Search

Funding Acknowledgements Type of funding sources: None. Background Stroke is a major global health issue and Climate change is the biggest and most urgent challenges. The Asia and Pacific region have been more vulnerable to climate change and extreme heat exposure than other regions of the world. Despite the growing concern for heat waves, few studies have investigated heat exposure and the risk of Stroke in the elderly considering effect of Asian meteorological factors. Purpose We aimed to examine the association between heat exposure and the risk of Stroke in the elderly and to evaluate possible effect-measure modifications by the rainy season, which is a characteristic climatic occurrence in East Asia. Methods Our study was designed as a time-stratified case-crossover. The study included 3367 residents in the city, Japan, aged 65 years or older who were dispatched to emergency hospitals between 2012 and 2019 for the onset of Stroke during and a few months after the rainy seasons (Picture 1). We examined the association between temperature and Stroke onset during and a few months after the rainy seasons with conditional logistic analysis adjusted for relative humidity, barometric pressure, and particulate matter less than 2.5 µm in diameter (pm 2.5). Furthermore, we examined analyses on effect-measure modification where is the exposure of a 1°C increase in temperature and potential effect modifier as stratified during and after the rainy seasons. Results Heat exposure during one month after the rainy season was associated with Stroke risk; the adjusted odds ratio (OR) for a 1°C increase in temperature was 1.34 (95% confidence interval [CI]: 1.29-1.39). In stratified type of the stroke, Hemorrhagic stroke (OR: 1.37, 95% CI: 1.24-1.51), Ischemic stroke (OR: 1.37, 95% CI: 1.24-1.53), and Transient ischemic attack (OR: 1.43, 95%CI: 1.23-1.68) were significantly associated with heat exposure during one month after the rainy season respectively (Picture 2). In the results of analyses on effect modification, one month after the rainy season group was highest than other groups when reference was during the rainy seasons (OR: 1.34, 95% CI: 1.3-1.39, P Conclusions The present study suggests that heat exposure increases the risk of Stroke onset during the month after the end of the rainy season in the elderly. We propose that public health measures, such as maintenance designed high-insulated housing and improved air conditioning control, be implemented in the Asia and Pacific region to address heat exposure during one month after the rainy season, which can affect the incidence of stroke in the elderly.

Phishing emails have permeated our digital communication, taking advantage of vulnerabilities that the information technology system poses to users. Given the potential for further cybersecurity incidents, theft of personally identifiable information, and damage to organizations’ assets, cybersecurity professionals have implemented various mitigation practices to combat phishing emails. This paper categorizes current mitigation practices in relation to a sequential schema adopted from the situational crime prevention approach, so as to enable a more organized and strategic assessment of human and environmental vulnerabilities. Our model could be useful for cybersecurity professionals to further advance mitigation measures as an incident progresses and for criminologists and other academic researchers to reduce the severity of subsequent criminal incidents.

Funding Acknowledgements Type of funding sources: None. Background Climate change and global warming are some of the biggest issues in our society. Despite the growing concern for heat waves, while some previous studies have examined the effects of heat on CVD by focusing on maximum or mean daily temperature or long heat exposure periods, few studies have investigated the hourly effects of heat exposure and the risk of cardiovascular diseases (CVDs) in the elderly. Purpose We aimed to examine the association between heat exposure and the risk of CVD in the elderly and to evaluate possible effect-measure modifications by the rainy season in East Asia. Methods Our study was designed as a time-stratified case-crossover. The study included 6527 residents in Japan, aged 65 years or older who were dispatched to emergency hospitals between 2012 and 2019 for the onset of CVD during and a few months after the rainy seasons. We examined the association between temperature and CVD onset for each year and for hourly intervals (lag) before the emergency call during the most relevant months. Results Heat exposure during one month after the rainy season was associated with CVD risk; the odds ratio (OR) for a 1°C increase in temperature was 1.34 (95% confidence interval [CI]: 1.29–1.39). By hourly time interval (lag) before the emergency call during the month after the end of the rainy season, 0-6 hour before the case event (lag 0–6) were associated with CVD risk, particularly for lag 0–1 (OR: 1.33, 95% CI: 1.28–1.39). For longer periods, the highest risk was at lag 0-23 (OR: 1.40, 95% CI: 1.34-1.46) (Picture). Conclusions The present study suggests that heat exposure increases the risk of CVD onset during the month after the end of the rainy season in the elderly. Hourly exposure in less than one day to heat rise obtained from the temporal resolution may triggers CVD onset.

