Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410215289

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To ascertain the characteristics of achromatopsia (ACHM) in Japan by analyzing the genetic and phenotypic features of patients with ACHM. METHODS: The medical records of 52 patients from 47 Japanese families who were clinically diagnosed with ACHM were reviewed in this retrospective observational study. RESULTS: Thirty-six causative variants of ACHM were identified in 26 families via whole-exome sequencing: PDE6C (12 families), CNGA3 (10 families), CNGB3 (two families), and GNAT2 (two families). However, none of the 6 causative variants that are known to cause ACHM, or the 275 other genes listed in RetNet, were observed in 19 families. A significant trend toward older age and worsening of ellipsoid zone disruption on optical coherence tomography images was observed (P < 0.01). Progressive ellipsoid zone disruptions were observed in 13 eyes of seven patients during the follow-up visits. These patients harbored one or more variants in PDE6C. CONCLUSION: The ACHM phenotype observed in this study was similar to those observed in previous reports; however, the causative gene variants differed from those in Europe. The low identification ratio of causative genes in whole-exome sequencing suggests the presence of unique hotspots in Japanese patients with ACHM that were not detectable via ordinal whole-exome sequencing.

DOI： 10.1097/IAE.0000000000004170

Scopus

PubMed

Language：English   Publisher：Investigative Ophthalmology and Visual Science  

PURPOSE. To examine the changes in aqueous humor cytokine levels and clinical outcomes of switching from aflibercept to faricimab in eyes with neovascular age-related macular degeneration (nAMD). METHODS. Fifty-four eyes of 54 patients with AMD undergoing treatment with aflibercept under a treat-and-extend (TAE) regimen were switched to faricimab and studied prospectively. Best-corrected visual acuity (BCVA; in logarithm of the minimum angle of resolution), central retinal thickness (CRT), central choroidal thickness (CCT), and exudative status were analyzed using optical coherence tomography. Aqueous humor was collected before and after the switch, and angiopoietin-2 (Ang-2), placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) A levels were measured. RESULTS. After switching from aflibercept to faricimab, exudative changes improved in 28 eyes (52%), remained stable in eight eyes (15%), and worsened in 18 eyes (33%). BCVA changed from 0.27 ± 0.31 to 0.26 ± 0.29 (P = 0.46), CRT decreased from 306.2 ± 147.5 μm to 278.6 ± 100.4 μm (P = 0.11), and CCT changed from 189.5 ± 92.8 μm to 186.8 ± 93.9 μm (P = 0.21). VEGF-A levels were below the detection sensitivity in many cases throughout the pre- and post-switching periods. Ang-2 significantly decreased from 23.8 ± 23.5 pg/mL to 16.4 ± 21.9 pg/mL (P < 0.001), and PlGF significantly increased from 0.86 ± 0.85 pg/mL to 1.72 ± 1.39 pg/mL (P < 0.001). CONCLUSIONS. Switching from aflibercept to faricimab in patients with nAMD may not only suppress VEGF-A but also Ang-2 and reduce exudative changes.

DOI： 10.1167/iovs.65.11.15

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PubMed

Language：English   Publisher：Radiological Physics and Technology  

We investigated whether magnetic resonance imaging can visualize the distribution in the vitreous cavity via eye drops of ophthalmic solutions, gadolinium-based contrast agent, and 17O-water, and to clarify the usefulness of ultra-heavily T2-weighted sequences in the research of intraocular distribution. Five different solutions (V-ROHTO, TRAVATANZ, gadobutrol, H217O, and saline) were administered to excised pig eye specimens. The samples were scanned using T1 mapping, T2 mapping, 3D T2-weighted (echo times (TE): 500, 3200, and 4500 ms), a half-Fourier single-shot turbo-spin echo sequence (HASTE; TE: 440 and 3000 ms), and 3D-real inversion-recovery before eye drops administration. Subsequently, we used a plastic dropper to drop a 0.5 mL solution each, and images were obtained up to 26 h later. Temporal changes in the T1 and T2 values of the anterior chamber and vitreous cavity were compared. The other sequences were evaluated by determining temporal signal changes as signal intensity ratio (SIR) compared to “No drop.” The T1 and T2 values of samples treated with gadobutrol and H217O decreased over time. The SIR of samples treated with gadobutrol and H217O showed remarkable changes in the 3D T2-weighted images, whereas no remarkable temporal changes were observed in the other solutions. Longer TEs resulted in remarkable changes. We demonstrated that visualization of distribution in the vitreous cavity via eye drops could be achieved with excised pig eyes using gadobutrol and H217O, but not with ophthalmic solutions. Ultra-heavily T2-weighted sequences may be promising for the early and highly sensitive visualization of the intraocular distribution of eye drops.

DOI： 10.1007/s12194-024-00826-6

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Scopus

PubMed

Language：English   Publisher：Japanese Journal of Ophthalmology  

Purpose: To assess the feasibility of swept-source optical coherence tomography angiography (SS-OCTA) to differentiate macular diseases, including nonpolypoidal macular neovascularization (MNV), polypoidal choroidal vasculopathy (PCV), type 3 MNV, and chronic central serous chorioretinopathy (CSC) without indocyanine green angiography (ICGA). Study design: Retrospective observational study. Methods: This study examined 63 eyes of 63 patients with treatment-naive neovascular age-related macular degeneration (AMD), including 23 eyes with nonpolypoidal MNV, 17 eyes with PCV, and 1 eye with type 3 MNV and 22 eyes with chronic CSC. Two independent retina specialists, blinded to the clinical diagnosis, assessed each case of neovascular AMD and chronic CSC using only B-scan and en face images of SS-OCTA without referring to other examination outcomes. Results: By SS-OCTA alone, 19 eyes were diagnosed with nonpolypoidal MNV, 17 eyes with PCV, 2 eyes with type 3 MNV, and 22 eyes with chronic CSC, indicating high sensitivity (82.6%, 94.1%, 100%, and 100%, respectively) and specificity (100%, 97.8%, 98.4%, and 100%, respectively); however, three eyes could not be diagnosed because of obscure images. The agreement of diagnosis with SS-OCTA alone was high between the two specialists (κ = 0.82). Conclusion: SS-OCTA showed high sensitivity and specificity in the differentiation of nonpolypoidal MNV, PCV, type 3 MNV, and chronic CSC. The differential criteria based on SS-OCTA could be a substitute for the ICGA-based diagnoses.

DOI： 10.1007/s10384-024-01115-w

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Scopus

PubMed

Language：English  

Accurate interpretation of sequence variants in inherited retinal dystrophy (IRD) is vital given the significant genetic heterogeneity observed in this disorder. To achieve consistent and accurate diagnoses, establishment of standardized guidelines for variant interpretation is essential. The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for variant interpretation serve as the global "cross-disease" standard for classifying variants in Mendelian hereditary disorders. These guidelines propose a systematic approach for categorizing variants into 5 classes based on various types of evidence, such as population data, computational data, functional data, and segregation data. However, for clinical genetic diagnosis and to ensure standardized diagnosis and treatment criteria, additional specifications based on features associated with each disorder are necessary. In this context, we present a comprehensive framework outlining the newly specified ACMG/AMP rules tailored explicitly to IRD in the Japanese population on behalf of the Research Group on Rare and Intractable Diseases (Ministry of Health, Labour and Welfare of Japan). These guidelines consider disease frequencies, allele frequencies, and both the phenotypic and the genotypic characteristics unique to IRD in the Japanese population. Adjustments and modifications have been incorporated to reflect the specific requirements of the population. By incorporating these IRD-specific factors and refining the existing ACMG/AMP guidelines, we aim to enhance the accuracy and consistency of variant interpretation in IRD cases, particularly in the Japanese population. These guidelines serve as a valuable resource for ophthalmologists and clinical geneticists involved in the diagnosis and treatment of IRD, providing them with a standardized framework to assess and classify genetic variants.

