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This prospective cohort study searched for factors associated with a response to nucleos(t)ide analogue/peg-interferon (NUC/peg-IFN) sequential therapy. A total of 95 patients with chronic hepatitis B being treated with NUCs were enrolled. Immediately following NUC cessation, peg-IFN was administered at 180 µg/dose weekly for 48 weeks. Twenty-six patients (27%) were judged to be responders at 48 weeks after the completion of peg-IFN. Analysis of baseline factors revealed that hepatitis B surface antigen (HBsAg)

Accessory spleens (ASs), ectopic splenic tissue at intrapancreatic and extrapancreatic sites, rarely contain epidermoid cysts. Our aim was to analyze the incidence of epidermoid cysts in ASs and perform an immunohistochemical analysis of its epithelial lining. We included in the study 148 ASs from 135 patients, for which pathological data were available. Eleven were intrapancreatic ASs (IPASs) and 137 were extrapancreatic ASs (EPASs). Six of the eleven (55%) IPASs contained epidermoid cysts, but they were not detected in EPASs. Immunohistochemical analysis showed that both the superficial/luminal and basal layer of the epithelial lining of epidermoid cysts in IPASs are negative for MUC2, MUC5AC, MUC6, WT-1, calretinin, thrombomodulin, uroplakin-II, and uroplakin-III. The superficial/luminal layer was positive for MUC4, CK7, and CA19-9 in all cases (100%), for CEA and HBME-1 in three cases (50%), and for MUC1, CK5/6, and CK20 in two cases (33%). The superficial/luminal layer was negative for p63 and D2-40 in all cases. The basal layer was positive for MUC1, CK5/6, p63, and HBME-1 in all six cases (100%), for CK7 and D2-40 in two cases (33%), and for CEA in one case (17%). The basal layer was negative for MUC4, CK20, and CA19-9 in all cases. Epidermoid cysts are a characteristic feature of IPASs but not of EPASs. Immunohistochemical analysis showed that the epithelial lining of epidermoid cysts in IPASs has a mixed character of glandular, squamous, mesothelial, and urothelial epithelium.

New strategies for the care of irritable bowel syndrome (IBS) are developing and several novel treatments have been globally produced. New methods of care should be customized geographically because each country has a specific medical system, life style, eating habit, gut microbiota, genes and so on. Several clinical guidelines for IBS have been proposed and the Japanese Society of Gastroenterology (JSGE) subsequently developed evidence-based clinical practice guidelines for IBS. Sixty-two clinical questions (CQs) comprising 1 definition, 6 epidemiology, 6 pathophysiology, 10 diagnosis, 30 treatment, 4 prognosis, and 5 complications were proposed and statements were made to answer to CQs. A diagnosis algorithm and a three-step treatment was provided for patients with chronic abdominal pain or abdominal discomfort and/or abnormal bowel movement. If more than one alarm symptom/sign, risk factor and/or routine examination is positive, colonoscopy is indicated. If all of them, or the subsequent colonoscopy, are/is negative, Rome III or compatible criteria is applied. After IBS diagnosis, step 1 therapy consisting of diet therapy, behavioral modification and gut-targeted pharmacotherapy is indicated for four weeks. Non-responders to step 1 therapy proceed to the second step that includes psychopharmacological agents and simple psychotherapy for four weeks. In the third step, for patients non-responsive to step 2 therapy, a combination of gut-targeted pharmacotherapy, psychopharmacological treatments and/or specific psychotherapy is/are indicated. Clinical guidelines and consensus for IBS treatment in Japan are well suited for Japanese IBS patients; as such, they may provide useful insight for IBS treatment in other countries around the world.

