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Moyamoya disease is a rare cause of stroke, radiologically characterised by progressive stenosis of the terminal portion of the internal carotid arteries and compensatory capillary collaterals. The discovery that RNF213, which encodes an unconventional E3 ubiquitin ligase, is the major susceptibility gene for moyamoya disease in people from east Asia has opened new avenues for investigation into the mechanisms of disease and potential treatment targets. The Arg4810Lys variant of the gene is most strongly associated with moyamoya disease, but the penetrance is lower than 1%, suggesting a synergistic relationship with additional environmental and genetic risk factors. White people carry less common non-Arg4810Lys variants of RNF213, which partly explains the lower prevalence of moyamoya disease in European countries and in the USA than in east Asian countries. Several monogenic moyamoya syndromes possess the radiological characteristics of moyamoya disease and have been associated with multiple genes and pathways involved in moyamoya angiopathy pathogenesis. Further clarification of the genetic and environmental factors that contribute to the emergence of moyamoya angiopathy could enable development of new treatment strategies for moyamoya disease.

Human exposure to persistent organic pollutants (POPs) is reflected by POP concentrations in breast milk. Many studies of POPs in breast milk have been performed in Japan, but insufficient information is available about some legacy POPs (e.g., mirex and toxaphenes, included in the Stockholm Convention in 2001) and novel POPs (e.g., dicofol and endosulfans, included in the Stockholm Convention in 2019 and 2011, respectively). In this study, dicofol, endosulfan, mirex, and toxaphene concentrations in breast milk from 10 prefectures in Japan were determined. The samples were collected between 2005 and 2010, before Stockholm Convention restrictions on endosulfans and mirex were implemented. Common POPs (e.g., polychlorinated biphenyls) were also analyzed to allow the contamination statuses to be compared. The α-endosulfan and β-endosulfan concentrations were 0.26-13 and 0.012-0.82 ng/g lipid, respectively. The toxaphene #26 and #50 concentrations were0.08-5.6 and 0.1-8.5 ng/g lipid, respectively. The dicofol concentrations were0.01-4.8 ng/g lipid. The mirex concentrations were0.2-3.5 ng/g lipid. The α- and β-endosulfan concentrations on a lipid weight basis negatively correlated with the lipid contents of the milk samples (ρ = -0.65, p 0.01 for α-endosulfan; ρ = -0.58, p 0.01 for β-endosulfan). The toxaphene concentrations positively correlated with the lipid contents. The mirex concentrations positively correlated with the maternal age but negatively correlated with the maternal body mass index. No correlations between the dicofol concentrations and the factors were found. Principal component analysis divided the data into four groups, (1) chlordanes, dichlorodiphenyltrichloroethanes and related compounds, hexachlorobenzene, hexachlorocyclohexanes, hexachloroethane, and polychlorinated biphenyls, (2) endosulfans, (3) dicofol, dieldrin, and toxaphenes, and (4) bromodiphenyl ether 47. This indicated that bromodiphenyl ether 47, dicofol, endosulfans, and toxaphenes have different exposure routes or different kinetics to the other legacy POPs.

Moyamoya disease (MMD) is a rare cerebrovascular disease endemic in East Asia. The p.R4810K mutation in RNF213 gene confers a risk of MMD, but other factors remain largely unknown. We tested the association of gut microbiota with MMD. Fecal samples were collected from 27 patients with MMD, 7 patients with non-moyamoya intracranial large artery disease (ICAD) and 15 control individuals with other disorders, and 16S rRNA were sequenced. Although there was no difference in alpha diversity or beta diversity between patients with MMD and controls, the cladogram showed Streptococcaceae was enriched in patient samples. The relative abundance analysis demonstrated that 23 species were differentially abundant between patients with MMD and controls. Among them, increased abundance of Ruminococcus gnavus > 0.003 and decreased abundance of Roseburia inulinivorans P = 0.0024; odds ratio 11.1, P = 0.0051). Also, Ruminococcus gnavus was more abundant and Roseburia inulinivorans was less abundant in patients with ICAD than controls (P = 0.046, P = 0.012). The relative abundance of Ruminococcus gnavus or Roseburia inulinivorans was not different between the p.R4810K mutant and wildtype. Our data demonstrated that gut microbiota was associated with both MMD and ICAD.

Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive occlusion of the internal carotid arteries. Genetic studies originally identified RNF213 as an MMD susceptibility gene that encodes a large 591 kDa protein with a functional RING domain and dual AAA+ ATPase domains. As the functions of RNF213 and its relationship to MMD onset are unknown, we set out to characterize the ubiquitin ligase activity of RNF213, and the effects of MMD patient mutations on these activities and on other cellular processes. In vitro ubiquitination assays, using the RNF213 RING domain, identified Ubc13/Uev1A as a key ubiquitin conjugating enzyme that together generate K63-linked polyubiquitin chains. However, nearly all MMD patient mutations in the RING domain greatly reduced this activity. When full-length proteins were overexpressed in HEK293T cells, patient mutations that abolished the ubiquitin ligase activities conversely enhanced nuclear factor κB (NFκB) activation and induced apoptosis accompanied with Caspase-3 activation. These induced activities were dependent on the RNF213 AAA+ domain. Our results suggest that the NFκB- and apoptosis-inducing functions of RNF213 may be negatively regulated by its ubiquitin ligase activity and that disruption of this regulation could contribute towards MMD onset.