STUDY QUESTIONDo monosomy rescue (MR) and trisomy rescue (TR) in preimplantation human embryos affect other developmental processes, such as X-chromosome inactivation (XCI)?SUMMARY ANSWERAneuploid rescue precedes XCI and increases the incidence of XCI skewness by reducing the size of the embryonic progenitor cell pools.WHAT IS KNOWN ALREADYMore than half of preimplantation human embryos harbor aneuploid cells, some of which can be spontaneously corrected through MR or TR. XCI in females is an indispensable process, which is predicted to start at the early-blastocyst phase.STUDY DESIGN, SIZE, DURATIONWe examined the frequency of XCI skewness in young females who carried full uniparental disomy (UPD) resulting from MR or TR/gamete complementation (GC). The results were statistically analyzed using a theoretical model in which XCI involves various numbers of embryonic progenitor cells.PARTICIPANTS/MATERIALS, SETTING, METHODSWe studied 39 children and young adults ascertained by imprinting disorders. XCI ratios were determined by DNA methylation analysis of a polymorphic locus in the androgen receptor gene. We used Bayesian approach to assess the probability of the occurrence of extreme XCI skewness in the MR and TR/GC groups using a theoretical model of 1–12 cell pools.MAIN RESULTS AND THE ROLE OF CHANCEA total of 12 of 39 individuals (31%) showed skewed XCI. Extreme skewness was observed in 3 of 15 MR cases (20%) and 1 of 24 TR/GC cases (4.2%). Statistical analysis indicated that XCI in the MR group was likely to have occurred when the blastocyst contained three or four euploid embryonic progenitor cells. The estimated size of the embryonic progenitor cell pools was approximately one-third or one-fourth of the predicted size of normal embryos. The TR/GC group likely had a larger pool size at the onset of XCI, although the results remained inconclusive.LIMITATIONS, REASONS FOR CAUTIONThis is an observational study and needs to be validated by experimental analyses.WIDER IMPLICATIONS OF THE FINDINGSThis study provides evidence that the onset of XCI is determined by an intrinsic clock, irrespectively of the number of embryonic progenitor cells. Our findings can also be applied to individuals without UPD or imprinting disorders. This study provides a clue to understand chromosomal and cellular dynamics in the first few days of human development, their effects on XCI skewing and the possible implications for the expression of X-linked diseases in females.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by the Grants-in-aid for Scientific Research on Innovative Areas (17H06428) and for Scientific Research (B) (17H03616) from Japan Society for the Promotion of Science (JSPS), and grants from Japan Agency for Medical Research and Development (AMED) (18ek0109266h0002 and 18ek0109278h0002), National Center for Child Health and Development and Takeda Science Foundation. The authors declare no conflict of interest.TRIAL REGISTRATION NUMBERNot applicable.

Background Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. Methods We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. Results A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P

Objective Venous thromboembolism (VTE) is increasingly being treated with oral direct Xa inhibitors, including edoxaban. However, direct evidence supporting the use of edoxaban for thrombosis associated with gynecological cancer is limited. Thus, we compared edoxaban to warfarin with regard to their efficacy, safety and convenience in gynecological cancer patients with VTE. Method We reviewed the medical records of 317 gynecological cancer patients who received edoxaban or warfarin treatment for VTE between January 2011 and December 2018. Result The median follow-up period was 712 days (16–2868). Of the 317 patients, 180 and 137 were treated with edoxaban or warfarin, respectively. Details of cancer types were as follows: ovarian cancer 110 (62%), endometrial cancer 40 (22%), cervical cancer 22 (12%) and others 8 (4%) in edoxaban group and 81 (59%), 37 (27%), 16 (12%), 3 (2%) in warfarin group. There was no significant difference between two treatments groups in terms of BMI, VTE site, cancer type, histological subtype and stage. Recurrence of VTE occurred in 16 patients (8.9%) in edoxaban group and 18 (13.1%) in warfarin group (p=0.31). Adverse events that required discontinuation of anticoagulation occurred in 1 patient (0.6%) with edoxaban and 6 patients (4.4%) with warfarin (p=0.06), and no fatal events in either group. Initial heparin bridge was employed in 63 patients (37.7%) and 115 patients (92.0%) of edoxaban and warfarin group, respectively (p Conclusion Edoxaban is effective, safe and convenient for VTE patients with gynecological cancers.

Objective Adult type granulosa cell tumor (aGCT) of the ovary is characterized by late recurrence, and no effective treatment strategy is established. The diagnosis of aGCT is difficult because of its rarity. Recently, FOXL2 C402G mutation was detected in 92% of aGCTs, and the presence of TERT promoter mutation was reported to be associated with worse prognosis. We analyzed the mutational status of FOXL2 and TERT promoter of aGCT tumor samples to investigate the impact on accurate diagnosis and prognosis. Methods FOXL2 and TERT promoter mutational status of the 64 primary and 8 recurrent aGCT FFPE samples were assessed by allelic discrimination assay. H&E slides of the primary samples which had wild-type(wt) FOXL2 were reviewed by two gynecologic pathologists and the cases with ambiguous morphology were excluded as aGCt mimicking tumor. The characteristics and prognosis of molecularly/pathologically confirmed aGCTs (MP-aGCTs) were analyzed in each clinical parameters and mutational status. Results Median follow-up duration was 73 months. Three primary samples were diagnosed as aGCT mimicking tumor. Of the 61 MP-aGCTs, 46 (75%) harbored FOXL2 mutation and 10 (16%) cases had TERT promoter mutation. Clinical stage and older age were the prognostic factor for recurrence. TERT promoter mutation was highly identified in older patients and larger tumors. The presence of heterozygous FOXL2 C402G mutation showed the tendency of worse prognosis. Conclusions The importance of mutational analysis in the diagnosis, long term observation of the patients, and the functional analysis of FOXL2 C402G mutation was highlighted.

Interest has increased in comorbidities associated with psoriasis and their effects on health‐related quality of life (HRQoL). This study aimed to evaluate the prevalence of metabolic syndrome (MetS) and psoriatic arthritis (PsA) and to investigate HRQoL and the prevalence of hypertension, type 2 diabetes mellitus (T2DM), obesity and dyslipidemia. In a cross‐sectional design, patients diagnosed with plaque psoriasis answered an interview and standardized questionnaires (Dermatology Life Quality Index questionnaire [DLQI], 36‐Item Short Form Health Survey [SF‐36] and EuroQol Five‐Dimension Questionnaire Three‐Level version [EQ‐5D‐3L]). Physical examination and several tests to assess desired outcomes were performed by a dermatologist and a rheumatologist during three visits. The prevalence of MetS and PsA was 50.0% and 41.8%, respectively. Dyslipidemia was the most prevalent (74.5%) secondary comorbidity, followed by hypertension (61.8%), obesity (52.5%) and T2DM (30.9%). The mean (standard deviation) DLQI score was 6.5 (6.9), and mean physical and mental SF‐36 measures were 45.2 (10.4) and 45.5 (12.3), respectively, and for EQ‐5D‐3L, mean utility index and EQ‐VAS scores were 0.68 (0.27) and 72.7 (19.7), respectively. PsA and MetS are important comorbidities; a reduced HRQoL is noted among plaque psoriasis patients with these comorbidities, emphasizing the relevance of diagnosis and treatment beyond the care of skin lesions.

