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三木 明子医学部附属病院 眼科講師
研究活動情報
■ 受賞- 2019年 一般社団法人神緑会田中千賀子学術奨励賞受賞
- 2018年10月 神戸大学, 平成30年度神戸大学優秀若手研究者賞その他の賞
- 2017年05月 ARVO, ARVO HOT TOPICS POSTER AWARD 2018, Association between CFH variants and Choroidal Thickness in Central Serous Chorioretinopathy国際学会・会議・シンポジウム等の賞
- 2016年11月 日本眼科学会, 第120回日本眼科学会学術展示優秀賞, 中心性漿液性脈絡網膜症における脈絡膜厚と補体H因子遺伝子多型の関連解析国内学会・会議・シンポジウム等の賞
- 2015年10月 神戸大学医学部, 平成26年度神戸大学医学部優秀学術論文賞 神戸大学医学部, Common Variants in the Complement Factor H Gene Confer Genetic Susceptibility to Central Serous Chorioretinopathyその他の賞
- 2011年09月 日本緑内障学会, 第２２回緑内障学会学術展示優秀賞, ラット網膜神経節細胞死とアクアポリン9の発現変化の相関国内学会・会議・シンポジウム等の賞
- Central serous chorioretinopathy (CSC) is a major cause of vision loss, especially in middle-aged men, and its chronic subtype can lead to legal blindness. Despite its clinical importance, the underlying mechanisms of CSC need further clarification. In this study, we conducted a meta-analysis of three genome-wide association studies (GWASs) for CSC consisting of 8811 Asians and Caucasians, followed by replication in an additional 4338 Asians. We identified four genome-wide hits, including a novel hit (rs12960630 at LINC01924-CDH7, Pmeta = 2.97 × 10-9). A phenome-wide association study for rs12960630 showed a positive correlation between its CSC risk allele with plasma cortisol concentration. Expression/splicing quantitative trait loci (QTL) analyses showed an association of all these hits with the expression and/or splicing of genes in genital organs, which may explain the sex differences in CSC. Protein QTL also suggested the protein-level contribution of the complement factor H pathway to CSC pathogenesis.2025年03月, Scientific Reports, 15(1) (1), 9158, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (公財)日本眼科学会, 2024年03月, 日本眼科学会雑誌, 128(臨増) (臨増), 174 - 174, 日本語高濃度フィブリノーゲンによるICAM-1経路を介した網膜組織傷害の検討
- PURPOSE: To investigate the incidence of intraocular inflammation (IOI) and its risk factors following intravitreal injections of brolucizumab for neovascular age-related macular degeneration (nAMD) in Japan. METHODS: A total of 1351 Japanese consecutive patients with nAMD who were treated with brolucizumab from May 2020 to May 2022 at 14 institutions were examined. The variables analyzed were the number of brolucizumab injections, time to onset of IOI, and risk factors. RESULTS: IOI developed in 152 eyes (11.3%). Retinal vasculitis and/or retinal occlusion (RV and/or RO) occurred in 53 eyes (3.9%). Ninety-four patients received bilaterally, bilateral IOI occurred in 5 patients (5.3%). Sixteen eyes (1.2%) had irreversible visual acuity loss and nine eyes (0.67%) had visual loss of 3 lines or more due to RV and/or RO. The cumulative IOI incidence was 4.5%, 10.3%, and 12.2% at 30, 180, and 365 days (1-year), respectively. Prior history of IOI (including RV) and/or RO (odds ratio[OR], 5.41; P = 0.0075) and female sex (OR, 1.99; P = 0.0004) were significantly associated with IOI onset. CONCLUSION: The 1-year cumulative incidence of IOI in Japanese nAMD patients treated with brolucizumab was 12.2%. Prior history of IOI (including RV) and/or RO and female sex were significant risk factors.2023年11月, Retina (Philadelphia, Pa.), 英語, 国際誌研究論文（学術雑誌）
- This study investigated aniseikonia after reduced-fluence photodynamic therapy (RFPDT) for central serous chorioretinopathy (CSC). We examined 48 eyes of 48 patients (38 men; mean age, 49.2 ± 9.9 years) with CSC resolved after RFPDT. Horizontal and vertical aniseikonia were measured using the New Aniseikonia Test at baseline, 6 months, and 12 months after RFPDT. The maximum absolute value of the horizontal and vertical measurements indicated the aniseikonia score. The aniseikonia score was 2.2 ± 2.3 at 6 months and 2.2 ± 2.0 at 12 months after RFPDT, both of which improved significantly from the baseline score of 4.1 ± 2.9 (P < 0.05 and P < 0.01, respectively). The 12-month aniseikonia score significantly correlated with the baseline aniseikonia score (P = 0.047), outer nuclear thickness at baseline (P = 0.027) and 12 months after RFPDT (P = 0.014), baseline SRD area (P = 0.005), and ellipsoid zone disruption at 12 months after RFPDT (P = 0.021). In multivariate analysis, baseline serous retinal detachment (SRD) area (P = 0.034) was significantly associated with aniseikonia score at 12 months after RFPDT. Eyes with a larger SRD area might have higher aniseikonia scores even after SRD resolution following RFPDT.2023年10月, Scientific reports, 13(1) (1), 17133 - 17133, 英語, 国際誌研究論文（学術雑誌）
