Involvement of intracellular free Ca(2+ )in enhanced release of herpes simplex virus by hydrogen peroxide

BACKGROUND: It was reported that elevation of the intracellular concentration of free Ca(2+ )([Ca(2+)]i) by a calcium ionophore increased the release of herpes simplex virus type 1 (HSV-1). Freely diffusible hydrogen peroxide (H(2)O(2)) is implied to alter Ca(2+ )homeostasis, which further enhances abnormal cellular activity, causing changes in signal transduction, and cellular dysfunction. Whether H(2)O(2 )could affect [Ca(2+)]i in HSV-1-infected cells had not been investigated. RESULTS: H(2)O(2 )treatment increased the amount of cell-free virus and decreased the proportion of viable cells. After the treatment, an elevation in [Ca(2+)]i was observed and the increase in [Ca(2+)]i was suppressed when intracellular and cytosolic Ca(2+ )were buffered by Ca(2+ )chelators. In the presence of Ca(2+ )chelators, H(2)O(2)-mediated increases of cell-free virus and cell death were also diminished. Electron microscopic analysis revealed enlarged cell junctions and a focal disintegration of the plasma membrane in H(2)O(2)-treated cells. CONCLUSION: These results indicate that H(2)O(2 )can elevate [Ca(2+)]i and induces non-apoptotic cell death with membrane lesions, which is responsible for the increased release of HSV-1 from epithelial cells

p38 mitogen-activated protein kinase determines the susceptibility to cigarette smoke-induced emphysema in mice

BACKGROUND: There is a need for agents that suppress inflammation and progression of chronic obstructive pulmonary disease. p38 mitogen-activated protein kinase (p38 MAPK) has been associated with this disorder, and several inhibitors of this cascade are in clinical trials for its treatment, but their efficacy and utility are unknown. This study evaluated the relationship between p38 MAPK activation and susceptibility to cigarette smoke (CS)-induced emphysema, and whether its inhibition ameliorated the lung inflammation and injury in murine models of cigarette smoke exposure. METHODS: In acute and chronic CS exposure, the activation and expression of p38 MAPK in the lungs, as well as lung inflammation and injury (proteinase production, apoptosis, and oxidative DNA damage), were compared between two mouse strains: C57BL/6 (emphysema-susceptible) and NZW (emphysema-resistant). The selective p38 MAPK inhibitor SB203580 (45 mg/kg) was administrated intra-peritoneally to C57BL/6 mice, to examine whether it ameliorated cigarette smoke-induced lung inflammation and injury. RESULTS: Acute CS-induced lung inflammation (neutrophil infiltration, mRNA expressions of TNF-α and MIP-2), proteinase expression (MMP-12 mRNA), apoptosis, and oxidative DNA damage were significantly lower in NZW than C57BL/6 mice. p38 MAPK was significantly activated and up-regulated by both acute and chronic CS exposure in C57BL/6 but not NZW mice. mRNA expression of p38 MAPK was also upregulated in C57BL/6 by chronic CS exposure and tended to be constitutively suppressed in NZW mice. SB203580 significantly attenuated lung inflammation (neutrophil infiltration, mRNA expressions of TNF-α and MIP-2, protein levels of KC, MIP-1α, IL-1β, and IL-6), proteinase expression (MMP-12 mRNA), oxidative DNA damage, and apoptosis caused by acute CS exposure. CONCLUSIONS: Cigarette smoke activated p38 MAPK only in mice that were susceptible to cigarette smoke-induced emphysema. Its selective inhibition ameliorated lung inflammation and injury in a murine model of cigarette smoke exposure. p38 MAPK pathways are a possible molecular target for the treatment of chronic obstructive pulmonary disease

