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

Inflammation plays an important role in pathological angiogenesis. Receptor-interacting protein 1 (RIP1) is highly expressed in inflammatory cells and is known to play an important role in the regulation of apoptosis, necroptosis, and inflammation; however, a comprehensive description of its role in angiogenesis remains elusive. Here, we show that RIP1 is abundantly expressed in infiltrating macrophages during angiogenesis, and genetic or pharmacological inhibition of RIP1 kinase activity using kinase-inactive RIP1^K45A/K45A mice or necrostatin-1 attenuates angiogenesis in laser-induced choroidal neovascularization, Matrigel plug angiogenesis, and alkali injury-induced corneal neovascularization in mice. The inhibitory effect on angiogenesis is mediated by caspase activation through a kinase-independent function of RIP1 and RIP3. Mechanistically, infiltrating macrophages are the key target of RIP1 kinase inhibition to attenuate pathological angiogenesis. Inhibition of RIP1 kinase activity is associated with caspase activation in infiltrating macrophages and decreased expression of proangiogenic M2-like markers but not M1-like markers. Similarly, in vitro, catalytic inhibition of RIP1 down-regulates the expression of M2-like markers in interleukin-4–activated bone marrow-derived macrophages, and this effect is blocked by simultaneous caspase inhibition. Collectively, these results demonstrate a nonnecrotic function of RIP1 kinase activity and suggest that RIP1-mediated modulation of macrophage activation may be a therapeutic target of pathological angiogenesis.

DOI： 10.1073/pnas.1908355116

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

Oxidative stress is implicated in various neurodegenerative disorders, including retinitis pigmentosa (RP), an inherited disease that causes blindness. The biological and cellular mechanisms by which oxidative stress mediates neuronal cell death are largely unknown. In a mouse model of RP (rd10 mice), we show that oxidative DNA damage activates microglia through MutY homolog-mediated (MUYTH-mediated) base excision repair (BER), thereby exacerbating retinal inflammation and degeneration. In the early stage of retinal degeneration, oxidative DNA damage accumulated in the microglia and caused single-strand breaks (SSBs) and poly(ADP-ribose) polymerase activation. In contrast, Mutyh deficiency in rd10 mice prevented SSB formation in microglia, which in turn suppressed microglial activation and photoreceptor cell death. Moreover, Mutyh-deficient primary microglial cells attenuated the polarization to the inflammatory and cytotoxic phenotype under oxidative stress. Thus, MUTYH-mediated BER in oxidative microglial activation may be a novel target to dampen the disease progression in RP and other neurodegenerative disorders that are associated with oxidative stress.

DOI： 10.1172/jci.insight.87781

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

PURPOSE: To investigate the correlation between aqueous flare values and central visual function in patients with retinitis pigmentosa (RP). DESIGN: Retrospective, observational case series. METHODS: We retrospectively studied 160 patients diagnosed with typical RP and 59 control subjects. Aqueous flare values were measured by laser flare cell meter. The relationships between aqueous flare and best-corrected visual acuity (VA) and mean deviation (MD) of static perimetry tests were analyzed in RP patients. RESULTS: The aqueous flare values were significantly higher in the RP patients compared to the control subjects (10.6 ± 7.9 vs 5.0 ± 2.1 photon counts per millisecond [pc/ms], P < .0001). In the RP patients, the aqueous flare values were negatively correlated with VA (r = 0.359, P < .0001) and MD (r = -0.330, P < .0001). Age-subgroup analysis showed a significant correlation between aqueous flare and VA in the RP patients' 40s, 50s, and 60s and between aqueous flare and MD in the 30s, 40s, 50s, and 60s. The RP patients with MD values ≥-15 decibels (dB) showed significantly higher levels of aqueous flare than those with MD values <-15 dB (12.0 ± 6.2 vs 8.7 ± 5.8, P = .0001). CONCLUSIONS: Aqueous flare is increased in RP patients and negatively correlates with central visual function. These results suggest a close relationship between inflammation and central vision loss in RP.

DOI： 10.1016/j.ajo.2015.02.001

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

DOI： 10.1038/cdd.2013.109

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

Retinitis pigmentosa (RP) is a genetically heterogenous group of inherited retinal degenerative diseases resulting from photoreceptor cell death and affecting >1 million persons globally. Although oxidative stress has been implicated in the pathogenesis of RP, the mechanisms by which oxidative stress mediates photoreceptor cell death are largely unknown. Here, we show that oxidation of nucleic acids is a key component in the initiation of death-signaling pathways in rd10 mice, a model of RP. Accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) increased in photoreceptor cells, and especially within their nuclei, in rd10 mice as well as in Royal College of Surgeons rats, another model of RP caused by different genetic mutations. Vitreous samples from humans with RP contained higher levels of 8-oxo-dG excreted than samples from nondegenerative controls. Transgenic overexpression of human MutT homolog-1, which hydrolyzes oxidized purine nucleoside triphosphates in the nucleotide pool, significantly attenuated 8-oxo-dG accumulation in nuclear DNA and photoreceptor cell death in rd10 mice, in addition to suppressing DNA single-strand break formation, poly(ADP-ribose) polymerase activation, and nuclear translocation of apoptosis-inducing factor. These findings indicate that oxidative DNA damage is an important process for the triggering of photoreceptor cell death in rd10 mice and suggest that stimulation of DNA repair enzymes may be a novel therapeutic approach to attenuate photoreceptor cell loss in RP.

DOI： 10.1016/j.ajpath.2012.06.026

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

Retinitis pigmentosa comprises a group of inherited retinal photoreceptor degenerations that lead to progressive loss of vision. Although in most cases rods, but not cones, harbor the deleterious gene mutations, cones do die in this disease, usually after the main phase of rod cell loss. Rod photoreceptor death is characterized by apoptotic features. In contrast, the mechanisms and features of subsequent nonautonomous cone cell death remain largely unknown. In this study, we show that receptor-interacting protein (RIP) kinase mediates necrotic cone cell death in rd10 mice, a mouse model of retinitis pigmentosa caused by a mutation in a rod-specific gene. The expression of RIP3, a key regulator of programmed necrosis, was elevated in rd10 mouse retinas in the phase of cone but not rod degeneration. Although rd10 mice lacking Rip3 developed comparable rod degeneration to control rd10 mice, they displayed a significant preservation of cone cells. Ultrastructural analysis of rd10 mouse retinas revealed that a substantial fraction of dying cones exhibited necrotic morphology, which was rescued by Rip3 deficiency. Additionally, pharmacologic treatment with a RIP kinase inhibitor attenuated histological and functional deficits of cones in rd10 mice. Thus, necrotic mechanisms involving RIP kinase are crucial in cone cell death in inherited retinal degeneration, suggesting the RIP kinase pathway as a potential target to protect cone-mediated central and peripheral vision loss in patients with retinitis pigementosa.

DOI： 10.1073/pnas.1206937109

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

Apoptosis has been shown to be a significant form of cell loss in many diseases. Detachment of photoreceptors from the retinal pigment epithelium, as seen in various retinal disorders, causes photoreceptor loss and subsequent vision decline. Although caspase-dependent apoptotic pathways are activated after retinal detachment, caspase inhibition by the pan-caspase inhibitor Z-VAD fails to prevent photoreceptor death; thus, we investigated other pathways leading to cell loss. Here, we show that receptor interacting protein (RIP) kinase-mediated necrosis is a significant mode of photoreceptor cell loss in an experimental model of retinal detachment and when caspases are inhibited, RIP-mediated necrosis becomes the predominant form of death. RIP3 expression, a key activator of RIP1 kinase, increased more than 10-fold after retinal detachment. Morphological assessment of detached retinas treated with Z-VAD showed decreased apoptosis but significantly increased necrotic photoreceptor death. RIP1 kinase inhibitor necrostatin-1 or Rip3 deficiency substantially prevented those necrotic changes and reduced oxidative stress and mitochondrial release of apoptosis-inducing factor. Thus, RIP kinase-mediated programmed necrosis is a redundant mechanism of photoreceptor death in addition to apoptosis, and simultaneous inhibition of RIP kinases and caspases is essential for effective neuroprotection and may be a novel therapeutic strategy for treatment of retinal disorders.

DOI： 10.1073/pnas.1009179107

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

Photoreceptor apoptosis is a critical process of retinal degeneration in retinitis pigmentosa (RP), a group of retinal degenerative diseases that result from rod and cone photoreceptor cell death and represent a major cause of adult blindness. We previously demonstrated the efficient prevention of photoreceptor apoptosis by intraocular gene transfer of pigment epithelium-derived factor (PEDF) in animal models of RP; however, the underlying mechanism of the neuroprotective activity of PEDF remains elusive. In this study, we show that an apoptosis-inducing factor (AIF)-related pathway is an essential target of PEDF-mediated neuroprotection. PEDF rescued serum starvation-induced apoptosis, which is mediated by AIF but not by caspases, of R28 cells derived from the rat retina by preventing translocation of AIF into the nucleus. Nuclear translocation of AIF was also observed in the apoptotic photoreceptors of Royal College of Surgeons rats, a well-known animal model of RP that carries a mutation of the Mertk gene. Lentivirus-mediated retinal gene transfer of PEDF prevented the nuclear translocation of AIF in vivo, resulting in the inhibition of the apoptotic loss of their photoreceptors in association with up-regulated Bcl-2 expression, which mediates the mitochondrial release of AIF. These findings clearly demonstrate that AIF is an essential executioner of photoreceptor apoptosis in inherited retinal degeneration and provide a therapeutic rationale for PEDF-mediated neuroprotective gene therapy for individuals with RP.

DOI： 10.2353/ajpath.2008.080466

Publisher：Ophthalmology Science  

Purpose: To compare the usefulness of microperimetry and static automated perimetry in patients with retinitis pigmentosa (RP), using macular anatomical metrics as a reference. Design: Prospective observational study. Participants: Forty-eight eyes of 48 patients with RP in Kyushu University Hospital who underwent microperimetry-3 (MP-3) and Humphrey Field Analyzer (HFA) 10-2 testing ≥3 times during ≥2 years were included. Methods: Macular anatomy (ellipsoid zone [EZ] length) was assessed by OCT, and macular function was assessed by MP-3 (mean retinal sensitivity at radii 2°, 4°, and 8°) and HFA10-2 program (mean retinal sensitivity at radii 2°, 4°, and 8°). Correlations between functional and anatomical parameters were analyzed cross sectionally at baseline and longitudinally by comparing the rate of progression. Main Outcome Measures: Correlation coefficients between anatomical and functional metrics. Results: The mean age at baseline was 50.1 ± 12.3 years, and the mean follow-up period was 2.8 ± 0.7 years. At baseline, EZ length was significantly correlated with MP-3 mean retinal sensitivity at radii 2°, 4°, and 8° (Spearman's ρ = 0.65, 0.84, 0.89; all P < 0.005) and HFA10-2 mean retinal sensitivity at radii 2°, 4°, and 8° (Spearman's ρ = 0.61, 0.73, 0.78; all P < 0.005). Longitudinal analysis showed that the slope of EZ length (−88.92 μm/year) was significantly correlated with the slope of MP-3 retinal sensitivity at 8° radius (−0.62 decibels [dB]/year; Spearman's ρ = 0.31, P=0.03) and the slope of HFA retinal sensitivity at 8° radius (−0.60 dB/year; Spearman's ρ = 0.43, P < 0.005). Conclusions: Both MP-3 and HFA values were cross sectionally well-correlated with EZ length in patients with patients; however, these associations became weaker in the longitudinal analysis. This highlights the need for researchers to explore additional or more sensitive parameters to better monitor RP progression. 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.xops.2024.100582

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Language：English   Publisher：Translational vision science &amp; technology  

Purpose: To investigate the profiles and correlations between local and systemic inflammatory molecules in patients with retinitis pigmentosa (RP). Methods: The paired samples of aqueous humor and serum were collected from 36 eyes of 36 typical patients with RP and 25 eyes of age-matched patients with cataracts. The concentration of cytokines/chemokines was evaluated by a multiplexed immunoarray (Q-Plex). The correlations between ocular and serum inflammatory molecules and their association with visual function were analyzed. Results: The aqueous levels of IL-6, Eotaxin, GROα, I-309, IL-8, IP-10, MCP-1, MCP-2, RANTES, and TARC were significantly elevated in patients with RP compared to controls (all P < 0.05). The detection rate of aqueous IL-23 was higher in patients with RP (27.8%) compared with controls (0%). In patients with RP, Spearman correlation test demonstrated positive correlations for IL-23, I-309, IL-8, and RANTES between aqueous and serum expression levels (IL-23: ⍴ = 0.8604, P < 0.0001; I-309: ρ = 0.4172, P = 0.0113; IL-8: ρ = 0.3325, P = 0.0476; RANTES: ρ = 0.6685, P < 0.0001). In addition, higher aqueous IL-23 was associated with faster visual acuity loss in 10 patients with RP with detected aqueous IL-23 (ρ = 0.4119 and P = 0.0264). Multiple factor analysis confirmed that aqueous and serum IL-23 were associated with visual acuity loss in patients with RP. Conclusions: These findings suggest that ocular and systemic inflammatory responses have a close interaction in patients with RP. Further longitudinal studies with larger cohorts are needed to explore the correlation between specific inflammatory pathways and the progression of RP. Translational Relevance: This study demonstrates the local-systemic interaction of immune responses in patients with RP.

DOI： 10.1167/tvst.13.8.18

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Language：English   Publisher：Japanese Journal of Ophthalmology  

Purpose: Extracellular Adenosine triphosphate (ATP) released by dying cells may cause a secondary cell death in neighboring cells in retinal degeneration. We investigated intraocular ATP kinetics to gain mechanical insights into the pathology in rhegmatogenous retinal detachment (RRD). Study design: Retrospective clinical study. Methods: Vitreous or subretinal fluids (SRF) were obtained from patients with RRD (n=75), macular hole (MH; n=20), and epiretinal membrane (ERM; n=35) during vitrectomy. ATP levels in those samples were measured by luciferase assay. Results: Mean ATP levels in the vitreous from RRD patients were significantly higher compared to those from MH and ERM patients (2.3 and 0.3 nM, respectively. P<0.01). Mean ATP levels in the SRF from RRD (11.7 nM) were higher than those in the vitreous from RRD (P<0.01). Mean ATP levels in the vitreous with short durations (1–8 days) of RRD were higher compared to those with long durations (>8 days) (3.2 and 1.4 nM, respectively. P<0.05). Similarly, ATP in SRF with short durations were higher than those with long durations (23.8 and 3.6 nM, respectively. P<0.05). Furthermore, the concentrations of ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1), a major ATP degradative enzyme, in the vitreous from RRD were higher than those from MH/ERM (1.2 and 0.2 ng/ml, respectively. P<0.01). ENTPD1 expression was localized in the cytoplasm of CD11b-positive infiltrating cells in the vitreous and retinal cells. Conclusion: ATP increased in the vitreous and SRF in RRD and decreased over time with an upregulation of ENTPD1. The kinetics indicate the pathological mechanism of the excessive extracellular ATP after RRD.

DOI： 10.1007/s10384-024-01087-x

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

Background/Objective: Acute retinal necrosis (ARN) is a vision-threatening disease caused by herpesvirus infection. This study aimed to investigate the visual prognostic factors that could be determined at the initial visit. Subjects and Methods: This retrospective study included 34 patients with ARN. Logistic regression analysis was employed to evaluate the associations between poor final visual outcomes and various factors, including poor initial visual acuity, presence of retinal detachment at the initial visit, posterior extension of necrotizing retinitis, and circumferential extension of necrotizing retinitis. Posterior extension was evaluated with three zonings, from the periphery (zone 3), mid-periphery (zone 2), and macula (zone 1). Circumferential extension was evaluated according to the degree of necrotizing retinitis lesions using ultra-wide fundus imaging. Results: The mean logarithm of the minimum angle of resolution was 0.63 ± 0.68 at the initial visit and 0.83 ± 0.65 at 12 months after the initial visit. Seven patients had a retinal detachment. The distribution of posterior extension at the initial visit was 5 in zone 1, 20 in zone 2, and 9 in zone 3. The average of necrotizing retinitis lesion angle was 249 ± 115°. The logistic regression analysis revealed that participants with wide angles of necrotizing retinitis were associated with final poor vision, with an odds ratio of 1.28 per 30° increase (95%CI: 1.00–1.65, p = 0.03). Conclusions: Assessment of the widespread circumferential extension of white necrotizing retinal lesions at the initial visit is a crucial risk factor for the visual prognosis in ARN.

DOI： 10.1038/s41433-024-03207-w

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Graefe's Archive for Clinical and Experimental Ophthalmology  

PURPOSE: To investigate the relationships between macular complications and causative genes frequently found in Japanese patients with retinitis pigmentosa (RP). METHODS: In the retrospective and observational study, we analyzed the data of 75 patients with RP (EYS-RP: 42 patients; USH2A-RP: 19 patients; RHO-RP: 14 patients) who were followed-up at Kyushu University Hospital and whose causative genes had been identified. Macular complications including epiretinal membrane (ERM), macular edema (ME), and macular hole (MH) were evaluated using optical coherence tomography and fundus photography. Main outcome was the proportion of macular complications. RESULTS: The proportion of ERM was 35.7% in the EYS group, 10.5% in the USH2A group and 14.3% in the RHO group. The proportion of ME was 7.1% in the EYS group, 5.3% in the USH2A group and 14.3% in the RHO group, and that of MH was 2.4% in the EYS group, 5.3% in the USH2A group and 0% in the RHO group. In the EYS group, the proportion of ERM was relatively higher (p = 0.06), and the presence of EYS was significantly associated with a higher age- and sex-adjusted OR for ERM (OR = 5.67, 95% CI = 1.59-25.20). There was no significant difference in the proportion of MH or ME among causative genes. CONCLUSIONS: EYS causative gene may be associated with higher rate of ERM complication in RP.

