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To date, a recognized treatment for refractory membranous nephropathy (MN) has not been established. Recently, several reports have indicated the efficacy of rituximab as a novel treatment option. However, only a few published accounts exist of rituximab therapy for idiopathic MN (IMN) in the Asian population. We present the cases of three IMN patients who were treated with single-dose rituximab after they showed no response to conventional therapies, including corticosteroids, cyclosporine, cyclophosphamide, mizoribine, and mycophenolate mofetil. Although one case showed no response, a complete or incomplete remission was achieved in the other two cases. Rituximab may therefore be a beneficial treatment option for IMN.

A 35-year-old woman, who was an HBV carrier, complained of fever for 2 weeks, and thus, she was admitted in our hospital. Both serum AFP and PIVKA-II levels were abnormally high, and an abdominal enhanced CT revealed the presence of multiple masses in both lobes of the liver. She was diagnosed with hepatocellular carcinoma (T4, N0, M0, and Vp4) and was treated with transcatheter arterial infusion chemotherapy. On the 4th day of her illness, her serum glucose level was 26mg/dl. Glucose infusion and intravenous hyperalimentation were not effective, and she experienced repeated hypoglycemic attacks. Based on the low levels of both insulin (0.4μU/ml) and insulin-like growth factor (IGF)-I (14ng/ml), we made a diagnosis of non-islet cell tumor hypoglycemia associated with hepatocellular carcinoma. The patient was orally administered prednisolone at a dose of 20mg/day. On the 49th day of illness, the hepatocellular carcinoma ruptured, and 2 days later, she died because of hemorrhage shock. Postmortem immunohistochemical staining for IGF-II was positive in the tumor cells of the liver. Furthermore, Western immunoblotting revealed the presence of high-molecular-weight form of IGF-II in the serum of the patient.

Background/aims: Ineffective esophageal motility (IEM) is the most common gastrointestinal motility disorder. Studies have reported that IEM is related to gastroesophageal reflux disease (GERD). However, the relationship between IEM and GERD remains uncertain. This study aims to clarify this relationship retrospectively., Methods: We analyzed 195 subjects who underwent high-resolution manometry between January 2011 and September 2016. Of these subjects, 72 had normal esophageal motility (NEM) and 26 had IEM. We investigated differences in the clinical characteristics, severity and duration of GERD symptoms, and comorbid extra-esophageal symptoms of the subjects. Comorbid extra-esophageal symptoms were assessed with the Gastrointestinal Symptom Rating Scale questionnaire. Investigation-defined GERD was diagnosed when erosive esophagitis or abnormal multichannel intraluminal impedance was present., Results: We found no significant difference in the prevalence of IEM between patients with and without GERD (37.5 and 21.1%, respectively; p = 0.174). There were no differences in age, gender, body mass index, presence of hiatal hernia, or duration of GERD between the groups. Compared to patients with NEM, those with IEM were significantly less likely to have comorbid extra-esophageal symptoms (p < 0.05)., Conclusion: There is no association between IEM and GERD., (© 2017 S. Karger AG, Basel.)

Background and Aim: Proton pump inhibitors (PPI) are effective at healing artificial ulcers after endoscopic submucosal dissection (ESD) for gastric neoplasms; however, the efficacy of vonoprazan is not completely understood. The aim of the present study was to determine the healing effect of vonoprazan on artificial ulcers post-gastric ESD relative to PPI., Methods: Thirty-five patients who underwent gastric ESD between April and November 2015 were treated with vonoprazan 20 mg/day for 4 weeks and subsequently underwent endoscopy for evaluation of ulcer size (V group). Ulcer contraction rate was determined by the following formula: ([ESD specimen size] - [ulcer size at 4 weeks after ESD])/(ESD specimen size) × 100%. We compared the results with those of a historical control group treated with esomeprazole 20 mg/day for 4 weeks after gastric ESD and subsequently measured their ulcer size (33 patients, E group) by propensity score-matching methods., Results: Sixty-two subjects were enrolled after propensity score-matching. Ulcer contraction rate at 4 weeks after ESD in the V group was significantly higher than that of the E group (97.7 ± 3.2% vs 94.5 ± 6.7%, respectively, P = 0.025). Number of subjects with a scar-stage ulcer (100% contraction rate) tended to be higher in the V group relative to the E group (32% [10 of 31] vs 13% [4 of 31], respectively, P = 0.070, McNemar's chi-squared test)., Conclusion: Vonoprazan has a faster post-gastric ESD artificial ulcer contraction rate than esomeprazole. Vonoprazan may supersede PPI in treating post-ESD artificial ulcers of the stomach., (© 2016 Japan Gastroenterological Endoscopy Society.)

Macrophages are multifunctional immune cells that may either drive or modulate disease pathogenesis, depending on the activated phenotype. In this study, we investigated the protective effects of CD206 + M2 macrophages against nephrotoxic serum nephritis in mice. We found that these immunosuppressive macrophages, derived from bone marrow and stimulated with IL-4/IL-13 [CD206 + M2 bone marrow-derived macrophages (M2BMMs)], protected against renal injury, decreased proteinuria, and diminished the infiltration of CD68 + macrophages, neutrophils, and T cells into glomerular tissue. Comparable therapeutic results were obtained with CD206 + M2 cells derived from induced pluripotent stem cells. Notably, CD206 + M2BMMs, which retained an M2 signature, could elicit a switch of M1 to M2 phenotype in co-cultured macrophages. Moreover, these cells were found to induce the production of regulatory T cells in the spleen and renal draining lymph node. Accordingly, mRNA expression of the T helper 1 cytokines tumor necrosis factor-α, interferon-β, interferon-γ, and IL-12 was significantly reduced in kidneys from mice treated with CD206 + M2BMMs. Taken together, the data suggest that CD206 + M2 may have therapeutic potential against antibody-mediated glomerular injury and presents its therapeutic value for the treatment of crescentic nephritis in humans., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Here we report three cases in which the cellophane wall of the PillCam ® patency capsule (tag-less PC), lacking a radio frequency identification tag, was retained. Case 1 A 33-year-old man with Crohn's disease (CD) who was administered the tag-less PC, subsequently underwent resection for perforated colon. We recovered the cellophane wall that could perforate the intestine and cause peritonitis. Case 2 A 34-year-old man with a recurring intestinal obstruction of unknown cause was administered the tag-less PC test. Computed tomography (CT) detected the cellophane wall at the oral side of an ileal stenosis. He was subsequently diagnosed with CD. Case 3 A 60-year-old woman with recurrent diarrhea was examined using CT, which revealed a thickened ileal wall. She was administered the tag-less PC test. CT detected the cellophane wall at the oral side of an ileal stenosis. Double-balloon enteroscopy revealed that the stenosis was caused by a malignant lymphoma, and the cellophane wall was simultaneously removed. Although there are numerous studies that report the usefulness and safety of tag-less PCs, few studies mention entrapment of the cellophane wall. Our present report indicated that tag-less PCs may cause such adverse effects and illustrated the usefulness of CT for detecting the trapped cellophane wall.