Lower gastrointestinal bleeding is a frequent cause of hospitalization, particularly in the elderly, and its incidence appears to be on the rise. Colonic diverticular bleeding is the most common form of lower gastrointestinal bleeding and is responsible for 30-40 % of bleeding episodes. Risk factors associated with diverticular bleeding include obesity, hypertension, anticoagulants, diabetes mellitus, and ischemic heart disease. Recent studies have suggested a relationship between usage of non-steroidal anti-inflammatory drugs (NSAIDs) and colonic diverticular bleeding; however, most studies were small with wide confidence intervals. We identified studies by searching the PubMed and Scopus databases (from inception through 31 December 2012) and by searching bibliographies of relevant articles. Summary relative risks (RRs) with 95 % confidence intervals (CIs) were calculated with fixed-effects and random-effects models. A total of six studies (five case-control studies and one cohort study) met inclusion criteria for analysis. Non-aspirin NSAIDs (NANSAIDs) and aspirin were associated with an increased risk of colonic diverticular bleeding (summary RR = 2.48, 95 % CI 1.86-3.31), with moderate heterogeneity among these studies (P heterogeneity = 0.11, I (2) = 44.4 %). Stratification to evaluate the heterogeneity found that both NANSAIDs (summary RR = 2.24, 95 % CI 1.63-3.09; 5 studies) and aspirin (summary RR = 1.73; 95 % CI 1.31-2.30; 3 studies) were associated with the risk of diverticular bleeding. Aspirin/NANSAIDs use was strongly and consistently associated with an increased risk of colonic diverticular bleeding. Further studies are needed to stratify individuals at risk of diverticular bleeding associated with the use of these agents.

Ursodeoxycholic acid (UDCA) partly exerts choleretic effects by modifying the function of the bile salt export pump (Bsep, ABCB11). UDCA induces insertion of Bsep into the canalicular membrane of hepatocytes; however, underlying mechanisms remain unknown. We aimed to elucidate molecular mechanisms behind UDCA-induced Bsep activation.We established MDCK II cells stably expressing both Bsep and Na(+)-taurocholate cotransporting polypeptide, and investigated the effect of UDCA on activity and protein expression of Bsep using these cells. We performed inhibitor study to know the molecules involved in UDCA-induced Bsep activation, and also tested the influence of UDCA on Bsep having a disease-associated mutation.UDCA activated Bsep in a dose-dependent manner. UDCA did not affect Bsep protein expression in whole cell lysates but increased its apical surface expression by extending the half-life from 2.4 to 5.0 h. This effect was specific to Bsep because UDCA did not affect other apical and basolateral proteins, and was independent of protein kinase A, adenylate cyclase, p38(MAPK), phosphatidylinositide 3-kinase, Ca(2+), and microtubules. NorUDCA activated Bsep similar to UDCA; however, cholic acid, taurocholic acid, and tauroUDCA had no effect. UDCA significantly increased the activity of Bsep with a benign recurrent intrahepatic cholestasis 2 mutation (A570T) but did not affect Bsep with a progressive familial intrahepatic cholestasis 2 mutation (G982R or D482G).We demonstrated that UDCA stabilizes Bsep protein in the apical membrane and increases its activity in MDCK II cells, presumably by retarding the endocytotic process.

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is the most frequent complication of ERCP. Several meta-analyses have examined the effects of protease inhibitors (gabexate mesilate, ulinastatin, and nafamostat mesilate) and non-steroidal anti-inflammatory drugs (NSAIDs) on post-ERCP pancreatitis, but the results have been confusing. Since the previous meta-analysis, several new studies have been published on this topic. To provide an updated quantitative assessment of the effectiveness of protease inhibitors and NSAIDs in preventing post-ERCP pancreatitis, we conducted a meta-analysis of randomized trials for patients at risk of post-ERCP pancreatitis. Twenty-six articles were included in this meta-analysis. Nafamostat mesilate (summary RR = 0.41; 95 %CI 0.28-0.59; n = 4 studies) and NSAIDs (summary RR = 0.58; 95 %CI = 0.44-0.76; n = 7 studies) were associated with decreased risk of post-ERCP pancreatitis in the high-quality studies. However, gabexate mesilate (summary RR = 0.64; 95 %CI = 0.36-1.13; n = 6 studies) and ulinastatin (summary RR = 0.65; 95 %CI = 0.33-1.30; n = 2 studies) were not associated with decreased risk of post-ERCP pancreatitis in the high-quality studies. This is the first meta-analysis to compare the effects of three protease inhibitors. Solid evidence supports the use of nafamostat mesilate and NSAIDs for preventing post-ERCP pancreatitis.

