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Purpose The effects of statins on insulin resistance (IR) and type 2 diabetes mellitus (T2DM) are still controversial and its effects on pancreatic fibrosis are poorly defined. The purpose of this study is to examine the effects of atorvastatin on these issues using the Otsuka Long–Evans Tokushima Fatty (OLETF) rat, an animal model of IR, T2DM and pancreatic fibrosis. Methods Male OLETF rats were divided into 2 groups at 6 weeks of age. The first group received a standard diet until the end of experimental period at age 28 weeks. The second group was given a diet containing 0.05% atorvastatin from 6 weeks of age, before the onset of IR and pancreatic fibrosis. The age-matched Long–Evans Tokushima Otsuka rats without presence of IR, T2DM and pancreatic fibrosis, received a standard diet and were used as a normal control. Results Atorvastatin slightly decreased serum fasting glucose and insulin levels, but significantly improved index of IR compared with the untreated OLETF rats. In addition, atorvastatin markedly decreased transforming growth factor-β1 mRNA expression, myeloperoxidase activity and proportion of fibrotic area, and elevated superoxide dismutase activity in the pancreas compared with the untreated OLETF rats. Conclusions These findings suggest that atorvastatin exerts favorable influence on progression of IR and pancreatic inflammation and fibrosis via pleiotropic effect such as anti-oxidative property. [ABSTRACT FROM AUTHOR]

Autoimmune pancreatitis (AIP) is a unique form of chronic pancreatitis characterised by a high serum IgG4 concentration and complications that include various extrapancreatic manifestations, one of which is sclerosing cholangitis. In AIP patients, infiltration of abundant IgG4-positive plasma cells and dense fibrosis are commonly observed in the pancreas and wall of the bile duct and gallbladder. The major symptom at onset of AIP is obstructive jaundice caused by stricture of the bile duct, and this requires differential diagnosis of AIP from pancreato-biliary malignancies and primary sclerosing cholangitis (PSC). Recently, there have been reports of particular cases of sclerosing cholangitis with a high serum IgG4 level and cholangiographic and pathological findings comparable to those observed in AIP patients. Being apparently different from PSC and similar to that in AIP, sclerosing cholangitis with and without AIP shows a clinical response to steroid therapy and thus is designated as ‘IgG4-associated sclerosing cholangitis’. The pathogenesis of AIP and IgG4-associated sclerosing cholangitis remains at yet undetermined. [Copyright &y& Elsevier]

Abstract: RECQL1 and RECQL5 as well as BLM reportedly interact with TOP3α whose defect is lethal for the cell. Therefore in this study, we characterized recql5/recql1/blm triple mutants from DT40 cells to determine whether the triple mutants show a top3α disrupted cell-like phenotype. The triple mutants are viable. Moreover, both blm/recql1 and recql5/blm cells, and recql5/recql1/blm cells grew slightly slower than blm cells, that is, triple mutant cells grew almost the same rate as either of the double mutant cells. The blm cells showed sensitivity to methyl methanesulfonate (MMS) and ultraviolet light (UV), about a 10-fold increase in sister chromatid exchange (SCE), and about a 3-fold increase in damage-induced mitotic chiasma compared to wild-type cells. The triple mutants showed the same sensitivity to MMS or UV and the same frequency of damage-induced mitotic chiasma compared to those of blm cells, indicating that unlike BLM, RECQL1 and RECQL5 play a little role in the repair of or tolerance to DNA damages. However, recql5/blm cells showed higher frequency of SCE than blm cells, whereas the RECQL1 gene disruption had no effect on SCE in blm cells and even in recql5/blm cells. [Copyright &y& Elsevier]

