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This study examined the similarities/differences between the social phenotypes of Williams syndrome (WS) and autism spectrum disorder (ASD). As cultural norms may affect symptom evaluation, this study administered the Social Responsiveness Scale-2 to Japanese individuals with WS (n = 78, 4.4–44.0 years) and ASD (n = 75, 4.7–55.4 years). The scores for Social Motivation and Social Communication were significantly more severe in the ASD than WS group. Overall, the similarities and differences between the social phenotypes of the syndromes were consistent with the findings of a recent study conducted in the UK, except for the social awareness subscale score. This highlights the importance of cross-cultural investigations of WS and ASD. [ABSTRACT FROM AUTHOR]

Background: In the recent years, a high risk of developmental delay not only in very low birth weight infants and late preterm infants but also in early term infants (37–38 weeks) have increasingly been reported. However, in Japan, there are virtually no studies regarding the development delays in early term infants. Methods: This study used the data from the Japan Environment and Children's Study (JECS), a birth cohort study conducted in Japan. Data were selected for analysis from the records of 104,065 fetal records. The risk of neurodevelopmental delays at 6 months and 12 months after birth was evaluated using multivariate analysis for infants of various gestational ages, using the 40th week of pregnancy as a reference value. Neurodevelopment was evaluated at 6 months and 12 months after birth using the Ages and Stages Questionnaires, Japanese translation (J-ASQ-3). Results: The proportion of infants born at a gestational age of 37 to 38 weeks who did not reach the J-ASQ-3 score cutoff value was significantly higher in all areas at both 6 months and 12 months after birth, when compared to that of infants born at 40 weeks. The odds ratio decreased at 12 months after birth compared to that at 6 months after birth. Conclusion: Early term infants in Japan are at an increased risk of neurodevelopmental delay at 12 months after birth. Significance: What's known on this subject: Early term infants with gestational ages of 37 to 38 weeks and not only premature babies may be at an increased risk of developmental delay. What this study adds: This study was conducted using data from a birth cohort of 104,065 fetal records. Early term infants had an increased risk of developmental delay at 6 months, and while the risk decreased by 12 months after birth, it was still high. [ABSTRACT FROM AUTHOR]

Background: Muscle weakness is associated with adverse clinical outcomes including disability and mortality. We report demographic, anthropometric and lifestyle correlates of grip strength in UK and Japanese population-based cohorts. Aim: To report prevalence of low grip strength according to 2019 European Working Group on Sarcopenia in Older People (EWGSOP2) and 2019 Asian Working Group for Sarcopenia (AWGS 2019) thresholds and to consider correlates of grip strength in Eastern and Western populations. Methods: UK (1572 men; 1415 women) and Japanese (519 men; 1027 women) participants were recruited from two cohorts harmonised by consensus. Muscle strength was measured by grip strength dynamometry. Potential correlates of grip strength were examined using sex-stratified linear regression; univariate correlates (p < 0.05) were included in mutually adjusted models. Results: Mean (SD) age was 66.2 (2.8) and 65.8 (12.3) in UK and Japanese cohorts, respectively. Prevalence of low grip strength was higher in Japanese participants (EWGSOP2 5.4% versus 2.4%, AWGS 2019 9.0% versus 3.7%). In both cohorts and sexes, univariate correlates of lower grip strength were older age, shorter height, not consuming alcohol, leaving education earlier and greater comorbidity. Apart from older age and shorter height, the only factors related to lower grip strength in mutually adjusted analyses were greater comorbidity among UK participants (kg difference in grip strength (95%CI) per additional comorbidity − 0.60(− 0.98, − 0.21) among men and − 0.50(− 0.86, − 0.13) among women) and not consuming alcohol among Japanese men (− 1.33(− 2.51, − 0.15)). Discussion: Correlates of muscle strength were similar in both cohorts. Conclusions: A global approach to age-related muscle weakness prevention may be appropriate. [ABSTRACT FROM AUTHOR]

Purpose: Preoperative deep vein thrombosis (DVT) is a risk factor for postoperative venous thromboembolism (VTE), causing severe mortality. Early detection of preoperative DVT is essential to prevent postoperative VTE. However, little is known regarding preoperative DVT in patients undergoing major surgery. The present study aimed to determine the incidence and risk factors of preoperative DVT in patients admitted for total hip arthroplasty (THA). Methods: From August 2017 to September 2022, 243 patients admitted for THA at our institution were enrolled in this study. Patients medical records and preoperative laboratory data were retrospectively collected. According to the results of lower-limb ultrasonography, patients were divided into either the non-DVT (n = 136) or DVT (n = 43) group. The incidence of DVT and independent risk factors for preoperative DVT were investigated using univariate and multivariate logistic regression analyses. Results: The mean age was 74.0 ± 8.4 years. Preoperative DVT was diagnosed in 43 of the 243 (17.7%) patients. The risk of DVT was significantly high (p < 0.05) in patients with advanced age, increased D-dimer levels, and malnutrition status, as assessed by the Geriatric Nutritional Risk Index (GNRI). Multivariate analysis showed that advanced age, increased D-dimer level, and malnutrition status assessed by the GNRI were independent risk factors for preoperative DVT. Conclusion: A high incidence of preoperative DVT was observed in patients undergoing THA. Advanced age, increased D-dimer levels, and malnutrition assessed by the GNRI increased the risk of preoperative DVT. Screening high-risk subgroups for preoperative DVT is necessary to prevent postoperative VTE. [ABSTRACT FROM AUTHOR]

Background: The immunosuppressant mizoribine (Miz) can reduce progression of childhood IgA nephropathy (IgAN). This study examined whether Miz affects CD163+ M2-type macrophages which are associated with kidney fibrosis in childhood IgAN. Methods: A retrospective cohort of 90 children with IgAN were divided into groups treated with prednisolone (PSL) alone (P group; n = 42) or PSL plus Miz (PM group; n = 48) for a 2-year period. Normal human monocyte-derived macrophages were stimulated with dexamethasone (Dex), or Dex plus Miz, and analyzed by DNA microarray. Results: Clinical and histological findings at first biopsy were equivalent between patients entering the P and PM groups. Both treatments improved proteinuria and haematuria, and maintained normal kidney function over the 2-year course. The P group exhibited increased mesangial matrix expansion, increased glomerular segmental or global sclerosis, and increased interstitial fibrosis at 2-year biopsy; however, the PM group showed no progression of kidney fibrosis. These protective effects were associated with reduced numbers of glomerular and interstitial CD163+ macrophages in the PM versus P group. In cultured human macrophages, Dex induced upregulation of cytokines and growth factors, which was prevented by Miz. Miz also inhibited Dex-induced expression of CD300E, an activating receptor which can prevent monocyte apoptosis. CD300e expression by CD163+ macrophages was evident in the P group, which was reduced by Miz treatment. Conclusion: Miz halted the progression of kidney fibrosis in PSL-treated pediatric IgAN. This was associated with reduced CD163+ and CD163+CD300e+ macrophage populations, plus in vitro findings that Miz can suppress steroid-induced macrophage expression of pro-fibrotic molecules. [ABSTRACT FROM AUTHOR]

Objective: We examined the impact of simulated Tokyo 2020 environmental condition on exercise performance, thermoregulatory responses and thermal perception among Dutch elite athletes. Methods: 105 elite athletes from different sport disciplines performed two exercise tests in simulated control (15.9 ± 1.2 °C, relative humidity (RH) 55 ± 6%) and Tokyo (31.6 ± 1.0 °C, RH 74 ± 5%) environmental conditions. Exercise tests consisted of a 20-min warm-up (70% HRmax), followed by an incremental phase until volitional exhaustion (5% workload increase every 3 min). Gastrointestinal temperature (Tgi), heart rate, exercise performance and thermal perception were measured. Results: Time to exhaustion was 16 ± 8 min shorter in the Tokyo versus the control condition (− 26 ± 11%, whereas peak power output decreased with 0.5 ± 0.3 W/kg (16 ± 7%). Greater exercise-induced increases in Tgi (1.8 ± 0.6 °C vs. 1.5 ± 0.5 °C, p < 0.001) and higher peak Tgi (38.9 ± 0.6 °C vs. 38.7 ± 0.4 °C, p < 0.001) were found in the Tokyo versus control condition. Large interindividual variations in exercise-induced increase in Tgi (range 0.7–3.5 °C) and peak Tgi (range 37.6–40.4 °C) were found in the Tokyo condition, with greater Tgi responses in endurance versus mixed- and skill-trained athletes. Peak thermal sensation and thermal comfort scores deteriorated in the Tokyo condition, with aggravated responses for power versus endurance- and mixed-trained athletes. Conclusion: Large performance losses and Tgi increases were found among elite athletes exercising in simulated Tokyo conditions, with a substantial interindividual variation and significantly different responses across sport disciplines. These findings highlight the importance of an individual approach to optimally prepare athletes for safe and maximal exercise performance during the Tokyo Olympics. [ABSTRACT FROM AUTHOR]