DOI： 10.1007/s10384-024-01063-5

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Scopus

PubMed

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410215196

CiNii Research

Language：English   Publisher：Translational Psychiatry  

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

DOI： 10.1038/s41398-024-02952-6

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PubMed

Language：English   Publisher：BMC Ophthalmology  

Purpose: Vitreous humor (VH) is used for postmortem biochemical studies because it is well protected in an uncontaminated state even after death. The goal of this research was to investigate electrolyte concentrations in the VH from human eyes with and without a history of vitrectomy surgery. Methods: We analyzed the sodium (Na), potassium (K), chloride (Cl) and magnesium (Mg) concentrations from 34 VH samples from 34 patients. Eleven samples were from eyes with a history of vitrectomy, and the remaining 23 eyes had no history of vitrectomy. The correlations of Na, K, Cl and Mg concentrations with patient age, interval between first and second vitrectomy, and lens status (history of cataract surgery) were also evaluated. Results: The Na, K, Cl and Mg concentrations in VH from vitrectomized eyes were 134.1 ± 7.9 mmol/L, 3.7 ± 0.2 mmol/L, 99.7 ± 6.7 mmol/L and 0.59 ± 0.09 mmol/L, respectively; all were significantly lower than the corresponding concentrations in VH from control eyes (lower by 5.0%, 11.0%, 11.7%, and 22.6%, respectively). Na, K, Cl and Mg concentrations in VH from vitrectomized eyes did not show significant correlations with patient ages or the interval between their first and second vitrectomies. There were no significant differences in Na, K, Cl and Mg concentrations in VH between phakic eyes and intraocular lens-implanted eyes. Conclusions: With the increasing number of vitrectomies being performed, it is necessary to consider the history of vitrectomy when using a subject’s VH in forensic examination.

DOI： 10.1186/s12886-024-03445-2

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PubMed

Language：English   Publisher：Graefe's Archive for Clinical and Experimental Ophthalmology  

Purpose: This study evaluated the long-term outcomes of eyes with neovascular age-related macular degeneration (nAMD) treated with aflibercept according to a treat-and-extend (T&E) regimen for up to 5 years. Methods This retrospective study included 112 eyes of 111 patients with nAMD who received aflibercept according to the T&E regimen. The patients received 3 monthly injections of aflibercept followed by a T&E regimen for at least 12 months. Data, including best-corrected visual acuity (BCVA), treatment interval, presence of exudation, central retinal thickness, and central choroidal thickness were analyzed. Results: Of the 112 consecutive eyes, 66 completed the 5-year follow-up. After 5 years of treatment, BCVA (logMAR) was significantly better than baseline (0.29 ± 0.31 at baseline and 0.18 ± 0.23 at 5 years, P < 0.01). A mean of 7.0 ± 1.5 injections in the first year and 4.9 ± 2.2 injections per year thereafter were required. In eyes with subretinal hyperreflective material (SHRM) at baseline, BCVA at baseline and 5 years were significantly worse than in eyes without SHRM at baseline and 5 years. However, the eyes with SHRM required fewer injections and exhibited greater BCVA improvement. Conclusion: This retrospective study demonstrated the effectiveness of the T&E regimen with aflibercept in managing nAMD over a 5-year period, maintaining significant improvements in BCVA.

DOI： 10.1007/s00417-024-06519-5

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PubMed

Publisher：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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Scopus

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410215151

CiNii Research

Language：English   Publisher：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

Language：English   Publisher：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

Scopus

PubMed

Language：English   Publisher：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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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ajo.2024.03.007

Scopus

PubMed

Language：English  

DOI： 10.7759/cureus.55716

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PubMed

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410215088

CiNii Research

Language：English   Publisher：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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PubMed

Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.gimo.2023.100839

Publisher：Ophthalmology  

Purpose: To assess the impact of genetic risk estimation for primary open-angle glaucoma (POAG) in Japanese individuals. Design: Cross-sectional analysis. Participants: Genetic risk scores (GRSs) were constructed based on a genome-wide association study (GWAS) of POAG in Japanese people. A total of 3625 Japanese individuals, including 1191 patients and 2434 controls (Japanese Tohoku), were used for the model selection. We also evaluated the discriminative accuracy of constructed GRSs in a dataset comprising 1034 patients and 1147 controls (the Japan Glaucoma Society Omics Group [JGS-OG] and the Genomic Research Committee of the Japanese Ophthalmological Society [GRC-JOS]) and 1900 participants from a population-based study (Hisayama Study). Methods: We evaluated 2 types of GRSs: polygenic risk scores using the pruning and thresholding procedure and a GRS using variants associated with POAG in the GWAS of the International Glaucoma Genetics Consortium (IGGC). We selected the model with the highest areas under the receiver operating characteristic curve (AUC). In the population-based study, we evaluated the correlations between GRS and ocular measurements. Main Outcome Measure: Proportion of patients with POAG after stratification according to the GRS. Results: We found that a GRS using 98 variants, which showed genome-wide significance in the IGGC, showed the best discriminative accuracy (AUC, 0.65). In the Japanese Tohoku, the proportion of patients with POAG in the top 10% individuals was significantly higher than that in the lowest 10% (odds ratio [OR], 6.15; 95% confidence interval [CI], 4.35–8.71). In the JGS-OG and GRC-JOS, we confirmed similar impact of POAG GRS (AUC, 0.64; OR [top vs. bottom decile], 5.81; 95% CI, 3.79–9.01). In the population-based study, POAG prevalence was significantly higher in the top 20% individuals of the GRS compared with the bottom 20% (9.2% vs. 5.0%). However, the discriminative accuracy was low (AUC, 0.56). The POAG GRS was correlated positively with intraocular pressure (r = 0.08: P = 4.0 × 10–4) and vertical cup-to-disc ratio (r = 0.11; P = 4.0 × 10–6). Conclusions: The GRS showed moderate discriminative accuracy for POAG in the Japanese population. However, risk stratification in the general population showed relatively weak discriminative performance. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

DOI： 10.1016/j.ophtha.2024.05.026

Scopus

Publisher：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

Language：English   Publishing type：Research paper (scientific journal)  

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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PubMed

Language：English   Publisher：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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PubMed

Language：Japanese   Publisher：(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)

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214923

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

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

Web of Science

Scopus

PubMed

Language：English   Publisher：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

Web of Science

Scopus

PubMed

Language：English   Publisher：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

Web of Science

Scopus

PubMed

Web of Science

Language：Japanese   Publisher：(公財)日本眼科学会  

Language：English   Publishing type：Research paper (scientific journal)  

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

Web of Science

Scopus

PubMed

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214775

CiNii Research

Language：English   Publisher：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

Web of Science

Scopus

PubMed

Language：Japanese   Publisher：(公財)日本眼科学会  

Language：Japanese   Publisher：(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)

Language：Japanese   Publisher：(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)