Background Carcinosarcoma of the ampulla of Vater is extremely rare, and to the best of our knowledge, this is the third reported study. Case presentation The patient was a 73-year-old man, who presented with a chief complaint of dark urine. After a work-up, we suspected duodenal papillary cancer and performed a subtotal stomach-preserving pancreaticoduodenectomy with lymph node dissection. Immunohistochemically, the sarcomatous atypical cells were diffusely positive for cytokeratin AE1&3 and vimentin and focally positive for α-smooth muscle actin; these cells were also negative for desmin, CD34, DOG1, c-kit, and S100. From these findings, we diagnosed the patient with so-called carcinosarcoma. There was no lymph node metastasis. Conclusions Carcinosarcoma of the ampulla of Vater has a poor prognosis, and lymph node metastases are often seen. For the complete cure of carcinosarcoma of the ampulla of Vater, resection with the dissection of the lymph nodes may be necessary.

A 67-year-old male patient presenting with chronic hepatitis C (CHC) achieved a sustained virological response (SVR) following 6 months of treatment with 6 million units of beta-interferon (IFN). The SVR state continued for 6 years. Hepatocellular carcinoma (HCC) developed in liver segments 4 and 5, and was treated with transcatheter arterial chemoembolization, followed by radiofrequency ablation of the tumors. A recurrence of HCC occurred in segment 4 one and a half years after the initial treatment for HCC and a new tumor also developed in segment 8. These tumors were diagnosed to be recurrent HCC, and the three hepatic segments were resected. The pathological examination and immunostaining of the tumors revealed the tumor in segment 4 to be a well to moderately differentiated typical HCC. On the other hand, the tumor in segment 8 was a moderately to poorly differentiated adenocarcinoma and was diagnosed as an intrahepatic cholangiocellular carcinoma (ICC). HCC developed from CHC in a patient who achieved a 6-year SVR after IFN therapy, followed one and a half years later by the development of a heterochronous ICC at a different site, thus indicating the presence of HCC-ICC double cancer. This was an exceedingly rare and clinically important case in terms of the carcinogenic mechanism of HCC and ICC from a post-SVR CHC patient. We have to be aware of the possible development not only of HCC but of ICC after SVR in CHC patients.

A cystic lesion of the pancreas was detected in a 25-year-old asymptomatic woman during a company medical checkup. Abdominal computed tomography (CT) revealed an ossified lesion in the pancreatic body, and the patient was referred to us for further management. Abdominal ultrasound and endoscopic ultrasound showed a hypoechoic mass with a large ossific focus, measuring 25 mm in the pancreatic body. CT and magnetic resonance imaging (MRI) showed a nonenhancing tumor lesion with a large calcific focus, measuring 20 mm in the pancreatic body. Endoscopic retrograde pancreatography revealed mild stenosis of the main pancreatic duct near the ossific focus in the pancreatic body. From the above, a pancreatic solid-pseudopapillary neoplasm (SPN) was suspected, and resection of the pancreatic body was performed. Intraoperatively, a whitish tumor measuring about 20 mm was recognized. Histopathologically, moderately large-sized tumor cells containing eosinophilic cytoplasm were arranged in a pseudopapillary formation, and infiltrated the surrounding normal tissue with ossification. Immunostaining was positive for α1-antitrypsin, not inconsistent with the diagnosis of SPN. We report this case of pancreatic SPN with ossification and a review of the literature.