An austenitic model alloy (316L) and a low alloy steel (A533B) were exposed to constant or fluctuating temperature after electron irradiation to a cumulative damage level of 1 displacement per atom. 316L model alloy was exposed to LWR operating temperature during electron irradiation, and were exposed to a higher temperature at a high heating and cooling rates. The annealing experiment after irradiation to 316L resulted in the change in irradiation-induced microstructure; both the size and the number density of Frank loop and black dots were decreased, while the volume fraction of void was increased. In the case of A533B, the aging experiment after electron irradiation resulted in the shrinkage or the disappearance of black dots and the growth of dislocation loops. It is suggested that during annealing and/or aging at a high temperature the excess vacancies could be provided and flew into each defect feature, resulting in that interstitial type feature could be diminished, while vacancy type increased in volume fraction if exists. (C) 2017 Elsevier B.V. All rights reserved.

Background and Objective Induced pluripotent stem cells (iPSCs) are a candidate cell source in periodontal regenerative therapy. Enamel matrix derivative (EMD) has been shown to regenerate periodontal tissues, and atelocollagen sponge (ACS) is considered a suitable scaffold or carrier for growth factors. This study aimed to investigate the effect of combined use of EMD and an ACS scaffold on cell behaviors and differentiation of mouse iPSCs (miPSCs) in vitro. Material and Methods Following embryonic body formation from miPSCs, dissociated cells (miPS-EB-derived cells) were seeded onto ACS with or without EMD, and cultured in osteoblast differentiation medium. Scanning electron microscopy and histological analyses were used to assess cell morphology and infiltration within the ACS. Cell viability (metabolism) was determined using an MTS assay, and expression of mRNA of osteoblastic differentiation markers was assessed by quantitative RT -PCR. Alkaline phosphatase (ALP) staining intensity and activity were evaluated. Mineralization was assessed by von Kossa staining, and calcium content was quantitated using the methylxylenol blue method. Results By 24 hours after seeding, miPS-EB-derived cells in both the EMD and control groups had attached to and infiltrated the ACS scaffold. Scanning electron microscopy images revealed that by day 14, many cytoplasmic protrusions and extracellular deposits, suggestive of calcified matrix, were present in the EMD group. There was a time-dependent increase in cell viability up to day 3, but no difference between groups was observed at any time point. The levels expressed of ALP and osterix genes were significantly higher in the EMD group than in the control group. Expression of runt-related transcription factor 2 was increased in the EMD group compared with the control group on day 7. EMD upregulated the expression of bone sialoprotein and osteopontin on day 14, whereas expression of osteocalcin was lower at all time points. The staining intensity and activity of ALP were higher in the EMD group than in the control group. Mineralization levels and calcium contents were significantly higher in the EMD group throughout the observation period. Conclusion These data suggest that combining ACS with EMD increases levels of osteoblastic differentiation and mineralization in miPS-EB-derived cells, compared with ACS used alone.

Few studies examine the role of friends in victims’ decisions to seek help from health professionals. This study used a sample of college students (N = 637) to examine the factors that may influence whether students would advise a friend to seek help from health professionals. After providing an open-ended response to a vignette, students answered a series of questions about formal support providers, attitudes toward women and rape victims, and their background. Findings suggest a gender divide on the advice given, and more students who responded to an acquaintance-rape scenario recommended that a victim contact health professionals in comparison to those whose scenario depicted an intimate partner rape. Implications are discussed, focusing on the role of friends and campus policy in minimizing the impacts of victimization.

Gunung Leuser National Park (NP) is the biggest NP in North Sumatra. Though very few plant ecological studies were conducted there. Most studies in Gunung Leuser NP are related with protected animals, such as Sumatran Tiger, Elephant or Orang Utan. Thus, the aim of this preliminary study is to understand the plant structure and composition in the tropical forest of Gunung Leuser National Park. A 0.5-ha plot was established near Gua Kambing, Tangkahan area in November 2015. All tree species bigger than 15 cm girth were recorded, measured, and identified. The dominant species were from Dipterocarpaceae, followed by Myrtaceae and Achariaceae. The total number of trees was 693 trees or 1,386 trees/ha with the total Basal area was 42.9m2/ha and the biggest diameter was 147cm. The results from diversity index analysis ((H’=4.43; D=0.97; α=75) confirm that the forest area had a relatively high diversity, with Agrostistachis sessilifolia dominates the understory layer. The Gua Kambing area had relatively high plant diversity, less disturbance, and bigger trees than other studied areas in tropical Indonesian forests in Sumatra.