Background: Two issues in clinical trials with multiple endpoints were surveyed: (1) the terminology of multiple endpoints, the relationship between rare events and endpoints, and the differences in multiplicity adjustment between regions, and (2) the current practice on multiplicity adjustment and sample size calculation. This article summarizes the results of the survey on the second issue. Methods: Eligible trials for this survey fulfilled the following conditions: (1) confirmatory phase 3 trial; (2) use of multiple primary endpoints, co-primary endpoints, key secondary endpoint(s) or composite endpoint(s); (3) inclusion of Japanese participants; and (4) protocols created in 2010 or later. The survey was conducted at member companies of the Japan Pharmaceutical Manufacturers Association from October 2017 to November 2017. Results: Useable responses were obtained from 78 trials in 13 companies based in Japan and 9 companies based in other countries. The Bonferroni procedure was mostly used in clinical trials with multiple primary endpoints, while multiple testing procedures that consider a hierarchy of endpoints or a structure of hypotheses were used in clinical trials with key secondary endpoint(s). In sample size calculation, we can consider the probability of study success, such as the probability of statistical significance in at least one comparison of primary endpoints; however, other probabilities were also considered. This survey reveals that multiplicity adjustment and the correlation of endpoints were not always considered in sample size calculation. Conclusions: In clinical trials with multiple endpoints, clinical importance was considered when determining multiple testing procedures. Challenges remain with the definition of power, the consideration of multiple testing procedures and the correlation between endpoints in sample size calculation. [ABSTRACT FROM AUTHOR]

Background: Reducing non-completion of quality-of-life assessment in clinical trials is an important challenge in obtaining accurate data and unbiased interpretation of patients' quality-of-life for each regimen. We evaluated the effect of changing our questionnaire distribution procedure in a multicenter phase II/III trial on the response rate to a quality-of-life questionnaire. Methods: In the trial, we distributed 1767 questionnaires and 1045 were returned. We adopted a regression discontinuing design and estimated the change in response rate between pre-intervention (quality-of-life questionnaires were sent to each center soon after patient registration) and post-intervention (a set of tailored questionnaires was sent just before the first quality-of-life assessment). Results: The post-intervention response rate was higher (odds ratio = 1.62) than the pre-intervention response rate. Conclusions: A simple logistic intervention reduced the non-completion of QOL assessment in this case, suggesting that a simple change can contribute to improving clinical trial accomplishment. [ABSTRACT FROM AUTHOR]

Introduction: In Japan, after receiving human papillomavirus vaccination, a significant number of adolescent girls experienced various symptoms, the vast majority of which have been ascribed to chronic regional pain syndrome, orthostatic intolerance, and/or cognitive dysfunction. However, a causal link has not been established between human papillomavirus vaccination and the development of these symptoms.Objective: The aim of this study was to clarify the temporal relationship between human papillomavirus vaccination and the appearance of post-vaccination symptoms.Methods: Between June 2013 and December 2016, we examined symptoms and objective findings in 163 female patients who had received human papillomavirus vaccination. We used newly defined diagnostic criteria for accurate inclusion of patients who experienced adverse symptoms after human papillomavirus vaccination; these diagnostic criteria were created for this study, and thus their validity and reliability have not been established.Results: Overall, 43 female patients were excluded. Among the remaining 120 patients, 30 were diagnosed as having definite vaccine-related symptoms, and 42 were diagnosed as probable. Among these 72 patients, the age at initial vaccination ranged from 11 to 19 years (average 13.6 ± 1.6 years), and the age at appearance of symptoms ranged from 12 to 20 years (average 14.4 ± 1.7 years). The patients received the initial human papillomavirus vaccine injection between May 2010 and April 2013. The first affected girl developed symptoms in October 2010, and the last two affected girls developed symptoms in October 2015. The time to onset after the first vaccine dose ranged from 1 to 1532 days (average 319.7 ± 349.3 days).Conclusions: The period of human papillomavirus vaccination considerably overlapped with that of unique post-vaccination symptom development. Based on these sequential events, it is suggested that human papillomavirus vaccination is related to the transiently high prevalence of the previously mentioned symptoms including chronic regional pain syndrome and autonomic and cognitive dysfunctions in the vaccinated patients. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examines the lateral posing bias for displaying trustworthiness during a trust game in which participants and their virtual partners cooperated or did not cooperate with their counterparts to earn a monetary reward. Topics discussed include the number of posers showing the left or right cheek as a function of cooperativeness and the mean rating of facial trustworthiness as a function of posing orientation and cooperativeness.

Many single adult children in countries around the world live with their parents. Such coresidence has been thought to delay the transition to first marriage, although the exact reasons for the delay have not been sufficiently examined. Using panel data from Japan, we investigate whether changes in never-married adults' residential status lead to alterations in their marital aspirations, courtship behaviors, romantic opportunities, and perceived obstacles to marrying. Our estimation of fixed-effects models helps address potential bias caused by single individuals' selection into living in the parental home. The analysis indicates that living with parents is associated with a lower probability of forming romantic relationships, thereby decelerating the transition to first marriage. The never-married, however, do not desire marriage less, put less effort into finding romantic partners, or have fewer opportunities to meet potential partners when coresiding with parents. Overall, the findings suggest that living in the parental home increases never-married men's contentment with their immediate social environment, whereas it decreases women's psychological readiness to transition into adult roles, making both men and women less eager to settle into a romantic relationship. [ABSTRACT FROM AUTHOR]

Purpose: Few epidemiological studies have assessed the relationship between the traditional Japanese dietary pattern and longitudinal changes in cardiovascular disease risk factors among Japanese people. We designed a 3-year longitudinal study of 980 subjects living in Japan to evaluate how the Japanese dietary pattern is related to longitudinal changes in well-recognized risk factors for cardiovascular disease among apparently healthy Japanese adults. Methods: Dietary consumption was assessed via a validated food frequency questionnaire. Principal component analysis was used to derive three major dietary patterns-'Japanese,' 'sweets-fruits-cooked wheaten food,' and 'Izakaya (Japanese Pub)' from 39 food groups. Results: After adjustment for potential confounders, the mean (95 % confidence interval) for the change per year in diastolic blood pressure for men, systolic blood pressure, and diastolic blood pressure for women related to the 'Japanese' dietary pattern factor score tertiles were 0.89 (0.10, 1.68), 2.25 (0.19, 4.31), and 0.75 (−1.00, 2.50) for the lowest tertile, 0.77 (−0.02, 1.56), 1.01 (−1.13, 3.15), and 0.44 (−1.38, 2.26) for the middle tertile and − 0.04 (−0.81, 0.72), −0.48 (−2.52, 1.56), and −0.77 (−2.51, 0.96) for the highest tertile (trend P value = 0.03, <0.01, and 0.04, respectively). A significant detrimental relationship was found between the 'Izakaya (Japanese Pub)' pattern factor score tertiles and the longitudinal change in serum triglyceride concentration only in men (trend P value = 0.02). Conclusions: Greater adherence to a traditional Japanese diet was independently related to a decreased change every year in diastolic blood pressure in men and women and in systolic blood pressure in women over a 3-year follow-up period. The findings suggest that the 'Japanese' dietary pattern appeared to be related to a fall in blood pressure, which might have a beneficial effect on cardiovascular disease. A randomized trial is required to clarify the underlying mechanism. [ABSTRACT FROM AUTHOR]

Auditory hyper-reactivity is a common sensory-perceptual abnormality in autism spectrum disorders (ASD), which interrupts behavioral adaptation. We investigated acoustic startle response (ASR) modulations in 17 children with ASD and 27 with typical development (TD). Compared to TD, children with ASD had larger ASR magnitude to weak stimuli and more prolonged peak startle-latency. We could not find significant difference of prepulse inhibition (PPI) or habituation in ASD children compared to TD. However, habituation and PPI at 70-dB prepulses were negatively related to several subscales of Social Responsiveness Scale and the Strengths and Difficulties Questionnaire, when considering all children. Comprehensive investigation of ASR and its modulation might increase understanding of the neurophysiological impairments underlying ASD and other mental health problems in children. [ABSTRACT FROM AUTHOR]