Objectives After the Fukushima Daiichi nuclear power plant disaster in 2011, residents of Kawauchi village who experienced evacuation had a high risk of suffering from diabetes and metabolic syndrome compared with non-evacuees. In addition to evacuation, lifestyle characteristics can be important factors influencing the development and prognosis of diabetes or glucose tolerance. The current study aimed to evaluate the effects of evacuation (i.e., lifestyle changes) on the incidence of diabetes among the non-diabetic residents of Kawauchi village. Methods Design is retrospective cohort study. Annual health examination data of residents of Kawauchi village and control area (Ono town) in Fukushima prefecture from 2008 to 2017, as available from the Japanese National Health Insurance system. Participants were classified into three groups: “Diabetes (DM)” (FBG ≥ 126 mg/dL or HbA1c ≥ 6.5% or hospital visit for DM or usage of diabetic medication), “Borderline DM” (126 mg/dL > FBG ≥ 110 mg/dL or 6.5% > HbA1c ≥ 6.0%, and without hospital visit, and without diabetic medication), and “Normoglycemic” (FBG < 110 mg/dL and HbA1c < 6.0%, and without hospital visit, and without diabetic medication). New onset of diabetes was evaluated and the events or missing data were occurred at health checkup. For this survival analysis, 339 residents in Kawauchi and 598 residents in Ono were included. Average follow-up periods after 2010 were 3.9 years in Kawauchi village and 3.6 years in Ono town. Results Compared with the normoglycemic group, incidence of DM was much greater in the borderline DM group, where DM occurred among 38.2% of the group in 2012 and increased to over 60% cumulatively through 2017 in Kawauchi village. DM had a prevalence of 16.3% in 2012, and below 30% in 2017 in borderline DM group of Ono town. Cox proportional hazard regression analysis was applied to non-DM groups at both study sites separately to evaluate the effects of lifestyle changes at each site. While BMI, BMI change, and the lack of regular exercise (HR = 1.29, 1.72, and 5.04, respectively) showed significant associations with the onset of diabetes in Ono town, only BMI and late-night dinner (HR = 1.21 and 4.86, respectively) showed significant associations with diabetes onset in Kawauchi village. Conclusions The current results confirmed that diabetes incidence was increased 6 years after the Daiichi nuclear power plant disaster in Kawauchi. We also found changes in lifestyle habits, suggesting that diabetes prevention with promotion of healthy lifestyle behaviors is an urgent priority.

RNF213, a susceptibility gene for moyamoya disease, is associated with stress responses to various stressors. We previously reported that Rnf213 knockout (KO) mitigated endoplasmic reticulum (ER) stress-induced diabetes in the Akita mouse model of diabetes. However, the role of RNF213 in ER stress regulation remains unknown. In the present study, RNF213 knockdown significantly inhibited the upregulation of ER stress markers (CHOP and spliced XBP1) by chemical ER stress-inducers in HeLa cells. Levels of SEL1L, a critical molecule in ER-associated degradation (ERAD), were increased by RNF213 knockdown, and SEL1L knockdown prevented the inhibitory effect of RNF213 suppression on ER stress in HeLa cells, indicating SEL1L involvement in this inhibition of ER stress. SEL1L upregulation was also confirmed in pancreatic islets of Rnf213 KO/Akita mice and in Rnf213 KO mouse embryonic fibroblasts. Additionally, RNF213 suppression increased levels of HRD1, which forms a complex with SEL1L to degrade misfolded protein in cells under ER stress. In conclusion, we demonstrate that RNF213 depletion inhibits ER stress possibly through elevation of the SEL1L-HRD1 complex, thereby promoting ERAD in vitro and in vivo.

Chronic kidney disease of uncertain etiology (CKDu) in areas in and around Sri Lanka's North Central Province has been identified as a major non-communicable disease due to its high prevalence and the burden on the public health system. Controversial evidence relating to the etiology and risk factors of CKDu has been reported. The most debated is the role of trace elements such as Cd and As in the pathogenesis of CKDu. Urine and hair samples collected from CKDu patients and healthy controls were measured for the concentration of different elements including Cd and As. To assess the possible environmental exposures, drinking water and rice samples collected from the affected areas as well as unaffected areas in the country were analyzed. Transmission electronic microscopic analysis of renal biopsies from CKDu patients was also performed. Analysis of drinking water and rice samples indicated that the levels of all minerals and trace elements analyzed including Cd and As were within the levels recommended by World Health Organization and Sri Lanka drinking water guidelines and did not suggest any form of contamination. Analysis of biological samples, including urine, hair and renal tissue, did not provide evidence to support Cd or As toxicity in CKDu patients. Overall, the observations of this integrated, comprehensive study, which included biological, environmental and pathological investigations, strongly support our previous reports on the absence of Cd and As toxicity in areas with high prevalence of CKDu. Further, these observations do not provide evidence on the involvement of Cd and As in pathogenesis of CKDu in Sri Lanka.

