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Aims The aim of this study was to clarify the genetic background of a family with multiple cases of diabetes accompanied by absolute insulin deficiency using whole-exome sequencing (WES). Methods In a Japanese family, WES was performed in four affected members with absolute insulin deficiency and two unaffected members. We focused on variants that were predicted to be disease-causing by bioinformatics and were shared by all of the four affected members but were not present in the two unaffected members. We assumed that the familial clustering of diabetes was caused by rare variants excluding those with allele frequency of more than 0.01 in the 1000 Genomes Project, the Human Genetic Variation Database, or a cohort of 105 normoglycemic controls in Japan. The rare variants were then genotyped in 2102 Japanese without diabetes and 119 Japanese with diabetes. Results Among the variants detected by WES and predicted to be disease-causing, 16 variants shared by all of the four of the affected members and not present in the two unaffected members were confirmed to be rare. Genotyping of the 16 rare variants revealed that only A137T in ADAMTSL3 (rs181914721) was observed more frequently in the 119 subjects with diabetes than in the 105 normoglycemic controls, and the allele frequency of the variant was significantly higher in the 119 subjects with diabetes than in another cohort of 2102 Japanese without diabetes. Conclusions We propose that A137T in ADAMTSL3 is a candidate mutation for susceptibility to diabetes in this family and in the Japanese population.

Almost 20 years after the first case reported in 1955, moyamoya disease (MMD) was still thought to be specific to Asian populations. During the past 60 years, however, MMD has become globally recognized and tremendous therapeutic advances have been made. In 2011, RNF213 (mysterin) was identified as the major susceptibility gene for MMD. RNF213 is a large protein (591 kDa) and contains both AAA+ ATPase and E3 ligase domains. The p.R4810K variant, a founder mutation common to East Asians, is found at a rate of 70–90% in Japanese and Korean MMD patients and even shows a 1–3% allelic frequency in the general Japanese and Korean populations. As only a minor proportion (approx. 1 out of 200) of carriers develop MMD, environmental factors are thought to be major contributors to the progress of MMD. Recent in vitro molecular studies have revealed that p.R4810K induces endothelial dysfunction, which may ultimately lead to arterial stenosis and development of moyamoya vessels. Furthermore, RNF213 is found to be involved in interferon (IFN), noncanonical wnt, and PTP1B/α-ketoglutarate-dependent dioxygenase signal cascades. Such pathways are known to be activated in response to environmental stress signals, such as infection, inflammation, or hypoxia, which may therefore be involved in promoting the development of MMD.

In order to investigate shear failure surface of decayed wood, wood pieces of ezomatsu (Picea jezoensis) were exposed to brown-rot fungus (Fomitopsis palustris), and standard shear test in radial plane was conducted. The failure surfaces were examined by scanning electron microscopy and surface roughness measurements were also conducted. Transwall failure that the crack elongated parallel to the tracheid axis was observed in the earlywood region through all phases of decay. Intrawall failure principally occurred in the latewood region on the early phase of decay. When decay progressed considerably, transwall failure that the crack elongated perpendicularly to the tracheid axis occurred. And transwall failure was also dominant failure morphology in the latewood region. Fragments of tracheids which were partly peeled out from S-2 layers were observed in some specimens. Size and appearance frequency of fragments of tracheid were smaller and lower when decay progressed. Arithmetic average roughness, which was the index of fragment size and appearance frequency, had positive correlation to shear strength ratio. Especially, line surface roughness of radial direction, which was measured across the radial files of tracheid, had the highest correlation to the shear strength ratio. The surface roughness would be a good indicator to evaluate the decay degree.

This study investigated human exposure to neutral, phenolic, and methoxylated organohalogen contaminants (OHCs) in a duplicate diet study to evaluate their concentrations in breast milk and serum of Okinawan people from Japan during 2004–2009. Dietary intakes of phenolic OHCs were predominantly 2,4,6-tribromophenol (TriBP), followed by tetrabromobisphenol A (TBBPA), and 6-hydroxy-2,2′,4,4′-tetrabromodiphenyl ether (6-OH-BDE47). After exposure, TriBP and TBBPA were transferred to breast milk, whereas 6-OH-BDE47 was selectively retained in serum. Despite a lower dietary exposure to pentachlorophenol and 4-hydroxy-CB187, both were retained in serum. For the methoxylated OHCs, 2,4,6-tribromoanisole (TriBA) and 6-methoxy-BDE47 were the predominant dietary contaminants, of which TriBA was present in both breast milk and serum, whereas 6-methoxy-BDE47 was selectively transferred to breast milk. These findings suggest that dietary exposure to phenolic and methoxylated OHCs may result in differential partitioning between breast milk and serum with different pharmacokinetic or exposure routes. Keywords: Dietary exposure, Breast milk, Serum, 6-Hydroxy-BDE47, 6-Methoxy-BDE47

We investigated the incidence of human T-cell leukemia virus type I (HTLV-1) infection in a total of 17 regions in four countries, including 13 regions in Japan, as well as Korea (Seoul and Busan), China, and Vietnam, by testing breast milk using a particle agglutination assay (PA) and line immunoassay (LIA). Among 266 samples from Japan, 24 (9.0%) were positive on PA and 3 (1.1%) were positive on LIA. Among 50 samples from Seoul, 2 were positive on PA and 1 was positive on LIA. In contrast, all 50 samples from Busan were negative on both tests, suggesting the maldistribution of HTLV-1 infectants in South Korea. The numbers of positive samples were 2/91 on PA and 1/91 on LIA for China and 1/88 on both PA and LIA for Vietnam. In China, one sample with a high probability of HTLV-2 infection was identified by LIA and synthetic peptide enzyme-linked immunosorbent assay (ELISA). We examined HTLV-1 antibody in breast milk samples using commercially available test kits, suggesting the existence of HTLV-1 carriers in endemic areas in Southeast Asia and an HTLV-2 infectant in China. As a part of human ethno-epidemiological research, these results constitute valuable epidemiological data. Further studies on the sensitivity, specificity, and reliability of assays using antibodies to HTLV-1 and 2 in breast milk will be necessary for large-scale epidemiological surveys of HTLV infection.