Aims Axonal aggregates of phosphorylated (p-) transactive response DNA-binding protein 43 kDa (TDP-43) in sporadic amyotrophic lateral sclerosis (sALS) were examined in relation to propagation of the protein in the nervous system. Methods Brains and spinal cords of Japanese patients with sALS and control subjects were examined immunohistochemically using formalin-fixed paraffin-embedded specimens with special reference to the topographical distribution, microscopic features, presynaptic aggregates, and correlation between the aggregates in axons and the clinical course. Results (i) Aggregates of p-TDP-43 were frequently present in axons of the hypoglossal and facial nerve fibres and the spinal anterior horn cells. (ii) Aggregates of p-TDP-43 in the axons showed two characteristic microscopic features – dash-like granuloreticular aggregates (GRAs) and massive aggregates (MAs). (iii) MAs were surrounded by p-neurofilaments, but p-neurofilament immunnoreactivity decreased at the inside of axons with GRAs. (iv) Patients showing MAs and GRAs had a relatively shorter clinical course than patients without the aggregates. (v) Some neurones in the red nucleus in patients were surrounded by synapses containing p- and p-independent (i)-TDP-43, and almost all neurones had lost their nuclear TDP-43 immunoreactivity; 17% of those neurones in the red nucleus also had TDP-43-immunopositive neuronal cytoplasmic inclusions, but no postsynaptic p-TDP-43 deposition was evident. Conclusions There are two types of axonal p-TDP-43 aggregates, MAs and GRAs, located predominantly in the facial and hypoglossal nuclei and anterior horn cells. These aggregates may influence the function of neurones, and presynaptic aggregates of the protein induce loss of p-i-TDP-43 in the nuclei of postsynaptic neurones.

In 1999, major changes to Japan’s criminal justice system were proposed, and over the next 10 years, many were implemented. One of the changes created the lay judge system ( saiban-in seido), wherein citizens serve as fact finders during trials of serious criminal cases. The purpose of the lay judge is to enhance public trust in the judiciary while improving the quality of justice through the common sense of the average person. This article reviews how this major change to Japan’s court system was implemented, describes the process by which lay judges are selected and the requirements of their service, and then discusses some of the reviews and evaluations that have been completed of the system itself. The conclusion suggests that an understanding of Japan’s model could be instructive for other jurisdictions considering justice reform.

Genetic abnormalities in mitochondrial complex assembling factors are associated with leukoencephalopathy. We present a 1-year-old girl with consciousness disturbance after a respiratory infection. Brain MRI revealed leukoencephalopathy with bilaterally symmetrical hyperintensity in the substantia nigra, medial thalamic nuclei, and basal nuclei, as well as cavities in the cerebral white matter and corpus callosum. Lactate levels in the spinal fluid were high, while magnetic resonance spectroscopy of the cerebral white matter and basal nuclei showed high peak lactate levels, suggesting mitochondrial dysfunction. The respiratory enzyme activity of complex I was reduced to 17% to 21% in skeletal muscle. Whole exome sequencing identified compound heterozygous variations in NDUFAF3, involved in the assembly of mitochondrial complex I (c.342_343insGTG:p.117Valdup, c.505C > A:p.Pro169Thr). Two-dimensional, blue-native polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate-PAGE revealed reductions in Q-module (NDUFS2, NDUFS3, and NDUFA9) and P-module (NDUFB10 and NDUFB11) subunits, indicating disruption of mitochondrial complex I assembly. Our report expands the spectrum of clinical phenotypes associated with pathogenic variants of NDUFAF3.

National Institute of Science and Technology-Stem Cells in Human Genetic Diseases Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) In a previous genome-wide expression profiling study, we identified E2F2 as a hyperexpressed gene in stem-like cells of distinct glioblastoma multiforme (GBM) specimens. Since the encoded E2F2 transcription factor has been implicated in both tumor suppression and tumor development, we conducted a functional study to investigate the pertinence of E2F2 to human gliomagenesis. E2F2 expression was knocked down by transfecting U87MG cells with plasmids carrying a specific silencing shRNA. Upon E2F2 silencing, in vitro cell proliferation was significantly reduced, as indicated by a time-course analysis of viable tumor cells. Anchorage-independent cell growth was also significantly inhibited after E2F2 silencing, based on cell colony formation in soft agar. Subcutaneous and orthotopic xenograft models of GBM in nude mice also indicated inhibition of tumor development in vivo, following E2F2 silencing. As expression of the E2F2 gene is associated with glioblastoma stem cells and is involved in the transformation of human astrocytes, the present findings suggest that E2F2 is involved in gliomagenesis and could be explored as a potential therapeutic target in malignant gliomas. Universidade Federal de São Paulo, Dept Neurol & Neurosurg, Expt Neurol Unit, BR-04023900 São Paulo, Brazil Univ São Paulo, Human Genome & Stem Cell Res Ctr, Inst Biosci, Dept Genet & Evolutionary Biol, BR-05508090 São Paulo, Brazil Universidade Federal de São Paulo, Dept Neurol & Neurosurg, Expt Neurol Unit, BR-04023900 São Paulo, Brazil Web of Science

Purpose Gemcitabine (GEM)-based chemotherapy has been used worldwide as the first-line treatment for advanced biliary tract cancer (BTC). However, no standard regimens have been established yet for patients with GEM-refractory BTC. A previous phase II trial of S-1 as a first-line treatment in patients with advanced BTC revealed promising activity of this drug. The present study was conducted to evaluate the efficacy and safety of S-1 in patients with GEM-refractory BTC. Methods The subjects were patients with pathologically proven BTC who had shown disease progression while receiving GEM-based chemotherapy. Each treatment cycle consisted of administration of S-1 orally at the dose of 40 mg/m2 twice daily for 28 days, followed by a rest period of 14 days. The primary endpoint of this study was objective response, and the secondary endpoints were the toxicity, progression-free survival (PFS), and overall survival (OS). Results Forty patients were assessed for efficacy and safety from 8 hospitals in Japan between June 2007 and September 2008. There were 3 cases of confirmed partial response (7.5 %) and 22 patients (55 %) of stable disease. The median PFS and OS were 2.5 and 6.8 months, respectively. Toxicity was generally mild, and the most common grade 3 or 4 toxicities were anorexia (10.0 %), anemia (7.5 %), mucositis (7.5 %), hypoalbuminemia (5.0 %), and pneumonia (5.0 %). There were no treatment-related deaths. Conclusions Monotherapy with S-1 was well tolerated, but showed modest efficacy in patients with GEM-refractory BTC.