[Objectives] Although the association between genetic factors, such as RNF213 mutations, and moyamoya disease (MMD) has been well investigated, environmental factors are largely undetermined. Thus, we aimed to examine whether viral infection increases the risk of MMD. [Materials and Methods] To eliminate the effect of presence or absence of the RNF213 p.R4810K mutation, the entire study population was positive for this mutation. We collected whole blood from 111 patients with MMD (45 familial and 66 sporadic cases) and 67 healthy volunteers, and we measured the immunoglobulin G titer of 11 viruses (cytomegalovirus, varicella-zoster virus, measles virus, rubella virus, herpes simplex virus, mumps virus, Epstein–Barr virus, human parvovirus B19, human herpesvirus 6 [HHV6], human herpesvirus 8, and John Cunningham virus) that were presumed to be associated with vasculopathy using the enzyme-linked immunosorbent assay. Positivity for past viral infection was determined by cut-off values obtained from previous reports and the manufacturer's instructions, and the positive rate was compared between cases and age- and sex-matched controls. We performed familial case-specific and sporadic case-specific analyses, as well as a case–control analysis. [Results] There was no significant difference in the positive rate between the case group and the control group in any of the analyses. A significant difference was only observed in the combined case–control analysis for HHV6 (p = 0.046), but the viral antibody-positive rate in control individuals was higher than in MMD cases. [Conclusions] Our cross-sectional study suggest that the investigated 11 viruses including HHV6 are unlikely to have an impact on MMD development.

[Objectives] It is sometimes difficult to differentiate middle cerebral artery disease from moyamoya disease because the two can present similarly yet have different treatment strategies. We investigated whether the presence of a narrow carotid canal and the RNF213 mutation can help differentiate between the two phenotypes. [Population and Methods] We analyzed 78 patients with moyamoya disease, 27 patients with middle cerebral artery disease, and 79 controls from 2 facilities. The carotid canal diameter was measured using computed tomography. The p.R4810K mutation was genotyped by TaqMan assay. A receiver operating characteristics analysis was performed to assess the significance of the carotid canal diameter for the accurate diagnosis of moyamoya disease. [Results] The carotid canal diameter was significantly narrower in patients with moyamoya disease than in controls. The optimal cutoff values were 5.0 mm for adult males and 4.5 mm for adult females and children (sensitivity: 0.82; specificity: 0.92). Among the patients with middle cerebral artery disease, 18.5% and 25.0% of the affected hemispheres had the p.R4810K mutation and narrow canal (i.e., below the cutoff), respectively, whereas only 3.1% of those had both. Contrastingly, 68.8% of the affected hemispheres in patients with moyamoya disease had both these characteristics. Among the patients with moyamoya disease, those with the p.R4810K mutation tended to have narrower carotid canals. [Conclusions] Although the presence of a narrow carotid canal or the p.R4810K mutation alone could not be used to distinguish those with moyamoya disease from those with middle cerebral artery disease, the combination of these factors could better characterize the two phenotypes.

Gastroesophageal reflux disease (GERD) is a common disease encountered in daily medical care and clinical problem which hampers daily life and reduces quality of life (QOL). The coexistence of GERD-related symptoms with the typical GERD symptoms, such as heartburn or acid regurgitation, and various upper abdominal symptoms is frequently observed in patients with GERD. However, the effect of these coexisting symptoms on the daily life and QOL of patients with GERD has not been clarified. Therefore, the effects of the various upper abdominal symptoms coexisting with GERD on the daily life and QOL of such patients were compared. A total of 113 newly diagnosed patients who visited our hospital with typical GERD symptoms were assessed using the modified frequency scale for the symptoms of GERD (MFSSG), gastroesophageal reflux and dyspepsia therapeutic efficacy and satisfaction test (GERD-TEST), and short-form 8-item health survey (SF-8) questionnaires. The “gastroesophageal reflux symptom” (7 items) and “dyspepsia symptom” (7 items) groups were divided into two “typical symptoms” and two “atypical symptoms” for a total of four categories. The Pearson’s correlation coefficient and multiple regression analysis were used to evaluate the correlations between each symptom category and dissatisfaction for daily life [eating, sleeping, daily activities, mood, as well as dissatisfaction for daily life-symptom subscale (SS), which is the average of the four items in the GERD-TEST, the physical component summary [PCS] and mental component summary [MCS] of the SF-8, and the influence of each symptom category on the daily life and QOL. The incidences of each symptom category in patients with GERD were high: typical GERD (100%), atypical GERD symptoms (67.3%), typical functional dyspepsia (FD) (71.7%), and atypical FD (75.2%). Pearson’s correlation analysis demonstrated significant correlations between each symptom category and living status (dissatisfactions of eating, sleeping, daily activities, daily life-SS) and almost all items in SF-8 (PCS, MCS) (P

Fluoride is an element that is widely distributed in the environment. The involvement of fluoride in pathogenesis of Chronic Kidney Disease of uncertain aetiology (CKDu) in Sri Lanka is a much-debated topic. This study aimed to investigate the fluoride concentration in drinking water in CKDu affected areas in Sri Lanka and to evaluate the possible effect of renal impairment on serum fluoride levels in CKDu patients. Drinking water (n = 60) from the common water sources from two CKDu prevalent areas and serum samples of CKDu patients (n = 311) and healthy controls (n = 276) were collected. Both environmental and biological samples were analysed for the concentration of fluoride. The fluoride concentration in over 95% of drinking water samples was below the WHO guideline of 1.5 mg/L. Serum fluoride concentrations in majority of the unaffected and early-stage CKDu patients (stages 1 and 2, eGFR >60 ml/min/1.73m2) were below the normal upper concentration of 50 μg/l and significantly higher levels were observed in patients in late stages of CKDu compared to the healthy controls. The available guidelines for drinking water are solely based on healthy populations with normal renal function. But, it is evident that once the kidney function is impaired, patients enter a vicious cycle as fluoride gradually accumulates in the body, further damaging the kidney tissue. Thus, close monitoring of serum fluoride levels in CKDu patients and establishing health-based target guidelines for fluoride in drinking water for the CKDu patients are recommended to impede the progression to end stage renal disease.