DOI： 10.1007/s00417-024-06534-6

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Language：English   Publishing type：Research paper (scientific journal)   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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Language：English   Publishing type：Research paper (scientific journal)   Publisher：British Journal of Ophthalmology  

AIMS: To investigate the association between corneal hysteresis and the presence of glaucoma and its subtypes in a general Japanese population. METHODS: We analysed the data of 2338 Japanese community-dwellers aged ≥40 years (1059 men, 1279 women) who underwent an eye examination in 2018 as part of the population-based, cross-sectional Hisayama Study. Participants were divided into quartile levels of corneal hysteresis, which had been measured with an ocular response analyzer. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria. We conducted a logistic regression analysis to determine the ORs and their 95% CIs for the presence of outcomes according to the corneal hysteresis quartiles. RESULTS: Glaucoma was diagnosed in 154 participants: primary open-angle glaucoma (POAG), n=115; primary angle-closure glaucoma, n=17; exfoliation glaucoma, n=21 and secondary glaucoma without exfoliation glaucoma, n=1. After adjustment for confounders, the OR for prevalent glaucoma was significantly increased in the participants in the first corneal-hysteresis quartile compared with those in the fourth quartile (OR: 1.80; 95% CI: 1.03 to 3.17). Regarding glaucoma subtypes, the first-quartile participants had significantly greater likelihoods of the presence of POAG (OR: 1.63; 95% CI: 1.02 to 2.61) and exfoliation glaucoma (OR: 6.49; 95% CI: 1.44 to 29.30) compared with those in the third and fourth quartiles after adjustment for potential confounders. CONCLUSIONS: These results demonstrated a significant inverse association between corneal hysteresis and the likelihood of glaucoma, suggesting that the measurement of corneal hysteresis would provide useful information for elucidating the aetiology of glaucoma.

DOI： 10.1136/bjo-2023-323987

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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)   Publisher：American Journal of Ophthalmology  

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

DOI： 10.1016/j.ajo.2024.03.007

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Ophthalmology  

PURPOSE: To report the genotypes and clinical features of RHO-associated retinitis pigmentosa (RHO-RP) in the Kyushu region of Japan. STUDY DESIGN: Retrospective, single-center study. METHODS: Sixteen RP patients with pathogenic RHO variants seen at Kyushu University Hospital were investigated. Clinical data including age, best-corrected visual acuity (BCVA) in logarithm of the minimum angle of resolution (logMAR) units, visual field, fundus photography, and optical coherence tomography were retrospectively obtained. Visual outcomes were compared between classical and sector phenotypes and among genetic variants. RESULTS: The mean age at the first visit was 54.0 ± 15.7 years, with a mean follow-up of 7.6 ± 4.0 years. Fourteen patients (87.5%) showed the classical RP phenotype, of whom four were associated with p.[Pro23Leu] and two had p.[Pro347Leu] variants. In addition, two patients with the sector phenotype harbored p.[Ala164Val] variants. Among the classical RHO-RP patients, the mean BCVA decreased from 0.60 to 1.08 logMAR over the follow-up period (7.4 ± 4.1 years) whereas BCVA was preserved at 0.04 logMAR in sector RHO-RP patients (9.0 ± 3.0 years). Genotype-to-phenotype analysis demonstrated that p.[Pro347Leu] was associated with severe vision loss at an earlier age. Macular complications such as epiretinal membrane and cystoid macular edema were observed in 5 classical RHO-RP patients. CONCLUSION: p.[Pro23Leu], but not p.[Pro23His], was a frequent variant causing RHO-RP in the Kyushu region of Japan. As reported in previous studies, patients with the p.[Pro347Leu] variant showed a more severe phenotype, and variants causing sector RHO-RP were associated with a good prognosis.

DOI： 10.1007/s10384-023-01036-0

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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

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Language：Japanese   Publisher：(株)メディカル葵出版  

目的:線維柱帯切開術眼外法(LOT-ext)とマイクロフックを用いた眼内法(LOT-int)の術後2年間の成績を比較した.対象および方法:2017年1月～2018年12月に九州大学病院においてLOT-extおよびLOT-intを白内障手術と同時に行った患者を後ろ向きに抽出し,術後1年以上経過観察できた39例39眼(LOT-ext:20眼,LOT-int:19眼)を対象とした.術後6,12,18,24ヵ月時点での術後眼圧値,および術後合併症の有無について両術式間で比較した.結果:術後の平均眼圧下降値および平均眼圧下降率は術式間で差はなかった.また,生存時間分析でも術後眼圧値は術式間で差はなかった.術後合併症は,LOT-extでニボーを伴う前房出血(p=0.001)および術後1ヵ月以内の眼圧スパイクが有意に多かった(p=0.002).結論:LOT-extとLOT-intの眼圧下降効果に違いはなかった.LOT-extは術後前房出血の頻度および術後眼圧スパイクがLOT-intより多くみられ,術後管理により注意を要する.(著者抄録)

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

We aimed to verify whether the intravitreal injection of small molecule compounds alone can create photoreceptor cells in mouse models of retinal degeneration. Primary cultured mouse Müller cells were stimulated in vitro with combinations of candidate compounds and the rhodopsin expression was measured on day 7 using polymerase chain reaction and immunostaining. We used 6-week-old N-methyl-N-nitrosourea-treated and 4-week-old rd10 mice as representative in vivo models of retinal degeneration. The optimal combination of compounds selected via in vitro screening was injected into the vitreous and the changes in rhodopsin expression were investigated on day 7 using polymerase chain reaction and immunostaining. The origin of rhodopsin-positive cells was also analyzed via lineage tracing and the recovery of retinal function was assessed using electroretinography. The in vitro mRNA expression of rhodopsin in Müller cells increased 30-fold, and 25% of the Müller cells expressed rhodopsin protein 7 days after stimulation with a combination of 4 compounds: transforming growth factor-β inhibitor, bone morphogenetic protein inhibitor, glycogen synthase kinase 3 inhibitor, and γ-secretase inhibitor. The in vivo rhodopsin mRNA expression and the number of rhodopsin-positive cells in the outer retina were significantly increased on day 7 after the intravitreal injection of these 4 compounds in both N-methyl-N-nitrosourea-treated and rd10 mice. Lineage tracing in td-Tomato mice treated with N-methyl-N-nitrosourea suggested that the rhodopsin-positive cells originated from endogenous Müller cells, accompanied with the recovery of the rhodopsin-derived scotopic function. It was suggested that rhodopsin-positive cells generated by compound stimulation contributes to the recovery of retinal function impaired by degeneration.

DOI： 10.1371/journal.pone.0282174

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Language：Japanese   Publisher：眼科臨床紀要会  

目的:九州大学病院における2007～2012年までの5年間の緑内障手術の術式別の成績,および5年生存率と関連する予後因子について検討した.対象:2007年1月～2012年12月にかけて施行され,12ヵ月以上経過観察可能であった原発開放隅角緑内障(POAG)と落屑緑内障(EXG)の115例153眼を対象とし,線維柱帯切開術(LOT)と線維柱帯切除術(LEC)の術後成績,合併症,予後因子を調査した.結果:対象者115名の平均年齢は70.5±10.1歳,男女の割合は97:56であった.眼圧21mmHg以下の5年生存率はLOT群88%,LEC群84%であった.術後成績の予後因子解析においてLOT群は水晶体再建術併施が有意な防御因子となり,LEC群は術前眼圧高値(30mmHg以上)が有意な危険因子となった.結論:LOT群は水晶体再建術併施で術後成績は良好,LEC群は術前眼圧が高値で術後成績不良であった.(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Translational Vision Science and Technology  

PURPOSE: To estimate the prevalence of glaucoma and its risk factors in a Japanese community. METHODS: This study included 3405 Japanese community dwellers who were ≥40 years of age and enrolled in the Hisayama Study. This population-based, cross-sectional study was conducted from 2017 to 2018. A glaucoma screening test was performed using stereo fundus images and swept-source optical coherence tomography. Glaucoma was defined based on the International Society of Geographical and Epidemiological Ophthalmology criteria. RESULTS: The prevalence of glaucoma was 7.6% (95% confidence interval [CI], 6.7-8.6) overall. The prevalence of primary open-angle glaucoma (POAG) was 5.8% (95% CI, 5.0-6.6); that of primary angle-closure glaucoma (PACG) was 0.7% (95% CI, 0.5-1.1); and that of exfoliation glaucoma was 1.1% (95% CI, 0.7-1.4). In addition to aging, lower estimated glomerular filtration rate (eGFR) (odds ratio [OR] = 1.15; 95% CI, 1.02-1.33), higher intraocular pressure (OR = 1.06; 95% CI, 1.01-1.12), longer axial length (OR = 1.44; 95% CI, 1.31-1.59), and thinner central corneal thickness (CCT) (OR = 1.09; 95% CI, 1.04-1.15) were significant risk factors for POAG. Diabetes (OR = 2.81; 95% CI, 1.19-6.62) was a significant risk factor for PACG, and diabetes (OR = 2.15; 95% CI, 1.03-4.47) and thinner CCT (OR = 1.14; 95% CI, 1.02-1.28) were significant risk factors for exfoliation glaucoma. CONCLUSIONS: The prevalence of glaucoma was approximately 8%, probably due to the increase in the Japanese aging population. Not only ocular factors but also lower eGFR for POAG and diabetes for PACG and exfoliation glaucoma were risk factors in a general Japanese population. TRANSLATIONAL RELEVANCE: Systemic factors such as eGFR and diabetes must also be considered when implementing preventive measures against glaucoma.

DOI： 10.1167/tvst.11.11.11

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Publisher：株式会社医学書院  

DOI： 10.11477/mf.1410214595

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

Intraretinal hyperreflective foci (HRF) are significant biomarkers for diabetic macular edema. However, HRF at the vitreoretinal interface (VRI) have not been examined in diabetic retinopathy (DR). A prospective observational clinical study with 162 consecutive eyes using OCT imaging showed significantly increased HRF at the VRI during DR progression (P<0.01), which was reversed by anti-VEGF therapy. F4/80+ macrophages increased significantly at the VRI in Kimba (vegfa+/+) or Akimba (Akita × Kimba) mice (both P<0.01), but not in diabetic Akita (Ins2+/-) mice, indicating macrophage activation was modulated by elevated VEGF rather than the diabetic milieu. Macrophage depletion significantly reduced HRF at the VRI (P<0.01). Furthermore, BrdU administration in Ccr2rfp/+Cx3cr1gfp/+vegfa+/- mice identified a significant contribution of M2-like tissue-resident macrophages (TRMs) at the VRI. Ki-67- and CD11b-positive cells were observed in preretinal tissues of DR patients while exposure of vitreal macrophages to vitreous derived from PDR patients induced a significant proliferation response in vitro (P<0.01). Taken together, the evidence suggests that VEGF drives a local proliferation of vitreous resident macrophages (VRMs) at the VRI during DR. This phenomenon helps to explain the derivation and disease-relevance of the HRF lesions observed through OCT imaging in patients.

DOI： 10.2337/db21-0247

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

Human cytomegalovirus (HCMV) infections develop into CMV diseases that result in various forms of manifestations in local organs. CMV-retinitis is a form of CMV disease that develops in immunocompromised hosts with CMV-viremia after viruses in the peripheral circulation have entered the eye. In the HCMV genome, extensive diversification of the UL40 gene has produced peptide sequences that modulate NK cell effector functions when loaded onto HLA-E and are subsequently recognized by the NKG2A and NKG2C receptors. Notably, some HCMV strains carry UL40 genes that encode peptide sequences identical to the signal peptide sequences of specific HLA-A and HLA-C allotypes, which enables these CMV strains to escape HLA-E-restricted CD8⁺T cell responses. Variations in UL40 sequences have been studied mainly in the peripheral blood of CMV-viremia cases. In this study, we sought to investigate how ocular CMV disease develops from CMV infections. CMV gene sequences were compared between the intraocular fluids and peripheral blood of 77 clinical cases. UL40 signal peptide sequences were more diverse, and multiple sequences were typically present in CMV-viremia blood compared to intraocular fluid. Significantly stronger NK cell suppression was induced by UL40-derived peptides from intraocular HCMV compared to those identified only in peripheral blood. HCMV present in intraocular fluids were limited to those carrying a UL40 peptide sequence corresponding to the leader peptide sequence of the host's HLA class I, while UL40-derived peptides from HCMV found only in the peripheral blood were disparate from any HLA class I allotype. Overall, our analyses of CMV-retinitis inferred that specific HCMV strains with UL40 signal sequences matching the host's HLA signal peptide sequences were those that crossed the blood-ocular barrier to enter the intraocular space. UL40 peptide repertoires were the same in the intraocular fluids of all ocular CMV diseases, regardless of host immune status, implying that virus type is likely to be a common determinant in ocular CMV disease development. We thus propose a mechanism for ocular CMV disease development, in which particular HCMV types in the blood exploit peripheral and central HLA-E-mediated tolerance mechanisms and, thus, escape the antivirus responses of both innate and adaptive immunity.

DOI： 10.3389/fimmu.2022.1008220

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Case Reports in Ophthalmology  

The aim of this paper was to report the cases of 3 consecutive patients with mitogen-activated protein kinase kinase inhibitor (MEKi)-associated retinopathy with characteristic multiple serous retinal detachments (SRDs). A functional analysis of the retinal pigment epithelium was performed in 2 patients by electro-oculography (EOG). In all 3 patients, SRD lesions were observed in the posterior pole including the fovea of both eyes. Interestingly, neither obvious leakage in fluorescein/indocyanine angiography nor abnormal fundus autofluorescence was associated. SRDs and associated cystoid macular edema in one case rapidly resolved with the cessation of MEKi but recurred quickly after treatment resumption. In EOG tests, three of four eyes with multiple SRDs showed a marked decrease in the light-peak-to-dark-trough ratio (LP:DT ratio). The LP:DT ratio in EOG reflects the transepithelial potential of the retinal pigment epithelium, suggesting the involvement of disrupted tight junctions and impaired active transport of fluid/ions in MEKi-associated retinopathy. The latter may be the major cause of SRDs as we observed that fluid leakage in angiography was absent in the areas of the patients' SRDs.

DOI： 10.1159/000524558

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Language：Japanese   Publisher：眼科臨床紀要会  

背景:クリスタリン網膜症はCYP4V2を原因遺伝子とする遺伝性網膜変性疾患で、常染色体劣性遺伝形式をとるが、近親婚家系で親子発症する場合もある。症例:症例1は59歳の女性。初診時の矯正視力は右0.9、左0.7で、眼底にクリスタリン顆粒と網脈絡膜萎縮を認めた。15年の経過中に網脈絡膜萎縮が拡大し、最終受診時には視力が右0.4、左0.1に低下した。症例2は39歳の男性で、症例1の子。初診時の黄斑部網膜変性は軽微で、矯正視力両眼1.5と良好であった。8年の経過中に網脈絡膜萎縮が進行し、視力は右0.9、左0.6と低下した。家系内に複数の近親婚歴があり、両者にCYP4V2 c.G1020A(p.W340X)ホモ接合型変異を認めた。結論:近親婚家系に生じたクリスタリン網膜症の親子症例を経験した。長期経過で網脈絡膜変性が進行し、中高年で高度の視力障害をきたした。(著者抄録)

Authorship：Corresponding author   Language：English   Publisher：Frontiers in Neuroscience  

Necroptosis mediates the chronic inflammatory phenotype in neurodegeneration. Receptor-interacting protein kinase (RIPK) plays a pivotal role in the induction of necroptosis in various cell types, including microglia, and it is implicated in diverse neurodegenerative diseases in the central nervous system and the retina. Targeting RIPK has been proven beneficial for alleviating both neuroinflammation and degeneration in basic/preclinical studies. In this review, we discuss the role of necroptosis in retinal degeneration, including (1) the molecular pathways involving RIPK, (2) RIPK-dependent microglial activation and necroptosis, and (3) the interactions between necroptosis and retinal neuroinflammation/degeneration. This review will contribute to a renewed focus on neuroinflammation induced by necroptosis and to the development of anti-RIPK drugs against retinal degeneration.

DOI： 10.3389/fnins.2022.911430

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Medical Genetics  

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

DOI： 10.1136/jmedgenet-2022-108428

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Graefe's Archive for Clinical and Experimental Ophthalmology  

PURPOSE: Uveitis accounts for 10-15% of all cases of blindness in the developed world. Uveitic macular edema (UME) is a primary cause of permanent visual impairment in patients with uveitis. Because proinflammatory mediators elicit inflammation and lead to UME, we determined the profiles of proinflammatory mediators associated with complications, such as ME, in the vitreous humor of patients with panuveitis related to Behçet's disease (BD) and sarcoidosis. METHODS: In this retrospective study, we enrolled 21 patients with uveitis, including 6 with BD and 15 with sarcoidosis, and 15 patients with idiopathic epiretinal membrane (iERM) at the Department of Ophthalmology, Kyushu University Hospital, between January 2008 and April 2016. Vitreous concentrations of 32 proinflammatory mediators, including cytokines and soluble receptors of tumor necrosis factor (TNF) and interleukin (IL)-6 families, were assessed using a bead-based multiplex assay and their association with clinical data was examined. RESULTS: The levels of proinflammatory mediators, including a proliferation-inducing ligand (APRIL), B cell activating factor belonging to the TNF family (BAFF), soluble cluster of differentiation 30 (sCD30), soluble TNF receptor-1 (sTNFR1), sTNFR2, TNF-α, IL-6, and soluble IL-6 receptor-α (sIL-6Rα), were significantly higher in patients with uveitis. With regard to clinical parameters in patients with uveitis, vitreous levels of BAFF and sIL-6Rα were prominently elevated in patients with UME compared to in those without UME (P < 0.01, respectively). CONCLUSIONS: Our results suggest that elevated vitreous levels of BAFF and sIL-6Rα are associated with the pathogenesis of UME in patients with panuveitis related to BD and sarcoidosis.

