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Familial episodic pain syndrome (FEPS) is an autosomal-dominant inherited disorder characterized by paroxysmal pain episodes. FEPS appears in early childhood, gradually disappearing with age, and pain episodes can be triggered by fatigue, bad weather, and cold temperatures. Several gain-of-function variants have been reported for SCN9A, SCN10A, or SCN11A, which encode the voltage-gated sodium channel α subunits Nav1.7, Nav1.8, and Nav1.9, respectively. In this study, we conducted genetic analysis in a four-generation Japanese pedigree. The proband was a 7-year-old girl, and her brother, sister, mother, and grandmother were also experiencing or had experienced pain episodes and were considered to be affected. The father was unaffected. Sequencing of SCN9A, SCN10A, and SCN11A in the proband revealed a novel heterozygous variant of SCN11A: g.38894937G>A (c.2431C>T, p.Leu811Phe). This variant was confirmed in other affected members but not in the unaffected father. The affected residue, Leu811, is located within the DII/S6 helix of Nav1.9 and is important for signal transduction from the voltage-sensing domain and pore opening. On the other hand, the c.2432T>C (p.Leu811Pro) variant is known to cause congenital insensitivity to pain (CIP). Molecular dynamics simulations showed that p.Leu811Phe increased the structural stability of Nav1.9 and prevented the necessary conformational changes, resulting in changes in the dynamics required for function. By contrast, CIP-related p.Leu811Pro destabilized Nav1.9. Thus, we speculate that p.Leu811Phe may lead to current leakage, while p.Leu811Pro can increase the current through Nav1.9.
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OBJECTIVES: The characteristics and clinical implications of posterior cerebral artery (PCA) involvement in unilateral moyamoya disease (U-MMD), such as laterality, frequency of the RNF213 p.R4810K mutation, and clinical outcomes, have not been well studied. POPULATION AND METHODS: We analyzed a cohort of 93 patients with U-MMD who participated in the SUPRA Japan study. Clinical characteristics and radiological examinations were collected from medical records. The presence of the p.R4810K mutation was determined using a TaqMan assay. The clinical outcome was assessed using the modified Rankin Scale (mRS). Univariate and multivariate logistic regression analyses were performed to assess the associations. RESULTS: Among the patients with U-MMD, PCA involvement was observed in 60.0 % (3/5) of patients with homozygous mutation, 11.3 % (7/62) of those with heterozygous mutation, and 3.8 % (1/26) of those with wild type, showing a significant linear trend (p < 0.001 for trend). PCA involvement was observed exclusively on the same side as the affected anterior circulation. Dyslipidemia and cerebral infarction at initial onset were independently associated with mRS ≥1. Hypertension was associated with mRS ≥1 and it was also linked to infarction at initial onset, suggesting a potential confounding effect. Although PCA involvement showed a trend for higher mRS, it was not statistically significant. CONCLUSIONS: Our findings indicate a gene dose effect of the p.R4810K mutation on PCA involvement, with the homozygous state showing the most significant effect. Both genetic and modifiable factors such as dyslipidemia may influence the progression of U-MMD.
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Dislipidemias , Enfermedad de Moyamoya , Humanos , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/genética , Enfermedad de Moyamoya/complicaciones , Arteria Cerebral Posterior/diagnóstico por imagen , Japón , Predisposición Genética a la Enfermedad , Mutación , Dislipidemias/complicaciones , Adenosina Trifosfatasas/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
Familial episodic pain syndrome (FEPS) is an early childhood onset disorder of severe episodic limb pain caused mainly by pathogenic variants of SCN11A, SCN10A, and SCN9A, which encode three voltage-gated sodium channels (VGSCs) expressed as key determinants of nociceptor excitability in primary sensory neurons. There may still be many undiagnosed patients with FEPS. A better understanding of the associated pathogenesis, epidemiology, and clinical characteristics is needed to provide appropriate diagnosis and care. For this study, nationwide recruitment of Japanese patients was conducted using provisional clinical diagnostic criteria, followed by genetic testing for SCN11A, SCN10A, and SCN9A. In the cohort of 212 recruited patients, genetic testing revealed that 64 patients (30.2%) harbored pathogenic or likely pathogenic variants of these genes, consisting of 42 (19.8%), 14 (6.60%), and 8 (3.77%) patients with variants of SCN11A, SCN10A, and SCN9A, respectively. Meanwhile, the proportions of patients meeting the tentative clinical criteria were 89.1%, 52.0%, and 54.5% among patients with pathogenic or likely pathogenic variants of each of the three genes, suggesting the validity of these clinical criteria, especially for patients with SCN11A variants. These clinical diagnostic criteria of FEPS will accelerate the recruitment of patients with underlying pathogenic variants who are unexpectedly prevalent in Japan.
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Pruebas Genéticas , Canal de Sodio Activado por Voltaje NAV1.7 , Canal de Sodio Activado por Voltaje NAV1.8 , Canal de Sodio Activado por Voltaje NAV1.9 , Humanos , Canal de Sodio Activado por Voltaje NAV1.7/genética , Canal de Sodio Activado por Voltaje NAV1.9/genética , Japón/epidemiología , Canal de Sodio Activado por Voltaje NAV1.8/genética , Masculino , Femenino , Pruebas Genéticas/métodos , Adulto , Adolescente , Niño , Predisposición Genética a la Enfermedad , Adulto Joven , Preescolar , Mutación , Dolor , Recto/anomalíasRESUMEN
BACKGROUND: Perfluorooctanoic acid (PFOA) is one of the major per- and polyfluoroalkyl substances. The role of ATP-binding cassette (ABC) transporters in PFOA toxicokinetics is unknown. METHODS: In this study, two ABC transporters, ABCB1 and ABCB4, were examined in mice with single intravenous PFOA administration (3.13 µmol/kg). To identify candidate renal PFOA transporters, we used a microarray approach to evaluate changes in gene expression of various kidney transporters in Abcb4 null mice. RESULTS: Biliary PFOA concentrations were lower in Abcb4 null mice (mean ± standard deviation: 0.25 ± 0.12 µg/mL) than in wild-type mice (0.87 ± 0.02 µg/mL). Immunohistochemically, ABCB4 expression was confirmed at the apical region of hepatocytes. However, renal clearance of PFOA was higher in Abcb4 null mice than in wild-type mice. Among 642 solute carrier and ABC transporters, 5 transporters showed significant differences in expression between wild-type and Abcb4 null mice. These candidates included two major xenobiotic transporters, multidrug resistance 1 (Abcb1) and organic anion transporter 3 (Slc22a8). Abcb1 mRNA levels were higher in Abcb4 null mice than in wild-type mice in kidney. In Abcb4 null mice, Abcb1b expression was enhanced in proximal tubules immunohistochemically, while that of Slc22a8 was not. Finally, in Abcb1a/b null mice, there was a significant decrease in the renal clearance of PFOA (0.69 ± 0.21 vs 1.1 mL ± 0.37/72 h in wild-type mice). A homology search of ABCB1 showed that several amino acids are mutated in humans compared with those in rodents and monkeys. CONCLUSIONS: These findings suggest that, in the mouse, Abcb4 and Abcb1 are excretory transporters of PFOA into bile and urine, respectively.
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Caprilatos , Fluorocarburos , Eliminación Hepatobiliar , Humanos , Ratones , Animales , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Fluorocarburos/toxicidad , Fluorocarburos/metabolismo , Riñón , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismoRESUMEN
Our previous studies reported that perfluorooctanoic acid (PFOA) contamination decreased in well, tap, and surface water around a fluoropolymer plant in Osaka, Japan, between 2003 and 2016. In this study, we evaluated the degradability of PFOA and perfluorohexanoic acid in river soils to identify the influence of the degradation on the perfluorocarboxylic acids (PFCAs) in the Yodo River Basin. We also investigated the influence of abiotic oxidation on the formation of PFCAs in soils and measured the fluorotelomer alcohols (FTOHs) as precursors of PFCAs in the soil and air samples collected at Osaka and Kyoto. No major degradations were observed in soils contaminated with PFCA during the 24-week experimental period, while the PFOA levels increased only in the control group. The PFCA levels significantly increased after oxidation in this group. The dominant FTOH in soils was 10:2 FTOH, whereas 6:2 FTOH was dominant in the air samples. These findings suggest that PFOA was rapidly removed from water system but persist in soils. Moreover, the results indicate the need to evaluate not only the PFCAs, but also the FTOHs and other precursors for the accurate prediction of PFCA accumulation and fates in the environment.
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Polímeros de Fluorocarbono , Fluorocarburos , Suelo , Japón , Ríos , Fluorocarburos/análisis , AguaRESUMEN
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.
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Estrés del Retículo Endoplásmico , Enfermedad de Moyamoya , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Animales , Estrés del Retículo Endoplásmico/genética , Degradación Asociada con el Retículo Endoplásmico , Fibroblastos/metabolismo , Células HeLa , Humanos , Ratones , Enfermedad de Moyamoya/genética , Proteínas/metabolismo , Factores de Transcripción/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Regulación hacia ArribaRESUMEN
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.
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Infecciones por Virus de Epstein-Barr , Enfermedad de Moyamoya , Virosis , Adenosina Trifosfatasas/genética , Estudios Transversales , Predisposición Genética a la Enfermedad , Herpesvirus Humano 4 , Humanos , Enfermedad de Moyamoya/genética , Ubiquitina-Proteína Ligasas/genética , Virosis/complicaciones , Virosis/diagnósticoRESUMEN
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.
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Adenosina Trifosfatasas , Enfermedad de Moyamoya , Ubiquitina-Proteína Ligasas , Adenosina Trifosfatasas/genética , Adulto , Niño , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Enfermedad de Moyamoya/diagnóstico por imagen , Enfermedad de Moyamoya/genética , Factores de Transcripción , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
BACKGROUND: 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. METHODS: 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. RESULTS: 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 < 0.001). In multivariate logistic regression analysis, blood group O remained an independent risk factor for the bleeding (adjusted odds ratio, 1.60 [95% confidence interval, 1.18-2.17]; P = 0.002). CONCLUSIONS: Blood group O was associated with an increased risk of delayed bleeding in patients undergoing colorectal endoscopic resection. Preoperative screening for ABO blood group could improve risk assessments.
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Antígenos de Grupos Sanguíneos , Neoplasias Colorrectales , Hemorragia Gastrointestinal/epidemiología , Hemorragia Gastrointestinal/etiología , Humanos , Hemorragia Posoperatoria/epidemiología , Hemorragia Posoperatoria/etiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Type 1 diabetes (T1D) development, in part, is due to ER stress-induced ß-cell apoptosis. Activation of the Ca2+-independent phospholipase A2 beta (iPLA2ß) leads to the generation of pro-inflammatory eicosanoids, which contribute to ß-cell death and T1D. ER stress induces iPLA2ß-mediated generation of pro-apoptotic ceramides via neutral sphingomyelinase (NSMase). To gain a better understanding of the impact of iPLA2ß on sphingolipids (SLs), we characterized their profile in ß-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 iPLA2ß-overexpressing (OE) INS-1 and Akita (AK, spontaneous model of ER stress) and WT-littermate (AK-WT) ß-cells. As expected, iPLA2ß 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 iPLA2ß 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 iPLA2ß-mediated shift in the ß-cell sphingolipid profile is an important contributor to ß-cell death associated with T1D.
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Apoptosis , Estrés del Retículo Endoplásmico , Células Secretoras de Insulina/metabolismo , Lipasa/metabolismo , Proteínas de la Membrana/metabolismo , Esfingolípidos/metabolismo , Apoptosis/genética , Línea Celular , Cromatografía Liquida , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/metabolismo , Estrés del Retículo Endoplásmico/genética , Expresión Génica , Humanos , Lipasa/genética , Lipidómica/métodos , Proteínas de la Membrana/genética , Modelos Biológicos , Espectrometría de Masas en TándemRESUMEN
BACKGROUND AND AIM: 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. METHODS: 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. RESULTS: 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 < 0.05). Multiple regression analysis indicated the largest influences of each symptom category on living status and QOL in descending order: dissatisfaction for eating (atypical FD, typical FD), daily activities (atypical FD, typical FD, typical GERD), mood (atypical FD), daily life-SS (atypical FD, typical FD), PCS (typical FD), and MCS (atypical FD) (P < 0.05). CONCLUSION: Coexisting FD symptoms, particularly atypical FD symptoms, had a large influence on the impairments of daily life and decreases in QOL. Daily medical care of GERD requires attention to coexisting symptoms and their treatment instead of just focusing on the chief complaints by patients.
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Dispepsia , Reflujo Gastroesofágico , Dispepsia/complicaciones , Dispepsia/tratamiento farmacológico , Dispepsia/epidemiología , Reflujo Gastroesofágico/diagnóstico , Pirosis/complicaciones , Humanos , Calidad de Vida , Encuestas y CuestionariosRESUMEN
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 ( IKACh 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 IKACh channel function by increasing the basal current, even in the absence of m2 muscarinic receptor stimulation. We generated transgenic zebrafish expressing mutant human KCNJ3 in the atrium specifically. It is interesting to note that the selective IKACh channel blocker NIP-151 repressed the increased current and improved bradyarrhythmia phenotypes in the mutant zebrafish. CONCLUSIONS: The IKACh channel is associated with the pathophysiology of bradyarrhythmia and atrial fibrillation, and the mutant IKACh channel ( KCNJ3 p.N83H) can be effectively inhibited by NIP-151, a selective IKACh channel blocker. Thus, the IKACh channel might be considered to be a suitable pharmacological target for patients who have bradyarrhythmia with a gain-of-function mutation in the IKACh channel.
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Fibrilación Atrial , Bloqueo Atrioventricular , Bradicardia , Canales de Potasio Rectificados Internamente Asociados a la Proteína G , Enfermedades Genéticas Congénitas , Mutación Missense , Sustitución de Aminoácidos , Animales , Animales Modificados Genéticamente , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Fibrilación Atrial/fisiopatología , Bloqueo Atrioventricular/genética , Bloqueo Atrioventricular/metabolismo , Bloqueo Atrioventricular/patología , Bloqueo Atrioventricular/fisiopatología , Benzopiranos/farmacología , Bradicardia/genética , Bradicardia/metabolismo , Bradicardia/patología , Bradicardia/fisiopatología , Técnicas Electrofisiológicas Cardíacas , Femenino , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/antagonistas & inhibidores , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/genética , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/metabolismo , Enfermedades Genéticas Congénitas/patología , Enfermedades Genéticas Congénitas/fisiopatología , Humanos , Masculino , Xenopus laevis , Pez CebraRESUMEN
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.
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Dominio AAA , Adenosina Trifosfatasas/química , Adenosina Trifosfatasas/genética , Apoptosis , Enfermedad de Moyamoya/genética , Mutación/genética , FN-kappa B/metabolismo , Dominios RING Finger , Ubiquitina-Proteína Ligasas/química , Ubiquitina-Proteína Ligasas/genética , Secuencia de Aminoácidos , Células HEK293 , Humanos , Lisina/metabolismo , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Poliubiquitina/metabolismo , Factores de Transcripción/metabolismo , Enzimas Ubiquitina-Conjugadoras/metabolismoRESUMEN
BACKGROUND AND STUDY AIMS: An automatic carbon dioxide (CO2) insufflating system (SPACE) was developed to stabilize intra-lumenal pressure (ILP) during endoscopic interventions. This study investigated whether SPACE could improve the control and monitoring of extra-lumenal intra-abdominal pressure (IAP) after establishing a perforation during endoscopic full-thickness resection (EFTR) of the gastric wall in porcine models. MATERIALS AND METHODS: After first establishing the optimal preset pressure for gastric EFTR in four pigs, we compared IAP dynamics during EFTR between manual insufflation and SPACE using a block-randomized study (n = 10). IAP was percutaneously monitored and plotted on a timeline graph every 5 s. The maximal IAP and the area under the IAP curve exceeding 10 mmHg (AUC≥10 mmHg) were compared between groups, with the agreement between IAP and endolumenally monitored ILP also analyzed for animals in the SPACE group. RESULTS: In the first study, 8 mmHg was identified as the most preferable preset pressure after establishment of the perforation. In the randomized study, the mean maximal IAP in the SPACE group was significantly lower than that in the manual insufflation group (11.0 ± 2.0 mmHg vs. 17.0 ± 3.5 mmHg; P = 0.03). The mean AUC≥10 mmHg was also significantly smaller in the SPACE group. Bland-Altman analysis demonstrated agreement between IAP and ILP within a range of ± 1.0 mmHg. CONCLUSIONS: SPACE could be used to control and safely monitor IAP during gastric EFTR by measuring ILP during perforation of the gastric wall.
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Endoscopía , Insuflación , Monitoreo Intraoperatorio , Animales , Femenino , Dióxido de Carbono , Endoscopía/métodos , Insuflación/métodos , Monitoreo Intraoperatorio/instrumentación , Monitoreo Intraoperatorio/métodos , Presión , PorcinosRESUMEN
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.
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Diabetes Mellitus/epidemiología , Estilo de Vida , Anciano , Estudios de Cohortes , Diabetes Mellitus/etiología , Femenino , Accidente Nuclear de Fukushima , Encuestas Epidemiológicas , Humanos , Incidencia , Japón/epidemiología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
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<0.01) but in only one patient (9%) with intracranial posterior circulation stenosis. Conventional atherosclerotic risk factors did not differ between variant carriers and noncarriers. 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.
Asunto(s)
Adenosina Trifosfatasas/genética , Isquemia Encefálica/genética , Estenosis Carotídea/genética , Variación Genética , Accidente Cerebrovascular/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Factores de Edad , Isquemia Encefálica/epidemiología , Estenosis Carotídea/epidemiología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Accidente Cerebrovascular/epidemiologíaRESUMEN
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.
Asunto(s)
Adenosina Trifosfatasas/genética , Aneurisma Intracraneal/genética , Ubiquitina-Proteína Ligasas/genética , Población Blanca/genética , Adulto , Anciano , Alelos , Canadá , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Técnicas de Genotipaje , Humanos , Aneurisma Intracraneal/diagnóstico , Masculino , Persona de Mediana Edad , Linaje , Polimorfismo de Nucleótido Simple , Reproducibilidad de los Resultados , Análisis de Secuencia de ADNRESUMEN
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.
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Envejecimiento , Tasa de Natalidad/tendencias , Proyectos de Investigación/normas , Sociedades Científicas/organización & administración , Niño , Salud Infantil , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/prevención & control , Femenino , Directrices para la Planificación en Salud , Humanos , Japón/epidemiología , Masculino , Salud Laboral , Salud Reproductiva/educación , Estrés Psicológico/prevención & control , Salud de la MujerRESUMEN
Radiation dose rates were evaluated in three areas neighboring a restricted area within a 20- to 50-km radius of the Fukushima Daiichi Nuclear Power Plant in August-September 2012 and projected to 2022 and 2062. Study participants wore personal dosimeters measuring external dose equivalents, almost entirely from deposited radionuclides (groundshine). External dose rate equivalents owing to the accident averaged 1.03, 2.75, and 1.66 mSv/y in the village of Kawauchi, the Tamano area of Soma, and the Haramachi area of Minamisoma, respectively. Internal dose rates estimated from dietary intake of radiocesium averaged 0.0058, 0.019, and 0.0088 mSv/y in Kawauchi, Tamano, and Haramachi, respectively. Dose rates from inhalation of resuspended radiocesium were lower than 0.001 mSv/y. In 2012, the average annual doses from radiocesium were close to the average background radiation exposure (2 mSv/y) in Japan. Accounting only for the physical decay of radiocesium, mean annual dose rates in 2022 were estimated as 0.31, 0.87, and 0.53 mSv/y in Kawauchi, Tamano, and Haramachi, respectively. The simple and conservative estimates are comparable with variations in the background dose, and unlikely to exceed the ordinary permissible dose rate (1 mSv/y) for the majority of the Fukushima population. Health risk assessment indicates that post-2012 doses will increase lifetime solid cancer, leukemia, and breast cancer incidences by 1.06%, 0.03% and 0.28% respectively, in Tamano. This assessment was derived from short-term observation with uncertainties and did not evaluate the first-year dose and radioiodine exposure. Nevertheless, this estimate provides perspective on the long-term radiation exposure levels in the three regions.