Objectives We investigated the quality of life (QOL) of patients using the Free/Low-Cost Medical Care Program, which is a system that enables people in financial difficulities to receive treatment free of charge or at a low cost. We also investigated the background charateristics and lifestyle of the patients. Methods The subjects were 226 outpatients who used the Free/Low-Cost Medical Care Program (use group) and 226 outpatients who did not use the program (non-use group). The method was an anonymous cross-sectional servey by mail. The survey items included basic attributes, health-related QOL (HRQOL), feeling of being poor, lifestyle diseases, lifestyle, and connection with the community. Results The number of respondants with valid responses was 97 in the use group and 85 in the non-use group. Among the basic attributes, there were a significant differense between the use group and the non-use group in the family structure, type of work, household income, and educational background. The HRQOL scores of the physical and social summary components were significantly lower in the use group than in the non-use group. The HRQOL scores of mental summary component were higher than the national standard HRQOL score in both the use and non-use groups. Conclusions In this study, it was considered that old age affected the HRQOL scores of the physical and social components. It was considered from the HRQOL scores of the mental aspect that the use of the Free/Low-Cost Medical Care Program might have contributed to mental stability a certain to extent.

This study investigated contamination trends and factors affecting the levels of brominated flame retardants (BFRs), including hexabromocyclododecane (HBCD) diastereomers, tetrabromobisphenol A (TBBP-A), and 2,4,6-tribromophenol (2,4,6-TBP), in breast milk in Japan. Breast milk samples (n = 64) were collected from mothers living in six prefectures in Japan. The mean concentrations were 2.2, 0.19, 0.29, 3.0, and 0.59 ng/g lipid weight for α-HBCD, β-HBCD, γ-HBCD, TBBP-A, and 2,4,6-TBP, respectively. Based on the previous studies, the levels of ΣHBCD in Japanese women's milk appear to be increasing, and the levels of TBBP-A are higher than those in other Asian countries. Although ΣHBCD were not correlated to phenolic BFRs, the concentration of β-HBCD was significantly correlated to the concentrations of TBBP-A (r = 0.440, p 0.01) and 2,4,6-TBP (r = 0.320, p 0.01). The concentration of γ-HBCD increased significantly with maternal age (r = 0.378, p 0.01), but the concentrations of the other analytes were not dependent on age. The concentration of α-HBCD was higher in primiparae than in multiparae (p 0.05), while TBBP-A was higher in multiparae. No significant correlation was found between the phenolic BFR levels in milk and mothers' age, working place, and drinking/smoking habits. These results suggest that exposure to α- and γ-HBCD diastereomers could be affected by maternal age and parity, respectively, because of their different kinetics and sources. Therefore, these factors should be considered when conducting infant risk assessments.

Type 1 diabetes (T1D) development, in part, is due to ER stress-induced β-cell apoptosis. Activation of the Ca2+-independent phospholipase A2 beta (iPLA2β) leads to the generation of pro-inflammatory eicosanoids, which contribute to β-cell death and T1D. ER stress induces iPLA2β-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA2β on sphingolipids (SLs), we characterized their profile in β-cells undergoing ER stress. ESI/MS/MS analyses followed by ANOVA/Student’s t-test were used to assess differences in sphingolipids molecular species in Vector (V) control and iPLA2β-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) β-cells. As expected, iPLA2β induction was greater in the OE and AK cells in comparison with V and WT cells. We report here that ER stress led to elevations in pro-apoptotic and decreases in pro-survival sphingolipids and that the inactivation of iPLA2β restores the sphingolipid species toward those that promote cell survival. In view of our recent finding that the SL profile in macrophages—the initiators of autoimmune responses leading to T1D—is not significantly altered during T1D development, we posit that the iPLA2β-mediated shift in the β-cell sphingolipid profile is an important contributor to β-cell death associated with T1D.

Objective We utilized job safety analysis (JSA) and hazard identification for work accident prevention in Para rubber wood sawmills, which aimed to investigate occupational health risk exposures and assess the health hazards at sawmills in the Trang Province, located in southern Thailand. Methods We conducted a cross-sectional study which included a walk-through survey, JSA, occupational risk assessment, and environmental samplings from March through September 2015 at four Para rubber wood sawmills. Results We identified potential occupational safety and health hazards associated with six main processes, including: 1) logging and cutting, 2) sawing the lumber into sheets, 3) planing and re-arranging, 4) vacuuming and wood preservation, 5) drying and planks re-arranging, and 6) grading, packing, and storing. Working in sawmills was associated with high risk of wood dust and noise exposure, occupational accidents injuring hands and feet, chemicals and fungicide exposure, and injury due to poor ergonomics or repetitive work. Discussion Several high-risk areas were identified from JSA and hazard identification of the working processes, especially high wood dust and noise exposure when sawing lumber into sheets and risk of occupational accidents of the hands and feet when struck by lumber. All workers were strongly recommended to use personal protective equipment in any working processes. Exposures should be controlled using local ventilation systems and reducing noise transmission. We recommend that the results from the risk assessment performed in this study be used to create an action plan for reducing occupational health hazards in Para rubber sawmills.