- 眼科臨床紀要会, 2023年09月, 眼科臨床紀要, 16(9) (9), 668 - 669, 日本語コロナ禍における滲出型加齢黄斑変性症患者の外来受診動向 J-CREST(第2報)
- 眼科臨床紀要会, 2023年09月, 眼科臨床紀要, 16(9) (9), 668 - 669, 日本語コロナ禍における滲出型加齢黄斑変性症患者の外来受診動向 J-CREST(第2報)
- 2023年09月, あたらしい眼科, 40(9) (9), 127 - 128アフリベルセプトからファリシマブへの切り替えを契機に網膜色素上皮裂孔を生じた滲出型加齢黄斑変性の一例[査読有り]
- To evaluate the functional and anatomical effects of switching to faricimab for patients with neovascular age-related macular degeneration (nAMD) refractory to intravitreal aflibercept, this retrospective study evaluated patients with nAMD who received intravitreal injections of aflibercept (IVA) every <8 weeks and were switched to faricimab. After switching, the patients were treated with a treatment and extended regimen that started with the interval just before switching and received at least three injections. We evaluated changes in the best-corrected visual acuity (BCVA), central retinal thickness (CRT), central choroidal thickness (CCT), treatment interval, and presence of retinal fluid. Overall, 55 eyes from 55 patients were examined. After three injections of faricimab, the BCVA and CCT did not change significantly. However, the CRT decreased significantly (p < 0.05), the injection interval was significantly extended (7.5 ± 2.3 vs. 5.9 ± 1.5 weeks, p < 0.01), and the rates of the presence of intraretinal fluid and subretinal fluid decreased significantly to 16.4% and 40% of eyes, respectively (both p < 0.01). An ocular adverse event (retinal pigment epithelium tear) developed in one eye. Switching to faricimab was effective for anatomic changes. It may be an additional treatment option for some eyes refractory to IVA.2023年08月, Journal of clinical medicine, 12(15) (15), 英語, 国際誌研究論文（学術雑誌）
- To report the usefulness of intraoperative real-time adjustment of intraocular lens (IOL) tilt during the intrascleral fixation with intraoperative optical coherence tomography (iOCT) as a clinical evaluation and investigate the factors contributing to IOL tilt using iOCT as an experimental evaluation. Retrospective cohort study and experimental research. As a clinical evaluation, the medical records of 43 eyes of 41 patients who underwent intrascleral IOL fixation combined with real-time iOCT observation were retrospectively reviewed. As an experimental evaluation, in order to investigate the factors contributing to IOL tilt, the four experiments were performed using iOCT. The mean IOL tilt angle (°) at the end of surgery and 3 months after surgery were 1.81 ± 1.15 and 2.10 ± 1.66, respectively (p = 0.46). No apparent intra- or postoperative complications occurred during the follow-up period. The experimental evaluation indicated that the IOL tilt was influenced by the insertion angle of the haptic in the vertical direction. The mean IOL tilt angle (°) was 1.94 ± 0.09, 4.67 ± 0.11, 8.90 ± 0.11, and 15.78 ± 0.85 when the insertion angle of the haptic was 0°, 10°, 27.5°, and 45° in the vertical direction, respectively (p < 0.01). Clinical and experimental IOL tilt assessment using iOCT is interactively useful for better quality surgery and better postoperative outcome.2023年07月, Scientific reports, 13(1) (1), 12065 - 12065, 英語, 国際誌研究論文（学術雑誌）
- The appropriate surgical technique to improve the closure rate of perioperative full-thickness macular hole (FTMH) secondary to submacular hemorrhage (SMH) with sub-internal limiting membrane (ILM) hemorrhage caused by retinal arterial macroaneurysm (RAM) rupture remains an unsolved clinical problem. Several ILM transplantation techniques have been attempted, but these are challenging. Our new technique can remove sub-ILM hemorrhage with the central fovea ILM intact, without peeling the ILM. The medical records of three eyes from three patients with SMH and sub-ILM hemorrhage secondary to RAM rupture were retrospectively reviewed. During the surgery, a small ILM fissure was made outside the central fovea