The gut microbiota is reported to be related to obesity, and visceral fat is reported to be strongly associated with cardiovascular disease and overall mortality. However, the association between the gut microbiota and obesity has mainly been studied using body mass index (BMI) as a proxy for obesity. We investigated the relationship of both visceral fat and BMI with the gut microbiota stratified by sex in a population-based cross-sectional study of Japanese men and women 20–76 years of age (n = 1001). Women with a higher visceral fat area (VFA) harboured a higher relative abundance of the Firmicutes phylum (P for trend <0.001) and a lower relative abundance of the Bacteroidetes phylum (P for trend 0.030), whereas men with higher VFA harboured a lower relative abundance of the Firmicutes phylum (P for trend 0.076) and a higher relative abundance of the Bacteroidetes phylum (P for trend 0.013). Similar results were obtained using BMI as an index, but the differences were not significant in men. At the genus level, Blautia was the only gut microbe significantly and inversely associated with VFA regardless of sex. In conclusion, at the genus level we found that Blautia was the only gut microbe significantly and inversely associated with VFA, regardless of sex.

Scleroderma is a disorder characterized by fibrosis of the skin and internal organs and autoimmunity. Whereas the cause is unknown, interleukin-4 and transforming growth factor-beta have been postulated to play a major part in the fibrosis. To investigate the part played by these cytokines, we prepared TSK/+ mice with a targeted mutation in the interleukin-4R alpha or transforming growth factor-beta genes. The breeding failed to produce TSK/+ transforming growth factor-beta -/- mice so analysis of the role of transforming growth factor-beta was limited to TSK/+ transforming growth factor-beta +/- mice. We observed that TSK/+ interleukin-4R alpha -/- did not develop dermal thickening, and deletion of one allele of the transforming growth factor-beta gene resulted in diminished dermal thickness compared with TSK/+ mice; however, the deletion of interleukin-4R alpha or transforming growth factor-beta had no effect on lung emphysema, which is another characteristic of TSK syndrome. Electron microscopic analysis of skin showed that the collagen fibrils in TSK/+ interleukin-4R alpha -/- mice exhibit normal periodicity but have a smaller diameter than the fibers found in C57BL/6 mice. Analysis of skin and serum samples showed that the deletion of interleukin-4R alpha or one allele of transforming growth factor-beta prevented the increase of skin thickness paralleled with a decrease in the dermal hydroxyproline content and development of autoantibodies associated with TSK syndrome. These results demonstrate the importance of interleukin-4 and transforming growth factor-beta for the development of cutaneous fibrosis in vivo and suggest an important part for these cytokines in wound healing and connective tissue maintenance in general.

Tight-skin (TSK) mouse represents an experimental for systemic sclerosis, displaying cutaneous hyperplasia, connective tissue alterations in the internal organs and developing autoantibodies against several scleroderma target autoantigens. TSK mouse syndrome is associated with a mutation in fibrillin-1 (Fbn-1), the major component of 10 nm microfibrils. Here, we have investigated whether TSK mouse develops autoimmunity to Fbn-1 similar to scleroderma target autoantigens. Our results show that anti-Fbn-1 IgG autoantibodies are present in high titer in many TSK mice. Specificity of these antibodies was confirmed by competitive inhibition assays and Western blotting analysis using recombinant human Fbn-1 protein. TSK mouse autoantibodies recognize a conserved epitope present in the C region of Fbn-1. These results indicate the presence of Fbn-1 specific T and B cells in TSK mouse repertoire.

The long-term ingestion of tea catechins has been reported to reduce body fat. The aim of this study was to investigate the effect of the long-term ingestion of tea catechins on postprandial energy expenditure and dietary fat oxidation. Twelve healthy men aged 27-48 years participated in the study. The subjects consumed 350 ml of a test beverage/day that contained either a high dose of catechin (592.9 mg) or a low dose of catechin (77.7 mg) for a period of 12 weeks. Respiratory analyses were conducted before and at 4, 8, and 12 weeks during the test period, in which oxygen consumption and the excretion of 13 CO 2 were monitored over 8 hr after a single ingestion of a test meal containing 13 C labeled triglyceride. The excretion of 13 CO 2 in the high dose catechin group (the HC group) was significantly increased at 4 and 12 weeks of the test period compared to that for the low dose catechin group (the LC group) (p < 0.05), and this elevation persisted at 8.9% at week 0 to 12.9% at week 12. Dietary induced thermogenesis (DIT), defined as an increased energy expenditure from the fasting baseline for 8 hr after the single ingestion of a test meal, was significantly higher in the HC group at 8 and 12 weeks compared to that in the LC group (p < 0.05) with elevation to 90.3 kcal at week 12 from 51.4 kcal at week 0. In conclusion, enhanced dietary fat oxidation and an increased DIT may play an important role in the mechanism of the anti-obesity effect of tea catechins.