Annual change in bone mineral density in COPD

Background: Osteoporosis is a well-known comorbidity in COPD. It is associated with poor health status and prognosis. Although the exact pathomechanisms are unclear, osteoporosis is suggested to be either a comorbidity due to shared risk factors with COPD or a systematic effect of COPD with a cause–effect relationship. This study aimed to evaluate whether progression of osteoporosis is synchronized with that of COPD. Materials and methods: Data from 103 patients with COPD included in the Hokkaido COPD cohort study were analyzed. Computed tomography (CT) attenuation values of thoracic vertebrae 4, 7, and 10 were measured using custom software, and the average value (average bone density; ABD4,7,10) was calculated. The percentage of low attenuation volume (LAV%) for each patient was also calculated for evaluation of emphysematous lesions. Annual change in thoracic vertebral CT attenuation, which is strongly correlated with dual-energy X-ray absorptiometry-measured bone mineral density, was compared with that in FEV1.0 or emphysematous lesions. Results: In the first CT data set, ABD4,7,10 was significantly correlated with age (ρ=–0.331; p=0.0006), body mass index (BMI; ρ=0.246; p=0.0136), St George’s Respiratory Questionnaire (SGRQ) activity score (ρ=–0.248; p=0.0115), eosinophil count (ρ=0.229; p=0.0198), and LAV% (ρ=–0.372; p=0.0001). However, ABD4,7,10 was not associated with FEV1.0. After adjustment for age, BMI, SGRQ activity score, and eosinophil count, no significant relationship was found between ABD4,7,10 and LAV%. Annual change in ABD4,7,10 was not associated with annual change in LAV% or FEV1.0. Conclusion: Progression of osteoporosis and that of COPD are not directly related or synchronized with each other

A unique B2 B cell subset in the intestine

Over 80% of the body's activated B cells are located in mucosal sites, including the intestine. The intestine contains IgM+ B cells, but these cells have not been characterized phenotypically or in terms of their developmental origins. We describe a previously unidentified and unique subset of immunoglobulin M+ B cells that present with an AA4.1−CD21−CD23− major histocompatibility complex class IIbright surface phenotype and are characterized by a low frequency of somatic hypermutation and the potential ability to produce interleukin-12p70. This B cell subset resides within the normal mucosa of the large intestine and expands in response to inflammation. Some of these intestinal B cells originate from the AA4.1+ immature B2 cell pool in the steady state and are also recruited from the recirculating naive B cell pool in the context of intestinal inflammation. They develop in an antigen-independent and BAFF-dependent manner in the absence of T cell help. Expansion of these cells can be induced in the absence of the spleen and gut-associated lymphoid tissues. These results describe the existence of an alternative pathway of B cell maturation in the periphery that gives rise to a tissue-specific B cell subset

EPR based Estimation of Radiation-Induced Reactive Oxygen Species

Generation of reactive oxygen species (ROS) is considered as essential trigger of biological effects of ionizing radiations, and may be deeply linked with the radiation quality.Amounts of total oxidation reactions (i.e. oxidative free radical species, •OH and HO2•), H2O2 generations, Oxygen consumptions, and •OH generations induced by X-ray, 20 keV/μm carbon beam, and 80 keV/μm carbon beam were estimated using EPR based techniques.Total oxidation reactions were estimated as 3, 1.3, and 0.66 μmol/L/Gy, amount of H2O2 generations were 0.2, 0.57, and 0.35 μmol/L/Gy, oxygen consumptions were 0.4, 0.39, and 0.15 μmol/L/Gy for X-ray, 20 keV/μm carbon beam, and 80 keV/μm carbon beam, respectively. The ratio of H2O2 generation per oxygen consumption were increased with LET, and were 0.5, 1.46, 2.33 for X-ray, 20 keV/μm carbon beam, and 80 keV/μm carbon beam, respectively. The •OH generations expected to be localized on the track/range of the radiation beam/ray, and both sparse (≈ 3.3 mM) and very dense (> 1.7 M) •OH generations were suggested. Percentage of sparse •OH generation decreased with LET becoming higher.The SFRBM\u27s 23rd Annual Meeting, a joint meeting with the Society for Free Radical Research International (SFRBM/SFRRI 2016