Language：English   Publisher：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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Language：English   Publisher：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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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214679

CiNii Research

Language：English   Publisher：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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Language：English   Publisher：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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Language：English   Publisher：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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214491

CiNii Research

Publisher：医歯薬出版  

DOI： 10.32118/ayu28206634

CiNii Research

Publisher：金原出版  

DOI： 10.18888/ga.0000002697

CiNii Research

Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214400

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Language：Japanese   Publisher：(公財)日本眼科学会  

Language：Japanese   Publisher：(公財)日本眼科学会  

Language：Japanese   Publisher：(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)

Language：Japanese   Publisher：眼科臨床紀要会  

Language：English  

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

Language：English   Publishing type：Research paper (scientific journal)  

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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Language：English   Publishing type：Research paper (scientific journal)  

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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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214208

CiNii Research

Language：Japanese   Publisher：JAPAN SOCIETY FOR COMPUTATIONAL ENGINEERING AND SCIENCE  

<p>To obtain the conceptual structure of an automobile frame from a large area of metal blocks by topology optimization, a volume constraint of less than 1% and sufficient element resolution are required. By using the building cube method framework, usually a finite volume method solver using hierarchical orthogonal lattices, as a voxel finite element method solver for orthogonal lattices with connectivity, we perform iterative topology optimization in a massively parallel environment. Topology optimization of billions of elements intended for a vehicle frame is performed using tens of thousands of processors and its parallel performance is measured.</p>

DOI： 10.11421/jsces.2021.20210019

CiNii Research

Language：Japanese   Publisher：眼科臨床紀要会  

Language：English  

Purpose: Polypoidal choroidal vasculopathy (PCV) is a subtype of age-related macular degeneration that is seen frequently in Asians. Nevertheless, it is rare for this condition to be combined with retinitis pigmentosa (RP). The purpose of this paper is to present findings from this rare combination in a Japanese patient, and to describe its successful treatment with intravitreal aflibercept (IVA). Observations: The patient was a 71-year-old Japanese woman with RP (diagnosed at the age of 30) and PCV. She noticed a decrease in vision in her right eye 6 months previously. Decimal best-corrected visual acuity (BCVA) was 0.05 in her right eye. Optical coherence tomography and indocyanine green angiography (IA) revealed serous retinal detachment (SRD) and PCV in her right eye. The SRD was initially resolved after 3 monthly treatments with IVA, but recurrences began 5 months later, requiring four more treatments with IVA, performed about every 4 months within the next 12 months, for successful resolution. There were no recurrences of PCV in 7 more months of follow-up, as confirmed with IA at the final appointment. Final decimal BCVA in the right eye improved to 0.15. Furthermore, macular retinal sensitivity, measured with microperimetry, increased after the treatment, and RP-related visual field narrowing, determined by Goldmann perimetry, did not progress throughout follow up of 26 months. Conclusion: More than 2 years of follow up showed that IVA may be effective for treating PCV, even in RP patients, and can increase central visual function without causing progression of RP-related visual field narrowing.

DOI： 10.1016/j.ajoc.2021.101123

PubMed

Language：Japanese   Publisher：(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。

Other Link： 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

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：Japanese   Publisher：(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)

Language：English   Publishing type：Research paper (scientific journal)  

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

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: This study searched for early predictive vascular biomarkers for visual outcomes in eyes with macular edema caused by branch retinal vein occlusion (BRVOME). METHODS: Twenty-four eyes of 24 subjects with BRVOME were treated with the intravitreal injection of ranibizumab (IVR) for at least 6 months. We measured mean blur rate (MBR) in the optic nerve head (ONH) and vessel density (VD) in the macula with laser speckle flowgraphy and optical coherence tomography angiography, respectively. RESULTS: Six-month post-IVR best-corrected visual acuity (BCVA) was correlated positively with age, pre-IVR BCVA, 1-month post-IVR BCVA, 3-month post-IVR BCVA and pre-IVR systolic blood pressure (P < 0.001, P < 0.001, P < 0.001, P < 0.001 and P = 0.02, respectively) and negatively with pre-IVR overall MBR, 1-month post-IVR overall MBR, 6-month post-IVR overall MBR, 3-month post-IVR deep retinal capillary plexus (DCP) VD and 6-month post-IVR DCP VD (P = 0.03, P = 0.03, P = 0.02, P = 0.01 and P = 0.005, respectively). Furthermore, a multiple regression analysis showed that pre-IVR overall MBR (β =  - 0.67, P = 0.009) was among independent prognostic factors predicting 6-month post-IVR BCVA. Six-month post-IVR DCP VD was also correlated with overall MBR at all time points. CONCLUSION: ONH blood flow may be a pre-IVR biomarker of both visual outcomes and post-IVR deep macular microcirculation in eyes with BRVOME.

DOI： 10.1007/s10792-020-01562-7

PubMed

Publisher：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

Publisher：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

Language：English   Publishing type：Research paper (scientific journal)  

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

Web of Science

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Calpain activation induces retinal ganglion cell (RGC) death, while calpain inhibition suppresses RGC death, in animal studies. However, the role of calpain in human retinal disease is unclear. This study investigated a new strategy to study the role of calpain based on real-time imaging. We synthesized a novel fluorescent probe for calpain, acetyl-L-leucyl-L-methionine-hydroxymethyl rhodamine green (Ac-LM-HMRG) and used it for real-time imaging of calpain activation. The toxicity of Ac-LM-HMRG was evaluated with a lactate dehydrogenase (LDH) cytotoxicity assay, retinal sections, and electroretinograms (ERG). Here, we performed real-time imaging of calpain activation in a rat model. First, we administered N-methyl-D-aspartate (NMDA) to induce retinal injury. Twenty minutes later, we administered an intravitreal injection of Ac-LM-HMRG. Real-time imaging was then completed with a non-invasive confocal scanning laser ophthalmoscope. The inhibitory effect of SNJ-1945 against calpain activation was also examined with the same real-time imaging method. Ac-LM-HMRG had no toxic effects. The number of Ac-LM-HMRG-positive cells in real-time imaging significantly increased after NMDA injury, and SNJ-1945 significantly lowered the number of Ac-LM-HMRG-positive cells. Real-time imaging with Ac-LM-HMRG was able to quickly quantify the NMDA-induced activation of calpain and the inhibitory effect of SNJ-1945. This technique, used as a companion diagnostic system, may aid research into the development of new neuroprotective therapies.

DOI： 10.1021/acs.bioconjchem.0c00435

PubMed

Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/15421406.2020.1743447

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Retinal detachment due to giant retinal tears (GRTs), tears larger than 90°, is rare and difficult to treat. Here, we show and compare surgical results of 23-, 25- and 27-gauge (G) micro-incision vitrectomy surgery (MIVS) for GRT. STUDY DESIGN: Retrospective and interventional case series. METHODS: Retrospective review of 41 eyes of 38 patients with GRT who underwent MIVS. Surgical outcomes after MIVS, including reattachment rates and postoperative complications, were compared between instrument gauges. All patients were followed for at least 6 months postoperatively. RESULTS: MIVS with 23G, 25G and 27G instruments was performed in 7, 19 and 15 eyes, respectively. Silicone oil (SO) was used in 34 of 41 eyes (83%) with a mean removal time of 43.8 days after first surgery. Best-corrected visual acuity (BCVA) was recovered or maintained in 39 eyes (95%). Reattachment was attained after initial surgery in 38 of 41 eyes (93%) (23G: 6/7 [86%]; 25G: 17/19 [89%]; 27G: 15/15 [100%]). Final reattachment was eventually achieved in all eyes (two eyes needed support from scleral encircling). Postoperative complications occurred in 16 eyes (39%) (23G: 3/7 [43%]; 25G: 8/19 [42%]; 27G: 5/15 [33%]), including macular pucker, cystoid macular edema, macular hole, subretinal perfluorocarbon liquid, retinal folds, vitreous hemorrhage and redetachment. There were no significant differences between the three groups in rate of high myopia, GRT size, operation time, phacovitrectomy rate, SO usage rate, initial reattachment rate, final reattachment rate, preoperative BCVA, final BCVA or rate of postoperative complications. CONCLUSION: Despite occasional postoperative complications, primary MIVS, regardless of gauge size, appears to be a safe and feasible option for GRT surgery.

