapeutic option for para-stomal ulcers related to BD.

Summary Background : In functional gastrointestinal (GI) disorders including functional dyspepsia (FD) and irritable bowel syndrome (IBS), there might be no small extent of contributions of psychosomatic factors. As a therapy for IBS patients, the effectiveness of antidepressants has been reported. Aim : In this study, we evaluated the efficacy of H2-receptor antagonist (famotidine) and 5-HT4 receptor agonist (mosapride citrate). In addition, the effect of antidepressants was assessed as the second-step therapy. Methods : Patients complaining upper GI symptoms were diagnosed as FD excluding organic diseases. Randomized patients received 20 mg/day of famotidine or 15 mg/day of mosapride citrate for 4 weeks and the efficacy was compared between the two groups based on a 10-point visual analogue scale. When symptoms were not relieved (score improvement 0–2 points), patients received amitriptyline (30 mg/day) or no medication for 4 weeks randomly. Patients who had depression in psychological test (SDS) were omitted. Results : As the first-step therapy, both famotidine and mosapride showed beneficial effects regardless of FD subtypes, age and gender. The efficacy of these two drugs in relieving FD symptoms was not significantly different. In patients who failed in the first-step therapy, amitriptyline showed beneficial effects. Conclusions : These findings might be clinically important in view of the efficient relief of symptoms in FD patients.

D-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor-alpha (TNF-alpha) plays a pivotal role. We examined the effects of a highly selective adenosine A2A receptor agonist (ATL-146e) on GalN/LPS-induced fulminant hepatic failure.Mice were given an intraperitoneal dose of GalN (800 mg/g body weight)/LPS (100 ng/g body weight) with and without ATL-146e (0.01 microg/kg) treatment. Liver injury was assessed biochemically and histologically. Also, TNF-alpha levels in the serum were determined.The serum liver enzyme (ALT) level in vehicle-treated mice was 20 960 +/- 2800 IU/ml and was reduced by 63% to 7800 +/- 1670 IU/ml by treatment with 0.01 microg/kg per minute ATL146e, P0.05. Treatment with ATL-146e significantly reduced serum TNF-alpha and greatly reduced inflammation assessed by histopathologic examination compared with control mice treated with GalN/LPS. ATL-146e also reduced lethality at 12 h from 65% to 13%.The present findings suggest that the highly selective adenosine A2A receptor agonist (ATL-146e) prevents endotoxin-induced lethal liver injury by suppression of TNF-alpha secretion.

Background: Activation of adenosine A2A receptors reduces the production of various pro-inflammatory cytokines and suppresses neutrophil activation. Water-immersion restraint is well known to cause gastric mucosal lesions due to stress. The pathogenesis of stress-induced gastric mucosal lesions is characterized by activation of inflammatory cells and production of inflammatory cytokines. Agonists of adenosine A2A receptors are known to be anti-inflammatory, but the effects of these compounds on the development of gastric mucosal lesions has not been reported. In the present study, the effect of a potent and selective adenosine A2A receptor agonist, ATL-146e, on water-immersion stress-induced gastric mucosal lesions was studied. Methods: Rats were subjected to water-immersion stress with or without pretreatment with a single intraperitoneal injection of a potent and selective agonist of the adenosine A2A receptor. The gastric concentrations of myeloperoxidase (MPO), as an index of neutrophil accumulation, and the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), were measured. Results: The total length of gastric erosions (ulcer index) in control rats was 21.6 ± 3.23 mm and was reduced by 86% to 3.1 ± 0.83 mm by pretreatment with 5.0 µg/kg ATL146e (P

We herein describe the case of a 51-year-old man with a duodenocolic fistula (DCF) caused by a stomal ulcer. The patient complained of watery diarrhea, dysgeusia and malnutrition. His medical history included distal gastrectomy with Billroth I reconstruction for duodenal ulcer perforation. A combination study using endoscopy and contrast imaging confirmed the presence of DCF. Laparotomic fistulectomy was performed, which resulted in the patient's recovery from diarrhea and malnutrition. The histological findings suggested that the fistula had originated from a stomal ulcer. In patients with chronic watery diarrhea of obscure origin following gastrectomy, DCF is a possible cause of the diarrhea.