Moyamoya disease (MMD) is a cerebrovascular disease characterized by occlusive lesions in the Circle of Willis. The RNF213 R4810K polymorphism increases susceptibility to MMD. In the present study, we characterized phenotypes caused by overexpression of RNF213 wild type and R4810K variant in the cell cycle to investigate the mechanism of proliferation inhibition. Overexpression of RNF213 R4810K in HeLa cells inhibited cell proliferation and extended the time of mitosis 4-fold. Ablation of spindle checkpoint by depletion of mitotic arrest deficiency 2 (MAD2) did not shorten the time of mitosis. Mitotic morphology in HeLa cells revealed that MAD2 colocalized with RNF213 R4810K. Immunoprecipitation revealed an RNF213/MAD2 complex: R4810K formed a complex with MAD2 more readily than RNF213 wild-type. Desynchronized localization of MAD2 was observed more frequently during mitosis in fibroblasts from patients (n=3, 61.0 ± 8.2%) compared with wild-type subjects (n=6, 13.1 ± 7.7%; p

Perfluorinated carboxylic acids (PFCAs), including perfluorooctanoic acid (PFOA), are persistent organic pollutants that pose human health risks. However, sources of contamination and exposure pathways of PFCAs have not been explored. In this study, PFCA concentrations were quantified in personal care products. Among 24 samples that listed fluorinated compounds, such as polyfluoroalkyl phosphate esters (PAPs), in their international nomenclature of cosmetic ingredients (INCI) labels, 21contained PFCAs (13 of 15 cosmetic samples, and 8 of 9 sunscreen samples). The concentrations of total PFCAs ranged from not detected to 5.9 μg g(-1) for cosmetics and from not detected to 19 μg g(-1) for sunscreens. We also investigated components of PFCAs in cosmetics and sunscreens. Commercially available compounding agents, mica and talc, which were treated with PAPs were analyzed and high concentrations of PFCAs were detected (total PFCAs 2.5 μg g(-1) for talc treated with PAPs, 35.0 μg g(-1) for mica treated with PAPs). To the best of our knowledge, this is the first report on contamination of end consumer products containing PAPs with high concentrations of PFCAs.

Insulin release from pancreatic β-cells plays a critical role in blood glucose homeostasis, and β-cell dysfunction leads to the development of diabetes mellitus. In cases of monogenic type 1 diabetes mellitus (T1DM) that involve mutations in the insulin gene, we hypothesized that misfolding of insulin could result in endoplasmic reticulum (ER) stress, oxidant production, and mitochondrial damage. To address this, we used the Akita+/Ins2T1DM model in which misfolding of the insulin 2 gene leads to ER stress-mediated β-cell death and thapsigargin to induce ER stress in two different β-cell lines and in intact mouse islets. Using transformed pancreatic β-cell lines generated from wild-type Ins2+/+(WT) and Akita+/Ins2mice, we evaluated cellular bioenergetics, oxidative stress, mitochondrial protein levels, and autophagic flux to determine whether changes in these processes contribute to β-cell dysfunction. In addition, we induced ER stress pharmacologically using thapsigargin in WT β-cells, INS-1 cells, and intact mouse islets to examine the effects of ER stress on mitochondrial function. Our data reveal that Akita+/Ins2-derived β-cells have increased mitochondrial dysfunction, oxidant production, mtDNA damage, and alterations in mitochondrial protein levels that are not corrected by autophagy. Together, these findings suggest that deterioration in mitochondrial function due to an oxidative environment and ER stress contributes to β-cell dysfunction and could contribute to T1DM in which mutations in insulin occur.

Analysis of (137)Cs trapped in biomass in highly contaminated zones is crucial in predicting the long-term fate of (137)Cs following the explosion at the Fukushima Daiichi Nuclear Power Plant. We surveyed forest 20-50 km from the plant in July and September 2011 to evaluate (137)Cs trapped in biomass within 20 km of the plant. We determined the ambient dose rate and collected forest soils and twigs at 150 sampling points. Removability from the canopy was evaluated by washing leaves and branches with water and organic solvents. The biomass of the forest canopy was then calculated. (137)Cs fallout was simulated with an atmospheric transport model. The modeled dose rate agreed with observations (n = 24) (r = 0.62; p0.01). Washing experiments demonstrated that unremovable portions accounted for 53.9 ± 6.4% of (137)Cs trapped by deciduous canopy (n = 4) and 59.3 ± 13.8% of (137)Cs trapped by evergreen canopy (n = 10). In total, it was estimated that 74.5 × 10(12) Bq was trapped by canopy in the forest within the no-go zone, with 44.2 × 10(12) Bq allocated to unremovable portions, and that 0.86% of the total release was trapped in biomass as of September 2011.

The aim of this study was to investigate the genetic background of familial clustering of diabetes using genome-wide linkage analysis combined with exome sequencing. We recruited a Japanese family with a 3-generation history of diabetes. The family comprised 16 members, 13 having been diagnosed with diabetes. Nine members had been diagnosed before the age of 40. Linkage analysis was performed assuming an autosomal dominant model. Linkage regions were observed on chromosomes 4q34, 5q11-q13, and 12p11-q22 and the logarithm of odds (LOD) scores were 1.80. To identify the susceptibility variants, we performed exome sequencing of an affected family member. We predicted that the familial clustering of diabetes is caused by a rare non-synonymous variant, and focused our analysis on non-synonymous variants absent in dbSNP131. Exome sequencing identified 10 such variants in the linkage regions, 7 of which were concordant with the affection status in the family. One hundred five normal subjects and 67 lean diabetes subjects were genotyped for the 7 variants; the only variant found to be significantly more frequent in the diabetes subjects than in the normal subjects was the N1072K variant of the early endosome antigen 1 (EEA1) gene (0 in normal subjects and 4 in diabetes subjects, p=0.022). We therefore propose that the N1072K variant of the EEA1 gene is a candidate mutation for susceptibility to diabetes in the Japanese population.

Familial goiter is a genetic disease showing heterogeneous expression. To identify causative genes, we investigated three multigenerational goiter families with an autosomal dominant inheritance pattern. We performed genome-wide linkage analysis on all the families, combined with whole-exome sequencing in two affected individuals from each family. For linkage analysis, we considered loci with logarithm of odds (LOD) scores >1.5 as candidate regions for identification of rare variants. In one of the families, we found two rare heterozygous missense variants, p.V56M in RGS12 and p.G37D in GRPEL1, which segregate with goiter and are both located within the same haplotype on 4p16. This haplotype was not observed in 150 controls. In the other two families, we identified two additional rare missense variants segregating with goiter, p.A551T in CLIC6 on 21q22.12 and p.V412A in WFS1 on 4p16. In controls, the minor allele frequency (MAF) of p.V412A in WFS1 was 0.017 while p.A551T in CLIC6 was not detected. All identified genes (RGS12, GRPEL1, CLIC6 and WFS1) show expression in the human thyroid gland, suggesting that they may play a role in thyroid gland function. Moreover, these four genes are novel with regard to their involvement in familial goiter, supporting genetic heterogeneity of this disease.