To determine the best discriminative items for identifying young children with autism spectrum disorders (ASD), we conducted a secondary analysis using longitudinal cohort data that included the Japanese version of the 23-item modified checklist for autism in toddlers (M-CHAT-JV). M-CHAT-JV data at 18 months of age and diagnostic information evaluated at age 3 or later from 1851 Japanese children was used to isolate six highly discriminative items. Using data from two different community samples (n = 1851, n = 665) these items were shown to have comparable psychometric values with those of the full version. Our results suggest that these items might work as a short form screener for early identification of ASD in primary care settings where there are time constraints on screening. [ABSTRACT FROM AUTHOR]

Study design:This is a cross-sectional study.Objectives:The objective of this study was to ascertain the essential items mediating adequate dietary intake based on the Japanese Food Guide in common among the transtheoretical model (TTM), self-efficacy (SE) and outcome expectancy (OE).Setting:Members of the organization Spinal Injuries Japan.Methods:We posted a questionnaire survey to 2731 community-dwelling Japanese adults with spinal cord injury (SCI), and responses from 841 individuals were analyzed. Food intake was assessed as the frequency scores of 10 food items eaten in a daily diet in Japan. The correlations between the frequency scores of food intake and TTM, SE and OE were determined by binominal logistic regression analysis.Results:The frequency scores of food intake were significantly associated with 'To eat vegetable dishes (dishes made mainly from vegetables or potatoes) not less than twice a day', 'To eat green/yellow vegetables not less than twice a day', 'To eat dairy products not less than once a day' and 'To eat fruits not less than once a day' in TTM. 'To eat vegetable dishes (dishes made mainly from vegetables or potatoes) not less than twice a day', 'To eat dairy products not less than once a day' and 'To eat fruits not less than once a day' were significantly associated with the frequency scores of food intake in SE. In OE, no differences were shown.Conclusion:This study finds that vegetable dishes, dairy products and fruits are the key items mediating adequate dietary intake. Dietary guidelines promoting the intake of these dishes for SCI individuals are needed. [ABSTRACT FROM AUTHOR]

Purpose: The medial branch of the posterior ramus of the lumbar spinal nerve is well known to be innervated independently and to end in the multifidus muscle without anastomosis. This prospective cohort study aimed to determine the diagnostic specificity and sensitivity of multifidus muscle denervation (MMD) by needle electromyography (N-EMG) for lumbar foraminal and lateral exit-zone stenosis (LF/LEZS).Methods: We enrolled 61 consecutive patients experiencing unilateral dysesthesia and/or leg pain in the L4 or L5 regions with suspicious LF/LEZS. The Japanese Orthopedic Association (JOA) score, Visual Analog Scale (VAS) for leg pain, and N-EMG were examined. In this study protocol, all patients received at least 3 months of conservative therapy. Surgery was performed on patients who experienced less than 50% VAS pain relief compared with their initial score after confirming the responsible level by lumbar nerve root block. The specificity of N-EMG was the proportion of patients who improved with conservative therapies (non-surgery) after 3 months. The sensitivity of N-EMG was the proportion of patients who improved with surgical therapies (surgery) after more than 12 months.Results: Twenty-three patients underwent surgery. The initial lower JOA, positive Kemp test and motor weakness were significantly higher in the surgery group. The MMD by N-EMG indicated that 34 of 38 patients were negative in the non-surgery group. In the surgery group, 21 of 23 patients were positive. The diagnostic sensitivity and specificity were 91.3 and 92.1%, respectively.Conclusions: Needle electromyography is a simple and available additional method for the diagnosis of LF/LEZS. [ABSTRACT FROM AUTHOR]

Study design:Cross-sectional study.Objectives:To determine the effect of injury duration on plantar-flexor elastic properties in individuals with chronic spinal cord injury (SCI) and spasticity.Setting:National Rehabilitation Center for Persons with Disabilities, Japan.Methods:A total of 16 chronic SCI patients (age, 33±9.3 years; injury localization, C6-T12; injury duration, 11-371 months) participated. Spasticity of the ankle plantar-flexors was assessed using the Modified Ashworth Scale (MAS). The calf circumference and muscle thickness of the medial gastrocnemius (MG), lateral gastrocnemius and soleus were assessed using tape measure and ultrasonography. In addition, the ankle was rotated from 10° plantar-flexion to 20° dorsiflexion at 5 deg s−1 with a dynamometer, and the ankle angle and torque were recorded. After normalizing the data (the initial points of angle and torque were set to zero), we calculated the peak torque and energy. Furthermore, angle-torque data (before and after normalization) were fitted with a second- and fourth-order polynomial, and exponential (Sten-Knudsen) models, and stiffness indices (SISOP, SIFOP, SISK) and AngleSLACK (the angle at which plantar-flexor passive torque equals zero) were calculated. The stretch reflex gain and offset were determined from 0-10° dorsiflexion at 50, 90, 120 and 150 deg s−1. After logarithmic transformation, Pearson's correlation coefficients were calculated.Results:MAS, calf circumference, MG thickness, peak torque and SIFOP significantly decreased with injury duration (r log-log=−0.63, −0.69, −0.63, −0.53 and −0.55, respectively, P<0.05). The peak torque and SIFOP maintained significant relationships even after excluding impacts from muscle morphology.Conclusion:Plantar-flexor elasticity in chronic SCI patients decreased with increased injury duration. [ABSTRACT FROM AUTHOR]

Background: Prevention of chronic kidney allograft injury (CAI) is a major goal in improving kidney allograft survival; however, the mechanisms of CAI are not clearly understood. The current study investigated whether alternatively activated M2-type macrophages are involved in the development of CAI. Methods: A retrospective study examined kidney allograft protocol biopsies (at 1 h and at years 1, 5, and 10-a total of 41 biopsies) obtained from 13 children undergoing transplantation between 1991 and 2008 who were diagnosed with CAI: interstitial fibrosis and tubular atrophy (IF/TA) not otherwise specified (IF/TA-NOS). Results: Immunostaining identified a significant increase in interstitial fibrosis with accumulation of CD68 + CD163+ M2-type macrophages. CD163+ cells were frequently localized to areas of interstitial fibrosis exhibiting collagen I deposition and accumulation of α-smooth muscle actin (SMA) + myofibroblasts. There was a significant correlation between interstitial CD163+ cells and the parameters of interstitial fibrosis ( p < 0.0001), and kidney function ( r =−0.82, p < 0.0001). The number of interstitial CD163+ cells at years 1 and 5 also correlated with parameters of interstitial fibrosis at years 5 and 10 respectively. Notably, urine CD163 levels correlated with interstitial CD163+ cells ( r = 0.79, p < 0.01) and parameters of interstitial fibrosis ( p < 0.0001). However, CD3+ T lymphocytic infiltration did not correlate with macrophage accumulation or fibrosis. In vitro, dexamethasone up-regulated expression of CD163 and cytokines (TGF-β1, FGF-2, CTGF) in human monocyte-derived macrophages, indicating a pro-fibrotic phenotype. Conclusions: Our findings identify a major population of M2-type macrophages in patients with CAI, and suggest that these M2-type macrophages might promote the development of interstitial fibrosis in IF/TA-NOS. [ABSTRACT FROM AUTHOR]

Background: Recently, we demonstrated that urinary angiotensinogen (AGT) levels are increased and reflect intrarenal renin-angiotensin system (RAS) status in pediatric patients with chronic glomerulonephritis. Therefore, this study was performed to test the hypothesis that urinary AGT (UAGT) levels provide a specific index of intrarenal RAS status associated with RAS blockade treatment in pediatric IgA nephropathy (IgAN) patients. Methods: We measured plasma and UAGT levels and urinary transforming growth factor beta (TGF-β) levels, after which we performed immunohistochemical analysis of AGT, angiotensin II (Ang II), and TGF-β in 24 pediatric IgAN patients treated with RAS blockades for 2 years. Paired tests were used to analyze the changes from baseline to study end. Results: Although there was no change in plasma AGT levels, UAGT and TGF-β levels were significantly decreased after RAS blockade, which was accompanied by the expression levels of AGT, Ang II, and TGF-β, as well as the magnitude of glomerular injury. Baseline UAGT levels positively correlated with diastolic blood pressure, urinary protein levels, scores for mesangial hypercellularity, and the expression levels of AGT, Ang II, and TGF-β in renal tissues. Conclusions: These data indicate that UAGT is a useful biomarker of intrarenal RAS activation, which is associated with glomerular injury during RAS blockade in pediatric IgAN patients. [ABSTRACT FROM AUTHOR]