DOI： 10.1007/s00417-022-05600-1

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

Age-related macular degeneration (AMD) and central serous chorioretinopathy (CSC) are common diseases that can cause vision loss in older and younger populations. These diseases share pathophysiological conditions derived from retinal pigment epithelium (RPE) dysfunction. Tumor necrosis factor receptor superfamily 10A (TNFRSF10A)-LOC389641 with the same lead single-nucleotide polymorphism (SNP) (rs13278062) is the only overlapped susceptibility locus found in both AMD and CSC through genome-wide association studies. This lead SNP has been reported to alter the transcriptional activity of TNFRSF10A. This study aimed to elucidate the function of TNFRSF10A in RPE degeneration using human primary RPE cells and Tnfrsf10 knockout (Tnfrsf10-/-) mice. TNFRSF10A was found to be localized in human RPE. In vitro assays revealed that a T allele of rs13278062, the risk allele for AMD and CSC, downregulated TNFRSF10A transcription in RPE, leading to decreased cell viability and increased apoptosis through protein kinase C-α (PKCA) downregulation. Treatment with phorbol 12-myristate 13-acetate, a PKC activator, rescued the cell viability. Morphological RPE abnormality were found in the retina of Tnfrsf10-/- mice. Our data suggest that downregulation of TNFRSF10A expression inactivates PKCA signaling and causes cellular vulnerability of the RPE, which may contribute to the pathogenesis of AMD and CSC.

DOI： 10.1093/hmg/ddac020

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

PURPOSE: To investigate the rate of the recurrence of cystoid macular edema (CME) secondary to retinitis pigmentosa (RP) after the initiation of topical dorzolamide and the recurrence risk factors. METHODS: We retrospectively analyzed the data of RP patients at Kyushu University Hospital. We included patients who showed a treatment response to 1.0% topical dorzolamide. The day of treatment initiation was set as the baseline. Topical dorzolamide treatment was continued during the follow-up. The recurrence of CME (defined as a >20% increase in central subfield thickness compared to previous visit, or a central subfield thickness value that exceed baseline value) was evaluated at each follow-up visit. Risk factors for RP-CME recurrence were analyzed by Cox proportional hazards modeling. A Kaplan-Meier survival analysis was used to evaluate the time to recurrent RP-CME. RESULTS: Forty RP-CME patients showed a treatment response to topical dorzolamide. During the mean 3.9-year follow-up, 14 patients exhibited recurrence; its rate was 15.6%, 34.7%, and 48.7% at 1, 3, and 5 years, respectively. A high baseline central subfield thickness was significantly associated with recurrent (hazard ratio 1.11, 95% CI: 1.05-1.18, P = 0.0004). CONCLUSION: The recurrence rate of RP-CME increased with time. A high baseline central subfield thickness value was a risk factor for recurrence.

DOI： 10.1097/IAE.0000000000003286

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

PURPOSE: To investigate the long-term outcomes of cataract surgery in patients with retinitis pigmentosa (RP). DESIGN: Retrospective, observational study. PARTICIPANTS: Sixty-four patients with typical RP (22 men, 42 women; average age, 62.8 ± 10.1 years) who underwent cataract surgery at Kyushu University Hospital between May 2007 and October 2015 and were followed up for ≥3 years after the surgery. METHODS: Differences between presurgery and postsurgery visual function, including best-corrected visual acuity (BCVA) and parameters in the Humphrey field analyzer (HFA) examination using the central 10-2 program, were investigated. The presurgery conditions of the foveal ellipsoid zone (EZ) were classified into 3 grades (grade 1: invisible; grade 2: abnormal; grade 3: normal) based on OCT findings. MAIN OUTCOME MEASURES: BCVA, the retinal sensitivity in the HFA 10-2 test. RESULTS: Cataract surgery was performed in 96 eyes, with an average follow-up period of 5.8 ± 2.4 years. The mean presurgery BCVA was 0.64 ± 0.52 logarithm of the minimum angle of resolution (logMAR), and the final postsurgery BCVA was 0.61 ± 0.67 logMAR (P = 0.57). Significant improvement in the postsurgery BCVA was observed only in eyes with preserved foveal EZ (grade 3) (P < 0.01). In 62 eyes of 45 patients who underwent the HFA 10-2 test, the mean values of deviation, macular sensitivity, and foveal sensitivity at the final visit were significantly decreased compared with preoperative values (P < 0.01), whereas those in grade 3 eyes did not change significantly after the surgery (P = 0.13). CONCLUSIONS: In the long-term course after cataract surgery in patients with RP, many patients experienced vision loss with progression of the disease. The preoperative finding of preserved foveal EZ was associated with a better visual prognosis, suggesting that EZ evaluation is useful for predicting the long-term visual outcome of cataract surgery in patients with RP.

DOI： 10.1016/j.oret.2021.12.010

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Purpose: To evaluate the pre- and post-operative outcomes of phacoemulsification in patients with uveitis-associated cataract in remission, such as conventional visual acuity (VA), photopic and mesopic contrast visual acuity (CVA), and flares in the anterior chamber objectively assessed as intraocular inflammation. Patients and Methods: This prospective study included 26 eyes of 19 patients with uveitis and 45 eyes of 26 controls who underwent cataract surgery at the Kyushu University Hospital and Kyushu Medical Center in Fukuoka, Japan, from October 2016 to December 2018. Conventional VA and flare values in the anterior chamber were evaluated preoperatively and 1 and 3 months postoperatively. Photopic and mesopic CVAs were assessed preoperatively and 3 months postoperatively. Results: The best-corrected VA (BCVA) was improved significantly from baseline to 1 and 3 months postoperatively in both groups (P < 0.01 in both groups). The mean preoperative 100&#37; and 10&#37; CVAs under the photopic condition were significantly lower in the uveitis group than in the control group (P < 0.05 for both CVA), whereas the mean preoperative 100&#37; CVA under the mesopic condition was comparable between the two groups. Although the mean preoperative 100&#37; and 10&#37; CVAs improved significantly from baseline under both photopic and mesopic conditions in both groups (P < 0.01 in both groups), the postoperative contrast sensitivities under both photopic and mesopic conditions remained lower in the uveitis group than in the control group (P < 0.01 for both conditions). The postoperative complications included recurrence of active inflammation in five eyes and cystoid macular edema in one eye and were managed by topical steroid therapy alone. Conclusion: Cataract surgery for uveitis-associated cataracts during remission is well tolerated. However, the present results suggest that amelioration of hemeralopia and/or nyctalopia is not as good as expected after cataract surgery in patients with uveitis.

DOI： 10.2147/OPTH.S314173

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DOI： 10.1016/j.oret.2020.05.012

Language：English  

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

PURPOSE. To determine the relationship between the macular curvature and the causative genes of retinitis pigmentosa (RP). METHODS. We examined the medical records of the right eyes of 65 cases with RP (31 men and 34 women; average age, 47.6 years). There were 31 cases with the EYS variants, 11 cases with the USH2A variants, six cases with the RPGR variants, 13 cases with the RP1 variants, and four cases with the RP1L1 variants. The mean curvature of Bruch’s membrane was calculated within 6 mm of the fovea as the mean macular curvature index (MMCI, 1/μm). We used multiple linear regression analysis to determine the independence of the causative genes contributing to the MMCIs after adjustments for age, sex, axial length, and width of the ellipsoid zone. RESULTS. The median MMCI was -31.2 × 10-5/μm for the RPGR eyes, -16.5 × 10-5/μm for the RP1L1 eyes, -13.0 × 10-5/μm for the RP1 eyes, -9.8 × 10-5/μm for the EYS eyes, and -9.0 × 10-5/μm for the USH2A eyes. Compared with the EYS gene as the reference gene, the RPGR gene was significantly related to the MMCI values after adjusting for the other parameters (P = 5.30 × 10-6). In contrast, the effects of the other genes, USH2A, RP1, and RP1L1, were not significantly different from that of the EYS gene (P = 0.26, P = 0.49, and P = 0.92, respectively). CONCLUSIONS. The RPGR gene had a stronger effect on the steep macular curvature than the other ciliopathy-related genes.

DOI： 10.1167/IOVS.61.10.6

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

PURPOSE: To investigate the association between aqueous flare and progression of visual field loss using the Humphrey Field Analyzer in patients with retinitis pigmentosa (RP). METHODS: We examined a total of 101 eyes of 101 patients who were diagnosed with typical RP. Sixty-one percent of the patients were female, and the mean age of the total group was 47.4 years. Aqueous flare, visual field (by an Humphrey Field Analyzer, the central 10-2 SITA-Standard program), and optical coherence tomography measurements were obtained for all patients. The slope, which was derived from serial values of mean deviation, macular sensitivity, or foveal sensitivity for each eye with univariate linear regression, was used for analysis. RESULTS: Aqueous flare values were significantly correlated with the mean deviation slope (r = -0.20, P = 0.046), macular sensitivity slope (r = -0.28, P = 0.005) and foveal sensitivity slope (r = -0.20, P = 0.047). The values of the retinal sensitivity slope significantly decreased as the aqueous flare level increased (all P < 0.05). These associations remained unchanged after adjustment for age, sex, and posterior subcapsular cataract, and epiretinal membrane. CONCLUSIONS: Elevation of aqueous flare is a risk factor for the decline of central visual function in RP. Aqueous flare may be a useful marker for disease progression in RP.

DOI： 10.1167/iovs.61.8.26

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Purpose: Two diabetic case reports of serous retinal detachment (SRD) accompanied by pachychoroid in hypotony maculopathy after trabeculectomy for neovascular glaucoma (NVG). Observations: Case 1: A 66-year-old female with stage 3 NVG and decreased vision acuity in the left eye. After trabeculectomy, postoperative laser suture lysis (LSL) resulted in development of hypotony maculopathy, followed by pachychoroid and SRD. Injection of C3F8 gas in the anterior chamber was unsuccessful and transconjunctival scleral re-suturing was performed. Intraocular pressure (IOP) consequently increased and SRD improved. Case 2: A 60-year-old man with stage 2 NVG and decreased vision acuity in the right eye. Trabeculectomy was uneventful, but postoperative LSL also resulted in development of hypotony maculopathy followed by pachychroid and SRD. Intravitreal bevacizumab injection had no effect and transconjunctival flap re-suturing was performed. IOP consequently increased and SRD improved. Conclusions: SRD accompanied by pachychoroid was observed in hypotony maculopathy in diabetic cases. VEGF-independent exudative change in hypotony maculopathy may be due to hydrostatic pressure elevation in choroidal blood vessels based on Starling's hypothesis with the consequent breakdown of retinal pigment epithelium barrier in diabetic patients.

DOI： 10.1016/j.ajoc.2020.100682

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

Purpose: To investigate periostin (PN) and tenascin-C (TNC) expression in the aqueous humor and trabeculectomy specimens of patients with neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy (PDR). Methods: This study enrolled 37 eyes of 37 patients who were grouped into (1) NVG secondary to PDR (NVG; n = 8); (2) PDR without NVG (PDR; n = 9); (3) primary open-angle glaucoma (POAG; n = 11); and (4) cataract surgery patients as a control group (CG; n = 9). Aqueous humor samples were collected from the anterior chamber at the start of surgery or intravitreal injection of anti-VEGF drug. The concentrations of PN, TNC, VEGF, and TGF-β2 (transforming growth factor-beta 2) were measured by ELISA. Sclerostomy tissues containing trabecular meshwork were obtained from two NVG patients and a POAG patient who underwent trabeculectomy surgery. Immunohistochemical analyses were performed to determine the localization of PN and TNC expression in the sclerostomy tissues. Results: PN and TNC-C levels were below detection threshold in the POAG and CG groups. The NVG group had significantly higher levels of PN and TNC compared with the PDR group (84.7 ng/ml vs 2.2 ng/ml and 18.5 ng/ml vs 4.6 ng/ml, respectively; p < 0.05). There was a significant correlation between the levels of PN and TNC-C in the NVG group (r = 0.86, p < 0.05). We found significant expression of PN in the trabecular meshwork and Schlemm’s canal of sclerostomy tissues excised from patients with NVG. Conclusions: Increased PN and TNC expression suggests their possible involvement in the pathogenesis of NVG secondary to PDR.

DOI： 10.1007/s00417-019-04574-x

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

Innate immune cells such as neutrophils, monocyte-macrophages and microglial cells are pivotal for the health and disease of the retina. For the maintenance of retinal homeostasis, these cells and immunosuppressive molecules in the eye actively regulate the induction and the expression of inflammation in order to prevent excessive activation and subsequent tissue damage. In the disease context, these regulatory mechanisms are modulated genetically and/or by environmental stimuli such as damage-associated molecular patterns (DAMPs), and a chronic innate immune response regulates or contributes to the formation of diverse retinal disorders such as uveitis, retinitis pigmentosa, retinal vascular diseases and retinal fibrosis. Here we summarize the recent knowledge regarding the innate immune response in both ocular immune regulation and inflammatory retinal diseases, and we describe the potential of the innate immune response as a biomarker and therapeutic target.

DOI： 10.1016/j.preteyeres.2019.100778

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

PURPOSE: The purpose of the study was to investigate the characteristics of the parafoveal cone density changes in patients with retinitis pigmentosa (RP) using adaptive optics scanning laser ophthalmoscopy (AO-SLO). METHODS: A total of 14 eyes of RP patients and 10 eyes of control subjects were examined. High-resolution images of cone photoreceptor cells were obtained with a Canon AO-SLO system in the four retinal regions of the superior, inferior, temporal, and nasal areas located 1.0 mm from the central fovea. The relationships of cone density with optical coherence tomography (OCT) findings and the visual sensitivity of the static perimetry tests were analyzed in RP patients. RESULTS: The averaged cone densities in RP patients were decreased at 1.0 mm eccentricity from the fovea (11,899 cells/mm2) compared with those in control subjects (16,647 cells/mm2; P < 0.01). The cone density was substantially decreased even in RP patients with an intact interdigitation zone at the examined area (12,865 cells/mm2; P < 0.01 vs. controls) and preserved visual sensitivity with > 35 dB (13,019 cells/mm2; P < 0.001 vs. controls). CONCLUSIONS: In RP, cone photoreceptor cell loss occurred in the parafoveal region with a preserved EZ/IZ or visual sensitivity. AO-SLO may be a useful modality to detect early changes of cone photoreceptor cells in RP patients.

DOI： 10.1007/s00417-019-04307-0

Language：Japanese  

＜文献概要＞目的:九州大学病院における過去10年間の強膜内陥術の成績,および網膜非復位に関する危険因子について検討する。対象と方法:2008年4月～2018年3月に,裂孔原性網膜剥離に対して初回手術として強膜内陥術を九州大学病院眼科(当科)で施行された264例288眼を対象とし,初回復位率,最終復位率,視力予後,術後合併症について調査した。また,非復位の危険因子についてロジスティック回帰分析を用い,裂孔位置や形態,網膜剥離範囲を含む17項目で検討した。結果:初回手術で復位が得られたものは265眼,初回復位率は92%であり,最終復位率は98%であった。裂孔位置の上下で復位率に差があったが,有意な危険因子ではなかった。結論:当科における強膜内陥術の初回復位率は92%と既報と同様であり,裂孔位置や形態などは非復位の危険因子ではなかった。

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

Purpose: From an early stage, retinitis pigmentosa (RP) patients suffer from night blindness which causes nocturnal mobility difficulties. We created a wearable visual aid that uses a high-performance see-through display, and added a high-sensitivity camera with a complementary metal-oxide-semiconductor sensor. Here, we evaluate the device’s efficacy for helping night-blindness sufferers walk in the dark. Study design: Prospective clinical study. Methods: Twenty-eight subjects underwent binocular visual acuity testing in the dark without (power off) and with (power on) the device. The test was carried out in a darkened room. We recorded the number of trial errors and the time it took each subject to arrive at the goal both with and without the aid of our device. Results: Our device effectively assists walking in RP patients with mobility problems in the dark. Conclusion: Binocular visual acuity in the dark was significantly improved with the aid of our device. In the walking test, the number of errors decreased greatly with the device, and the travel time was significantly shortened.

DOI： 10.1007/s10384-018-00644-5

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

Purpose To evaluate the retinal structure-function relationships in the macula of retinitis pigmentosa (RP) patients by comparing microperimetry-3 (MP-3) images with co-registered optical coherence tomography (OCT) images. Methods Thirty patients with typical RP were recruited from our hospital. The maculae of patients were examined with MP-3 and OCT. The retinal sensitivity was measured by MP-3 at 40 testing points arranged concentrically in a 16∘ diameter of the central retina, and we divided the 40 points into four zones according to degree from the fovea (2∘, 4∘, 6∘, and 8∘). We analyzed the correlation coefficients between the retinal sensitivity and the total retinal thickness (TRT), the length from the inner limiting membrane to the retinal pigment epithelium (RPE), and between the retinal sensitivity and the outer retinal thickness (ORT), the length from the outer plexiform layer to the RPE at each stimulus point. Results TRT showed moderate correlations with the retinal sensitivity at 2∘ (median ρ = 0.59 interquartile range (IQR) [0.38–0.72]), 4∘ (ρ = 0.59 [0.55–0.68]) and 6∘ (ρ = 0.60 [0.54–0.63]), and TRT was weakly-to-moderately related to the retinal sensitivity at 8∘ (ρ = 0.27 [0.19–0.48]). ORT exhibited strong correlations at 2∘ (ρ = 0.72 [0.60–0.81]), 4∘ (ρ = 0.71 [0.75–0.67]) and 6∘ (ρ = 0.70 [0.54–0.74]), and a weak-to-moderate correlations at 8∘ (ρ = 0.34 [0.29–0.53]). ORT was more strongly correlated with the retinal sensitivity compared to TRT (p = 0.018). Conclusion ORT, rather than TRT, within 6∘ eccentricity was strongly correlated with the retinal sensitivity, suggesting that measuring ORT in those areas will help evaluate the macular status and progression in RP.