with ILM forceps, and sub-ILM hemorrhage was washed out through it by manually spraying balanced salt solution. Sub-ILM hemorrhage removal was achieved successfully in all eyes, with no occurrences of FTMH or other complications. Best-corrected decimal visual acuity improved from 0.05 (Snellen equivalent (SE), 20/400), 0.05 (SE, 20/400), and 0.05 (SE, 20/400) preoperatively to 0.3 (SE, 20/63), 0.4 (SE, 20/50), and 0.15 (SE, 20/125) at 3 months postoperatively, respectively. This new technique may help keep the foveal ILM intact and prevent perioperative FTMH formation.2023年05月, Journal of clinical medicine, 12(9) (9), 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: To investigate the genetic architecture of age-related macular degeneration (AMD) in a Japanese population. DESIGN: Genome-wide association study (GWAS). PARTICIPANTS: Three thousand seven hundred seventy-two patients with AMD and 16 770 control participants from the Japanese population were enrolled in the association analyses. METHODS: We conducted a meta-analysis of 2 independent GWASs that included a total of 2663 patients with AMD and 9471 control participants using the imputation reference panel for genotype imputation specified for the Japanese population (n = 3541). A replication study was performed using an independent set of 1109 patients with AMD and 7299 control participants. MAIN OUTCOME MEASURES: Associations of genetic variants with AMD. RESULTS: A meta-analysis of the 2 GWASs identified 6 loci significantly associated with AMD (P < 5.0 × 10-8). Of these loci, 4 were known to be associated with AMD (CFH, C2/FB, TNFRSF10A, and ARMS2), and 2 were novel (rs4147157 near WBP1L and rs76228488 near GATA5). The newly identified associations were confirmed in a replication study (P < 0.01). After the meta-analysis of all datasets, we observed strong associations in these loci (P = 1.88 × 10-12 and P = 1.35 × 10-9 for meta-analysis for rs4147157 and rs76228488, respectively). When we looked up the associations in the reported central serous chorioretinopathy (CSC) GWAS conducted in the Japanese population, both loci were associated significantly with CSC (P = 4.86 × 10-3 and P = 4.28 × 10-3 for rs4147157 and rs76228488, respectively). We performed a genetic colocalization analysis for these loci and estimated that the posterior probabilities of shared causal variants between AMD and CSC were 0.39 and 0.60 for WBP1L and GATA5, respectively. Genetic correlation analysis focusing on the epidemiologically suggested clinical risk factors implicated shared polygenic architecture between AMD and smoking cessation (rg [the measure of genetic correlation] = -0.33; P = 0.01; false discovery rate, 0.099). CONCLUSIONS: Our findings imply shared genetic components conferring the risk of both AMD and CSC. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.2023年04月, Ophthalmology, 130(4) (4), 361 - 372, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: The aim of this study is to explore the clinical features and associated factors of intraocular inflammation (IOI) following intravitreal brolucizumab (IVBr) administration for neovascular age-related macular degeneration (nAMD). METHODS: This retrospective study included 87 eyes from 87 Japanese patients with nAMD who were followed up for 5 months after the initial administration of IVBr as switching therapy. Clinical pictures of IOI post-IVBr and changes in best corrected visual acuity (BCVA) at 5 months were evaluated between eyes with and without IOI (non-IOI). The association between IOI and baseline factors (age, sex, BCVA, hypertension, and/or arteriosclerotic changes in the fundus, subretinal hyperreflective material [SHRM], and macular atrophy) was evaluated. RESULTS: Of the 87 eyes, 18 (20.6%) developed IOI and 2 (2.3%) developed retinal artery occlusion. There were 9 (50%) cases of posterior or pan-uveitis among eyes with IOI. The mean interval from initial IVBr administration to IOI was 2 months. The mean changes in logMAR BCVA at 5 months were significantly worse in IOI eyes than in non-IOI eyes (0.09 ± 0.22 vs. - 0.01 ± 0.15, P = 0.03). There were 8 (44.4%) and 7 (10.1%) cases of macular atrophy and 11 (61.1%) and 13 (18.8%) cases of SHRM in the IOI and non-IOI groups, respectively. SHRM and macular atrophy were significantly associated with IOI (P = 0.0008 and P = 0.002, respectively). CONCLUSION: In IVBr therapy for nAMD, eyes with SHRM and/or macular atrophy should be observed more meticulously, given the increased risk of developing IOI, which is associated with insufficient BCVA gain.2023年03月, Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 261(8) (8), 2359 - 2366, 英語, 国際誌研究論文（学術雑誌）