Background: Endoscopic submucosal dissection (ESD), particularly the process of submucosal incision with a knife, is technically difficult and carries a high risk of perforation. Submucosal injection of a viscous substance, eg, jelly, obviates the need of submucosal incision with a knife. Sodium carboxymethylcellulose (SCMC), known as cellulose gum, is highly viscous when dissolved in water. Objective: To evaluate the efficacy and the safety of ESD by submucosal injection of SCMC solution in a porcine stomach. Design and Setting: A prospective, single-center study. Interventions: The viscosity of various concentrations (0.5%-3.5%) of SCMC was measured by a viscometry. First, we injected 10 mL of various concentrations of SCMC solution into the submucosal layer of resected porcine stomachs in vitro and examined whether the submucosal injection dissected the mucosal layer from the muscular layer by EUS. Second, we performed ESD by injecting, with an 18-gauge needle, the SCMC solution into the submucosal layer of the stomach in white domestic pigs in vivo to evaluate the efficacy and the safety of SCMC for ESD. Main Outcome Measurements and Results: Submucosal injection of the SCMC solution dissected most of the mucosal layer from the muscular layer at the concentration above 2.0%. We, therefore, decided to use 2.5% SCMC for ESD with a 18-gauge needle to ensure dissection. Submucosal injection of 2.5% SCMC dissected the mucosal layer from the muscular layer without complications, such as massive bleeding or perforation, in white domestic pigs. Histologically, injection of 2.5% SCMC revealed no damage to the muscular layer and surrounding tissue. Limitations: Our novel injection technique was evaluated in an animal model with a normal stomach; it was relatively easy to approach the target mucosa. Conclusions: ESD by submucosal injection of viscous SCMC solution appeared to be an easy, safe, and technically efficient method for dissection of gastric lesions. [Copyright &y& Elsevier]

Background: Endoscopic mucosal resection with a cap-fitted panendoscope (EMRC) such as a soft prelooped hood is a useful, effective, and safe technique. One problem with this method is that the lesion cannot always be maintained in the center of the cap because the procedure is performed blindly after aspiration. Objective: We developed a 2-channel prelooped hood that facilitates EMRC while simultaneously allowing both grip of the center in the lesion and irrigation of the aspiration site and evaluated the usefulness of this end hood for early gastric cancer. Design: Retrospective study. Setting: Between August 2003 and October 2004, patients underwent our novel EMR. Patients: Twelve cases of early gastric cancer. Interventions: Two side holes were fabricated by drilling in the cap portion of a conventional soft prelooped hood, and then the irrigation tube and the accessory channel tube were glued to the exterior surface of the holes. We placed the fabricated transparent hood at the tip of the endoscope and performed grasping forceps–assisted endoscopic aspiration mucosectomy. Main Outcome Measurements: Accurate aspiration and the rate of en bloc resection. Results: We obtained a satisfactory field of view and accurate aspiration in the center of the tumor in all lesions. The rate of en bloc resection was 91.7% (11/12). Limitations: Gastric intramucosal cancer. Conclusion: Grasping forceps–assisted endoscopic mucosal resection with a novel 2-channel prelooped hood is safe and useful for mucosal resection of intramucosal cancers less than 20 mm and may help center the lesion in the cap before resection. [Copyright &y& Elsevier]

Abstract: Oral administration of α-glucosidase inhibitor reduces postprandial serum glucose and insulin concentrations; thus, α-glucosidase inhibitor is used for the treatment of diabetes mellitus worldwide. In our study, we have evaluated the effect of α-glucosidase inhibitor, acarbose, on age-related glucose intolerance and pancreatic atrophy in the Long-Evans Tokushima Otsuka (LETO) rat. The first group of rats received a standard rat diet (control). The second group received a diet containing acarbose (150 mg/100 g food) from 12 to 28 weeks and then switched to a standard rat diet until 72 weeks of age (A12-28W). The third group was administered the same diet containing acarbose from 12 to 72 weeks of age (A12-72W). Fasting serum glucose and insulin concentrations gradually increased with increasing age in the control group, but these increases were completely prevented (A12-72W) or delayed (A12-28W) by acarbose treatment. In addition, acarbose treatment prevented the deterioration in insulin resistance with increasing age. At 72 weeks of age, pancreatic wet weight and DNA content in the A12-72W group were significantly higher than those in the control group. Although most islets were enlarged, and some portions of pancreatic tissue contained fatty and connective tissue in the control group, these alterations were mild in the A12-28W group and remained minimal in the A12-72W group. Our study suggests that acarbose is useful in the prevention of age-related glucose intolerance and pancreatic atrophy. [Copyright &y& Elsevier]