This prospective multicenter phase II study was carried out to investigate the efficacy, safety and pharmacokinetics of S-1 monotherapy in elderly patients over 75 years of age, with unresectable advanced or recurrent gastric cancer. Patients had measurable or evaluable lesions according to the Japanese Classification of Gastric Carcinoma. S-1 (25–60 mg determined by the body surface area and creatinine clearance) was given orally, twice daily. A course of treatment consisted of 4-week administration followed by a 2-week rest period, and the patients received repeated courses. Thirty-three patients were enrolled. Pharmacokinetics of S-1 was studied in six patients, and the maximum plasma concentrations of respective metabolites after S-1 administration were found to be similar to those reported for younger cancer patients. The overall response rate in 33 patients was 21.2% (95% CI, 10.7–37.8%), and median progression-free survival was 3.9 months, with a median overall survival of 15.7 months. Frequently noted adverse events include leukopenia, neutropenia, anemia, anorexia, and fatigue. As for serious adverse events, relatively higher frequencies of anemia (9%) and anorexia (12%) of grade 3 severity were found, but there were no grade 4 episodes. The results suggest that S-1 monotherapy is safe and useful for elderly patients with unresectable advanced or recurrent gastric cancer when the dose is selected with caution, taking into account renal function.

We experienced a patient with severe protein-losing enteropathy and generalized inflammatory polyposis. In addition, this case was complicated by deep venous thrombosis and pulmonary embolism. Patients with inflammatory bowel disease are at increased risk for thromboembolic events, most commonly in the setting of active colitis. However, our patient was in the remission stage. We report the occurrence of deep venous thrombosis and pulmonary embolism as a complication of inflammatory polyposis and protein-losing enteropathy in the remission stage of ulcerative colitis.

Until the development of wireless capsule endoscopy (CE) and double-balloon enteroscopy (DBE), it was extremely difficult to examine the entire small intestine. To assess the usefulness of DBE for diagnosing suspected small intestinal bleeding, we retrospectively compared the diagnoses and treatments of cases before and after its introduction at one hospital. Between September 2003 and December 2005, 21 consecutive patients with suspected small intestinal bleeding underwent DBE at Tokai University Hospital (group A), and subsequently 2 were excluded from the study after being diagnosed with bleeding from a diverticulum and an angiodysplasia in the ascending colon, respectively. For comparison, inpatients who were negative for gastrointestinal bleeding on colonoscopy and gastroscopy between May 1998 and August 2003 were reviewed and 27 consecutive patients who had not undergone DBE were selected as the control group (group B). All patients had been diagnosed negative for a source of bleeding on more than one colonoscopy and gastroscopy. There were no significant differences between the two groups in terms of age, gender, history of blood transfusion, blood hemoglobin value on admission, or symptoms. The diagnostic yield of DBE in identifying the source of bleeding was 78.9%: six cases of small intestinal ulcers, five cases of angiodysplasia, two cases of hard submucosal tumor (SMT), one case of small pulsating SMT, and one case of small intestinal cancer. DBE was also used to successfully treat three cases of angiodysplasia with argon plasma coagulation. In the control group, conventional investigations, including enteroclysis, angiography, Meckel scan, scintigraphy with technetium-labeled red blood cells, and/or push enteroscopy, were performed in 88.9%, 29.6%, 29.6%, 55.6%, and 25.9%, respectively. The overall diagnostic yield of the conventional approaches was only 11.1% (P < 0.01), comprising a Meckel's diverticulum, a polyp, and an angiodysplasia. We conclude that DBE can be used to diagnose suspected small intestinal bleeding and to treat some cases, such as angiodysplasia.

Adrenomedullin (AM) is a novel vasorelaxant peptide isolated from pheochromocytoma. Proadrenomedullin N-terminal 20 peptide (PAMP) is a hypotensive peptide generated by posttranslational enzymatic processing of a 185-amino acid pro-AM molecule, the same precursor as AM. In this study, we investigated localizations of these peptides by immunocytochemistry and AM mRNA by non-radioisotopic in situ hybridization followed by the streptavidin and biotin complex (ABC) method and catalyzed signal amplification (CSA) in the rat adrenal medulla and gastric mucosa. In the gastric mucosa, both AM- and PAMP-like immunoreactivities were found in the neuroendocrine cells, but PAMP-positive cells were more abundant than AM-positive ones. By immunoelectron microscopy, AM and PAMP were localized exclusively in the secretory granules. The distribution pattern of AM mRNA-positive cells, only a limited portion of which had AM and/or PAMP, was also similar to that of the two peptides. But AM mRNA was detected also in a few epithelial cells as well as neuroendocrine cells. The two peptides might play an important role in the control of local circulation in the rat stomach.