Background: In addition to classically activated macrophages that have effector roles in tissue injury, alternatively activated M2 macrophages are involved in the resolution of inflammation in animal models of kidney disease. To clarify the clinical relevance of macrophage phenotypes in human glomerular diseases, we evaluated the renal accumulation of macrophages and plasma and urine levels of CD163, an M2 marker, in lupus nephritis (LN) patients., Methods: Kidney biopsies and plasma and urine samples were obtained from LN patients who underwent renal biopsy between 2008 and 2012. CD163 + , CD68 + and CD204 + cells were counted in paraffin-embedded and frozen sections. LN histological activity was evaluated semiquantitatively using the biopsy activity index. Plasma and urinary soluble CD163 (sCD163) concentrations were also measured and evaluated for their significance as potential LN biomarkers., Results: Immunohistological analysis of glomeruli from LN patients revealed that >60% of CD68 + macrophages had merged with CD163 + cells. The increased number of glomerular CD163 + macrophages was correlated with LN severity, as determined by the biopsy active index (r = 0.635). Urinary (u-) sCD163 level was strongly correlated with glomerular CD163 + cell counts and histological disease score as well as urinary monocyte chemoattractant protein 1 levels (r = 0.638 and 0.592, respectively). Furthermore, the u-sCD163 level was higher in patients with active LN than in those with other diseases., Conclusions: Glomerular CD163 + macrophages are the predominant phenotype in the kidneys of lupus patients. These findings indicate that the u-sCD163 level can serve as a biomarker for macrophage-dependent glomerular inflammation in human LN., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Septins are guanosine triphosphate-binding proteins that are evolutionally conserved in all eukaryotes other than plants. They function as multimeric complexes that interact with membrane lipids, actomyosin, and microtubules. Based on these interactions, septins play essential roles in the morphogenesis and physiological functions of many mammalian cell types including the regulation of microtubule stability, vesicle trafficking, cortical rigidity, planar cell polarity, and apoptosis. The inner ear, which perceives auditory and equilibrium sensation with highly differentiated hair cells, has a complicated gross morphology. Furthermore, its development including morphogenesis is dependent on various molecular mechanisms, such as apoptosis, convergent extension, and cell fate determination. To determine the roles of septins in the development of the inner ear, we specifically deleted Septin7 (Sept7), the non-redundant subunit in the canonical septin complex, in the inner ear at different times during development. Foxg1Cre-mediated deletion of Sept7, which achieved the complete knockout of Sept7 within the inner ear at E9.5, caused cystic malformation of inner ears and a reduced numbers of sensory epithelial cells despite the existence of mature hair cells. Excessive apoptosis was observed at E10.5,E11.5 and E12.5 in all inner ear epithelial cells and at E10.5 and E11.5 in prosensory epithelial cells of the inner ears of Foxg1Cre;Septin7 floxed/floxed mice. In contrast with apoptosis, cell proliferation in the inner ear did not significantly change between control and mutant mice. Deletion of Sept7 within the cochlea at a later stage (around E15.5) with Emx2Cre did not result in any apparent morphological anomalies observed in Foxg1Cre;Septin7 floxed/floxed mice. These results suggest that SEPT7 regulates gross morphogenesis of the inner ear and maintains the size of the inner ear sensory epithelial area and exerts its effects at an early developmental stage of the inner ear., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest. Ethical standard All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008. Human and animal rights This article does not contain any studies with human or animal subjects performed by the any of the authors. Informed consent Informed consent was obtained from participant included in the study.

Background: A non-invasive diagnostic marker of membranous nephropathy (MN) is desirable. The urinary level of podocalyxin (PCX) is higher in various glomerular diseases, including MN. The aim of this study was to construct a diagnostic model of MN with the combination of urinary PCX and clinical parameters., Methods: We performed this cross-sectional study to construct the diagnostic models for MN by using data and samples from the multicenter kidney biopsy registry of Nagoya University and its affiliated hospitals. Urinary (u-) PCX was measured by sandwich ELISA. We constructed 3 types of diagnostic models in 105 training samples: u-PCX univariate model, the combined model of clinical parameters other than u-PCX (clinical model), and the combined model of both u-PCX and clinical parameters (combined model). We assessed the clinical usefulness of the diagnostic models through the comparison of c-statistics and decision curve analysis (DCA) in 209 validation samples., Results: The clinical model consisted of age, glomerular filtration rate, and diabetes mellitus. In the training cohort, the c-statistics were 0.868 [95% CI, 0.799-0.937] in the combined model. In the validation cohort, sensitivity was 80.5% and specificity was 73.5% on the cut-off value. The net benefit of the combined model was better between threshold probabilities of 40-80% in DCA., Conclusions: In this study, we demonstrated the utility of u-PCX as a diagnostic marker for MN and the clinical usefulness of the diagnostic models, through the combination of u-PCX and clinical parameters including age, glomerular filtration rate, and diabetes mellitus., Competing Interests: Two authors [HK, YH] are employed by Denka Co., Ltd. The Department of Nephrology, Nagoya University Graduate School of Medicine, received research promotion grants from Astellas, Alexion, Otsuka, Kyowa Hakko Kirin, Daiichi Sankyo, Dainippon Sumitomo, Takeda, Torii, Pfizer, and Mochida. The Center for Advanced Medicine and Clinical Reseach, Nagoya University Hospital received a donation from Pfizer. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Ulcerative colitis is a lifelong, immunologically mediated disease. Direct-acting antivirals (DAAs) are now available for the treatment of chronic hepatitis C virus (HCV) infection. An interferon-free regimen appears useful, safe and effective for many patients for whom interferon-based treatment is contraindicated., Case Presentation: We studied a 56-year-old treatment-naïve Japanese man with chronic HCV genotype 2b infection who had ulcerative colitis. This patient was treated with sofosbuvir and ribavirin for 12 weeks. During treatment, diarrhoea and bloody faeces were frequent. After ribavirin was reduced to 400 mg daily, these symptoms decreased. Finally, the patient achieved a sustained virologic response 12 weeks after the stoppage of the treatment., Conclusion: Clinicians should pay careful attention to the ribavirin dose in the treatment of certain HCV patients with inflammatory bowel disease who are receiving sofosbuvir plus ribavirin.

Introduction: A 12-week prospective study was previously performed to assess the effect of add-on therapy with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in patients with type 2 diabetes mellitus (T2DM) receiving insulin treatment. Patients were followed until week 48 to investigate the medium-term efficacy and safety of the add-on therapy with sitagliptin., Methods: In the 70 patients with T2DM, glycemic control, insulin dosage, concomitant medications, body weight, laboratory parameters, and adverse events were evaluated for 48 weeks., Results: Hemoglobin A1c (HbA1c) improved significantly from 8.03% at week 0 (at initiation of the add-on therapy) to 7.45% at week 48 (P < 0.01). Body weight remained nearly the same. The daily insulin dose was significantly reduced by 2.5 U, from 25.8 to 23.3 U/day (P < 0.001). Stratified analysis of the improvement of HbA1c based on age, duration of diabetes, body mass index, insulin regimen, and oral antidiabetic drugs did not identify any significant differences in relation to these parameters. During the 48-week follow-up period, there were no problematic adverse events, such as severe hypoglycemia, and the add-on therapy with sitagliptin showed good tolerability., Conclusions: In Japanese patients with T2DM receiving insulin treatment, add-on therapy with sitagliptin was not associated with weight gain and allowed for the reduction of the insulin dosage. Consistent efficacy was noted for 48 weeks without an increasing hypoglycemic effect, and the add-on therapy with sitagliptin was effective irrespective of the insulin regimen.

Objectives: Previous studies have shown that water exchange is superior to air insufflation in attenuating insertion pain during colonoscopy. We conducted a randomized controlled trial with head-to-head comparison of these methods to assess their effectiveness in colonoscopy without sedation., Methods: A total of 447 outpatients were randomized to either water exchange (WE) or the standard air (CO2) insufflation (AI). The primary outcome was the improvement of patient intraprocedural pain (pain score), evaluated using a questionnaire (scores 1 to 5)., Results: After exclusion of 44 patients from further analysis, 403 patients were analyzed. There was no difference in clinical background between the WE and AI groups. Patients in the WE group reported less intraprocedural pain than those in the AI group (2.17 ± 1.06 vs. 2.42 ± 1.03; unpaired t test, p = 0.021). We divided the cases into two groups, more or less painful colonoscopy, based on age, body mass index, use of anti-peristaltic drugs or not, and physician's experience. In less painful colonoscopy, the WE method could reduce pain effectively but its effect was limited in the more painful group., Conclusion: WE is superior to AI for attenuating insertion pain during colonoscopy without sedation, but its efficacy is limited in more painful endoscopy.