DOI： 10.1371/journal.pone.0226097

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

PURPOSE. To investigate the serum changes of antioxidant/oxidant markers and the relationship between these factors and visual function in patients with retinitis pigmentosa (RP). METHODS. Fifty-two RP patients <40 years old and 25 controls were included. Serum samples were analyzed for superoxide dismutase 3 (SOD3) activity, glutathione peroxidase (GPx), potential antioxidant (PAO), and hexanoyl-lysine (HEL). The relationships between these markers and visual parameters, including best-corrected visual acuity (BCVA), mean deviation (MD), and average retinal sensitivity of 4 or 12 central points on static perimetry tests (Humphrey Field Analyzer, the central 10–2 program) were examined in the RP patients. RESULTS. Although there was no significant difference in the serum SOD3 activity between RP patients and controls, serum SOD3 activity in the severe degeneration group with macular involvement (16.3 6 11.3 U/mL) was significantly lower compared with those in the mild degeneration group (those with midperipheral scotomas; 28.5 6 16.6 U/mL, P ¼ 0.0459). SOD3 was significantly related to visual acuity (r ¼ -0.3701, P ¼ 0.0069) and the average retinal sensitivity of four central points (r ¼ 0.3463, P ¼ 0.0137) in RP patients. The linear trends of these two parameters across SOD3 levels were also significant (P ¼ 0.0264 and 0.0172, respectively). There was no consistent correlation between other serum antioxidant/ oxidant markers and visual parameters. CONCLUSIONS. Lower serum SOD3 activity was associated with the severe retinal degeneration in RP patients. Our results suggest that serum SOD3 activity may be related to disease severity in RP.

DOI： 10.1167/iovs.19-26927

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

Purpose. To investigate the effect of ocular hypertension-induced isomerization of aspartic acid in retinal proteins. Methods. Adult Wistar rats with ocular hypertension were used as an experimental model. D-β-aspartic acid-containing proteins were isolated by SDS-PAGE and western blot with an anti-D-β-aspartic acid antibody and identified by liquid chromatography-mass spectrometry analysis. The concentration of ATP was measured by ELISA. Results. D-β-aspartic acid was expressed in a protein band at around 44.5 kDa at much higher quantities in the retinas of rats with ocular hypertension than in those of normotensive rats. The 44.5 kDa protein band was mainly composed of α-enolase, S-arrestin, and ATP synthase subunits α and β, in both the ocular hypertensive and normotensive retinas. Moreover, increasing intraocular pressure was correlated with increasing ATP concentrations in the retinas of rats. Conclusion. Ocular hypertension affected the expression of proteins containing D-β-aspartic acid, including ATP synthase subunits, and up-regulation of ATP in the retinas of rats.

DOI： 10.1155/2019/2431481

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

In order to clarify the disease progression in retinitis pigmentosa (RP) and its related factors, reliable data on the changes in central visual function in RP are needed. In this longitudinal study, we examined 118 patients who were diagnosed with typical RP. Visual acuity (VA), visual field using a Humphrey Field Analyzer with the central 10-2 SITA-Standard program, and optical coherence tomography measurements were obtained. The slopes, which were derived from serial values of mean deviation (MD), macular sensitivity (MS), or foveal sensitivity (FS) obtained for each eye by a linear mixed model, were used for analysis. MS and FS were calculated as the average retinal sensitivity of 12 and 4 central points respectively. There were statistically significant interactions of times with levels of the central subfield thickness (CST) on the slopes of MS and FS. Compared to the eyes without macular complications, the eyes with macular complications had steeper MD, MS and FS slopes, and this interaction was no significant, but marginal trend for the MS or FS slope (P = 0.10, 0.05, respectively). The central retinal sensitivity (i.e., MS and FS) slopes calculated were effective indices of the progression of central visual function in RP.

DOI： 10.1038/s41598-018-26231-9

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

The purpose of this study is to determine the factors related to anxiety and depression in patients with retinitis pigmentosa (RP). The status of anxiety and depression was determined in RP patients with the Hospital Anxiety and Depression Scale (HADS) questionnaire which consisted of subscales for HADS-anxiety (HADS-A) and HADS-depression (HADS-D). The vision-specific quality of life (VSQOL) was assessed with the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ25). The correlations between the HADS-A or HADS-D scores and vision-related clinical parameters such as the best-corrected visual acuity (BCVA), Functional Acuity Score, Functional Field Score, Functional Vision Score, the NEI- VFQ25 subscale score were determined. The socioeconomic status, such as the work status and membership in the RP society, was investigated to determine the factors related to the HADS-A and HADS-D scores. One hundred and twelve RP patients (46 men and 66 women) with mean age of 60.7±15.4 (standard deviation) years were studied. The HADS-A score was not significantly correlated with any visual functions but was significantly correlated with the general health condition (r = -0.34, P<0.001) and the role limitation (r = -0.20, P = 0.03) of the NEI-VFQ25 subscale. The HADS-D score was significantly correlated with all the visual functions (r = -0.38 to 0.29, P<0.001), the NEI-VFQ25 subscale score (r = - 0.58 to -0.33, P<0.001) by Spearman’s correlations. The HADS-A score was significantly higher in the members of the RP society than in non-members (P = 0.013). The mean HADS-D score of employed individuals was significantly lower than that of unemployed ones (P = 0.001) by the Mann-Whitney U test. The results indicate that visual function impairments and vision-related quality of life are associated with a depressive state, and the general health condition is related to anxiety in RP patients. Being employed may be strongly correlated with the degree of depression in RP patients.

DOI： 10.1371/journal.pone.0195983

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

PURPOSE: Chronic inflammation is involved in retinitis pigmentosa (RP). We demonstrated previously that intraocular inflammatory levels, as measured by slit-lamp ophthalmoscopy or laser flare photometry, are inversely correlated with central visual function in patients with RP. Here, we investigated the relationship between serum high-sensitivity C-reactive protein (hs-CRP) and visual parameters in RP. METHODS: We studied 58 consecutive typical patients with RP <40 years old and 29 age- and gender-matched controls. High-sensitivity C-reactive protein (hs-CRP) was detected by immunoturbidimetry. The relationships between hs-CRP and visual parameters including best-corrected visual acuity (BCVA), mean deviation (MD) of static perimetry tests (Humphrey Field Analyzer, the central 10-2 programme) and VA changes over the prior 5 years and MD changes over the prior 3 years were analysed in the patients with RP. RESULTS: The serum hs-CRP levels of the patients with RP were significantly higher than those of the controls (0.06 ± 0.08 versus 0.03 ± 0.04 mg/dl, p = 0.0119). In the patients with RP, there was no correlation of hs-CRP with cross-sectionally assessed VA or MD, but the baseline hs-CRP was significantly correlated with the MD deterioration (r = -0.4073, p = 0.0314). CONCLUSION: The average serum hs-CRP was significantly increased in the patients with RP, and higher hs-CRP was associated with faster deterioration of central visual function. These results suggest that the systemic inflammatory profile is altered and may be associated with disease progression in RP.

DOI： 10.1111/aos.13502

Language：Japanese  

視神経乳頭腫脹による視力低下からムコ多糖症(mucopolysaccharidosis:MPS)II型と診断された1例を報告する。症例は12歳男児、両眼の視力低下と視野異常、視神経乳頭腫脹を認めて当院入院精査となった。視神経の炎症を示唆する所見は乏しく、著明な強膜肥厚と遠視を認めた。低身長、骨・関節の異常、心臓弁膜疾患、アデノイド肥大、臍・鼠径ヘルニア、水腎症など様々な全身疾患を伴っており、尿中のムコ多糖の排泄増加と白血球の酵素活性異常を認めたためMPSII型と診断された。視神経乳頭腫脹は約1ヵ月の自然経過で改善したが、両眼とも視神経はやや萎縮した色調となった。酵素補充療法を開始され、その後は視神経や強膜肥厚は著変なく経過している。また、全身的には身体の発達や水腎症の改善を認めた。眼所見からMPSの診断と治療につながることがあり、原因不明の小児の視神経乳頭腫脹はMPSも鑑別に挙げる必要がある。(著者抄録)

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

PURPOSE: To investigate the macular microvasculature changes by optical coherence tomography angiography (OCTA) and analyse the correlation between these changes and central visual function in patients with retinitis pigmentosa (RP). METHODS: We measured the area of the foveal avascular zone (FAZ) and the foveal and parafoveal flow density (FFD and PFD, respectively) in the superficial (S) and deep (D) retinal plexus by OCTA (AngioVue) and compared these values between 73 RP patients and 36 healthy controls. We analysed the relationships between these microvasculature measurements and central visual functions such as visual acuity (VA) and the values of static perimetry tests (Humphrey Field Analyzer, the central 10-2 program) in the RP patients. RESULTS: The FFD-S, PFD-S and PFD-D were significantly decreased in the RP patients compared to the controls (all p < 0.05), whereas there was no significant difference in the FAZ-S, FAZ-D or FFD-D (all p > 0.05). A subgroup analysis showed that the RP patients with VA <20/20 had increased FAZ-S compared to the controls and RP patients with VA ≥20/20 (p = 0.01 and p = 0.007, respectively). Spearman rank testing demonstrated that PFD-S and PFD-D were significantly correlated with all of the central visual parameters (all p < 0.01). The FAZ-S and FFD-S were significantly correlated with VA, and FAZ-D and FFD-D showed no significant correlation. CONCLUSION: Both the superficial and deep layers of the parafoveal microvasculature are attenuated in RP and correlated with reduced central visual function. The foveal microvasculature, especially in the deep layer, was relatively preserved until mild-to-moderately advanced stages.

DOI： 10.1111/aos.13475

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

PURPOSE: To investigate the relationships between foveal blood flow as measured by laser speckle flowgraphy (LSFG), the retinal-choroidal structure in enhanced depth imaging-optical coherence tomography (EDI-OCT), and central visual function in patients with retinitis pigmentosa (RP). METHODS: We studied 52 consecutive typical RP patients ≤50 years old and 21 age- and sex-matched controls. The mean blur rate (MBR), which represents the blood flow volume, was calculated in a 2.4-mm2 area centered on the fovea by LSFG. Subfoveal horizontal EDI-OCT images were recorded, and the choroidal area, choroidal hyporeflective area, and choroidal hyperreflective area were analyzed in the central 2.4-mm-wide region. The central foveal thickness (CFT), subfoveal choroidal thickness (SCT), and ellipsoid zone (EZ) width were also measured. Visual acuity (VA) and retinal sensitivity (Humphrey 10-2 program) were measured in the RP patients. RESULTS: The MBR, choroidal area, hyporeflective area, hyperreflective area, and SCT were significantly decreased in the RP patients (all P < 0.001, versus controls). Spearman's rank testing demonstrated no significant correlation between the MBR and the choroidal structural parameters in the RP patients. Decreased MBR was significantly associated with reductions in VA, retinal sensitivity, CFT, and EZ width (all P < 0.05). The choroidal structural parameters did not correlate with central visual function, and the choroidal area, hyperreflective area, and SCT were inversely associated with CFT (all P < 0.05). CONCLUSIONS: These results demonstrated the divergence between the choroidal structure and blood function, and suggest that decreased choroidal flow, rather than the structural alteration, is closely associated with foveal degeneration in RP.

DOI： 10.1167/iovs.17-23050

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

Language：English  

We report the case of a patient with mucopolysaccharidosis (MPS) II that was diagnosed after the appearance of optic nerve head swelling. A 12-year-old boy was admitted to our hospital because of bilateral decreased visual acuity, a visual field defect, and optic nerve head swelling. Both of his eyes had thickened sclera and hyperopia without findings of apparent optic neuritis. In addition, he was affected with systemic complications, such as growth retardation, skeletal problems, joint contractures, cardiac valve disease, adenoidal hypertrophy, umbilical hernia, inguinal hernia, and hydronephrosis, which together were suggestive of MPS. By quantitative measurement of urinary glycosaminoglycans and quantification of blood enzyme activity, he was diagnosed with MPS II. The optic nerve head swelling improved spontaneously within 4-6 weeks, but a degree of optic nerve atrophy remained. Thereafter, the optic nerve abnormalities and the thickened sclera were unchanged after initiation of enzyme replacement therapy (ERT). However, ERT ameliorated his systemic complications such as growth retardation and hydronephrosis. These ocular manifestations can lead to the diagnosis and systemic treatment of MPS, suggesting the importance of MPS as a differential diagnosis of optic nerve swelling of unknown cause.

DOI： 10.11476/shinkeiganka.35.59

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

Purpose: To examine retinal changes after vitrectomy with internal limiting membrane (ILM) peeling, we used a cynomolgus monkey model and focused on surgical damages of ILM peeling for long observational period of 3 years. Methods: Vitrectomy was performed followed by ILM peeling similar to clinical settings in humans. Ultrastructural changes of the retina were investigated by light, transmission, and scanning electron microscopy at 3 months and 3 years after ILM peeling. Results: Ultrastructural study showed that the ILM peeled area was still clearly recognized after 3 years. The Müller cell processes covered most of the retina; however, the nerve fiber layer was partly uncovered and exposed to the vitreous space. The arcuate linear nerve fiber bundles were observed as comparable with dissociated optic nerve fiber layer appearance. Small round retinal surface defects were also observed around macula, resembling the dimple sign. Forceps-related retinal thinning was also found on the edge of ILM peeling, where we started peeling with fine forceps. Conclusion: The ultrastructural studies showed that most of ILM peeling area was covered with glial cells during wound healing processes. Retinal changes were found comparable with dissociated optic nerve fiber layer appearance or dimple sign, which were clinically observed with optical coherence tomography.

DOI： 10.1097/IAE.0000000000001388

Language：English  

Sixty-one cases suspected of optic neuropathy
Purpose : To report 61 cases who were initially suspected of optic neuropathy. Cases and Method : This retrospective study was made on 61 cases who were seen at Kyushu University Hospital during the past 3 years and who were initially suspected of optic neuropathy. The series comprised 34 males and 27 females. The age ranged from 7 to 89 years, average 51 years. All the cases were examined by magnetic resonance imaging (MRl). Lumbar puncture was performed in 22 cases. Findings were analyzed based on clinical records. Results : The most common underlying lesion was inflammatory in 16 cases (26&#37;), followed by ischemic (13&#37;), compression (l 1&#37;), hereditary (7&#37;) and infectious (5&#37;) among others. Pulsed corticsteroid therapy was performed in 27 cases (44&#37;). Conclusion ; There was no difference among age groups regarding the underlying cause of optic neuropathy. Hospitalization was useful in the diagnosis and treatment by enabling lumbar puncture and pulsed corticosteroid therapy.

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

PURPOSE. Posterior subcapsular cataract (PSC) is a frequent complication in patients with retinitis pigmentosa (RP). The risk factors for PSC formation in RP are largely unknown. The purpose of this study was to investigate the risk factors for PSC. METHODS. We retrospectively studied a total of 322 eyes of 173 patients who were diagnosed with typical RP. We considered the following possible risk factors for PSC: age, sex, hypertension, diabetes mellitus, high myopia, asthma, history of steroid intake, and aqueous flare. Aqueous flare values were measured consecutively in 2012 and 2013 using a laser flare cell meter. The lens including PSC was examined with a slit lamp after dilation with tropicamide 1&#37; and phenylephrine 2.5&#37;. RESULTS. The geometric mean values of aqueous flare and mean values of visual acuity were significantly higher for the RP patients with PSC compared to those without PSC (P = 0.0003, P = 0.0004, respectively). When the aqueous flare values were assessed continuously, each 1-log-transformed increase in flare levels was associated with an elevation of the likelihood of having PSC after multivariable adjustment (odds ratio: 1.71; 95&#37; confidence interval: 1.05-2.77). There were no significant associations of the other possible risk factors with PSC. CONCLUSIONS. Our analysis demonstrated that elevated aqueous flare is a significant risk factor for PSC formation. This result might provide insights into the association of inflammation and the pathogenesis of PSC formation in RP.

DOI： 10.1167/iovs.17-21612

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

PURPOSE:: To examine retinal changes after vitrectomy with internal limiting membrane (ILM) peeling, we used 3-dimensional optical coherence tomography (3D-OCT) in rhegmatogenous retinal detachment cases. METHODS:: The 68 eyes from 67 patients with rhegmatogenous retinal detachment were studied, including 35 detached macula cases (51&#37;) and 33 attached macula cases. Internal limiting membrane peeling was performed with fine forceps after brilliant blue G staining. The 3D-OCT images were obtained with volume-rendering technologies from cross-sectional OCT images. RESULTS:: The 3D-OCT detected 45 eyes (66&#37;) with ILM peeling-dependent retinal changes, including dissociated optic nerve fiber layer appearance, dimple sign, temporal macular thinning, ILM peeling area thinning, or forceps-related retinal thinning. The ILM peeled area was detectable in only 9 eyes with 3D-OCT, whereas it was undetectable in other 59 eyes. The dissociated optic nerve fiber layer appearance was detected in 8 of the total cases (12&#37;), and dimple signs were observed in 14 cases (21&#37;). Forceps-related thinning was also noted in eight cases (24&#37;) of attached macula cases and in four cases (11&#37;) of detached macula cases. No postoperative macular pucker was noted in the observational period. CONCLUSION:: The 3D-OCT clearly revealed spatial and time-dependent retinal changes after ILM peeling. The changes occurred in 2 months and remained thereafter.