This study was conducted to investigate the effects of inhibin on hepatic glucose metabolism. We have previously reported that activin A induced a dose-dependent glycogenolytic action on hepatocytes, and that 10(-9) M activin A induced a maximum glycogenolytic effect. Inhibin itself induced no increase or decrease in glucose output at any dose tested. At a concentration of 10(-10) M, inhibin was seen to inhibit 10(-9) M activin A-induced glucose output by 30% as compared to the control. In contrast to its inhibitory effect on the action of activin A, 10(-10) M and higher concentrations of inhibin did not inhibit angiotensin II-or vasopressin-induced glycogenolysis. We further investigated the mechanism of the inhibitory effect of inhibin on activin A-induced glycogenolysis, and found that 10(-10) M inhibin did inhibit the increase in cytoplasmic-free calcium concentration that was seen with 10(-9) M activin A.We also investigated the effects of inhibin on the activin A-induced production of inositol trisphosphates, and the results showed that 10(-10) M inhibin inhibited the activin A-induced production of inositol trisphosphates by 30% compared to the control. Furthermore, it was demonstrated that inhibin did not affect the binding of activin A to isolated hepatocytes. These data demonstrated that inhibin inhibited the activin A-induced glycogenolysis by inhibiting the increases of inositol trisphosphates and cytoplasmic free calcium concentrations.

To determine the involvement of prostaglandins in the action of secretin on the promotion of the healing process in injured gastric mucosa, the effect of secretin infusion on the content of PGE2 and 6-keto PGF1 alpha (a major metabolite of PGI2) in human gastric mucosa was investigated. Specimens of both normal and injured mucosa were obtained from each of the patients who underwent polypectomy a week prior to the study. The specimens were obtained before and 20 min after intravenous infusion of secretin [2 Crick, Harper and Raper (CHR) units/kg] or saline. The basal content of PGE2 in injured mucosa was three times higher than that in normal gastric mucosa. Secretin did not increase the PGE2 content of normal gastric mucosa. However, secretin induced a sevenfold increase in the PGE2 content of injured mucosa. The content of 6-keto PGF1 alpha was not affected by secretin. These results suggest that, in injured mucosa, PGE2 is involved in the healing process and in the action of secretin as well.

Gastric mucosal blood flow and oxygen tension in the corporal mucosa gradually declined after water immersion in the control animals. Neither cimetidine nor prostaglandin E2 had any influence on the decrease of the corporal mucosal blood flow or mucosal oxygen tension during seven hours of stress loading. The stress ulceration began to occur starting three hours after cold immersion in the control rats, and the deficit of energy metabolism was attributed to reduced oxidative phosphorylation from tissue hypoxia resulting from lowered blood flow and oxygen tension under stress. Cimetidine (4 mg/kg) maintained aerobic glycolysis, continued to produce high-energy phosphates and kept the energy charge unchanged in the gastric mucosa. In addition, PG E2-Me (100 micrograms/kg) showed similar, but less marked and shorter-lived effects on aerobic glycolysis and ATP production, whereas the energy charge of the adenosine pool decreased significantly from that produced by cimetidine. These results indicated that cimetidine significantly reduced energy requirements as compared with the control and PG E2 groups due to marked inhibition of gastric secretion and produced inhibition of mucosal ulceration by water immersion. On the other hand, increased energy requirements due to the rise of cytoprotective mucoprotein production and a resultant decrease of the energy charge were seen with PG E2 as compared with cimetidine.