Background: Data regarding the association between 24h urinary sodium and potassium excretion with kidney outcomes in patients with diabetes mellitus is currently scarce., Methods: We conducted a single-center, retrospective cohort study in which 1230 patients with diabetes who had undergone a 24h urinary sodium and potassium excretion test were analyzed. Patients with incomplete urine collection were excluded based on 24h urinary creatinine excretion. Outcomes were the composite of a 30% decline in eGFR or death. Multivariate cox regression analysis was used to investigate the association between urinary sodium and potassium excretion and outcomes., Results: With a mean follow up period of 5.47 years, 130 patients reached the outcomes (30% decline in eGFR: 124, death: 6). Mean (SD) eGFR and 24h urinary sodium and potassium excretion at baseline were 78.6 (19.5) ml/min/1.73m2, 4.50 (1.64) g/day, and 2.14 (0.77) g/day. Compared with sodium excretion < 3.0 g/day, no significant change in risk of outcomes was observed with increased increments of 1.0 g/day. Compared with potassium excretion of < 1.5 g/day, 2.0-2.5 g/day, and 2.5-3.0 g/day were significantly associated with a lower risk of outcomes (hazard ratio [HR], 0.49 and 0.44; 95% confidence interval [CI], 0.28 to 0.84 and 0.22 to 0.87)., Conclusions: 24h urinary sodium excretion was not significantly associated with a risk of 30% decline in eGFR or death in patients with diabetes. However, an increased risk of 30% decline in eGFR or death was significantly associated with 24h urinary potassium excretion < 1.5 g/day than with 2.0-2.5 g/day and 2.5-3.0 g/day.

Proteinuria is an established risk factor for diabetic nephropathy. Recent studies indicate that some xanthine oxidase inhibitors have a renoprotective effect. The aim of this study was to assess whether topiroxostat reduces albuminuria in hyperuricemic patients with diabetic nephropathy and overt proteinuria. The ETUDE study is an ongoing 24-week, multicenter, open-label, randomized (1:1), parallel group study involving hyperuricemic patients with diabetic nephropathy (estimated glomerular filtration rate [eGFR] ≥ 20 mL/min/1.73 m(2)) and overt proteinuria (0.3 ≤ urine protein to creatinine ratio (UPCR) < 3.5 g/g Cr). Patients are randomly assigned to high dose (topiroxostat 160 mg daily) or low dose (topiroxostat 40 mg daily) on top of standard of care. The primary endpoint is the change in albuminuria indicated by urine albumin-to-creatinine ratio after 24 treated weeks relative to the baseline values. This trial was registered at the Japanese University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR: UMIN 000015403). The background, rationale, and study design of this trial are presented here. Seventy-six patients from four registered facilities have already been enrolled and received at least one dose of topiroxostat. This trial will end in 2017. The ETUDE trial is the first randomized controlled study of topiroxostat in hyperuricemic patients with diabetic nephropathy and overt proteinuria. We will clarify the pleiotropic function of topiroxostat including an anti-albumiuric effect as well as its effects on safely decreasing serum uric acid levels.

Aims/introduction: The aims of the present study were to investigate the performance of a novel sandwich enzyme-linked immunosorbent assay (ELISA) for measuring glucagon (1-29) with monoclonal antibodies against both the C- and N-terminal regions of glucagon (1-29), and to analyze the differences in plasma levels and responses of glucagon (1-29) to oral glucose loading in normal glucose tolerance (NGT) subjects and patients with type 2 diabetes mellitus., Materials and Methods: The cross-reactivity against proglucagon fragments using the ELISA kit and two types of conventional radioimmunoassay (RIA) kits was evaluated. A 75-g oral glucose tolerance test was carried out with NGT subjects and patients with type 2 diabetes mellitus, and the glucagon (1-29) concentration was measured using three types of kit., Results: The ELISA kit clearly had the lowest cross-reactivity against miniglucagon (19-29) and glicentin (1-61). The oral glucose tolerance test was carried out with 30 NGT and 17 patients with type 2 diabetes mellitus. The glucagon (1-29) levels measured by the ELISA kit after glucose loading were significantly higher at all time-points in the type 2 diabetes mellitus group than in the NGT group. However, the glucagon (1-29) levels measured by one RIA kit were significantly higher in the NGT group, and those measured with the other RIA kit were approximately the same among the groups., Conclusions: The novel sandwich ELISA accurately determines plasma glucagon (1-29) concentrations with much less cross-reactivity against other proglucagon fragments than conventional RIA kits.

A recently developed method enabled us to simultaneously characterize and quantitate glycosidically bound volatiles (GBVs) at picomole levels using liquid chromatography-mass spectrometry (LC-MS). On the basis of the analytical data it is possible to screen tea varieties most suitable for black tea processing, in which higher concentrations of primeverosides accumulate. The primeverosides decreased at the rolling step in black tea processing, whereas the glucopyranosides did not change much. The total contents of GBVs gradually increased at the withering steps and then remarkably increased after the fixing step at 230 °C, during oolong tea processing. The presence of 6'-O-malonyl ester type β-D-glucopyranosides in the tea samples suggested a contribution to the increment in glucopyranosides during oolong tea processing. The method was also used to analyze GBVs and their derivatives to understand their possible role in the metabolic pathway of tea.

Tight junctions (TJs) are structures that seal the space between the epithelial cell sheets. In the inner ear, the barrier function of TJs is indispensable for the separation of the endolymphatic and perilymphatic spaces, which is essential for the generation and maintenance of the endocochlear potential (EP). TJs are formed by the intercellular binding of membrane proteins, known as claudins, and mutations in these proteins cause deafness in humans and mice. Within the epithelial cell sheet, however, a bound structure is present at the site where the corners of three cells meet (tricellular tight junctions (tTJs)), and the maintenance of the barrier function at this location cannot be explained by the claudins alone. Tricellulin and the angulin family of proteins (angulin-1/LSR, angulin-2/ILDR1, and angulin-3/ILDR2) have been identified as tTJ-associated proteins. Tricellulin and ILDR1 are localized at the tTJ and alterations in these proteins have been reported to be involved in deafness. In this review, we will present the current state of knowledge for tTJs.

A 73-year-old woman was diagnosed with pulmonary Mycobacterium avium complex (MAC) infection and received no treatment. Disease progression was evident one year later with the development of myeloperoxidase-antineutrophil cytoplasmic antibody (ANCA) titers and systemic symptoms of a fever, polyarthritis, purpura, and rapidly progressive glomerulonephritis. Her symptoms did not improve with antibiotic treatment. A renal biopsy revealed crescentic glomerulonephritis with immunodeposition. According to these findings, she was diagnosed with ANCA-associated vasculitis (AAV) superimposed on infection-related glomerulonephritis (IRGN). Although there was a risk of aggravating an underlying infection, the combination therapy of corticosteroid and antibiotics improved AAV, IRGN, and even the lung radiological findings. To the best of our knowledge, this is the first case of AAV and IRGN secondary to pulmonary MAC infection.

Regulation of plant growth and development by light wavelength has been extensively studied. Less attention has been paid to effect of light wavelength on formation of plant metabolites. The objective of this study was to investigate whether formation of volatiles in preharvest and postharvest tea (Camellia sinensis) leaves can be regulated by light wavelength. In the present study, in contrast to the natural light or dark treatment, blue light (470 nm) and red light (660 nm) significantly increased most endogenous volatiles including volatile fatty acid derivatives (VFADs), volatile phenylpropanoids/benzenoids (VPBs), and volatile terpenes (VTs) in the preharvest tea leaves. Furthermore, blue and red lights significantly up-regulated the expression levels of 9/13-lipoxygenases involved in VFADs formation, phenylalanine ammonialyase involved in VPBs formation, and terpene synthases involved in VTs formation. Single light wavelength had less remarkable influences on formation of volatiles in the postharvest leaves compared with the preharvest leaves. These results suggest that blue and red lights can be promising technology for remodeling the aroma of preharvest tea leaves. Furthermore, our study provided evidence that light wavelength can activate the expression of key genes involved in formation of plant volatiles for the first time.