Introduction Estimating the national prevalence of child sexual abuse (CSA) and its association with health and developmental outcomes is the first step in developing prevention strategies. While such data are available from many countries, less is known about the epidemiology of CSA in Japan. Methods For this systematic review, we searched English databases: Embase, Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R), Ovid OLDMEDLINE(R), PsycINFO, and Japanese databases: Cinii, J-Stage, Children’s Rainbow Center Japan, Japan Child and Family Research Institute, Japanese Journal of Child Abuse and Neglect to identify articles published before July 2015 examining the lifetime prevalence of CSA in Japan using non-clinical samples. Data were extracted from published reports. Results We initially identified 606 citations and after abstract review, retrieved 120 publications. Six studies that met the selection criteria and additional two relevant studies were reviewed. The range of contact CSA for females was 10.4%–60.7%, and the prevalence of this type of CSA for males was 4.1%. The range of penetrative CSA for females was 1.3%–8.3% and that for males was 0.5%–1.3%. A number of methodological issues were identified, including a lack of validated measures of CSA, and low response rates. Conclusion In contrast to a lower prevalence of penetrative CSA, the prevalence of contact CSA among Japanese females may be comparable or higher in relation to international estimates. Future research on children's perceptions of and exposure to sexual abuse, crime and exploitation in Japan is discussed.

Glucocorticoid receptor (GR) gene mutations may cause familial or sporadic generalized glucocorticoid resistance syndrome. Most of the missense forms distribute in the ligand-binding domain and impair its ligand-binding activity and formation of the activation function (AF)-2 that binds LXXLL motif-containing coactivators. We performed molecular dynamics simulations to ligand-binding domain of pathologic GR mutants to reveal their structural defects. Several calculated parameters including interaction energy for dexamethasone or the LXXLL peptide indicate that destruction of ligand-binding pocket (LBP) is a primary character. Their LBP defects are driven primarily by loss/reduction of the electrostatic interaction formed by R611 and T739 of the receptor to dexamethasone and a subsequent conformational mismatch, which deacylcortivazol resolves with its large phenylpyrazole moiety and efficiently stimulates transcriptional activity of the mutant receptors with LBP defect. Reduced affinity of the LXXLL peptide to AF-2 is caused mainly by disruption of the electrostatic bonds to the noncore leucine residues of this peptide that determine the peptide's specificity to GR, as well as by reduced noncovalent interaction against core leucines and subsequent exposure of the AF-2 surface to solvent. The results reveal molecular defects of pathologic mutant receptors and provide important insights to the actions of wild-type GR.

The objective of this experiment was to evaluate the selection of a pig line with improved resistance to swine mycoplasmal pneumonia and meat production in Landrace pigs. The selection was conducted over 5 generations using estimated breeding values of daily gain (DG), backfat thickness (BF), and mycoplasmal pneumonia scores (MPS). In order to evaluate various lung lesions, we established two different rearing environments (regularly cleaned vs. not cleaned) for the pigs. The heritability estimates for DG, BF, and MPS were found to be 0.65, 0.60, and 0.07, respectively. To compensate for the low heritability of MPS we examined the genetic correlation of immunity traits with MPS to determine their usefulness in a selection index. Cortisol (COR) plasma levels at 105 kg body weight had a high positive genetic correlation (0.65) with MPS, and therefore used as an immunity trait. The average breeding values in the fifth generation, as expressed in standard deviation units, were 1.32 for DG, −0.70 for MPS, and −0.04 for BF and COR. The selection traits showed good genetic progress in 5 generations demonstrating the possibility of selecting for both disease resistance and high meat production in animals.

SummaryBackground Oral tolerance is a classically used strategy for antigen-specific systemic immunotherapy. However, the roles of IL-17 in modification of oral tolerance are not yet understood. Objective To define the effects of IL-17 on the modification of oral tolerance, the effects of transfer of Th17 cells, administration of IL-17 or anti-IL-17 antibody (αIL-17Ab) to a murine allergic airway inflammation model were investigated. Methods Mice sensitized to and challenged with OVA, received OVA feeding, followed by OVA challenges. Transfer of Th17 cells, administration of IL-17 or αIL-17Ab were executed during OVA feeding. Airway hyperresponsiveness (AHR), airway inflammation, Th2 cytokine response and lung pathology were assessed. Results Administration of IL-17 as well as transfer of Th17 cells aggravated AHR and airway allergic inflammation as compared with the findings in mice subjected to OVA feeding alone, whereas administration of αIL-17Ab ameliorated AHR and airway eosinophilia. The effects of Th17 transfer were presumably attributable to augmentation of endogenous IL-6 production in gut. The number of Foxp3-positive regulatory T (Treg) cells in lungs and Payer's patches was increased in the OVA fed mice, whereas the number of these cells was decreased in the mice subjected to OVA feeding + Th17 cell transfer. Neutralization of IL-6 by monoclonal antibody in the mice subjected to OVA feeding + transfer of Th17 cells restored the effects of oral tolerance. Conclusions and Clinical Relevance These data suggest that IL-17 may inhibit the induction of tolerance to antigen through, at least in part augmenting IL-6 production, thereby suppressing the expansion of Treg cells.