- Background and Objectives: Faricimab is a novel bispecific antibody with Fab regions inhibiting both vascular endothelial growth factor-A and angiopoietin-2. Therefore, this study aimed to obtain short-term outcomes of intravitreal injection of faricimab (IVF) for the treatment of diabetic macular edema (DME) in daily clinical practice. Materials and Methods: A retrospective review was carried out on consecutive patients with DME who had been treated with IVF and were followed up for at least 1 month. Outcome measures included changes in logMAR best-corrected visual acuity (logMAR BCVA), central retinal thickness (CRT), number of IVF administrations, and safety. Clinical outcomes were also compared between the treatment-naïve and switch groups. Results: A total of 21 consecutive DME eyes from 19 patients were identified. The mean number of IVFs was 1.6 ± 0.8 during the mean follow-up time of 5.5 months. The overall mean logMAR BCVA following IVF was 0.236, 0.204, 0.190, and 0.224 at baseline, 1, 3, and 6 months, respectively, without a significant change from baseline to 1 month (p = 0.176) or for 6 months (p = 0.923). The overall mean CRT (μm) following IVF was 400.6, 346.6, 342.1, and 327.5 at baseline, 1, 3, and 6 months, respectively. CRT significantly decreased from baseline to 1 month (p = 0.001) but did not reach a significant level over 6 months following IVF (p = 0.070). No significant difference in BCVA or CRT was observed between the treatment-naïve and switch groups. No serious safety concerns were noted. Conclusions: IVF for the treatment of DME may preserve visual acuity and improve macular thickness without serious safety concerns in the short term in a real-world clinical setting.2023年03月, Medicina (Kaunas, Lithuania), 59(4) (4), 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: We investigated potential risk factors for visual prognosis in Japanese patients with exogenous endophthalmitis. METHODS: In this retrospective observational multicenter cohort study, risk factors for legal blindness at 12 weeks after treatment initiation were evaluated based on patient characteristics, initial BCVA, causative events, pathogens, ocular symptoms, duration from symptom onset to initial treatment, and selected treatments. RESULTS: Overall, 23.1% of eyes developed legal blindness. The six risk factors for legal blindness were presence of eye pain, pathogen identification, poor BCVA at the initial visit, longer duration from symptom onset to initial treatment, type of causative event, and type of causative pathogen. Regarding the type of causative pathogen, coagulase-negative staphylococci was associated with a better visual impairment outcome. CONCLUSION: Exogenous endophthalmitis remains a severe ocular infection; however, it can be managed with rapid treatment, as well as other advances in medical knowledge and technology.2023年01月, Ocular immunology and inflammation, 1 - 9, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: To compare the two-year outcome of half-time photodynamic therapy (htPDT) in chronic central serous chorioretinopathy (cCSC) with and without choroidal neovascularization (CNV). METHODS: In this retrospective study, we included 88 eyes of 88 patients with cCSC who underwent htPDT and were followed up for more than 24 months. Patients were divided into two groups with (21 eyes) or without (67 eyes) CNV before htPDT treatment. The best-corrected visual acuity (BCVA), central retinal thickness (CRT), subfoveal choroidal thickness (SCT), and the presence of subretinal fluid (SRF) were evaluated at baseline and at 1, 3, 6, 12, and 24 months after PDT. RESULTS: A significant intergroup difference was noted in terms of age (P = 0.038). Significant