Background: Acute kidney injury (AKI) is a critical condition associated with high mortality. However, the available treatments for AKI are limited. Stem cells from human exfoliated deciduous teeth (SHED) have recently gained attention as a novel source of stem cells. The purpose of this study was to clarify whether SHED have a therapeutic effect on AKI induced by ischemia-reperfusion injury., Methods: The left renal artery and vein of the mice were clamped for 20 min to induce ischemia. SHED, bone marrow derived mesenchymal stem cells (BMMSC) or phosphate-buffered saline (control) were administered into the subrenal capsule. To confirm the potency of SHED in vitro, H2O2 stimulation assays and scratch assays were performed., Results: The serum creatinine and blood urea nitrogen levels of the SHED group were significantly lower than those of the control group, while BMMSC showed no therapeutic effect. Infiltration of macrophages and neutrophils in the kidney was significantly attenuated in mice treated with SHED. Cytokine levels (MIP-2, IL-1β, and MCP-1) in mice kidneys were significantly reduced in the SHED group. In in vitro experiments, SHED significantly decreased MCP-1 secretion in tubular epithelial cells (TEC) stimulated with H2O2. In addition, SHED promoted wound healing in the scratch assays, which was blunted by anti-HGF antibodies., Discussion: SHED attenuated the levels of inflammatory cytokines and improved kidney function in AKI induced by IRI. SHED secreted factors reduced MCP-1 and increased HGF expression, which promoted wound healing. These results suggest that SHED might provide a novel stem cell resource, which can be applied for the treatment of ischemic kidney injury.

Objective: The diagnostic values of antiproteinase 3 and antimyeloperoxidase tests using antineutrophil cytoplasmic antibodies (ANCA) are well established. Our study determined whether an increase in ANCA level was a predictor of disease flareup., Methods: Our study included 126 patients with ANCA-associated renal vasculitis treated at 9 nephrology centers in Japan. The relationship between increased ANCA levels and relapse was assessed using time-dependent multivariate Cox regression models adjusted for clinically relevant factors. The outcome of interest was the time from remission to first relapse., Results: During the observation period [median 41 mos, interquartile range (IQR) 23-66 mos], 118 patients (95.8%) achieved remission at least once. After achieving remission, 34 patients relapsed (21.7%). Time-dependent multivariate Cox regression models revealed that lung involvement (adjusted HR 2.29, 95% CI 1.13-4.65, p = 0.022) and increased ANCA levels (adjusted HR 17.4, 95% CI 8.42-36.0, p < 0.001) were significantly associated with relapse. The median time from ANCA level increase to relapse was 0.6 months (IQR 0-2.1 mos)., Conclusion: In our study, an increase in ANCA level during remission was associated with a risk of disease relapse. A rise in ANCA level may be useful for guiding treatment decisions in appropriate subsets of patients with ANCA-associated vasculitis.

It was generally thought that aroma of oolong tea resulted from hydrolysis of glycosidically bound volatiles (GBVs). In this study, most GBVs showed no reduction during the oolong tea manufacturing process. β-Glycosidases either at protein or gene level were not activated during the manufacturing process. Subcellular localization of β-primeverosidase provided evidence that β-primeverosidase was located in the leaf cell wall. The cell wall remained intact during the enzyme-active manufacturing process. After the leaf cell disruption, GBV content was reduced. These findings reveal that, during the enzyme-active process of oolong tea, nondisruption of the leaf cell walls resulted in impossibility of interaction of GBVs and β-glycosidases. Indole, jasmine lactone, and trans-nerolidol were characteristic volatiles produced from the manufacturing process. Interestingly, the contents of the three volatiles was reduced after the leaf cell disruption, suggesting that mechanical damage with the cell disruption, which is similar to black tea manufacturing, did not induce accumulation of the three volatiles. In addition, 11 volatiles with flavor dilution factor ≥4(4) were identified as relatively potent odorants in the oolong tea. These results suggest that enzymatic hydrolysis of GBVs was not involved in the formation of volatiles of oolong tea, and some characteristic volatiles with potent odorants were produced from the manufacturing process.

Background: Previous studies have suggested that high neutrophil/lymphocyte ratios are related to worse outcome in patients with cardiovascular diseases. Patients with end-stage renal disease, especially those with inflammation, are at an increased risk of premature mortality, primarily because of cardiovascular disease. We aimed to clarify if high neutrophil/lymphocyte ratio is associated with increasing cardiovascular events in Japanese patients with end-stage renal disease., Methods: We enrolled 86 incident Japanese dialysis patients (58 men, age 58 ± 11 years) in a prospective cohort study. The median follow-up was for 38.7 months. The association between neutrophil/lymphocyte ratio at the start of dialysis therapy and clinical biomarkers was investigated. Relative risks and cumulative cardiovascular disease events were calculated., Results: The median neutrophil/lymphocyte ratio reported was 3.72. The duration from the start of the dialysis therapy to the first cardiovascular disease event was significantly shorter as a neutrophil/lymphocyte ratio increased (log-rank test, P = 0.003). The relative risk of cardiovascular disease events in patients with neutrophil/lymphocyte ratio > median to cardiovascular events in patients with the ratio < median as a reference was 3.02 (95 % CI 1.32-8.00) in a Cox proportional hazard model. The cumulative cardiovascular disease events during the observational period was higher in patients with neutrophil/lymphocyte ratio > median (23.0 events 100 person-years) than in patients with the ratio < median (6.8 events 100 person-years)., Conclusions: A higher neutrophil/lymphocyte ratio is associated with increased risk of cardiovascular disease events and is a stronger predictor of future events.

Background: Laterally spreading tumors (LSTs) are generally defined as lesions >10 mm in diameter, are characterized by lateral expansion along the luminal wall with a low vertical axis. In contrast to other forms of tumor, LSTs are generally considered to have a superficial growth pattern and the potential for malignancy. We focused on this morphological character of LSTs, and analyzed the gene expression profile of LSTs., Methods: The expression of 168 genes in 41 colorectal tumor samples (17 LST-adenoma, 12 LST-carcinoma, 12 Ip [pedunculated type of the Paris classification)-adenoma, all of which were 10 mm or more in diameter] was analyzed by PCR array. Based on the results, we investigated the expression levels of genes up-regulated in LST-adenoma, compared to Ip-adenoma, by hierarchical and K-means clustering. To confirm the results of the array analysis, using an additional 60 samples (38 LST-adenoma, 22 Ip-adenoma), we determined the localization of the gene product by immunohistochemical staining., Result: The expression of 129 genes differed in colorectal tumors from normal mucosa by PCR array analysis. As a result of K-means clustering, the expression levels of five genes, AKT1, BCL2L1, ERBB2, MTA2 and TNFRSF25, were found to be significantly up-regulated (p < 0.05) in LST-adenoma, compared to Ip-adenoma. Immunohistochemical analysis showed that the BCL2L1 protein was significantly and meaningfully up-regulated in LST-adenoma compared to Ip-adenoma (p = 0.010). With respect to apoptosis status in LST-Adenoma, it assumes that BCL2L1 is anti-apoptotic protein, the samples such as BCL2L1 positive and TUNEL negative, or BCL2L1 negative and TUNEL positive are consistent with the assumption. 63.2 % LST-adenoma samples were consistent with the assumption., Conclusions: LSTs have an unusual profile of gene expression compared to other tumors and BCL2L1 might be concerned in the organization of LSTs.