Background This study aimed to determine the effectiveness of genetic testing for the p.R4810K variant (rs112735431) of the Mysterin/RNF213 gene, which is associated with moyamoya disease and other intracranial vascular diseases, in the family members of patients with moyamoya disease. Methods We performed genotyping of the RNF213 p.R4810K polymorphism and magnetic resonance angiography on 59 relatives of 18 index patients with moyamoya disease. Nineteen individuals had follow-up magnetic resonance angiography with a mean follow-up period of 7.2 years. Results Six of the 34 individuals with the GA genotype (heterozygotes for p.R4810K) showed intracranial steno-occlusive lesions in the magnetic resonance angiography, whereas none of the 25 individuals with the GG genotype (wild type) showed any abnormalities. Follow-up magnetic resonance angiography revealed de novo lesions in 2 and disease progression in 1 of the 11 individuals with the GA genotype, despite none of the 8 individuals with the GG genotype showing any changes. Accordingly, 8 individuals had steno-occlusive lesions at the last follow-up, and all had the p.R4810K risk variant. The prevalence of steno-occlusive intracranial arterial diseases in family members with the p.R4810K variant was 23.5% (95% confidence interval: 9.27%-37.78%), which was significantly higher than in those without the variant (0%, P = .0160). Conclusions Genotyping of the p.R4810K missense variant is useful for identifying individuals with an elevated risk for steno-occlusive intracranial arterial diseases in the family members of patients with moyamoya disease.

Blood group O of ABO blood group system is considered as a risk factor for various bleeding events, but the relationship with endoscopic treatment-associated bleeding has yet to be investigated. This study aimed to evaluate whether blood group O is associated with delayed bleeding after colorectal endoscopic resection. This was a retrospective observational study based on medical records at four university hospitals in Japan. We reviewed the records for consecutive patients who underwent colorectal endoscopic resection from January 2014 through December 2017. The primary outcome was the incidence of delayed bleeding, defined as hematochezia or melena, requiring endoscopy, transfusion, or any hemostatic intervention up to 28 days after endoscopic resection. Multivariate logistic regression analysis was performed to adjust the impact of blood group O on the delayed bleeding. Among 10,253 consecutive patients who underwent colorectal endoscopic resection during the study period, 8625 patients met the criteria. In total, delayed bleeding occurred in 255 patients (2.96%). The O group had significantly more bleeding events compared with the non-O group (A, B, and AB) (relative risk, 1.62 [95% confidence interval, 1.24–2.10]; P

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive stenosis of large intracranial arteries and a hazy network of basal collaterals called moyamoya vessels. A polymorphism (R4810K) in the Ring Finger Protein 213 (RNF213) gene, at chromosome 17q25.3, is the strongest genetic susceptibility factor for MMD in East Asian populations. MMD was regarded prevalent in childhood and in East Asian populations. However, the so-called MMD could represent only the tip of the iceberg. MMD is increasingly reported in adult patients and in Western populations. Moreover, the RNF213 variant was recently reported to be associated with non-MMD disorders, such as intracranial atherosclerosis and systemic vasculopathy (e.g., peripheral pulmonary artery stenosis and renal artery stenosis). In this review, we summarize the spectrums of RNF213 vasculopathy in terms of clinical and genetic phenotypes. Continuous efforts are required for pathophysiology-based diagnoses and treatment, which will benefit from collaboration between clinicians and researchers, and between stroke and vascular physicians.

Background and Purpose— The ring finger protein 213 gene ( RNF213 ) is a susceptibility gene for moyamoya disease and large-artery ischemic stroke in East Asia. We examined the prevalence and correlates of the RNF213 p.R4810K variant in patients with early-onset ischemic stroke in a Japanese single-center cohort. Methods— We analyzed 70 early-onset stroke patients with intracranial arterial stenosis who developed a noncardioembolic stroke or transient ischemic attack from 20 to 60 years of age. Patients with moyamoya disease were excluded. Results— The RNF213 p.R4810K variant was found in 17 patients (24%), and more often in women than men (38% versus 16%, odds ratio 3.3; 95% CI, 1.1–10.2, P =0.04). The variant was identified in 35% of patients with stenosis in the M1 segment of the middle cerebral artery or the A1 segment of the anterior cerebral artery (odds ratio, 25.0; 95% CI, 1.4–438; P Conclusions— The RNF213 p.R4810K variant is common in early-onset ischemic stroke with anterior circulation stenosis in Japan. Further investigation of the RNF213 gene will provide new insights into pathogenetic mechanisms of early-onset stroke.

