Risk Factors for Infection in Patients with Remitted Rheumatic Diseases Treated with Glucocorticoids

It is well known that infection is one of the major causes of morbidity and mortality in rheumatic disease patients treated with high-dose glucocorticoids, especially in the early phase after achievement of disease remission. The aim of this study was to identify the risk factors for infection, with a focus on the dose of glucocorticoids administered, following the achievement of disease remission in rheumatic diseases patients. We retrospectively analyzed the medical records of rheumatic disease patients who had been treated with glucocorticoids. The primary endpoint was the incidence rate of infection during a period from 1 to 2 months after the commencement of treatment. From April 2006 to March 2010, 19 of 92 patients suffered from infection during the observation period. Age≧65 yrs, presence of interstitial pneumonia, diagnosis of systemic vasculitis and serum creatinine level≧2.0mg/dl were found to be univariate predictors for infection. However, only the presence of interstitial pneumonia was an independent risk factor for infection (HR＝4.50, 95%CI＝1.65 to 14.44) by the Cox proportional hazard model. Even after achievement of clinical remission, careful observation is needed for patients with interstitial pneumonia, more so than for those receiving high-dose glucocorticoids

Decreased serum pyridoxal levels in schizophrenia : meta-analysis and Mendelian randomization analysis

Background: Alterations in one-carbon metabolism have been associated with schizophrenia, and vitamin B6 is one of the key components in this pathway. Methods: We first conducted a case–control study of serum pyridoxal levels and schizophrenia in a large Japanese cohort (n = 1276). Subsequently, we conducted a meta-analysis of association studies (n = 2125). Second, we investigated whether rs4654748, which was identified in a genome-wide association study as a vitamin B6-related single nucleotide polymorphism, was genetically implicated in patients with schizophrenia in the Japanese population (n = 10 689). Finally, we assessed the effect of serum pyridoxal levels on schizophrenia risk using a Mendelian randomization (MR) approach. Results: Serum pyridoxal levels were significantly lower in patients with schizophrenia than in controls, not only in our cohort, but also in the pooled data set of the meta-analysis of association studies (standardized mean difference –0.48, 95% confidence interval [CI] –0.57 to –0.39, p = 9.8 × 10–24). We failed to find a significant association between rs4654748 and schizophrenia. Furthermore, an MR analysis failed to find a causal relationship between pyridoxal levels and schizophrenia risk (odds ratio 0.99, 95% CI 0.65–1.51, p = 0.96). Limitations: Food consumption and medications may have affected serum pyridoxal levels in our cross-sectional study. Sample size, number of instrumental variables and substantial heterogeneity among patients with schizophrenia are limitations of an MR analysis. Conclusion: We found decreased serum pyridoxal levels in patients with schizophrenia in this observational study. However, we failed to obtain data supporting a causal relationship between pyridoxal levels and schizophrenia risk using the MR approach

トクシマシ イシカイ ニオケル ザイタク イリョウ エノ トリクミ

Japan is heading toward a super-aging society at a rate unparalleled with other countries. The vast increase in demand for medical treatment and care will exceed existing social resources by 2025 when the baby boom generation becomes older than 75 years. There are concerns that this may lead to the collapse of acute medical care, break out refugee Home Medical Care, and the loss of end-of-life care facilities in various areas. Therefore, Japan is promoting the establishment of a comprehensive community care system designed to allow elderly individuals to live in their own community with dignity for as long as possible. The development of home medical care is being promoted as the core component of this system. The Tokushima City Medical Association has assessed the possible risks associated with this super-aging society that should emerge at a relatively early stage. Furthermore, the development of home medical care for the public to support community medical care is regarded as the best means of tackling future challenges. Therefore, we set up the Home Care Cooperation Committee in 2008 and have worked to develop home care in Tokushima City. The Tokushima City Medical Association participated in the Home Medical Care Cooperation Base Service of commissioned projects by the Ministry of Health, Labour and Welfare as one of 105 institutions in whole country in 2012. Since 2013, we have already been implementing this with Tokushima City administration as a subsidized institution under the three year’s Home Medical Care Cooperation Base Service which was performed by the Tokushima prefecture. This base of operations incorporates the following five mandatory directives : 1. identify solutions to multidisciplinary cooperation issues, 2. develop a multidisciplinary cooperation system and a 24-h response system, 3. raise awareness among residents, 4. educate personnel engaged in home medical care, and 5. set up a consultation service for home medical care. Because of community demands for projects to be implemented in a more area-wise appropriate manner, the Tokushima Home Care Cooperation Committee was newly established following general consensus within the association. This committee was composed of 14members not limited to individuals from medical associations ; individuals from the local government and various professions involved in home medical care were recruited and made decisions regarding operating policies. The current major challenge in Tokushima City is the lack of a means to disseminate proposed solutions for home medical care throughout the entire community. Therefore, we are promoting the establishment of multiple working groups on home medical care to tackle this challenge in the future. In addition, we intend to summarize the various challenges and their solutions that we identified during the course of our operations, draw up guidelines on home medical care based on the agreement of the local government and various professions and disseminate these guidelines throughout the community. We aim to effectively operate and from multiple levels a mutual support system between doctors who have long been working in medical associations, a multidisciplinary, conscientious cooperation system to support patients, a streamlined cooperation system for hospital admission and discharge, and a patient information sharing system utilizing ICT. These systems will be operated in parallel with our base operations. We also aim to promote the future improvement of environments in which as many family doctors as possible can examine their patients at home with ease until their patient’s final breath. This should enable us to provide high-quality home medical care equally and widely throughout the community. We hereby report the home medical care initiatives and future projects of the Tokushima City Medical Association centered on the Home Medical Care Cooperation Based Project