improvements in the BCVA and SCT were found at all time points in eyes without CNV but only at 24 months in eyes with CNV. CRT was significantly reduced in both groups at all time points. No significant intergroup differences were noted in terms of BCVA, SCT and CRT at all time points. There were significant differences in the rate of recurrent and persistent SRF between groups (22.4% (without CNV) vs. 52.4% (with CNV), P = 0.013, and 26.9% (without CNV) vs. 57.1% (with CNV), P = 0.017, respectively). The presence of CNV was significantly associated with the recurrence and persistence of SRF after initial PDT (P = 0.007 and 0.028, respectively). Logistic regression analyses showed that the baseline BCVA, and not the presence of CNV, was significantly associated with BCVA at 24 months after initial PDT (P < 0.01). CONCLUSIONS: A htPDT for cCSC was less effective in eyes with CNV than in those without CNV regarding the recurrence and persistence of SRF. Additional treatment might be required in eyes with CNV during 24-month follow-up periods.2023年, PloS one, 18(5) (5), e0284979, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: To investigate potential clinical and multimodal imaging factors in central serous chorioretinopathy (CSC) recurrence. METHODS: The study was performed at nine Japanese medical institutions for patients who had experienced an active CSC episode. Demographic data and medical history were reviewed retrospectively. Significant differences in chronic manifestation, leakage site, leakage point number, leakage intensity, choroidal hyperpermeability, central retinal thickness (CRT) and subfoveal choroidal thickness were analysed between the recurrence and non-recurrence groups. RESULTS: In total, 538 eyes (538 patients) diagnosed with CSC (402 men, 136 women; mean age: 53.4 ± 11.9 years) were enrolled. Among them, 253 eyes (47.0%) developed ≥1 recurrence (follow-up: 15.9 ± 13.5 months, range 3-86 months). Univariate and multivariate analyses indicated that a history of corticosteroid use (odds ratio [OR], 5.52; 95% confidence interval [CI], 1.39-21.92; p = 0.015), bilateral disease (OR, 3.94; 95% CI, 1.47-10.6; p = 0.007), chronic manifestations (OR, 7.12; 95% CI, 2.93-17.28; p < 0.001), non-intense fluorescein leakage (OR, 3.34; 95% CI, 1.44-7.75; p = 0.005) and initial CRT (OR, 0.997; 95% CI, 0.993-0.999; p = 0.049) were significantly associated with CSC recurrence. Receiver operating characteristic curves were created, and the area under the curve for the multivariate logistic regression model of these five factors was 0.814. CONCLUSION: Patients with CSC who received corticosteroids and had bilateral disease, chronic manifestation, non-intense fluorescein leakage on fluorescein angiography or a relatively thinner CRT should be closely monitored to identify whether they are at high risk of recurrence.2022年12月, Acta ophthalmologica, 100(8) (8), e1729-e1736, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: To report the usefulness of a new surgical method using intraoperative optical coherence tomography that can more accurately place the buckling material for scleral buckling using a noncontact wide-angle viewing system with a cannula-based chandelier endoilluminator for the treatment of rhegmatogenous retinal detachment. METHODS: The medical records of 12 eyes of 11 patients with rhegmatogenous retinal detachment treated with scleral buckling combined with real-time intraoperative optical coherence tomography observation were retrospectively reviewed. RESULTS: Real-time observations of the positional relationship between the protrusion of buckling material and retinal breaks with intraoperative optical coherence tomography revealed that retinal breaks were not properly placed on the protrusion of the buckling material in five eyes, requiring the intraoperative repositioning of the buckling material. Eventually, the scleral buckling combined with real-time intraoperative optical coherence tomography observation yielded the initial anatomical success rates of 100% without noteworthy intraoperative or postoperative complications. CONCLUSION: This procedure is a novel approach that enables safer and more accurate placement of the buckling material and may contribute to improving the outcomes of scleral buckling in the future.2022年12月, Retina (Philadelphia, Pa.), 42(12) (12), 2395 - 2400, 英語, 国際誌研究論文（学術雑誌）