Since the nuclear power plant accident in Fukushima in March 2011, the Japanese government has conducted screening and removal of contaminated foods from the market that exceed provisional regulation limits for radionuclides. This study aimed to provide an urgent estimate of the dietary exposure of adult residents recruited from three areas in Japan to cesium 134 ((134)Cs), cesium 137 ((137)Cs), and, for comparison, natural potassium 40 ((40)K) on December 4, 2011. Fifty-three sets of 24-h food-duplicate samples were collected in Fukushima Prefecture and neighboring regions. The (134)Cs, (137)Cs, and (40)K levels in the samples were measured using a germanium detector. Items in the food-duplicate samples were recorded and analyzed for radiocesium intake. Radiocesium was detected in 25 of 26 samples from Fukushima. The median dietary intake of radiocesium was 4.0 Bq/day (range0.26-17 Bq/day). The estimated annual dose from radiocesium was calculated assuming that the daily intake of radiocesium was constant throughout the year. The median estimated dose level was 23 μSv/year (range2.6-99 μSv/year). The estimated dose level of radiocesium was significantly higher in Fukushima than in the Kanto region and western Japan. Stepwise multiple linear regression analyses demonstrated that the intake of fruits and mushrooms produced in Fukushima were significant factors for the dietary intake of (137)Cs in the 26 participants from Fukushima. The average radioactivity (±SD) of locally produced persimmons and apples (n = 16) were 23 ± 28 and 30 ± 35 Bq/kg for (134)Cs and (137)Cs, respectively. The preliminary estimated dietary dose levels among Fukushima residents were much lower than the maximum permissible dose 1 mSv/year, based on new Japanese standard limits for radiocesium in foods (100 Bq/kg for general foods). In future studies, the exposure estimates should be refined by probability sampling to eliminate biases.

Tumours exist in a hypoxic microenvironment and must limit excessive oxygen consumption. Hypoxia-inducible factor (HIF) controls mitochondrial oxygen consumption, but how/if tumours regulate non-mitochondrial oxygen consumption (NMOC) is unknown. Protein-tyrosine phosphatase-1B (PTP1B) is required for Her2/Neu-driven breast cancer (BC) in mice, although the underlying mechanism and human relevance remain unclear. We found that PTP1B-deficient HER2(+) xenografts have increased hypoxia, necrosis and impaired growth. In vitro, PTP1B deficiency sensitizes HER2(+) BC lines to hypoxia by increasing NMOC by α-KG-dependent dioxygenases (α-KGDDs). The moyamoya disease gene product RNF213, an E3 ligase, is negatively regulated by PTP1B in HER2(+) BC cells. RNF213 knockdown reverses the effects of PTP1B deficiency on α-KGDDs, NMOC and hypoxia-induced death of HER2(+) BC cells, and partially restores tumorigenicity. We conclude that PTP1B acts via RNF213 to suppress α-KGDD activity and NMOC. This PTP1B/RNF213/α-KGDD pathway is critical for survival of HER2(+) BC, and possibly other malignancies, in the hypoxic tumour microenvironment.

We investigated temporal changes of perfluoroalkyl carboxylic acids (PFCAs) with 8-14 carbon atoms (C8 to C14) in duplicate diet and serum samples in Japan. The sum dietary intakes of PFCAs (C8 to C13) in the Kansai and Tohoku region were highest in the 2010s (mean; 177 ng/day for Kansai, 107 ng/day for Tohoku) followed by the 2000s (77 ng/day for Kansai, 34 ng/day for Tohoku) and the 1990s (53 ng/day for Kansai, 58 ng/day for Tohoku), then the 1980s (19 ng/day for Kansai, 23 ng/day for Tohoku). The sum of the serum concentartions (C8 to C13) was also highest in the 2010s (mean; 17 ng/mL for Kansai, 7.4 ng/mL for Tohoku), followed by the 2000s (12 ng/mL for Kansai, 6.3 ng/mL for Tohoku), then the 1990s (6.8 ng/mL for Kansai, 5.5 mg/mL for Tohoku) and the 1980s (3.8 ng/mL for Kansai, 0.4 ng/mL for Tohoku). A positive correlation was observed between dietary intakes and serum concentration for C8 to C11 (r = 0.94, p 0.05 for C8; r = 0.80, p 0.05 for C9; r = 0.98, p 0.05 for C10; and r = 0.84, p 0.05 for C11). The levels of C8, C9 and C10 in serum and dietary intake in the 2010s were much higher in Kansai than those in Tohoku, although those of C11 did not show such differences. Kansai has a fluoropolymer manufacture known as a specific source of PFOA (C8), and is more urbanized than Tohoku, which may be attributed to the higher levels of PFCAs (C8 to C10). On the other hand, C11 is common to residents in Kansai and Tohoku.

To investigate short-chain chlorinated paraffin (SCCP) levels in human breast milk, pooled breast milk samples (BMSs) collected between 2007 and 2010 from Chinese (Beijing, n = 17), Korean (Seoul, Busan, n = 16), and Japanese (Kyoto, Sendai, n = 44) women were analyzed. SCCPs found in air samples in Beijing ( n = 4, in 2008) were also analyzed and compared with BMSs to estimate the possible source of contamination in Beijing. The electron-capture negative ionization method demonstrated the different sensitivities for SCCPs, and pentachlorinated alkanes had the highest method detection limit (MDL) among congeners. In Beijing, SCCPs were detected in 8 of 17 pooled BMSs at concentrations more than the highest MDL of each homolog. The total SCCP concentration ranged from below the MDL to 54 ng g −1 lipid weight. Among the SCCP homologs, polychlorinated tridecanes were most frequently detected in Beijing. In Korea and Japan, no samples contained detectable total SCCP concentrations at more than the highest MDL. In Seoul, only two samples showed trace levels of polychlorinated undecanes. In Kyoto and Sendai, congeners of polychlorinated dodecanes were most frequently detected. C 10 components were the major contributors to the SCCPs in the atmosphere of Beijing. Congener profiles in breast milk in Beijing provided a clear contrast to the profiles found in food and air. The unique congener profiles necessitate the monitoring of breast milk for exposure of infants to SCCPs. The calculated mean exposure of SCCPs in 1-year-olds in China was 337 ng (kg body weight) −1 d −1 . These results demonstrate the body burden of SCCPs in the study areas and potential lactational exposure to SCCPs in Asian countries.

This study was conducted to clarify the spatial distributions of perfluorooctanoic acid (PFOA) and perfluorohexanoic acid (PFHxA) in well, surface and tap water around a fluoropolymer plant in Osaka between 2003 and 2016 and to predict the fate of those chemicals in these aquatic environments. We analyzed 44 well, six surface and six tap water samples collected within a 5 km radius of the plant. The PFOA concentrations in well water ranged from 45.2 to 7440 ng/L (median = 240 ng/L), while PFHxA concentrations ranged from 9.68 to 970 (median = 45.4 ng/L) in 2015-2016. The concentration of other perfluoroalkyl carboxylic acids were lower than PFOA and PFHxA in well water. Fixed-point observation showed that the levels of PFOA decreased greatly over the last few decades, whereas those of PFHxA increased in both well and surface water. Further monitoring and investigation are suggested to understand PFOA and PFHxA contamination and fate in the environment, as well as their potential for human exposure in this region.

