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Morita T.,Japan National Institute of Health Sciences | Uno Y.,Mitsubishi Group | Honma M.,Japan National Institute of Health Sciences | Kojima H.,Japan National Institute of Health Sciences | And 5 more authors.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis | Year: 2015

The Japanese Center for the Validation of Alternative Methods (JaCVAM) sponsored an international prevalidation and validation study of the in vivo rat alkaline pH comet assay. The main objective of the study was to assess the sensitivity and specificity of the assay for correctly identifying genotoxic carcinogens, as compared with the traditional rat liver unscheduled DNA synthesis assay. Based on existing carcinogenicity and genotoxicity data and chemical class information, 90 chemicals were identified as primary candidates for use in the validation study. From these 90 chemicals, 46 secondary candidates and then 40 final chemicals were selected based on a sufficiency of carcinogenic and genotoxic data, differences in chemical class or genotoxic or carcinogenic mode of action (MOA), availability, price, and ease of handling. These 40 chemicals included 19 genotoxic carcinogens, 6 genotoxic non-carcinogens, 7 non-genotoxic carcinogens and 8 non-genotoxic non-carcinogens. "Genotoxicity" was defined as positive in the Ames mutagenicity test or in one of the standard in vivo genotoxicity tests (primarily the erythrocyte micronucleus assay). These chemicals covered various chemicals classes, MOAs, and genotoxicity profiles and were considered to be suitable for the purpose of the validation study. General principles of chemical selection for validation studies are discussed. © 2015 Elsevier B.V.. Source


Taniguchi M.,Public Interest Incorporated Foundation | Nakabayashi M.,Bell Medical Solutions Inc. | Oshiba I.,MD and R Corporation | Sugihara S.,EPS Assoct. Corporation Ltd. | And 3 more authors.
Japanese Journal of Clinical Pharmacology and Therapeutics | Year: 2015

In April 2012, the Chiken(clinical study for drug application)Promotion Committee of Osaka Pharmaceutical Manufacturers Association(OPMA)and Osaka Clinical Research Collaborative Network(OCRCN)organized three Working Groups(WG)composed of clinical research coordinators(CRCs)and clinical research associates(CRAs) to discuss the improvement of the efficiency of Chiken execution. Each group had regular monthly meetings for one and a half years. The firstWG focused on the current understanding and treatment of "source data/document. " It is revealed that a so-called "work sheet" is widely used to record clinical data/comments in Chiken;data /comments are directly recorded on Case Report Forms(CRFs)only in around 50% of the cases. The second WG focused on the method to develop a more intelligible protocol in order to avoid misunderstanding of a protocol by clinical trial sites. It is agreed that a protocol should be developed that further reflects the actual work process of Chiken in a clinical site, and that more detailed explanations of the execution process in a protocol should be helpful. The third WG focused on "standardization of checklist for both clinical sites and study sponsors", covering the selection of clinical trial sites and execution of clinical trial agreements. It is also recognized that the checklist, apart from the original purpose of increasing the efficiency of the execution of clinical trials, is expected to be used as a training tool for beginners. After completing all tasks, a survey was made to assess this activity. Most of the members expressed positive opinions on this project, and the activity to develop a standardized checklist is on-going. © 2015 the Japanese Society of Clinical Pharmacology and Therapeutics (JSCPT). Source


Shiga A.,Public Interest Incorporated Foundation | Narama I.,Public Interest Incorporated Foundation
Toxicologic Pathology | Year: 2015