We report a case of gastric hamartomatous inverted polyps that are a rare histological type of gastric polyp and difficult to diagnose. Gastric submucosal tumor was detected by upper gastrointestinal X-ray series in 37-year-old man. Endoscopy revealed a submucosal tumor (SMT) , which eroded with a depression on its surface in the fornix. Endoscopic ultrasonography showed a heterogeneous tumor in the third layer. Endoscopic submucosal dissection (ESD) was performed to resect the tumor completely. The pathological diagnosis was a gastric hamartomatous inverted polyp. The patient was later discharged without any complications. Hamartomatous inverted polyps without a stalk are classified as the SMT type because the tumor is inverted down growth into the submucosal layer, otherwise polyps with a stalk are classified as the polyp type. All of the polyps were resected endoscopically, however, surgical resection was performed for those of the SMT type, because it is difficult to remove this type completely by en-block resection using conventional EMR technique. ESD method may be indicated for SMT-type hamartomatous inverted polyps.

Inhibition of type IV phosphodiesterase (PDE4) activity is beneficial in various inflammations. However, the effect of phosphodiesterase inhibitors on the development of stress-induced gastric mucosal lesions has not been reported. In the present study, we examined the effect of a specific PDE4 inhibitor (rolipram) on stress-induced gastric mucosal lesions. Rats were exposed to water-immersion stress with or without pretreatment with rolipram. Ulcer index and myeloperoxidase activity of the gastric mucosa were evaluated. Gastric mucosal lesions and mucosal myeloperoxidase activity were suppressed by treatment with rolipram without acid suppression. The effect of intraperitoneal administration of 2.5 mg/kg rolipram on suppression of mucosal lesions was almost equal to that of treatment with 200 mg/kg cimetidine. We demonstrated that a specific PDE4 inhibitor has a potent anti-ulcer effect presumably mediated by an increment in intracellular cAMP in inflammatory cells, in which this enzyme is abundantly and specifically expressed.

Background and Aim: Leptin, the product of the obese (ob) gene, is a circulating peptide mainly synthesized by adipocytes. Leptin inhibits food intake and decreases body weight. A recent report has suggested that the gastric mucosa is also the source of leptin, and that the stomach leptin also contributes to the regulation of the serum leptin level. The aim of the present study was to investigate the effect of water-immersion stress on serum, stomach and adipose tissue leptin levels to understand the relationship between stress and eating behavior. Methods: Male Sprague–Dawley rats were used in this experiment. The leptin level in the serum, gastric mucosa and adipose tissue was measured using ELISA system before and after the initiation of water-immersion stress. Results: The serum leptin level was significantly increased by water-immersion stress. The peak was observed 9 h after the initiation of the stress (P

Concanavalin A (Con A) activates T lymphocytes and induces CD4+ T cell-mediated hepatic injury in mice. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-6 (IL-6), are critical mediators in this experimental model. Activation of adenosine A2A receptors reduces the production of various pro-inflammatory cytokines and suppresses T cell activation. A selective adenosine A2A receptor agonist (ATL-146e) has been shown to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP (cAMP) in leukocytes. The aim of the present study was to determine whether ATL-146e could ameliorate Con A-induced hepatic injury, reduction of pro-inflammatory cytokine production.Balb/c mice were injected with 25mg/kg Con A with or without a single injection of ATL-146e (0.5-50 microg/kg), 5 min prior to Con A administration. Liver enzymes, histology, and serum levels of tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 were examined. We also assessed the effects of ATL-146e on pro-inflammatory cytokine production with CD4+ T cell.Pretreatment with ATL-146e significantly reduced serum levels of liver enzymes (P0.001). The serum pro-inflammatory cytokines were all increased after Con A administration and reduced to near normal levels by ATL-146e. ATL-146e also inhibited CD4+ T cell pro-inflammatory cytokine production.A selective adenosine A2A receptor agonist, ATL-146e, can prevent concanavalin A-induced hepatic injury that is presumably mediated by its anti-inflammatory properties.