DOI： 10.1007/s10384-020-00755-y

PubMed

Language：English  

DOI： 10.1007/s10384-020-00732-5

PubMed

Language：Japanese   Publisher：眼科臨床紀要会  

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To evaluate retinal vessel density and retinal sensitivity (RS) after macular hole surgery with the superior inverted internal limiting membrane flap technique. METHODS: Retrospective, observational case series. Twenty-one patients with idiopathic macular hole underwent 27-gauge vitrectomy with the superior inverted internal limiting membrane flap technique and triamcinolone acetonide. Measurements included RS, which was measured with microperimetry, as well as retinal vessel density in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), which was measured with optical coherence tomography angiography. All parameters were evaluated in the superior and inferior sectors of the macula preoperatively and 1, 3, and 6 months postoperatively. RESULTS: Six months postoperatively, retinal thickness in the inferior sector was unchanged, but retinal thickness in the superior sector decreased significantly (P < 0.01). SCP vessel density in both sectors was unchanged at all postoperative time points. DCP vessel density in both sectors increased very significantly at 3 months (P < 0.01) and returned to baseline at 6 months. RS in the inferior sector increased by 47% 3 months postoperatively and by 61% 6 months postoperatively (P < 0.05 and P < 0.001, respectively), but RS in the superior sector increased only at 6 months postoperatively and only by 22% (P < 0.05). CONCLUSION: Lower recovery of RS in the superior sector suggests that internal limiting membrane peeling might affect the postoperative visual function.

DOI： 10.1097/IAE.0000000000002839

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: The success of surgical treatment for idiopathic epiretinal membrane (ERM) is measured by postoperative best-corrected visual acuity (BCVA), metamorphopsia, and foveal retinal sensitivity (RS).This study searched for predictive biomarkers of surgical success by determining the association between foveal RS and various aspects of vessel density (VD) in the fovea of patients with ERM. METHODS: The study examined 25 eyes of 25 patients with ERM who underwent 27-gauge microincision vitrectomy surgery (MIVS). RS was measured with microperimetry (MP-3; NIDEK) at four central points in the fovea with an interpoint distance of 2°. VD was measured with SD-OCT (RS 3000; NIDEK) within the 1-mm2 square defined by the 4 RS points at various depths, including the superficial and deep retinal capillary plexus (SCP and DCP, respectively). RESULTS: Though VD did not change throughout the follow-up period, BCVA and RS significantly improved 1 and 3 months after surgery, respectively (both P < 0.0017). Postoperative RS at 6 months was positively correlated with postoperative DCP VD at 1, 3, and 6 months (r = 0.62, P = 0.001; r = 0.40, P = 0.049; r = 0.53, P = 0.007, respectively), but not with SCP VD at any time point. Multiple regression analysis confirmed that postoperative RS at 6 months was associated with postoperative DCP VD at 1 month (P = 0.03). CONCLUSION: Higher postoperative DCP VD at 1 month contributed to better postoperative foveal RS at 6 months. Early postoperative VD in the fovea might be a useful predictive biomarker of late postoperative RS in the fovea in ERM patients.

DOI： 10.1007/s00417-020-04754-0

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.ophtha.2020.02.020

PubMed

Language：Japanese   Publisher：(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。

Language：Japanese   Publisher：(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。

Other Link： 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

Language：English  

DOI： 10.1007/s00417-020-04664-1

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Group B streptococcus (GBS), a gram-positive coccus that occasionally causes neonatal sepsis or invasive infection in the elderly, has been considered a rare cause of endogenous bacterial endophthalmitis (EBE). However, the number of invasive GBS infections is increasing, particularly in elderly patients with underlying conditions such as diabetes mellitus (DM), cardiovascular disease and cancer. We report 6 cases of EBE caused by GBS and review the literature. METHODS: Retrospective case series and literature review. RESULTS: In the current case series, 6 eyes of 6 patients developed EBE caused by GBS. The average age was 73.5 years. The focus of infection included the urinary tract, cellulitis, arthritis, peritonitis, catheter-associated infection and endocarditis. Four patients had DM. While all 6 strains were sensitive to β-lactams (penicillins and cephems), 4 strains were resistant to levofloxacin (no data for 1 isolate). Each case was treated with the systemic antibiotic to which the individual strain was sensitive. All cases showed poor visual acuity at presentation (decimal visual acuity: less than 0.03). Vitrectomy with intravitreal antibiotics injection was performed in 4 cases. Visual acuity recovered in 4 cases and did not recover in 2 cases, even after vitrectomy. The literature review of 53 eyes of 41 patients revealed that 60% of eyes finally lost all vision, and death occurred in 2 cases. Initial visual acuity of less than counting fingers was associated with a final outcome of lost vision. Of 41 patients, 13 (32%) had DM as an underlying medical condition. The most common extra-ocular infection focus was endocarditis (37%). CONCLUSIONS: DM is common in patients with EBE caused by GBS. While the 4 cases in the current report had a relatively good visual acuity outcome, despite poor initial visual acuity, the literature review indicated that EBE caused by GBS is generally a severe condition with a poor prognosis. The current study also indicates the importance of considering the possibility of endocarditis on encountering EBE caused by GBS.

DOI： 10.1186/s12886-020-01378-0

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To investigate the genetic variants associated with the onset and progression of primary open-angle glaucoma (POAG). DESIGN: Case-control genetic association study. METHODS: Japanese POAG patients (n=505) and control subjects (n=246) were genotyped for 22 genetic variants predisposing to POAG that can be classified into those associated with intraocular pressure (IOP) elevation (IOP-related genetic variants) and optic nerve vulnerability independent of IOP (non-IOP-related genetic variants). The total number of risk alleles of the 17 IOP-related and 5 non-IOP-related genetic variants were calculated as the genetic risk score (GRS), and the associations between the GRS and family history of glaucoma as an indicator of POAG onset and age at the diagnosis of glaucoma as an indicator of POAG progression were evaluated. RESULTS: There was a significant association (P=0.014, odds ratio: 1.26 per GRS) between the non-IOP-related GRS, but not IOP-related GRS, and a family history of glaucoma in POAG. As the non-IOP-related GRS increased, the risk of a family history of glaucoma increased. In contrast, a significant association (P=0.0014, Beta=-0.14) was found between the IOP-related GRS, but not non-IOP-related GRS, and age at the diagnosis of glaucoma. As the IOP-related GRS increased, age at the diagnosis of glaucoma decreased. CONCLUSIONS: The results indicate that non-IOP-related (optic nerve vulnerability) rather than IOP-related (IOP elevation) genetic variants may play an important role in the onset of POAG (family history of glaucoma) and that IOP-related rather than non-IOP-related genetic variants may play an important role its progression (age at the diagnosis of glaucoma).