Background In the international, phase III, randomized, double-blind CORRECT trial, regorafenib significantly prolonged overall survival (OS) versus placebo in patients with metastatic colorectal cancer (mCRC) that had progressed on all standard therapies. This post hoc analysis evaluated the efficacy and safety of regorafenib in Japanese and non-Japanese subpopulations in the CORRECT trial. Methods Patients were randomized 2 : 1 to regorafenib 160 mg once daily or placebo for weeks 1-3 of each 4-week cycle. The primary endpoint was OS. Outcomes were assessed using descriptive statistics. Results One hundred Japanese and 660 non-Japanese patients were randomized to regorafenib ( n = 67 and n = 438) or placebo ( n = 33 and n = 222). Regorafenib had a consistent OS benefit in the Japanese and non-Japanese subpopulations, with hazard ratios of 0.81 (95 % confidence interval [CI] 0.43-1.51) and 0.77 (95 % CI 0.62-0.94), respectively. Regorafenib-associated hand-foot skin reaction, hypertension, proteinuria, thrombocytopenia, and lipase elevations occurred more frequently in the Japanese subpopulation than in the non-Japanese subpopulation, but were generally manageable. Conclusion Regorafenib appears to have comparable efficacy in Japanese and non-Japanese subpopulations, with a manageable adverse-event profile, suggesting that this agent could potentially become a standard of care in patients with mCRC. [ABSTRACT FROM AUTHOR]

Background Elpamotide is an HLA-A*24:02-restricted epitope peptide of vascular endothelial growth factor receptor 2 (VEGFR-2) and induces cytotoxic T lymphocytes (CTLs) against VEGFR-2/KDR. Given the high expression of VEGFR-2 in biliary tract cancer, combination chemoimmunotherapy with elpamotide and gemcitabine holds promise as a new therapy. Patients and Methods Patients with unresectable advanced or recurrent biliary tract cancer were included in this single-arm phase II trial, with the primary endpoint of overall survival. Survival analysis was performed in comparison with historical control data. The patients concurrently received gemcitabine once a week for 3 weeks (the fourth week was skipped) and elpamotide once a week for 4 weeks. Results Fifty-five patients were registered, of which 54 received the regimen and were included in the full analysis set as well as the safety analysis set. Median survival was 10.1 months, which was longer than the historical control, and the 1-year survival rate was 44.4 %. Of these patients, injection site reactions were observed in 64.8 %, in whom median survival was significantly longer (14.8 months) compared to those with no injection site reactions (5.7 months). The response rate was 18.5 %, and all who responded exhibited injection site reactions. Serious adverse reactions were observed in five patients (9 %), and there were no treatment-related deaths. Conclusion Gemcitabine and elpamotide combination therapy was tolerable and had a moderate antitumor effect. For future development of therapies, it will be necessary to optimize the target population for which therapeutic effects could be expected. [ABSTRACT FROM AUTHOR]

Purpose: Coffee and green tea consumption may be associated with circulating adipokines, but data are inconsistent, scarce or lacking. We examined the association of coffee and green tea consumption with serum adiponectin, leptin, visfatin, resistin and plasminogen activator inhibitor-1 (PAI-1) among a Japanese working population. Methods: The authors analyzed data ( n = 509) from a cross-sectional survey among Japanese workers aged 20-68 years. Serum adipokines were measured using a Luminex suspension bead-based multiplexed array. Coffee and green tea consumption was assessed using a validated diet history questionnaire, and caffeine consumption from these beverages was estimated. Multiple regression analysis was performed with adjustment for potential confounding variables. Results: Coffee consumption was significantly, inversely associated with leptin and PAI-1 ( P for trend = 0.007 and 0.02, respectively); compared with subjects consuming <1 cup per day, those consuming ≥4 cups per day had 13 and 10 % lower means of leptin and PAI-1, respectively. Similar associations were observed for caffeine consumption ( P for trend = 0.02 for both leptin and PAI-1). Additionally, we noted a significant positive association between coffee consumption and adiponectin in men ( P for trend = 0.046), but not in women ( P for trend = 0.43, P for interaction = 0.11). Moreover, there was a positive association between coffee consumption and resistin in current male smokers ( P for trend = 0.01), but not in male non-smokers ( P for trend = 0.35, P for interaction = 0.11). Green tea consumption was not associated with any adipokine. Conclusions: Higher consumption of coffee and caffeine but not green tea was associated with lower serum levels of leptin and PAI-1 in Japanese adults. [ABSTRACT FROM AUTHOR]

Summary: The associations between mid-femoral cross-sectional geometry and exercise characteristics were investigated in female athletes. The effects on bone geometry for weight-bearing sports with low-to-high-impact were greater than those for non-impact weight-bearing sports, whereas low-impact or high-strain-magnitude/low-strain-rate sports had less of an effect on bone geometry compared with higher-impact sports. Introduction: Many previous studies have investigated tibial geometry in athletes; however, few studies have examined the associations between femoral cross-sectional geometry and exercise characteristics. The aim of this study was to investigate these relationships using magnetic resonance imaging (MRI) at the femoral mid-shaft. Methods: One hundred and fifty-three female elite athletes, aged 18-34 years, were classified into five groups based on the characteristics of their sports. Sports were considered non-impact ( n = 27), low- or moderate-impact ( n = 39), odd-impact ( n = 38), high-strain-magnitude/low-strain-rate ( n = 10), or high-impact ( n = 39). Bone geometrical parameters, including cortical area, periosteal perimeter, and moment of inertia (bone strength index), were determined using MRI images. Results: Higher-impact groups displayed bone expansion, with significantly greater periosteal perimeters, cortical areas (~37.3 %), and minimum moments of inertia ( I, ~92.3 %) at the mid-femur than non- and low-impact groups. After adjusting for age, height, and weight, the cortical area and I of the low-impact and high-strain-magnitude/low-strain-rate groups were also significantly greater than those of the non-impact group. Conclusions: Higher-impact sports with high strain rates stimulated periosteal bone formation and improved bone geometry and strength indices at the femoral mid-shaft. Although our results indicate that weight-bearing sports are beneficial even if they are low impact, the effects of lower-impact or high-strain-magnitude/low-strain-rate sports on bone geometry were less pronounced than the effects of higher-impact sports at the femoral mid-shaft. [ABSTRACT FROM AUTHOR]

Summary: A 12-month extension phase of DIRECT in Japanese subjects with osteoporosis showed that total 3 years of denosumab treatment in Japanese postmenopausal women and men with osteoporosis was associated with low fracture rates, persistent bone turnover marker (BTM) reductions, continuous bone mineral density (BMD) increases, and a favorable overall benefit/risk profile. Introduction: The DIRECT trial demonstrated that 2 years of treatment with denosumab 60 mg subcutaneously every 6 months significantly reduced the incidence of vertebral fracture compared to placebo in Japanese postmenopausal women and men with osteoporosis. The purpose of this study is to evaluate the efficacy and safety of denosumab treatment for up to 3 years. Methods: This study includes a 2-year randomized, double-blind, placebo-controlled phase and a 1-year open-label extension phase in which all subjects received denosumab. The data correspond to 3 years of denosumab treatment in subjects who received denosumab (long-term group) and 1 year of denosumab treatment in subjects who received placebo (cross-over group) in the double-blind phase. Results: Eight hundred and ten subjects who completed the double-blind phase enrolled into the extension phase, and 775 subjects completed the study. All subjects received denosumab with daily supplements of calcium and vitamin D. The cumulative 36-month incidences of new or worsening vertebral fractures and new vertebral fractures were 3.8 and 2.5 %, respectively, in the long-term group. In this group, the BMD continued to increase, and the reduction in BTMs was maintained. In the cross-over group, comparable BMD increases and BTMs reductions to those of in their first year of the long-term group were confirmed. Adverse events did not show a notable increase with long-term denosumab administration. One event of osteonecrosis of the jaw occurred in the cross-over group. Conclusions: Three-year denosumab treatment in Japanese subjects with osteoporosis showed a favorable benefit/risk profile. [ABSTRACT FROM AUTHOR]