DOI： 10.1097/IAE.0000000000001558

Language：English  

Purpose: The analysis of gene expression in idiopathic epiretinal membranes (iERMs) may help elucidate ERM formation and its pathology. Here, we conducted a case-control study, in order to determine the expression levels of cytokines and other genes in eyes with macular hole (MH) or iERM. Methods: Twenty eyes, obtained from seven male and 13 female patients, were included in the study. The average age of the study subjects was 69.1 ± 7.67 years, and 15 eyes had iERM, while five eyes had MH. Irrigation solution samples were collected during vitrectomy, centrifuged, and the levels of cytokine and other mRNAs in the sediment were assessed using real-time PCR. The expression level of 11 cytokine genes, four transcription factor genes, two cytoskeletal genes, and genes encoding two extracellular matrix proteins in eyes with MH or iERM were determined and compared. Results: The expression levels of interleukin 6 (IL6), tumor growth factor B2 (TGFB2), vascular endothelial growth factor A (VEGFA), chemokine C-X-C motif ligand 1 (CXCL1), v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA), glial fibrillary acidic protein (GFAP), and tenascin C (TNC) were significantly higher in eyes with iERM than in eyes with MH. The expression of these genes was not associated with the preoperative visual acuity of the investigated patients. Conclusions: The obtained results indicate that real-time PCR analysis of irrigation solution samples collected during vitrectomy can help assess the expression levels of several genes, and that iERM is associated with the expression of pro-inflammatory genes and the genes expressed during angiogenesis and wound healing process (IL6, TGFB2, VEGFA, CXCL1, RELA, GFAP, and TNC).

DOI： 10.1371/journal.pone.0164355

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

PURPOSE. Epiretinal membrane (ERM) is a frequent macular complication in patients with retinitis pigmentosa (RP). The etiology of ERM formation in RP is largely unknown. The purpose of this study was to investigate the association between aqueous flare, a surrogate index of intraocular inflammation, and ERM secondary to RP. METHODS. We retrospectively studied a total of 206 eyes of 117 patients who were diagnosed with typical RP. Aqueous flare values were measured consecutively in 2012 and 2013 using a laser flare cell meter. Spectral-domain optical coherence tomography images and fundus photographs taken on the same day of the aqueous flare measurements were analyzed for ERM detection. RESULTS. The mean values of aqueous flare, age, and frequency of male sex were significantly higher in the RP patients with ERM compared with the RP patients without ERM (P < 0.0001, P = 0.007, and P = 0.004, respectively). After adjustment for age and sex, the eyes in the highest quartile of aqueous flare had significantly higher odds of having ERM than those in the lowest quartile (odds ratio [OR], 2.68; 95&#37; confidence interval [CI], 1.04-6.93), and the linear trend across flare levels was significant (P = 0.005). In addition, each 1-log-transformed increase in flare values was associated with an elevation of the likelihood of having ERM (OR, 2.59; 95&#37; CI, 1.33-5.06). CONCLUSIONS. Our analysis demonstrated that elevated aqueous flare is associated with ERM secondary to RP, suggesting that inflammation may be implicated in the pathogenesis of ERM formation in RP.

DOI： 10.1167/iovs.16-19686

Language：English  

Background: The purpose of this study was to report a case of traumatic maculopathy with para-central visual field defects following an impact by airbag deployment using adaptive optics scanning laser ophthalmoscopy (AO-SLO). Case presentation: A 51-year-old man was involved in a motor vehicular accident and his left eye was struck by the deployed airbag, resulting in a para-central scotoma. The patient underwent a full ophthalmologic examination, spectral-domain optical coherence tomography (SD-OCT), and imaging with prototype AO-SLO systems (Canon Inc.) at 14 and 22 months after the injury. Images focused on the photoreceptor layer were recorded in the foveal area, and a montage of AO-SLO images was created. On AO-SLO, focal dark areas could be observed in the left eye at 14 months after the injury. The analysis showed that the cone mosaic (cone density, 16503/mm²; ratio of hexagonal Voronoi domain, 36.3 &#37;; average nearest-neighbor distance (NND)/expected NND, 0.606) was disordered compared with the normal area of the same eye (cone density, 24821/mm²; ratio of hexagonal Voronoi domain, 44.1 &#37;; average NND/expected NND, 0.739). The cone defect area corresponded to the area of the scotoma. A second AO-SLO was performed on the patient at 22 months after the injury and although there were still areas with reduced cone reflectivity, partial improvement of cone mosaic was detected by AO-SLO at this time point. Conclusion: Partial recovery of damaged cone photoreceptors following closed globe blunt ocular trauma can be documented using AO-SLO longitudinal tracking.

DOI： 10.1186/s12886-016-0275-4

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

DOI： 10.1038/cddiscovery.2015.58

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

DOI： 10.1038/cddis.2015.385

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

PURPOSE: To investigate the changes in macular blood flow and the correlation between those changes and central visual function in patients with retinitis pigmentosa (RP). METHODS: The mean blur rate (MBR), a quantitative blurring index of the laser speckle pattern that represents retinal and choroidal blood flow, was measured by laser speckle flowgraphy. Mean blur rate values in the macular area were compared between 70 patients with RP and 28 control subjects. The relationships between MBR on the one hand and, on the other, visual acuity (VA), mean deviation (MD) and averaged macular sensitivity of static perimetry tests (Humphrey Filed Analyzer, the central 10-2 program) were analysed in patients with RP. RESULTS: Macular MBR was decreased to 75&#37; in patients with RP compared with control subjects (p < 0.0001, Student's t-test). Spearman's rank testing showed that macular MBR was significantly correlated with VA (r = -0.261, p = 0.0299), MD values (r = 0.438, p = 0.0002) and averaged macular sensitivity at the central 4 and 12 points of static perimetry tests (r = 0.426 and 0.442, p = 0.0003 and 0.0002, respectively). Multivariable-adjusted analysis confirmed that MBR was independently associated with MD (p = 0.0002) and macular sensitivity at the central 4 and 12 points (p < 0.0001 and 0.0002, respectively). CONCLUSIONS: Decreased macular blood flow was associated with reduced macular visual sensitivity in patients with RP. Although the cause-effect relationships remain to be elucidated, these findings suggest that vascular defects may be involved in the pathogenesis of RP such as central vision loss.

DOI： 10.1111/aos.12693

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

Purpose: To determine the prevalence of vitreous cysts in patients with retinitis pigmentosa (RP). Methods: We retrospectively reviewed the charts of 435 consecutive patients diagnosed as having typical RP. Results: Vitreous cysts were diagnosed in 37 eyes of 28 patients with RP (13 males and 15 females; mean age 47.0 ± 19.8 years; range 15–79 years), for an overall prevalence of 6.4 &#37;. The cysts were observed bilaterally in nine of the patients (32.1 &#37;). Among these 28 patients, 11 (39.3 &#37;) were younger than 40 years. In all, 81.8 &#37; of the vitreous cysts were detected around the optic nerve head. Conclusions: We demonstrated that the prevalence of vitreous cysts was 6.4 &#37; in patients with RP. These cysts were considered to be asymptomatic.

DOI： 10.1007/s10384-015-0405-1

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

Macular complications such as an epiretinal membrane (ERM), a cystoid macular edema and a macular hole lead to unexpected central vision impairment especially for patients with retinitis pigmentosa (RP). To evaluate the long-term surgical outcomes of pars plana vitrectomy (PPV) for ERM in patients with RP, we retrospectively reviewed the charts of a consecutive series of 10 RP patients who underwent PPV for ERM at Kyushu University Hospital. Visual acuity (VA) testing, a fundus examination, and an optical coherence tomography (OCT) analysis were conducted. The standard PPV using three sclerotomies was performed for ERM. PPV was performed in 12 eyes of 10 patients. One eye was excluded from the outcome assessment due to short period observation (18 months). There was no significantly deleterious change from the baseline to final VA between the operation eyes and the fellow eyes (P = 0.19). Moreover, morphological improvement was obtained in 9 of 11 eyes based on OCT. Our present data suggest that PPV may be tolerable in the management for ERM in RP patients over the long-term. Furthermore, the appearance of the ellipsoid zone was an important factor in the prediction of visual outcome and determination of surgical indication.

DOI： 10.1038/srep13078

Language：English  

Detachment of photoreceptors from the retinal pigment epithelium is seen in various retinal disorders, resulting in photoreceptor death and subsequent vision loss. Cell death results in the release of endogenous molecules that activate molecular platforms containing caspase-1, termed inflammasomes. Inflammasome activation in retinal diseases has been reported in some cases to be protective and in others to be detrimental, causing neuronal cell death. Moreover, the cellular source of inflammasomes in retinal disorders is not clear. Here, we demonstrate that patients with photoreceptor injury by retinal detachment (RD) have increased levels of cleaved IL-1β, an end product of inflammasome activation. In an animal model of RD, photoreceptor cell death led to activation of endogenous inflammasomes, and this activation was diminished by Rip3 deletion. The major source of Il1b expression was found to be infiltrating macrophages in the subretinal space, rather than dying photoreceptors. Inflammasome inhibition attenuated photoreceptor death after RD. Our data implicate the infiltrating macrophages as a source of damaging inflammasomes after photoreceptor detachment in a RIP3-dependent manner and suggest a novel therapeutic target for treatment of retinal diseases.

DOI： 10.1038/cddis.2015.73

Language：English  

Fas ligand (FasL) triggers apoptosis of Fas-positive cells, and previous reports described FasL-induced cell death of Fas-positive photoreceptors following a retinal detachment. However, as FasL exists in membrane-bound (mFasL) and soluble (sFasL) forms, and is expressed on resident microglia and infiltrating monocyte/macrophages, the current study examined the relative contribution of mFasL and sFasL to photoreceptor cell death after induction of experimental retinal detachment in wild-type, knockout (FasL - / -), and mFasL-only knock-in (ΔCS) mice. Retinal detachment in FasL - / - mice resulted in a significant reduction of photoreceptor cell death. In contrast, ΔCS mice displayed significantly more apoptotic photoreceptor cell death. Photoreceptor loss in ΔCS mice was inhibited by a subretinal injection of recombinant sFasL. Thus, Fas/FasL triggered cell death accounts for a significant amount of photoreceptor cell loss following the retinal detachment. The function of FasL was dependent upon the form of FasL expressed: mFasL triggered photoreceptor cell death, whereas sFasL protected the retina, indicating that enzyme-mediated cleavage of FasL determines, in part, the extent of vision loss following the retinal detachment. Moreover, it also indicates that treatment with sFasL could significantly reduce photoreceptor cell loss in patients with retinal detachment.

DOI： 10.1038/cddis.2015.334

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

Purpose To investigate the factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa (RP). Design Retrospective, observational study. Participants We retrospectively reviewed the charts of a consecutive series of 40 patients with RP who underwent cataract surgery. Methods The changes in preoperative and postoperative best-corrected visual acuity (BCVA) were measured. We investigated the relation between preoperative mean deviation (MD) value on the Humphrey Field Analyzer (HFA: the central 10-2 program; Humphrey Instruments, Inc, San Leandro, CA) and final BCVA. We also investigated the relationship between preoperative ellipsoid zone (EZ; also called the inner/outer segment junction) conditions and final BCVA. In addition, we showed the prevalence of macular complications and capsule complications. Main Outcome Measures The BCVA, slit-lamp biomicroscopic analysis, visual field, and optical coherence tomography (OCT) were obtained. Results The mean of the BCVA significantly improved after cataract surgery from 0.76 (range, -0.08 to 2.30) to 0.45 (range, -0.18 to 2.00) (P < 0.005). However, final BCVA did not improve in 30 eyes (53.6&#37;). The preoperative MD value and the final BCVA were significantly correlated, and the final BCVA significantly improved in the less advanced RP group (MD was >-15 decibels [dB]). The final BCVA was significantly better in the group in which preoperative OCT showed a normal EZ than in the groups in which the EZ was abnormal or not visible. Posterior capsular opacification was observed in 47 eyes (83.9&#37;), and 23 eyes (41.1&#37;) underwent YAG laser capsulotomy within a mean follow-up time of 3 years. Conclusions Final BCVA in approximately half of the eyes improved after cataract surgery in patients with RP. The preoperative ophthalmic examinations that may reflect macular (or foveal) function, such as HFA 10-2 program and OCT, are important parameters to assess postoperative visual outcome.

DOI： 10.1016/j.ophtha.2014.12.003

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

PURPOSE:: Brilliant Blue G is used as a surgical adjuvant for retinal surgery. Although BBG double or multiple staining was reported, the effectiveness and safety of repeated staining is still elusive. To further examine the effectiveness and safety, we examined BBG in clinical cases in vivo, primary cell culture in vitro, and surgically resected specimen ex vivo. METHODS:: A retrospective interventional case series with in vitro and ex vivo studies were performed. Vitrectomy was performed in 28 cases of epiretinal membrane with BBG single to multiple staining. The surgically resected membranes were stained by BBG with or without cellular fixation. Primary cell cultures were examined with BBG and live/death cell markers, such as Calcein AM and TUNEL. RESULTS:: Single staining provided satisfactory staining in seven cases. Double or multiple staining substantially visualized internal limiting membrane (21 cases), especially the edges of remaining internal limiting membrane (11 cases). Adverse retinal staining was not noted and the final visual acuity showed no difference with multiple staining. The live cells barely stained with BBG, while some dead cells were stained. CONCLUSION:: Brilliant Blue G multiple staining substantially enhanced the visualization of internal limiting membrane. The absence of abnormal staining supports the safety of repeated BBG staining.

DOI： 10.1097/IAE.0000000000000289

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

Purpose: Patients in the early stage of retinitis pigmentosa (RP) suffer from night blindness and, therefore, have mobility problems at night. To assist such patients with walking in the dark, we developed a wearable visual aid utilizing a see-through display upon which assistive images from a high-sensitivity video camera are superimposed. We evaluated the efficacy of our new visual aid for RP patients. Methods: The device is equipped with a camera with a minimum illuminance of 0.08 lux and a view angle of 53° × 40°. The experiment was conducted in a room with dimmed light (illuminance level 0.2–1.2 lux). Eight subjects with RP were instructed to arrive at a goal 16 m away from the starting point, both with and without the device, passing through four 1.5-m-wide gates consisting of pairs of black square carpet pieces, white poles, red and white traffic cones and cardboard boxes with and without the device in a darkened room. Three gates, except for the boxes, which were nearest the goal, were randomly arranged along the x-axis at each trial. The number of trial failures and the time required to walk the course were assessed as outcomes. Results: Seven of the 8 subjects could walk with the aid of the device without any failure. With the device, the number of trial failures significantly decreased in number (p < 0.05) in all subjects. Conclusions: This device enabled the subjects to see objects that could not be recognized by the unaided eye. Our visual aid effectively assisted RP patients with night blindness.

DOI： 10.1007/s10384-014-0354-0

Language：English  

In this study, we show augmented autophagy in the retinal pigment epithelial cell line ARPE-19 when cultured in the presence of the lipofuscin pigment A2E. A2E alone does not induce RPE cell death, but cell death was induced in the presence of A2E with the autophagy inhibitor 3-methyladenine (3MA), with a concomitant increase in the generation of mitochondrial reactive oxygen species. On the other hand, the ATP production capacity of mitochondria was decreased in the presence of A2E, and pharmacological inhibition of autophagy had no additional effects. The altered mRNA expression level of mitochondrial function markers was confirmed by real-time polymerase chain reaction, which showed that the antioxidant enzymes SOD1 and SOD2 were not reduced in the presence of A2E alone, but significantly suppressed with the addition of 3MA. Furthermore, transmission electron micrography revealed autophagic vacuole formation in the presence of A2E, and inhibition of autophagy resulted in the accumulation of abnormal mitochondria with loss of cristae. Spheroid culture of human RPE cells demonstrated debris accumulation in the presence of A2E, and this accumulation was accelerated in the presence of 3MA. These results indicate that autophagy in RPE cells is a vital cytoprotective process that prevents the accumulation of damaged cellular molecules.

DOI： 10.1016/j.fob.2014.11.003

Language：English  

Photoreceptor cell death is the definitive cause of vision loss in retinal detachment (RD). Mammalian STE20-like kinase (MST) is a master regulator of both cell death and proliferation and a critical factor in development and tumorigenesis. However, to date the role of MST in neurodegeneration has not been fully explored. Utilizing MST1^-/- and MST2^-/- mice we identified MST2, but not MST1, as a regulator of photoreceptor cell death in a mouse model of RD. MST2^-/- mice demonstrated significantly decreased photoreceptor cell death and outer nuclear layer (ONL) thinning after RD. Additionally, caspase-3 activation was attenuated in MST2^-/- mice compared to control mice after RD. The transcription of p53 upregulated modulator of apoptosis (PUMA) and Fas was also reduced in MST2^-/- mice post-RD. Retinas of MST2^-/- mice displayed suppressed nuclear relocalization of phosphorylated YAP after RD. Consistent with the reduction of photoreceptor cell death, MST2^-/- mice showed decreased levels of proinflammatory cytokines such as monocyte chemoattractant protein 1 and interleukin 6 as well as attenuated inflammatory CD11b cell infiltration during the early phase of RD. These results identify MST2, not MST1, as a critical regulator of caspase-mediated photoreceptor cell death in the detached retina and indicate its potential as a future neuroprotection target.