Autophagy is an intracellular degradation system that plays an important role in T-cell survival. However, the precise mechanism linking autophagy and cell death in primary human T cells is unclear because methods for monitoring autophagy in small numbers of primary human cells remain controversial. We established a novel method for assessing autophagy in activated human T cells using a retroviral GFP-LC3 expression system. We found that autophagy was induced after TCR stimulation and that autophagydefective naïve CD4 + T cells were susceptible to apoptosis through the intrinsic apoptotic pathway. Enhanced apoptosis of autophagy-defective T cells resulted from accumulation of ROS due to impaired mitophagy. We also demonstrated that effector memory CD4+ T cells had lower autophagic activity than naïve CD4 + T cells, which contributed to their enhanced apoptosis due to increased ROS. Moreover, blocking autophagy increased intracellular mitochondrial volume and ROS levels in activated T cells. These results suggest a protective role of autophagy as an anti-oxidant system in activated human T cells. The combination of an autophagy blocker and a mitochondrial electron transport chain inhibitor has a synergistic effect on T-cell death, which could be a novel strategy for induction of T-cell apoptosis.Keywords: Apoptosis r Autophagy r Human T cell r Mitophagy r Reactive oxygen speciesAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacroautophagy (hereafter referred to as autophagy) is an evolutionally conserved intracellular degradation system. During autophagy, a small vesicle known as a sequestering phagophore or an isolation membrane engulfs cytoplasmic materials and organelles to form a double membrane structure, an autophagosome. The autophagosome subsequently fuses with a lysoCorrespondence: Dr. Hiroshi Fujii e-mail: hfujii@med.tohoku.ac.jp some to become an autolysosome, leading to degradation of the enclosed materials for recycling or energy production [1]. Autophagy is activated in response to nutrient starvation and various cellular stresses such as hypoxia, ER stress, and pharmacological treatment. Basal levels of autophagy under nutrientsufficient conditions act as a quality control mechanism to degrade damaged organelles or aggregated proteins [2]. Autophagy is considered to be involved in a wide range of normal physiological processes, whereas its dysregulation may contribute to the pathogenesis of numerous diseases such as neurodegeneration, Crohn's disease, infections, and cancers [3].C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2508-2520 New technology 2509Autophagy involves a set of gene products, termed Atg proteins [2]. Unc-51-like kinase 1 (ULK1), which is a mammalian homolog of Atg1, initiates autophagosome formation. Subsequently, Atg9 and the Atg12-Atg5-Atg16 complex provide membranes required for elongation, after which Atg8 is incorporated into autophagosomes [4]. ULK...

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This is the first report to evaluate whether community pharmacists are equipped to ensure the safe use of oral anticancer agents in Japan. The results are similar to those previously reported for Canadian pharmacists, namely a low rate of positive responses for education in oncology and oral chemotherapy, demonstrating a similar need for additional education and training in oral chemotherapy.

Background Computerized provider order entry (CPOE) has been developed and implemented within cancer center hospitals nationwide in Japan. To ensure that high-quality services are routinely provided by oncology pharmacists, this study was designed to evaluate the interventions through reviewing the orders that are generated by CPOE. Methods The objective of this retrospective chart review was to evaluate how pharmacists contributed to safe cancer treatment using paper-based pharmacy records. Data were collected from a total of 35,062 chemotherapy regimens for 18,515 outpatients between January and December 2013. Results Of these 35,062 chemotherapy regimens, the rate of pharmacists' interventions was 1.1% ( n = 408). Among them, 53.1% (217/408) of the chemotherapy prescriptions were modified due to pharmacist interventions. The reasons for interventions included "changes in the chemotherapy regimen were unclear" in 49.5%, "physicians' prescription errors" (22.0%), "pharmacist suggestions to improve chemotherapy" (15.1%), and "finding differences between physicians' chemotherapy records and their chemotherapy prescriptions" (13.2%). The top three reasons for the 217 prescription modifications due to pharmacist interventions were "finding prescription errors" (34.5%), "reasons for change in the chemotherapy regimen were unclear" (32.7%), and "finding differences between physicians' chemotherapy records and their chemotherapy prescriptions" (28.5%). Conclusion The computer could not evaluate chemotherapy protocols or adjust doses of anticancer medicines according to patients' conditions. Therefore, oncology pharmacists should continue to ensure safe and appropriate administration of cancer chemotherapy.