Background: In times of disaster, public servants face multiple burdens as they engage in a demanding and stressful disaster-response work while managing their own needs caused by the disaster. Purpose: We investigated the effects of work-related factors on the mental health of prefectural public servants working in the area devastated by the Great East Japan Earthquake to identify some ideas for organizational work modifications to protect their mental health. Methods: Two months after the earthquake, Miyagi prefecture conducted a self-administered health survey of prefectural public servants and obtained 4,331 (82.8 %) valid responses. We investigated relationships between mental health distress (defined as K6 ≥ 13) and work-related variables (i.e., job type, overwork, and working environment) stratified by level of earthquake damage experienced. Results: The proportion of participants with mental health distress was 3.0 % in the group that experienced less damage and 5.9 % in the group that experienced severe damage. In the group that experienced less damage, working >100 h of overtime per month (adjusted odds ratio [OR], 2.06; 95 % confidence interval [CI], 1.11-3.82) and poor workplace communication (adjusted OR, 10.96; 95 % CI, 6.63-18.09) increased the risk of mental health distress. In the group that experienced severe damage, handling residents' complaints (adjusted OR, 4.79; 95 % CI, 1.55-14.82) and poor workplace communication (adjusted OR, 9.14; 95 % CI, 3.34-24.97) increased the risk, whereas involvement in disaster-related work (adjusted OR, 0.39; 95 % CI, 0.18-0.86) decreased the risk. Conclusions: Workers who have experienced less disaster-related damage might benefit from working fewer overtime hours, and those who have experienced severe damage might benefit from avoiding contact with residents and engaging in disaster-related work. Facilitating workplace communication appeared important for both groups of workers. [ABSTRACT FROM AUTHOR]

Purpose: Clobazam (CLB) is metabolized by cytochrome P450 (CYP) 3A4 to yield N-desmethylclobazam ( N-CLB), which is further inactivated by CYP2C19. The aim of this study was to retrospectively evaluate the relationship between CYP2C19 polymorphisms and the efficacy of low-dose, add-on CLB therapy in Japanese patients with epilepsy. Methods: Fifty patients were divided into three groups according to their CYP2C19 polymorphism. CLB and N-CLB serum concentrations and seizure frequency before and after starting CLB were analyzed. Results: Extensive metabolizers (EMs, n = 11), intermediate metabolizers (IMs, n = 22), and poor metabolizers (PMs, n = 17) were included. Although the dose-normalized CLB serum concentrations were not significantly different, the dose-normalized N-CLB serum concentrations were significantly higher in PMs than in EMs or IMs. Seizure frequency was significantly decreased by the CLB therapy in PMs ( p < 0.01), but not in EMs or IMs. CLB serum concentrations did not correlate with seizure reduction rate, but median N-CLB serum concentrations were significantly higher in patients with excellent seizure control (≧90 % seizure reduction) compared to those with ≧50 % seizure reduction or with <50 % seizure reduction (1103, 341, and 570 ng/mL, respectively). Conclusions: The efficacy of low-dose CLB therapy was significantly influenced by CYP2C19 polymorphisms. Ideally, CLB therapy should be started with a low dose (2.5 mg/day) and dosage increased until N-CLB serum concentration reaches 1100 ng/mL or until the desired effect is acquired, a recommendation that is particularly important for PMs. [ABSTRACT FROM AUTHOR]

Purpose: Nutritional control has been proposed as a potential therapy for slowing the senescence of immune function and decreasing mortality. This study investigated whether sesamin could modify host defense systems and extend the lifespan of the nematode Caenorhabditis elegans. Methods: Nematodes were fed standard food (the bacterium Escherichia coli strain OP50) supplemented with various doses of sesamin/γ-cyclodextrin inclusion compounds starting from young adulthood. The mean lifespan, muscle function, lipofuscin accumulation, protein carbonyl content, and stress resistance of the worms were examined. Then, C. elegans mutants harboring loss-of-function lesions in longevity- and host defense-related signaling pathways were supplemented with sesamin to identify the genes involved in the longevity effects. Results: Worms supplemented with sesamin displayed higher locomotion and prolongevity and produced offspring at levels similar to unsupplemented control animals. The growth curves of nematodes were similar to those of controls, suggesting that sesamin did not induce prolongevity effects through dietary restriction. Notably, sesamin made the worms more resistant to infection by Legionella pneumophila and more resistant to oxidative stressors such as paraquat and hydrogen peroxide and prolonged the lifespan of a mev- 1 mutant that produces abundant superoxide anions. However, the accumulation of protein carbonyls and lipofuscin was similar in sesamin-exposed and control worms, suggesting that sesamin is unlikely to work simply as an antioxidant. Sesamin supplementation failed to extend the lifespan of loss-of-function mutants of daf-2, daf- 16, pmk- 1, and skn- 1. Conclusions: Sesamin enhances the host defense of C. elegans and increases the average lifespan via activation of both skn- 1 (encoding a component of the p38 MAPK pathway) and daf- 16 (encoding a component of the IGF-1 pathway). [ABSTRACT FROM AUTHOR]

Summary: Patients with rheumatoid arthritis showed greater response to 18-month administration of daily teriparatide especially in the increase of bone formation markers at 1 month and femoral neck bone mineral density at 18 months compared to postmenopausal osteoporosis patients. Introduction: The aim of this study was to evaluate the effects of 18-month administration of daily teriparatide (TPTD) in osteoporosis patients with rheumatoid arthritis (RA) by comparing that of postmenopausal osteoporosis patients (Porosis). Methods: The effects of TPTD were examined between RA ( n = 70; age 68.4 years; disease activity score assessing 28 joints with CRP [DAS28-CRP] 2.8; rheumatoid factor [RF] positivity 75.5 %) with 77.1 % of prior bisphosphonate (BP), 84.3 % of oral prednisolone (PSL) (4.4 mg/day at baseline), 25.7 % of biologics, and Porosis ( n = 62; age 71.3 years) with 77.4 % of prior BP. Results: Femoral neck (FN) bone mineral density (BMD) increase at 18 months was significantly greater in RA compared to Porosis (4.7 vs. 0.7 %, P = 0.038), whereas it was 9.7 versus 7.9 % ( P = 0.736) in the lumbar spine (LS). The increase of bone formation markers (bone alkaline phosphatase [bone ALP] and N-terminal type I procollagen propeptide [PINP]) at 1 month were all significantly greater in RA compared to Porosis. A multivariate logistic regression analysis revealed that the significant indicator of 18-month BMD increase in RA was a 3-month increase of under-carboxylated osteocalcin (ucOC) for LS ( β = 0.446, P = 0.005) and baseline ucOC for FN ( β = 0.554, P = 0.001), in which both showed significant negative correlation with baseline PSL dose. Conclusions: RA showed greater response to daily TPTD administration, especially in the increase of bone formation markers at 1 month and FN BMD increase at 18 months compared to Porosis. [ABSTRACT FROM AUTHOR]

Purpose: Although a few prospective studies have addressed the question as to which biomarker of infection in adult patients with febrile neutropenia (FN) is superior, procalcitonin (PCT) or C-reactive protein (CRP), the results have been inconsistent and inconclusive. This was possibly due to the poor sensitivity of previous PCT tests that have a functional sensitivity of 0.5 ng/ml. Methods: Between November 2010 and February 2012, we prospectively compared the diagnostic utility of serum high-sensitivity (hs) PCT (lower limit of detection, 0.02 ng/ml) and CRP levels for detecting bacterial infection in patients with FN. Serum was collected within 72 h after the onset of FN in patients with hematological disorders. Results: Seventy-five febrile episodes were evaluable. The areas under the receiver operating characteristic curves for life-threatening infection defined as septic shock and bacteremia caused by non-coagulase negative staphylococcus were 0.824 (95 % CI 0.711-0.937; P = 0.001) for hsPCT and 0.673 (0.505-0.842; P = 0.068) for CRP, respectively. In contrast, CRP, but not hsPCT, tended to increase significantly with the clinical severity, as indicated by the diagnostic classification ( P = 0.002 for trend). Conclusions: The serum hsPCT test may be more useful than the serum CRP test in the detection of life-threatening infection at an early phase after the onset of FN. In contrast, the serum CRP test may be more useful in diagnosing the severity of infection. However, neither of these tests was able to differentiate the cause of FN with a low probability of fatal outcome. [ABSTRACT FROM AUTHOR]