Suzuki E., Aoyama K., Fukui T., Nakamura Y., Yamane A. The function of platelet-derived growth factor in the differentiation of mouse tongue striated muscle. Orthod Craniofac Res 2012;15:39–51. © John Wiley & Sons A/S Structured Abstract Objective – to determine the function of platelet-derived growth factor (PDGF) in the final differentiation phase of tongue striated muscle cells. Materials and Methods – We analyzed the expressions of PDGF-A, -B, platelet-derived growth factor receptor (PDGFR)-α, and PDGFR-β in mouse tongues between embryonic days (E) 11 and 15. Furthermore, we examined the effects of human recombinant PDGF-AB and the peptide antagonist for PDGFRs using an organ culture system of mouse embryonic tongue. Mouse tongues at E12 were cultured in BGJb medium containing human recombinant PDGF-AB for 4 days or the peptide antagonist for PDGF receptors for 8 days. Results – PDGF-A, -B, PDGFR-α, and -β were expressed in the differentiating muscle cells between E11 and 15. The human recombinant PDGF-AB induced increases in the mRNA expressions of myogenin and muscle creatine kinase (MCK) and the number of fast myosin heavy chain (fMHC)-positive cells, markers for the differentiation of muscle cells. On the other hand, the peptide antagonist for PDGFRs induced suppressions in the mRNA expressions of myogenin and MCK, and the number of fMHC-positive cells. Both the PDGF-AB and the antagonist failed to affect the expressions of cell proliferation markers. Conclusion – These results suggest that PDGF functions as a positive regulator in the final differentiation phase of tongue muscle cells in mouse embryos.

There is no standard regimen for gemcitabine (Gem)-refractory pancreatic cancer (PC) patients. In a previous phase II trial, S-1 was found to exhibit marginal efficacy. Gem administration by fixed dose rate infusion of 10 mg/m(2)/min (FDR-Gem) should maximize the rate of intracellular accumulation of gemcitabine triphosphate and might improve clinical efficacy. We conducted the phase I/II of FDR-Gem and S-1 (FGS) in patients with Gem-refractory PC.The patients received FDR-Gem on day 1 and S-1 orally twice daily on days 1-7. Cycles were repeated every 14 days. Patients were scheduled to receive Gem (mg/m(2)/week) and S-1 (mg/m(2)/day) at four dose levels in the phase I: 800/80 (level 1), 1,000/80 (level 2), 1,200/80 (level 3) and 1,200/100 (level 4). Forty patients were enrolled in the phase II study at recommended dose.The recommended dose was the level 3. In the phase II, a partial response has been confirmed in seven patients (18%). The median overall survival time and median progression-free survival time are 7.0 and 2.8 months, respectively. The common adverse reactions were anorexia, leukocytopenia and neutropenia.This combination regimen of FGS is active and well tolerated in patients with Gem-refractory PC.

Attempting to lose weight by normal or underweight adolescent girls is a serious issue in many countries. It has been reported that the mode of attempted weight loss does not differ between normal weight and overweight girls. These inappropriate weight loss attempts (IWLA) by normal or underweight adolescent girls is associated with various health issues, but factors associated with IWLA have only been marginally elucidated. In this study, we applied a single multivariate regression analysis to clarify independent factors for IWLA. Study subjects were 134 pairs of early adolescent girls (aged 12-15) and their mothers. In addition to IWLA, many factors including height, weight, body image, perceived weight status, depressive symptoms, media influence and self-esteem were surveyed in both mothers and daughters and subjected to multivariate analysis. Approximately half of girls surveyed had IWLA, even though all were of normal weight and 62.9% knew that they were of normal weight. IWLA were independently associated with depressive symptoms (OR (95% CI); 2.80 (1.21-6.50), p=0.016) independent of actual or perceived weight status. Factors significantly associated with IWLA by the girls were percentage deviation of weight from standard weight (%DW) and media influence on the girls themselves, and media influence on and self-esteem of their mothers. IWLA, which were frequently observed among early adolescent girls even among those of normal weight, were closely related to depressive status. IWLA were significantly associated with not only factors related to the girls (1.09 (1.04-1.14), p=0.001), but also with maternal psychological factors (1.06 (1.00-1.13), p=0.035) conveyed by the media. Future prospective or interventional studies are required to clarify whether these factors could be targeted in an effort to prevent IWLA.

This paper presents a noise suppression sheet containing magnetic flakes and carbon fibers. Permeability of the magnetic flakes and conductivity of the carbon fibers provide noise suppression effectively in the GHz range. Furthermore, the carbon fibers improve thermal conductivity of the sheet compared with conventional sheets containing only magnetic flakes. The sheet is expected to provide measures for both of electromagnetic noise and thermal problem.

Objective The aim was to determine the recommended dose of combined chemotherapy with mitoxantrone and uracil/tegafur (Phase I part) and to clarify its efficacy and safety in patients with advanced hepatocellular carcinoma at the recommended dose (Phase II part). Methods Patients eligible had histologically confirmed, chemo-naive advanced hepatocellular carcinoma and were amenable to established forms of treatment. The therapy consisted of mitoxantrone administered intravenously at one of three dosages (6, 8 and 10 mg/m(2)/day) on day 1 and uracil/tegafur administered orally at 300 mg/m(2) from day 1 through day 21. The treatment was repeated every 4 weeks until evidence of tumor progression or unacceptable toxicity. Results A total of 25 patients were enrolled. In the Phase I part, dose-limiting toxicities occurred in all three patients, given mitoxantrone at the dosage of 10 mg/m(2)/day, and the recommended mitoxantrone dosage was determined to be 8 mg/m(2)/day. Among 19 patients administered the drug at the recommended dosage, 1 patient (5.3%) showed partial response, 8 patients (42.1%) showed stable disease and 10 patients (52.6%) showed progressive disease. The median survival and median progression-free survival were 8.4 and 2.5 months, respectively. The most common toxicities were Grade 3-4 leukopenia (63.2%) and neutropenia (68.4%). Conclusions Mitoxantrone at 8 mg/m(2) combined with uracil/tegafur at 300 mg/m(2)/day was determined to be the recommended regimen. Although this regimen was generally well tolerated, it appeared to have little activity against advanced hepatocellular carcinoma. These findings do not support the use of this combination regimen in practice.