Objective: Presepsin is highlighted as a diagnostic and prognostic marker of sepsis. Little information is available regarding the accurate association between presepsin levels and the degree of kidney function. We analyzed presepsin levels in patients with a glomerular filtration rate (GFR) in the categories G1 to G5, evaluated via inulin renal clearance test, and receiving hemodialysis (HD)., Methods: Patients who were not receiving HD were included if they had undergone inulin renal clearance measurements for the accurate measurement of GFR (measured GFR), and patients who were receiving hemodialysis (HD) were included if they had anuria. Exclusion criteria were infection, cancer, liver disease, autoimmune disorders, or steroid or immunosuppressant use. GFR category was defined as follows; G1: GFR ≥ 90 ml/min/1.73 m2, G2: GFR = 60 to 90 ml/min/1.73 m2, G3: GFR = 30 to 60 ml/min/1.73 m2, G4: GFR = 15 to 30 ml/min/1.73 m2, G5: GFR ≤ 15 ml/min/1.73 m2., Results: Seventy-one patients were included. The median (IQR) presepsin values of patients in each GFR category were as follows: G1 + G2: 69.8 (60.8-85.9) pg/ml; G3: 107.0 (68.7-150.0) pg/ml; G4: 171.0 (117.0-200.0) pg/ml; G5: 251.0 (213.0-297.5) pg/ml; and HD: 1160.0 (1070.0-1400.0) pg/ml. The log-transformed presepsin values, excluding patients receiving HD, inversely correlated with the measured GFR (Pearson's correlation coefficient = -0.687, P < 0.001). The multivariate analysis revealed that measured GFR and hemoglobin levels significantly correlated with elevated presepsin levels., Conclusion: Presepsin levels were markedly high in patients receiving HD, similar to values seen in patients with severe sepsis or septic shock. In patients who were not receiving HD, presepsin levels increased as GFR decreased. Thus, the evaluation of presepsin levels in patients with chronic kidney disease requires further consideration, and a different cutoff value is needed for diagnosing sepsis in such patients.

A man in his 20s was referred to our hospital with hematochezia and rectal pain. Total colonoscopy revealed a reddish, protruding, ulcerated lesion occupying approximately half of the luminal circumference of the rectum. Examination of biopsy specimens showed proliferating spindle cells infiltrating the lamina propria, a finding consistent with Kaposi's sarcoma. The patient was also found to be anti-human immunodeficiency virus (HIV) antibody positive;therefore, we diagnosed acquired immunodeficiency syndrome (AIDS). The lesions of Kaposi's sarcoma were also seen in the skin, lung, and lymph nodes, but there were no lesions elsewhere in the gastrointestinal tract other than the rectum. We started anti-HIV therapy and chemotherapy against these lesions, and the lesions subsequently reduced in size. We present a rare case of a man with Kaposi's sarcoma presenting with a rectal lesion.

Cardiovascular (CV) complications are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis being a common risk factor for prospective crisis of coronary artery diseases and/or cerebral infarction in DM subjects. From another point of view, asymmetric dimethylarginine (ADMA) has been established as an inhibitor of endogenous nitric oxide synthesis and the relationship between ADMA and arteriosclerosis has been reported. In our study with 87 type 2 DM (T2DM) patients, we have examined whether ADMA and other CV risk factors are the useful predictors of DMCV complications. After the measurement of the respective CV risk factors, we have followed the enrolled T2DM patients for 5 years. We have finally analyzed 77 patients. DMCV complications developed in 15 cases newly within 5 years, and 4 cases recurred. The concentrations of ADMA in plasma were markedly more elevated in 19 DM patients with CV complications than in 58 DM patients without CV complications. Urinary albumin (U-Alb), mean intimal-medial thickness (IMT) and ankle brachial index (ABI) were also higher in patients with CV complications. Multiple regression analyses showed that U-Alb had an influence on the high level of ADMA (standardized β = 6.59, P = 0.00014) independently of age, systolic BP, fibrinogen, mean IMT, plaque score, and ABI. The review indicates what is presently known regarding plasma ADMA that might be a new and meaningful biomarker of CV complications in DM subjects.

Aims: Accurate assessment of blood glucose fluctuation is essential for managing blood glucose control while avoiding hypoglycemia in patients with diabetes mellitus. In this study, blood glucose was measured by continuous glucose monitoring (CGM) in patients with type 1 diabetes mellitus (T1DM) whom self-monitoring of blood glucose (SMBG) was carried out three or more times per day, and evaluation was performed using blood glucose fluctuation parameters obtained by CGM and SMBG., Methods: Twenty-nine insulin-depleted patients with T1DM were enrolled. Their blood glucose fluctuations were measured at the same time by SMBG and CGM, and the correlations were evaluated., Results: Correlations were found between the following values obtained by SMBG and CGM: mean and standard deviation of blood glucose levels, average daily risk range, Morbus value and high-blood-glucose index. The hypoglycemia duration and the nocturnal hypoglycemia duration showed no correlation with any of the blood glucose fluctuation parameters obtained by SMBG., Conclusions: The findings suggest that routine SMBG and glycated hemoglobin (HbA1c) measurement are sufficient for evaluation of hyperglycemia in T1DM. On the other hand, blood glucose fluctuation parameters obtained by SMBG and HbA1c have been shown to have no correlations with either hypoglycemia duration or nocturnal hypoglycemia duration., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Tolvaptan selectively binds to the vasopressin V2 receptor and inhibits reabsorption of free water. Although its efficacy for heart failure has been proven, its efficacy for chronic kidney disease (CKD) patients has not been assessed in detail., Methods: We examined 20 CKD patients (13 men and 7 women) who presented with volume overload and who were administered tolvaptan. We assessed urine volume (UV) and blood biochemistry before administration (dO), 1 day after administration (d1), and 7 to 14 days after administration (d7-14)., Results: The mean age was 74.0 +/- 13.1 years. Besides CKD, there were 9, 8, and 5 patients with heart failure, liver failure or liver cirrhosis, andsevere oedema, respectively. UV significantly increased from 959.0 +/- 503.8 mL/day at d0 to 1605.4 +/- 964.0 mL/day at d7-14 (P<0.01). Serum creatinine levels were not exacerbated (3.89 +/- 3.43 mg/dL at d0 and 3.66 +/- 3.02 mg/dL at d7-14). Serum albumin (ALB) levels and urinary protein creatinine ratio (uPCR) did not correlate with UV change. Estimated glomerular filtration rate (eGFR) correlated with UV change from d0 to d1 (r=0.6619, P<0.01). Serum sodium elevation correlated with increased UV (r=0.4951, P<0.05)., Conclusion: Tolvaptan is useful to reduce volume overload without exacerbation of the renal function; its effect does not depend on ALB or uPCR. the eGFR correlated with the efficacy of tolvaptan. If UV increases drastically after tolvaptan administration, serum Na levels should be carefully monitored.

Tricellular tight junctions seal the extracellular spaces of tricellular contacts, where the vertices of three epithelial cells meet, and are required for the establishment of a strong barrier function of the epithelial cellular sheet. Angulins and tricellulin are known as specific protein components of tricellular tight junctions, where angulins recruit tricellulin. Mutations in the genes encoding angulin-2/ILDR1 and tricellulin have been reported to cause human hereditary deafness DFNB42 and DFNB49, respectively. To investigate the pathogenesis of DFNB42, we analyzed mice with a targeted disruption of Ildr1, which encodes angulin-2/ILDR1. Ildr1 null mice exhibited profound deafness. Hair cells in the cochlea of Ildr1 null mice develop normally, but begin to degenerate by two weeks after birth. Tricellulin localization at tricellular contacts of the organ of Corti in the cochlea was retained in Ildr1 null mice, but its distribution along the depth of tricellular contacts was affected. Interestingly, compensatory tricellular contact localization of angulin-1/LSR was observed in the organ of Corti in Ildr1 null mice although it was hardly detected in the organ of Corti in wild-type mice. The onset of hair cell degeneration in Ildr1 null mice was earlier than that in the reported Tric mutant mice, which mimic one of the tricellulin mutations in DFNB49 deafness. These results indicate that the angulin-2/ILDR1 deficiency causes the postnatal degenerative loss of hair cells in the cochlea, leading to human deafness DFNB42. Our data also suggest that angulin family proteins have distinct functions in addition to their common roles of tricellulin recruitment and that the function of angulin-2/ILDR1 for hearing cannot be substituted by angulin-1/LSR.