Summary: This study assessed the effects of physical activity on a 10-year incidence of self-reported vertebral fractures in adult women of a large Japanese cohort. Medium levels of strenuous activity and long-duration sedentary activity were associated with a lower incidence of vertebral fractures; association patterns appear to be different from hip fractures. Introduction: Physical activity helps prevent hip fracture, but little is known about the longitudinal association between physical activity and vertebral fractures. The purpose of this study was to evaluate the effects of physical activity on the 10-year incidence of symptomatic vertebral fractures using data from the Japan Public Health Center-based Prospective Study. Methods: Baseline studies were conducted in 1993-1994, and the follow-up study was conducted 10 years later. We analyzed 23,757 women aged 40-69 years. At baseline, physical activity was assessed as a predictor by using a questionnaire. Subjects were asked to report vertebral fractures that occurred during the 10-year follow-up period. Relative risks (RRs) adjusted for confounders were estimated by multiple logistic regression analysis. Results: The 10-year cumulative incidence of vertebral fractures was 0.67 %. Those who engaged in strenuous physical activity of <1 h/day had a significantly lower incidence of vertebral fractures than those who did not engage in such activity (RR = 0.52, 95 % CI 0.28-0.97), while those engaged in such activity ≥1 h/day did not (RR = 0.82, 95 % CI 0.58-1.14). Long-duration sedentary activity was associated with a low incidence of vertebral fractures ( P for trend = 0.0002), but the frequencies of sports activities and metabolic equivalents were not ( P for trend = 0.0729 and 0.4341, respectively). Conclusions: Strenuous activity and sedentary activity are associated with the incidence of vertebral fractures, although the association may not be linear. The pattern of association between physical activity and vertebral fractures appears to be different from that of hip fractures. [ABSTRACT FROM AUTHOR]

Background: Residual risk of cardiovascular disease from increased small dense low-density lipoprotein (sdLDL)-cholesterol levels and low n-3 polyunsaturated fatty acid (PUFA) levels is a considerable therapeutic issue. The purpose of this study was to evaluate the effect of ezetimibe as an add-on to statins and supplemental eicosapentaenoic acid (EPA) on sdLDL cholesterol and absorption of EPA in patients with coronary artery disease. Methods: The study population consisted of ten male patients who were concurrently receiving statins and EPA 1,800 mg/day. Serum lipids and PUFAs, including EPA and arachidonic acid, were measured in blood samples collected before ezetimibe (baseline), 4 weeks after starting 10-mg/day ezetimibe, and 4 weeks after discontinuing ezetimibe. Results: Ezetimibe significantly decreased sdLDL-cholesterol levels after 4 weeks of treatment (baseline 35 ± 13 mg/dl; treatment 27 ± 9 mg/dl), but the levels returned to baseline after discontinuation of ezetimibe (37 ± 13 mg/dl). The concentration of EPA did not significantly change during the study. Conclusion: Ezetimibe shows great promise as an add-on therapy to statins to reduce sdLDL-cholesterol-related residual risk of cardiovascular disease without affecting absorption of supplemental EPA in patients with coronary artery disease. [ABSTRACT FROM AUTHOR]

Background: Perceived stress and coping strategies may influence the risk of cardiovascular disease through their possible association with inflammation, but data remain controversial for perceived stress or scanty for coping strategies. Purpose: We examined the associations of perceived stress and coping strategies with serum high-sensitivity C-reactive protein (CRP) in a Japanese general population. Methods: This cross-sectional study included 2,971 men and 4,902 women aged 40-69 years who were enrolled between 2005 and 2007. Subjects with possible inflammation-related disease, CRP levels ≥3,000 ng/mL, or currently used analgesics or lipid-lowering drugs were excluded. Analyses were performed by gender with adjustment for lifestyle, socioeconomic, and psychosocial factors. Results: Unexpectedly, elevated perceived stress was significantly associated with lower CRP levels in men ( P < 0.001) but not in women ( P = 0.90) after adjustment for age and covariates. Among five items of coping strategies evaluated, 'disengagement' showed a significant inverse association with CRP in men only ( P = 0.027). In addition, a possible interaction between 'emotional support seeking' and perceived stress on CRP was detected in men ( P = 0.021); 'emotional support seeking' was associated with lower CRP at the high stress level only ( P = 0.028). Conclusions: Both perceived stress and coping strategies may be associated with systemic inflammation in Japanese men, yet caution must be exercised before accepting the stress-inflammation-disease pathway. [ABSTRACT FROM AUTHOR]

Purpose We aimed to investigate the recommended dose for the combination of TSU-68, a multiple-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2 and platelet-derived growth factor receptor-β, and S-1, an oral fluoropyrimidine, in patients with advanced hepatocellular carcinoma (HCC) based on its associated dose-limiting toxicity (DLT) frequency. We also determined the safety, tolerability, pharmacokinetics (PK), and efficacy of the combination treatment. Patients and methods Patients without any prior systemic therapy received 400 mg/day TSU-68 orally and 80 mg/day (level 1) or 100 mg/day (level 2) S-1 for 4 or 2 weeks followed by a 2- or 1-week rest period (groups A and B, respectively). According to the treatment, patients progressed from level 1B to level 2A, then level 2B. Safety and response rates were assessed. Results Eighteen patients were enrolled. Two patients at levels 1B and 2A but none at level 2B showed DLTs. The common adverse drug reactions were a decrease in hemoglobin levels, hypoalbuminemia, and anorexia, which were mild in severity (grades 1-2). PK data from levels 1B and 2A indicated that the area under the curve for TSU-68 and 5-fluorouracil was unlikely to be affected by the combination treatment. Response rate, disease control rate, median time to progression, and median overall survival were 27.8 %, 61.1 %, 5.3 months, and 12.8 months, respectively. Conclusion The recommended dose for advanced HCC should be 400 mg/day TSU-68 and 100 mg/day S-1 for 4 weeks followed by 2-week rest. [ABSTRACT FROM AUTHOR]

The article discusses a study which describes the ethnic differences in toxicity during early phase clinical trials for oncology drugs. The researchers have evaluated the Phase I clinical trials for new drug applications and approved doses in Japan and other Western countries. The findings indicate that differences in toxicity for oncology drugs are associated with ethnic differences.

Purpose: Faster eating is positively associated with body mass index in apparently healthy Japanese populations. In the present study, we examined the associations between self-reported rate of eating and visceral and subcutaneous fat areas in apparently healthy middle-aged Japanese men. Methods: We conducted a cross-sectional study of men who participated in health checkups in Japan. We removed participants who were diagnosed with metabolic diseases by the time of their health checkups. A total of 320 subjects aged 30-64 years (mean ± standard deviation, 47.4 ± 8.6 years) were selected. We compared the associations between rate of eating and various clinical parameters including visceral and subcutaneous fat areas, using analysis of covariance (ANCOVA), which was adjusted by age and lifestyle factors such as alcohol intake, energy intake, smoking, and physical activity. Multivariate logistic regression analyses (MLRA) were performed with visceral fat area (cm) as the dependent variable and independent variables that included self-reported rate of eating. Results: Tukey's multiple test following ANCOVA showed that self-reported rate of eating was positively associated with visceral fat area (cm), but not with subcutaneous fat area (cm). MLRA showed that the odds ratio of rate of eating for visceral fat area in tertile (T) 3 (>100 cm) compared with T1 (≤70 cm) was 1.99 (95 % CI 1.40-2.90, P < 0.01), and the association remained after adjustment for the subcutaneous fat area. Conclusions: The present results show that self-reported faster eating is positively associated with visceral fat accumulation, independently of subcutaneous fat accumulation, in apparently healthy Japanese men. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to examine the possible effects of healthcare resource factors, socioeconomic factors, and sociodemographic factors on variations in hospitalization expenditures of elderly patients in Japan at different levels of urbanization. Subject and methods: A secondary analysis was conducted using data obtained from a regional health care cost report and the Portal Site of Official Statistics of Japan. The regional unit of analysis used was the secondary medical care area. We divided these areas into three groups based on their levels of urbanization (low, middle, and high urbanization), indicated by their respective population densities of inhabitable areas. Multiple linear regression models were used to analyze the candidate factors affecting per capita hospitalization expenditures of elderly residents. Results: The significance and magnitude of associations were observed to vary according to different levels of urbanization. Our findings showed that medical resource factors and sociodemographic factors were more influential in areas of low urbanization, whereas the number of hospital beds and socioeconomic factors appeared more influential in high urbanization areas. Conclusion: Policies designed to contain healthcare expenditures should take regional characteristics and levels of urbanization into account in order to support the development and implementation of region-specific improvements that ensure affordable healthcare for the elderly. [ABSTRACT FROM AUTHOR]