Cdh23 and Prepulse Inhibition

We previously identified quantitative trait loci (QTL) for prepulse inhibition (PPI), an endophenotype of schizophrenia, on mouse chromosome 10 and reported Fabp7 as a candidate gene from an analysis of F2 mice from inbred strains with high (C57BL/6N; B6) and low (C3H/HeN; C3H) PPI levels. Here, we reanalyzed the previously reported QTLs with increased marker density. The highest logarithm of odds score (26.66) peaked at a synonymous coding and splice-site variant, c.753G>A (rs257098870), in the Cdh23 gene on chromosome 10; the c.753G (C3H) allele showed a PPI-lowering effect. Bayesian multiple QTL mapping also supported the same variant with a posterior probability of 1. Thus, we engineered the c.753G (C3H) allele into the B6 genetic background, which led to dampened PPI. We also revealed an e-QTL (expression QTL) effect imparted by the c.753G>A variant for the Cdh23 expression in the brain. In a human study, a homologous variant (c.753G>A; rs769896655) in CDH23 showed a nominally significant enrichment in individuals with schizophrenia. We also identified multiple potentially deleterious CDH23 variants in individuals with schizophrenia. Collectively, the present study reveals a PPI-regulating Cdh23 variant and a possible contribution of CDH23 to schizophrenia susceptibility

Fabp7 Maps to a Quantitative Trait Locus for a Schizophrenia Endophenotype

Deficits in prepulse inhibition (PPI) are a biological marker for schizophrenia. To unravel the mechanisms that control PPI, we performed quantitative trait loci (QTL) analysis on 1,010 F2 mice derived by crossing C57BL/6 (B6) animals that show high PPI with C3H/He (C3) animals that show low PPI. We detected six major loci for PPI, six for the acoustic startle response, and four for latency to response peak, some of which were sex-dependent. A promising candidate on the Chromosome 10-QTL was Fabp7 (fatty acid binding protein 7, brain), a gene with functional links to the N-methyl-D-aspartic acid (NMDA) receptor and expression in astrocytes. Fabp7-deficient mice showed decreased PPI and a shortened startle response latency, typical of the QTL's proposed effects. A quantitative complementation test supported Fabp7 as a potential PPI-QTL gene, particularly in male mice. Disruption of Fabp7 attenuated neurogenesis in vivo. Human FABP7 showed altered expression in schizophrenic brains and genetic association with schizophrenia, which were both evident in males when samples were divided by sex. These results suggest that FABP7 plays a novel and crucial role, linking the NMDA, neurodevelopmental, and glial theories of schizophrenia pathology and the PPI endophenotype, with larger or overt effects in males. We also discuss the results from the perspective of fetal programming

Diagnosis of Myocardial Viability by Fluorodeoxyglucose Distribution at the Border Zone of a Low Uptake Region

Purpose: In cardiac 2-[F-18]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) examination, interpretation of myocardial viability in the low uptake region (LUR) has been difficult without additional perfusion imaging. We evaluated distribution patterns of FDG at the border zone of the LUR in the cardiac FDG-PET and established a novel parameter for diagnosing myocardial viability and for discriminating the LUR of normal variants. Materials and Methods: Cardiac FDG-PET was performed in patients with a myocardial ischemic event (n = 22) and in healthy volunteers (n = 22). Whether the myocardium was not a viable myocardium (not-VM) or an ischemic but viable myocardium (isch-VM) was defined by an echocardiogram under a low dose of dobutamine infusion as the gold standard. FDG images were displayed as gray scaled-bull’s eye mappings. FDG-plot profiles for LUR ( = true ischemic region in the patients or normal variant region in healthy subjects) were calculated. Maximal values of FDG change at the LUR border zone (a steepness index; Smax scale/pixel) were compared among not-VM, isch-VM, and normal myocardium. Results: Smax was significantly higher for n-VM compared to those with isch-VM or normal myocardium (ANOVA). A cut-off value of 0.30 in Smax demonstrated 100 % sensitivity and 83 % specificity for diagnosing n-VM and isch-VM. Smax less than 0.23 discriminated LUR in normal myocardium from the LUR in patients with both n-VM and isch-VM with a 94 % sensitivity and a 93 % specificity. Conclusion: Smax of the LUR in cardiac FDG-PET is a simple and useful parameter to diagnose n-VM and isch

Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer

Gastric cancer cells often show altered Ras signaling, though the underlying molecular mechanism is not fully understood. We examined the expression profile of eight ras-association domain family (RASSF) genes plus MST1/2 and found that RASSF2A is the most frequently downregulated in gastric cancer. RASSF2A was completely silenced in 6 of 10 gastric cancer cell lines as a result of promoter methylation, and expression was restored by treating the cells with 5-aza-2′-deoxycytidine. Introduction of RASSF2A into non-expressing cell lines suppressed colony formation and induced apoptosis. These effects were associated with the cytoplasmic localization of RASSF2A and morphological changes to the cells. Complementary DNA microarray analysis revealed that RASSF2A suppresses the expression of inflammatory cytokines, which may in turn suppress angiogenesis and invasion. In primary gastric cancers, aberrant methylation of RASSF2A was detected in 23 of 78 (29.5%) cases, and methylation correlated significantly with an absence of the lymphatic invasion, absence of venous invasion, absence of lymph node metastasis, less advanced stages, Epstein–Barr virus, absence of p53 mutations and the presence of the CpG island methylator phenotype-high. These results suggest that epigenetic inactivation of RASSF2A is required for tumorigenesis in a subset of gastric cancers

Genome-Wide Association Study of Schizophrenia in Japanese Population

Schizophrenia is a devastating neuropsychiatric disorder with genetically complex traits. Genetic variants should explain a considerable portion of the risk for schizophrenia, and genome-wide association study (GWAS) is a potentially powerful tool for identifying the risk variants that underlie the disease. Here, we report the results of a three-stage analysis of three independent cohorts consisting of a total of 2,535 samples from Japanese and Chinese populations for searching schizophrenia susceptibility genes using a GWAS approach. Firstly, we examined 115,770 single nucleotide polymorphisms (SNPs) in 120 patient-parents trio samples from Japanese schizophrenia pedigrees. In stage II, we evaluated 1,632 SNPs (1,159 SNPs of p<0.01 and 473 SNPs of p<0.05 that located in previously reported linkage regions). The second sample consisted of 1,012 case-control samples of Japanese origin. The most significant p value was obtained for the SNP in the ELAVL2 [(embryonic lethal, abnormal vision, Drosophila)-like 2] gene located on 9p21.3 (p = 0.00087). In stage III, we scrutinized the ELAVL2 gene by genotyping gene-centric tagSNPs in the third sample set of 293 family samples (1,163 individuals) of Chinese descent and the SNP in the gene showed a nominal association with schizophrenia in Chinese population (p = 0.026). The current data in Asian population would be helpful for deciphering ethnic diversity of schizophrenia etiology

Association of Transcription Factor Gene LMX1B with Autism

Multiple lines of evidence suggest a serotoninergic dysfunction in autism. The role of LMX1B in the development and maintenance of serotoninergic neurons is well known. In order to examine the role, if any, of LMX1B with autism pathophysiology, a trio-based SNP association study using 252 family samples from the AGRE was performed. Using pair-wise tagging method, 24 SNPs were selected from the HapMap data, based on their location and minor allele frequency. Two SNPs (rs10732392 and rs12336217) showed moderate association with autism with p values 0.018 and 0.022 respectively in transmission disequilibrium test. The haplotype AGCGTG also showed significant association (p = 0.008). Further, LMX1B mRNA expressions were studied in the postmortem brain tissues of autism subjects and healthy controls samples. LMX1B transcripts was found to be significantly lower in the anterior cingulate gyrus region of autism patients compared with controls (p = 0.049). Our study suggests a possible role of LMX1B in the pathophysiology of autism. Based on previous reports, it is likely to be mediated through a seretoninergic mechanism. This is the first report on the association of LMX1B with autism, though it should be viewed with some caution considering the modest associations we report

Ablation of Mrds1/Ofcc1 Induces Hyper-γ-Glutamyl Transpeptidasemia without Abnormal Head Development and Schizophrenia-Relevant Behaviors in Mice

Mutations in the Opo gene result in eye malformation in medaka fish. The human ortholog of this gene, MRDS1/OFCC1, is a potentially causal gene for orofacial cleft, as well as a susceptibility gene for schizophrenia, a devastating mental illness. Based on this evidence, we hypothesized that this gene could perform crucial functions in the development of head and brain structures in vertebrates. To test this hypothesis, we created Mrds1/Ofcc1-null mice. Mice were examined thoroughly using an abnormality screening system referred to as “the Japan Mouse Clinic”. No malformations of the head structure, eye or other parts of the body were apparent in these knockout mice. However, the mutant mice showed a marked increase in serum γ-glutamyl transpeptidase (GGT), a marker for liver damage, but no abnormalities in other liver-related measurements. We also performed a family-based association study on the gene in schizophrenia samples of Japanese origin. We found five single nucleotide polymorphisms (SNPs) located across the gene that showed significant transmission distortion, supporting a prior report of association in a Caucasian cohort. However, the knockout mice showed no behavioral phenotypes relevant to schizophrenia. In conclusion, disruption of the Mrds1/Ofcc1 gene elicits asymptomatic hyper-γ-glutamyl-transpeptidasemia in mice. However, there were no phenotypes to support a role for the gene in the development of eye and craniofacial structures in vertebrates. These results prompt further examination of the gene, including its putative contribution to hyper-γ-glutamyl transpeptidasemia and schizophrenia