Background: Bradyarrhythmia is a common clinical manifestation. Although the majority of cases are acquired, genetic analysis of families with bradyarrhythmia has identified a growing number of causative gene mutations. Because the only ultimate treatment for symptomatic bradyarrhythmia has been invasive surgical implantation of a pacemaker, the discovery of novel therapeutic molecular targets is necessary to improve prognosis and quality of life. Methods: We investigated a family containing 7 individuals with autosomal dominant bradyarrhythmias of sinus node dysfunction, atrial fibrillation with slow ventricular response, and atrioventricular block. To identify the causative mutation, we conducted the family-based whole exome sequencing and genome-wide linkage analysis. We characterized the mutation-related mechanisms based on the pathophysiology in vitro. After generating a transgenic animal model to confirm the human phenotypes of bradyarrhythmia, we also evaluated the efficacy of a newly identified molecular-targeted compound to upregulate heart rate in bradyarrhythmias by using the animal model. Results: We identified one heterozygous mutation, KCNJ3 c.247A>C, p.N83H, as a novel cause of hereditary bradyarrhythmias in this family. KCNJ3 encodes the inwardly rectifying potassium channel Kir3.1, which combines with Kir3.4 (encoded by KCNJ5 ) to form the acetylcholine-activated potassium channel ( I KACh channel) with specific expression in the atrium. An additional study using a genome cohort of 2185 patients with sporadic atrial fibrillation revealed another 5 rare mutations in KCNJ3 and KCNJ5 , suggesting the relevance of both genes to these arrhythmias. Cellular electrophysiological studies revealed that the KCNJ3 p.N83H mutation caused a gain of I KACh channel function by increasing the basal current, even in the absence of m 2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective I KACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. Conclusions: The I KACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant I KACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective I KACh channel blocker. Thus, the I KACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the I KACh channel.

Human exposure to polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) may result in retention of specific congeners of hydroxylated PCBs (OH-PCBs) and hydroxylated/methoxylated PBDEs (OH-/MeO-PBDEs) in serum. However, dietary sources and biotransformation of OH-/MeO-PBDEs in humans are poorly understood. Therefore, this study was conducted to investigate the levels, profiles, and exposure sources of OH-/MeO-PBDEs along with OH-PCBs present in human serum. Twenty serum samples pooled from women of four age groups (30s/40s/50s/60s) living in four districts of Japan were analyzed for OH-/MeO-PBDEs, and their profiles were then compared with those of seafood (seaweed and fish). The major component of OH-PCBs in the phenolic fraction of serum was 4-OH-CB187 (mean: 85 pg g−1 wet weight (ww)). Total OH-PCBs accounted for about 1/20 of the total PCBs (mean; 1800 pg g−1 ww). In contrast, the predominant component of OH-PBDEs in serum was 6-OH-BDE47 (mean: 183 pg g−1 ww), which was about 20-fold higher than BDE-47 (mean; 8.7 pg g−1 ww). In the neutral fraction, 2′-MeO-BDE68 was primarily found at a similar concentration (mean 5.6 pg g−1 ww) to BDE-47. Both 4-OH-PCB187 and 2′-MeO-BDE68 were significantly correlated with woman's age (p

Background Quasi-moyamoya disease is an angiographical moyamoya disease equivalent accompanied by known underlying diseases. Mysterin/RNF213 is a major susceptibility gene for moyamoya disease, of which the p.R4810K variant is a founder polymorphism. The genetics of quasi-moyamoya disease is poorly understood, therefore, this study investigated a potential association between the p.R4810K polymorphism and quasi-moyamoya disease. Methods Genotyping of the p.R4810K variant was performed on 18 quasi-moyamoya disease cases and 91 controls, who visited Kyoto University Hospital or Kobe City Medical Center, Japan, between 2006 and 2015. Results The p.R4810K variant was found in 12 of 18 quasi-moyamoya disease patients. The frequency of p.R4810K carriers was significantly higher in quasi-moyamoya disease cases than in controls (66.7% versus 2.2%, odds ratio 89.0, 95% confidence interval: 19.2-669.4). Conclusions Our data showed that the RNF213 p.R4810K polymorphism was significantly associated with quasi-moyamoya disease.

Objectives Neonicotinoid insecticides have been widely used around the world since the 1990s. Reports have been made since the 1990s of rice paddy farmers in the North Central Region (NCR) of Sri Lanka suffering from chronic kidney disease with unknown etiology (CKDu). A preliminary evaluation of the exposure of local farmers in the NCR of Sri Lanka to neonicotinoids was performed. Methods We analyzed neonicotinoid and neonicotinoid metabolite concentrations in spot urine samples. We selected 40 samples, 10 from farmers with CKDu and 10 from controls from each of two areas, Medawachchiya and Girandurukotte. Results Imidacloprid and desmethyl-acetamiprid were found at significantly higher concentrations in the control samples (with medians of 51 ng/l and 340 ng/l, respectively) than in the CKDu samples (medians of 15 ng/l and 150 ng/l, respectively) when the results were not adjusted for the creatinine contents. None of the six compounds that were measured in the urine samples were found at significantly higher concentrations in the CKDu samples than in the control samples. None of the neonicotinoid concentrations in the samples analyzed in this study exceeded the concentrations that have been found in samples from the general population of Japan. Conclusions Farmers (both with and without CKDu) living in CKDu-endemic areas in the NCR of Sri Lanka are exposed to lower neonicotinoid concentrations than non-occupationally exposed residents of Japan.

Background:Helicobacter pylori eradication rates have decreased worldwide. Gastric acid inhibition during treatment is important to eradicate these bacteria successfully. A new potassium-competitive acid blocker, vonoprazan (VPZ), has been shown to achieve high eradication rates in a previous randomized controlled trial. Objective: To determine the efficacy of VPZ for H. pylori eradication. Methods: A total of 874 patients were enrolled; 431 received esomeprazole (EPZ) and 443 received VPZ. First-line regimens contained clarithromycin (CAM) 200 mg b.i.d., amoxicillin 750 mg b.i.d., and either EPZ 20 mg b.i.d. or VPZ 20 mg b.i.d. for 7 days. Metronidazole 250 mg b.i.d. replaced CAM in the second-line regimens. The eradication of H. pylori was assessed by 13C-urea breath tests 4-8 weeks after each therapy. Results: The overall first-line eradication rate was 79.9% (341/427) with EPZ vs. 86.3% (377/439) with VPZ (p = 0.019). The second-line eradication rate was 83.3% (45/51) with EPZ vs. 91.1% (41/45) with VPZ (p = 0.900). Conclusion: VPZ was significantly more effective than EPZ for first-line treatment. However, for second-line treatment, there was no significant difference between EPZ and VPZ.