Background: High residual platelet reactivity in patients receiving clopidogrel is associated with an increased risk of a cardiovascular event after coronary stenting. The aim of our study was to evaluate the impact of the cytochrome P450 (CYP) 3A5 and CYP2C19 polymorphisms on platelet reactivity during dual antiplatelet therapy. Methods: We determined the CYP2C19 and CYP3A5 genotypes of 101 angina patients (65 male patients, mean age 64 years) receiving dual antiplatelet therapy with aspirin and clopidogrel and evaluated the effect of these polymorphism on platelet reactivity at the early and late phases of treatment using a conventional light transmission aggregometry. Early and late phases were defined as 24 h after the loading dose and after 9 months on a maintenance dose of 75 mg daily, respectively. Results: The distribution of the CYP2C19 genotype was 30 % in extensive metabolizers (EM; CYP2C19*1/*1), 46 % in intermediate metabolizers (IM; *1/*2, *1/*3), and 25 % in poor metabolizers (PM; *2/*2, *2/*3, *3/*3). Platelet reactivity levels in during the early and late phases were 3,793 ± 1,476 and 2,960 ± 1,410, respectively, in EM, 4,706 ± 1,417 and 3,239 ± 1,479, respectively, in IM, and 5,402 ± 776 and 4,736 ± 1,356 aggregation units (AU)•min, respectively in EM. The distribution of the CYP3A5 genotype was 33 % in patients carrying the wild-type or one loss-of-function allele (Expressor phenotype; *1/*1 and *1/*3, respectively) and 67 % in those carrying two loss-of-function alleles (Non-expressor; *3/*3). In total, eight patients were EM+Expressor, 22 were EM+Non-expressor, 18 were IM+Expressor, 28 were IM+Non-expressor, eight were PM+Expressor, and 17 were PM+Non-expressor. In the late phase of PM with the CYP2C19 polymorphism, the levels of platelet reactivity according to CYP3A5 genotype were 3,963 ± 1,436 and 5,100 ± 1,190 AU•min in Expressor and Non-expressor, respectively ( P < 0.05), however, there was no difference in platelet reactivity between Expressor and Non-expressor in EM and IM. Conclusions: Our results suggest that antiplatelet response to clopidogrel in the late phase depends on the CYP3A5 polymorphism in PM with CYP2C19. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to assess the association between the cortical shape of the mandible, as detected on panoramic radiographs, and trabecular bone structure, as assessed by cone-beam computed tomography (CBCT), in Japanese adults. Methods: Panoramic radiographs and CBCT images of the mandibles of 50 subjects (18 men, 32 women), aged 45-86 years, were evaluated. An experienced oral and maxillofacial radiologist categorized the cortical shape of the mandible as detected on panoramic radiographs as normal, mildly to moderately eroded, and severely eroded cortices, respectively. All mandibles were scanned using CBCT. Four bone structure parameters of the basal portion of the mandible were calculated in three dimensions using an image-analysis system: total bone volume (mm); cortical bone volume fraction (%); trabecular bone volume fraction (%); fractal dimension. One-way analysis of covariance with Bonferroni correction was employed to evaluate differences in the four bone parameters among the three cortical shape groups. Pearson's correlation coefficient was calculated to examine correlations between age and cortical and trabecular bone volume fractions. Results: Progression of cortical bone erosion was significantly associated with increased trabecular bone volume fraction ( P < 0.001) and increased fractal dimension ( P = 0.01). Cortical bone volume fraction decreased significantly with age ( P = 0.04). However, trabecular bone volume fraction tended to increase with age ( P = 0.06). Conclusions: The change in the trabecular bone structure of the mandible may differ from that of the general skeleton in Japanese adults. [ABSTRACT FROM AUTHOR]

Purpose: The effect of an AA deficiency on catecholamine biosynthesis in adult mice in vivo is unknown. Therefore, we quantified catecholamine and the expression of catecholamine synthetic enzymes in the adrenal glands of senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice placed in an AA-deficient state. Methods: At 30 days of age, mice were divided into the following 4 groups: AA (−) SMP30/GNL KO, AA (+) SMP30/GNL KO, AA (−) wild type (WT), and AA (+) WT. The AA (+) groups were given water containing 1.5 g/L AA, whereas the AA (−) groups received water without AA until the experiment ended. In addition, all mice were fed an AA-depleted diet. Catecholamine levels were measured by a liquid chromatographic method. Tyrosine hydroxylase, dopa decarboxylase, dopamine β-hydroxylase, and phenylethanolamine N-methyltransferase mRNA expression levels were measured with the quantitative real-time polymerase chain reaction (qPCR). Tyrosine hydroxylase and dopamine β-hydroxylase protein levels were quantified by Western blot analysis. Results: In the adrenals of AA (−) SMP30/GNL KO mice, noradrenaline and adrenaline levels decreased significantly compared to other three groups of mice, although there were no significant differences in dopamine β-hydroxylase or phenylethanolamine N-methyltransferase mRNA content. Moreover, there was no significant difference in their dopamine β-hydroxylase protein levels. On the other hand, AA depletion did not affect dopamine levels in adrenal glands of mice. Conclusion: An AA deficiency decreases the noradrenaline and adrenaline levels in adrenal glands of mice in vivo. [ABSTRACT FROM AUTHOR]

Summary: We used quantitative computed tomography and finite element analysis to classify women with and without hip fracture. Highly accurate classifications were achieved indicating the potential for these methods to be used for subject-specific assessment of fracture risk. Introduction: Areal bone mineral density (aBMD) is the current clinical diagnostic standard for assessing fracture risk; however, many fractures occur in people not defined as osteoporotic by aBMD. Finite element (FE) analysis based on quantitative computed tomography (QCT) images takes into account both bone material and structural properties to provide subject-specific estimates of bone strength. Thus, our objective was to determine if FE estimates of bone strength could classify women with and without hip fracture. Methods: Twenty women with femoral neck fracture and 15 women with trochanteric fractures along with 35 age-matched controls were scanned with QCT at the hip. Since it is unknown how a specific subject will fall, FE analysis was used to estimate bone stiffness and bone failure load under loading configurations with femoral neck internal rotation angles ranging from −30° to 45° with 15° intervals. Support vector machine (SVM) models and a tenfold cross-validation scheme were used to classify the subjects with and without fracture. Results: High accuracy was achieved when using only FE analysis for classifying the women with and without fracture both when the fracture types were pooled (82.9 %) and when analyzed separately by femoral neck fracture (87.5 %) and trochanteric fracture (80.0 %). The accuracy was further increased when FE analysis was combined with volumetric BMD (pooled fractures accuracy, 91.4 %) Conclusions: While larger prospective studies are needed, these results demonstrate that FE analysis using multiple loading configurations together with SVM models can accurately classify individuals with previous hip fracture. [ABSTRACT FROM AUTHOR]

Summary: A 3-year follow-up study on 334 young Japanese females enrolled in a university at the age of 18 years revealed that discontinuation of leisure time impact-loading exercises performed in junior high and/or high school was associated with increased risk of reduction in calcaneus osteo-sono assessment index (OSI). Introduction: Bone strength rapidly increases during puberty and reaches its peak by the end of adolescence. The aim of this study was to determine the lifestyle factors that influence the maintenance of calcaneus OSI in young adult females around the time when peak bone mass is attained. Methods: Annual health checkups including OSI measurements, anthropometrics, lifestyle analysis, and blood examination were performed 4 times on 334 Japanese females enrolled in a university at the age of 18 years. According to the slope of OSI change during the 3-year follow-up, the subjects were grouped into two categories: OSI loss (the lowest tertile) and OSI gain/stable (the second and third tertiles). Results: At the baseline assessment, the OSI loss group had higher OSI and height and an earlier menarche age than the OSI gain/stable group. Performing leisure time impact-loading exercise in junior high and/or high school but discontinuing it at university was associated with increased risk of OSI loss, independent of OSI, height and weight at the age of 18 years, weight change during follow-up, age of menarche, energy-adjusted nutrient intake, and alcohol drinking; the odds ratios were 4.1-4.9 compared with those performing impact-loading exercise at university. In particular, duration, frequency, and subjective intensity of impact-loading exercise during high school were positively associated with OSI loss. Conclusion: Discontinuation of leisure time impact-loading exercises performed during late adolescence is associated with an increased risk of OSI loss in young adult females during the 3-year follow-up period. [ABSTRACT FROM AUTHOR]

To determine whether the Modified Checklist for Autism in Toddlers (M-CHAT) in conjunction with the routine 18-month health check-up identifies Japanese toddlers with autism spectrum disorder (ASD). Two-stage screening using the M-CHAT was conducted with 1,851 children attending the check-up. Final ASD diagnosis was confirmed at age ≥3 years. Screening identified 20/51 children with ASD: 12/20 true positives were developmentally delayed, whereas 16/22 false negatives were high-functioning. Sensitivity was 0.476, specificity 0.986, positive predictive value 0.455, and likelihood ratio 33.4 for children with ASD. With a few modifications, M-CHAT screening successfully detected toddlers with ASD with and without developmental delay and is a promising screening tool to complement existing community surveillance. [ABSTRACT FROM AUTHOR]