DOI： 10.1038/cddis.2014.218

Language：English  

Retinal ganglion cell (RGC) death is the ultimate cause of vision loss in glaucoma. Apoptosis has been thought to be a major form of cell death in various diseases including glaucoma; however, attempts to develop neuroprotective agents that target apoptosis have largely failed. Recent accumulating evidence has shown that non-apoptotic forms of cell death such as necrosis are also regulated by specific molecular machinery, such as those mediated by receptor-interacting protein (RIP) kinases. In this review, we summarize recent advances in our understanding of RIP kinase signaling and its roles in RGC loss. These data suggest that not only apoptosis but also necrosis is involved in RGC death and that combined targeting of these pathways may be an effective strategy for glaucoma.

DOI： 10.1007/978-4-431-54965-9_8

Language：Japanese  

眼内細胞増殖は後天視覚障害の上位を占める糖尿病網膜症(diabetic retinopathy:DR),加齢黄斑変性(age-related macular degeneration:AMD)や増殖硝子体網膜症(proliferative vitreoretinopathy:PVR)などで観察される.これらの眼内増殖性疾患においては,網膜の上下に生じる線維(血管)増殖組織(以下,増殖組織)が主要病態である.これは一種の創傷治癒反応であるが,眼内で過剰に起こると難治となる.近年,AMDやDRの治療に抗血管内皮増殖因子(vascular endothelial growth factor:VEGF)療法が導入され,一定の成果をあげている.しかしその効果は限定的であり,増殖組織の病因に基づいた新しい分子標的薬の創製が期待される.一方,ゲノム医科学の進歩によりヒトゲノム配列や発現遺伝子の情報が飛躍的に蓄積され,眼疾患を新たな視点からとらえることが可能となった.我々は,ゲノムワイド遺伝子発現解析により眼内増殖性疾患の遺伝子レベルの知見を蓄え,これを基盤とした新しい分子標的療法の開発を試みた.I.PDR・PVR増殖組織のゲノムワイド遺伝子発現解析 眼内増殖性疾患の責任遺伝子を抽出する目的で,増殖糖尿病網膜症(proliferative diabetic retinopathy:PDR)とPVRに伴う増殖組織,続発黄斑上膜,正常網膜のゲノムワイド遺伝子発現解析を行った.PVRに伴う増殖組織と増殖のより緩やかな続発黄斑上膜の遺伝子発現プロファイルの比較により増殖組織活動性規定遺伝子群を,PDR・PVR増殖組織と正常網膜由来遺伝子発現プロファイルの比較により増殖組織特徴的遺伝子群を抽出した.増殖組織活動性規定遺伝子群は細胞接着,増殖などの機能単位に,特徴的遺伝子群は細胞外マトリックス,細胞接着,分化,増殖などに分類できた.組織修復に関与するマトリセルラー蛋白質であるペリオスチンは両群に含まれており,正常網膜に比べて増殖組織で特異的に発現が亢進し,その増殖活性を促進する重要分子であると考えられた.II.ペリオスチンの機能解析 ペリオスチンはPDR・PVRいずれにおいても患者硝子体で高値を示し,病期と正の相関を示した.また,正常網膜には発現せず,PDR・PVR増殖組織のα-smooth muscle actin(α-SMA)陽性細胞に特異的に発現していた.In vitroでペリオスチン蛋白質投与により,増殖組織の構成細胞であるヒト網膜色素上皮細胞の増殖,遊走,接着,コラーゲン合成が亢進した.また,ペリオスチン阻害によりtransforming growth factor-β2(TGF-β2)あるいは患者硝子体依存性の細胞接着と遊走が抑制された.In vivoでは,ペリオスチン阻害によりPVRの進行や網脈絡膜線維(血管)増殖が抑制された.以上よりペリオスチンは眼内増殖抑制治療の分子標的になると考えられた.III.虚血網膜のゲノムワイド遺伝子発現解析 眼内増殖の前駆病変として重要な虚血の分子病態を把握する目的で,酸素負荷虚血網膜血管新生モデルマウス網膜のゲノムワイド遺伝子発現解析を行った.虚血網膜で発現が変動した遺伝子群は,血管新生,神経形成関連因子,炎症,抗アポトーシス,解糖系などの機能単位に分類された.虚血網膜では,代表的な虚血関連因子であるvascular endothelial growth factorA(Vegfa)やhypoxia inducible factor1α(Hif1α)に加えて,macrophage inflammatory protein1β(Mip1β)の発現レベルが最も上昇していた.そこで同モデルを用いて,MIP-1βの骨髄由来単球系細胞誘導の役割について検討した.MIP-1βは,網膜の虚血部位に発現を認め,その受容体であるCCR5は,虚血網膜中の骨髄由来単球系細胞に発現していた.MIP-1β中和抗体の硝子体内投与により,骨髄由来単球系細胞の虚血網膜への浸潤が減少し,網膜内生理的血管新生は抑制され,網膜上病的新生血管面積は増加した.MIP-1β中和抗体投与網膜では,VEGF-Aの発現が亢進し,MIP-1βとVEGF中和抗体同時投与により網膜上病的血管新生は著明に抑制された.以上より,MIP-1βは虚血網膜に骨髄由来単球系細胞を誘導し,網膜内生理的血管新生を促進することが明らかとなった.IV.革新的ペリオスチン標的核酸医薬の創製 増殖性網膜硝子体疾患の硝子体においてペリオスチンとVEGF-Aの相関はなく,ペリオスチンを標的とした分子標的薬を創製できれば,抗VEGF薬と相加的効果をもたらすことが期待された.そこで,日本独自の技術である一本鎖RNA干渉をプラットフォームとしてペリオスチン標的一本鎖核酸配列を最適化した.最適化ペリオスチン標的一本鎖核酸は網脈絡膜線維血管増殖を抑制した.将来,オープンイノベーションによりこの画期的新薬が臨床応用され,DRやAMDなど眼内増殖性疾患の治療予後向上につながることが期待される.(著者抄録)

Language：English  

Purpose To evaluate the therapeutic effect of topical unoprostone isopropyl (unoprostone) on patients with retinitis pigmentosa (RP). Methods Forty patients with typical forms of RP were included in the study. Seventeen of 40 patients were treated with 0.12&#37; topical unoprostone twice daily in a randomly selected eye. Patients underwent follow-up examinations every 3 months after treatment. The efficacy of the treatment was monitored by visual acuity and visual field measurement testing using the Humphrey Field Analyzer (HFA: the central 10-2 programme). Moreover, 12 RP patients who were included this study and 12 normal subjects were evaluated in terms of their macular blood flow of both eyes after instillation of unoprostone using the laser speckle method. Results One year after treatment, the 'macular sensitivity', calculated by HFA as the average sensitivity of the central 12 points, was preserved in the fellow eyes as well as the unoprostone-treated eyes. On the other hand, that in the eyes of the control RP patient was significantly decreased. Moreover, there were significantly greater improvements of the 'macular sensitivity' in the unoprostone-treated eyes than the fellow eyes. The change ratios of macular blood flow obtained from both RP patients and normal subjects were significantly increased in both the treated and the fellow eyes. No severe side-effects were observed. Conclusions These results demonstrate that topical unoprostone might have a therapeutic efficacy in patients with RP as a consequence of the macular blood flow improvement as well as its direct neuroprotective effect.

DOI： 10.1111/aos.12293

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

Photoreceptor cell death is the ultimate cause of vision loss in various retinal disorders, including retinal detachment (RD). Photoreceptor cell death has been thought to occur mainly through apoptosis, which is the most characterized form of programmed cell death. The caspase family of cysteine proteases plays a central role for inducing apoptosis, and in experimental models of RD, dying photoreceptor cells exhibit caspase activation; however, there is a paradox that caspase inhibition alone does not provide a sufficient protection against photoreceptor cell loss, suggesting that other mechanisms of cell death are involved. Recent accumulating evidence demonstrates that non-apoptotic forms of cell death, such as autophagy and necrosis, are also regulated by specific molecular machinery, such as those mediated by autophagy-related proteins and receptor-interacting protein kinases, respectively. Here we summarize the current knowledge of cell death signaling and its roles in photoreceptor cell death after RD and other retinal degenerative diseases. A body of studies indicate that not only apoptotic but also autophagic and necrotic signaling are involved in photoreceptor cell death, and that combined targeting of these pathways may be an effective neuroprotective strategy for retinal diseases associated with photoreceptor cell loss.

DOI： 10.1016/j.preteyeres.2013.08.001

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

Aim: To evaluate the therapeutic effect of continuous treatment with topical dorzolamide (a carbonic anhydrase inhibitor) for cystoid macular oedema (CME) associated with retinitis pigmentosa (RP). Methods: 18 eyes in 10 patients with CME secondary to RP were included. Baseline visual acuity, visual field and optical coherence tomography (OCT) measurements were obtained for all patients. All patients used 1&#37; dorzolamide three times daily in each affected eye. Patients underwent follow-up examinations at 1, 3, 6, 12 and 18 months after treatment. The response to treatment was monitored by the Humphrey field analyser (HFA: the central 10-2 program); in addition, foveal thickness was measured by OCT. Evaluation of 'macular sensitivity' was calculated by HFA as the average of 12 central points. Results: The 'macular sensitivity' in 10 eyes in which CME was almost completely resolved was significantly improved (p<0.05). In eight of the nine eyes in which CME was almost completely resolved within 6 months, the therapeutic efficacy persisted through 18 months. Five eyes which were almost completely resolved or showed an initial response within 6 months experienced recurrence of CME. Conclusions: The prolonged (longer than 1 year) use of topical dorzolamide is effective for the treatment of CME in patients with RP. Therefore, we propose topical dorzolamide treatment as a first choice.

DOI： 10.1136/bjophthalmol-2012-303005

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

Purpose: To study the nature of retinal inflammatory response in rd10 mice, an animal model of retinitis pigmentosa (RP), and to investigate the effect of an antioxidant on retinal inflammation and photoreceptor apoptosis. Design: Experimental study. Participants and Controls: This study included 42 untreated rd10 mice, 30 N-acetylcysteine (NAC)-treated rd10 mice, and 20 C57BL/6 mice as controls. Methods: Real-time polymerase chain reaction (PCR) was performed to evaluate the expression levels of inflammatory factors (proinflammatory cytokines and chemokines) in rd10 mouse retinas. Rd10 mice were treated with an antioxidant NAC, and its effect on retinal inflammation and photoreceptor apoptosis were examined by immunohistochemistry. Main Outcome Measures: Real-time PCR and immunohistochemistry. Results: We demonstrated sequential events involving increased expression of proinflammatory cytokines and chemokines, activation of microglia, and photoreceptor apoptosis during retinal degeneration of rd10 mice. Furthermore, antioxidant treatment with NAC prevented the photoreceptor cell death along with suppression of inflammatory factors and microglial activation. Conclusions: Sustained chronic inflammatory reaction may contribute to the pathogenesis of retinal degeneration in rd10 mice, suggesting interventions for ocular inflammatory reaction using antioxidants as a potential treatment for patients with RP. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

DOI： 10.1016/j.ophtha.2012.07.008

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

Photoreceptor degeneration is the most critical cause of visual impairment in age-related macular degeneration (AMD). In neovascular form of AMD, severe photoreceptor loss develops with subretinal hemorrhage due to choroidal neovascularization (CNV), growth of abnormal blood vessels from choroidal circulation. However, the detailed mechanisms of this process remain elusive. Here we demonstrate that neovascular AMD with subretinal hemorrhage accompanies a significant increase in extracellular ATP, and that extracellular ATP initiates neurodegenerative processes through specific ligation of Purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7; P2X7 receptor). Increased extracellular ATP levels were found in the vitreous samples of AMD patients with subretinal hemorrhage compared to control vitreous samples. Extravascular blood induced a massive release of ATP and photoreceptor cell apoptosis in co-culture with primary retinal cells. Photoreceptor cell apoptosis accompanied mitochondrial apoptotic pathways, namely activation of caspase-9 and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, as well as TUNEL-detectable DNA fragmentation. These hallmarks of photoreceptor cell apoptosis were prevented by brilliant blue G (BBG), a selective P2RX7 antagonist, which is an approved adjuvant in ocular surgery. Finally, in a mouse model of subretinal hemorrhage, photoreceptor cells degenerated through BBG-inhibitable apoptosis, suggesting that ligation of P2RX7 by extracellular ATP may accelerate photoreceptor cell apoptosis in AMD with subretinal hemorrhage. Our results indicate a novel mechanism that could involve neuronal cell death not only in AMD but also in hemorrhagic disorders in the CNS and encourage the potential application of BBG as a neuroprotective therapy.

DOI： 10.1371/journal.pone.0053338

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

Purpose: To study the nature of inflammatory reaction in eyes of patients with retinitis pigmentosa (RP) and its possible role in the pathogenesis of RP. Design: Retrospective, observational study. Participants and Controls: Three hundred seventy-one consecutive patients diagnosed with typical RP were included in this study. We included 165 patients without active inflammatory diseases, including 20 patients diagnosed with cataract, and 36 patients diagnosed with idiopathic epiretinal membrane as controls. Methods: Density of the inflammatory cells in the anterior vitreous cavity was measured and graded by slit-lamp biomicroscopy. A multiplex enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the concentration of cytokines and chemokines in aqueous humor and vitreous fluid of patients with RP and controls. In addition, we investigated the relationship between visual function and anterior vitreous cells in these patients. Main Outcome Measures: Slit-lamp biomicroscopic analysis, best-corrected visual acuity, visual field analysis, and multiplex ELISA. Results: In 190 of 509 eyes with RP (37.3&#37;), "1+" (5-9 cells per field) or more cells were observed in the anterior vitreous cavity. Strong inflammatory reaction with "2+" cells (10-30 cells per field) was associated with younger age. In the elderly patients with RP, significantly decreased visual function was seen in a group with "1+" or more cells (P<0.05). Moreover, the levels of a variety of proinflammatory cytokines and chemokines, including monocyte chemotactic protein-1, were increased both in the aqueous humor and vitreous fluid of RP patients compared with the levels in control patients. Conclusions: Sustained chronic inflammatory reaction may underlie the pathogenesis of RP, suggesting interventions for ocular inflammatory reaction as a potential treatment for patients with RP. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article.

DOI： 10.1016/j.ophtha.2012.07.006

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

Language：Others  

Preclinical safety study of simian immunodeficiency virus-based lentiviral vector for retinal gene transfer in non-human primates

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

DOI： 10.1371/journal.pone.0040065

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

The role of apoptosis in the formation and regression of neovascularization is largely hypothesized, although the detailed mechanism remains unclear. Inflammatory cells and endothelial cells both participate and interact during neovascularization. During the early stage, these cells may migrate into an angiogenic site and form a pro-angiogenic microenvironment. Some angiogenic vessels appear to regress, whereas some vessels mature and remain. The control mechanisms of these processes, however, remain unknown. Previously, we reported that the prevention of mitochondrial apoptosis contributed to cellular survival via the prevention of the release of proapoptotic factors, such as apoptosis-inducing factor (AIF) and cytochrome c. In this study, we investigated the regulatory role of cellular apoptosis in angiogenesis using two models of ocular neovascularization: laser injury choroidal neovascularization and VEGF-induced corneal neovascularization in AIF-deficient mice. Averting apoptosis in AIF-deficient mice decreased apoptosis of leukocytes and endothelial cells compared to wild-type mice and resulted in the persistence of these cells at angiogenic sites in vitro and in vivo. Consequently, AIF deficiency expanded neovascularization and diminished vessel regression in these two models. We also observed that peritoneal macrophages from AIF-deficient mice showed anti-apoptotic survival compared to wild-type mice under conditions of starvation. Our data suggest that AIF-related apoptosis plays an important role in neovascularization and that mitochondria-regulated apoptosis could offer a new target for the treatment of pathological angiogenesis.

DOI： 10.1016/j.ajpath.2012.03.022

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

PURPOSE: To investigate the anti-inflammatory effect of an adenosine monophosphate (AMP) analog, aminoimidazole carboxamide ribonucleotide (AICAR), in experimental autoimmune uveoretinitis (EAU). METHODS: C57BL/6 mice were injected daily with AICAR (200 mg/kg, intraperitoneally [IP]) from day 0, the day of interphotoreceptor retinoid-binding protein (IRBP) immunization, until day 21. The severity of uveitis was assessed clinically and histopathologically. T-cell proliferation and cytokine production of IFN-γ, IL-17, and IL-10 in response to IRBP stimulation were determined. In addition, regulatory T-cell (Treg) populations were measured. Co-stimulatory molecule expression (CD40, 80, 86, and I-Ab) on dendritic cells (DCs) in EAU and on bone marrow-derived dendritic cells (BMDCs) treated with AICAR was measured. RESULTS: AICAR treatment significantly reduced clinical and histologic severity of EAU as well as ocular cytokine production. An anti-inflammatory effect associated with the inhibition of T-cell proliferation and Th1 and Th17 cytokine production was observed. Increases in the Th2 response and Treg population were not observed with AICAR treatment. AICAR did significantly inhibit BMDC maturation by reducing co-stimulatory molecule expression. CONCLUSIONS: AICAR attenuates EAU by preventing generation of Ag-specific Th1 and Th17 cells. Impaired DC maturation may be an underlying mechanism for this anti-inflammatory effect observed with AICAR.