In 1952, the Japanese Society for Hygiene had once passed a resolution at its 22nd symposium on population control, recommending the suppression of population growth based on the idea of cultivating a healthier population in the area of eugenics. Over half a century has now passed since this recommendation; Japan is witnessing an aging of the population (it is estimated that over 65-year-olds made up 27.7% of the population in 2017) and a decline in the birth rate (total fertility rate 1.43 births per woman in 2017) at a rate that is unparalleled in the world; Japan is faced with a “super-aging” society with low birth rate. In 2017, the Society passed a resolution to encourage all scientists to engage in academic researches to address the issue of the declining birth rate that Japan is currently facing. In this commentary, the Society hereby declares that the entire text of the 1952 proposal is revoked and the ideas relating to eugenics is rejected. Since the Society has set up a working group on the issue in 2016, there have been three symposiums, and working group committee members began publishing a series of articles in the Society’s Japanese language journal. This commentary primarily provides an overview of the findings from the published articles, which will form the scientific basis for the Society’s declaration. The areas we covered here included the following: (1) improving the social and work environment to balance between the personal and professional life; (2) proactive education on reproductive health; (3) children’s health begins with nutritional management in women of reproductive age; (4) workplace environment and occupational health; (5) workplace measures to counter the declining birth rate; (6) research into the effect of environmental chemicals on sexual maturity, reproductive function, and the children of next generation; and (7) comprehensive research into the relationship among contemporary society, parental stress, and healthy child-rearing. Based on the seven topics, we will set out a declaration to address Japan’s aging society with low birth rate.

RNF213 is a susceptibility gene for moyamoya disease, yet its exact functions remain unclear. To evaluate the role of RNF213 in adaptation of cerebral blood flow (CBF) under cerebral hypoperfusion, we performed bilateral common carotid artery stenosis surgery using external microcoils on Rnf213 knockout (KO) and vascular endothelial cell-specific Rnf213 mutant (human p.R4810K orthologue) transgenic (EC-Tg) mice. Temporal CBF changes were measured by arterial spin-labelling magnetic resonance imaging. In the cortical area, no significant difference in CBF was found before surgery between the genotypes. Three of eight (37.5%) KO mice died after surgery but all wild-type and EC-Tg mice survived hypoperfusion. KO mice had a significantly more severe reduction in CBF on day 7 than wild-type mice (KO, 29.7% of baseline level; wild-type, 49.3%; p = 0.038), while CBF restoration on day 28 was significantly impaired in both KO (50.0%) and EC-Tg (56.1%) mice compared with wild-type mice (69.5%; p = 0.031 and 0.037, respectively). Changes in the subcortical area also showed the same tendency as the cortical area. Additionally, histological analysis demonstrated that angiogenesis was impaired in both EC-Tg and KO mice. These results are indicative of the essential role of RNF213 in the maintenance of CBF.

Over the last two decades, usage of neonicotinoid (NEO) insecticides has increased due to their high selectivity for insects versus mammals and their effectiveness for extermination of insects resistant to conventional pesticides such as pyrethroids and organophosphates (OPs). However, historical change of the NEO exposure level in humans is poorly understood. The aim of this study is to reveal changes in the levels of NEO and OP exposure in the human body over the last two decades using biomonitoring technique. We quantified urinary concentrations of 7 NEOs (acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam) and 4 metabolites of OPs (dimethylphosphate, dimethylthiophosphate, diethylphosphate, and diethylthiophosphate) in 95 adult females aged 45-75 in 1994, 2000, 2003, 2009, and 2011 (n = 17-20 different individuals in each year). The results show that the detection rates of urinary NEOs in Japanese women increased significantly between 1994 and 2011, suggesting that intakes of NEOs into the human body rose during that period. In contrast, exposure to OPs having O,O-dimethyl moieties decreased steadily according to a finding that geometric means of urinary dimethylphosphate concentrations kept diminishing considerably. These changes may reflect the amounts of NEOs and OPs used as insecticides in Japan.

We investigated perfluorinated carboxylic acids (PFCAs) with 7–14 carbon atoms (C7–C14) in the Yodo River system in 2013. C7–C11 were detected at most sampling sites. The range and median of total PFCAs (ΣPFCAs) concentrations were 1.0–89.7 and 11.2 ng L−1, respectively. The dominant component was C8 (average for all samples = 53.3 ± 8.8%), followed by C7 (19.2 ± 6.7%) and C9 (17.6 ± 7.1%). The levels of C8 were confirmed to decrease greatly over the last 10 years. We assessed the fluxes in C7–C11 discharged from the basin based on the concentrations in river water and river flow rate. The flux of discharged ΣPFCAs was 237.0 g d−1 at the most downriver point of the assessment areas. Considering the variability in flow rate due to precipitation, the annual ΣPFCAs flux was estimated to be 86.5–173.4 kg y−1. Identification and quantification of PFCAs sources is difficult because the strength of the sources changes with time, and available information is quite limited. Further monitoring and investigation are necessary to understand sources of PFCAs, as well as their potential for human exposure.