Although it has been suggested that obesity is 'contagious' within the social network, direct cause of this spread of obesity remains unclear. This study hypothesized that Body Image (BI), the perception of one's own body size, may play a role in this obesity spread, since a high prevalence of obesity could shift people's perception of 'what is normal'. Young Japanese females (n = 53) were interviewed within 1 month after moving to New York City, where the prevalence of obesity is substantially higher than that of their home country, Japan. Each participant was examined for her BI in terms of current body size (CBS) and ideal body size (IBS). They were interviewed again 2 months after the first examination. Between the two interviews, the participants' CBS was decreased (having thinner self-image), while the IBS increased (having fatter ideal-image), leading to less dissatisfaction (smaller CBS-IBS) with their body size. These results suggest that one's BI could change in a period as short as 2 months, possibly because of being surrounded by more obese people. The IBS change was positively associated with BMI change (increased by 0.4 ± 0.6 kg/m²), warranting further study on the role of BI in the spread of obesity. [ABSTRACT FROM AUTHOR]

Purpose: The pharmacokinetics of orally administered immediate-release, twice-daily (BID) and modified-release, once-daily (QD) formulations of tacrolimus have high interindividual variability. We investigated factors affecting interindividual variability of tacrolimus bioavailability in renal transplant patients. Methods: Ninety-seven Japanese renal transplant patients (47 patients on tacrolimus BID and 50 patients on tacrolimus QD) were enrolled in this study. The tacrolimus absolute bioavailability was calculated using the area under the concentration-time curve from 0 to 24 h (AUC) after continuous intravenous infusion and oral formulations of tacrolimus in the same recipient. Results: The median (quartile 1-quartile 3) tacrolimus relative bioavailability for recipients with the CYP3A5*1 or CYP3A5*3/*3 alleles was significantly lower for the tacrolimus QD group [9.1 % (6.3-10.7 %) and 15.4 % (11.5-18.7 %), respectively] than for the tacrolimus BID group [12.6 % (9.9-14.2 %) and 19.3 % (16.5-24.8 %), respectively] ( P = 0.004 and 0.028, respectively). Consequently, tacrolimus absolute bioavailability was lowest for recipients with the CYP3A5*1 allele taking tacrolimus QD. The CYP3A5 polymorphism had no impact on the dose-adjusted AUC of tacrolimus in patients on continuous intravenous infusion ( P = 0.906). Conclusion: The larger interindividual variability of tacrolimus bioavailability for oral formulations appears to be due to the effects of the CYP3A5 polymorphism and the tacrolimus oral formulation. These factors should therefore be taken into account when determining individualized tacrolimus dosing. [ABSTRACT FROM AUTHOR]

We applied an American medical necessity scale, Level of Care Utilization System for Psychiatric and Addiction Services (LOCUS), to psychiatric practice in Japan. This is an exploratory analysis of empirical data of 272 patients. We examined the relationships between levels of care of LOCUS and clinical variables, contribution of care levels on admission decision, and changes in care levels over time. Inpatients showed significantly higher levels of care than outpatients. Levels of care showed significant strong inverse correlations to Global Assessment Scale (GAS) scores, and significant moderate correlations to admission types, care environment, and diagnostic subgroups in almost all groups. Levels of care contributed as much to the admission decision as GAS scores. Levels of care significantly decreased from the time of admission to discharge. Our preliminary evidence indicates that LOCUS is valid and sensitive to change, and applicable for clinical use in Japan. [ABSTRACT FROM AUTHOR]

Purpose: Omeprazole has ( R)- and ( S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose ( R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals. Methods: Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. Results: Mean plasma concentrations of ( R)- and ( S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of ( R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of ( S)-5-hydroxyomeprazole. Similarly, ( R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the ( S)-omeprazole HI. Conclusion: Our findings demonstrate that ( R)-omeprazole HI correlated better with CYP2C19 genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment. [ABSTRACT FROM AUTHOR]

The objective was to examine the association between lifestyle and risk for diabetes. For an average of 9.9 years, this study prospectively followed a cohort of 7,211 (2,524 men and 4,687 women) community residents aged 30-69 years without diabetes at a health check-up conducted between April 1990 and March 1992 until diabetes was confirmed or until the end of 2006. The subjects were divided into 6 groups according to their total scores of Breslow's lifestyle index (1-2, 3, 4, 5, 6 and 7 points). The association between lifestyle and diabetes incidence was investigated using Cox proportional hazards regression models. The results showed that the multivariate-adjusted hazard ratios were 0.45 in subjects who scored 5 points, 0.39 in subjects who scored 6 points, and 0.31 in subjects who scored 7 points, compared with subjects who scored 1-2 points. These data indicate that the healthy behaviors prevent the incidence of diabetes. [ABSTRACT FROM AUTHOR]

Objective: This study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene ( NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis. Methods: In a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2*4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2*4: intermediate acetylators; 2.5 mg/kg, patients without NAT2*4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the8th week. Results: One hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen. Conclusion: Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis. [ABSTRACT FROM AUTHOR]

Purpose: Elevated circulating activities of alanine aminotransferase (ALT), a marker for liver injury, and the lifestyle of a higher rate of eating in healthy and preclinical subjects are associated with increased risk of obesity and diabetes. In this study, we examined the associations between self-reported rate of eating and circulating ALT activity in middle-aged apparently healthy Japanese men. Methods: We conducted a cross-sectional study of 3,929 apparently healthy men aged 40-59 years (mean ± SD age, 49.2 ± 5.8 years; BMI, 23.5 ± 2.8 kg/m) who participated in health checkups in Japan. We analyzed their clinical serum parameters and lifestyle factors, including self-reported rate of eating. Associations between self-reported rate of eating and liver injury markers [ALT, γ-glutamyl transpeptidase (GTP), and aspartate aminotransferase (AST)], other clinical parameters or lifestyle factors were determined using analysis of variance followed by Tukey's test. Multivariate logistic regression analyses (MLRA) were performed with ALT activity as the dependent variable and independent variables that included self-reported rate of eating. Results: MLRA showed that ALT activity showed trends for higher self-reported rate of eating after adjustment for age, energy intake, and smoking status. The association between ALT activity and self-reported rate of eating disappeared after adjustment for BMI. Conclusion: The results of this study show that ALT activity is positively associated with self-reported rate of eating in middle-aged apparently healthy Japanese men. [ABSTRACT FROM AUTHOR]

Purpose: In Japan, a national surveillance study of antimicrobial consumption has never been undertaken. This study aimed to describe antimicrobial consumption and resistance to Pseudomonas aeruginosa in 203 Japanese hospitals, to identify targets for quality improvement. Methods: We conducted an ecological study using retrospective data (2010). Antimicrobial consumption was collected in the World Health Organization (WHO) anatomical therapeutic chemical/defined daily dose (ATC/DDD) format. Rates of imipenem (IPM), meropenem (MEPM), ciprofloxacin (CPFX), or amikacin (AMK) resistance were expressed as the incidence of non-susceptible isolates. Additionally, hospitals were asked to provide data concerning hospital characteristics and infection control policies. Hospitals were classified according to functional categories of the Medical Services Act in Japan. Results: Data were collected from 203 Japanese hospitals (a total of 91,147 beds). The total antimicrobial consumption was 15.49 DDDs/100 bed-days (median), with consumptions for penicillins, carbapenems, quinolones, and glycopeptides being 4.27, 1.60, 0.41, and 0.49, respectively. The median incidences of IPM, MEPM, CPFX, and AMK resistance were 0.15, 0.10, 0.13, and 0.03 isolates per 1,000 patient-days, respectively. Antimicrobial notification and/or approval systems were present in 183 hospitals (90.1 %). In the multivariate analysis, the piperacillin/tazobactam, quinolones, and/or total consumptions and the advanced treatment hospitals showed a significant association with the incidence of P. aeruginosa resistant to IPM, MEPM, CPFX, and AMK [adjusted R (a R) values of 0.23, 0.30, 0.22, and 0.35, respectively). Conclusion: This is the first national surveillance study of antimicrobial consumption in Japan. A continuous surveillance program in Japan is necessary in order to evaluate the association among resistance, antimicrobial restriction, and consumption. [ABSTRACT FROM AUTHOR]