In most eukaryotes, replication origins are composed of long chromosome regions, and the exact sequences required for origin recognition complex (ORC) and minichromosome maintenance (MCM) complex association remain elusive. Here, we show that two stretches of adenine/thymine residues are collectively essential for a fission yeast chromosomal origin. Chromatin immunoprecipitation assays revealed that the ORC subunits are located within a 1 kb region of ori2004. Analyses of deletion derivatives of ori2004 showed that adenine stretches are required for ORC binding in vivo. Synergistic interaction between ORC and adenine stretches was observed. On the other hand, MCM subunits were localized preferentially to a region near the initiation site, which is distant from adenine stretches. This association was dependent on adenine stretches and stimulated by a non-adenine element. Our results suggest that association of multiple ORC molecules with a replication origin is required for efficient MCM loading and origin firing in fission yeast.

Fragility fractures associated with age-related bone loss are of urgent concern worldwide because they reduce QOL and pose financial burdens for health care services. Currently, national data in Japan are limited. This study provides quantitative data for older patients throughout Japan who, although otherwise relatively healthy, sustained fragility fractures and were hospitalized for them. The National Database of Health Insurance Claims and Specific Health Checkups of Japan was accessed to target patients aged 65 years or older who sustained fractures between May 2013 and September 2014 and were not hospitalized for at least 13 months prior to fracture. We investigated whether the first fracture sustained was fragility related at any of four locations (proximal humerus, distal radius, vertebra, or femoral neck) and whether it necessitated hospitalization. Fragility fractures were identified in 490138 of 1188754 patients (41.2%, 345980 patients/ year; 1 : 4 male-to-female ratio). Regardless of gender, vertebral fractures were most common across the age cohorts studied (43286 males and 162767 females/year), and femoral neck fractures increased markedly with increased patient age. Approximately 80% of patients with femoral neck fractures were hospitalized (62.3% of males, 71.1% of females) compared with up to 10.4% of patients with other fragility fractures. Data provided in this study can be used as a baseline for evaluating the health economy and establishing health policy in Japan.

No abstract

Central nervous system (CNS) agents cause fractures among the elderly, but fracture risks of a wide range of CNS agent classes have not been analyzed in a study with the same population and definitions of variables. This study aimed to estimate the degree of fragility fracture risk of a wide range of CNS agent classes in elderly Japanese people. A case-crossover design study, with a case window and three control windows of 3 d each, as well as longer windows up to 15 d, was conducted among opioid non-users who lived without hospitalization for ≥13 months and incurred fragility fractures at ≥65 years of age, using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Conditional logistic regression estimated adjusted odds ratios (ORs) of CNS agent classes for fragility fractures for groups including and excluding users of pro re nata CNS agents (PRN-CNS agents) and for windows of 3-15 d. Antiepileptic agents had the highest adjusted ORs, 2.4 (95% confidence interval 2.3-2.5) for the group including PRN-CNS agent users (n 446101). The next-highest classes were anti-dementia agents 1.5 (1.5-1.6), antipsychotics 1.5 (1.4-1.6), anti-Parkinson agents 1.3 (1.2-1.5), and antidepressants 1.1 (1.1-1.2). Similar ORs were found when PRN-CNS agent users were excluded (n 352828), and slightly higher ORs were found for longer windows, with almost the same order of classes. Elderly individuals who use antiepileptic agents or a combination of antiepileptic agents and CNS agent classes with the next-highest ORs should be carefully monitored.

No abstract

Some patients do not inform healthcare professionals of adverse drug reactions (ADRs) because they fear termination of aggressive medication therapies. Preferences for aggressive medication therapies may diŠer between patients and pharmacists. The goal of this study was to estimate whether pharmacists were able to accurately assess patient preference for aggressive medication therapies with potentially stronger ADRs. A cross-sectional study was conducted of hospitalized patients (35 to 74 years of age) receiving oral medications for a chronic disease or systemic chemotherapy at three hospitals in Japan. We estimated the extent of agreement between patient responses and pharmacist predictions using a scenario-based investigation (1) to examine the choice between an aggressive medication therapy and the standard therapy, and (2) to assess increased life expectancy as a result of aggressive medication therapy. The extent of agreement was estimated using the kappa statistic. Of 113 patients, 43 (38.1％) chose the aggressive medication therapy. Pharmacists correctly predicted the choice of 25 (58.1％) of these patients [kappa 0.32 (95％ conˆdence interval 0.15 0.50)]. Of 111 patients, 42 (37.8％) expected one additional life expectancy year. However, pharmacists predicted that as many as 36 (85.7％) of these patients would require more years of added life expectancy before choosing an aggressive medication therapy [kappa 0.24 (0.08 0.40)]. Agreement between patients and pharmacists on the choice of aggressive medication therapy was generally poor. Pharmacists should make an eŠort to identify patients who might prefer more aggressive medication therapies with potentially stronger ADRs in order to minimize ADR risk.