Objectives: Kawauchi Village lies 20 km west of the Fukushima Daiichi nuclear power plant. On 16 March 2011, evacuation was ordered due to the threat of radiological exposure, and was lifted in April 2012. In this study, we aimed to evaluate the predisaster and postdisaster health status of the Kawauchi Villagers, measured by routine yearly physical examinations. Methods: We analysed the annual health examination data of residents of Kawauchi Village from 2008 to 2013, as available from the Japanese National Health Insurance system. Data from 2011 were not available due to the disaster. Since the health data included the same participants repeatedly from year to year, the sample was non-independent and generalised estimated equation modelling was used. A predisaster time period (2008–2010) was categorised for comparison with postdisaster 2012 and 2013. The outcome examined was the prevalence of metabolic disease, and was adjusted for confounding factors. Results: Data for 20.6%–25.9% of the total residents were available in this period. In 2013, the prevalence of metabolic syndrome (from 17.0% to 25.2%, p

Cardiovascular complications are the leading cause of death in autosomal dominant polycystic kidney disease (ADPKD), and intracranial aneurysm (ICA) causing subarachnoid hemorrhage is among the most serious complications. The diagnostic and therapeutic strategies for ICAs in ADPKD have not been fully established. We here generated induced pluripotent stem cells (iPSCs) from seven ADPKD patients, including four with ICAs. The vascular cells differentiated from ADPKD-iPSCs showed altered Ca2+ entry and gene expression profiles compared with those of iPSCs from non-ADPKD subjects. We found that the expression level of a metalloenzyme gene, matrix metalloproteinase (MMP) 1, was specifically elevated in iPSC-derived endothelia from ADPKD patients with ICAs. Furthermore, we confirmed the correlation between the serum MMP1 levels and the development of ICAs in 354 ADPKD patients, indicating that high serum MMP1 levels may be a novel risk factor. These results suggest that cellular disease models with ADPKD-specific iPSCs can be used to study the disease mechanisms and to identify novel disease-related molecules or risk factors.

RNF213 p.R4810K is a founder polymorphism that confers genetic susceptibility to moyamoya disease in East Asia. Only a few studies have investigated the symptoms and disease histories of RNF213 p.R4810K carriers in Japan. This study investigated the frequency of RNF213 p.R4810K in the general Japanese population and the health characteristics of the carriers. Through a health-promotion campaign in the city of Uji, Japan, 519 subjects (120 males and 399 females) of the general Japanese population were genotyped for RNF213 p.R4810K and interviewed to determine health characteristics. Nine RNF213 p.R4810K heterozygous carriers (GA genotype) and no RNF213 p.R4810K homozygous carriers (AA genotype) were found among the 519 individuals. The estimates of the genotypes and allele frequencies for RNF213 p.R4810K were 1.73 and 0.87 %, respectively. There were no obvious differences in age, gender ratio, body mass index, hypertension, dyslipidemia, diabetes, kidney disease, liver disease, heart disease, or drinking or smoking habits between carriers and non-carriers. Interestingly, one patient with moyamoya disease was found among the nine RNF213 p.R4810K carriers. This study showed the genotypes and allele frequencies of RNF213 p.R4810K in the general Japanese population to be similar to results of previous reports.

Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used exome sequencing to prioritize risk variants in a discovery cohort of six FC families affected by IA, and the analysis revealed an increased variation burden for ring finger protein 213 (RNF213). We resequenced RNF213 in a larger FC validation cohort, and association tests on further identified variants supported our findings (SKAT-O, p = 0.006). RNF213 belongs to the AAA+ protein family, and two variants (p.Arg2438Cys and p.Ala2826Thr) unique to affected FC individuals were found to have increased ATPase activity, which could lead to increased risk of IA by elevating angiogenic activities. Common SNPs in RNF213 were also extracted from the NeuroX SNP-chip genotype data, comprising 257 FC IA-affected and 1,988 control individuals. We discovered that the non-ancestral allele of rs6565666 was significantly associated with the affected individuals (p = 0.03), and it appeared as though the frequency of the risk allele had changed through genetic drift. Although RNF213 is a risk factor for moyamoya disease in East Asians, we demonstrated that it might also be a risk factor for IA in the FC population. It therefore appears that the function of RNF213 can be differently altered to predispose distinct populations to dissimilar neurovascular conditions, highlighting the importance of a population’s background in genetic studies of heterogeneous disease.

Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8-9 weeks old; n = 10-12 for each group) and mature (36-38 weeks old; n = 5-6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8-9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations., 乳幼児期に特異的な手足の痛み発作を起こす病気を見つけ原因を解明 －この病気を小児四肢疼痛発作症と命名－. 京都大学プレスリリース. 2016-05-27.

Background Neonicotinoids, which are novel pesticides, have entered into usage around the world because they are selectively toxic to arthropods and relatively non-toxic to vertebrates. It has been suggested that several neonicotinoids cause neurodevelopmental toxicity in mammals. The aim was to establish the relationship between oral intake and urinary excretion of neonicotinoids by humans to facilitate biological monitoring, and to estimate dietary neonicotinoid intakes by Japanese adults. Methodology/Principal Findings Deuterium-labeled neonicotinoid (acetamiprid, clothianidin, dinotefuran, and imidacloprid) microdoses were orally ingested by nine healthy adults, and 24 h pooled urine samples were collected for 4 consecutive days after dosing. The excretion kinetics were modeled using one- and two-compartment models, then validated in a non-deuterium-labeled neonicotinoid microdose study involving 12 healthy adults. Increased urinary concentrations of labeled neonicotinoids were observed after dosing. Clothianidin was recovered unchanged within 3 days, and most dinotefuran was recovered unchanged within 1 day. Around 10% of the imidacloprid dose was excreted unchanged. Most of the acetamiprid was metabolized to desmethyl-acetamiprid. Spot urine samples from 373 Japanese adults were analyzed for neonicotinoids, and daily intakes were estimated. The estimated average daily intake of these neonicotinoids was 0.53–3.66 μg/day. The highest intake of any of the neonicotinoids in the study population was 64.5 μg/day for dinotefuran, and this was

RNF213/Mysterin has been identified as a susceptibility gene for moyamoya disease, a cerebrovascular disease characterized by occlusive lesions in the circle of Willis. The p. R4810K (rs112735431) variant is a founder polymorphism that is strongly associated with moyamoya disease in East Asia. Many non-p.R4810K rare variants of RNF213 have been identified in white moyamoya disease patients, although the ethnic mutations have not been investigated in this population. In the present study, we screened for RNF213 variants in 19 Slovakian and Czech moyamoya disease patients. A total of 69 RNF213 coding exons were directly sequenced in 18 probands and one relative who suffered from moyamoya disease in Slovakia and the Czech Republic. We previously reported one proband harboring RNF213 p.D4013N. Results from the present study identified four rare variants other than p.D4013N (p.R4019C, p.E4042K, p.V4146A, and p.W4677L) in four of the patients. P.V4146A was determined to be a novel de novo mutation, and p.R4019C and p. E4042K were identified as double mutations inherited on the same allele. P.W4677L, found in two moyamoya disease patients and an unaffected subject in the same pedigree, was a rare single nucleotide polymorphism. Functional analysis showed that RNF213 p.D4013N, p.R4019C and p.V4146A-transfected human umbilical vein endothelial cells displayed significant lowered migration, and RNF213 p.V4146A significantly reduced tube formation, indicating that these are disease-causing mutations. Results from the present study identified RNF213 rare variants in 22.2% (4/18 probands) of Slovakian and Czech moyamoya disease patients, confirming that RNF213 may also be a major causative gene in a relative large population of white patients.