DOI： 10.1167/iovs.11-9323

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

BACKGROUND: Cystoid macular edema (CME) is one of the common complications of retinitis pigmentosa (RP), and is responsible for patient complications such as blurred and reduced visual acuity and for subsequent atrophic changes in the fovea. The objective of this work was to evaluate the clinical efficacy of a topical dorzolamide (a carbonic anhydrase inhibitor) in CME associated with RP. METHODS: Sixteen eyes of nine patients with CME secondary to typical forms of RP were included in the study. Baseline visual acuity, visual field, and optical coherence tomography (OCT) measurements were obtained for all patients. All patients used 1&#37; dorzolamide three times daily in each eye. Patients underwent follow-up exams at 1, 3, and 6 months after treatment. The response to treatment was monitored by visual acuity and visual field measurement testing using the Humphrey Field Analyzer (HFA: the central 10-2 Program); in addition, foveal thickness was measured by OCT. Evaluation of macular sensitivity calculated by HFA as the average of 12 central points. RESULTS: Thirteen (81.3&#37;) of 16 eyes showed a clear decrease in retinal thickness after treatment. Evaluation of macular sensitivity, calculated by HFA as the average of 12 central points (with the exception of foveal point data, showed an improvement of more than 1.0 dB in nine (56.3&#37;) of 16 eyes. Moreover, both the mean deviation value and macular sensitivity were significantly improved. No severe side-effects were seen in any of the patients examined. CONCLUSIONS: The results demonstrated that a topical dorzolamide is effective for the treatment of CME in patients with RP, and that the positive treatment effects last for up to 6 months.

DOI： 10.1007/s00417-011-1904-5

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

The increasing popularity of the Cre/loxP recombination system has led to the generation of numerous transgenic mouse lines in which Cre recombinase is expressed under the control of organ- or cell-specific promoters. Alterations in retinal pigment epithelium (RPE), a multifunctional cell monolayer that separates the retinal photoreceptors from the choroid, are prevalent in the pathogenesis of a number of ocular disorders, including age-related macular degeneration. To date, six transgenic mouse lines have been developed that target Cre to the RPE under the control of various gene promoters. However, multiple lines of evidence indicate that high levels of Cre expression can be toxic to mammalian cells. In this study, we report that in the Trp1-Cre mouse, a commonly used transgenic Cre strain for RPE gene function studies, Cre recombinase expression alone leads to RPE dysfunction and concomitant disorganization of RPE layer morphology, large areas of RPE atrophy, retinal photoreceptor dysfunction, and microglial cell activation in the affected areas. The phenotype described herein is similar to previously published reports of conditional gene knockouts that used the Trp1-Cre mouse, suggesting that Cre toxicity alone could account for some of the reported phenotypes and highlighting the importance of the inclusion of Cre-expressing mice as controls in conditional gene targeting studies.

DOI： 10.1016/j.ajpath.2012.01.017

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

BACKGROUND: Neovascular glaucoma (NVG) is a serious complication for patients with proliferative diabetic retinopathy (PDR). Bevacizumab is a full-length humanized monoclonal antibody that binds all isoforms of vascular endothelial growth factor (VEGF). Recently, encouraging results regarding the off-label use of intravitreal bevacizumab (IVB) for the treatment of NVG have been reported. We evaluated the histology of bevacizumab-treated trabeculectomy specimens to clarify IVB's biological effects on angle neovascularization. METHODS: We retrospectively reviewed the charts of a consecutive series of 15 eyes of 13 patients who underwent trabeculectomy to treat NVG caused by PDR. In ten eyes of eight patients, 1.25 mg bevacizumab was injected intravitreally via the pars plana. Using light or electron microscopy, the surgically excised trabecular tissue was compared to that without IVB. RESULTS: Light microscopy revealed decreased edema, fibrin deposition, inflammation and vascular congestion in the trabecular meshwork in specimens with IVB compared to those without IVB. Electron microscopy revealed endothelial cell degeneration in the bevacizumab-treated specimens. CONCLUSIONS: The biological effects on angle neovascularization after IVB may involve reduced vascular permeability, decreased inflammatory reaction, loss of vascular function, and endothelial cell degeneration.

DOI： 10.1007/s00417-011-1761-2

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

DOI： 10.1371/journal.pone.0024245

Language：English  

PURPOSE. To investigate the anti-inflammatory effect of aminoimidazole carboxamide ribonucleotide (AICAR), an analog of adenosine monophosphate (AMP), in endotoxin-induced uveitis (EIU). METHODS. EIU was induced by subcutaneous injection of lipopolysaccharide (LPS) (200 μg) in Lewis rats. AICAR (50 mg/kg, intraperitoneally) was given 6 hours prior and at the same time as LPS injection. Clinical uveitis scores, number of anterior chamber (AC) infiltrating cells, anterior chamber protein concentration, retinal vessel leukocyte adhesion, and protein leakage were measured 24 hours later. Protein levels of C-C chemokine ligand-2 (CCL-2)/monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α) and intercellular adhesion molecule-1 (ICAM-1) in aqueous humor and retina and nuclear translocation of nuclear factor-κB (NF-κB) in the retina were determined by enzyme-linked immunosorbent assay (ELISA). Both mRNA and protein levels of CD14 in peripheral blood mononuclear cells were also measured. RESULTS. AICAR treatment significantly reduced EIU clinical severity as well as inflammatory cell infiltration and protein concentration in aqueous humor. Similarly, the number of retinal vessel-adherent leukocytes and protein leakage were decreased by AICAR treatment. Protein levels of TNF-α, CCL-2/MCP-1, and ICAM-1 in aqueous humor and CCL-2/MCP-1 and ICAM-1 levels in retina were suppressed with AICAR treatment. AICAR also reduced NF-κB translocation and CD14 expression. CONCLUSIONS. AICAR reduces systemic LPS susceptibility and attenuates intraocular inflammation in a rat EIU model by limiting infiltration of leukocytes, suppressing inflammatory mediators, and inhibiting the NF-κB pathway.

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

Photoreceptor cell death is the terminal event in a variety of retinal disorders including age-related macular degeneration, retinitis pigmentosa, and retinal detachment. Apoptosis has been thought to be the major form of cell death in these diseases, however accumulating evidence suggests that another pathway, programmed necrosis is also important. Recent studies have shown that, when caspase pathways are blocked, receptor interacting protein (RIP) kinases promote necrosis and overcome apoptosis inhibition. Therefore, targeting of both caspase and RIP kinase pathways are required for effective photoreceptor protection. Here, we summarize the current knowledge of RIP kinase-mediated necrotic signaling and its contribution to photoreceptor death.

Language：English  

Pigment epithelium-derived factor gene therapy targeting retinal ganglion cell injuries Neuroprotection against loss of function in two animal models
Lentiviral vectors are promising tools for the treatment of chronic retinal diseases including glaucoma, as they enable stable transgene expression. We examined whether simian immunodeficiency virus (SIV)-based lentiviral vector-mediated retinal gene transfer of human pigment epithelium-derived factor (hPEDF) can rescue rat retinal ganglion cell injury. Gene transfer was achieved through subretinal injection of an SIV vector expressing human PEDF (SIV-hPEDF) into the eyes of 4-week-old Wistar rats. Two weeks after gene transfer, retinal ganglion cells were damaged by transient ocular hypertension stress (110mmHg, 60min) and N-methyl-d-aspartic acid (NMDA) intravitreal injection. One week after damage, retrograde labeling with 4′,6-diamidino-2-phenylindole (DAPI) was done to count the retinal ganglion cells that survived, and eyes were enucleated and processed for morphometric analysis. Electroretinographic (ERG) assessment was also done. The density of DAPI-positive retinal ganglion cells in retinal flat-mounts was significantly higher in SIV-hPEDF-treated rats compared with control groups, in both transient ocular hypertension and NMDA-induced models. Pattern ERG examination demonstrated higher amplitude in SIV-hPEDF-treated rats, indicating the functional rescue of retinal ganglion cells. These findings show that neuroprotective gene therapy using hPEDF can protect against retinal ganglion cell death, and support the potential feasibility of neuroprotective therapy for intractable glaucoma.

DOI： 10.1089/hum.2010.132

Language：English  

Purpose. To investigate whether edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a free radical scavenger, would be neuroprotective against photoreceptor cell death in a rat model of retinal detachment (RD). Methods. RD was induced in adult Brown Norway rats by subretinal injection of sodium hyaluronate. Edaravone (3, 5, or 10 mg/kg) or physiologic saline was administered intraperitoneally once a day until death on day 3 or 5. Oxidative stress in the retina was assessed by 4-hydroxynonenal staining or ELISA for protein carbonyl content. Photoreceptor death was assessed by TUNEL and measurement of the outer nuclear layer thickness. Western blot analysis and caspase activity assays were performed. Inflammatory cytokine secretion and inflammatory cell infiltration were evaluated by ELISA and immunostaining, respectively. Results. RD resulted in increased generation of ROS. Treatment with 5 mg/kg edaravone significantly reduced the ROS level, along with a decrease in TUNEL-positive cells in the photoreceptor layer. A caspase assay also confirmed decreased activation of caspase-3, -8, and -9 in RD treated with edaravone. The level of the antiapoptotic Bcl-2 was increased in detached retinas after edaravone treatment, whereas the levels of the stress-activated p-ERK1/2 were decreased. In addition, edaravone treatment resulted in a significant decrease in the levels of TNF-α, MCP-1, and macrophage infiltration. Conclusions. Oxidative stress plays an important role in photoreceptor cell death after RD. Edaravone treatment may aid in preventing photoreceptor cell death after RD by suppressing ROS-induced photoreceptor damage.

DOI： 10.1167/iovs.10-6797

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

Matrix metalloproteinase-9 (MMP-9) plays a critical role in tissue remodeling under both physiological and pathological conditions. Although MMP-9 expression is low in most cells and is tightly controlled, the mechanism of its regulation is poorly understood. We utilized mouse embryonic fibroblasts (MEFs) that were nullizygous for the catalytic α subunit of AMP-activated protein kinase (AMPK), which is a key regulator of energy homeostasis, to identify AMPK as a suppressor of MMP-9 expression. Total AMPKα deletion significantly elevated MMP-9 expression compared with wild-type (WT) MEFs, whereas single knock-out of the isoforms AMPKα1 and AMPKα2 caused minimal change in the level of MMP-9 expression. The suppressive role of AMPK on MMP-9 expression was mediated through both its activity and presence. The AMPK activators 5-amino-4-imidazole carboxamide riboside and A769662 suppressed MMP-9 expression in WT MEFs, and AMPK inhibition by the overexpression of dominant negative (DN) AMPKα elevated MMP-9 expression. However, in AMPKα^-/- MEFs transduced with DN AMPKα, MMP-9 expression was suppressed. AMPKα^-/- MEFs showed increased phosphorylation of IκBα, expression of IκBα mRNA, nuclear localization of nuclear factor-κB (NF-κB), and DNA-binding activity of NF-κB compared with WT. Consistently, selective NF-κB inhibitors BMS345541 and SM7368 decreased MMP-9 expression in AMPKα^-/- MEFs. Overall, our results suggest that both AMPKα isoforms suppress MMP-9 expression and that both the activity and presence of AMPKα contribute to its function as a regulator of MMP-9 expression by inhibiting the NF-κB pathway.

DOI： 10.1074/jbc.M110.199398

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

Photoreceptor apoptosis is a major cause of vision loss in many ocular diseases. Significant progress has been made to elucidate the molecular pathways involved in this process, yet little is known about proteins counteracting these apoptotic pathways. It is established that heat shock proteins (HSPs) function as molecular helper proteins (chaperones) by preventing protein aggregation and facilitating refolding of dysfunctional proteins, critical to the survival of all organisms. Here, we investigated the role of HSP70 on photoreceptor survival after experimental retinal detachment (RD) in mice and rats. We found that HSP70 was up-regulated after RD and associated with phosphorylated Akt, thereby preventing its dephosphorylation and further activation of cell death pathways. Administration of quercetin, which inhibits HSP70 and suppresses Akt phosphorylation significantly increased photoreceptor apoptosis. Similarly, RD-induced photoreceptor apoptosis was augmented in mice carrying hypomorphic mutations of the genes encoding HSP70. On the other hand, administration of geranylgeranylacetone, which induces an increase in HSP70 significantly decreased photoreceptor apoptosis after RD through prolonged activation of Akt pathway. Thus, HSP70 may be a favorable potential target to increase photoreceptor cell survival after RD.

DOI： 10.1016/j.ajpath.2010.11.072

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

Background: Asteroid hyalosis (AH) is a condition in which cream-colored or white spherical particles are suspended in the vitreous body. Asteroid hyalosis is considered not to cause decreased vision or any other visual symptoms except in rare cases. There have been a few reports of AH in patients with retinitis pigmentosa (RP). Methods: To assess the prevalence of AH in patients with RP, 320 patients with typical forms of RP were studied. One patient was offered a standard three-port vitrectomy, and the spherical particles obtained from her vitrectomy sample were analyzed using an energy-dispersive x-ray spectrometer. Results: Ten patients (two men and eight women) developed AH. Among them, four had bilateral AH and two had rapidly increasing vitreous opacity that led to decreased vision. One patient was a 48-year-old woman with progressive AH in the left eye. After treatment with a vitrectomy, her vision improved from 0.4 to 0.8. The spherical particles were composed of mainly calcium and phosphorus. Conclusion: The prevalence of AH in RP was higher than in previous reports, and we encountered two rare cases of progressive AH with decreased vision. We conclude that AH might lead to decreased vision in patients with RP.

DOI： 10.1097/IAE.0b013e3181dcfc0a

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

Lentiviral vectors are promising tools for the treatment of chronic retinal diseases, including age-related macular degeneration (AMD), as they enable stable transgene expression. On the other hand, Sendai virus (SeV) vectors provide the unique advantage of rapid gene transfer. Here we show that novel simian immunodeficiency viral vectors pseudotyped with SeV envelope proteins (SeV-F/HN-SIV) achieved rapid, efficient, and long-lasting gene transfer in the mouse retina. Subretinal exposure to SeV-F/HN-SIV vectors for only a few minutes resulted in high-level gene transfer to the retinal pigment epithelium, whereas several hours were required for gene transfer by standard vesicular stomatitis virus G-pseudotyped SIV vectors. Transgene expression continued over a 1-year period. SeV-F/HN-SIV vector-mediated retinal overexpression of soluble Fms-like tyrosine kinase-1 (sFlt-1) or pigment epithelium-derived factor (PEDF) significantly suppressed laser-induced choroidal neovascularization (CNV). Histologically, 6-month-long sustained overexpression of PEDF did not adversely affect the retina; however, that with sFlt-1 resulted in photoreceptor degeneration associated with choroidal circulation defects. These data demonstrate that brief subretinal administration of SeV-F/HN-SIV vectors may facilitate safe and efficient retinal gene transfer, and suggest the therapeutic potential of PEDF with a higher safety profile for treating CNV in AMD patients.

DOI： 10.1089/hum.2009.102

Language：English  

Purpose: To report 3 children who developed retinoblastoma with atypical clinical manifestations at the age of 8 years each. Cases: All the 3 cases were girls and were unilaterally affected. One case had hyperemia of affected eye as chief complaint. Her left eye simulated uveitis with visual acuity of 1.5. The other 2 cases showed vitreous opacity or hemorrhage with visual acuity of hand motion. Diagnostic imaging showed no intraocular tumor or calcification in all the cases. Enucleation led to the diagnosis of retinoblastoma with vitreous dissemination in the 3 cases. There has been no recurrence or metastasis during the follow-up for 16 months, 4 years and 7 years respectively. Conclusion: The present cases illustrate that retinoblastoma in children of advanced age may show atypical clinical manifestations. This particular feature needs due attention.

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

A phase 1 clinical trial evaluating the safety of gene therapy for patients with wet age-related macular degeneration (AMD) or retinoblastoma has been completed without problems. The efficacy of gene therapy for Leber's congenital amaurosis (LCA) was reported by three groups. Gene therapy may thus hold promise as a therapeutic method for the treatment of intractable ocular diseases. However, it will first be important to precisely evaluate the efficiency and safety of alternative gene transfer vectors in a preclinical study using large animals. In the present study, we evaluated the acute local (ophthalmic) and systemic toxicity of our simian immunodeficiency virus from African green monkeys (SIVagm)-based lentiviral vectors carrying human pigment epithelium-derived factor (SIV-hPEDF) for transferring genes into nonhuman primate retinas. Transient inflammation and elevation of intraocular pressure were observed in some animals, but these effects were not dose dependent. Electroretinograms (ERGs), including multifocal ERGs, revealed no remarkable change in retinal function. Histopathologically, SIV-hPEDF administration resulted in a certain degree of inflammatory reaction and no apparent structural destruction in retinal tissue. Regarding systemic toxicity, none of the animals died, and none showed any serious side effects during the experimental course. No vector leakage was detected in serum or urine samples. We thus propose that SIVagm-mediated stable gene transfer might be useful and safe for ocular gene transfer in a clinical setting.

DOI： 10.1089/hum.2009.048

Language：English  

Purpose : To report a case who developed multiple basal cell carcinoma on the eyelids and the face. Case : A 70-year-old female presented with a tumor of the upper and lower right eyelid. She had been engaged in agriculture. She had no history of malignancy, intake of arsenics, or radiation. Findings : The tumor of the upper eyelid showed an elevated margin and was 5 mm by 3 mm in size. The tumor of the lower eyelid was black and flat and was 4 mm by 2 mm in size. Biopsy showed the diagnosis of basal cell carcinoma. She developed 6 tumors on the eyelids and one each on the left cheek, upper lip, and forehead during the ensuing 10 years. The tumor was resected at each occasion and proved to be basal cell carcinoma. Conclusion : The present case illustrates that basal cell carcinoma may recur heterotopically. Prolonged exposure to sunlight, particularly to ultraviolet, is suspected as an underlying cause in this patient.

