SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

Neighborhood Walkability in Relation to Knee and Low Back Pain in Older People: A Multilevel Cross-Sectional Study from the JAGES

Few studies have focused on a relationship between the built environment and musculoskeletal pain. This study aimed to investigate an association between neighborhood walkability and knee and low back pain in older people. Data were derived from the Japan Gerontological Evaluation Study (JAGES) 2013, a population-based study of independently living people ≥65 years old. A cross-sectional multilevel analysis was performed, of 22,892 participants in 792 neighborhoods. Neighborhood walkability was assessed by residents’ perceptions and population density. Dependent variables were knee and low back pain restricting daily activities within the past year. The prevalence of knee pain was 26.2% and of low back pain 29.3%. After adjusting for sociodemographic covariates, the prevalence ratio (PR) of knee and low back pain was significantly lower in neighborhoods with better access to parks and sidewalks, good access to fresh food stores, and higher population densities. After additionally adjusting for population density, easier walking in neighborhoods without slopes or stairs was significantly inversely correlated with knee pain (PR 0.91, 95% confidence interval 0.85–0.99). Neighborhoods with walkability enhanced by good access to parks and sidewalks and fresh food stores, easy walking without slopes or stairs, and high population densities, had lower prevalences of knee and low back pain among older people. Further studies should examine environmental determinants of pain

Motor planning error in Parkinson's disease and its clinical correlates.

This study aimed to investigate (a) motor planning difficulty by using a two-step test in Parkinson's disease (PD) compared with age-matched healthy subjects and (b) the relationship between motor planning difficulty and clinical factors. The two-step test was performed by 58 patients with PD with Hoehn & Yahr (H&Y) stage I-IV and 110 age-matched healthy older adult controls. In the two-step test, the participants estimated the two-step distance with maximum effort. Subsequently, they performed the actual two-step trial to measure the actual maximum distance. We calculated the accuracy of the estimation (estimated distance minus actual distance). In both groups, subjects who estimated >5 cm were defined as the overestimation group, and those who estimated <5 cm over- and underestimation were defined as the non-overestimation group. The overestimation group consisted of 17 healthy older adults (15.5%) and 23 patients with PD (39.7%). The number of patients with PD with overestimation was significantly more than that of healthy controls by Chi-squared test. H&Y stage and the Unified Parkinson's Disease Rating Scale (UPDRS) part II and III scores in overestimation group in PD patients were significantly higher than those in overestimation group in PD patients. Moreover, multiple regression using H&Y stage and UPDRS parts II and III as independent variables showed that the UPDRS part II score was the only related factor for the estimation error distance. Estimation error distance was significant correlated with UPDRS parts II and III. Patients with PD easily have higher rates of motor-related overestimation than age-matched healthy controls. In addition, UPDRS parts II and III expressed ability of activities of daily living and motor function as influences on motor-related overestimation. Particularly, multiple regression indicated that UPDRS part II directly showed the ability of daily living as an essential factor for overestimation

In Vitro Activity of E1210, a Novel Antifungal, against Clinically Important Yeasts and Molds▿

E1210 is a new antifungal compound with a novel mechanism of action and broad spectrum of antifungal activity. We investigated the in vitro antifungal activities of E1210 compared to those of fluconazole, itraconazole, voriconazole, amphotericin B, and micafungin against clinical fungal isolates. E1210 showed potent activities against most Candida spp. (MIC90 of ≤0.008 to 0.06 μg/ml), except for Candida krusei (MICs of 2 to >32 μg/ml). E1210 showed equally potent activities against fluconazole-resistant and fluconazole-susceptible Candida strains. E1210 also had potent activities against various filamentous fungi, including Aspergillus fumigatus (MIC90 of 0.13 μg/ml). E1210 was also active against Fusarium solani and some black molds. Of note, E1210 showed the greatest activities against Pseudallescheria boydii (MICs of 0.03 to 0.13 μg/ml), Scedosporium prolificans (MIC of 0.03 μg/ml), and Paecilomyces lilacinus (MICs of 0.06 μg/ml) among the compounds tested. The antifungal action of E1210 was fungistatic, but E1210 showed no trailing growth of Candida albicans, which has often been observed with fluconazole. In a cytotoxicity assay using human HK-2 cells, E1210 showed toxicity as low as that of fluconazole. Based on these results, E1210 is likely to be a promising antifungal agent for the treatment of invasive fungal infections