Background: It is well known that in patients with sporadic nonampullary duodenal adenoma/carcinoma (SNADA) with no polyposis syndrome, including familial adenomataous polyposis, the rates of colorectal adenoma/carcinoma are high. However, the prevalence rates of other tumor types, for example, gastric cancer, in SNADA patients remain unknown. In this study, we aimed to analyze the prevalence rate of comorbid diseases in SNADA patients., Methods: We retrospectively analyzed 78 patients with SNADA treated by endoscopic resection between May 2005 and September 2014 at our institution., Results: Overall, 51 of the 78 (65.4%) SNADA patients had comorbid colorectal adenoma/carcinoma. Further, 10 of the 78 (12.8%) SNADA patients had comorbid gastric cancer, and all of them were positive for Helicobacter pylori infection. SNADA lesions were located significantly more frequently at the oral side of the major papilla in patients with H. pylori infection than in those without H. pylori infection (27 of 36 [75.0%] vs. 19 of 42 [45.2%], p = 0.008, chi-square test). In contrast, SNADA lesions were located significantly more frequently at the anal side of the major papilla in patients with colorectal adenoma/carcinoma than in those without colorectal adenoma/carcinoma (27 of 51 [52.9%] vs. 5 of 27 [18.5%], p = 0.003, chi-square test)., Conclusion: SNADA patients showed comorbidity with not only colorectal adenoma/carcinoma but also gastric cancer. H. pylori infection is known to cause gastric cancer and may influence tumorigenesis of SNADA lesions at the oral side of the major papilla.

Transcription factors are believed to play key roles in determining cell fate in inner ear development. Olig genes, which are basic helix-loop-helix transcription factors, have been reported to play important roles in the development of the central nervous system. However, members of this family have not previously been implicated in inner ear development, despite the similarity between otocyst and neural tube development. Olig1 begins to be expressed at the ventral domain of the otocyst at embryonic day (E) 9.5, and Olig1 expression in the epithelium of the developing inner ear persists to E15.5. Olig2 expression is localized to the cochleovestibular ganglia from E12.5 through E14.5. Olig3 has a diffuse expression pattern in the developing inner ear from E12.5 through the postnatal stage. Furthermore, at early stages of inner ear development, the Olig1 expression domain overlaps a region that is positive for Sox2 and Jagged1. This observation indicates that Olig1 may play an important role in the specification of the prosensory domain in the developing inner ear. As Olig genes are expressed in the mouse developing inner ear in a temporospatially distinct fashion, they may play substantial roles in the regulation of mammalian inner ear development., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background and Aim: Mosapride citrate-a prokinetic agent-improves hemoglobin A1c levels in diabetic patients; however, the underlying mechanism is unclear. We aimed to clarify this mechanism., Methods: Preprandial and postprandial (90 min after a meal) blood was obtained from 12 healthy men, and serum insulin and plasma active glucagon-like peptide-1 concentrations were measured. Measurements were also taken after the administration of 5 mg of mosapride citrate three times per day after every meal for 14 days. In addition, C57BL/6 mice were permitted free access to water containing 0.04 % domperidone (D group) or 0.02 % mosapride citrate (M group) for 2 weeks (four mice per group). T1r2 (taste receptor, type 1, member 2), T1r3, and Gnat3 (guanine nucleotide-binding protein, alpha transducing 3) mRNA expression levels of the stomach, duodenum, and proximal and mid-jejunum were evaluated., Results: In human subjects, postprandial plasma active glucagon-like peptide-1 and serum insulin concentrations after administration of mosapride citrate were significantly higher than those pre-administration (4.8 ± 2.2 pmol/L, 45.6 ± 41.6 μIU/mL, and 3.7 ± 1.2 pmol/L, 34.1 ± 28.4 μIU/mL, respectively). The mouse expression levels of T1r2 and Gnat3 in the proximal jejunum and mid-jejunum in the M group (4.1 ± 1.8-fold, 3.1 ± 1.6-fold, and 4.6 ± 0.8-fold, 3.1 ± 0.9-fold increases, respectively), were significantly higher than those of the control group., Conclusions: The administration of mosapride citrate for 2 weeks enhanced postprandial plasma active glucagon-like peptide-1 and serum insulin concentration and increased the expression of sweet taste receptors in the upper intestine.

Aims/introduction: The aim of this study in patients with gestational diabetes mellitus (GDM) was to evaluate the relationship of insulin resistance and secretion to area-under-the-sensor glucose concentration-time curve from before to 120 min postmeal (CGM-AUC(0-120 min)) as determined with continuous glucose monitoring (CGM)., Materials and Methods: Immunoreactive insulin and HbA1c were determined in 22 Japanese patients with GDM undergoing a 75 g oral glucose tolerance test. Patients underwent CGM within 3 weeks of receiving a diagnosis of GDM., Results: HbA1c (NGSP) was 5.5 ± 0.4%, BMI was 24.8 ± 5.3 kg/m(2), mean sensor glucose by CGM was 94.2 ± 10.3 mg/dL, standard deviation was 17.5 ± 4.4 mg/dL, and CGM-AUC(0-120 min) was 204.2 ± 23.8 h mg/dL. The insulin resistance indices the homeostasis model assessment ratio (HOMA-R), quantitative insulin sensitivity check index (QUICKI), and the Matsuda Index were correlated with CGM-AUC(0-120 min). The disposition index (DI), which was used to evaluate insulin secretion, was negatively correlated with CGM-AUC(0-120 min)., Conclusions: Not only insulin resistance but also beta cell dysfunction contributes to postprandial hyperglycemia in Japanese patients with GDM.

Irsogladine maleate (2,4-diamino-6-[2,5-dichlorophenyl]-s-triazine maleate; IM), an anti-peptic ulcer drug, may have a protective effect on the gastrointestinal mucosa. This study investigated the effects of IM on spontaneous colitis in interleukin-10 gene-deficient (IL-10(-/-)) mice. Five-week-old IL-10(-/-) mice were fed a control diet or one containing 100 ppm of IM for 10 weeks. Colonic tissues were evaluated morphologically and histologically. J774A.1 murine monocyte/macrophage cells were incubated with IM after lipopolysaccharide stimulation. mRNA expression was assessed by quantitative polymerase chain reaction (PCR) and protein concentration by enzyme-linked immunosorbent assay (ELISA). Colonic length, weight, and histological scores clearly demonstrated that spontaneous colitis was prevented in IL-10(-/-) mice fed a diet containing IM compared with those fed control diet. Levels of tumor necrosis factor-alpha (TNF-α) (-2.5-fold), IL-1β (-5.4), interferon-gamma (IFN-γ) (-4.5), IL-17 (-113.0), IL-12p35 (-21.0), IL-12p40 (-3.4), and IL-23p19 (-4.2) mRNA expression were significantly decreased in the colonic tissues of IM-treated animals, suggesting that oral treatment with IM suppressed the T-helper (Th)1/Th17 immune response in the colonic mucosa. An in vitro study using monocyte/macrophage cells to clarify the pharmacological action of IM indicated that IL-12p40 and IL-23p19 mRNA expression levels were dose-dependently decreased by IM treatment. ELISA showed that IL-12p40 and IL-23 protein secretion were significantly decreased by IM in a dose-dependent manner. Oral treatment with IM prevented spontaneous colitis in IL-10(-/-) mice by suppressing the colonic mucosal Th1/Th17 immune response through inhibition of IL-12 and -23 production in monocyte/macrophage cells.

Objectives. The aim of this study was to investigate and compare the eradication rate of Helicobacter pylori as the third-line triple therapy with rabeprazole (RPZ) + amoxicillin (AMPC) + levofloxacin (LVFX) and high-dose RPZ + AMPC. Methods. 51 patients who failed Japanese first-line (proton pump inhibitor (PPI) + AMPC + clarithromycin) and second-line (PPI + AMPC + metronidazole) eradication therapy were randomly assigned at a 1 : 1 ratio to one of the following third-line eradication groups: (1) RAL group: RPZ 10 mg (b.i.d.), AMPC 750 mg (b.i.d.), and LVFX 500 mg (o.d.) for 10 days; (2) RA group: RPZ 10 mg (q.i.d.) and AMPC 500 mg (q.i.d.) for 14 days. Patients who failed to respond to third-line eradication therapy received salvage therapy. Results. The rates of eradication success, based on intention to treat (ITT) analysis, were 45.8% in the RAL group and 40.7% in the RA group. The overall eradication rates were 73.9% in the RAL group and 64.0% in the RA group. There was no significant difference between the two groups. Conclusions. The third-line triple therapy with RPZ, AMPC, and LVFX was as effective as that with high-dose RPZ and AMPC.