DOI： 10.1016/j.ajo.2020.03.014

PubMed

Language：Japanese   Publisher：(公財)日本眼科学会  

Language：English   Publishing type：Research paper (scientific journal)  

IMPORTANCE: A framework for understanding the phenotypic features of CRX retinopathy was established. BACKGROUND: To perform a phenotype-genotype correlation analysis in two groups of patients with heterozygous mutations in distinct locations of the CRX gene, encoding the cone-rod homeobox. DESIGN: Multicentre retrospective study. PARTICIPANTS: Twenty-one Japanese patients from 14 families with a heterozygous CRX mutation. METHODS: Retrospective data analysis. MAIN OUTCOME MEASURES: Clinical records on CRX mutation, symptoms, best-corrected visual acuity (BCVA), visual field, fundus photography, fundus auto-fluorescence, optical coherence tomography and electroretinograms (ERGs). RESULTS: Six different CRX heterozygous mutations were identified in the subjects. Twelve patients from 9 families shared the p.R41W mutation and 1 patient had the p.R43C mutation, both of which affect the homeobox domain of CRX. These patients often displayed adult-onset retinal dystrophy with macular degeneration. In contrast, five patients with downstream mutations (p.S204fs, p.S213fs, p.G243X and p.L299F) displayed retinal degeneration or macular degeneration with bone-spicule pigmentation. Three asymptomatic carriers with different mutations (p.R41W, p.S213fs and p.G243X) were present in both groups. Nearly all patients and carriers had an electronegative ERG in response to a bright flash under dark adaptation. There was no cross-sectional association between patients' age and BCVA, despite progressive decline in BCVA. CONCLUSIONS AND RELEVANCE: Heterozygous mutations within or downstream of the homeobox domain in CRX relate to the difference associated retinal phenotypes, which was confounded by variable expressivity and electronegative ERGs. CRX mutations should be considered in patients with an electronegative ERG with minimal or no macular changes.

DOI： 10.1111/ceo.13743

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To screen for anti-recoverin antibodies in elderly patients with retinitis pigmentosa (RP) with or without cancer and cross-sectionally characterize the seropositive patients clinically. METHODS: Serum from 75 RP patients who had been tested for mutations in a panel of 83 RP genes and 73 normal controls, all aged 50-80 years, were screened for anti-recoverin antibodies by Western blot using recombinant recoverin, retinal lysate from a marmoset and commercial anti-recoverin antibodies as a control. RESULTS: Three RP patients with typical pigmentary degeneration of the 75 (4.0%) were seropositive for anti-recoverin antibody. Pathogenic mutations were identified in two seropositive RP patients. All three patients had visual impairment since childhood and were diagnosed as RP by the age of 30. The severity of the retinopathy varied greatly among these three patients, ranging in visual acuity from light perception OU to 20/30 OU. Retinitis pigmentosa (RP) patients with a history of cancer were more likely to have anti-recoverin antibodies (3/14; 21.4%) than those without (0/61; 0%; p = 0.005, Fischer exact test). All 73 healthy controls with no history of cancer were also seronegative. CONCLUSION: Our results show that serum anti-recoverin antibodies can be detected in typical RP patients with identified pathogenic mutations and that a history of cancer may increase the risk of developing anti-recoverin antibodies.

DOI： 10.1111/aos.14373

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Supplementing wildtype copies of functionally defective genes with adeno-associated virus (AAV) is a strategy being explored clinically for various retinal dystrophies. However, the low cargo limit of this vector allows its use in only a fraction of patients with mutations in relatively small pathogenic genes. To overcome this issue, we developed a single AAV platform that allows local replacement of a mutated sequence with its wildtype counterpart, based on combined CRISPR-Cas9 and micro-homology-mediated end-joining (MMEJ). In blind mice, the mutation replacement rescued approximately 10% of photoreceptors, resulting in an improvement in light sensitivity and an increase in visual acuity. These effects were comparable to restoration mediated by gene supplementation, which targets a greater number of photoreceptors. This strategy may be applied for the treatment of inherited disorders caused by mutations in larger genes, for which conventional gene supplementation therapy is not currently feasible.

DOI： 10.1038/s41467-019-14181-3

PubMed

Language：English  

DOI： 10.1016/j.ophtha.2019.09.015

PubMed

DOI： 10.1038/s41598-019-57066-7

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To present phenotypic features of 22 patients with S-antigen (SAG) mutations. DESIGN: Retrospective cohort study. PARTICIPANTS: Twenty-one Japanese patients from 16 families with a homozygous c.924delA mutation and 1 patient with a homozygous c.636delT mutation in the SAG gene. METHODS: Clinical records on symptoms; best-corrected visual acuity; and Goldmann perimetry, fundus photography, fundus autofluorescence (FAF), OCT, and electroretinography results were reviewed. MAIN OUTCOME MEASURES: Best-corrected visual acuity, Goldmann perimetry results, imaging findings, and electroretinography results. RESULTS: Ten patients had Oguchi disease and 12 had retinitis pigmentosa (RP) with mean follow-up periods of 13.8 and 10.2 years, respectively. Retinitis pigmentosa patients were older (mean age, 56.0 years) than those with Oguchi disease (mean age, 22.1 years; P < 0.001) at the initial visit. Night blindness noted in childhood was the most common initial symptom for both Oguchi disease (80.0%) and RP (91.7%) patients. Best-corrected visual acuity in the logarithm of the minimum angle of resolution (logMAR) was well preserved in Oguchi disease patients (mean, 0.02 logMAR in both eyes) but reduced in most RP patients (mean, 1.32 logMAR [right eye] and 1.35 logMAR [left eye]). Similarly, the visual field in the retinal area was preserved in Oguchi disease patients (mean, 677 mm2 right eye and 667 mm2 left eye) and reduced in RP patients (mean, 369 mm2 right eye and 294 mm2 left eye). Fundus images revealed a characteristic golden sheen with no retinal degeneration in Oguchi disease patients, excluding 2 with macular degeneration detected by FAF, OCT, or both and 1 with mild retinal degeneration confirmed by OCT and fluorescein angiography. Pigmentary retinal degeneration most evident posteriorly was observed in RP patients, accompanied by a characteristic golden sheen in 12 of 14 patients undergoing ultra-widefield fundus imaging. OCT showed disrupted macular structure, and FAF revealed variable hypofluorescence. Electroretinography identified absent rod responses in both diseases, along with relative preservation of cone responses in Oguchi disease patients. Three patients showed progressive loss of the golden sheen based on fundus images, including 1 who demonstrated RP 26 years after the initial diagnosis of Oguchi disease. CONCLUSIONS: Retinitis pigmentosa with SAG mutations often shows a characteristic golden sheen surrounding posterior pigmentary retinal degeneration. Oguchi disease can show progressive degeneration in adulthood, rarely resulting in RP.

DOI： 10.1016/j.ophtha.2019.05.027

PubMed

Language：English  

DOI： 10.1016/j.bbrc.2019.10.155

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMJ  

<sec><title>Background</title>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.

</sec><sec><title>Methods</title>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.