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

DOI： 10.1038/eye.2008.299

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

Gene therapy may hold promise as a therapeutic approach for the treatment of intractable ocular diseases, including retinitis pigmentosa (RP). Gene transfer vectors that are able to show long-lasting transgene expression in vivo are highly desirable to treat RP; however, there is a dearth of information regarding long-term transgene expression in the eyes of large animals. We previously reported that the simian immunodeficiency virus from African green monkeys (SIVagm)-based lentiviral vector showed efficient, stable, and safe retinal gene transfer, resulting in significant prevention of retinal degeneration by gene transfer of a neurotrophic factor, human pigment epithelium-derived factor (hPEDF), in rodents. Before applying this strategy in a clinical setting, we here assessed the long-lasting transgene expression of our third-generation SIVagm-based lentiviral vectors in the retinal tissue of nonhuman primates. Approximately 20-50μl of SIV-EGFP (enhanced green fluorescent protein) or SIV-hPEDF was injected into the subretinal space via a glass capillary tube. To detect EGFP expression in the retina, we used a fluorescence fundus camera at various time points after gene transfer. Human PEDF expression was assessed by immunohistochemical analysis, Western blot assay, and enzyme-linked immunosorbent assay. The retinas demonstrated frequent EGFP expression that was preserved for at least 4 years without significant decline. The expression of hPEDF was stable, and occurred mainly in the retinal pigment epithelium. The secreted protein was detected in vitreous and aqueous humor. We thus propose that SIVagm-mediated stable gene transfer might be significantly useful for ocular gene transfer in a clinical setting.

DOI： 10.1089/hum.2009.009

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

Background: We previously demonstrated that a new lentiviral vector derived from nonpathogenic simian immunodeficiency virus (SIVagm) was efficient and safe for long-lasting retinal gene transfer, and that it provided the significant therapeutic effect of expressing human pigment epithelium-derived factor (hPEDF) in Royal College of Surgeons (RCS) rats. In the present study, to obtain a more pronounced outcome, we assessed the potential synergistic effect of the simultaneous gene transfer of hPEDF and human fibroblast growth factor-2 (hFGF-2) by improved third-generation SIV on RCS rats and retinal degeneration slow (rds) mice, because the former targets the primary neurons, including photoreceptor cells (PCs), whereas the latter is effective for targeting secondary neural cells, including Muller cells. Methods: Vector solution (SIV-hPEDF, SIV-hFGF-2, a 1:1 mixture of SIV-hPEDF and SIV-hFGF-2, or SIV-enhanced green fluorescent protein) was injected into the peripheral subretinal space of 3-week-old RCS rats or rds mice. Histopathological and electroretinographic assessments were made at several points after gene transfer. Results: Administration of SIV-hPEDF or SIV-hFGF-2 significantly delayed the histological PC degeneration and electrical deficit in RCS rats, and these delays were synergistically and significantly pronounced by SIV-hPEDF + SIV-hFGF-2 (1:1 mixture). In rds mice, functional therapeutic effects were observed even by SIV-PEDF, or SIV-FGF-2 alone and, moreover, both SIV-PEDF and SIV-FGF-2 showed higher therapeutic effects. Conclusions: These synergistic rescues of retinitis pigmentosa (RP) model animals are the 'proof concept' that the 'dual' expression of hPEDF and hFGF-2 dramatically improved therapeutic efficacy by keeping lower titers. This strategy may contribute to safer and more effective gene therapy for RP.

DOI： 10.1002/jgm.1257

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

DOI： 10.1002/jgm.1142

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

DOI： 10.1038/sj.eye.6702730

Language：Japanese  

Language：Japanese   Book type：Scholarly book

Language：Japanese   Book type：General book, introductory book for general audience

Language：Japanese   Book type：Scholarly book

Language：Japanese   Book type：General book, introductory book for general audience

Language：Japanese   Book type：General book, introductory book for general audience

Language：Japanese   Book type：General book, introductory book for general audience

Language：Japanese   Book type：General book, introductory book for general audience

Event date： 2019.4

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：Seoul   Country：Korea, Republic of  

網膜色素変性は遺伝性の網膜変性疾患であるが、近年の研究から神経炎症が病態の進展に関与していることが示唆されている。我々は臨床・基礎研究の両面から、網膜色素変性病態への炎症の関与について研究を進めており、本シンポジウムでその成果を発表した。シンポジウムは網膜変性や網膜視覚生理のスペシャリストで構成されており、網膜色素変性病態の新しい考え方について発表・ディスカッションを行った。

Event date： 2018.12

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：京都   Country：Japan  

網膜色素変性は遺伝性の網膜変性疾患であるが、近年の研究から神経炎症が病態の進展に関与していることが示唆されている。我々は臨床・基礎研究の両面から、網膜色素変性病態への炎症の関与について研究を進めており、本シンポジウムでその成果を発表した。シンポジウムのテーマである"New concept of pathology of vitreoretinal diseases"の中で、RPの炎症性疾患としての側面や炎症を標的とした治療の可能性について示した。

Event date： 2018.10

Language：Japanese  

Venue：広島   Country：Japan  

Event date： 2017.12

Language：Japanese   Presentation type：Oral presentation (invited, special)  

Country：Japan  

Event date： 2017.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：大阪   Country：Japan  

Event date： 2017.6

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京   Country：Japan  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2016.6

Language：Japanese  

Venue：Cork   Country：Ireland  

Language：Japanese  

Venue：仙台   Country：Japan  

Language：Japanese  

Venue：Florida   Country：United States  

Language：Japanese  

Venue：Florida   Country：United States  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Berlin   Country：Germany  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Florida   Country：United States  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Florida   Country：United States  

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：鹿児島   Country：Japan  

Event date： 2024.6

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：大分県   Country：Japan  

Event date： 2024.6

Language：Japanese  

Venue：大分県   Country：Japan  

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Event date： 2024.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2024.5

Language：Japanese  

Venue：福岡   Country：Japan  

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Event date： 2024.3

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：神奈川県   Country：Japan  

Event date： 2024.3

Language：Japanese  

Venue：神奈川県   Country：Japan  

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Event date： 2024.3

Language：English   Presentation type：Oral presentation (general)  

Venue：Tokyo   Country：Japan  

Event date： 2024.3

Language：English  

Venue：Tokyo   Country：Japan  

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Event date： 2024.2

Language：Japanese  

Venue：福岡県   Country：Japan  

Event date： 2024.2

Language：Japanese  

Venue：福岡県   Country：Japan  

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Event date： 2023.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：兵庫県   Country：Japan  

Event date： 2023.12

Language：Japanese  

Venue：兵庫県   Country：Japan  

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Event date： 2023.11

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：東京都（Webinar）   Country：Japan  

Event date： 2023.11

Language：Japanese  

Venue：東京都（Webinar）   Country：Japan  

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Event date： 2023.11

Language：Japanese  

Venue：神奈川県   Country：Japan  

Event date： 2023.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：神奈川県   Country：Japan  

Event date： 2023.11

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：神奈川県   Country：Japan  

Event date： 2023.11

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：神奈川県   Country：Japan  

Event date： 2023.11

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：神奈川県   Country：Japan  

Event date： 2023.11

Language：English  

Venue：神奈川県   Country：Japan  

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Event date： 2023.11

Language：Japanese  

Venue：神奈川県   Country：Japan  

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Event date： 2023.11

Language：Japanese  

Venue：神奈川県   Country：Japan  

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Event date： 2023.11

Language：English  

Venue：神奈川県   Country：Japan  

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Event date： 2023.11

Language：English  

Venue：神奈川県   Country：Japan  

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Event date： 2023.10

Language：English  

Venue：New York   Country：United States  

Event date： 2023.10

Language：English  

Venue：New York   Country：United States  

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Event date： 2023.10

Language：English   Presentation type：Oral presentation (general)  

Venue：東京都   Country：Japan  

Event date： 2023.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京都   Country：Japan  

Event date： 2023.10

Language：English  

Venue：東京都   Country：Japan  

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Event date： 2023.10

Language：Japanese  

Venue：東京都   Country：Japan  

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Event date： 2023.10

Language：Japanese  

Venue：東京都   Country：Japan  

Event date： 2023.10

Language：Japanese  

Venue：東京都   Country：Japan  

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Event date： 2023.9

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：鹿児島県   Country：Japan  

Event date： 2023.9

Language：Japanese  

Venue：鹿児島県   Country：Japan  

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Event date： 2023.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：熊本県   Country：Japan  

Event date： 2023.9

Language：Japanese  

Venue：熊本県   Country：Japan  

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Event date： 2023.9 - 2023.8

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：東京都   Country：Japan  

Event date： 2023.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：岐阜県   Country：Japan  

Event date： 2023.6

Language：Japanese  

Venue：岐阜県   Country：Japan  

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Event date： 2023.5

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：福岡   Country：Japan  

Event date： 2023.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2023.5

Language：Japanese  

Venue：福岡   Country：Japan  

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Event date： 2023.5

Language：Japanese  

Venue：福岡   Country：Japan  

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Event date： 2023.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：富山   Country：Japan  

Event date： 2023.5

Language：Japanese  

Venue：富山   Country：Japan  

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Event date： 2023.4

Language：English  

Venue：New Orleans   Country：United States  

Event date： 2023.4

Language：English  

Venue：New Orleans   Country：United States  

Event date： 2023.4

Language：English  

Venue：New Orleans   Country：United States  

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Event date： 2023.4

Language：English  

Venue：New Orleans   Country：United States  

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Event date： 2023.4

Language：English  

Venue：New Orleans   Country：United States  

Event date： 2023.4

Language：English  

Venue：New Orleans   Country：United States  

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Event date： 2023.4

Language：English   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2023.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2023.4

Language：English  

Venue：東京   Country：Japan  

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Event date： 2023.4

Language：Japanese  

Venue：東京   Country：Japan  

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Event date： 2023.4

Language：English   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2023.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2023.4

Language：English  

Venue：東京   Country：Japan  

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Event date： 2023.4

Language：Japanese  

Venue：東京   Country：Japan  

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Event date： 2023.2

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Country：Japan  

Event date： 2023.2

Language：Japanese  

Country：Japan  

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Event date： 2022.12

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：岡山   Country：Japan  

Event date： 2022.12

Language：Japanese  

Venue：岡山   Country：Japan  

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Event date： 2022.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪   Country：Japan  

Event date： 2022.12

Language：Japanese  

Venue：大阪   Country：Japan  

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Event date： 2022.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2022.10

Language：Japanese  

Venue：東京   Country：Japan  

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Event date： 2022.10

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：東京   Country：Japan  

Event date： 2022.10

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2022.10

Language：Japanese  

Venue：東京   Country：Japan  

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Event date： 2022.10

Language：Japanese  

Venue：東京   Country：Japan  

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Event date： 2022.9

Language：English   Presentation type：Oral presentation (general)  

Venue：Beijing   Country：China  

Event date： 2022.9

Language：English   Presentation type：Oral presentation (general)  

Venue：Beijing   Country：China  

Event date： 2022.9

Language：English   Presentation type：Oral presentation (general)  

Venue：Beijing   Country：China  

Event date： 2022.9

Language：English  

Venue：Beijing   Country：China  

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Event date： 2022.9

Language：English  

Venue：Beijing   Country：China  

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Event date： 2022.9

Language：English  

Venue：Beijing   Country：China  

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Event date： 2022.8

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都   Country：Japan  

Event date： 2022.8

Language：Japanese  

Venue：京都   Country：Japan  

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Event date： 2022.6

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：福岡   Country：Japan  

Event date： 2022.6

Language：Japanese  

Venue：福岡   Country：Japan  

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Event date： 2022.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：沖縄   Country：Japan  

Event date： 2022.5

Language：Japanese  

Venue：沖縄   Country：Japan  

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Event date： 2022.5

Language：Japanese  

Venue：San Francisco（オンライン）   Country：United States  

Event date： 2022.5

Language：English  

Venue：San Francisco（オンライン）   Country：United States  

Event date： 2022.5

Language：English  

Venue：San Francisco（オンライン）   Country：United States  

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Event date： 2022.5

Language：English  

Venue：Denver   Country：United States  

Event date： 2022.4

Language：English  

Venue：Tokyo   Country：Japan  

Event date： 2022.4

Language：English  

Venue：Tokyo   Country：Japan  

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Event date： 2022.4

Language：English  

Venue：Tokyo   Country：Japan  

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Event date： 2022.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪府   Country：Japan  

Event date： 2022.4

Language：Japanese  

Venue：大阪府   Country：Japan  

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Event date： 2022.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京都   Country：Japan  

Event date： 2022.3

Language：Japanese  

Venue：東京都   Country：Japan  

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Event date： 2022.3 - 2021.3

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：福岡県   Country：Japan  

Event date： 2022.3

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Country：Japan  

Event date： 2022.3

Language：Japanese  

Country：Japan  

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Event date： 2022.2

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：福岡県   Country：Japan  

Event date： 2022.2

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：福岡県   Country：Japan  

Event date： 2022.2

Language：Japanese  

Venue：福岡県   Country：Japan  

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Event date： 2022.2

Language：Japanese  

Venue：福岡県   Country：Japan  

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Event date： 2021.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京都   Country：Japan  

Event date： 2021.11 - 2022.11

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Event date： 2021.11 - 2022.11

Language：English  

Venue：Fukuoka   Country：Japan  

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Event date： 2021.11

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Event date： 2021.11

Language：English  

Venue：Fukuoka   Country：Japan  

Event date： 2021.10

Language：Japanese  

Venue：福岡県   Country：Japan  

Event date： 2021.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2021.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：佐賀県（オンライン）   Country：Japan  

Event date： 2021.5

Language：English  

Venue：San Francisco（オンライン）   Country：United States  

Event date： 2021.5

Language：English  

Venue：San Francisco（オンライン）   Country：United States  

Event date： 2021.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪府   Country：Japan  

Event date： 2021.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪府   Country：Japan  

Event date： 2021.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪府   Country：Japan  

Event date： 2021.1

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：福岡県   Country：Japan  

Event date： 2020.11

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：福岡県   Country：Japan  

Event date： 2020.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡県   Country：Japan  

Event date： 2020.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡県   Country：Japan  

Event date： 2020.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京都   Country：Japan  

Event date： 2020.10

Language：Japanese  

Venue：東京都   Country：Japan  

Event date： 2020.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京都   Country：Japan  

Event date： 2020.10

Language：Japanese  

Venue：大分県   Country：Japan  

Event date： 2020.10

Language：English   Presentation type：Oral presentation (general)  

Venue：Netherlands   Country：Netherlands  

Event date： 2020.9

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：島根県   Country：Japan  

Event date： 2020.7

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：福岡県   Country：Japan  

Event date： 2020.5 - 2020.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大分   Country：Japan  

Event date： 2020.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2020.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2020.4

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.4

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.4

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.4

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.4

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪府   Country：Japan  

Event date： 2020.2

Language：Japanese  

Venue：福岡県   Country：Japan  

Event date： 2020.2

Language：Japanese  

Venue：福岡   Country：Japan  

Event date： 2019.12 - 2020.6

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2019.11 - 2020.6

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：大阪   Country：Japan  

Event date： 2019.11 - 2020.6

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2019.10 - 2020.6

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2019.10 - 2020.6

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2019.10

Language：Japanese  

Venue：京都   Country：Japan  

Event date： 2019.5 - 2020.6

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2019.5

Language：English  

Venue：Barcelona   Country：Spain  

Event date： 2019.5

Language：English  

Venue：Honolulu   Country：United States  

Event date： 2019.5

Language：English  

Venue：Honolulu   Country：United States  

Event date： 2019.4 - 2019.5

Language：English   Presentation type：Oral presentation (general)  

Venue：Vancouver   Country：Canada  

Event date： 2019.4 - 2019.5

Language：English  

Venue：Vancouver   Country：Canada  

Event date： 2019.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2019.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2019.3

Language：Japanese  

Venue：兵庫   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Seoul   Country：Korea, Republic of  

Event date： 2018.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Fukuoka   Country：Japan  

Event date： 2018.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2018.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2018.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2018.10

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：新潟   Country：Japan  

Event date： 2018.8

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2018.4

Language：English  

Venue：Honolulu   Country：United States  

Event date： 2018.4

Language：English  

Venue：Honolulu   Country：United States  

Event date： 2018.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪   Country：Japan  

Event date： 2018.2

Language：English  

Venue：Hong Kong  

Event date： 2017.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2017.10

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2017.10

Language：Japanese  

Venue：東京   Country：Japan  

Event date： 2017.6

Language：Japanese  

Venue：Baltimore   Country：United States  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Florence   Country：Italy  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都   Country：Japan  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2017.6

Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：東京   Country：Japan  

Event date： 2017.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2017.6

Language：Japanese  

Venue：Baltimore   Country：United States  

Event date： 2017.6

Language：Japanese  

Venue：Baltimore   Country：United States  

Event date： 2016.11

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：京都   Country：Japan  

Event date： 2016.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2016.11

Language：English  

Venue：Chicago   Country：United States  

Event date： 2016.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2016.6

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2016.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Event date： 2014.4

Language：Japanese  

Venue：Tokyo   Country：Japan  

Event date： 2014.4

Language：Japanese  

Venue：Tokyo   Country：Japan  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：仙台   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪   Country：Japan  

Language：Japanese  

Venue：Florida   Country：United States  

Language：Japanese   Presentation type：Oral presentation (general)  

Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan