担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

出版者・発行元：Computers and Fluids  

We propose a monolithic fluid–structure interaction (FSI) method that presents the advantages of both the reference map technique (RMT) and the Lagrangian Markers approach on a unified, cell-centered finite volume Eulerian framework. Full Eulerian methods that use a Cartesian mesh are attractive for FSI problems that require large-scale computing and involve complex geometries and large solid deformations. However, conventional full Eulerian methods use the velocity gradient to evaluate solid deformations, hence they suffer from numerical instability caused by the discontinuity of the velocity gradient near the interface. In this work, we develop a novel algorithm that interpolates and transfers a reference mapping information field between a collection of Lagrangian Markers and a Eulerian finite volume framework. As a result of integrating these approaches, our method is able to (1) evaluate solid deformations without computing the velocity gradient in the Eulerian framework thanks to RMT, and (2) remove the numerical dissipation of interfaces and internal variables caused by advection in the full Eulerian RMT, thanks to the use of the Lagrangian Markers to compute the constitutive equations. We illustrate with numerical examples that the proposed method preserves geometrical features and yields more accurate results for the deformation and energy than conventional Eulerian FSI method and the full Eulerian RMT.

DOI： 10.1016/j.compfluid.2024.106210

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出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1410215151

CiNii Research

記述言語：英語   出版者・発行元：American Journal of Human Genetics  

Copy-number variants (CNVs) play a substantial role in the molecular pathogenesis of hereditary disease and cancer, as well as in normal human interindividual variation. However, they are still rather difficult to identify in mainstream sequencing projects, especially involving exome sequencing, because they often occur in DNA regions that are not targeted for analysis. To overcome this problem, we developed OFF-PEAK, a user-friendly CNV detection tool that builds on a denoising approach and the use of “off-target” DNA reads, which are usually discarded by sequencing pipelines. We benchmarked OFF-PEAK on data from targeted sequencing of 96 cancer samples, as well as 130 exomes of individuals with inherited retinal disease from three different populations. For both sets of data, OFF-PEAK demonstrated excellent performance (>95% sensitivity and >80% specificity vs. experimental validation) in detecting CNVs from in silico data alone, indicating its immediate applicability to molecular diagnosis and genetic research.

DOI： 10.1016/j.ajhg.2024.03.001

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PubMed

記述言語：英語   出版者・発行元：Retina  

Purpose:To investigate the incidence of intraocular inflammation (IOI) and its risk factors following intravitreal injections of brolucizumab for neovascular age-related macular degeneration in Japan.Methods:A total of 1,351 Japanese consecutive patients with neovascular age-related macular degeneration who were treated with brolucizumab from May 2020 to May 2022 at 14 institutions were examined. The variables analyzed were the number of brolucizumab injections, time to onset of IOI, and risk factors.Results:Intraocular inflammation developed in 152 eyes (11.3%). Retinal vasculitis and/or retinal occlusion occurred in 53 eyes (3.9%). Ninety-four patients received bilaterally, bilateral IOI occurred in five patients (5.3%). Sixteen eyes (1.2%) had irreversible visual acuity loss and nine eyes (0.67%) had visual loss of three lines or more due to retinal vasculitis and/or retinal occlusion. The cumulative IOI incidence was 4.5%, 10.3%, and 12.2% at 30, 180, and 365 days (1-year), respectively. History of IOI (including retinal vasculitis) and/or retinal occlusion (odds ratio [OR], 5.41; P = 0.0075) and female sex (OR, 1.99; P = 0.0004) were significantly associated with IOI onset.Conclusion:The 1-year cumulative incidence of IOI in Japanese neovascular age-related macular degeneration patients treated with brolucizumab was 12.2%. History of IOI (including retinal vasculitis) and/or retinal occlusion and female sex were significant risk factors.

DOI： 10.1097/IAE.0000000000004009

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PubMed

記述言語：英語   出版者・発行元：Journal of Medical Genetics  

Background As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP–allied diseases. Methods We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines. Results A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases. Conclusion A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.

DOI： 10.1136/jmg-2023-109750

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Journal of Ophthalmology  

Purpose: To clarify the genetic and clinical features of Japanese patients with ABCA4-associated retinopathy. Design: Retrospective, multicenter cohort study. Methods: Patients with retinal degeneration and biallelic ABCA4 variants were recruited from 13 different hospitals. Whole exome sequencing analysis was used for genetic testing. Comprehensive ophthalmic examinations were performed on matched patients. The primary outcome measure was identifying multimodal retinal imaging findings associated with disease progression. Results: This study included 63 patients: 19 with missense/missense, 23 with missense/truncation, and 21 with truncation/truncation genotypes. In total, 62 variants were identified, including 29 novel variants. Six patients had a mild phenotype characterized by foveal-sparing or preserved foveal structure, including 4 with missense/missense and 2 with missense/truncation genotypes. The p.Arg212His variant was the most frequent in patients with mild phenotypes (4/12 alleles). Clinical findings showed a disease duration-dependent worsening of the phenotypic stage. Patients with the truncation/truncation genotype exhibited rapid retinal degeneration within a few years and definite fundus autofluorescence imaging patterns, including hyper autofluorescence at the macula and few or no flecks. Conclusions: Our results indicate that missense/missense or missense/truncation genotypes, including the p.Arg212His variant, are associated with a relatively mild phenotype. In contrast, the truncation/truncation genotype causes rapid and severe retinal degeneration in Japanese patients with ABCA4-associated retinopathy. These data are vital in predicting patient prognosis, guiding genetic counseling, and stratifying patients for future clinical trials.

DOI： 10.1016/j.ajo.2024.03.007

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記述言語：英語  

DOI： 10.7759/cureus.55716

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PubMed

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1410215088

CiNii Research

記述言語：英語   出版者・発行元：British Journal of Ophthalmology  

Background/aims The accuracy of pattern deviation (PD) in estimating the damage to the glaucomatous visual field (VF) in the central 10° in eyes with glaucoma and cataract is unclear. Methods This retrospective study includes 63 eyes of 52 glaucoma patients who successfully underwent cataract surgery or cataract surgery plus iStent implantation. Using the Humphrey Field Analyser 10-2 test, VF was measured within 6 months preoperatively and postoperatively (VF pre and VF post, respectively). The mean total deviation values in VF post (mTD post) indicates glaucomatous damage without cataract and the difference between this value and mean PD values in VF pre (mPD pre) was evaluated (ϵmPD). The effect of cataract was then evaluated as the difference between mTD post and mTD pre ( "mTD), while the effects of mTD post and "mTD on ϵmPD were also assessed. In addition, based on preoperative visual acuity (VA pre) and VF pre, the optimal model for predicting mTD post was identified. The error of this method (ϵOptimalModel) was estimated as the difference against mTD post, which was compared with ϵmPD. Results Compared with mTD pre, there was a significant improvement in mTD post (p=0.028). A significant difference was observed between mPD pre and mTD post (p<0.001). Further, ϵmPD significantly increased with the increase of mTD post or "mTD (p<0.001 and p=0.0444, respectively). The absolute ϵOptimalModel was significantly smaller than the absolute ϵmPD (p<0.001). Conclusions This study warns clinicians that PD of the central 10° VF might underestimate the glaucomatous VF damage with the progression of glaucoma and overestimate it as a cataract progresses.

DOI： 10.1136/bjo-2022-322274

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

DOI： 10.1016/j.gimo.2023.100839

出版者・発行元：Cold Spring Harbor Laboratory  

Abstract

Background

As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)–related genes in a large number of Japanese RP patients by applying the standardized variant interpretation guidelines for Japanese IRD patients (J-IRD-VI guidelines) built upon ACMG/AMP rules and assess the contribution of these genes in RP-allied diseases.

Methods

We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, all newly analyzed), including Usher syndrome, Leber congenital amaurosis, and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines.

Results

A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 RP patients. This led to a genetic diagnostic rate in 38.6% of RP patients, withEYSaccounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for CRD patients was 28.2%, with RP-related genes significantly contributing over other allied diseases.

Conclusion

A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the unique genetic findings for Japanese IRD patients; these findings serve as a foundation for the clinical application of gene-specific therapies.

DOI： 10.1101/2023.11.09.23297953

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology  

Purpose: To clarify the abilities of circumpapillary retinal nerve fiber layer thickness (cpRNFLT) obtained by optical coherence tomography (OCT) and circumpapillary vessel density (cpVD) measured by OCT-angiography to distinguish different stages in primary open-angle glaucoma determined by 24–2 or 30–2 static visual field (VF) testing. Methods: This retrospective study includes 25 healthy normal eyes of 25 subjects and 87 primary open-angle glaucoma eyes of 87 patients. Areas under the receiver operating characteristic curves (AUROC) were evaluated for determining glaucoma stages using cpRNFLT and cpVD. The absolute errors of the estimated mean total deviation (mTD) using optimal models with cpRNFLT and cpVD were also compared. Results: The AUROCs for discriminating glaucomatous eyes from normal eyes was significantly higher for cpRNFLT than the respective AUROCs for cpVD (0.969 [95% CI 0.939 to 0.998] vs. 0.872 [95% CI 0.806 to 0.938], p = 0.006), whereas cpVD had significantly higher AUROC for discriminating severe glaucoma eyes from moderate glaucoma eyes than cpRNFLT (0.771 [95% CI 0.655 to 0.886] vs. 0.578 [95% CI 0.420 to 0.736], p = 0.022). The mean absolute error in estimating mTD using both cpRNFLT and cpVD was significantly less than the error using cpRNFLT alone (4.56 ± 3.76 dB vs. 5.39 ± 4.00 dB, p = 0.027). Conclusion: Our results suggest that cpVD is better for follow-ups after moderate stage. The combination of cpRNFLT and cpVD may improve VF estimation compared to cpRNFLT alone.

DOI： 10.1007/s00417-023-06302-y

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記述言語：英語   出版者・発行元：Redox Biology  

Toxoplasmosis is a major infectious disease, affecting approximately one-third of the world's population; its main clinical manifestation, ocular toxoplasmosis (OT), is a severe sight-threatening disease. Nevertheless, the diagnosis of OT is based on clinical findings, which needs improvement, even with biochemical tests, such as polymerase chain reaction and antibody detections. Furthermore, the efficacy of OT-targeted treatment is limited; thus, additional measures for diagnosis and treatments are needed. Here, we for the first time report a significantly reduced iron concentration in the vitreous humor (VH) of human patients infected with OT. To obtain further insights into molecular mechanisms, we established a mouse model of T. gondii infection, in which intravitreally injected tracer 57Fe, was accumulated in the neurosensory retina. T. gondii-infected eyes showed increased lipid peroxidation, reduction of glutathione peroxidase-4 expression and mitochondrial deformity in the photoreceptor as cristae loss. These findings strongly suggest the involvement of ferroptotic process in the photoreceptor of OT. In addition, deferiprone, an FDA-approved iron chelator, reduced the iron uptake but also ameliorated toxoplasma-induced retinochoroiditis by reducing retinal inflammation. In conclusion, the iron levels in the VH could serve as diagnostic markers and iron chelators as potential treatments for OT.

DOI： 10.1016/j.redox.2023.102890

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記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

目的:脳回状脈絡網膜萎縮症(GACR)は,本邦ではまれな常染色体潜性遺伝(劣性遺伝)の先天性代謝異常症で,ビタミンB6(VitB6)依存性オルニチンアミノ基転移酵素活性の低下による高オルニチン血症を特徴とし,進行性の脈絡網膜変性を来す.今回,GACR症例を報告するとともに,過去の日本人GACR報告例の遺伝学的解析結果と比較検討した.症例:3歳,男児.外斜視の精査を目的に紹介受診となった.以前より夜盲を呈していたが,明らかな眼底異常はなく経過観察となった.6歳時の眼底検査で両眼の耳側網膜周辺部に特徴的な脳回状の網脈絡膜萎縮がみられた.全視野刺激網膜電図の杆体系・錐体系反応はいずれも消失していた.高オルニチン血症を認め,GACRが疑われたため,VitB6投与を開始したが,血中オルニチン値は低下しなかった.低蛋白質食治療を併用したところ血中オルニチン値は低下した.最終的に必須アミノ酸を補った蛋白質制限とVitB6投与によって血中オルニチン値の低下が維持された.全エクソーム解析を行い,ornithine aminotransferase(OAT)遺伝子に複合ヘテロ接合性変異(p.Arg271Lysとp.Arg426Ter)が検出された.8歳時の眼底検査で網脈絡膜萎縮は明らかに拡大していた.結論:低蛋白質食治療とVitB6投与の併用によって血中オルニチン値の低下が維持されたが,網脈絡膜萎縮は進行性に拡大した.本症例も含め,過去の日本人GACR症例(13例)のOAT遺伝子変異をまとめた結果,p.Arg426Terが高頻度変異(27%,7/26アレル)であることが見出された.(著者抄録)

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1410214923

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：American Journal of Ophthalmology  

PURPOSE: To determine the correlation between the presence of torque teno virus (TTV) in the aqueous humor of patients with uveitis and clinical information, including immunodeficiency history. DESIGN: Multicenter, retrospective, cross-sectional study. METHODS: Fifty-eight patients with uveitis with a suspected infectious etiology and 24 controls with cataract or age-related macular degeneration were included. We used quantitative polymerase chain reaction to test all subjects for TTV and multiplex polymerase chain reaction to test uveitis subjects for common ocular pathogens. When possible, both serum and aqueous humor samples were tested. Ocular TTV positivity was compared with age, sex, and a history of systemic immunodeficiency with logistic analysis. RESULTS: Ocular TTV positivity was found in 23%, 11%, and 0% of patients with herpetic uveitis, nonherpetic uveitis, and controls, respectively. Among patients with herpes infection, positivity for ocular TTV was found in 43%, 8%, 14%, and 50% of patients with cytomegalovirus retinitis, iridocyclitis, acute retinal necrosis, and Epstein–Barr virus–positive uveitis, respectively. Patients with cytomegalovirus retinitis showed a significantly higher rate of ocular TTV infection than controls (P =.008). Serum analysis revealed TTV positivity in 90% of patients with uveitis and in 100% of controls. Age- and gender-adjusted logistic analysis revealed a correlation between ocular TTV positivity and systemic immunodeficiency (P =.01), but no correlations between ocular TTV and age, gender, or viral pathogenic type. CONCLUSIONS: These findings suggest that positivity for ocular TTV was correlated with a clinical history of systemic immunodeficiency.

DOI： 10.1016/j.ajo.2023.06.012

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記述言語：英語   出版者・発行元：Ophthalmic Genetics  

Background: Nanophthalmos (NNO) is a rare condition with significantly shorter axial length than normal. Several genes are known to cause NNO, among them the MFRP and PRSS56 genes have been reported to cause majority of NNOs. The purpose of this study was to determine the genetic basis of Japanese patients with NNO. Materials and Methods: We studied seven patients with NNO. Whole exome sequencing (WES) and Sanger sequencing were performed to determine the variants causing the NNO. We also reviewed the medical charts of the patients to determine the phenotype of these seven patients. Results: WES revealed that four patients from three families carried homozygous frameshift variants of the PRSS56 gene (c.1066dupC). Two novel variants of the MFRP gene were detected in the other two patients: one proband had a homozygous missense variant (c.1486 G>A) and the other had a compound heterozygous variant (c.1486 G>A and c.662_663insT). The axial length of the eight eyes with the PRSS56 variant was 15.69 ± 0.48 mm (mean ± SD) and that for the 4 eyes with the MFRP variant was 15.63 ± 0.69 mm. Three of the six cases with the PRSS56 or MFRP variant had the uveal effusion syndrome. Conclusions: NNOs in Japanese patients are caused by variants of the PRSS56 and MFRP genes as in other ethnic populations. In addition, two new variants of the MFRP gene were found in our cohort. The phenotypes and anomalies in Japanese patients with NNO were similar to those reported for other ethnic populations.

DOI： 10.1080/13816810.2023.2208220

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記述言語：英語   出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology  

Purpose: To assess the effects of half-dose photodynamic therapy (PDT) combined with an intravitreous aflibercept (IVA) injection for pachychoroid neovasculopathy (PNV) and its predictive factors. Methods: Clinical information of 43 patients (43 eyes) with PNV obtained before and 6 months after treatment with half-dose PDT combined with IVA was retrospectively analyzed. Patients were categorized into the sufficient (25 eyes, 58.1%) or insufficient (18 eyes, 41.9%) group based on resolution or persistence/recurrence of subretinal fluid (SRF), respectively, and clinical data were compared. Macular neovascularization (MNV) change was studied in 30 cases with available pre- and post-treatment optical coherence tomography angiography images. Results: The sufficient group included younger patients with better baseline best-corrected visual acuity (BCVA), more treatment-naïve eyes, and smaller MNV lesions at baseline than the insufficient group (all, P < 0.047). Complete SRF resolution was 81.8% in treatment-naïve eyes and only 33.3% in previously treated eyes. MNV expanded after half-dose PDT was combined with IVA regardless of the treatment outcome (P = 0.003). Conclusion: Half-dose PDT combined with IVA was effective for PNV treatment, especially for younger patients with good baseline BCVA, treatment-naïve eyes, and small MNV sizes at baseline. MNV expanded after treatment regardless of the treatment outcomes.

DOI： 10.1007/s00417-023-06030-3

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PLoS ONE  

Purpose To determine the factors significantly associated with the amplitudes and implicit times of the flicker electroretinograms (ERGs) recorded with the RETeval system by analyzing the comprehensive data obtained during a health checkup screening. Methods Flicker ERGs were recorded with the RETeval system from 373 individuals who had a normal fundus and optical coherence tomography images. The sex, age, anthropometric, ophthalmologic, and hematologic data were collected from all participants who were 40- to 89- years-of-age. Univariable and multivariable linear mixed effects regression analyses were performed to identify factors that were significantly associated with the implicit times and amplitudes of the RETeval flicker ERGs. Results Univariable linear mixed effects regression analysis showed significant correlations between the implicit times and the best-corrected visual acuity, the age, the axial length, the blood sugar level, and the blood urea nitrogen level. Analyses by multivariable linear mixed effects regression identified that the axial length (β = 0.28), the age (β = 0.24), and the blood sugar level (β = 0.092) were three independent factors that were significantly correlated with the implicit times of the RETeval flicker ERGs. Univariable linear mixed effects regression analysis also showed significant correlations between the amplitudes of the RETeval flicker ERGs and the age, the platelet count, and the creatinine level. Multivariable linear mixed effects regression models identified the age (β = -0.092), the platelet count (β = 0.099), and the creatinine level (β = -0.12) as three independent factors that were significantly correlated with the amplitudes of the RETeval flicker ERGs. However, the smoking habits, body mass index, and the blood pressure were not significantly correlated with either the implicit times or amplitudes of the RETeval flicker ERGs. Conclusions Our results indicate that the age and some ophthalmologic and hematologic findings but not the anthropometric findings were significantly associated with the implicit times and amplitudes of the RETeval flicker ERGs. Thus, clinicians should remember these factors when analyzing the RETeval flicker ERGs.

DOI： 10.1371/journal.pone.0284686

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出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1410214775

CiNii Research

記述言語：英語   出版者・発行元：Ophthalmology  

Purpose: To investigate the genetic architecture of age-related macular degeneration (AMD) in a Japanese population. Design: Genome-wide association study (GWAS). Participants: Three thousand seven hundred seventy-two patients with AMD and 16 770 control participants from the Japanese population were enrolled in the association analyses. Methods: We conducted a meta-analysis of 2 independent GWASs that included a total of 2663 patients with AMD and 9471 control participants using the imputation reference panel for genotype imputation specified for the Japanese population (n = 3541). A replication study was performed using an independent set of 1109 patients with AMD and 7299 control participants. Main Outcome Measures: Associations of genetic variants with AMD. Results: A meta-analysis of the 2 GWASs identified 6 loci significantly associated with AMD (P < 5.0 × 10–8). Of these loci, 4 were known to be associated with AMD (CFH, C2/FB, TNFRSF10A, and ARMS2), and 2 were novel (rs4147157 near WBP1L and rs76228488 near GATA5). The newly identified associations were confirmed in a replication study (P < 0.01). After the meta-analysis of all datasets, we observed strong associations in these loci (P = 1.88 × 10–12 and P = 1.35 × 10–9 for meta-analysis for rs4147157 and rs76228488, respectively). When we looked up the associations in the reported central serous chorioretinopathy (CSC) GWAS conducted in the Japanese population, both loci were associated significantly with CSC (P = 4.86 × 10–3 and P = 4.28 × 10–3 for rs4147157 and rs76228488, respectively). We performed a genetic colocalization analysis for these loci and estimated that the posterior probabilities of shared causal variants between AMD and CSC were 0.39 and 0.60 for WBP1L and GATA5, respectively. Genetic correlation analysis focusing on the epidemiologically suggested clinical risk factors implicated shared polygenic architecture between AMD and smoking cessation (rg [the measure of genetic correlation] = –0.33; P = 0.01; false discovery rate, 0.099). Conclusions: Our findings imply shared genetic components conferring the risk of both AMD and CSC. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.

DOI： 10.1016/j.ophtha.2022.10.034

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記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

眼科領域でのゲノム医療のプレゼンスは現時点では限定的である.しかし,来るべきゲノム医療時代を見据え,ゲノム情報を用いた先端的な研究を牽引することは,臨床検体にアクセスのある眼科アカデミアの使命である.我々は,眼感染症のゲノム診断と網膜ジストロフィに対するゲノム編集遺伝子治療のトランスレーショナルリサーチを重点テーマとして定め,それらの開発に取り組んでいる.本稿では,これらの新しいゲノム診療プラットフォームの構築と臨床実装を目指した研究の最新の成果を紹介する.I.Nanopore長鎖シークエンシングの眼感染症診断への応用 近年,感染症の領域では,培養するプロセスを経ることなく,検体中の微生物群のDNAやRNAを直接精製し,網羅的にシークエンシングする「メタゲノム解析」が研究に広く用いられている.我々は,簡便性・迅速性に優れた人工知能搭載の長鎖シークエンサーであるNanoporeを用いた眼感染症診断のための新しいメタゲノム解析プラットフォームの開発に取り組んでいる.Multiplexポリメラーゼ連鎖反応(mPCR)でヘルペス属ウイルスなどが検出され診断のついた症例の前房水・硝子体液を対象にNanoporeを用いてメタゲノム解析を行ったところ,多くの検体で診断どおりの病原体が確認された.しかし,一部の検体では病原体が検出されず,さらに,微生物ゲノムのコンタミネーションがあることも判明した.そこで,これらの問題を克服し,起炎微生物を網羅的に探索することを目的に,mPCR陰性症例と対照を複数例解析し,結果を両群で比較するメタゲノム関連解析を行った.しかし,解析により起炎微生物由来と推測されるゲノム断片は検出できたものの,それはChlamydia Trachomatisなど複数の微生物が共通に持つ配列であることが後に判明した.以上より,現時点では,メタゲノム関連解析で検出されたmPCR陰性ぶどう膜炎に関連するゲノムの正体は絞り切れていない.現在,検出されたゲノム断片の由来である病原体を特定するために,多面的なゲノム解析を実施中である.また,Nanoporeメタゲノム解析では一部のぶどう膜炎症例においてtorque teno virusが検出された.同ウイルスは,これまで免疫抑制状態との関連が報告されているが,眼科領域での報告は未だ少ない.そこで,ぶどう膜炎症例において,定量的PCR(qPCR)を用いて前房水中のtorque teno virusの有無を調べ,全身性の免疫能低下の病歴との関連を解析した.その結果,ベースに全身性の免疫能低下がある患者では同ウイルスの検出率が高いことが判明した.このことは,torque teno virusの眼内感染と眼内の免疫能低下の関連性を示唆している可能性がある.II.網膜疾患に対するゲノム編集遺伝子治療戦略 現在行われている眼疾患に対する遺伝子治療の多くはadeno-associated virus(AAV)ベクターを用いた遺伝子補充療法である.この治療の基本コンセプトは,機能喪失型の変異を持つ病的細胞に正常コピーの全長遺伝子を導入することで,欠損遺伝子の機能を補完することである.しかし,AAV容量の制約により,遺伝子補充療法では小さい病因遺伝子しか治療できない.したがって,この方法で治療できる日本人の網膜色素変性患者は,現状で全体のわずか数%程度である.それに対して,ゲノム編集遺伝子治療ではゲノム局所を標的とするため,治療対象の遺伝子のサイズに依存せず,理論的にはほとんどの遺伝子変異の治療が可能である.しかし,ゲノム編集遺伝子治療の治療効率は低く,そのことが臨床応用を妨げている.我々は,臨床応用を念頭にAAVゲノム編集遺伝子治療の効率改善に取り組み,3つの異なるゲノム編集手法を開発した.最初に,汎用性の高いプラットフォームとして,変異を正常配列に置換可能な単一AAVゲノム編集遺伝子治療プラットフォームを開発し(変異置換ゲノム編集遺伝子治療),その有効性をマウスモデルで証明した.続いて,塩基の挿入や欠失によって生じるフレームシフト変異を対象とし,ずれたフレームを元に戻すことに主眼を置いたシンプルかつ治療効率の高いゲノム編集法(リフレームゲノム編集遺伝子治療)を開発した.この方法を用いて,日本人網膜色素変性患者の約12%が保有するeyes shut homolog(EYS)遺伝子のS1653Kfs変異を有する患者由来細胞株を対象に,その有効性を実証した.最後に,マイクロホモロジー媒介末端結合(MMEJ)とhomology-independent targeted integration(HITI)の異なる2つのゲノム修復法をコンパクトに組み合わせたMMEJ-Hゲノム編集遺伝子治療を新たに考案し,イントロンなどの非翻訳領域を主なターゲットとする治療の開発を進めている.今後も,幅広い眼疾患に対して,ゲノム関連技術の応用にフォーカスを当てた挑戦的なトランスレーショナルリサーチを展開し,眼科アカデミアとして,ゲノム医療の発展に貢献していきたい.(著者抄録)

記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

眼科領域でのゲノム医療のプレゼンスは現時点では限定的である.しかし,来るべきゲノム医療時代を見据え,ゲノム情報を用いた先端的な研究を牽引することは,臨床検体にアクセスのある眼科アカデミアの使命である.我々は,眼感染症のゲノム診断と網膜ジストロフィに対するゲノム編集遺伝子治療のトランスレーショナルリサーチを重点テーマとして定め,それらの開発に取り組んでいる.本稿では,これらの新しいゲノム診療プラットフォームの構築と臨床実装を目指した研究の最新の成果を紹介する.I.Nanopore長鎖シークエンシングの眼感染症診断への応用 近年,感染症の領域では,培養するプロセスを経ることなく,検体中の微生物群のDNAやRNAを直接精製し,網羅的にシークエンシングする「メタゲノム解析」が研究に広く用いられている.我々は,簡便性・迅速性に優れた人工知能搭載の長鎖シークエンサーであるNanoporeを用いた眼感染症診断のための新しいメタゲノム解析プラットフォームの開発に取り組んでいる.Multiplexポリメラーゼ連鎖反応(mPCR)でヘルペス属ウイルスなどが検出され診断のついた症例の前房水・硝子体液を対象にNanoporeを用いてメタゲノム解析を行ったところ,多くの検体で診断どおりの病原体が確認された.しかし,一部の検体では病原体が検出されず,さらに,微生物ゲノムのコンタミネーションがあることも判明した.そこで,これらの問題を克服し,起炎微生物を網羅的に探索することを目的に,mPCR陰性症例と対照を複数例解析し,結果を両群で比較するメタゲノム関連解析を行った.しかし,解析により起炎微生物由来と推測されるゲノム断片は検出できたものの,それはChlamydia Trachomatisなど複数の微生物が共通に持つ配列であることが後に判明した.以上より,現時点では,メタゲノム関連解析で検出されたmPCR陰性ぶどう膜炎に関連するゲノムの正体は絞り切れていない.現在,検出されたゲノム断片の由来である病原体を特定するために,多面的なゲノム解析を実施中である.また,Nanoporeメタゲノム解析では一部のぶどう膜炎症例においてtorque teno virusが検出された.同ウイルスは,これまで免疫抑制状態との関連が報告されているが,眼科領域での報告は未だ少ない.そこで,ぶどう膜炎症例において,定量的PCR(qPCR)を用いて前房水中のtorque teno virusの有無を調べ,全身性の免疫能低下の病歴との関連を解析した.その結果,ベースに全身性の免疫能低下がある患者では同ウイルスの検出率が高いことが判明した.このことは,torque teno virusの眼内感染と眼内の免疫能低下の関連性を示唆している可能性がある.II.網膜疾患に対するゲノム編集遺伝子治療戦略 現在行われている眼疾患に対する遺伝子治療の多くはadeno-associated virus(AAV)ベクターを用いた遺伝子補充療法である.この治療の基本コンセプトは,機能喪失型の変異を持つ病的細胞に正常コピーの全長遺伝子を導入することで,欠損遺伝子の機能を補完することである.しかし,AAV容量の制約により,遺伝子補充療法では小さい病因遺伝子しか治療できない.したがって,この方法で治療できる日本人の網膜色素変性患者は,現状で全体のわずか数%程度である.それに対して,ゲノム編集遺伝子治療ではゲノム局所を標的とするため,治療対象の遺伝子のサイズに依存せず,理論的にはほとんどの遺伝子変異の治療が可能である.しかし,ゲノム編集遺伝子治療の治療効率は低く,そのことが臨床応用を妨げている.我々は,臨床応用を念頭にAAVゲノム編集遺伝子治療の効率改善に取り組み,3つの異なるゲノム編集手法を開発した.最初に,汎用性の高いプラットフォームとして,変異を正常配列に置換可能な単一AAVゲノム編集遺伝子治療プラットフォームを開発し(変異置換ゲノム編集遺伝子治療),その有効性をマウスモデルで証明した.続いて,塩基の挿入や欠失によって生じるフレームシフト変異を対象とし,ずれたフレームを元に戻すことに主眼を置いたシンプルかつ治療効率の高いゲノム編集法(リフレームゲノム編集遺伝子治療)を開発した.この方法を用いて,日本人網膜色素変性患者の約12%が保有するeyes shut homolog(EYS)遺伝子のS1653Kfs変異を有する患者由来細胞株を対象に,その有効性を実証した.最後に,マイクロホモロジー媒介末端結合(MMEJ)とhomology-independent targeted integration(HITI)の異なる2つのゲノム修復法をコンパクトに組み合わせたMMEJ-Hゲノム編集遺伝子治療を新たに考案し,イントロンなどの非翻訳領域を主なターゲットとする治療の開発を進めている.今後も,幅広い眼疾患に対して,ゲノム関連技術の応用にフォーカスを当てた挑戦的なトランスレーショナルリサーチを展開し,眼科アカデミアとして,ゲノム医療の発展に貢献していきたい.(著者抄録)

記述言語：英語   出版者・発行元：Retina  

Purpose:To examine the morphologic changes in macular neovascularization (MNV) secondary to age-related macular degeneration after 2 years of aflibercept treatment under a treat-and-extend (T&E) regimen.Methods:This retrospective study analyzed the medical records for 26 eyes of 25 patients diagnosed with treatment-naive neovascular age-related macular degeneration and treated with aflibercept under a treat-and-extend regimen for 2 years. The areas of the MNV and vascular structures were assessed using swept-source optical coherence tomography angiography at baseline and after 2 years of treatment.Results:The mean MNV area increased significantly from 0.65 ± 0.42 mm2 at baseline to 0.78 ± 0.45 mm2 at 2 years. At 2 years, the mean change in the MNV area from baseline was 22% (interquartile range: 4%-60%). The baseline MNV area was negatively correlated with the change ratio of the MNV areas at 2 years and baseline (R = -0.68, P < 0.001). Nine of the 26 eyes (34.6%) showed newly formed mature vessels, and 7 eyes (26.9%) showed prominently developing preexisting mature vessels.Conclusion:Macular neovascularization expanded and showed vascular maturation under aflibercept treatment with a treat-and-extend regimen. The smaller the MNV at baseline, the greater is its expansion in 2 years.

DOI： 10.1097/IAE.0000000000003676

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Scopus

PubMed

記述言語：英語   出版者・発行元：Frontiers in Cell and Developmental Biology  

Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.

DOI： 10.3389/fcell.2023.1112270

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PubMed

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1410214679

CiNii Research

記述言語：英語   出版者・発行元：Antioxidants  

The purpose of this study is to investigate the protective effect of dimethyl fumarate (DMF), the methyl-ester of fumaric acid, against blue-light (BL) exposure in retinal pigment epithelial (RPE) cells. ARPE-19 cells, a human RPE cell line, were cultured with DMF followed by exposure to BL. Reactive oxygen species (ROS) generation, cell viability, and cell death rate were determined. Real-time polymerase chain reaction and Western blotting were performed to determine the change in nuclear factor (erythroid-derived)-like 2 (NRF2) expression. Twenty-seven inflammatory cytokines in the supernatant of culture medium were measured. BL exposure induced ROS generation in ARPE-19 cells, which DMF alleviated in a concentration-dependent manner. BL exposure increased the ARPE-19 cell death rate, which DMF alleviated. BL exposure induced ARPE-19 cell apoptosis, again alleviated by DMF. Under BL exposure, DMF increased the NRF2 mRNA level and promoted NRF2 expression in the nucleus. BL also strongly increased interleukin (IL)-1β and fibroblast growth factor (FGF) expression. BL strongly induced RPE cell damage with apoptotic change while DMF mainly reduced inflammation in BL-induced RPE damage, resulting in blockade of cell death. DMF has a protective effect in RPE cells against BL exposure via activation of the NRF2 pathway.

DOI： 10.3390/antiox12010045

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PubMed

記述言語：英語   出版者・発行元：Retina  

Purpose:To assess the effects of half-dose photodynamic therapy on subretinal fluid and macular neovascularization (MNV) using optical coherence tomography angiography in patients with chronic central serous chorioretinopathy.Methods:Clinical information on 168 patients (168 eyes) with chronic central serous chorioretinopathy obtained before and 6 months after treatment with half-dose photodynamic therapy was retrospectively analyzed. Patients were categorized into a success (145 eyes) or failure (23 eyes) group based on the absence or presence of subretinal fluid, respectively, and clinical data were compared between them. Macular neovascularization was studied in 147 cases with available optical coherence tomography angiography images. P < 0.05 indicated statistical significance.Results:The success group showed a younger patient age, better posttreatment best-corrected visual acuity, and thicker pretreatment central choroidal thickness (all, P < 0.047) than did the failure group. Regarding MNV analysis, nine, eight, and 130 eyes had definite, possible, and no MNV, respectively, at baseline; among them, 100.0%, 75.0%, and 2.3%, respectively, had MNV at 6 months posttreatment. Patients with definite MNV at baseline were less likely to show successful subretinal fluid resolution.Conclusion:Although half-dose photodynamic therapy is generally effective for the treatment of chronic central serous chorioretinopathy, coexisting MNV may compromise the outcome; thus, optical coherence tomography angiography-based assessment of chronic central serous chorioretinopathy is important.

DOI： 10.1097/IAE.0000000000003604

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Medical Genetics  

Despite the successful identification of causative genes and genetic variants of retinitis pigmentosa (RP), many patients have not been molecularly diagnosed. Our recent study using targeted short-read sequencing showed that the proportion of carriers of pathogenic variants in EYS, the cause of autosomal recessive RP, was unexpectedly high in Japanese patients with unsolved RP. This result suggested that causative genetic variants, which are difficult to detect by short-read sequencing, exist in such patients. Using long-read sequencing technology (Oxford Nanopore), we analysed the whole genomes of 15 patients with RP with one heterozygous pathogenic variant in EYS detected in our previous study along with structural variants (SVs) in EYS and another 88 RP-associated genes. Two large exon-overlapping deletions involving six exons were identified in EYS in two patients with unsolved RP. An analysis of an independent patient set (n=1189) suggested that these two deletions are not founder mutations. Our results suggest that searching for SVs by long-read sequencing in genetically unsolved cases benefits the molecular diagnosis of RP.

DOI： 10.1136/jmedgenet-2022-108428

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PubMed

記述言語：英語   出版者・発行元：Retina  

Purpose:To assess the macular function by focal macular electroretinography and static perimetry in eyes with retinitis pigmentosa.Methods:Eighty-eight eyes of 88 retinitis pigmentosa patients were analyzed. The relationships between the focal macular electroretinography components and the mean deviations (MDs) of the Humphrey Field Analyzer 10-2 were determined. Spectral-domain optical coherence tomography was used to determine the integrity of the ellipsoid zone (EZ) and the interdigitation zone.Results:Forward-backward stepwise regression analyses showed that the amplitudes (r = 0.45, P < 0.01) and implicit times (r = -0.29, P < 0.01) of the b-waves were significantly correlated with the MDs. Some of the eyes had reduced b-wave amplitudes (<1.0 µV) and disrupted interdigitation zone, despite having a better MD (≥ -10.0 dB) and intact EZ. Subgroup analyses of eyes with better MD (≥ -10.0 dB) showed that the EZ width was correlated with the MDs but not with the b-wave amplitude. The thickness of the EZ-retinal pigment epithelium as an alternative indicator of interdigitation zone was correlated with the b-wave amplitude (r = 0.32, P = 0.04) but not with the MDs (r = -0.10, P = 0.53).Conclusion:The fact that the focal macular electroretinography amplitudes are reduced before the shortening of the EZ in the early stage of retinitis pigmentosa indicates that the focal macular electroretinography amplitudes are an earlier indicator of macular dysfunction than the Humphrey Field Analyzer 10-2 findings.

DOI： 10.1097/IAE.0000000000003589

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

This retrospective study aimed to evaluate choroidal hemodynamics after half-dose photodynamic therapy (PDT) for central serous chorioretinopathy (CSC) and the effects of smoking using laser speckle flowgraphy. This study included 29 eyes of 29 patients treated with half-dose PDT for CSC, who were followed-up for at least 6 months. The mean blur rate (MBR) in the PDT irradiation area (whole area), the pachyvessel (PV) area, non-PV (NPV) area, and filling delay (FD) area were assessed at baseline and 1, 3, and 6 months post-PDT, respectively. The MBR was also assessed by smoking status. The MBR significantly decreased from baseline in the whole, PV, NPV, and FD areas at all time points (P < 0.001). Of the 29 patients, 6 were never smokers, 13 were past smokers, and 10 were current smokers. At baseline, no significant difference was found in the MBR in the whole, PV, NPV, and FD areas among never, past, and current smokers. The MBR changes showed a significantly smaller decrease in current smokers than in never smokers in the whole (P = 0.021), PV (P = 0.009), and NPV (P = 0.034) areas, but not in the FD area (P = 0.172). Half-dose PDT for CSC reduced choroidal blood flow in the PDT-irradiated area, which was blunted by current smoking status.

DOI： 10.1038/s41598-022-21584-8

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PubMed

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1410214491

CiNii Research

出版者・発行元：医歯薬出版  

DOI： 10.32118/ayu28206634

CiNii Research

出版者・発行元：金原出版  

DOI： 10.18888/ga.0000002697

CiNii Research

出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1410214400

CiNii Research

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Ophthalmology  

Purpose: To examine the 16-week outcomes of switching to brolucizumab in eyes with neovascular age-related macular degeneration (nAMD) refractory to aflibercept. Study design: Retrospective observational study. Methods: Data of eyes with nAMD who switched to brolucizumab because of resistance to aflibercept were collected. The best-corrected visual acuity (BCVA; in logarithm of the minimum angle of resolution), central retinal thickness (CRT), central choroidal thickness (CCT), and exudative status on optical coherence tomography were analyzed. Results: A total of 48 eyes of 48 patients were reviewed. At 4 to 7 weeks after switching, BCVA changed from 0.26 ± 0.19 to 0.25 ± 0.21 (not significant; P = 0.95), but CRT significantly decreased from 298.9 ± 108.4 µm to 241.9 ± 92.5 µm (P < 0.001) and CCT from 182.6 ± 89.3 µm to 169.7 ± 82.6 µm (P < 0.001). Of the 23 eyes refractory to monthly aflibercept injections, 12 (52.2%) achieved a dry macula, and 8 (34.8%) reduced exudative changes at 1 month. At 16 weeks, 31 eyes (64.6%) achieved the treatment interval ≥ 8 weeks. Two patients (4.2%) dropped out, 7 eyes (14.6%) developed intraocular inflammation (IOI), and 8 eyes (16.7%) switched back to aflibercept because of the failure to extend the treatment interval ≥ 8 weeks. Conclusion: Switching to brolucizumab in eyes refractory to aflibercept conferred favorable outcomes in controlling exudative changes. However, IOI and the regulation of the treatment interval to at least 8 weeks during the maintenance phase disrupted the continuation of brolucizumab treatment.

DOI： 10.1007/s10384-022-00908-1

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Investigative Ophthalmology and Visual Science  

PURPOSE. C1q/TNF-related protein (CTRP) 9 is one of the adiponectin paralogs, and a genetic ablation of its receptor, AdipoR1, is known to cause retinal degeneration. The purpose of this study was to determine the role played by CTRP9 in the retina. METHODS. The retinas of Ctrp9 gene knockout (KO) and wild type (WT) mice were examined by electroretinography (ERG), histology, RNA sequencing, and quantitative real-time PCR. RESULTS. The amplitude of the photopic ERG elicited by the maximum stimulus intensity was smaller by 40% in the Ctrp9 KO mice than in WT mice at 8 weeks of age. However, the photopic ERGs was not reduced from 8 weeks to 6 months of age. The amplitudes of the scotopic ERGs were not reduced in the Ctrp9 KO mice at 8 weeks and 6 months of age. No distinct histological abnormalities were found in the retinal sections but the density of peanut agglutinin-stained cells in the retinal flat mount of KO mice was reduced to about 70% of that of WT mice. Genomewide RNA sequencing of the retina revealed the absence of the expression of CTRP9 in both KO and WT mice. RNA sequencing and quantitative real-time PCR analysis showed that the expressions of the transcripts of genes expressed in cones, Opn1sw, Opn1mw, Gnat2, and Cnga3, were reduced in the KO mice retina, however, the degree of expression of the transcripts in rods was not significantly reduced. CONCLUSIONS. CTRP9 is released ectopically from other tissues, and it regulates the number of cones in the mouse retinas.

DOI： 10.1167/iovs.63.5.14

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology  

Purpose: To determine the characteristics of eyes diagnosed with Best vitelliform macular dystrophy (BVMD) and autosomal recessive bestrophinopathy (ARB) complicated by choroidal neovascularization (CNV). Methods: This was a retrospective, multicenter observational case series. Fourteen genetically confirmed BVMD patients and 9 ARB patients who had been examined in 2 ophthalmological institutions in Japan were studied. The findings in a series of ophthalmic examinations including B-scan optical coherence tomography (OCT) and OCT angiography (OCTA) were reviewed. Results: CNV was identified in 5 eyes (17.9%) of BVMD patients and in 2 eyes (11.1%) of ARB patients. Three of 5 eyes with BVMD were classified as being at the vitelliruptive stage and 2 eyes at the atrophic stage. The CNV in 2 BVMD eyes were diagnosed as exudative because of acute visual acuity reduction, retinal hemorrhage, and intraretinal fluid, while the CNV in 3 BVMD eyes and 2 ARB eyes were diagnosed as non-exudative. The visual acuity of the two eyes with exudative CNV did not improve despite anti-VEGF treatments. None of the eyes with non-exudative CNV had a reduction of their visual acuity for at least 4 years. All of the CNV were located within hyperreflective materials which were detected in 16 eyes (57.1%) of the BVMD eyes and in 7 eyes (38.9%) of the ARB eyes. Conclusions: CNV is a relatively common complication in BEST1-related retinopathy in Asian population as well. The prognosis of eyes with exudative CNV is not always good, and OCTA can detect CNV in eyes possessing hyperreflective materials.

DOI： 10.1007/s00417-021-05447-y

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PubMed

記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

目的:Enhanced S-conesyndrome(ESCS)は網膜電図(ERG)でshort-wavelength-sensitive(S)錐体応答が増大する遺伝性網膜疾患であるが,網膜機能の進行性についてははっきりしていない.日本人ESCS症例に関して,ERGを含む長期臨床経過および遺伝学的特徴について後ろ向きに検討する.対象と方法:ESCSと診断された9例を対象とし,このうち8例の初期臨床像は過去に報告されている.NR2E3遺伝子変異はSanger法で決定された.視力,光干渉断層計を用いた中心窩網膜厚,ERG所見について検討した.結果:初発症状を聴取できた7例は,就学前に夜盲を自覚していた.各施設の初診時平均年齢は36.2歳,平均観察期間は15.0年であった.初診時に視力不良であったほうの眼の視力は経過中に大きく変化していなかった.最終測定時の平均中心窩網膜厚は初回測定時に比べ有意に減少していた.特徴的全視野ERGおよびS錐体ERG所見は全例で観察された.20年以上の長期経過を追えた2例の錐体応答は明らかに減弱していた.全例でNR2E3遺伝子に両アレル変異が検出され,p.Arg104Gln変異が28%(5/18アレル)と最多であった.結論:ERGの結果から,ESCSは進行性の網膜変性疾患であることが確認できた.視力は黄斑部網膜分離を合併しなければ比較的長期にわたり維持される可能性がある.p.Arg104Gln変異が日本人ESCSの主要変異であると考えられた.(著者抄録)

記述言語：日本語   出版者・発行元：眼科臨床紀要会  

記述言語：英語  

We present surgical outcomes in a 10-year-old Japanese girl with neurofibromatosis type 2 (NF2)-induced epiretinal membrane (ERM). Her right eye underwent lens-sparing 27-gauge microincision vitrectomy surgery (MIVS) with ERM peeling. Decimal best-corrected visual acuity increased from 0.3 to 0.4 postoperatively. However, abnormal thickening of the macula persisted for 3 years. Staining of the extracted ERM revealed many cells positive for glial fibrillary acidic protein and nestin. Although removal of NF2-induced ERM with MIVS can improve visual acuity, the potential surgical risks require careful consideration on a case-by-case basis.

DOI： 10.5693/djo.02.2021.06.001

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology  

Purpose: To investigate whether previously reported seasonal variation and winter-dominant prevalence of acute massive submacular hemorrhages (SMHs) caused by age-related macular degeneration (AMD) disappeared, and those caused by retinal microaneurysms (RMAs) emerged. Method: The medical charts of 95 patients (95 eyes) with SMH caused by AMD and 76 patients (76 eyes) with SMH caused by RMAs in 2012–2019 were retrospectively reviewed. For each subject, the month of onset, the mean ambient temperature of that month were recorded. Results: The monthly numbers of cases of SMHs caused by AMD from January to December were 6, 8, 4, 9, 7, 10, 9, 11, 7, 11, 3, and 10. No significant seasonal variation in the monthly incidence was identified (Roger’s R = 1.89, p = 0.39). The monthly numbers of SMHs caused by RMAs from January to December were 3, 11, 11, 8, 7, 8, 5, 5, 2, 4, 7, and 5. There was significant seasonal variation in the monthly incidence (Roger’s R = 7.67, p = 0.02). There was no significant correlation between the monthly incidence of SMHs caused by RMAs and mean ambient temperature. Conclusion: Our previous study conducted for cases obtained in 1998–2005 showed seasonal cyclic trend in the number of SMHs caused by AMD, with the peak in winter. However, that significant seasonal variation disappeared in 2012–2019 in the present study. Common usage of OCT devices and anti-VEGF drugs might be the reason for the lack of seasonal variation in the cases of SMH caused by AMD. [Figure not available: see fulltext.]

DOI： 10.1007/s00417-021-05280-3

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Experimental Eye Research  

Glaucoma is a leading cause of blindness worldwide and is characterized by degeneration associated with the death of retinal ganglion cells (RGCs). It is believed that glaucoma is a group of heterogeneous diseases with multifactorial pathomechanisms. Here, we investigate whether anti-inflammation treatment with an ER stress blockade can selectively promote neuroprotection against NMDA injury in the RGCs. Retinal excitotoxicity was induced with an intravitreal NMDA injection. Microglial activation and neuroinflammation were evaluated with Iba1 immunostaining and cytokine gene expression. A stable HT22 cell line transfected with an NF-kB reporter was used to assess NF-kB activity after hesperidin treatment. CHOP-deficient mice were used as a model of ER stress blockade. Retinal cell death was evaluated with a TUNEL assay. As results, in the NMDA injury group, Iba1-positive microglia increased 6 h after NMDA injection. Also at 6 h, pro-inflammatory cytokines and chemokine increased, including TNFα, IL-1b, IL-6 and MCP-1. In addition, the MCP-1 promoter-driven EGFP signal, which we previously identified as a stress signal in injured RGCs, also increased; hesperidin treatment suppressed this inflammatory response and reduced stressed RGCs. In CHOP-deficient mice that received an NMDA injection, the gene expression of pro-inflammatory cytokines, chemokines, markers of active microglia, and inflammatory regulators was greater than in WT mice. In WT mice, hesperidin treatment partially prevented retinal cell death after NMDA injury; this neuroprotective effect was enhanced in CHOP-deficient mice. These findings demonstrate that ER stress blockade is not enough by itself to prevent RGC loss due to neuroinflammation in the retina, but it has a synergistic neuroprotective effect after NMDA injury when combined with an anti-inflammatory treatment based on hesperidin.

DOI： 10.1016/j.exer.2021.108826

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出版者・発行元：株式会社医学書院  

DOI： 10.11477/mf.1410214208

CiNii Research

記述言語：日本語   出版者・発行元：一般社団法人 日本計算工学会  

<p>大領域の金属ブロックから自動車フレームの概念構造をトポロジー最適化で得るには、1%以下の体積制約と十分な要素解像度を要する。階層直交格子を利用した有限体積法ソルバであるCUBEフレームワークを、コネクティビティつき直交格子のボクセル有限要素法ソルバとして利用することで、超並列環境でトポロジー最適化の反復解析を実行する。車体フレームを意図した数億要素のトポロジー最適化を実施し、その並列化性能を測定した。</p>

DOI： 10.11421/jsces.2021.20210019

CiNii Research

記述言語：日本語   出版者・発行元：眼科臨床紀要会  

記述言語：英語  

DOI： 10.1016/j.ajoc.2021.101123

PubMed

記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞目的:金属が体内に留置されている患者にはMRIは禁忌であり,その画像の報告は稀有である。今回,MRI撮影を契機に眼内鉄片異物が発見され,眼内炎に対して硝子体手術を行った症例を経験したので報告する。症例:40歳,男性。コンクリートを鏨で叩く作業中に左眼に違和感を自覚した。受傷翌日,近医を受診したが異常は認めなかった。受傷2ヵ月後に左眼の羞明を自覚し,同近医を再診した。左眼の瞳孔散大を認め,近医神経内科へ紹介となった。MRIにて左眼とその周辺の画像が大きく変形したことから金属片の迷入が疑われ,CTにて左眼内に金属片を認めたため当院に紹介となった。所見:左眼は視力(0.8),前房と水晶体は清明,虹彩は上鼻側が一部萎縮,眼底は軽度硝子体混濁と周辺部を圧迫して観察することで12時方向の鋸状縁付近に金属片を認めた。自覚症状,他覚的所見が乏しいため経過観察としたが,受傷2ヵ月半後に眼内炎を発症したため,硝子体手術と水晶体乳化吸引術(眼内レンズは挿入せず)を施行した。硝子体の培養からはCutibacterium acnesが検出された。抗菌薬の点滴,点眼加療などを行い眼内炎は治癒した。受傷6ヵ月後に眼内レンズを挿入し,左視力(1.2)となった。結論:金属片迷入が否定できない症例へのMRIは慎重に検討し注意すべきであるが,期せずして得られたそのMRI検査では,金属による特徴的な画像を呈することがある。

その他リンク： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J01537&link_issn=&doc_id=20210628130019&doc_link_id=10.11477%2Fmf.1410214048&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1410214048&type=%E5%8C%BB%E6%9B%B8.jp_%E3%82%AA%E3%83%BC%E3%83%AB%E3%82%A2%E3%82%AF%E3%82%BB%E3%82%B9&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Ophthalmology  

Purpose: To investigate the regional differences in the genes and variants causing retinitis pigmentosa (RP) in Japan Study design: Retrospective multicenter study Methods: In total, 1204 probands of each pedigree clinically diagnosed with nonsyndromic RP were enrolled from 5 Japanese facilities. The regions were divided into the Tohoku region, the Kanto and Chubu regions, and the Kyushu region according to the location of the hospitals where the participants were enrolled. We compared the proportions of the causative genes and the distributions of the pathogenic variants among these 3 regions. Results: The proportions of genetically solved cases were 29.4% in the Tohoku region (n = 500), 29.6% in the Kanto and Chubu regions (n = 196), and 29.7% in the Kyushu region (n = 508), which did not differ statistically (P =.99). No significant regional differences in the proportions of each causative gene in genetically solved patients were observed after correction by multiple testing. Among the 29 pathogenic variants detected in all 3 regions, only p.(Pro347Leu) in RHO was an autosomal dominant variant; the remaining 28 variants were found in autosomal recessive genes. Conversely, 78.6% (275/350) of the pathogenic variants were detected only in a single region, and 6 pathogenic variants (p.[Asn3062fs] in EYS, p.[Ala315fs] in EYS, p.[Arg872fs] in RP1, p.[Ala126Val] in RDH12, p.[Arg41Trp] in CRX, and p.[Gly381fs] in PRPF31) were frequently found in ≥ 4 patients in the single region. Conclusion: We observed region-specific pathogenic variants in the Japanese population. Further investigations of causative genes in multiple regions in Japan will contribute to the expansion of the catalog of genetic variants causing RP.

DOI： 10.1007/s10384-021-00824-w

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PubMed

記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

目的:網膜色素変性(RP)は現時点で有効な治療法のない難病で,新規の治療法開発が最も切望されている疾患の一つである.RPの基礎研究・治療研究を推進するために立ち上げた,RPおよびその類縁疾患に特化した患者レジストリである日本網膜色素変性レジストリプロジェクト(Japan Retinitis Pigmentosa Registry Project:JRPRP)の現状と登録されたデータの集計結果を報告する.対象と方法:2018年7月〜2020年3月までにJRPRPに登録されたRP患者1,817名の患者背景を検討した.結果:JRPRPに参加している25施設中13施設から登録があった.性別は男性851名,女性966名.年齢は55.0±17.4歳(平均値±標準偏差).病型の内訳は定型RP1,563名,錐体杆体ジストロフィ62名,無色素性RP59名,中心型・傍中心型RP37名,クリスタリン網膜症18名,Usher症候群15名,コロイデレミア14名,その他34名,不明15名であった.遺伝形式は常染色体優性遺伝12.7%,常染色体劣性遺伝18.5%,伴性劣性遺伝1.7%,孤発型64.3%,不明2.9%であった.定型RPの病因遺伝子診断率は44.3%で,EYS遺伝子異常が最も多かった.さらに,EYS遺伝子異常の患者はほかの常染色体劣性遺伝の患者より視力が良好な傾向がみられた.結論:JRPRPに登録された患者の遺伝形式の割合は既報と同程度であった.同様に,病因遺伝子としてはEYS遺伝子異常が最も多いことが分かった.さらなる患者データの集積により,本邦のRP患者の特徴が明らかとなることが予想される.(著者抄録)

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Communications Biology  

The genetic basis of Japanese autosomal recessive retinitis pigmentosa (ARRP) remains largely unknown. Herein, we applied a 2-step genome-wide association study (GWAS) in 640 Japanese patients. Meta-GWAS identified three independent peaks at P < 5.0 × 10−8, all within the major ARRP gene EYS. Two of the three were each in linkage disequilibrium with a different low frequency variant (allele frequency < 0.05); a known founder Mendelian mutation (c.4957dupA, p.S1653Kfs*2) and a non-synonymous variant (c.2528 G > A, p.G843E) of unknown significance. mRNA harboring c.2528 G > A failed to restore rhodopsin mislocalization induced by morpholino-mediated knockdown of eys in zebrafish, consistent with the variant being pathogenic. c.2528 G > A solved an additional 7.0% of Japanese ARRP cases. The third peak was in linkage disequilibrium with a common non-synonymous variant (c.7666 A > T, p.S2556C), possibly representing an unreported disease-susceptibility signal. GWAS successfully unraveled genetic causes of a rare monogenic disorder and identified a high frequency variant potentially linked to development of local genome therapeutics.

DOI： 10.1038/s42003-021-01662-9

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10792-020-01562-7

PubMed

出版者・発行元：9th International Conference on Computational Methods for Coupled Problems in Science and Engineering, COUPLED PROBLEMS 2021  

Full Eulerian methods constitute a family of numerical techniques used to simulate fluid-structure interaction problems. In a full Eulerian method, the velocity gradient tensor is used to compute deformation of solid. However, it is difficult to compute solid stress accurately near the interface, where the velocity between fluid and solid changes drastically. In this work, we propose an Eulerian formulation for fluid-structure interaction problems using Lagrangian marker particles with the Reference Map Technique to compute the deformation of solid accurately near material interfaces without using the gradient of the velocity. We illustrate and validate the proposed method through the presentation of various benchmark problems.

Scopus

出版者・発行元：Japanese Journal of Clinical Ophthalmology  

Purpose : To report a case of intraocular iron foreign body found by magnetic resonance imaging (MRI). MRI is prohibited in a patient who has metal in the body, and the reports of its images are rare. Case : A 40-year-old man felt pain of the left eye hitting a concrete wall with a chisel. The next day, he underwent a medical examination at the ophthalmology clinic. However, the left eye has no abnormal findings. After 2 months, he noted photophobia on the left eye and presented with mydriasis. The neurologist found intraocular iron foreign body on the left eye by MRI and CT and referred the patient to our clinic. Findings and clinical course : Left visual acuity was 0.8. The anterior chamber and lens were clear. The iris had a part of atrophy. A slightly vitreous opacity and intraocular iron foreign body were found near the ora serrata on the upper side. We selected an observasion because the subjective symptom and the objective symptom were mild. Endophthalmitis occured two and a half months after the accident. Phacoemulsification with aspiration ( without injection of intraocular lens) and vitrectomy were performed on the left eye. Cutibacterium acnes was detected in the culture from the vitreous body. Endophthalmitis was treated by eye drops and intravenous drip of antibiotics. Injection of intraocular lens was performed after 6 months of the accident. Finally, visual acuity recovered to 1.2. Conclusions : MRI should not be perform in a patient who cannot be denied with intraocular iron foreign body. However, we unexpectedlly obtained the characteristic MRI images.

Scopus

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Japanese Journal of Ophthalmology  

Purpose: To report the clinical course and high resolution images of autosomal recessive retinitis pigmentosa (RP) associated with a variant of the RP1 gene (c.4052_4053ins328/p.Tyr1352Alafs*9; m1), a high frequency founder variant in Japanese RP patients. Study design: Retrospective case series. Methods: Nine patients from 5 unrelated Japanese families were studied. Five patients had the m1 variant homozygously, and 4 patients had the m1 variant compound heterozygously with another frameshift variant (c.4196delG/p.Cys1399Leufs*5). Ophthalmic examinations including adaptive optics (AO) fundus imaging were performed periodically. Results: The fundus photographs, fundus autofluorescence (FAF) images, and optical coherence tomographic (OCT) images indicated severe retinal degeneration in all the patients involving the macula even at a young age (20 s). The areas of surviving photoreceptors in the central macula were seen as hyper-autofluorescent regions in the FAF images and preserved outer retinal structure in the OCT images; they were identifiable in the AO fundus images in 8 eyes. The borders of the surviving photoreceptor areas were surrounded by hyporeflective clumps, presumably containing melanin, and the size of these areas decreased progressively during the 4-year follow-up period. The disappearance of the surviving photoreceptor areas was associated with complete blindness. Conclusion: Patients with RP associated with the m1 variant have a progressive and severe retinal degeneration that begins at an early age. Monitoring the surviving photoreceptor areas by AO fundus imaging can provide a more precise pathological record of retinal degeneration.

DOI： 10.1007/s10384-020-00752-1

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1021/acs.bioconjchem.0c00435

PubMed

掲載種別：研究論文（学術雑誌）   出版者・発行元：Informa UK Limited  

DOI： 10.1080/15421406.2020.1743447

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10384-020-00755-y

PubMed

記述言語：英語  

DOI： 10.1007/s10384-020-00732-5

PubMed

記述言語：日本語   出版者・発行元：眼科臨床紀要会  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/IAE.0000000000002839

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00417-020-04754-0

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ophtha.2020.02.020

PubMed

記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞目的:落屑症候群ではチン小帯脆弱のため眼内レンズ強膜内固定術を要することが多いが,長期的には緑内障濾過手術も必要になりやすいため,硝子体切除術を併施する際にも結膜と強膜への侵襲は最小限にとどめたい。今回,眼内レンズ強膜内固定術の際の硝子体切除術を経角膜で行った落屑症候群3症例を報告する。対象と方法:対象は落屑症候群の3症例(男性1例,女性2例,平均年齢84歳)で,中間透光体は白内障2例,眼内レンズ亜脱臼1例であり,いずれにも水晶体振盪があった。術前の矯正視力は0.2〜0.5であった。これらに対して硝子体手術装置を用い経角膜硝子体切除を併施した強膜内固定術(ダブルニードルテクニックを用いたフランジ法)を行った。結果:白内障眼2例の硝子体切除は経角膜的に行うことができた。眼内レンズ亜脱臼の1例では術中に眼内レンズが眼底後極に落下し,後極操作の際に非接触式広角眼底観察システムに硝子体鑷子が干渉したため,経毛様体扁平部硝子体切除術に移行した。最終的に,全例で強膜内固定術を行えた。術後の矯正視力は0.6〜0.9と全例で改善した。全例で一時的に高眼圧(22〜28mmHg)となり,降圧点眼加療を要したことと,軽度の角膜浮腫とデスメ膜皺襞が生じた以外は合併症もなく順調に経過した。結論:将来的に緑内障手術を行う可能性がある落屑症候群などの症例での硝子体切除は,結膜強膜保護の観点から経角膜アプローチは利点があると思われる。現在のサイズの接触レンズや非接触式広角眼底観察システムを用いた手術では後極の操作に難があり,安全,かつスムースに行えない可能性があるため,さらなる工夫が必要と思われた。

記述言語：日本語   出版者・発行元：(株)医学書院  

＜文献概要＞目的:落屑症候群ではチン小帯脆弱のため眼内レンズ強膜内固定術を要することが多いが,長期的には緑内障濾過手術も必要になりやすいため,硝子体切除術を併施する際にも結膜と強膜への侵襲は最小限にとどめたい。今回,眼内レンズ強膜内固定術の際の硝子体切除術を経角膜で行った落屑症候群3症例を報告する。対象と方法:対象は落屑症候群の3症例(男性1例,女性2例,平均年齢84歳)で,中間透光体は白内障2例,眼内レンズ亜脱臼1例であり,いずれにも水晶体振盪があった。術前の矯正視力は0.2〜0.5であった。これらに対して硝子体手術装置を用い経角膜硝子体切除を併施した強膜内固定術(ダブルニードルテクニックを用いたフランジ法)を行った。結果:白内障眼2例の硝子体切除は経角膜的に行うことができた。眼内レンズ亜脱臼の1例では術中に眼内レンズが眼底後極に落下し,後極操作の際に非接触式広角眼底観察システムに硝子体鑷子が干渉したため,経毛様体扁平部硝子体切除術に移行した。最終的に,全例で強膜内固定術を行えた。術後の矯正視力は0.6〜0.9と全例で改善した。全例で一時的に高眼圧(22〜28mmHg)となり,降圧点眼加療を要したことと,軽度の角膜浮腫とデスメ膜皺襞が生じた以外は合併症もなく順調に経過した。結論:将来的に緑内障手術を行う可能性がある落屑症候群などの症例での硝子体切除は,結膜強膜保護の観点から経角膜アプローチは利点があると思われる。現在のサイズの接触レンズや非接触式広角眼底観察システムを用いた手術では後極の操作に難があり,安全,かつスムースに行えない可能性があるため,さらなる工夫が必要と思われた。

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01537&link_issn=&doc_id=20200525220013&doc_link_id=10.11477%2Fmf.1410213554&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.1410213554&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

記述言語：英語  

DOI： 10.1007/s00417-020-04664-1

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s12886-020-01378-0

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ajo.2020.03.014

PubMed

記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/ceo.13743

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/aos.14373

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41467-019-14181-3

PubMed

DOI： 10.1038/s41598-019-57066-7

PubMed

記述言語：英語  

DOI： 10.1016/j.ophtha.2019.09.015

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.ophtha.2019.05.027

PubMed

記述言語：英語  

DOI： 10.1016/j.bbrc.2019.10.155

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Medical Genetics  

Background The genetic profile of retinitis pigmentosa (RP) in East Asian populations has not been well characterised. Therefore, we conducted a large-scale sequencing study to investigate the genes and variants causing RP in a Japanese population. Methods A total of 1209 Japanese patients diagnosed with typical RP were enrolled. We performed deep resequencing of 83 known causative genes of RP using next-generation sequencing. We defined pathogenic variants as those that were putatively deleterious or registered as pathogenic in the Human Gene Mutation Database or ClinVar database and had a minor allele frequency in any ethnic population of ≤0.5% for recessive genes or ≤0.01% for dominant genes as determined using population-based databases. Results We successfully sequenced 1204 patients with RP and determined 200 pathogenic variants in 38 genes as the cause of RP in 356 patients (29.6%). Variants in six genes (EYS, USH2A, RP1L1, RHO, RP1 and RPGR) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in EYS [p.(Ser1653fs) and p.(Tyr2935∗)] and four East Asian-specific variants [p.(Gly2752Arg) in USH2A, p.(Arg658∗) in RP1L1, p.(Gly2186Glu) in EYS and p.(Ile535Asn) in PDE6B] and p.(Cys934Trp) in USH2A were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in RHO, p.(Arg872fs) in RP1, p.(Arg41Trp) in CRX and p.(Gly381fs) in PRPF31] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases. Conclusions East Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

DOI： 10.1136/jmedgenet-2018-105691

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PubMed

記述言語：日本語   出版者・発行元：日本緑内障学会  

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Communications  

Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1, neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p-value = 9.2 × 10−5). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

DOI： 10.1038/s41467-019-10746-4

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-019-45336-3

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1136/bjophthalmol-2018-312225

PubMed

DOI： 10.1167/iovs.18-26084

PubMed

DOI： 10.1080/13816810.2019.1571614

PubMed

記述言語：英語  

DOI： 10.1111/ceo.13365

PubMed

記述言語：英語   出版者・発行元：Molecular Therapy  

In patients born blind with retinal dystrophies, understanding the critical periods of cortical plasticity is important for successful visual restoration. In this study, we sought to model childhood blindness and investigate the plasticity of visual pathways. To this end, we generated double-mutant (Pde6ccpfl1/cpfl1Gnat1IRD2/IRD2) mice with absent rod and cone photoreceptor function, and we evaluated their response for restoring rod (GNAT1) function through gene therapy. Despite the limited effectiveness of gene therapy in restoring visual acuity in patients with retinal dystrophy, visual acuity was, unexpectedly, successfully restored in the mice at the level of the primary visual cortex in this study. This success in visual restoration, defined by changes in the quantified optokinetic response and pattern visually evoked potential, was achieved regardless of the age at treatment (up to 16 months). In the contralateral visual cortex, cortical plasticity, tagged with light-triggered transcription of Arc, was also restored after the treatment in blind mice carrying an Arc promoter-driven reporter gene, dVenus. Our results demonstrate the remarkable plasticity of visual circuits for one of the two photoreceptor mechanisms in older as well as younger mice with congenital blindness due to retinal dystrophies. Nishiguchi et al. show that recovery of rod-mediated visual acuity is possible at the level of the visual cortex after functional restoration of the rods, even in adults. The remarkable plasticity of visual circuits shown provides an important insight into the restoration of vision.

DOI： 10.1016/j.ymthe.2018.07.012

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PubMed

DOI： 10.1038/s41598-018-34413-8

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-018-30464-z

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1167/iovs.18-23784

PubMed

記述言語：英語  

DOI： 10.1111/ceo.13099

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1080/02713683.2018.1451544

PubMed

記述言語：英語  

DOI： 10.1111/ceo.13341

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Human Molecular Genetics  

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 diseaseassociated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P<5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.

DOI： 10.1093/hmg/ddy053

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Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1167/iovs.17-22958

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0197027

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/s41598-017-06969-4

Scopus

PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0186678

Scopus

PubMed

記述言語：英語  

DOI： 10.1111/aos.13353

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0183709

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.omtm.2017.04.003

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/jnc.13902

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PubMed

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.3109/02713683.2016.1153112

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PubMed

DOI： 10.1007/978-4-431-56511-6_8

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記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

J-GLOBAL

記述言語：日本語   出版者・発行元：眼科臨床紀要会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：眼科臨床紀要会  

記述言語：日本語   出版者・発行元：医学書院  

＜文献概要＞目的:治療抵抗性の緑内障に対して眼内毛様体光凝固術を施行した症例に関して,光凝固術式と眼圧下降効果について報告する。対象と方法:眼圧コントロールが困難となり,硝子体手術併用眼内毛様体光凝固術を施行した緑内障11例11眼を対象とし,光凝固部位(毛様体扁平部,毛様体突起),術前の眼圧,術後1,3,6ヵ月の眼圧の推移について調べた。結果:11症例はすべて続発緑内障であり,血管新生緑内障10例,術後緑内障1例であった。毛様体扁平部と毛様体突起の両方を光凝固した症例は6例であり,うち4症例(66.7%)では良好な眼圧コントロールが得られた。毛様体扁平部のみを光凝固した症例は5例であり,うち4症例(80.0%)は良好な眼圧コントロールが得られた。術前平均眼圧は48.2±16.5mmHg,術後1,3,6ヵ月の平均眼圧は15.7±6.3mmHg(p<0.01),15.5±7.0mmHg(p<0.01),16.1±6.3mmHg(p<0.01)であり,有意に低下した(対応のあるt検定,ボンフェローニ補正)。術後6ヵ月では,毛様体扁平部照射群と,毛様体扁平部および毛様体突起照射群の眼圧下降率に有意差はなかった(t検定,p=0.42)。結論:硝子体手術時に行う眼内毛様体光凝固術は,治療抵抗性緑内障における眼圧コントロールの手法として有効である。

記述言語：日本語   出版者・発行元：(公財)日本眼科学会  

網膜色素変性(RP)は、未だ有効な治療法の確立されていない難治性疾患で、我が国の失明原因の上位を占める。近年の分子遺伝学的研究の進歩により、疾患の原因となる遺伝子異常が多岐にわたることは明らかとなったものの、それぞれの病因遺伝子によってどのように視細胞死が生じるかについては不明な点が多く、遺伝子診断システムも十分には整備されていない。我々は、RPの克服を目指して、「RPの病態解明と治療法開発」というテーマでトランスレーショナルリサーチ(TR)を実践してきた。本総説では、その中から得られた新しい知見を紹介しながら、将来的な治療法確立へ向けた可能性を述べる。1.RPに対する視細胞保護遺伝子治療 さまざまな遺伝子異常によって生じるRPに共通する最終的な病態の一つは、視細胞のアポトーシスである。このアポトーシスを制御する方法として、神経栄養因子である色素上皮由来因子を搭載した国産ウイルスベクターを用いた視細胞保護遺伝子治療の臨床応用を目指した研究を進めてきた。フェーズ1相当の臨床研究(UMIN000010260)はすでにスタートしており、現在は次世代の標準治療としての定着を目指した医師主導治験(フェーズ1/2a)の準備を進めている。2.RPの病態解明 一般にRPでは、遺伝子異常によって杆体細胞死が引き起こされ、その後に錐体細胞死が生じる。この過程に、遺伝子異常に関連しない何らかの共通した病態(環境因子)が関与していると考えた。RPモデル動物を用いた基礎研究と600名を超える患者数に裏打ちされたデータや臨床サンプルの解析により、環境因子として「(慢性)炎症」、「酸化ストレス」、「循環障害(虚血)」が重要であり、これらが相互に作用しながらRPの病勢が進んでいくことが明らかとなった。3.夜間視覚補助装置の開発 視力低下、視野狭窄と並んでRP患者のquality of life(QOL)を低下させる症状に夜盲がある。夜盲は病初期から認められるため、多くの患者が夜間の外出を制限されている。夜盲に対する視覚補助を目指した夜間視覚補助装置として、ウェアラブルシースルーディスプレイと高感度カメラを用いたデバイスを産学連携研究で開発し、早期の製品化を目指している。4.RPのTRを成功させるために RPのTRにおける問題点としては、1)大型の疾患モデル動物が存在しないこと、2)適切な治療評価基準がないこと、3)RPがヘテロな疾患群であること、などがある。これらの問題点について解決することがRPのTRを成功させるための鍵になるのではないかと考え、それぞれについて解決策を検討した。(著者抄録)

その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J01049&link_issn=&doc_id=20180313470004&doc_link_id=%2Fdz1nigan%2F2018%2F012203%2F004%2F0200-0222%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdz1nigan%2F2018%2F012203%2F004%2F0200-0222%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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記述言語：日本語   出版者・発行元：メディカル葵出版  

CiNii Books

その他リンク： http://search.jamas.or.jp/link/ui/2017392158

記述言語：日本語   出版者・発行元：メディカル葵出版  

CiNii Books

その他リンク： http://search.jamas.or.jp/link/ui/2017319162

記述言語：日本語  

J-GLOBAL