</sec><sec><title>Results</title>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 (<italic>EYS</italic>, <italic>USH2A</italic>, <italic>RP1L1</italic>, <italic>RHO</italic>, <italic>RP1</italic> and <italic>RPGR</italic>) caused RP in 65.4% (233/356) of those patients. Among autosomal recessive genes, two known founder variants in <italic>EYS</italic> [p.(Ser1653fs) and p.(Tyr2935*)] and four East Asian-specific variants [p.(Gly2752Arg) in <italic>USH2A</italic>, p.(Arg658*) in <italic>RP1L1</italic>, p.(Gly2186Glu) in <italic>EYS</italic> and p.(Ile535Asn) in <italic>PDE6B</italic>] and p.(Cys934Trp) in <italic>USH2A</italic> were found in ≥10 patients. Among autosomal dominant genes, four pathogenic variants [p.(Pro347Leu) in <italic>RHO</italic>, p.(Arg872fs) in <italic>RP1</italic>, p.(Arg41Trp) in <italic>CRX</italic> and p.(Gly381fs) in <italic>PRPF31</italic>] were found in ≥4 patients, while these variants were unreported or extremely rare in both East Asian and non-East Asian population-based databases.

</sec><sec><title>Conclusions</title>East Asian-specific variants in causative genes were the major causes of RP in the Japanese population.

</sec>

DOI： 10.1136/jmedgenet-2018-105691

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PubMed

Language：Japanese   Publisher：日本緑内障学会  

Language：English   Publishing type：Research paper (scientific journal)  

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

Language：English   Publishing type：Research paper (scientific journal)  

This study evaluated age-related changes in the superficial and deep retinal capillary plexus (SCP and DCP, respectively) and in the foveal avascular zone (FAZ). SCP and DCP perfusion density (PD) were measured in optical coherence tomography angiography (OCTA) macular scans of 145 eyes of 145 healthy Japanese subjects, and findings were compared with SCP FAZ and clinical data. We found that age was negatively correlated with SCP and DCP PD (r = -0.17, P = 0.04 and r = -0.20, P = 0.02, respectively) and positively correlated with FAZ area (r = 0.18, P = 0.03). SCP and DCP PD were correlated with each other (r = 0.67, P < 0.001). FAZ area was negatively correlated with SCP PD, DCP PD and central macular thickness (CMT) (r = -0.18, P = 0.03; r = -0.25, P < 0.01; and r = -0.39, P < 0.001, respectively). FAZ was larger and CMT was lower (P = 0.01 and P < 0.001, respectively) in women than men. SCP and DCP PD were positively correlated with estimated glomerular filtration rate (r = 0.17, P = 0.03 and r = 0.24, P < 0.01, respectively). Multiple regression analysis confirmed that age independently affected DCP PD and FAZ (P = 0.02 and P < 0.01, respectively) and that CMT independently affected FAZ area (P < 0.001). Thus, normal subjects showed age-related decreases in macular PD and renal function. FAZ and CMT were related, suggesting that age-related changes in macular thickness also affect capillary vasculature.

DOI： 10.1038/s41598-019-45336-3

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIMS: To investigate the relationship between aqueous flare, visual function and macular structures in retinitis pigmentosa (RP). METHODS: Clinical data from 123 patients with RP (227 eyes), 35 patients with macular dystrophy (68 eyes) and 148 controls (148 eyes) were analysed. The differences in aqueous flare between clinical entities and the correlation between aqueous flare (measured with a laser flare cell meter) versus visual acuity, visual field area (Goldmann perimetry) and macular thickness (optical coherence tomography) in patients with RP were determined. Influence of selected clinical data on flare was assessed using linear mixed-effects model. RESULTS: Aqueous flare was higher in patients with RP than patients with macular dystrophy or controls (p=7.49×E-13). Aqueous flare was correlated with visual field area (R=-0.379, p=3.72×E-9), but not with visual acuity (R=0.083, p=0.215). Macular thickness (R=0.234, p=3.74×E-4), but not foveal thickness (R=0.122, p=0.067), was positively correlated with flare. Flare was not affected by the presence of macular complications. All these associations were maintained when the right and the left eyes were assessed separately. Analysis by linear mixed-effects model revealed that age (p=8.58×E-5), visual field area (p=8.01×E-7) and average macular thickness (p=0.037) were correlated with flare. CONCLUSION: Aqueous flare and visual field area were correlated in patients with RP. Aqueous flare may reflect the degree of overall retinal degeneration more closely than the local foveal impairment.

DOI： 10.1136/bjophthalmol-2018-312225

PubMed

DOI： 10.1167/iovs.18-26084

PubMed

DOI： 10.1080/13816810.2019.1571614

PubMed

Language：English  

DOI： 10.1111/ceo.13365

PubMed

Language：English  

DOI： 10.1016/j.ymthe.2018.07.012

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PubMed

DOI： 10.1038/s41598-018-34413-8

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

In glaucoma, although axonal injury drives retinal ganglion cell (RGC) death, little is known about the underlying pathomechanisms. To provide new mechanistic insights and identify new biomarkers, we combined latest non-targeting metabolomics analyses to profile altered metabolites in the mouse whole retina 2, 4, and 7 days after optic nerve crush (NC). Ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry and liquid chromatography Fourier transform mass spectrometry covering wide spectrum of metabolites in combination highlighted 30 metabolites that changed its concentration after NC. The analysis displayed similar changes for purine nucleotide and glutathione as reported previously in another animal model of axonal injury and detected multiple metabolites that increased after the injury. After studying the specificity of the identified metabolites to RGCs in histological sections using imaging mass spectrometry, two metabolites, i.e., L-acetylcarnitine and phosphatidylcholine were increased not only preceding the peak of RGC death in the whole retina but also at the RGC layer (2.3-fold and 1.2-fold, respectively). These phospholipids propose novel mechanisms of RGC death and may serve as early biomarkers of axonal injury. The combinatory metabolomics analyses promise to illuminate pathomechanisms, reveal biomarkers, and allow the discovery of new therapeutic targets of glaucoma.

DOI： 10.1038/s41598-018-30464-z

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: To assess the therapeutic potential of endothelin-converting enzyme-like 1 (Ecel1) in a mouse model of optic nerve crush. Methods: Ecel1 expression was evaluated with real time quantitative (qRT)-PCR, Western blotting, and immunohistochemistry in mouse retinas after optic nerve crush. Vinblastine administration to the optic nerve and the intravitreal injection of N-methyl-d-aspartate (NMDA) were used to assess Ecel1 gene expression. Ecel1 was deleted with an adeno-associated viral (AAV) clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas9 system, and retinal ganglion cell (RGC) survival was investigated with retrograde labeling, qRT-PCR, and visual evoked potential. Results: Optic nerve crush induced Ecel1 expression specifically in the RGCs, peaking on day 4 after optic nerve crush. Ecel1 gene expression was induced by the vinblastine-induced inhibition of axonal flow, but not by NMDA-induced excitotoxicity, even though both are triggers of RGC death. Knockdown of Ecel1 promoted the loss of RGCs after optic nerve crush. Conclusions: Our data suggest that Ecel1 induction is part of the retinal neuroprotective response to axonal injury in mice. These findings might provide insight into novel therapeutic targets for the attenuation of RGC damage, such as occurs in traumatic optic neuropathy.