Background: Sitagliptin inhibits dipeptidyl peptidase-4, which inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. To assess its antidiabetic potency, we used meal tolerance tests (MTTs) to determine the very short-term effects of sitagliptin on plasma concentrations of insulin and glucagon., Methods: On day 1, patients with newly diagnosed or uncontrolled type 2 diabetes mellitus started a calorie-restricted diet. On day 2, the first MTT was performed, before treatment with sitagliptin 50 mg/day started later the same day. On day 5, a second MTT was performed. Area under the concentration-time curves (AUCs) of relevant laboratory values were calculated [AUC from time zero to 2 h (AUC0-2h) and from time zero to 4 h (AUC0-4h)]., Results: Fifteen patients were enrolled. AUCs for postprandial plasma glucose were decreased after 3 days of sitagliptin treatment [AUC0-2h 457 ± 115 mg/dL·h (25.4 ± 6.4 mmol/L·h) to 369 ± 108 mg/dL·h (20.5 ± 6.0 mmol/L·h); AUC0-4h 896 ± 248 mg/dL·h (49.7 ± 13.8 mmol/L·h) to 701 ± 246 mg/dL·h (38.9 ± 13.7 mmol/L·h); both p < 0.001]. AUC0-2h and AUC0-4h for postprandial plasma glucagon also decreased: 195 ± 57 to 180 ± 57 pg/mL·h (p < 0.05) and 376 ± 105 to 349 ± 105 pg/mL·h (p < 0.01), respectively. The AUC0-2h [median with quartile values (25%, 75%)] for active GLP-1 increased: 10.5 (8.5, 15.2) to 26.4 (16.7, 32.4) pmol/L·h (p = 0.03)., Conclusions: Very short-term (3-day) treatment with sitagliptin decreases postprandial plasma glucose significantly. This early reduction in glucose may result partly from suppression of excessive glucagon secretion, through a direct effect on active GLP-1. Improvement in postprandial plasma glucose, through suppression of glucagon secretion, is believed to be an advantage of sitagliptin for the treatment of patients with type 2 diabetes.

Aim: To investigate the optimum period of treatment for post endoscopic submucosal dissection (ESD) ulcers., Methods: Patients who underwent ESD for gastric cancer were randomized to two groups and treated with esomeprazole 20 mg per day for 4 wk (4W group) or 2 wk (2W group). At 4 wk after ESD, we measured the size of the artificial ulcers by endoscopy and determined the ulcer healing rate, compared with the size of the ESD specimens. This randomized controlled trial study was approved by our ethics committee and registered in the UMIN Clinical Trial Registry., Results: A total of 60 consecutive patients were included in the study. All patients received rebamipide 300 mg per day for 4 wk. One patient in 2W group who showed bleeding within two weeks and received endoscopic treatment was excluded from further analysis. The numbers of patients with ulcers in the healing/scar stage in the 2W and 4W groups at 4 wk after ESD were 20/6 and 28/5, respectively, with no significant difference. The ulcer healing rate in the 2W and 4W groups were 96.1% [95% confidence interval (CI): 94.6%-97.55] vs 94.8% (95%CI: 92.6%-97.1%), respectively, with no statistical difference (UMIN000006951)., Conclusion: Two-wk treatment with a proton pump inhibitor is as effective as four-week treatment for healing post ESD ulcers.

The aim of this study was to analyze the blood glucose profile and the response of incretins in healthy young subjects by the 75 g oral glucose tolerance test (OGTT). We first reported that plasma glucose and GIP levels were higher in males during the early phase of the OGTT., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Idiopathic membranous nephropathy (IMN) is increasingly seen in older patients. However, differences in disease presentation and outcomes between older and younger IMN patients remain controversial. We compared patient characteristics between younger and older IMN patients., Methods: We recruited 171 Japanese patients with IMN, including 90 (52.6%) patients <65 years old, 40 (23.4%) patients 65-70 years, and 41 (24.0%) patients ≥ 71 years. Clinical characteristics and outcomes were compared between younger and older IMN patients., Results: During a median observation period of 37 months, 103 (60.2%) patients achieved complete proteinuria remission, which was not significantly associated with patient age (P = 0.831). However, 13 (7.6%) patients were hospitalized because of infection. Multivariate Cox proportional hazards models identified older age [adjusted hazard ratio (HR) = 3.11, 95% confidence interval (CI): 1.45-7.49, per 10 years; P = 0.003], prednisolone use (adjusted HR = 11.8, 95% CI: 1.59-242.5; P = 0.014), and cyclosporine used in combination with prednisolone (adjusted HR = 10.3, 95% CI: 1.59-204.4; P = 0.012) as significant predictors of infection. A <25% decrease in proteinuria at 1 month after immunosuppressive therapy initiation also predicted infection (adjusted HR = 6.72, 95% CI: 1.51-37.8; P = 0.012)., Conclusions: Younger and older IMN patients had similar renal outcomes. However, older patients were more likely to develop infection when using immunosuppressants. Patients with a poor response in the first month following the initiation of immunosuppressive therapy should be carefully monitored for infection and may require a faster prednisolone taper.

Atherosclerotic involvements are an essential causal element of prospect in diabetes mellitus (DM), with carotid atherosclerosis (CA) being a common risk-factor for prospective crisis of coronary artery diseases (CAD) and/or cerebral infarction (CI) in DM subjects. From another point of view, several reports have supplied augmenting proof that hepatocyte growth factor (HGF) has a physiopathological part in DM involvements. HGF has been a mesenchymal-derived polyphenic factor which modulates development, motion, and morphosis of diverse cells, and has been regarded as a humor intermediator of epithelial-mesenchymal interplays. The serum concentrations of HGF have been elevated in subjects with CAD and CI, especially during the acute phase of both disturbances. In our study with 89 type 2 DM patients, the association between serum concentrations of HGF and risk-factors for macrovascular complications inclusive of CA were examined. The average of serum HGF levels in the subjects was more elevated than the reference interval. The serum HGF concentrations associated positively with both intimal-media thickness (IMT) (r = 0.24, P = 0.0248) and plaque score (r = 0.27, P = 0.0126), indicating a relationship between the elevated HGF concentrations and advancement of CA involvements. Multivariate statistical analysis accentuated that serum concentrations of HGF would be associated independently with IMT (standardized = 0.28, P = 0.0499). The review indicates what is presently known regarding serum HGF might be a new and meaningful biomarker of macroangiopathy in DM subjects.

Background: Endoscopic submucosal dissection (ESD) has become widely accepted as a standard treatment for gastric epithelial neoplasms. Antithrombotic agents are widely used to prevent thromboembolic disease. However, the feasibility of endoscopic procedures for patients using such agents has been rarely investigated. The aim of this study was to identify risk factors for post-operative bleeding after gastric ESD and to evaluate the relationship between the use of antithrombotic agents and post-operative bleeding., Methods: From June 2005 to March 2014, 413 patients with 425 gastric neoplasms were treated by ESD. The demographic and clinical parameters associated with post-operative bleeding were investigated. 83 patients receiving antithrombotic agents were separately assessed using various methods of administration during the ESD procedure. Post-operative bleeding that occurred within 5 days of ESD was defined as early post-operative bleeding, whereas subsequent bleeding was defined as delayed bleeding., Results: The overall post-operative bleeding rate was 4.7%. In patients with continued low-dose aspirin (LDA), heparin replacement (HR), or continued LDA along with HR, post-operative bleeding rates were 9.5%, 23.8%, and 25.0%, respectively. On multivariate analysis, a specimen size of ≥40 mm was a risk factor for early post-operative bleeding [odds ratio (OR) 6.08, 95% CI: 1.74-21.27], and HR and chronic kidney disease (CKD) requiring hemodialysis were risk factors for delayed bleeding (OR 12.23, 95% CI: 2.63-56.77 and OR 28.35, 95% CI: 4.67-172.11, respectively). Continued LDA was not a risk factor for post-operative bleeding., Conclusions: Large specimen size is a risk factor for early post-operative bleeding, and HR and CKD requiring hemodialysis are risk factors for delayed bleeding. Patients with risk factors should be carefully watched, allowing for the timing of post-operative bleeding after ESD.

Background and Aim: Capsule endoscopy (CE) is now widely accepted as a first-line diagnostic modality for obscure gastrointestinal bleeding (OGIB), with a high diagnostic yield compared to other modalities. However, even after negative CE examination, re-bleeding is often known to occur. The aim of the present study was to identify predictive factors of re-bleeding after negative CE, and to clarify the clinical utility of double-balloon enteroscopy (DBE) after negative CE for OGIB., Methods: Two hundred and sixty patients who underwent CE for OGIB between October 2007 and September 2012 were included, and followed up for at least 1 year after CE examination. Demographic and clinical parameters associated with re-bleeding after negative CE were investigated., Results: A total of 154 patients (59.2%) had negative findings. Thirteen of those patients (8.4%) had one or more re-bleeding episodes during the follow-up period. In comparing patients with and without re-bleeding, Cox hazard regression analysis revealed that advanced age was a predictive factor for re-bleeding after negative CE (hazard ratio 1.05 [1.01-1.10], P = 0.03). Subsequent DBE for reasons other than re-bleeding was carried out in 51 patients (33.1%). Mucosal lesions (ulcer or multiple erosions) were subsequently detected in seven patients (13.7%), and endoscopic therapies were carried out in two patients (3.9%)., Conclusions: In patients of advanced age, more extensive follow up is needed, even if the CE result is negative. In addition, DBE subsequent to negative CE may be useful to detect lesions that were overlooked on CE., (© 2014 The Authors. Digestive Endoscopy © 2014 Japan Gastroenterological Endoscopy Society.)

Occludin is the first identified protein in the tight junction (TJ), but its function has remained for the most part obscure. TJs have been demonstrated to play important roles in the inner ear function, and occludin is expressed in all the epithelial TJs in the inner ear. Thus, we examined the inner ears of occludin-deficient (Occ(-/-)) mice. Although inner ears initially developed normally in Occ(-/-) mice, apoptosis occurs in hair cells in the organ of Corti around day 12 after birth, and deafness develops. Since hair cell degeneration was not observed in cochlear explant cultures of Occ(-/-) mice, environmental changes were considered to be the trigger of cell death. As for the vestibular system, both the morphologies and functions are normal in Occ(-/-) mice. These phenotypes of Occ(-/-) mice are very similar with those of claudin-14 or claudin-9 deficient mice, leading us to speculate on the existence of imbalance induced by TJ abnormalities, such as localized ionic components. Moreover, the occludin deficiency led to dislocalization of tricellulin, a gene responsible for human deafness DFNB49. The deafness in Occ(-/-) mice may be due to this dislocalization of tricellulin., (© 2014. Published by The Company of Biologists Ltd.)

Saxagliptin is a selective and potent dipeptidyl peptidase (DPP)-4 inhibitor, approved as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus (T2DM) in the USA on July 2009, and had been launched globally in over 86 countries by September 2013. In patients with T2DM, once-daily administration of saxagliptin before breakfast achieves sustained inhibition of plasma DPP-4 activity and reduction of postprandial hyperglycemia, including after dinner, associated with an increase in plasma glucagon-like peptide-1 levels. This paper reviews the safety and efficacy of saxagliptin in Japanese patients with T2DM. The clinical development study in Japan supported its usefulness for the disease. Saxagliptin 1, 2.5, and 5 mg led to significant improvements in glycated hemoglobin (HbA1c), and was generally well tolerated. Treatment with saxagliptin 5 mg induced a sustained reduction in HbA1c over 52 weeks. Long-term combination therapy with saxagliptin and other oral hypoglycemic agents also provided sustained glycemic control and was well tolerated for up to 52 weeks. Saxagliptin as add-on to sulfonylureas or glinides has a tendency to increase hypoglycemia, but not with other oral antidiabetic agents, such as α-glucosidase inhibitors, metformin, or thiazolidinediones. The results of clinical trials have confirmed the long-term efficacy and safety of saxagliptin monotherapy as well as its use as add-on combination therapy, and support its usefulness as a therapeutic agent for T2DM. Saxagliptin has less concern for hypoglycemia and weight gain, which often becomes problematic in routine care of T2DM. Meta-analysis of clinical trials in the USA showed no evidence of increased risk of cardiovascular events associated with saxagliptin, suggesting the superior of saxagliptin in terms of safety. Recently, investigators in the SAVOR-TIMI (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction) 53 study suggested that DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, although the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Saxagliptin is applicable for various pathological conditions, and is considered to be clinically significant as a new therapeutic option for Japanese patients with T2DM.

Background: Multiple studies have shown cigarette smoking to be a risk factor for chronic kidney disease. However, it is unknown whether smoking similarly increases the risk for progression of membranous nephropathy., Methods: This study used the Nagoya Nephrotic Syndrome Cohort Study (N-NSCS), including 171 patients with idiopathic membranous nephropathy (IMN) from 10 nephrology centers in Japan. The dose-response relationships between cigarette smoking and the outcomes were assessed by using multivariate Cox proportional hazards models adjusted for clinically relevant factors. The primary outcome was a 30% decline in the estimated glomerular filtration rate (eGFR). The secondary outcome was first complete remission (CR) of proteinuria., Results: During the observation period (median, 37 months; interquartile range, 16-71 months), 37 (21.6%) patients developed a 30% decline in eGFR and 2 (1.2%) progressed to ESRD. CR occurred in 103 (60.2%) patients. Multivariate Cox proportional hazards models revealed current smoking (adjusted hazard ratio [HR], 7.81 [95% confidence interval (CI), 3.17-19.7]), female sex (adjusted HR, 3.58 [95% CI, 1.87-8.00]), older age (adjusted HR, 1.71 [95% CI, 1.13-2.62] per 10 years), the number of cigarettes smoked daily (adjusted HR, 1.61 [95% CI, 1.23-2.09] per 10 cigarettes daily), and cumulative smoking of ≥40 pack-years (adjusted HR, 5.56 [95% CI, 2.17-14.6]) to be associated with a 30% decline in eGFR. However, smoking was not associated with CR., Conclusion: Smoking is a significant and dose-dependent risk factor for IMN progression. All patients with IMN who smoke should be encouraged to quit.

Objective: The aim of this study was to analyze the changes in daily blood glucose fluctuation and insulin dose in patients with type 1 diabetes mellitus (T1DM) undergoing basal-bolus therapy following a switching of basal insulin used from insulin glargine or detemir to insulin degludec., Methods: Seven patients with T1DM were enrolled. All patients treated with insulin glargine or detemir twice daily were switched to insulin degludec with 80-90 % of the prior insulin dose. During the study period, the basal insulin doses were adjusted by the attending physician. The patients underwent continuous glucose monitoring before, 3 days after, and 24 weeks after switching to insulin degludec. The daily insulin dose was analyzed before, 3 days after, and 24 weeks after switching. Glycated hemoglobin levels were measured before and 24 weeks after switching., Results: The blood glucose profile did not change significantly before and after switching. On the other hand, the total daily insulin dose and total daily basal insulin dose decreased significantly 24 weeks after switching., Discussion: In patients with T1DM undergoing insulin glargine or detemir treatment, it is possible to achieve similar glycemic control in the medium term with a once daily, lower dose of insulin degludec.