Involvement of the renin–angiotensin system in the development of vascular damage in a rat model of arthritis: Effect of angiotensin receptor blockers

Objective To explore the involvement of the renin–angiotensin system (RAS) in the development of vascular damage in adjuvant-induced arthritis (AIA) in rats. Methods Angiotensin II (Ang II; 0.25 or 1.0 mg/kg/day) was infused in control rats and rats with AIA for 21 days, and the impact of systemic inflammation on Ang II–induced hypertension, endothelial dysfunction, and vascular hypertrophy was evaluated. Expression of angiotensin II type 1 receptor (AT 1 R) and angiotensin-converting enzyme (ACE) in the aortas of rats with AIA were examined by real-time polymerase chain reaction (PCR) and Western blot analyses. Losartan (3 mg/kg/day) or irbesartan (5 mg/kg/day), both of which are AT 1 R blockers, was administered orally to rats with AIA for 21 days. In situ superoxide production in aortas was assessed according to the fluorogenic oxidation of dihydroethidium to ethidium. The expression and activity of NAD(P)H oxidases in aortas were examined by real-time PCR analysis and lucigenin chemiluminescence assay. Endothelial function in rats with AIA treated in vivo or ex vivo with AT 1 R blockers was also determined. Results The Ang II–induced hypertensive response, endothelial dysfunction, and vascular hypertrophy were exacerbated in rats with AIA. Expression of AT 1 R and ACE was increased in the aortas of rats with AIA. Both losartan and irbesartan decreased the levels of superoxide and the expression and activity NAD(P)H oxidases in the aortas of rats with AIA. The endothelial dysfunction in AIA was improved by the in vivo or ex vivo treatment with AT 1 R blockers. Conclusion The locally activated RAS is involved in the increased vascular oxidative stress and endothelial dysfunction in AIA. Our findings have important implications for clinical approaches to the reduction of cardiovascular risk in patients with rheumatoid arthritis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75773/1/27384_ftp.pd

Identification of mutations through dominant screening for obesity using C57BL/6 substrains

The discovery of leptin substantiated the usefulness of a forward genetic approach in elucidating the molecular network regulating energy metabolism. However, no successful dominant screening for obesity has been reported, which may be due to the influence of quantitative trait loci between the screening and counter strains and the low fertility of obese mice. Here, we performed a dominant screening for obesity using C57BL/6 substrains, C57BL/6J and C57BL/6N, with the routine use of in vitro fertilization. The screening of more than 5000 mutagenized mice established two obese pedigrees in which single nucleotide substitutions in Mc4r and Sim1 genes were identified through whole-exome sequencing. The mutation in the Mc4r gene produces a premature stop codon, and the mutant SIM1 protein lacks transcriptional activity, showing that the haploinsufficiency of SIM1 and MC4R results in obesity. We further examined the hypothalamic neuropeptide expressions in the mutant pedigrees and mice with diet-induced obesity, which showed that each obesity mouse model has distinct neuropeptide expression profiles. This forward genetic screening scheme is useful and applicable to any research field in which mouse models work

Synthesis of highly Li-ion conductive garnet-type solid ceramic electrolytes by solution-process-derived sintering additives

The sintering and processing of garnet-type solid ceramic electrolytes (e.g., Li7La3Zr2O12 (LLZ)) are challenging because the material composition and microstructure at high temperatures must be carefully controlled to obtain the stabilization of highly conductive cubic phase and dense ceramic. Liquid-phase sintering using sintering aids is typically used for densifying ceramic materials, as it is a faster and/or lower-temperature process. In this study, we used solution-process-derived sintering additives to sinter garnet-type solid electrolytes highly effective in terms of relative density and properties at 1000 degrees C (10 h). The liquid phase formation during the sintering was rationalized to establish the optimal sintering conditions. The use of 1.2-vol% 75Li(2)O center dot 25B(2)O(3) and 1.5-vol% Al2O3 as sintering additives was highly effective in densifying a Ta-doped LLZ, achieving a high ionic conductivity of 0.8 mS cm(-1) (25 degrees C) with low activation energy (9 kJ mol(-1)) and almost negligible contribution of the grain boundary resistance (10 %)

Fabrication of periodic microstructures for improving light-extraction efficiencies of light-emitting ZnO/Si devices

This article presents the first demonstration of integrating a simple one-dimensional (1-D) periodic microstructure and a light-emitting zinc oxide (ZnO) thin film on a silicon (Si) substrate using a simple process with two-beam interference lithography and sputtering. A 1-D microstructure composed of ZnO was obtained using our fabrication process without using a photomask and dry etching. The intensity of a photoluminescence (PL) peak observed from a sample with the periodic microstructure was approximately 5.3 times stronger than that without it. The light-extraction efficiency from the ZnO thin film seems to be improved by the integration of the 1-D periodic microstructure. Keywords: ZnO/Si, Luminescence, Periodic microstructure, Light-extraction efficiency, Sputtering, Two-beam interference lithograph