DOI： 10.1167/iovs.18-23784

PubMed

Language：English  

DOI： 10.1111/ceo.13099

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: The purpose of the study is to investigate the correlation between intraocular anti-retinal antibodies and clinical measurements in patients with rhegmatogenous retinal detachment (RRD) and proliferative vitreoretinopathy (PVR). MATERIAL AND METHODS: Aqueous humor and vitreous samples were collected from patients with RRD, PVR, and from control subjects with macular hole. The levels of total protein (TP), IgG, and anti-retinal antibodies were determined with a bicinchoninic acid assay, enzyme-linked immunosorbent assay, and dot blot, respectively. Correlations between these measurements were assessed using Pearson's correlation test. Analysis of variance followed by a post-hoc test or the Student t-test was used to compare differences between groups. RESULTS: The levels of anti-retinal antibodies and IgG were correlated with each other (P < 0.010). The IgG concentration was higher in patients with PVR than in controls in both the aqueous humor (P < 0.001) and the vitreous (P < 0.001), but not in patients with RRD. Conversely, TP levels and anti-retinal antibodies in both ocular fluids from RRD and PVR patients did not significantly differ from the controls. In a subgroup analysis, vitreal anti-retinal antibody levels were correlated with average macular thickness in the re-attached macula following surgery for macula-off RRD/PVR (P = 0.012). Furthermore, patients with post-operative cystoid macular edema had a higher level of vitreal anti-retinal antibodies than those without (P = 0.009). CONCLUSIONS: Intravitreal anti-retinal antibodies were increased in the eyes with maculopathy after surgical intervention for RRD/PVR.

DOI： 10.1080/02713683.2018.1451544

PubMed

Language：English  

DOI： 10.1111/ceo.13341

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press  

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&lt
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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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree. Methods: First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. Results: Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year-old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mother's older brother) and his mother was her younger half-sibling sister with a different father. Conclusions: The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys.

DOI： 10.1167/iovs.17-22958

PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The aims of this study were to investigate glaucomatous morphological changes quantitatively in the visual cortex of the brain with voxel-based morphometry (VBM), a normalizing MRI technique, and to clarify the relationship between glaucomatous damage and regional changes in the visual cortex of patients with open-angle glaucoma (OAG). METHODS: Thirty-one patients with OAG (age: 55.9 ± 10.7, male: female = 9: 22) and 20 age-matched controls (age: 54.9 ± 9.8, male: female = 10: 10) were included in this study. The cross-sectional area (CSA) of the optic nerve was manually measured with T2-weighed MRI. Images of the visual cortex were acquired with T1-weighed 3D magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequencing, and the normalized regional visual cortex volume, i.e., gray matter density (GMD), in Brodmann areas (BA) 17, 18, and 19, was calculated with a normalizing technique based on statistic parametric mapping 8 (SPM8) analysis. We compared the regional GMD of the visual cortex in the control subjects and OAG patients. Spearman's rank correlation analysis was used to determine the relationship between optic nerve CSA and GMD in BA 17, 18, and 19. RESULTS: We found that the normal and OAG patients differed significantly in optic nerve CSA (p < 0.001) and visual cortex GMD in BA 17 (p = 0.030), BA 18 (p = 0.003), and BA 19 (p = 0.005). In addition, we found a significant correlation between optic nerve CSA and visual cortex GMD in BA 19 (r = 0.33, p = 0.023), but not in BA 17 (r = 0.17, p = 0.237) or BA 18 (r = 0.24, p = 0.099). CONCLUSION: Quantitative MRI parametric evaluation of GMD can detect glaucoma-associated anatomical atrophy of the visual cortex in BA 17, 18, and 19. Furthermore, GMD in BA 19 was significantly correlated to the damage level of the optic nerve, as well as the retina, in patients with OAG. This is the first demonstration of an association between the cortex of the brain responsible for higher-order visual function and glaucoma severity. Evaluation of the visual cortex with MRI is thus a very promising potential method for objective examination in OAG.

DOI： 10.1371/journal.pone.0197027

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Nature Publishing Group  

We found that hesperidin, a plant-derived bioflavonoid, may be a candidate agent for neuroprotective treatment in the retina, after screening 41 materials for anti-oxidative properties in a primary retinal cell culture under oxidative stress. We found that the intravitreal injection of hesperidin in mice prevented reductions in markers of the retinal ganglion cells (RGCs) and RGC death after N-methyl-D-aspartate (NMDA)-induced excitotoxicity. Hesperidin treatment also reduced calpain activation, reactive oxygen species generation and TNF-α gene expression. Finally, hesperidin treatment improved electrophysiological function, measured with visual evoked potential, and visual function, measured with optomotry. Thus, we found that hesperidin suppressed a number of cytotoxic factors associated with NMDA-induced cell death signaling, such as oxidative stress, over-activation of calpain, and inflammation, thereby protecting the RGCs in mice. Therefore, hesperidin may have potential as a therapeutic supplement for protecting the retina against the damage associated with excitotoxic injury, such as occurs in glaucoma and diabetic retinopathy.

DOI： 10.1038/s41598-017-06969-4

Scopus

PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Public Library of Science  

Purpose To test the genetic association between Japanese patients with primary open-angle glaucoma (POAG) and the previously reported POAG susceptibility loci and to perform genotype–phenotype analysis. Methods Genetic associations for 27 SNPs from 16 loci previously linked to POAG were assessed using genome-wide SNP data of the primary cohort (565 Japanese POAG patients and 1,104 controls). Reproducibility of the assessment was tested in 607 POAG cases and 455 controls (second cohort) with a targeted genotyping approach. For POAG-associated variants, a genotype–phenotype correlation study (additive, dominant, recessive model) was performed using the objective clinical data derived from 598 eyes of 598 POAG patients. Results Among 27 SNPs from 16 loci previously linked to POAG, genotypes for total of 20 SNPs in 13 loci were available for targeted association study. Among 8 SNPs in 3 loci that showed at least nominal association (P &lt
5.00E-02) in the primary cohort, a representative SNP for each loci (rs2157719 for CDKN2B-AS1, rs33912345 for SIX6, and rs9913911 for GAS7) were selected. For these SNPs the association was found significant in both the second cohort analysis and meta-analysis. The genotype–phenotype analysis revealed significant correlations between CDKN2B-AS1 (rs2157719) and decreased intraocular pressure (? = -6.89 mmHg, P = 1.70E-04
dominant model) after multiple corrections. In addition, nominal correlation was observed between CDKN2B-AS1 (rs2157719) and optic nerve head blood flow (? = -0.54 and -0.67 arbitrary units (AU), P = 2.00E-02 and 1.39E-02), between SIX6 (rs33912345) and decreased total peripapillary retinal nerve fiber layer thickness (? = -2.16 and -2.82 ?m, P = 4.68E-02 and 2.40E-02, additive and recessive model, respectively) and increased optic nerve head blood flow (? = 0.44 AU, P = 2.20E-02
additive model) and between GAS7 (rs9913911) and increased cup volume (? = 0.03 mm3, P = 4.60E-02) and mean cup depth (? = 0.03 mm3, P = 4.11E-02
additive model) and decreased pattern standard deviation (? = -0.87 dB, P = 2.44E-02
dominant model). Conclusion The association between SNPs near GAS7 and POAG was found in Japanese patients for the first time. Clinical characterization of the risk variants is an important step toward understanding the pathology of the disease and optimizing treatment of patients with POAG.