Forestry is an important land-use type in tropical peatlands that provides socio-economic and environmental services. Currently, tropical peatland forestry has contributed to the timber industry, but timber harvest has unfortunately caused degradation and deforestation in massive areas of tropical peat swamp forests. Consequently, serious reductions of wood resources and environmental services occurred in peatland forests, with land managers being caught in a forest management dilemma between the needs for timber production, conservation and restoration of environmental services. The woody materials produced from peatland forests have various and unique characteristics; these forests also provide commercially valuable timber. Given that degraded peatland can be restored to forest composed of indigenous trees of high ecological and commercial value, land managers feel confident that they can provide the benefits of both timber production and improved environmental services. First, during planting one must understand which tree species are best adapted to local site-conditions if successful reforestation techniques are to be developed. Cost-effectiveness must also be concerned, especially in degraded peatland, where considerable flooding may determine the survival and growth rates of seedlings and the operating cost. Second, as a management strategy, a reforestation program should be required to provide multiple benefits, not only timber production and environmental services, but these programs should also improve socio-economic conditions that ensure the ongoing livelihood of local people. In the future, tropical peatland forestry should play the roles of providing for both the restoration and sustainable use of wood resources in a way that benefits both the local community and the global market.

Exposure of mothers to organochlorine pesticides (OCPs) was assessed by measuring the levels of 20 OCPs in 70 human breast milk samples pooled from 210 individuals from China, Korea and Japan. The OCPs were analyzed using gas chromatography/mass spectrometry (GC/MS) in electron capture negative ionization (ECNI) monitoring. The results showed that β-hexachlorocyclohexane and hexachlorobenzene were one order of magnitude higher in China than in the other nations, whereas chlordanes and polychlorinated biphenyl levels were highest in Japan. Heptachlor epoxide, dieldrin, endrin, toxaphenes and mirex were detected in most samples, and levels of these chemicals were significantly higher in Japan (0.8-4.5 ng g(-1) lipid), followed by Korea (0.2-4.7 ng g(-1) lipid), and lowest in China (less than 1.0 ng g(-1) lipid). α- and β-endosulfans were detected at a range of 0.9-1.5 ng g(-1) lipid levels in all samples analyzed, and their levels were higher in Korean than in Chinese samples.

Moyamoya disease-an idiopathic vascular disorder of intracranial arteries-is often accompanied by hypertension. RNF213 has been identified as a susceptibility gene for moyamoya disease. In the present study, the association of p.R4810K (GA) with blood pressure (BP) was investigated in a Japanese population.Three independent study populations, the Nyukawa (n = 984), Noshiro (n = 2,443) and Field (n = 881) studies, joined this study. BP, body weight and height were measured. Past and present symptoms and disease and medication histories were assessed by interview. Associations of p.R4810K (rs112735431, ss179362673) of RNF213 with BP were investigated. Two linkage disequilibrium blocks were constructed for moyamoya patients with p.R4810K (n = 140) and the general population (n = 384) using 39 single nucleotide polymorphisms (SNPs) spanning 390 kb around RNF213. A total of 60 carriers (3 for AA genotype and 57 for GA genotype) were found in these samples, and the minor allele frequencies were 1.4 % in the Nyukawa and Field studies and 0.2 % in the Noshiro study. Regression analyses adjusted for age, sex and body mass index based on an additive model demonstrated significant associations with systolic BP (mmHg/allele): β (standard error) was 8.2 (2.9) in the Nyukawa study (P = 4.7 × 10(-3)), 18.7 (5.4) in the Noshiro study (P = 4.6 × 10(-4)) and 8.9 (2.0) (P = 1.0 × 10(-5)) in the three populations. In contrast, diastolic BP showed significant associations only in the Noshiro study. Linkage disequilibrium blocks contained none of the BP-associated proxy SNPs reported by previous studies.Our study suggests that p.R4810K of RNF213 is associated strongly with systolic BP.

To develop a targeted drug delivery system for cerebrovascular disorders such as stroke, it is important to obtain detailed information on flow rates and hemodynamics of the human cerebrovascular system for individual patients. A patient-specific integrated numerical simulation system has been developed by the authors such that vascular geometry is constructed from medical images such as magnetic resonance imaging (MRI) or computed tomography (CT) data, and computational conditions are modeled mathematically to represent the realistic in vivo environments. In general, the three-dimensional numerical simulation using a patient-specific model is conducted only for a localized diseased region with atherosclerosis or an aneurysm. Although the analysis region is only a part of the circulatory system, the simulation should include the effects from the entire circulatory system. Since the peripheral network determines the flow distributions in the cerebrovascular system, the paper reviews the recent simulation methods to take into account the network by coupling the image-based three-dimensional simulation with a one- and zero-dimensional simulations as an outflow boundary condition The paper shows the mathematical modeling of the multi-scale outflow boundary condition and its applications to patient- specific models of the arterial circle of Willis. The results are compared to those using the conventional, free-stream boundary condition. As a result, the multi-scale outflow boundary condition shows a significant difference in flow rate of each artery and in flow distribution in the arterial circle of Willis.

Background: A variety of hereditary spinocerebellar ataxia (SCA) develops a broad spectrum of both ataxia and non-ataxia symptoms. Cognitive and affective changes are one such non-ataxia symptoms, but have been described only in hereditary SCAs with exonic CAG gene expansion. Methods: We newly found intronic hexanucleotide GGCCTG gene expansion in NOP56 gene as the causative mutation (=SCA36) in nine unrelated Japanese familial SCA originating from Asida river area in the western part of Japan, thus nicknamed Asidan for this mutation. These patients show unique clinical balance of cerebellar ataxia and motor neuron disease (MND), locating on the crossroad of these two diseases. In the nine families, 14 patients were clinically examined and genetically confirmed to Asidan. In the present study, we examined cognitive and affective analyses on 12 patients (seven men and five women) who agreed to join the examination with average age at onset of 53.1 ± 3.2 years, average duration of 12.1 ± 5.2 years, and current average age at 65.1 ± 6.2 years. Results: The 12 Asidan patients demonstrated a significant decrease in their frontal executive functions measured by frontal assessment battery (FAB) and Montreal cognitive assessment (MoCA) compared with age- and gender-matched controls, whilst mini-mental state examination (MMSE) and Hasegawa dementia score-revised (HDS-R) were within normal range. The decline of frontal executive function was related to their disease duration and scale for the assessment and rating of ataxias (SARA). They also demonstrated mild depression and apathy. Single-photon emission tomography (SPECT) analysis showed that these Asidan patients showed decline of regional cerebral blood flow (rCBF) in a particular areas of cerebral cortices such as Brodmann areas 24 and 44–46. Conclusion: These data suggest that the patients with Asidan mutation show unique cognitive and affective characteristics different from other hereditary SCAs with exonal CAG expansion or MND.