Evaluation of pharmaceutical intervention in direct-acting antiviral agents for hepatitis C virus infected patients in an ambulatory setting: a retrospective analysis

Abstract Background Direct-acting antivirals (DAAs) are known to improve tolerability and have higher efficacy and shorter treatment durations compared with conventional interferon (IFN)-based treatments for hepatitis C virus (HCV) infection. Management of drug interactions and maintenance of patient adherence are important to achieve adequate therapeutic effects, sustained virological response (SVR). In order to maximize the benefits of oral DAA therapy, we established an ambulatory care pharmacy practice, a model of integrated collaboration between physicians and pharmacists, for patients receiving IFN-free DAA therapy. In this study, we evaluated pharmaceutical intervention for patients visiting the ambulatory care pharmacy practice. Methods HCV-infected outpatients who visited our ambulatory care pharmacy practice between September 2014 and May 2017 were eligible for inclusion in the study. When IFN-free DAAs were first prescribed, the physicians recommended all patients to visit the ambulatory care pharmacy practice after their clinical examination. Subsequently, at the second visit or later, the patients visited the pharmacy service before the physician’s examination. The primary endpoint was SVR, defined as HCV RNA below the lower limit of quantification after the completion of treatment. We also evaluated the adherence rate to DAAs, suggestions to the physicians by the pharmacists, and questions from the patients. All data were obtained retrospectively using an electronic medical record system. Results Among the 401 study subjects, 386 patients completed the IFN-free DAA therapy. A total of 365 patients have reached 12 or 24 weeks after completing the treatment. The overall SVR rate was 98.1% (358/365). The proportion of patients with adherence ≥90% was 99.3% (398/401). Two-hundred and sixty-seven (84%) among 318 suggestions of prescription made by the pharmacists mainly to manage the adverse events were accepted by the physicians. The pharmacists received and answered 1072 questions on DAA therapy from the patients. Conclusions This study indicates that the pharmaceutical intervention may contribute to enhanced adherence to DAAs and higher SVR rates in comparison with previous reports. This study also demonstrates that collaboration between physicians and pharmacists in an ambulatory setting provides favorable outcomes for patients receiving IFN-free DAAs

“Spike” in acute asthma exacerbations during enterovirus D68 epidemic in Japan: A nation-wide survey

Background: In September 2015, Japan experienced an unusual increase in acute asthma hospitalizations of children that coincided with an enterovirus D68 (EV-D68) epidemic. The objective of this study is to investigate whether EV-D68 had a causal relationship with the spike in asthma hospitalizations. Methods: A nation-wide retrospective survey of asthma hospitalizations of children was performed for the period from January 2010 through October 2015. The Japanese Society of Pediatric Allergy and Clinical Immunology asked its affiliated hospitals to report monthly numbers of hospitalizations, ICU admissions and mechanical ventilations due to acute asthma exacerbation. The data were retrieved from medical databases using predefined search criteria: diagnosis of asthma or asthmatic bronchitis, admission, and age <20 years. Monthly numbers of EV-D68 detection were also obtained from the Infectious Disease Surveillance Center of Japan. A Granger causality test was used to analyze the association of EV-D68 detections for asthma exacerbation. Results: A total of 157 hospitals reported 87,189 asthma hospitalizations, including 477 ICU admissions and 1193 mechanical ventilations, during the survey period of 5 years and 10 months. The numbers of these events increased drastically in September 2015. The Granger causality test verified the association between EV-D68 and asthma hospitalizations/mechanical ventilations. The most-affected age group was 3–6 years old. Conclusions: The spike in pediatric asthma hospitalizations in Japan in September 2015 was found to be associated with the EV-D68 epidemic. Respiratory pathogens can cause “epidemics” of asthma exacerbation. Coordinated surveillance of infectious diseases and asthma may be beneficial for prevention and better control of both illnesses

Clinical impact of central nervous system‐directed therapies on intravascular large B‐cell lymphoma: A single institution's experience

Abstract Intravascular large B‐cell lymphoma (IVLBCL) is a rare subtype of B‐cell lymphoma characterized by aggressive disease progression with a high incidence of central nervous system (CNS) involvement. We retrospectively analyzed 16 patients with de novo IVLBCL treated at our hospital between 2004 and 2018 with either standard therapy plus CNS‐directed therapy or standard therapy alone. CNS‐directed therapy was associated with a significantly better 2‐year CNS‐free survival (100% vs. 63%, p = 0.0191), despite no significant effects on progression‐free or overall survival. Further studies should assess CNS‐focused treatment in patients with IVLBCL with or without primary CNS involvement

Correction: EBV induces persistent NF-κB activation and contributes to survival of EBV-positive neoplastic T- or NK-cells.

[This corrects the article DOI: 10.1371/journal.pone.0174136.]