Background: Esophageal mucosal breaks are found in less than half of patients with typical reflux symptom. Thus, endoscopy appears to be an insensitive test for GERD. Lugol chromoendoscopy has been used to detect early esophageal cancer, which is difficult to recognize by routine observation without dye staining. The aim of this study was to determine the efficacy of Lugol chromoendoscopy in the diagnosis of so-called endoscopy-negative GERD (ENRD). Methods: The study was conducted with 61 patients (21 women; mean age of 59.8 years) with reflux symptoms and 42 controls (15 women; mean age, 65.0 years). In the absence of any esophageal mucosal abnormalities at conventional endoscopy, Lugol''s iodine solution was sprayed onto the esophageal surface, followed by evaluation of the staining pattern. When Lugol-unstained streaks were observed at chromoendoscopy, biopsy specimens were obtained from unstained streaks and from adjacent stained mucosa. Histologic evaluation included basal cell hyperplasia, papillary length, and cellular infiltration. Results: Twenty-two (36%) of 61 patients with reflux, and 4 (10%) of 42 controls had visible esophagitis by conventional endoscopy. Lugol chromoendoscopy was performed in the remaining 39 patients and 38 controls. The entire esophageal mucosa was uniformly stained dark brown in 20 patients with reflux and 37 controls. In the remaining 19 patients with reflux and in one control, several unstained streaks were observed in the distal esophagus (p < 0.0001). Histologically, Lugol-unstained mucosa showed a significantly thicker basal cell layer (30.9% ± 7.6% vs. 12.3% ± 4.5% of total epithelial thickness, mean ± standard deviation [SD], p < 0.01) and longer papillae (57.9% ± 12.6% vs. 38.1% ± 12.6% of total epithelial thickness, mean [SD], p < 0.01) compared with stained mucosa. In addition, infiltration of lymphocytes in the epithelium was significantly increased in unstained mucosa than in stained mucosa (p < 0.01). Conclusions: Visible unstained streaks by Lugol chromoendoscopy seem to be indicative of mucosal injury, which was not detectable by conventional endoscopy. Lugol chromoendoscopy is simple and could be useful for the diagnosis of ENRD. This method could be appealing for the endoscopist as it is easy, safe, and can be performed at the same endoscopic session. [Copyright &y& Elsevier]

Abstract: Background: Otsuka Long-Evans Tokushima Fatty (OLETF) rat, a model of type 2 diabetes, lacks the expression of cholecystokinin-1 receptor mRNA and exhibits inflammation and degeneration of the pancreas and eventually develops insulinopenic diabetes. Protease inhibitors are known to modulate inflammatory response and fibrosis as well as inhibit proteases activity. Aim: To examine the effects of long-term treatment with camostat, a synthetic protease inhibitor, on metabolic and histopathological changes in the islets of OLETF rats. Method: OLETF rats were fed either camostat-containing food (200 mg/100 g) from 12 or 28 weeks of age to 72 weeks of age, or fed standard rat diet. Results: Camostat-fed rats gained less weight or lost weight, although they consumed more food than the control rat when food intake was adjusted for body weight. Camostat reduced visceral adipose depots and fasting serum concentrations of triglyceride, free fatty acids, cholesterol, glucose, and insulin. Pancreatic insulin content in camostat-treated rats was significantly higher than in control rats. Immunohistochemistry revealed marked suppression of expressions of tumor necrosis factor α, interleukin 1β, interleukin 6, and α-smooth muscle actin in the islets of camostat-treated rats, compared with control rats. Histologically, disruption of the islets and pancreatic fibrosis were noted in control rats but not in camostat-fed rats. Conclusion: Our findings suggest that camostat prevents and reverses obesity, hyperinsulinemia, hyperglycemia, and hyperlipidemia and markedly inhibits inflammation, fibrosis, and disruption of the islets in the genetically obese diabetic OLETF rats. [Copyright &y& Elsevier]