Type IV phosphodiesterase is a key enzyme to metabolize intracellular adenosine 3',5'-cyclic monophosphate (cAMP) expressed in inflammatory cells. The specific type IV phosphodiesterase inhibitor that increases intracellular cAMP is known to be potent suppressor of proinflammatory cytokines. However, the effect of phosphodiesterase inhibitors on the development of pancreatitis has not been well understood. In the present study, we examined the effect of a specific type IV phosphodiesterase inhibitor on experimentally induced pancreatitis.Severity of cerulein-induced pancreatitis and pancreatic proinflammatory cytokine levels were studied with or without pretreatment with a specific type IV phosphodiesterase inhibitor (rolipram) in Sprague-Dawley rats.Administration of rolipram clearly ameliorated severity of pancreatitis evaluated by edema, serum amylase (P0.05), and lipase levels (P0.05) in rats. Also, the level of pancreatic proinflammatory cytokine (interleukin-1beta (IL-1beta)) was significantly reduced when rats were treated with rolipram prior cerulein injection (P0.05).Our results demonstrated that intracellular cAMP and pancreatic proinflammatory cytokine level, which are regulated by type IV phosphodiesterase, might play an important role in the pathogenesis of acute pancreatitis.

To determine whether a specific adenosine A(2A) receptor agonist (ATL-146e) can ameliorate aspirin-induced gastric mucosal lesions in rats, and reduce neutrophil accumulation and production of pro-inflammatory cytokines.Gastric lesions were produced by oral gavage of aspirin (200 mg/kg) and HCl (0.15 mol/L, 8.0 mL/kg). 4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester (ATL-146e, 2.5-5 mug/kg, IP) was injected 30 min before the administration of aspirin. Tissue myeloperoxidase (MPO) concentration in gastric mucosa was measured as an index of neutrophil infiltration. Gastric mucosal concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined by ELISA. Also, we examined the effect of ATL-146e on tissue prostaglandin E2 (PGE2) production and gastric secretion.Intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. The total length of gastric erosions (ulcer index) in control rats was 29.8+/-7.75 mm and was reduced to 3.8+/-1.42 mm after pretreatment with 5.0 g/kg ATL-146e (P0.01). The gastric contents of MPO and pro-inflammatory cytokines were all increased after the administration of aspirin and reduced to nearly normal levels by ATL-146e. Gastric mucosal PGE2 concentration was not affected by intraperitoneal injection of ATL-146e.The specific adenosine A(2A) receptor agonist, ATL-146e, has potent anti-ulcer effects presumably mediated by its anti-inflammatory properties.

Background and Aims: Rolipram is a specific type IV phosphodiesterase inhibitor that suppresses the activity of immune cells and the production of pro-inflammatory cytokines. In this study, we assessed the effect of rolipram on acute liver injury using thioacetamide (TAA)-induced liver injury in rats as a model. Methods: Rats were treated with rolipram (0.5–5 mg/kg, intraperitoneally) or vehicle and injected 30 min later with TAA (100 mg/kg, subcutaneously). Serum transaminase concentrations and tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β) and growth related oncogene/cytokine-induced neutrophil chemoattractant-1 (GRO/CINC-1) levels were measured and livers were examined for microscopic changes. Dose-dependent protection against TAA liver injury was based on transaminase levels and inflammatory cytokine production, and was measured 9 h after TAA when the peak release of cytokines occurred. Result: Rolipram suppressed liver injury based on serum aspartate transaminase (AST), alanine transaminase (ALT) and histology and reduced TNF-α, IL-1β and GRO/CINC-1 levels. Rolipram, at doses of 0.5–5 mg/kg, suppressed serum transaminase and TNF-α production in a dose-dependent manner, and these effects were significant at doses of 2.5 and 5 mg/kg. Conclusion: In our rodent model of acute liver injury, rolipram clearly reduced liver damage and inhibited pro-inflammatory cytokine production. These results suggest that specific type IV phosphodiesterase inhibitors, such as rolipram, have potent hepatoprotective effects that are associated with suppressing inflammatory cytokine production.