The purpose of this study was to clarify a difference of mean power frequency (MPF) during speech between control and myalgia patients groups. The control group consisted of 20 asymptomatic volunteers and the myalgia patients group consisted of 19 patients. A bilateral electromyogram (EMG) of masseter muscles during speech movement was recorded using surface electrodes, and the EMG data were stored and analysed with a computer-based EMG analyzer. The MPF during the entire duration of EMG burst during speech was compared between the control and myalgia group. The average (SD) MPFs during speech in the myalgia and control groups were 214.06 (17.23) and 183.39 (22.35) Hz, respectively, significantly higher in the former (P < 0.001). In myalgia patients, firing rates or recruitment of motor units innervated by high threshold motoneurons might decrease and lead to a higher MPF. The result suggests the possibility that muscle pain, that is a subjective experience, could be evaluated by objective data that is calculated from electromyographic activities which is recorded during speech.

We visualized electromagnetic-energy flows by using newly developed electro-optic probes, which cause little interference with the surrounding electromagnetic fields. Amplitudes and phases of all electric- and magnetic-field components were measured near a coupled line and a patch antenna by the probes. The time-varying Poynting vectors near the objects were evaluated with the data and were visualized. The energy flows that are caused by crosstalk of the coupled line and that are radiated from the antenna are presented. This is the first visualization of Poynting vectors that are evaluated with only experimental data in near-field regions.

Flexibly controllable threshold voltage (V"t"h) asymmetric gate oxide thickness (T"o"x) independent double-gate (DG) FinFETs (4T-FinFETs) have been demonstrated. Thin drive-gate oxide (HfO"2 or SiON or SiO"2) and slightly thick V"t"h-control-gate oxide (thick SiO"2+drive-gate oxide) have been successfully incorporated into the 4T-FinFETs by utilizing the ion-bombardment-enhanced etching of SiO"2. It was experimentally confirmed that, all the asymmetric T"o"x 4T-FinFETs give the significantly improved subthreshold slope and thus gain higher on-current as compared to the symmetric one. Simulation results showed that the asymmetric T"o"x 4T-FinFETs are advantageous even in 20-nm-gate-length region.

We describe a new permeameter to evaluate all components of a permeability tensor. The permeameter consists of a shorted microstrip line and a revolving coil, which can operate well up to 300 MHz. All muij r (i, j = x, y, and z) of a relative permeability tensor of a magnetic thin film were evaluated by the permeameter. The measurements show that the sample has large off-diagonal components compared with diagonal ones, indicating that the examination of such off-diagonal components by the permeameter can be used to design new devices with high accuracy.

Study question What percentage of cases with non-syndromic hypospadias can be ascribed to mutations in known causative/candidate/susceptibility genes or submicroscopic copy-number variations (CNVs) in the genome? Summary answer Monogenic and digenic mutations in known causative genes and cryptic CNVs account for >10% of cases with non-syndromic hypospadias. While known susceptibility polymorphisms appear to play a minor role in the development of this condition, further studies are required to validate this observation. What is known already Fifteen causative, three candidate, and 14 susceptible genes, and a few submicroscopic CNVs have been implicated in non-syndromic hypospadias. Study design, size, duration Systematic mutation screening and genome-wide copy-number analysis of 62 patients. Participants/materials, setting, methods The study group consisted of 57 Japanese and five Vietnamese patients with non-syndromic hypospadias. Systematic mutation screening was performed for 25 known causative/candidate/susceptibility genes using a next-generation sequencer. Functional consequences of nucleotide alterations were assessed by in silico assays. The frequencies of polymorphisms in the patient group were compared with those in the male general population. CNVs were analyzed by array-based comparative genomic hybridization and characterized by fluorescence in situ hybridization. Main results and the role of chance Seven of 62 patients with anterior or posterior hypospadias carried putative pathogenic mutations, such as hemizygous mutations in AR, a heterozygous mutation in BNC2, and homozygous mutations in SRD5A2 and HSD3B2. Two of the seven patients had mutations in multiple genes. We did not find any rare polymorphisms that were abundant specifically in the patient group. One patient carried mosaic dicentric Y chromosome. Limitations, reasons for caution The patient group consisted solely of Japanese and Vietnamese individuals and clinical and hormonal information of the patients remained rather fragmentary. In addition, mutation analysis focused on protein-altering substitutions. Wider implications of the findings Our data provide evidence that pathogenic mutations can underlie both mild and severe hypospadias and that HSD3B2 mutations cause non-syndromic hypospadias as a sole clinical manifestation. Most importantly, this is the first report documenting possible oligogenicity of non-syndromic hypospadias. Study funding/competing interests This study was funded by the Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology; by the Grant-in-Aid from the Japan Society for the Promotion of Science; by the Grants from the Ministry of Health, Labour and Welfare, from the National Center for Child Health and Development and from the Takeda Foundation. The authors have no competing interests to disclose. Trial registration number Not applicable.