頭皮皮膚血管肉腫に対する根治的な寡分割高線量放射線治療の実行可能性と有効性の検討

Cutaneous angiosarcoma is a rare but highly aggressive vascular tumor resistant to all treatment modalities available. The aim of this study was to analyze the treatment outcomes of patients who received definitive hypofractionated high-dose radiotherapy (RT) for angiosarcoma of the scalp. Between April 2008 and December 2014, 11 patients with histologically proven cutaneous angiosarcoma of the scalp visited our Department of Radiation Oncology, because dermatologists suggested that there was no indication for surgery in those cases. One patient rejected all radical treatments and the other 10 patients were treated by RT with curative intent along with chemotherapy or immunotherapy. Eight patients were treated with 6 - 12 MeV electron beams and the other 2 patients were treated with 4 MV X-ray Intensity Modulated Radiation Therapy (IMRT) and electron beams. The total irradiated dose was 63 - 75 Gy (median: 72.5 Gy) in 26 - 30 fractions, and the fraction size was 2.5 Gy in principle. The median age of the patients treated with RT was 80 years old (range: 73 - 91) and the median follow-up time was 16.5 months (range: 5.6 - 86.3). Four patients are still alive. A complete response (CR) was achieved in 10 patients (100%) and only one patient suffered local relapse 20 months after RT. Medians of overall survival (OS), progression-free survival (PFS), and local relapse-free survival (LRFS) were 38.7, 13.4, and 19.8 months, respectively. Local control rates were 100 and 75% at 1 and 2 years, respectively. Skin ulceration was CTCAE grade 2 in 5 patients (50%) and grade 3 in 5 (50%), alopecia was grade 2 in all patients (100%), but no patient developed grade 4 or more severe adverse events after RT. Hypofractionated high-dose RT was feasible and achieved excellent local control of cutaneous angiosarcoma in the elderly patients.博士（医学）・甲第646号・平成28年3月15日Copyright: © 2015 Shimoda E. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The definitive version is available at " http://clinmedjournals.org/articles/ijccr/international-journal-of-cancer-and-clinical-research-ijccr-2-032.php?jid=ijccr

The relationship between long working hours and depression among first-year residents in Japan

Background:In Japan, some residents develop mental health problems. In previous studies, it was reported thatlong working hours might be a cause of stress reaction such as depression. There were some reports thatcompared residents with 80 or more working hours with those with less than 80 working hours. However, manyresidents are practically detained for extra-long time, designated as 100 h or more per week, for medical practice,training, self-study, etc. There have been few reports on extra-long hours of work. This study evaluated the workingenvironment and the amount of stress experienced by first-year residents, and examined the relationship betweenlong working hours and depression, especially in the group of extra-long working hours.Methods:The study included 1241 first-year residents employed at 250 training hospitals in 2011. A self-report questionnaire was administered at the beginning of the residency and 3 months later to collect data ondemographics, depressive symptoms, and training conditions (e.g., duration of work, sleep, disposable time, andnight shift). Depressive symptoms were rated using the Center for Epidemiologic Studies Depression Scale.Results:The mean duration of work per week was 79.4 h, with 97 residents (7.8%) working 100 h or more. At3 months, clinically significant depressive symptoms were reported by 45.5% of residents working 100 or more hper week, which proportion was significantly greater than that for respondents working less than 60 h (P< 0.001).Multivariate logistic regression analysis showed that a working week of 80 to 99.9 h was associated with a 2.83 foldhigher risk and 100 h or more was associated with a 6.96-fold higher risk of developing depressive symptomscompared with a working week of less than 60 h.Conclusion:Working excessively long hours was significantly associated with development of depressivesymptoms. Proper management of resident physicians’working hours is critical to maintaining their physical andmental health and to improve the quality of care they provide