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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.

Background and Aim: Gastric ulcer healing is a complex process involving cell proliferation and tissue remodeling. Sonic hedgehog (Shh) activates the Shh signaling pathway, which plays a key role in processes such as tissue repair. Shh and interleukin 1β (IL1β) have been reported to influence the proliferation of gastric mucosa. We evaluated the relationships between the speed of gastric ulcer healing and the levels of expression of Shh and IL1β., Methods: The study included 45 patients (mean age 71.9 ± 9.0 years; M/F, 30/15) who underwent endoscopic submucosal dissection (ESD) for gastric cancer, followed by standard dose of oral proton-pump inhibitor for 4 weeks. Subsequently, the size of ESD-induced artificial ulcers were measured to determine the speed of gastric ulcer healing, and regenerating mucosa around the ulcers and appropriately matched controls were collected from patients by endoscopic biopsy. Polymerase chain reaction (PCR) array analysis of genes in the Shh signaling pathway was performed, and quantitative reverse transcription (RT)-PCR was used to measure IL1β mRNA., Results: The levels of Shh and IL1β mRNA were 3.0 ± 2.7-fold and 2.5 ± 2.5-fold higher, respectively, in regenerating mucosa of artificial ulcers than in appropriately matched controls, with the two being positively correlated (r = 0.9, P < 0.001). Shh (r = 0.8, P < 0.001) and IL1β (r = 0.7, P < 0.005) expression was each positively correlated with the speed of gastric ulcer healing, but multivariate analysis showed that Shh expression was the only significant parameter (P = 0.045)., Conclusions: Expression of Shh was correlated with the speed of gastric ulcer healing, promoting the regeneration of gastric mucosa., (© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Background: We previously showed that fibrocytes, a hematopoietic stem cell source of fibroblasts/myofibroblasts, infiltrated the colonic mucosa of a murine colitis model., Aim: We investigated whether fibrocytes were involved in the pathogenesis of Crohn's disease., Methods: Human surgical intestinal specimens were stained with anti-leukocyte-specific protein 1 and anti-collagen type-I (ColI) antibodies. Circulating fibrocytes in the human peripheral blood were quantified by fluorescence-activated cell sorting with anti-CD45 and anti-ColI antibodies. Cultured human fibrocytes were prepared by culturing peripheral CD14(+) monocytes., Results: In the specimens of patients with Crohn's disease, the fibrocyte/total leukocyte percentage was significantly increased in inflammatory lesions (22.2 %, p < 0.01) compared with that in non-affected areas of the intestine (2.5 %). Interestingly, the percentage in fibrotic lesions was similar (2.2 %, p = 0.87) to that in non-affected areas. The percentages of circulating fibrocytes/total leukocytes were significantly higher in patients with Crohn's disease than in healthy controls. Both CXC-chemokine receptor 4(+) and intercellular adhesion molecule 1(+) fibrocyte numbers were significantly increased in Crohn's disease, suggesting that circulating fibrocytes have a higher ability to infiltrate injured sites and traffic leukocytes. In cultured fibrocytes, lipopolysaccharide treatment remarkably upregulated tumor necrosis factor (TNF)-α mRNA (17.0 ± 5.7-fold) and ColI mRNA expression (12.8 ± 5.7-fold), indicating that fibrocytes stimulated by bacterial components directly augmented inflammation as well as fibrosis., Conclusions: Fibrocytes are recruited early in the inflammatory phase and likely differentiate into fibroblasts/myofibroblasts until the fibrosis phase. They may enhance inflammation by producing TNF-α and can directly augment fibrosis by producing ColI.

We produced low temperature (15 °C) processed green tea (LTPGT) with higher aroma contents than normal green tea (Sencha). Normal temperature processed green tea (NTPGT), involved storing at 25 °C, and Sencha had no storing process. Sensory evaluation showed LTPGT had higher levels of floral and sweet odorants than NTPGT and Sencha. Aroma extract dilution analysis and gas chromatography-mass spectrometry-olfactometry indicated LTPGT had 12 aroma compounds with high factor dilution values (FD). Amongst LTPGT's 12 compounds, indole, jasmine lactone, cis-jasmone, coumarin, and methyl epijasmonate contributed to floral, fruity and sweet characters. In particular, indole increased initially, peaking at 16 h, then gradually decreased. Feeding experiments suggested [(15)N]indole and [(15)N]oxygenated indoles (OX-indoles) were produced from [(15)N]anthranilic acid. We proposed the increase in indole was due to transformation of anthranilic acid during the 16 h storage and the subsequent decline in indole level was due to its conversion to OX-indoles., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background Aims: In patients receiving peritoneal dialysis, fungal or yeast peritonitis has a poor prognosis. In rat peritoneum with mechanical scraping, severe peritonitis can be induced by zymosan, a component of yeast (Zy/scraping peritonitis). Administration of rat adipose tissue-derived stromal cells (ASCs) potentially can improve several tissue injuries. The present study investigated whether rat ASCs could improve peritoneal inflammation in Zy/scraping peritonitis., Methods: Rat ASCs were injected intraperitoneally on a daily basis in rats with Zy/scraping peritonitis., Results: Peritoneal inflammation accompanied by accumulation of inflammatory cells and complement deposition was suppressed by day 5 after injection of rat ASCs. The peritoneal mesothelial layer in Zy/scraping peritonitis with rat ASC treatment was restored compared with the peritoneal mesothelial layer without rat ASC treatment. Injected rat ASCs co-existed with mesothelial cells in the sub-peritoneal layer. In vitro assays showed increased cellular proliferation of rat mesothelial cells combined with rat ASCs by co-culture assays, confirming that fluid factors from rat ASCs might play some role in facilitating the recovery of rat mesothelial cells. Hepatocyte growth factor was released from rat ASCs, and administration of recombinant hepatocyte growth factor increased rat mesothelial cell proliferation., Conclusions: Because the peritoneal mesothelium shows strong expression of membrane complement regulators such as Crry, CD55 and CD59, restoration of the mesothelial cell layer by rat ASCs might prevent deposition of complement activation products and ameliorate peritoneal injuries. This study suggests the therapeutic possibilities of intraperitoneal rat ASC injection to suppress peritoneal inflammation by restoring the mesothelial layer and decreasing complement activation in fungal or yeast peritonitis., (Copyright © 2014 International Society for Cellular Therapy. All rights reserved.)

We encountered a rare case of severe diffuse duodenitis associated with ulcerative colitis (UC). A 23-year-old man underwent total proctocolectomy with ileal J-pouch anal anastomosis for UC. He suffered from severe abdominal pain, fever and bloody diarrhea for six months after the surgery. Upper double-balloon enteroscopy disclosed severe diffuse duodenitis, of which the findings were endoscopically and histologically similar to those of colonic lesions of UC. Although the administration of prednisolone was ineffective, treatment with intravenous tacrolimus markedly improved the clinical findings. This is the first report of the successful treatment of severe UC-associated diffuse duodenitis with intravenous tacrolimus.

The effects of exenatide on glycemic control, lipid metabolism, blood pressure, and gastrointestinal symptoms were investigated in obese Japanese patients with type 2 diabetes mellitus. Twenty-six outpatients were enrolled and administered 5 μg of exenatide twice daily. If there was insufficient weight loss and/or insufficient improvement in glycemic control, the dose was increased to 10 μg twice daily. Follow-up was continued until the 12th week of administration. Hemoglobin A1c, glycoalbumin, fasting plasma glucose, body weight, fasting serum C-peptide, serum lipids, blood pressure, and pulse rate were measured before and after the observation period. In the initial phase of exenatide therapy, each patient received a diary to record gastrointestinal symptoms. During treatment with exenatide, hemoglobin A1c decreased significantly and serum C-peptide increased significantly. Body weight, low-density lipoprotein cholesterol, and systolic blood pressure decreased significantly. Nausea was the most frequent gastrointestinal symptom and occurred in 16 patients. Its onset was noted at a mean of 1.7 h after injection, the mean duration was 1.1 h, and it continued for a mean of 9.3 days after the initiation of administration. Patients with nausea showed a significant decrease in hemoglobin Alc, glycoalbumin, or body weight compared with those without nausea. These findings suggest that a more marked improvement in metabolic parameters by exenatide can be partly dependent on the manifestation of gastrointestinal symptoms.

Introduction: Insulin degludec is a new, ultra-long-acting basal insulin. The aim of this study was to analyze the changes of basal insulin dose and blood glucose profile in basal-bolus therapy of type 1 diabetes mellitus (T1DM) at the switching of basal insulin from insulin glargine or detemir to insulin degludec., Methods: Sixteen patients with T1DM were enrolled. The patients underwent continuous glucose monitoring before and after the switching of insulin glargine or detemir to degludec. Ten patients treated with insulin glargine or detemir twice daily, were switched to insulin degludec with 80-90% of the prior insulin dose. The remaining six patients treated with insulin glargine once daily, were switched to insulin degludec without down titration. The changes of daily insulin dose and glycated hemoglobin (HbA1c) were also examined for 12 weeks after switching to insulin degludec., Results: In the patients switched from twice-daily basal insulin, no significant difference was found between before and after switching in the blood glucose profile. In the once-daily group, blood glucose levels showed a tendency to decrease after switching to the degludec treatment. During the study period, total daily insulin dose (TDD) and total daily basal insulin dose (TBD) decreased significantly in the twice-daily group, and TDD and TBD showed a tendency to decrease after switching to degludec in the once-daily group. In both groups, the changes of HbA1c were not significantly different., Conclusion: It is possible to achieve similar glycemic control with once-daily injection and lower doses of insulin degludec in patients with T1DM who have been treated with insulin glargine or detemir.

To investigate the differences between the effects of mesenchymal stem cells (MSCs) administered in the early and late phases of tumorigenesis, MSCs were isolated from bone marrow and colorectal tumors were produced by exposing 7-week-old F344 rats to 1,2-dimethylhydrazine and dextran sulfate sodium. We evaluated tumor number and volume (week 25), MSC localization, number of aberrant crypt foci (ACF), transforming growth factor (TGF)-β1 protein levels in the rectum after administration of MSCs (week 5 or 15), and the effects of MSC-conditioned medium on ACL15 cell proliferation. Administered MSCs labeled with PKH26 were observed in the rectum. Administered MSCs in the early phase (week 5) before tumor occurrence (week 12) significantly decreased tumor number and volume (1.5 vs 4 and 21 mm(3) vs 170 mm(3); p<0.01), but not administered MSCs in the late phase (week 15). Administered MSCs in the early phase reduced ACF number on days 14 and 35 (1.9 vs 4.1 and 3.7 vs 7.3; p<0.01). Rectal TGF-β1 increased 1.3 fold on day 3, and MSC-conditioned medium containing TGF-β1 abundantly inhibited ACL15 cell proliferation. MSCs administered in the early phase but not late phase inhibited colorectal tumor development in a rat model.

Patients with diabetes mellitus are at increased risk from cardiovascular-related morbidity and mortality as compared with healthy individuals. An association between the postprandial metabolic state and atherogenesis has been observed in patients with diabetes mellitus. In the Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM), treatment with an α-glucosidase inhibitor (α-GI) in patients with impaired glucose tolerance not only reduced the rate of conversion from impaired glucose tolerance to type 2 diabetes mellitus (T2DM), but was also associated with a reduction in the risk of cardiovascular events. These results suggested the importance of treating postprandial hyperglycemia in the early stages of T2DM. Glinides are rapid and short-acting insulin secretagogues that bind to the sulfonylurea receptors on pancreatic β-cells to facilitate rapid insulin secretion, restore postprandial early insulin secretion, and reduce the postprandial glucose spike. Moreover, α-GIs reduce postprandial hyperglycemia and insulin secretion by delaying the digestion of carbohydrates and polysaccharides in the small intestine. Then, both glinides and α-GI have beneficial effects for treating patients with T2DM and impaired glucose tolerance. Considering the ameliorating effects of these drugs on postprandial metabolic disorders, combinations of glinides and α-GI might constitute a promising therapeutic strategy for managing patients with T2DM, and also appear to be suitable for Japanese people, who consume more carbohydrates, such as polished rice, than Caucasians. It has recently been reported that combined use of mitiglinide and voglibose reduces postprandial insulin secretion and blunts diurnal glycemic changes in T2DM patients. This therapy can thus be regarded as being suitable for achieving strict postprandial glycemic control. In this report, we outline the effects of this combination therapy on postprandial plasma glucose and assess its safety.

Objective: Transnasal endoscopy may be used to observe the head and neck part readily without excessive reflexes. We aimed to evaluate the utility and stability of transnasal esophagogastroduodenoscopy (TN-EGD) in comparison with transoral EGD (TO-EGD) for observation of the pharynx., Study Design: Prospective study, Methods: A total of 497 patients received unsedated TN-EGD with a 5.5 mm diameter endoscope or unsedated TO-EGD with endoscopes of 6.5 mm, 7.9 mm and 9.2 mm diameter. The rate of completion of pharyngeal observation and numbers of gag reflexes and cough reflexes were recorded., Results: TN-EGD was performed in 175 patients and TO-EGD was performed in 322 patients. Pharyngeal observation was completed in 173 patients (98.9%) in the TN-EGD group and 235 patients (73.2%) in the TO-EGD group, a significant difference (p<0.001). The TN-EGD group had a low rate of occurrence of gag reflex (0.57%), in contrast, 28.3% of the TO-EGD group had a gag reflex, a significant difference (p<0.01). Multivariable analyses revealed that the use of TN-EGD was the only predictive factor for completion of pharyngeal observation (p<0.0001)., Conclusions: TN-EGD is ideally suited to observation of the pharynx by unsedated EGD.

Objectives: Emergence of image-enhanced endoscopy has enabled an early detection of pharyngeal carcinoma. Pharyngeal observation during esophagogastroduodenoscopy (EGD) is sometimes difficult because of excessive reflexes and is a great burden to the patients and impacts on their cardiopulmonary function. In this study, the authors aimed to evaluate the utility of transnasal EGD (TN-EGD) in comparison with sedated and unsedated transoral EGD (TO-EGD) in pharyngeal observation using a continuous monitoring device., Methods: A total of 70 patients receiving diagnostic EGD (unsedated TN-EGD, sedated TO-EGD, and unsedated TO-EGD) were enrolled in this study and were evaluated by the following three criteria: (1) numbers of patients with excessive gag and/or cough reflex, (2) vital signs before and during the pharyngeal observation, and (3) response to the request for vocalization or breath-holding., Results: Unsedated TN-EGD, sedated TO-EGD, and unsedated TO-EGD were performed in 30, 20, and 20 patients, respectively. The rate of gag reflex was significantly lower in TN-EGD than in both types of TO-EGD (0% vs. 30%, chi-square test, p < 0.005). The changes in average values of both arterial oxygen saturation (SpO2) and pulse rate (PR) in TN-EGD were smaller than those in sedated TO-EGD (-0.23% vs. -1.23% in SpO2 and 1.57 vs. 8.11 bpm in PR, p < 0.01, respectively). Unsedated TN-EGD patients could respond to the instructions of utterance and breath-holding during the observation (p < 0.05, p < 0.001, respectively)., Conclusion: Unsedated TN-EGD is safe and feasible for pharyngeal observation during normal EGD examination.

CD4(+) T cells play a central role in the development of inflammatory bowel disease (IBD) via high-level production of effector cytokines such as IFN-γ and TNF-α. To better characterize the colitogenic CD4(+) T cells, we examined their expression of CXCR6, a chemokine receptor that is expressed by T cells upon activation and is upregulated in several inflammatory diseases. We found that 80% of colonic lamina propria CD4(+) T cells expressed CXCR6 in the CD45RB(high) T cell-transferred colitis model. CXCR6 expression was similarly upregulated in inflamed mucosa of patients with Crohn's disease. Although surface marker analysis demonstrated that both CXCR6(+) and CXCR6(-) CD4(+) T-cell subsets consist of the cells with effector and effector-memory cells, the more cells in the CXCR6(+) subset produced IFN-γ and TNF-α compared to CXCR6(-) subset, and only the CXCR6(+) subset produced IL-17A. Nevertheless, adoptive retransfer of lamina propria CXCR6(+) T cells into Rag1 (-/-) recipients failed to induce the disease due to limited expansion of the transferred cells. By contrast, retransfer of CXCR6(-) cells evoked colitis similar to that observed in CD4(+)CD45RB(high) T cell-transferred mice, and resulted in their conversion into CXCR6(+) cells. Collectively, these observations suggest that the CXCR6(+)CD4(+) T-cell subset consists of terminally differentiated effector cells that serve as the major source of effector cytokines in the inflamed tissue, whereas CXCR6(-)CD4(+) T-cell subset serves as a colitogenic memory compartment that retains the ability to proliferate and differentiate into CXCR6(+)CD4(+) T cells.

Objective: Low-dose proton pump inhibitors (PPIs) are often administrated as maintenance therapy for gastroesophageal reflux disease (GERD) and on-demand PPI therapy is a viable option for long-term management of GERD. The aim of this study is to investigate intragastric acidity during the first day following the administration of low-dose PPIs., Subjects and Methods: The study employed a crossover design. The subjects were 10 healthy volunteers who were administrated lansoprazole 15 mg (orally disintegrating) or rabeprazole 10mg. All subjects underwent pH monitoring with a wireless system during the first day after PPI administration., Results: There was no significant difference in the average intragastric pH during the first day of administration of lansoprazole and rabeprazole (3.3±1.1 vs. 3.2±0.7, paired t test), although the pH was significantly higher with both drugs as compared with the baseline (1.8±0.4, P<0.01). The pH 4 holding time ratio during the first day showed no significant difference between lansoprazole and rabeprazole (35.2±22.4% vs. 34.3±15.0%), and was also significantly higher than at baseline (0.35±1.73%, P<0.01). The two PPIs differed with respect to the peak of the pH 4 holding time ratio., Conclusions: Lansoprazole 15 mg and rabeprazole 10 mg showed sufficient inhibition of intragastric acidity during the first day after PPI administration and the effects did not differ between drugs, although there was a difference in their time at which the peak effects were reached., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Aims/introduction: Incretins might play some pathophysiological role in glucose metabolism in diabetes and obesity; it is not clear whether or not the amount and the pattern of incretin secretion vary with different types of sugars. To evaluate the effect of two types of disaccharides on glucose metabolism and the kinetics of incretin secretion, plasma levels were measured after palatinose or sucrose ingestion in non-obese healthy participants., Materials and Methods: The study was carried out on healthy participants who were given a solution containing 50 g of palatinose or sucrose for ingestion. Blood samples were obtained before loading and after ingestion. Insulin, glucagon and incretins hormones were measured by the enzyme-linked immunosorbent assay method., Results: When the data were compared between palatinose and sucrose ingestion, both plasma glucose values at 15, 30 and 60 min, and plasma insulin values at 15 and 30 min after palatinose loading were significantly lower than those after sucrose loading. Plasma levels of total glucose-dependent insulinotropic polypeptide at 15-90 min after palatinose loading were significantly lower than those after sucrose loading. Plasma levels of total and active glucagon-like peptide-1 at 90 min and the area under the curve (60-120 min) of the total glucagon-like peptide-1 were significantly higher with palatinose-loading than with sucrose loading., Conclusion: Compared with sucrose, palatinose appears to have a more favorable effect on glucose metabolism and protection of pancreatic islets as a result of less hyperglycemic and hyperinsulinemic potency.

Backgrounds and Aims: Gastric submucosal tumors (SMTs) are often detected during routine gastroendoscopy but little is known about their natural history. The aim of this study was to evaluate the natural course of gastrointestinal mesenchymal tumors (GIMTs) in the stomach., Patients and Methods: From October 2001 to November 2011, a total of 228 gastric SMTs were evaluated by endoscopic ultrasonography (EUS). Based on the findings of EUS and enhanced CT, we diagnosed these tumors as lipomas, cysts, aberrant pancreases, extramural compressions, and GIMTs. The gastric GIMTs which were examined by EUS twice or more were included in this study and the factors associated with an increase in the size of gastric GIMTs were analyzed., Results: Fifty GIMTs were followed by EUS twice or more. The mean age was 66.4 ± 8.3 years old and the mean period of follow-up was 23.8 ± 21.7 months. Fourteen (28%) of 50 GIMTs increased in size and the time taken for gastric GIMTs to double in size was 19.1 ± 18.2 months. In multivariate logistic regression analysis, age (odds ratio [OR]=1.12, 95% confidence interval [CI]=1.03-1.21), non-upper area of the stomach (OR=5.08, 95%; CI=1.37-18.8) and the detection of an anechoic lesion on EUS (OR=5.90, 95%; CI=1.10-31.8) were the factors predicting an increase in size of gastric GIMTs., Conclusions: We evaluated gastric SMTs by EUS and clarified the factors predicting the growth of gastric GIMT. EUS is indispensable for the diagnosis and management of gastric SMTs., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Mesenchymal stromal cells (MSCs) derived from adipose tissue have immunomodulatory effects, suggesting that they may have therapeutic potential for crescentic GN. Here, we systemically administered adipose-derived stromal cells (ASCs) in a rat model of anti-glomerular basement membrane (anti-GBM) disease and found that this treatment protected against renal injury and decreased proteinuria, crescent formation, and infiltration by glomerular leukocytes, including neutrophils, CD8(+) T cells, and CD68(+) macrophages. Interestingly, ASCs cultured under low-serum conditions (LASCs), but not bone marrow-derived MSCs (BM-MSCs), increased the number of immunoregulatory CD163(+) macrophages in diseased glomeruli. Macrophages cocultured with ASCs, but not with BM-MSCs, adopted an immunoregulatory phenotype. Notably, LASCs polarized macrophages into CD163(+) immunoregulatory cells associated with IL-10 production more efficiently than ASCs cultured under high-serum conditions. Pharmaceutical ablation of PGE2 production, blocking the EP4 receptor, or neutralizing IL-6 in the coculture medium all significantly reversed this LASC-induced conversion of macrophages. Furthermore, pretreating LASCs with aspirin or cyclooxygenase-2 inhibitors impaired the ability of LASCs to ameliorate nephritogenic IgG-mediated renal injury. Taken together, these results suggest that LASCs exert renoprotective effects in anti-GBM GN by promoting the phenotypic conversion of macrophages to immunoregulatory cells, suggesting that LASC transfer may represent a therapeutic strategy for crescentic GN.

Incretin-based therapy was first made available for the treatment of type 2 diabetes mellitus (T2DM) in the US in 2006 and in Japan in 2009. Four DPP-4 inhibitors and two GLP-1 analog/receptor agonists are currently available. The effects of incretin-based therapy are assumed to be exerted mainly through the hormonal and neuronal actions of one of the incretins, GLP-1, which is secreted from L cells localized in the small intestine. The benefits of this therapy over conventional sulfonylureas or insulin injections, such as fewer hypoglycemic events and reduced body weight gain, derive from the glucose-dependent insulinotropic effect. The protective effects of this therapy on vulnerable pancreatic β-cells and against micro/macroangiopathy in T2DM are also most welcome. Indications and/or contraindications for incretin-based therapy should be clarified by prospectively studying the experiences of Japanese T2DM patients undergoing this therapy in the clinical setting.

Arterio enteric fistulas (AEFs) are rare. We herein report a case of a primary arterio enteric fistula of the rectum associated with Takayasu arteritis. A 77-year-old woman presented with acute massive hematochezia and was taken to our hospital. Colonoscopy revealed pulsatile extrinsic rectal wall compression with an exposed blood vessel. Transvaginal ultrasonography and Doppler ultrasound revealed a localized vascular growth laying on the dorsal surface of the uterus that showed an arterial blood-flow signal. We diagnosed the patient to have a pelvic aneurism that had formed a fistula within the rectal wall. We eliminated the aneurysm by ligating the drainage and feeder arteries. Following surgery, the patient did not experience any relapses of hematochezia.

Adipose tissue inflammation induces systemic insulin resistance in persons with obesity and heart failure, and has a crucial role in the progression of these diseases. Chronic inflammatory processes share a common mechanism in which increased production of reactive oxygen species activates p53 and NF-κB signaling, leading to up-regulation of pro-inflammatory cytokine expression and impairment of glucose metabolism. Since inhibition of these processes could slow the progression of various diseases, targeting adipose inflammation has the potential to become a new therapeutic approach for diabetes and heart failure., (Copyright © 2012 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

This study retrospectively analyzed the clinical outcomes of endoscopic resection of 26 sporadic (i. e., not associated with polyposis syndrome) nonampullary duodenal lesions representing high-grade dysplasia or intramucosal carcinoma (duodenal HGD/IMC) in 23 patients. No severe complications such as perforation were observed, but three cases of delayed bleeding were seen. The use of endoscopic clips significantly decreased the delayed bleeding rate (0/19, 0%) compared with cases in which clips were not used (3/7, 42.9%; P = 0.013, χ2 test). Eighteen lesions (69.2%) were removed by en bloc resection. The follow-up period after resection was 25.5 ± 23.3 months. Two lesions (7.7%) that recurred locally were detected at the first surveillance endoscopy 3 months after resection. These lesions were 22 and 15 mm in size respectively and were resected piecemeal. Endoscopic resection is an effective and safe procedure for treating duodenal HGD/IMC. En bloc resection and prophylactic clip usage are encouraged., (© Georg Thieme Verlag KG Stuttgart · New York.)

Current studies suggest that mesenchymal stromal cells (MSCs) improve acute kidney injury (AKI) via paracrine/endocrine effects. We established human adipose tissue-derived stromal cells (hASCs) cultured in low (2%) serum (hLASCs), which have great potential of tissue regeneration. The present study was performed to investigate the therapeutic effects of hLASCs on AKI and to clarify the mechanisms involved. In low serum, hASCs proliferated well, while human bone marrow-derived stromal cells (hBMSCs) did not. hLASCs secreted higher levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) than did hASCs cultured in high (20%) serum (hHASCs) or hBMSCs cultured in high serum (hHBMSCs). AKI was induced in nude rats by folic acid, and hLASCs, hHASCs or control medium were administered into the renal subcapsules. hLASCs significantly attenuated acute renal damage, while hHASCs showed far less effect. Furthermore, interstitial fibrosis observed on day 14 was less pronounced in the hLASCs group. Cell tracking experiment showed no evidence of transdifferentiation. Intravenous injection of hLASCs or hHBMSCs or subcapsular injection of hHBMSCs did not ameliorate AKI. Concerning the mechanisms, our in vivo experiments showed that HGF knockdown by siRNA impaired the ability of hLASCs to protect the kidney from acute injury whereas VEGF knockdown did not. In conclusion, hLASCs, but not hHASCs or hHBMSCs, ameliorated AKI via paracrine effects, and HGF is one of the key mediators.

Background and Objective. Cisplatin-based chemotherapy is widely recognized to cause severe gastrointestinal disorders like nausea, vomiting, and appetite loss. The aim of this study was to assess whether cisplatin-based transcatheter arterial infusion (TAI) chemotherapy reduces plasma ghrelin levels and food intake in hepatocellular carcinoma (HCC) patients. Methods. Seventeen patients with HCC who underwent cisplatin-based TAI chemotherapy (80-100 mg/body) were enrolled in this study. Changes in peptide hormones, including ghrelin and leptin, as well as cytokines, were measured before and after chemotherapy. Appetite was evaluated by visual analog scale (VAS) and food intake was scored by eleven stages (0-10). Results. Appetite and food intake were significantly decreased after chemotherapy (P < 0.05). Plasma acylated ghrelin levels before therapy and at day 1, day 7, and day 14 after chemotherapy were 10.4 ± 7.2, 4.7 ± 4.7, 11.7 ± 8.9, and 9.3 ± 6.6 fmol/mL, respectively. The level on day 1 was decreased significantly (P < 0.05). In contrast, the levels of leptin, granulocyte colony-stimulating factor (G-CSF), and monocyte chemotactic protein-1 (MCP-1) on day 1 were increased significantly (P < 0.05). Conclusions. TAI for HCC reduced plasma acylated ghrelin levels, appetite, and food intake significantly. In addition, it increased serum leptin levels.

Acarbose was administered at 300 mg/day to patients with type 2 diabetes mellitus (T2DM) who had been taking 25 mg/day of alogliptin, and levels of blood glucose were analyzed by continuous glucose monitoring (CGM) for 3 days. The mean blood glucose level with acarbose (136.4 ± 30.7 mg/dL) did not differ significantly from that without acarbose (141.7 ± 28.3 mg/dL). However, in the condition of the combination therapy, there were significant decreases in the standard deviation of the mean blood glucose levels for the 24-hour period (27.6 ± 9.1 vs. 16.2 ± 6.9 mg/dL, p<0.001) and mean amplitude of glycemic excursions (MAGE) (65.8 ± 26.1 vs. 38.8 ± 19.2 mg/dL, p=0.010). In addition, a meal tolerance test was conducted to monitor changes in insulin secretion and active GLP-1 and total GIP values. Ten subjects (5 males, 5 females) of 54.9 ± 6.9 years with BMI 25.9 ± 5.2 kg/m² and HbAlc 9.2 ± 1.2% were enrolled. In the meal tolerance test, active GLP-1 values before and after acarbose administration were 17.0 ± 5.8 and 24.1 ± 9.3 pmol·hr/mL (p=0.054), respectively, showing an increasing tendency, and total GIP(AUC0-180) values were 685.9 ± 209.7 and 404.4 ± 173.7 pmol·hr/mL, respectively, showing a significant decrease (p=0.010). The results indicate that the combined administration of both inhibitors is effective not only in decreasing blood glucose fluctuations and preventing postprandial insulin secretion. The beneficial effects may also protect the endocrine pancreas and inhibit body weight gain.

The effect of add-on therapy with sitagliptin on glycemic control was prospectively investigated in patients with type 2 diabetes mellitus (T2DM) receiving insulin alone or insulin combined with oral antidiabetic drugs. Seventy-one patients were evaluated (38 men and 33 women aged 63.9 ± 10.2 years). They were divided into three groups, which were 45 patients receiving premixed insulin twice daily, 15 patients receiving multiple daily insulin injections, and 11 patients receiving basal insulin with oral antidiabetic drugs (basal insulin therapy). Concomitant oral drugs included sulfonylureas, α-glucosidase inhibitors and metformin. The hemoglobin A1c (HbA1c) of all patients improved significantly from 8.1 ± 1.2% to 7.6 ± 1.1% after 12 weeks of add-on therapy with sitagliptin (p<0.01), and the insulin dosage was reduced from 27.3 ± 15.8 U/day to 24.5 ± 16.5 U/day (p<0.001). Body weight did not change after the start of concomitant therapy and severe hypoglycemia was not observed. The baseline HbA1c and glycated albumin levels were identified as factors that predicted the response to add-on therapy with sitagliptin. These findings suggest that add-on therapy with sitagliptin can be expected to achieve improvement of poor glycemic control irrespective of a patient's demographic profile. Stratified analysis based on the insulin regimen revealed a stronger antidiabetic effect and a high efficacy of sitagliptin when it was added to basal insulin therapy. The results of this investigation confirmed that add-on therapy with sitagliptin to various insulin regimens could improve glycemic control without severe hypoglycemia and/or weight gain.

Aroma is an essential factor affecting the quality of tea (Camellia sinensis) products. While changes of volatile compounds during tea manufacturing have been intensively studied, the effect of environmental factors on volatile contents of fresh tea leaves has received less attention. We found that C. sinensis var. Yabukita kept in darkness by shading treatment for 3 weeks developed etiolated leaves with significantly increased levels of volatiles, especially volatile phenylpropanoids/benzenoids (VPBs). Upstream metabolites of VPBs, in particular shikimic acid, prephenic acid, and phenylpyruvic acid, showed lower levels in dark treated than in control leaves, whereas the contents of most amino acids including l-phenylalanine, a key precursor of VPBs, were significantly enhanced. In addition, analysis by ultra performance liquid chromatography-time of flight mass spectrometry, capillary electrophoresis-time of flight mass spectrometry, high performance liquid chromatography, and gas chromatography-mass spectrometry indicated that volatile and non-volatile metabolite profiles differed significantly between dark treated and untreated leaves., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background/objectives: A significant proportion of Crohn's disease (CD) patients receiving infliximab (IFX) maintenance therapy show loss of responsiveness despite a good initial response. The factors other than immunomodulators that prevent IFX dose escalation have yet to be fully elucidated. This study was performed to identify clinical factors or concomitant therapies associated with sustained response to IFX., Subjects/methods: Seventy-four consecutive CD patients who had successful IFX induction therapy between 2002 and 2010 underwent IFX maintenance therapy. Patients showing loss of response to IFX were treated with IFX intensification therapy. Factors involved in the sustained response to IFX were investigated retrospectively., Results: After a median follow-up of 85 weeks, loss of response to IFX was observed in 30 (40.5%) cases. On logistic regression analysis, concomitant use of enteral nutrition (EN) therapy (elemental and/or polymeric formulas) was identified as an independent factor associated with sustained response to IFX. Receiver operating characteristic curve analysis indicated a cutoff value of 600 kcal/day. We divided the patients into the 'EN group' (≥ 600 kcal/day) and 'control group' (<600 kcal/day). The cumulative number of loss of response was significantly lower in the EN group (odds ratio: 0.23, P = 0.0043). Kaplan-Meier analysis confirmed the significantly lower rate of loss of response in the EN group (P = 0.013). Multivariate hazard ratio was 0.37 (P = 0.025). Type of EN formula did not affect the results., Conclusions: Concomitant use of EN ≥ 600 kcal/day is likely to yield a sustained response to IFX in CD patients.

There is increased interest in the Bn-receptor family because they are frequently over/ectopically expressed by tumors and thus useful as targets for imaging or receptor-targeted-cytotoxicity. The synthetic Bn-analog, [D-Tyr(6), β-Ala(11), Phe(13), Nle(14)]Bn(6-14) [Univ.Lig] has the unique property of having high affinity for all three human BNRs (GRPR, NMBR, BRS-3), and thus could be especially useful for this approach. However, the molecular basis of this property is unclear and is the subject of this study. To accomplish this, site-directed mutagenesis was used after identifying potentially important amino acids using sequence homology analysis of all BnRs with high affinity for Univ.Lig compared to the Cholecystokinin-receptor (CCK(A)R), which has low affinity. Using various criteria 74 amino acids were identified and 101 mutations made in GRPR by changing each to those of CCK(A)R or to alanine. 22 GRPR mutations showed a significant decrease in affinity for Univ.Lig (>2-fold) with 2 in EC2[D97N, G112V], 1 in UTM6[Y284A], 2 in EC4[R287N, H300S] showing >10-fold decrease in Univ.Lig affinity. Additional mutations were made to explore the molecular basis for these changes. Our results show that high affinity for Univ.Lig by human Bn-receptors requires positively charged amino acids in extracellular (EC)-domain 4 and to a lesser extent EC2 and EC3 suggesting charge-charge interactions may be particularly important for determining the general high affinity of this ligand. Furthermore, transmembrane amino acids particularly in UTM6 are important contributing both charge-charge interactions as well as interaction with a tyrosine residue in close proximity suggesting possible receptor-peptide cation-π or H-bonding interactions are also important for determining its high affinity., (Published by Elsevier Inc.)

Background: When treating patients with severe ulcerative colitis (UC), accurate prediction of drug efficacy contributes to early clinical decision-making., Aim: To identify predictive factors and to develop a reliable prediction formula and a decision tree of response to intravenous ciclosporin treatment for severe UC., Methods: Patients included in this study were those diagnosed with refractory severe UC who had undergone ciclosporin treatment between December 2004 and March 2011 at a tertiary referral centre in Japan. Demographic and clinical parameters from all patients were analysed by multivariate statistics., Results: Fifty-two patients were included in this study (36.5% men with an average age of ciclosporin initiation of 40.2 ± 15.6 years). Thirty-four patients (65.4%) were responders to the treatment with ciclosporin and avoided colectomy, 18 patients (34.6%) were nonresponders and underwent colectomy. Stepwise multiple logistic regression analysis identified four independent predictive factors of response to intravenous ciclosporin: age at hospitalisation (AGE), platelet count (×10(4) /μL) on the first day (PLA), Lichtiger score on the third day (LIC) and total protein (g/dL) on the third day minus total protein on the first day (ΔTP). The calculation formula (8.5 - 0.16 × AGE + 0.21 × PLA - 0.61 × LIC + 2.3 × ΔTP < 0) predicted colectomy with an accuracy of 88.5% and the decision tree predicted colectomy with an accuracy of 90.4%., Conclusion: The novel calculation formula and the decision tree effectively predict the clinical outcome of ciclosporin treatment for severe ulcerative colitis as early as on day 3 after starting ciclosporin treatment., (© 2012 Blackwell Publishing Ltd.)

Aim: To investigate whether flexible spectral color enhancement (FICE) improves diagnostic yields of capsule endoscopy (CE) for obscure gastro-intestinal bleeding (OGIB)., Methods: The study subjects consisted of 81 patients. Using FICE, there were three different sets with different wavelengths. Using randomly selected sets of FICE, images of CE were evaluated again by two individuals who were not shown the conventional CE reports and findings. The difference between FICE and conventional imaging was examined., Results: The overall diagnostic yields in FICE sets 1, 2, 3 and conventional imaging (48.1%) were 51.9%, 40.7%, 51.9% and 48.1%, respectively, which showed no statistical difference compared to conventional imaging. The total numbers of detected lesions per examination in FICE imaging and conventional imaging were 2.5 ± 2.1 and 1.8 ± 1.7, respectively, which showed a significant difference (P = 0.01)., Conclusion: The diagnostic yield for OGIB is not improved by FICE. However, FICE can detect significantly more small bowel lesions compared to conventional imaging.

Aim: Periodic surveillance colonoscopy is required for patients with ulcerative colitis to detect colitis-associated dysplasia at an early stage. However, sometimes colonoscopy may damage the fragile mucosa of patients with ulcerative colitis. The aim of this study was to devise a new method of surveillance colonoscopy for patients with mild to moderate ulcerative colitis., Methods: The 'flicking method' of colonoscope insertion was recently developed by our team. It is a completely novel method that involves using the elastic force of the colonoscope to introduce it into the deeper regions while using colon mucosa patterns as a guide. The subjects were 66 hospital outpatients with ulcerative colitis who underwent colonoscopies during a 2-year period, from April 2006 to March 2008, with both the conventional insertion method and the flicking method., Results: Cecal intubation rate, insertion time, patient pain level, change in number of defecations pre- and post-colonoscopy, and change in severity pre- and post-colonoscopy were compared between the conventional and flicking methods. The flicking method was superior in all respects., Conclusions: The flicking method is a novel colonoscope insertion method that is regarded as particularly useful in cases when the intestinal mucosa is fragile, as is the case with ulcerative colitis patients., (© 2012 The Authors. Digestive Endoscopy © 2012 Japan Gastroenterological Endoscopy Society.)

Background and Objectives: Genome-wide association studies have revealed a link between autophagy-related (ATG) genes and susceptibility to Crohn's disease. This suggests underlying involvement of autophagy impairment in the pathogenesis of Crohn's disease. This study was performed to investigate the pathophysiological importance of autophagy impairment in intestinal epithelial cells exposed to TNF-α., Methods: Human colonic epithelial cells (HT-29) and rat small intestinal epithelial cells (IEC-18) were used. Formation of phosphatidylethanolamine-conjugated microtubule-associated protein light chain 3 (LC3-II) was monitored as a marker of autophagy. Autophagy was inhibited using 3-methyladenine or short interfering RNA targeting ATG5 and ATG16L1., Results: TNF-α treatment elicited a significant dose-dependent increase in LC3-II protein levels, thus autophagy is induced in the presence of TNF-α. Combined autophagy inhibition and TNF-α treatment induced a marked increase in the number of detached cells and a decrease in activated integrin β1 protein levels. Trypan blue staining indicated 70-80 % of the detached cells were alive, suggesting that these cells became detached not because they were killed but because of dysfunction of cellular adhesion., Conclusions: This is the first study indicating that intestinal epithelial cells with impaired autophagy lose their adhesive capacity in the presence of TNF-α. These observations indicate that impairment of autophagy leads to disruption of the intestinal epithelial cell layers in TNF-α-rich environments.

Intestinal microfold cells (M cells) are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. The mechanisms of M-cell differentiation are poorly understood, as the rarity of these cells has hampered analysis. Exogenous administration of the cytokine RANKL can synchronously activate M-cell differentiation in mice. Here we show the Ets transcription factor Spi-B was induced early during M-cell differentiation. Absence of Spi-B silenced the expression of various M-cell markers and prevented the differentiation of M cells in mice. The activation of T cells via an oral route was substantially impaired in the intestine of Spi-B-deficient (Spib(-/-)) mice. Our study demonstrates that commitment to the intestinal M-cell lineage requires Spi-B as a candidate master regulator.

It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of (13)CO(2) excretion (T(max)) in the (13)C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of (13)CO(2) excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of (13)CO(2) excretion (T(max)) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 ± 22.7 min and 42.5 ± 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of (13)CO(2) excretion (T(max)) values without and with subthalamic deep brain stimulation after surgery were 44.0 ± 17.5 min and 30.0 ± 12.5 min (P < 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the (13)CO(2) excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of (13)CO(2) excretion (T(max)) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Δghrelin) and changes in T(max) values (ΔT(max)) in the subthalamic deep brain stimulation trial after surgery (r = -0.20), and no association between changes in other characteristics and ΔT(max) post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease.

Unlabelled: Aims/Introduction:  Since glycated albumin (GA) reflects shorter-term (about 2 weeks) control of plasma glucose levels compared with HbA1c, GA is thought to be a useful glycemic control indicator for the early period following commencement of the treatment of diabetes. In this study, we attempted to estimate HbA1c using the change in GA level before and after the first 2 weeks (ΔGA2w) of administration of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor., Materials and Methods:   The study included 28 patients with type 2 diabetes who were administered sitagliptin at a dose of 50 mg/day for 12 weeks., Results:   At 2 weeks after administration of sitagliptin, GA markedly decreased, while HbA1c had only slightly decreased. A significant positive correlation was observed between the ΔGA2w and the change in HbA1c before and after the first 12 weeks of administration of sitagliptin (ΔHbA1c12w) (R = 0.793, P < 0.0001). The latter was about 0.6 times the former. The estimated HbA1c after 12 weeks of therapy was calculated by adding ΔGA2w × 0.6 to the baseline HbA1c. A significant positive correlation was observed between the estimated HbA1c and the measured HbA1c after 12 weeks (R = 0.735, P < 0.0001) and both were similar levels., Conclusions:   HbA1c in the first 12 weeks after administration of sitagliptin could be estimated from the formula using the ΔGA2w. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00167.x, 2011).

Several clinical studies have shown that insulin resistance is prevalent among patients with heart failure, but the underlying mechanisms have not been fully elucidated. Here, we report a mechanism of insulin resistance associated with heart failure that involves upregulation of p53 in adipose tissue. We found that pressure overload markedly upregulated p53 expression in adipose tissue along with an increase of adipose tissue inflammation. Chronic pressure overload accelerated lipolysis in adipose tissue. In the presence of pressure overload, inhibition of lipolysis by sympathetic denervation significantly downregulated adipose p53 expression and inflammation, thereby improving insulin resistance. Likewise, disruption of p53 activation in adipose tissue attenuated inflammation and improved insulin resistance but also ameliorated cardiac dysfunction induced by chronic pressure overload. These results indicate that chronic pressure overload upregulates adipose tissue p53 by promoting lipolysis via the sympathetic nervous system, leading to an inflammatory response of adipose tissue and insulin resistance., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In this paper the authors discuss the use of Parse's humanbecoming theory in Japan. Elements of the theory are used in the nursing approach to an 88 year-old Japanese man who had complications following surgery. Process recordings of the dialogues between the patient, the patient's wife, and the nurse were made and considered in light of the three methodologies of Parse's theory; illuminating meaning, synchronizing rhythms, and mobilizing transcendence. The theory is seen as useful in Japan.

Background & Aims: Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1B-mediated protein sorting in the maintenance of gastrointestinal immune homeostasis., Methods: The role of AP-1B in intestinal immunity was examined in AP-1B-deficient mice (Ap1m2(-/-)) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1B-mediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2(-/-) mice., Results: Ap1m2(-/-) mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17A-producing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease., Conclusions: AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1B-mediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Aims/Introduction:  When monotherapy with an oral hypoglycemic agent (OHA) is not sufficiently effective for blood glucose control, combination therapy with OHA having different mechanisms of action might be indicated., Materials and Methods:   In the present study, we compared the efficacy of two options in type 2 diabetes mellitus patients whose blood glucose had not been well controlled with mitiglinide (30 mg/day) alone. A total of 20 patients were included in the study and divided into two groups: group A, in which mitiglinide was given concomitantly with the α-glucosidase inhibitor voglibose (0.6 mg/day); and group B, in which a double dose of mitiglinide was given (60 mg/day). Twelve weeks after changing the medication, HbA1c, glycoalbumin and 1,5-anhydroglucitol (1,5-AG) were measured. In addition, at weeks 0 and 12, a meal tolerance test was carried out, and plasma glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic polypeptide levels were measured., Results:   The plasma level of 1,5-AG improved in both groups at week 12. In group A, the plasma insulin level significantly decreased and the plasma active GLP-1 level significantly increased during the meal tolerance test at week 12; thus, bodyweight significantly decreased only in group A., Conclusions:   Our findings suggested that concomitant administration of mitiglinide with voglibose could achieve better glycemic control, particularly in the postprandial period, without bodyweight gain and might have beneficial effects in type 2 diabetic patients at risk of macrovascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.0082.x, 2011).

Background: Although the immunomodulatory effects of mesenchymal stromal cells (MSC) on T cells have been elucidated, little is known about their effects on B cells. Recently, we have established a novel culture method for adipose-derived MSC (ASC) using low (2%) serum medium containing fibroblast growth factor-2. We showed that low serum-cultured ASC (LASC) was superior to high (20%) serum-cultured ASC (HASC) when used in regenerative therapy. The aim of this study was to compare the action of LASC, HASC, and bone marrow-derived MSC (BM-MSC), on xenoantibody production by B cells., Methods: Adipose-derived mesenchymal stromal cells and BM-MSC were obtained from humans or F344 rats and expanded in a low-serum or a high-serum culture medium. Proliferation of human peripheral mononuclear cells (PBMC) or rat splenocytes was induced by phytohemagglutinin (PHA) or anti-IgM-antibody. These cells were then co-cultured with LASC, HASC, or BM-MSC, and cell proliferation was studied. Porcine red blood cells (pRBC) were intraperitoneally injected into Lewis rats, and LASC, HASC, or BM-MSC obtained from F344 rats were injected intravenously or intraperitoneally. The levels of antibodies (IgM and IgG) against pRBC were examined using flow cytometry., Results: Human LASC suppressed PBMC proliferation more effectively than human HASC. Human LASC suppressed both T-cell and B-cell proliferation when incubated with PHA (a T-cell stimulus). However, human LASC did not suppress B-cell proliferation after incubation with anti-IgM-antibody (a T-cell-independent stimulus). Rat LASC suppressed PHA-stimulated splenocyte proliferation more effectively than rat HASC or rat BM-MSC. In vivo studies showed that intravenous injection of rat LASC significantly reduced the levels of IgG antibodies against pRBC, while intravenous administration of the other two types of MSC (rat HASC or rat BM-MSC) or intraperitoneal administration of rat LASC did not impede IgG production. A significant number of LASC were observed in the spleen when injected intravenously while only a few LASC were observed when given intraperitoneally., Conclusions: Administration of LASC effectively impeded xenoantibody production by B cells through the inhibition of T-cell function, while HASC or BM-MSC showed less promising effects. These results suggest that intravenous injection of LASC may be useful in attenuating antibody-mediated rejection., (© 2011 John Wiley & Sons A/S.)

Objective: Capsule endoscopy (CE) is used widely for determining the cause of obscure gastrointestinal bleeding (OGIB). However, negative findings still arise from CE examination. The aim of this study was to determine the factors associated with negative findings on CE in patients with OGIB., Material and Methods: A total of 134 patients who underwent CE for overt (n = 104) or occult (n = 30) OGIB between October 2007 and April 2010 were included. The clinical backgrounds of the patients (age; sex; the use of anti-coagulant, anti-platelet drugs or NSAIDs; comorbidity and the timing of CE examination after bleeding) were noted., Results: The overall diagnostic yield of CE in detecting the relevant findings was 50% (n = 67). Multivariate analysis revealed that the use of anti-platelet drug and the timing of CE (≥ 16 days) were predictive factors for negative findings on CE (odds ratio 2.69 [1.01-7.21], p = 0.048 and odds ratio 2.32 [1.01-5.33], p = 0.047, respectively). Among the patients with the use of low-dose aspirin (LDA, n = 28) as anti-platelet drug, cessation of it before CE was the only predictive factor for negative findings on CE (odds ratio 12.0 [1.72-83.5], p = 0.012)., Conclusion: In the patients with OGIB, the use of LDA and the cessation of it before CE made it difficult to detect the cause of bleeding by CE. This might indicate that the source of OGIB related to LDA heals immediately after cessation of the drugs or is a very small lesion that could not be detected by CE.

Introduction: Recently, incretin-related therapy has been developed for the new treatment of diabetes mellitus; however, incretin response to glucose ingestion in normal glucose tolerant (NGT) subjects has not been clarified in detail with special reference to the role of incretin hormones, glucagon, and a family history of diabetes., Methods: We conducted a 75 g oral glucose tolerance test in 30 NGT subjects., Results: The total glucose-dependent insulinotropic peptide (GIP)-AUC(0-120) (area under the curve over a period of 0-120 minutes) was correlated with immunoreactive insulin (IRI)-AUC(0-120) (P<0.05), insulinogenic index (II; P<0.05), ΔIRI between 0 and 120 minutes (P<0.05). Active glucagon-like peptide-1 (GLP-1) AUC(0-120) was correlated inversely both with Δ glucose between 0 and 30 minutes (P<0.01) and with Δ immunoreactive glucagon between 0 and 30 minutes (P<0.05). Δ Total GIP between 0 and 15 minutes (P<0.01), Δ total GIP between 0 and 30 minutes (P<0.05), and the total GIP-AUC(0-120) (P<0.05) in the subjects with a family history of type 2 diabetes were significantly higher than those in the subjects without a family history., Conclusion: These results suggest that GIP possibly facilitates insulin secretion in response to oral glucose load directly and active GLP-1 may exert the glucoregulatory action via the suppression of glucagon secretion in NGT subjects. Notably, the subjects with a family history of diabetes exert significantly higher GIP response in the early phase of glucose load compared with those without a family history.

Deficiency of Smad3, an intracellular mediator of TGF-β, was shown to significantly accelerate re-epithelialization of the colonic mucosa. This study was performed to investigate the molecular mechanisms by which Smad3 controls colonic epithelial cell proliferation and crypt formation. Smad3(ex8/ex8) C57BL/6 mice were used in this study and wild-type littermates served as controls. The number of proliferating cells in the isolated colonic epithelium of Smad3(-/-) mice was significantly increased compared to that in wild-type littermates. Protein levels of the cell cycle inhibitors p21 and p27 were significantly decreased, while that of c-Myc was increased in the isolated colonic epithelium from Smad3(-/-) mice. In the colonic tissue of wild-type mice, cell proliferation was restricted to the bottom of the crypts in accordance with nuclear β-catenin staining, whereas proliferating cells were located throughout the crypts in Smad3(-/-) mice in accordance with nuclear β-catenin staining, suggesting that Smad3 is essential for locating proliferating cells at the bottom of the colonic crypts. Notably, in Smad3(-/-) mice, there was loss of EphB2 and EphB3 receptor protein expression, critical regulators of proliferating cell positioning, while EphB receptor protein expression was confirmed at the bottom of the colonic crypts in wild-type mice. These observations indicated that disturbance of the EphB/ephrin B system brings about mispositioning of proliferating cells in the colonic crypts of Smad3(-/-) mice. In conclusion, Smad3 is essential for controlling number and positioning of proliferating cells in the colonic crypts and contributes to formation of a "proliferative zone" at the bottom of colonic crypts in the normal colon., (Copyright © 2011 Elsevier Inc. All rights reserved.)