[Background and Aim] Since the technical advance and the development of new devices, endoscopic submucosal dissection (ESD) is widely utilized for the treatment of superficial esophageal squamous cell neoplasms (ESCNs). In the treatment of ESCNs without nodal metastasis, ESD achieves the similar clinical outcomes to those of esophagectomy and chemoradioherapy and is much less invasive than them. The intensive studies of histopathological analysis of surgically resected ESCNs have proven that the cases of non-invasive carcinoma (EP, carcinoma in situ) and intra-mucosal invasive carcinoma limited to the lamina propria mucosae (LPM) had an extremely low risks of lymph node and distant metastasis. Based on these findings, the Japanese guideline for the treatment of esophageal cancer states that both EP and LPM cases are suitable for ESD. On the other hand, the lymph node metastasis rate of ESCNs invading to the muscularis mucosae (MM) including both with and without lymphovascular invasion has been reported as 7-10 %. Thus, ESD treatment had not been positively recommended for MM cases. However, it is assumed that MM cases without lymphovascular invasion have no lymph node metastasis. Thus, there exists the possibility that MM cases without lymphovascular invasion can be suitable for ESD. In this study, therefore, we evaluated expanded ESD indication to the MM cases without lymphovascular invasion, by analyzing surgically resected specimens histopathologically and investigating the clinical outcomes both after surgery and ESD of MM cases without lymphovascular invasion. [Methods] MM cases without lymphovascular invasion surgically treated between January 2001 and December 2010 (11 cases) and those treated with ESD between January 2006 and August 2012 (30 cases) at Akita University Hospital were enrolled in this study. [Results] In the detailed histopathological analysis of the surgically resected specimens of 11 MM cases without lymphovascular invasion, no lymph node metastasis was detected. No recurrence or metastasis developed in any of these 11 cases until today. In the analysis of the ESD-treated, 30 MM cases were proven to have no lymphovascular invasion by the histopathological examination of the specimens endoscopically resectd en bloc. Then, no additional therapy such as chemoradiotherapy was performed for these cases. However, all of the 30 cases are still alive without recurrence or metastasis during the followup period (4-81 months, average 33.8 months). [Conclusion] Our current study elucidated that MM cases without lymphovascular invasion has no risk of lymph node metastasis, and clinical outcomes of the ESD-treated MM cases without lymphovascular invasion are extremely satisfactory. These data suggest that ESD indication for superficial ESCNs treatment can be expanded to the MM cases without lymphovascular invasion.

Double Balloon Enteroscopy (DBE): New Information and Limitations Defined Bradford H. Jones, M.E. Harrison, David E. Fleischer, Nancy L. Maltby, Jonathan A. Leighton Purpose: DBE is a new enteroscope that has the capability to examine most, if not all of the small intestine to aid in the diagnosis and therapy of small intestinal disease. This enteroscope device, which includes an overtube and two balloons, is capable of advancing to the distal ileum by cycling the inflation and deflation of the two balloons with coordinated alternating pushing and retraction of the endoscope and the overtube. The aims of this study include (1) to determine at what point during the procedure it is reasonable to cease advancement of the enteroscope and begin withdrawal; (2) to assess the complications and adverse effects of DBE. Methods: 6 patients underwent DBE. Estimated distance advanced and time elapsed with each balloon cycle of the enteroscope were recorded. Each patient completed a symptom survey 7 days following the procedure. Procedural complications were also recorded. Results: The average distance advanced and time elapsed per balloon cycle are graphed below. The progression per cycle diminished after 12 cycles or approximately 50 minutes into the procedure. Five of 6 (83%) patients reported transient sore throat following DBE. Three of 6 (50%) patients reported abdominal discomfort. In all cases, these symptoms resolved within 72 hours. The only serious complication was a case of pulmonary aspiration. The patient experienced mild hypoxemia that quickly resolved, and she was discharged home after 48 hours of inpatient observation. Conclusions: Our data suggest that the rate of advancement of the DBE diminishes after approximately 12 cycles or 50 minutes, and thus this may be an appropriate time to initiate withdrawal of the scope. This conclusion will be tested as more data is collected regarding the distance advanced and time elapsed with each balloon cycle. The most commonly reported adverse effects of DBE include transient sore throat and abdominal discomfort. Abstracts