ObjectiveTo investigate the efficacy of recombinant human soluble thrombomodulin (rTM) in preventing the development of walled-off necrosis (WON) in severe acute pancreatitis (SAP) patients.MethodsWe retrospectively analyzed 54 SAP patients divided into two groups: SAP patients treated by rTM (rTM group, 24 patients) and not treated by rTM (control group, 30 patients). rTM was administered to patients with disseminated intravascular coagulation (DIC). Initially, on the admission day, we recorded patient severity and pancreatic necrosis/ischemia positive or negative. Then we investigated development of WON using 4 weeks later CT/MRI. Finally we compared the proportions of patients developing WON in the rTM group and the control group.ResultsOn the admission day, the condition of patients treated by rTM was significantly worse than patients in the control group; rTM group vs. control: 71.8 ± 13.9 vs. 59.8 ± 15.3 years for age, 10.7 ± 3.5 vs. 8.0 ± 4.4 for Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and 3.3 ± 1.8 vs. 2.2 ± 1.8 for sequential organ failure assessment (SOFA) score (p

The familial clustering observed in chronic kidney disease of uncertain etiology (CKDu) characterized by tubulointerstitial damages in the North Central Region of Sri Lanka strongly suggests the involvement of genetic factors in its pathogenesis. The objective of the present study is to use whole-exome sequencing to identify the genetic variants associated with CKDu. Whole-exome sequencing of eight CKDu cases and eight controls was performed, followed by direct sequencing of candidate loci in 301 CKDu cases and 276 controls. Association study revealed rs34970857 (c.658G > A/p.V220M) located in the KCNA10 gene encoding a voltage-gated K channel as the most promising SNP with the highest odds ratio of 1.74. Four rare variants were identified in gene encoding Laminin beta2 (LAMB2) which is known to cause congenital nephrotic syndrome. Three out of four variants in LAMB2 were novel variants found exclusively in cases. Genetic investigations provide strong evidence on the presence of genetic susceptibility for CKDu. Possibility of presence of several rare variants associated with CKDu in this population is also suggested.

Background and Purpose— Rupture of intracranial aneurysms (IAs) causes subarachnoid hemorrhage, leading to immediate death or severe disability. Identification of the genetic factors involved is critical for disease prevention and treatment. We aimed to identify the susceptibility genes for IAs. Methods— Exome sequencing was performed in 12 families with histories of multiple cases of IA (number of cases per family ≥3), with a total of 42 cases. Various filtering strategies were used to select the candidate variants. Replicate association studies of several candidate variants were performed in probands of 24 additional IA families and 426 sporadic IA cases. Functional analysis for the mutations was conducted. Results— After sequencing and filtering, 78 variants were selected for the following reasons: allele frequencies of variants in 42 patients was significantly ( P GPR63 , ADAMST15 , MLL2 , IL10RA , PAFAH2 , THBD , IL11RA , FILIP1L , and ZNF222 ) to form 78 candidate variants by considering commonness in families, known disease genes, or ontology association with angiogenesis. Replicate association studies revealed that only p.E133Q in ADAMTS15 was aggregated in the familial IA cases (odds ratio, 5.96; 95% confidence interval, 2.40–14.82; P =0.0001; significant after the Bonferroni correction [ P =0.05/78=0.0006]). Silencing ADAMTS15 and overexpression of ADAMTS15 p.E133Q accelerated endothelial cell migration, suggesting that ADAMTS15 may have antiangiogenic activity. Conclusions— ADAMTS15 is a candidate gene for IAs.

1Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Yoshida Konoecho, Kyoto 606-8501, Japan 2Faculty of Medical Sciences, Department of Health Science, University of Fukui, Fukui 910-1193, Japan 3Department of Genetics, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Japan 4Ishikawa Prefectural Central Hospital, Kuratsukihigashi, Kanazawa, Ishikawa 920-8530, Japan 5Department of Pediatrics (NICU), Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan

Background/Aims: Currently, there is no study evaluating the effect of acotiamide on transient lower esophageal sphincter relaxations (TLESRs). The aim of this study was to evaluate the effect of acotiamide on TLESRs using simultaneous high-resolution manometry (HRM) and impedance-pH monitoring. Methods: Ten healthy subjects were enrolled. On day 1, subjects underwent HRM and impedance-pH recordings as a baseline. Subjects ate a 750-kcal liquid meal; recording was continued for 2 h while the subjects were in a sitting position. After the administration of acotiamide 100 mg three times a day for 1 week, subjects underwent HRM and impedance-pH recording under the same protocol. Results: A total of 208 TLESRs were identified at baseline. Acotiamide decreased the total number of TLESRs from 208 to 143 (p < 0.05). The rate of reflux events during TLESRs after acotiamide administration was similar to that at baseline (57% after acotiamide vs. 58% at baseline). Bolus clearance time was significantly reduced by acotiamide. Conclusions: Acotiamide was believed to have the potential for reducing TLESRs and for enhancing esophageal bolus clearance in healthy volunteers. Future research is needed to determine whether the effects of acotiamide that reduce TLESRs and enhance esophageal motility could improve symptoms in patients with refractory gastroesophageal reflux disease.

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.

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.

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.