To characterize the hepatic lesions in Fischer 344 (F344) rats afflicted with large granular lymphocyte (LGL) leukemia, the livers of rats with LGL leukemia at various stages were examined histopathologically and immunohistochemically. The morphologic features in the livers of rats afflicted with LGL leukemia were diffuse, uniform-sized, granular, or micronodular lesions consisting of hepatocytes showing centrilobular atrophy and perilobular hypertrophy (CAPH) without fibrosis. With progression in the stage of the LGL leukemia, the severity of the CAPH of hepatocytes increased resulting in fatty change and/or single-cell necrosis, along with compensatory hyperplasia of the hepatocytes, finally resulting in lesions similar to those seen in nodular regenerative hyperplasia (NRH) in the human liver. The CAPH of hepatocytes was a nonspecific tissue adaptation against ischemia or hypoxemia and/or imbalance in blood supply due to disturbance in the portal circulation and hemolytic anemia induced by the leukemia cells. In addition, direct and/or indirect hepatocellular injuries by leukemia cells were considered to be necessary for the formation of human NRH-like lesions. Morphogenetic investigation of the livers of rats afflicted with LGL leukemia may be helpful to clarify the pathogenesis of NRH in the human liver. © Society of Toxicologic Pathology. Source


Fukushima T.,Toho University | Iizuka H.,Toho University | Yokota A.,Toho University | Suzuki T.,Toho University | And 11 more authors.
PLoS ONE | Year: 2014

The serum levels of several metabolites are significantly altered in schizophrenia patients. In this study, we performed a targeted analysis of 34 candidate metabolites in schizophrenia patients (n = 25) and compared them with those in age- and gender-matched healthy subjects (n = 27). Orthogonal partial least square-discriminant analysis revealed that complete separation between controls and patients was achieved based on these metabolites. We found that the levels of γ-glutamylcysteine (γ-GluCys), linoleic acid, arachidonic acid, D-serine, 3-hydroxybutyrate, glutathione (GSH), 5-hydroxytryptamine, threonine, and tyrosine were significantly lower, while D-lactate, tryptophan, kynurenine, and glutamate levels were significantly higher in schizophrenia patients compared to controls. Using receiver operating characteristics (ROC) curve analysis, the sensitivity, specificity, and the area under curve of γ-GluCys, a precursor of GSH, and D-lactate, a terminal metabolite of methylglyoxal, were 88.00%, 81.48%, and 0.8874, and 88.00%, 77.78%, and 0.8415, respectively. In addition, serum levels of D-lactate were negatively correlated with γ-GluCys levels in patients, but not in controls. The present results suggest that oxidative stress-induced damage may be involved in the pathogenesis of schizophrenia. © 2014 Fukushima et al. Source


Miyashita C.,Hokkaido University | Sasaki S.,Hokkaido University | Ikeno T.,Hokkaido University | Araki A.,Hokkaido University | And 8 more authors.
Science of the Total Environment | Year: 2015

The adverse effects of in utero exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg), and the beneficial effects of nutrients from maternal fish intake might have opposing influences on fetal growth. In this study, we assessed the effects of in utero exposure to PCBs and MeHg on birth size in the Japanese population, which is known to have a high frequency of fish consumption. The concentrations of PCBs and polyunsaturated fatty acids in maternal blood, and the total mercury in hair (as a biomarker of MeHg exposure) were measured during pregnancy and at delivery. Maternal intakes of fish (subtypes: fatty and lean) and shellfishes were calculated from a food frequency questionnaire administered at delivery. Newborn anthropometric measurement data were obtained from birth records. The associations between chemical exposures and birth size were analyzed by using multiple regression analysis with adjustment for confounding factors among 367 mother-newborn pairs. The birth weight was 3073. ±. 37. g (mean. ±. SD). The incidence of babies small for gestational age (SGA) by weight was 4.9%. The median concentrations of total PCBs and hair mercury were 108. ng/g lipid and 1.41. μg/g, respectively. There was no overall association between mercury concentrations and birth weight, birth length, chest circumference, and head circumference. We observed that the risk of SGA by weight decreased with increasing mercury concentration in regression analyses with adjustment for polyunsaturated fatty acids. Our results suggest that the beneficial effect of essential nutrition may mask the adverse effects of MeHg on birth size. The concentrations of PCBs had no association with birth size. © 2015. Source

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