DOI： 10.1371/journal.pone.0186678

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PubMed

Language：English   Publisher：WILEY  

DOI： 10.1111/aos.13353

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

To investigate the association between the additive effects of genetic variants associated with intraocular pressure (IOP) and IOP, vertical cup-to-disc ratio (VCDR), and high tension glaucoma (HTG) or normal tension glaucoma (NTG) as phenotypic features of primary open-angle glaucoma (POAG), and to evaluate the clinical usefulness of the additive effects of IOP-related genetic variants for predicting IOP elevation, Japanese patients with HTG (n = 255) and NTG (n = 261) and 246 control subjects were genotyped for nine IOP-related genetic variants near CAV2, GAS7, GLCCI1/ICA1, ABCA1, ARHGEF12, FAM125B, FNDC3B, ABO, and PTPRJ/AGBL2. The total number of risk alleles of these genetic variants was calculated for each participant as a genetic risk score (GRS), and the association between the GRS and the maximum IOP, mean VCDR, and phenotype (HTG or NTG) of POAG was evaluated. As the GRS increased, the maximum IOP (P = 0.012) and VCDR (P = 0.010) significantly increased. The GRS (9.1 +/- 1.9) in patients with HTG was significantly higher (P = 0.011) than that (8.7 +/- 1.8) in control subjects. The patients with GRS &gt;= 12 as a cut-off value had a 2.54 times higher (P = 0.0085) risk on HTG (maximum IOP &gt;= 22mmHg) compared with all patients. The IOP-related GRS approach substantiated that the IOP and VCDR were increased by the additive effects of IOP-related genetic variants in POAG. The high IOP-related GRS in patients with HTG but not NTG shows that there are differences in the genetic background between HTG and NTG and supports the notion that the phenotype (HTG or NTG) in patients with POAG depends on the additive effects of IOP-related genetic variants. The above-mentioned cut-off value of IOP-related GRS may be clinically useful for predicting the risk of IOP elevation.

DOI： 10.1371/journal.pone.0183709

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Retinal ganglion cell degeneration triggered by axonal injury is believed to underlie many ocular diseases, including glaucoma and optic neuritis. In these diseases, retinal ganglion cells are affected unevenly, both spatially and temporally, such that healthy and unhealthy cells coexist in different patterns at different time points. Herein, we describe a temporally and spatially regulated adeno-associated virus gene therapy aiming to reduce undesired off-target effects on healthy retinal neurons. The Mcp-1 promoter previously shown to be activated in stressed retinal ganglion cells following murine optic nerve injury was combined with the neuroprotective intracellular transcription factor Nrf2. In this model, Mcp-1 promoter driven NRF2 expression targeting only stressed retinal ganglion cells showed efficacy equivalent to non-selective cytomegalovirus promoter-driven therapy for preventing cell death. However, cytomegalovirus promoter-mediated NRF2 transcription induced cellular stress responses and death of Brn3A-positive uninjured retinal ganglion cells. Such undesired effects were reduced substantially by adopting the Mcp-1 promoter. Combining a stress-responsive promoter and intracellular therapeutic gene is a versatile approach for specifically targeting cells at risk of degeneration. This strategy may be applicable to numerous chronic ocular and non-ocular conditions.

DOI： 10.1016/j.omtm.2017.04.003

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Latanoprost was first developed for use in glaucoma therapy as an ocular hypotensive agent targeting the prostaglandin F2 alpha (FP) receptor. Subsequently, latanoprost showed a neuroprotective effect, an additional pharmacological action. However, although it is well-known that latanoprost exerts an ocular hypotensive effect via the FP receptor, it is not known whether this is also true of its neuroprotective effect. Klotho was firstly identified as the gene linked to the suppression of aging phenotype: the defect of klotho gene in mice results aging phenotype such as hypokinesis, arteriosclerosis, and short lifespan. After that, the function of klotho was also reported to maintain calcium homeostasis and to exert a neuroprotective effect in various models of neurodegenerative disease. However, the function of klotho in eyes including retina is still poorly understood. Here, we show that klotho is a key factor underlying the neuroprotective effect of latanoprost during post-axotomy retinal ganglion cell (RGC) degeneration. Importantly, a quantitative RT-PCR gene expression analysis of klotho in sorted rat retinal cells revealed that the highest expression level of klotho in the retina was in the RGCs. Latanoprost acid, the biologically active form of latanoprost, inhibits post-traumatic calpain activation and concomitantly facilitates the expression and shedding of klotho in axotomized RGCs. This expression profile is a good match with the localization, not of the FP receptor, but of organic anion transporting polypeptide 2B1, known as a prostaglandin transporter, in the ocular tissue. Furthermore, an organic anion transporting polypeptide 2B1 inhibitor suppressed latanoprost acid-mediated klotho shedding exvivo, whereas an FP receptor antagonist did not. The klotho fragments shed from the RGCs reduced the intracellular level of reactive oxygen species, and a specific klotho inhibitor accelerated and increased RGC death after axotomy. We conclude that the shed klotho fragments might contribute to the attenuation of axonal injury-induced calpain activation and oxidative stress, thereby protecting RGCs from post-traumatic neuronal degeneration.

DOI： 10.1111/jnc.13902

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PubMed

Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS INC  

Purpose: To investigate changes in retinal ganglion cell (RGC) activity by measuring the positive scotopic threshold response (pSTR) of the electroretinogram (ERG) in axotomized eyes after brimonidine injection.Methods: In 50 adult Sprague-Dawley rats, the left eye was axotomized and injected with phosphate buffered saline (PBS) or brimonidine and the contralateral right eye was left untreated. Scotopic ERGs were recorded simultaneously from both eyes on days 1, 2, 3, 7, and 10 after the intravitreal injection, and the amplitude of the a- and b-waves and the pSTR were measured. Surviving RGCs in the flat-mounted retinas were counted 10 days after axotomy. In addition to brimonidine, K252a (an inhibitor of tyrosine kinase phosphorylation of the Trk receptors), U0126 (a MAPK/ERK kinase inhibitor), and LY294002 (phosphoinositide 3-kinases [PI3Ks]) were also injected intravitreally into the left eye, and ERGs were recorded using the same protocol.Results: The pSTR amplitude increased significantly in the axotomized eyes with brimonidine, to 122.9 5.0%, 161.8 +/- 8.3%, and 133.6 +/- 8.1% on days 1, 2, and 3 (P &lt; 0.01), respectively, compared to the axotomized eyes treated with PBS (control). The increased pSTR amplitude returned to normal (103.6 +/- 6.7%) on day 7, although there were a greater number of surviving RGCs in the treatment groups than in the controls. The intravitreal injection of K252a, U0126, or LY294002 significantly attenuated the increase in pSTR induced by intravitreal brimonidine (P &lt; 0.01).Conclusion: Intravitreal brimonidine enhanced the survival and electrophysiological activity of the RGCs in rats. The mechanism of this electrophysiological change may involve activation of the Trk-MAPK/ERK and Trk-PI3K signals.

DOI： 10.3109/02713683.2016.1153112

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PubMed

DOI： 10.1007/978-4-431-56511-6_8

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Language：Japanese  

J-GLOBAL

Language：Japanese   Publisher：眼科臨床紀要会  

J-GLOBAL

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Language：Japanese   Publisher：眼科臨床紀要会  

Language：Japanese   Publisher：医学書院  

Language：Japanese   Publisher：(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)

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CiNii Books

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Other Link： http://search.jamas.or.jp/link/ui/2017319162

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