During mitotic chromosome segregation, the protease separase severs cohesin between sister chromatids. A probe for separase activity has shown that separase undergoes abrupt activation shortly before anaphase onset, after being suppressed throughout metaphase; however, the relevance of this control remains unclear. Here, we report that separase activates precociously, with respect to anaphase onset, during prolonged metaphase in multiple types of cancer cell lines. The artificial extension of metaphase in chromosomally stable diploid cells leads to precocious activation and, subsequently, to chromosomal bridges in anaphase, which seems to be attributable to incomplete cohesin removal. Conversely, shortening back of a prolonged metaphase restores the activation of separase and ameliorates anaphase bridge formation. These observations suggest that retarded metaphase progression affects the separase activation profile and its enzymatic proficiency. Our findings provide an unanticipated etiology for chromosomal instability in cancers and underscore the relevance of swift mitotic transitions for fail-safe chromosome segregation. • Prolonged metaphase and separase deregulation are widespread among cancer cells • Delaying anaphase onset impairs activation profile and proficiency of separase • Shortening back of prolonged metaphase restores robust separase activation kinetics • Separase deregulation results in incomplete cohesin removal and anaphase bridges Using a separase sensor, Shindo et al. show that separase is widely deregulated in cancer cells and that this deregulation is attributable to prolonged metaphase. A swift progression through metaphase to anaphase ensures characteristic sharp activation and proficiency of separase and therefore underlies faithful chromosome segregation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: In patients with liver cirrhosis (LC), the incidence of diabetes mellitus (DM) is high, whereas that of hypertension and ischemic heart diseases is low. We measured carotid artery intima-media thickness (IMT) to determine the incidence of atherosclerosis in patients with LC+DM and to compare it with that in patients with type 2 DM, and evaluated the risk factors for atherosclerosis in these patients. Research design and methods: We determined IMT of the common carotid artery by B-mode ultrasound, serum lipid levels, C-reactive protein (CRP), plasma levels of fasting and postprandial glucose, glycated hemoglobin (HbA1c), fibrinogen and platelet counts in 14 patients of the LC+DM group, 16 patients with type 2 DM (DM group) and 14 patients with LC without impaired glucose tolerance (LC group). Results: The IMT in the LC+DM group (0.694±0.175mm) was similar to that in the LC group (0.693±0.151mm) but significantly smaller than the DM group (0.904±0.337mm). There were no significant differences between the LC+DM group and DM group in the duration of DM, proportion of smokers, arterial blood pressure, fasting and postprandial plasma glucose levels, and CRP, but HbA1c, platelet counts and fibrinogen were significantly lower in the LC+DM group than in the DM group. Conclusions: Our study suggests that the development of atherosclerosis in patients with DM is suppressed by the presence of LC, probably due to reduced platelet counts and fibrinogen levels. [Copyright &y& Elsevier]

Abstract: Background/aim: The renin–angiotensin system (RAS) exists in the pancreas, but the role of RAS in the regulation of pancreatic exocrine secretion under physiological conditions has been little known. The present study addressed the RAS''s effect on the pancreatic secretion by using valsartan, a specific angiotensin II receptor blocker, in conscious rats. Method: Male Wistar rats prepared with pancreatic, biliary, duodenal and jugular vein cannulas were used. To examine the role of RAS in the pancreatic secretion, valsartan at 1, 5, or 25mg/kg was administered into the duodenum via cannula, and volume of pancreatic juice and protein concentration were determined. In addition, to examine the role of RAS in hormone-stimulated pancreatic hypersecretion, pancreatic secretion was examined in response to stimulation of secretin or cholecystokinin after intraduodenal infusion of valsartan at 25mg/kg. Furthermore, to examine the mechanism of action of RAS on pancreatic secretion, intravenous infusion of atropine or perivagal application of capsaicin was conducted and then the pancreatic secretion was examined following intraduodenal infusion of valsartan at 25mg/kg. Results: Volume of pancreatic juice, but not protein output, significantly decreased after administration of valsartan. However, administration of valsartan did not exert significant effects on secretin- or cholesystokinin-stimulated pancreatic secretion. Treatment with atropine and perivagal application of capsaicin completely abolished the suppressive effect of valsartan on pancreatic juice secretion. Conclusion: Present results suggest that RAS plays a stimulatory role in pancreatic juice secretion via cholinergic afferent pathway without affecting protein secretion and hormonally stimulated pancreatic secretion under physiological conditions. [Copyright &y& Elsevier]