To examine the hypothesis that both stem and crown mass affect the resistance of a tree to uprooting and that tree resistance increases with the increase in crown mass, we conducted tree-pulling experiments on three Picea glehnii plantations (stands A, B, and C: 27-32 years old) that differed in tree density and slenderness ratio. Allometries between crown and stem masses and between the critical uprooting moment and stem mass differed significantly among the three stands, with the crown mass and critical moment significantly larger in Stand C than in Stands A or B, despite the same stem mass. These results quantitatively verified our hypothesis. Allometries between crown and stem masses and between critical uprooting moment and stem mass were highly significant in each stand but were stand specific. Therefore, these allometries can be used to estimate tree resistance to uprooting in a given stand but not for data compiled from stands of various conditions and tree shapes. The allometry between critical moment and aboveground mass did not differ among the three Picea stands; thus, it is not stand specific and is generally appropriate to use for estimating tree resistance. To increase tree resistance to uprooting, we recommend light management for Picea glehnii plantations and probably other coniferous plantations as well.

In this study, an experimental study was conducted on the nailed timber–plywood–timber joints extended from the standard wall–floor joints of wooden light frame constructions, where the bottom plates of shear walls are nailed to the floors consisting of joists and floor sheathings nailed to them. The principal conclusions are as follows: The allowable lateral resistance of the nailed timber–plywood–timber joints can roundly be estimated by neglecting the plywood panels if their densities are higher than those of the timber main-members and they are fastened effectively onto the timber main-members. The stiffness of the timber–plywood–timber joints is less than that of the control timber–timber joints, which is improved by increasing the number of nails used to fasten the plywood panels onto the timber main-members. The stiffness of the joints whose floor sheathings are glued onto the joists is equivalent to the control timber–timber joints. The timber–plywood–timber joints with appropriate specifications have greater energy capacity until the failure than that of the control timber–timber joints. This ensures their energy capacity, which is important in dynamic resistance, to be equivalent to the control timber–timber joints.

In this study, 90 human breast milk samples collected from Japan, Korea, and China were analyzed for perfluorooctanoic acid (PFOA) (C8), perfluorononanoic acid (PFNA) (C9), perfluorodecanoic acid (PFDA) (C10), perfluoroundecanoic acid (PFUnDA) (C11), perfluorododecanoic acid (PFDoDA) (C12), and perfluorotridecanoic acid (PFTrDA) (C13). In addition, infant formulas (n = 9) obtained from retail stores in China and Japan were analyzed. PFOA was the predominant compound and was detected in more than 60% of samples in all three countries. The PFOA, PFNA, PFDA, and PFUnDA levels in Japan were significantly higher than those in Korea and China (p0.05). The PFTrDA level was highest in Korea (p0.05). The median PFOA concentrations were 89 pg mL(-1) (48% of total perfluorinated carboxylic acids (PFCAs) (C8-C13)) in Japan, 62 pg mL(-1) (54%) in Korea, and 51 pg mL(-1) (61%) in China. The remaining ∑PFCAs (C9-C13) were 95 pg mL(-1) in Japan, 52 pg mL(-1) in Korea, and 33 pg mL(-1) in China. Among the long-chain PFCAs, odd-numbered PFCAs were more frequently detected than even-numbered PFCAs, except for PFDA in Japan. There were no evident correlations between the mother's demographic factors and the PFCA concentrations. PFOA, PFNA, and PFDA were frequently detected in both Japan and China, but there were no significant differences between the two countries. The total PFCA concentrations in the infant formulas were lower than those in the breast milk samples in Japan (p0.05), but not in China (p0.05). In conclusion, various PFCAs were detected in human breast milk samples from East Asian countries.

Japanese breast milk samples were tested for antibodies to human T-cell leukemia virus type I (HTLV-1) by particle agglutination (PA) and a line immunoassay (LIA). In the PA method, the agglutination reaction between the HTLV-1 antibody and sensitized particles occurred at a 1 : 128 dilution of some breast milk samples. The average antibody titer was one order of magnitude lower than that in the serum positive control. A total of 243 human breast milk specimens were assayed by PA, of which 21 samples from Okinawa, Hyogo, Miyagi and Hokkaido were positive or deferred. The results of the 21 positive samples were subsequently assayed by LIA (INNO-LIA™ HTLV I/II) for confirmation; and one sample was positive, and two were indeterminate. We attempted to use polymerase chain reaction (PCR) to detect HTLV-1 provirus DNA, but we did not detect PCR products for the pX1 region of the HTLV-1 genome in the LIA-positive samples. These negative PCR results are most likely due to the lower sensitivity of the PCR for amplification from milk than from HTLV-1-positive monocytes. In conclusion, the PA method to breast milk samples appears to be a suitable tool to screen for antibodies to HTLV-1 in the breast milk of carrier mothers in cases in which it would be difficult to use serum for the test. Although LIA may be able to confirm HTLV-1 infection, the presence of HTLV-1 provirus should be confirmed in the breast milk.

An experimental study on combined steel-to-timber joints with nails and bolts is conducted in this study. Principal results are as follows: The initial stiffness and effective allowable resistance of combined joints depend obviously on clearances in predrilled bolt-holes. The combined joints with nails and bolts have high potential of energy capacity to resist strong earthquake forces. There are upper limits of clearances in predrilled bolt-holes that allow advantages of considering the synthetic resistance of combined joints in practical structural design. Combining the joint components with appropriate design will give higher performance against strong earthquakes increasing the safety margin and energy capacity until the failure. The combined joints should be designed under the restrictions of particular specifications in closed design systems because the advantages of combining the joint components are influenced obviously by various actual conditions, which are too difficult to consider in detail in open design systems.

Perfluorooctanoic acid (PFOA) has long been an environmental contaminant of concern owing to its potential health risk. However, exposure to perfluorinated carboxylic acids (PFCAs) other than PFOA is not well understood. In this study, we investigated the concentrations of PFCAs in vacuum cleaner dust in Japan to measure the PFCAs contamination in an indoor environment. Most of the 77 samples contained PFCAs with 6-13 carbon atoms. The median concentration of perfluorononanoic acid (PFNA, 23.2 ng g(-1)) was highest among PFCAs, followed by PFOA (20.8 ng g(-1)) and perfluoroundecanoic acid (PFUnDA, 12.9 ng g(-1)). The 90th percentile concentrations of PFNA, PFUnDA and perfluorotridecanoic acid (PFTrDA) were 948, 283 and 110 ng g(-1), respectively, and these were detected at greater concentrations than neighboring, even-numbered PFCAs. The proportion of long-chain PFCAs in vacuum cleaner dust from Japan was relatively higher than those reported for other countries. Factor analysis showed three independent factors. Odd-numbered long chain PFCAs (PFNA, PFUnDA and PFTrDA), which can correspond to factor 1, were major components of PFCAs in vacuum cleaner dust. Short chain PFCAs (factor 2) and even numbered long chain PFCAs (factor 3) were also statistically separated. These findings suggest that there are several sources of PFCAs with different origins in indoor environment. Further investigations into the origins of PFCAs are needed to evaluate indoor contamination with PFCAs.

Perfluorooctanoic acid (PFOA) has recently attracted attention as a potential health risk following environmental contamination. However, information detailing exposure to perfluorinated carboxylic acids (PFCAs) other than PFOA is limited. We measured the concentrations of PFCAs (from perfluorohexanoic acid to perfluorotetradecanoic acid) in serum samples obtained from patients in Japan (Sendai, Takayama, Kyoto and Osaka) between 2002 and 2009, Korea (Busan and Seoul) between 1994 and 2008 and Vietnam (Hanoi) in 2007/2008. Total PFCA levels (geometric mean) were increased from 8.9 ng mL−1 to 10.3 ng mL−1 in Japan; from 7.0 ng mL−1 to 9.2 ng mL−1 in Korea; and were estimated at 4.7 ng mL−1 in Vietnam. PFCAs of greater length than PFOA were significantly increased in Sendai, Takayama and Kyoto, Japan, and levels of long-chain PFCAs exceeded PFOA levels in serum. Among these PFCAs, perfluoroundecanoic acid (PFUnDA) was the predominant component (28.5%), followed by perfluorononanoic acid (PFNA 17.5%), perfluorodecanoic acid (PFDA 7.9%), perfluorotridecanoic acid (PFTrDA 6.1%) and perfluorododecanoic acid (PFDoDA 1.8%). Odd-numbered PFCAs (PFNA, PFUnDA and PFTrDA) were also observed in Korea and Vietnam and their presence increased significantly in Korea between 1994 and 2007/2008. The proportion of long-chain PFCAs in serum was relatively high compared to reports in Western countries. Further investigations into the sources and exposure routes are needed to predict the future trajectory of these serum PFCA levels. Keywords: Perfluorocarboxylate, Perfluorooctanoic acid, Serum, Temporal trend, East Asia

The alarming rise in the prevalence of chronic kidney disease of uncertain etiology (CKDu) among the low socioeconomic farming community in the North Central Province of Sri Lanka has been recognized as an emerging public health issue in the country.This study sought to determine the possible factors associated with the progression and mortality of CKDu. The study utilized a single-center cohort registered in 2003 and followed up until 2009 in a regional clinic in the endemic region, and used a Cox proportional hazards model.We repeatedly found an association between disease progression and hypertension. Men were at higher risk of CKDu than women. A significant proportion of the patients in this cohort were underweight, which emphasized the need for future studies on the nutritional status of these patients.Compared with findings in western countries and other regions of Asia, we identified hypertension as a major risk factor for progression of CKDu in this cohort.

To evaluate windthrow resistance with respect to stem breakage, a nondestructive method for determining the shape of trunk cross sections was developed. In this method, the coordinates of multiple gauge points set on the perimeter of a trunk are calculated by measuring the distances between them. The shape between the gauge points is generated with the use of a profile gauge placed between them. Measurement tests were conducted using profile gauges with lengths of 300 and 900 mm on model specimens with four shape patterns and four different diameters. The accuracy of the estimation was verified by comparing the section modulus calculated for the generated image and for the photograph. The average ratio of section modulus (generated/photo) for all specimens was 0.994, which indicates that the proposed method is highly accurate. The section moduli of hollow trunks can be evaluated using the profile method together with the drill resistance technique on the condition that 26% of the trunk diameter could be drilled without skew.

This was a screening study that aimed to determine the presence of nephrotoxic mycotoxins in urine samples from patients with chronic kidney disease of uncertain etiology in the North Central Province of Sri Lanka. The percentage detection of aflatoxins, ochratoxins and fumonisins in 31 patients were 61.29%, 93.5% and 19.4%, respectively. Geometric means of urinary aflatoxins and ochratoxins were 30.93 creatinine and 34.62 ng/g creatinine in chronic kidney disease of uncertain etiology stage 1–2 patients and 84.12 ng/g creatinine and 63.52 ng/g creatinine in unaffected relatives of patients. In chronic kidney disease of uncertain etiology stage 3–5 patients, geometric means of urinary aflatoxins and ochratoxins were 10.40 and 17.08 ng/g creatinine, respectively. Non-affected relatives of patients (n = 6) had comparable levels of these mycotoxins, but healthy Japanese individuals (n = 4) had lower levels than in Sri Lanka. The higher detection rate of urinary ochratoxins in Sri Lankans indicates that exposure is common in the region.

Recently, the Stockholm Convention prohibited the use of toxaphene and has been reviewing endosulfan. The historical use of these pesticides may contaminate food and tend to accumulate in the food chain. In this study, to evaluate the spatial and temporal trends of food contamination, the endosulfan and toxaphene levels were measured in pooled 24-h food composite samples from Chinese (n=10), Korean (n=10) and Japanese (n=40) adults in the 1990s and 2007-2009. Endosulfan was detected in 32 of 40 samples from Japan, but its levels (sum of α- and β-isomers) were low in both the 1990s and 2009 (range as geometric mean (geometric standard deviation) [GM (GSD)]: 0.96 (1.6)-1.42 (1.4) ng kg(-1)d(-1)). The dietary intakes of endosulfan in Seoul as GM (GSD) were 38.68 (1.3) ng kg bw(-1)d(-1) in 1994 and 92.17 (4.4) ng kg bw(-1)d(-1) in 2007, and significantly higher than those in Japan (p

Objective The aim was to investigate the genetic background of familial clustering of type 2 diabetes. Subjects and methods We recruited Japanese families with a 3-generation history of diabetes. Genome-wide linkage analysis was performed assuming an autosomal dominant model. Genes in the linkage region were computationally prioritized using Endeavour. We sequenced the candidate genes, and the frequencies of detected nucleotide changes were then examined in normoglycemic controls. Results To exclude known genetic factors, we sequenced 6 maturity onset diabetes of the young (MODY) genes in 10 familial cases. Because we detected a MODY3 mutation HNF1A R583G in one case, we excluded this case from further investigation. Linkage analysis revealed a significant linkage region on 2p25-22 (LOD score = 3.47) for 4 families. The 23.6-Mb linkage region contained 106 genes. Those genes were scored by computational prioritization. Eleven genes, i.e., top 10% of 106 genes, were selected and considered primary candidates. Considering their functions, we eliminated 3 well characterized genes and finally sequenced 8 genes. GCKR ranked highly in the computational prioritization. Mutations (minor allele frequency less than 1%) in exons and the promoter of GCKR were found in index cases of the families (3 of 18 alleles) more frequently than in controls (0 of 36 alleles, P = 0.033). In one pedigree with 9 affected members, the mutation GCKR g.6859C>G was concordant with affection status. No mutation in other 7 genes that ranked highly in the prioritization was concordant with affection status in families. Conclusions We propose that GCKR is a susceptibility gene in Japanese families with clustered diabetes. The family based approach seems to be complementary with a large population study.

Environmental ecological modeling (EEM), which unifies models simulating transport of chemicals and exposure of humans to chemicals, was used to simulate long-term trends of female adult human blood lead levels (BLLs) and historical exposure to the atmospheric lead in four East Asian countries: Japan, Korea, China, and Vietnam. Anthropogenic lead emissions to the atmosphere in Vietnam were estimated from energy statistics to be 1931 t yr(-1). Calculated BLLs generally agreed with those observed in samples collected in these countries as the error factors were less than 2. The model results revealed that BLLs decreased significantly in Tokyo (by 58%) and Seoul (by 45%) in recent decades and confirmed the effects of efforts to reduce environmental lead in Japan and Korea. The model results also revealed that BLLs in Beijing did not decrease in this decade as much as in Tokyo and Seoul, despite the phasing out of leaded gasoline, and that the contribution from the atmospheric component was increasing (43% in 2009). Finally, we applied EEM to simulate BLLs of children in Hanoi. The probability of children having BLLs greater than 50 μg L(-1) was 7.5%, which was greater than those observed in developed countries.

Previously, we demonstrated that the concentrations of DDTs were greater in breast milk collected from Chinese mothers than from Japanese and Korean mothers. To investigate dicofol as a possible source of the DDTs in human breast milk, we collected breast milk samples from 2007 to 2009 in China (Beijing), Korea (Seoul, Busan) and Japan (Sendai, Takarazuka and Takayama). Using these breast milk samples, we quantified the concentrations of dichlorobenzophenone, a pyrolysis product of dicofol (simply referred to as dicofol hereafter), dichlorodiphenyltrichloroethane and its metabolites (DDTs) using GC–MS. Overall, 12 of 14 pooled breast milk samples from 210 mothers contained detectable levels of dicofol (>0.1 ng g−1 lipid). The geometric mean concentration of dicofol in the Japanese breast milk samples was 0.3 ng g−1 lipid and significantly lower than that in Chinese (9.6 ng g−1 lipid) or Korean breast milk samples (1.9 ng g−1 lipid) (p < 0.05 for each). Furthermore, the ΣDDT levels in breast milk from China were 10-fold higher than those from Korea and Japan. The present results strongly suggest the presence of extensive emission sources of both dicofol and DDTs in China. However, exposure to dicofol cannot explain the large exposure of Chinese mothers to DDTs because of the trace levels of dicofol in the ΣDDTs. In the present study, dicofol was confirmed to be detectable in human breast milk. This is the first report to identify dicofol in human samples.

We previously performed genetic analysis in six unrelated families with infantile limb pain episodes, characterized by cold-induced deterioration and mitigation in adolescence, and reported two new mutations p.R222H/S in SCN11A responsible for these episodes. As no term described this syndrome (familial episodic pain: FEP) in Japanese, we named it as”小児四肢疼痛発作症”. In the current study, we recruited an additional 42 new unrelated Japanese FEP families, between March 2016 and March 2018, and identified a total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p.V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with FEP in the Tohoku region of Japan. We also identified two novel missense variants of SCN11A, p.F814C and p.F1146S. To evaluate the effects of these latter two mutations, we generated knock-in mouse models harboring p.F802C (F802C) and p.F1125S (F1125S), orthologues of the human p.F814C and p.F1146S, respectively. We then performed electrophysiological investigations using dorsal root ganglion neurons dissected from the 6–8 week-old mice. Dissected neurons of F802C and F1125S mice showed increased resting membrane potentials and firing frequency of the action potentials (APs) by high input–current stimulus compared with WT mice. Furthermore, the firing probability of evoked APs increased in low stimulus input in F1125S mice, whereas several AP parameters and current threshold did not differ significantly between either of the mutations and WT mice. These results suggest a higher level of excitability in the F802C or F1125S mice than in WT, and indicate that these novel mutations are gain of function mutations. It can be expected that a considerable number of potential patients with FEP may be the result of gain of function SCN11A mutations.

The increase in the number of chronic kidney disease (CKD) patients from the north central region of Sri Lanka has become a environmental health issue of national concern. Unlike in other countries where long-standing diabetes and hypertension are the leading causes of renal diseases, the majority of CKD patients from this part of Sri Lanka do not show any identifiable cause. As the disease is restricted to a remarkably specific geographical terrain, particularly in the north central dry zone of the country, multidisciplinary in-depth research studies are required to identify possible etiologies and risk factors. During this study, population screening in the prevalent region and outside the region, analysis of geoenvironmental and biochemical samples were carried out. Population screening that was carried out using a multistage sampling technique indicated that the point prevalence of CKD with uncertain etiology is about 2-3% among those above 18 years of age. Drinking water collected from high-prevalent and non-endemic regions was analyzed for their trace and ultratrace element contents, including the nephrotoxic heavy metals Cd and U using ICP-MS. The results indicate that the affected regions contain moderate to high levels of fluoride. The Cd contents in drinking water, rice from affected regions and urine from symptomatic and non-symptomatic patients were much lower indicating that Cd is not a contributing factor for CKD with uncertain etiology in Sri Lanka. Although no single geochemical parameter could be clearly and directly related to the CKD etiology on the basis of the elements determined during this study, it is very likely that the unique hydrogeochemistry of the drinking water is closely associated with the incidence of the disease.

A global atmospheric transport model is used to calculate lead concentrations in the atmosphere. The model performance is evaluated through comparisons with observations in Europe. The model results of lead concentrations in surface air were compared with measurements in East Asia. The detailed comparisons showed generally good agreement for recent decades, although systematic underestimation was found in China. Anthropogenic lead emissions in China are estimated from economic statistics to be 56 000 t yr −1 , which is not small considering the economic scale of China. The underestimations suggest a hidden source of lead emissions. The emissions in Japan and Korea are derived from optimization by the model. The magnitude is about 2000 t yr −1 , which is much greater than that reported by the Pollutant Release and Transfer Register in Japan and Toxics Release Inventory in Korea.