This paper presents a new type of optical magnetic field probe designed to detect magnetic near-fields with high accuracy up to 15 GHz. The probe head consists of a loop antenna element and CdTe electrooptic crystals. The probe using CdTe has a resonant frequency higher than that of a previous probe using LiNbO/sub 3/ because CdTe has a dielectric constant lower than that of LiNbO/sub 3/. Through an optical technique, a probe doubly loaded with CdTe can work as a conventional double-loaded loop probe without metallic cables or an electrical hybrid junction. We examined probe characteristics up to 20 GHz. We confirmed that the probe could measure magnetic fields near a microstrip line with high accuracy in the gigahertz range.

This paper presents a new type of optical probe for simultaneous measurements of electric and magnetic near fields with high accuracy up to the gigahertz range. Its probe head consists of a loop antenna element that is doubly loaded with LiNbO3 electrooptic crystals. Using optical technology, it can work as a conventional double-loaded loop probe without metallic cables and electrical hybrid junction. We examined probe characteristics for electromagnetic field detection up to 20 GHz. We confirmed that the probe can measure electric and magnetic fields simultaneously with a high accuracy in the gigahertz range

The crystal structure of ordered and disordered Fe–Pt Invar alloys has been investigated under high pressures up to 13 GPa in the temperature range of 12–300 K by in situ angle dispersive X-ray diffraction using synchrotron radiation. An FCC structure was confirmed to be stable in whole pressure range, and pressure-induced lattice softening was observed. The relationship between the pressure-induced magnetic phase transition and the lattice softening was discussed in connection with a recent band calculation.

We propose a new type of optical probe designed to detect magnetic near-fields with high accuracy up to the gigahertz range. Its probe head consists of a loop antenna element doubly loaded with electrooptic crystals. Using optical technology, it realizes hybrid operation of a conventional double-loaded loop probe and requires no metallic cables or electrical hybrid junction. We examined probe characteristics for magnetic field detection up to 10 GHz. We confirmed that the probe can measure magnetic fields near a microstrip line with high accuracy in the gigahertz range and can suppress influence of electric fields.

A 25.6 kb region at chromosome 5q31, covering the entire human interleukin 13 (IL-13) and interleukin 4 (IL-4) genes, has been reported to be associated with bronchial asthma. We have examined nucleotide variations at this locus in African, European American, and Japanese populations, using 120 diallelic variants. A block of strong linkage disequilibrium (LD) (mid R:D'mid R:>0.7) spans a 10 kb region containing IL-4 in European American and Japanese populations, and is present but less clear in African samples. Two major haplotypes at IL-4 account for >80% of haplotypes in European Americans and Japanese. These haplotypes are common and quite diverged from each other and the ancestral haplotype, resulting in highly significant deviations from neutrality. F(ST) statistics show that European American and Japanese populations are unusually distinct at the IL-4 locus. The most common haplotype in the European American population is much less common in the Japanese population, and vice versa. This implies that natural selection has acted on IL-4 haplotypes differently in different populations. This selected variation at IL-4 may account for some genetic variance underlying susceptibility to asthma and other allergic diseases. The strong LD observed in the IL-4 region may allow more efficient disease-association studies using this locus.

Aims: To characterise a novel strain of adenovirus (Ad) type Ad8 (genome type Ad8I) involved in an epidemic keratoconjunctivitis (EKC) outbreak in Hiroshima city using serological testing and sequence analysis of the fibre and hexon gene. Methods: A neutralisation test (NT) was performed in microtitre plates containing a confluent monolayer of A549 cells using 100 tissue culture infectious doses of virus and type specific antisera. The haemagglutination inhibition test was also carried out in microtitre plates with rat erythrocytes using four haemagglutination units of virus and twofold dilutions of serum. The fibre gene was sequenced by generating overlapping polymerase chain reaction products or by direct sequencing of genomic DNA. Primer selection was based on alignment of the fibre genes of human adenovirus serotypes Ad8, Ad19, Ad37, Ad9, and Ad15 available from Gene Bank. Results: The virus strain was specifically neutralised by anti-Ad8 antibodies, although there was a major crossreaction with anti-Ad9 antibodies. Haemagglutination was equally inhibited by anti-Ad8 and anti-Ad9 antibodies. The predicted amino acid sequences of the hypervariable regions (HVRs) of the Ad8I hexon gene showed higher homology with Ad9 (83.3%) than with Ad8 (62.0%). However, the Ad8I fibre knob was more homologous to Ad8 (94.4%) than to Ad9 (91.6%). Conclusions: Ad8I is a unique strain of adenovirus because of its lower genomic homology with Ad8, major crossreactivity with Ad9 in NT, and mixed genetic organisation of HVRs of the hexon gene. These factors may have enabled the virus to circumvent acquired immunity, resulting in the outbreak.

We electrically measured AC losses in a Bi2223/Ag-sheathed pancake coil excited by a DC current in AC external magnetic field. Losses in the coil contain two kinds of loss components that are the magnetization losses and dynamic resistance losses. In the measurement, current leads to supply a current to the coil were specially arranged to suppress electromagnetic coupling between the coil current and the AC external magnetic field. A double pick-up coils method was used to suppress a large inductive voltage component contained in voltage signal for measuring the magnetization losses. It was observed that the magnetization losses were dependent on the coil current and that a peak of a curve of the loss factor vs. amplitude of the AC external magnetic field shifted to lower amplitude of the AC magnetic field as the coil current increased. This result suggests the full penetration magnetic field of the coil tape decreases as the coil current increases. The dynamic resistance losses were measured by measuring a DC voltage appearing between the coil terminals. It was observed that the DC voltage appearing in the coil subject to the AC external magnetic field was much larger than that in the coil subject to DC magnetic field.