- Laser therapy is the most effective treatment considered for retinopathy of prematurity (ROP). We compared the foveal morphology of the retina in eyes with a history of ROP to that of full-term children. This cross-sectional comparative study included 74 patients with a history of ROP, aged 4-6 years. Among them, 41 underwent laser treatment for ROP. The clinical findings and retinal morphology in these patients were compared to that of 33 patients who had spontaneous ROP regression and 30 age-matched full-term controls. All the patients with ROP had 20/40 or better best-corrected visual acuity (BCVA). The foveal thickness was significantly thicker in laser-treated ROP eyes than in regressed ROP eyes and controls. The outer nuclear layer was significantly thicker, and the inner segment (IS) of the photoreceptors and the inner retinal layer were significantly thicker in the laser-treated ROP eyes than that in the control eyes. In the patients with ROP and controls, better BCVA was associated positively with deeper foveal depression, which was associated with a later gestational age. Our results suggest that prematurity and laser treatment affect the foveal morphology and BCVA.2022年09月, Scientific reports, 12(1) (1), 16431 - 16431, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: We investigated potential predictive factors for visual prognosis in Japanese patients with endogenous endophthalmitis. DESIGN: Retrospective observational multicenter cohort study. METHODS: We examined the characteristics of 77 Japanese patients with endogenous endophthalmitis and performed statistical analyses of these real-world data. The primary endpoint was the identification of factors associated with visual prognosis. We examined differences between patients in the better vision and legal blindness groups at 12 weeks after treatment initiation. RESULTS: The five risk factors for visual impairment at 12 weeks after treatment initiation were presence of pressure injuries, severe clinical symptoms (presence of eye pain and ciliary injection), pathogen identification, and poor best-corrected visual acuity at baseline. Staphylococcus aureus and fungus were associated with a better visual impairment outcome. CONCLUSIONS: Endogenous endophthalmitis remains a severe ocular infection; however, it can be managed with rapid treatments, as well as other advances in medical knowledge and technology.2022年08月, Ocular immunology and inflammation, 1 - 8, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: To describe angiographic features of a case of delayed-onset retinal vascular occlusion and intraocular inflammation (IOI) following brolucizumab intravitreal injection (IVI). OBSERVATIONS: A 75-year-old woman with advanced age-related macular degeneration (AMD) complained of persistent distorted vision despite 1 aflibercept 2-mg IVI and subsequent 1 brolucizumab 6-mg IVI. At 20 days after brolucizumab IVI, clinical examination showed no signs of IOI, her right best-corrected visual acuity (BCVA) was 1.0 (Snellen equivalent, 20/20). Simultaneous fluorescein and indocyanine green angiography (FA/IA) performed 2 days later showed no abnormalities, but she noticed floaters and decreased vision in her right eye 5-6 hours after FA/IA. At 44 days after brolucizumab IVI, her right BCVA was 0.6 (Snellen equivalent, 20/33), and clinical examination revealed mutton-fat keratic precipitates, anterior chamber cells (2+), vitreous cells, vitreous haze (1+), and sheathed retinal vessels. FA showed filling defect and vascular staining/leakage at several retinal arteries and dye leakage from optic disc edge, where IA demonstrated dye staining as well. However, there was a retinal artery occlusion site which lacks angiographic signs indicative of active retinal vasculitis. The patient was diagnosed with retinal vascular occlusion and IOI which occurred approximately 3 weeks after brolucizumab IVI. CONCLUSIONS AND IMPORTANCE: Delayed brolucizumab-associated retinal vascular occlusion and IOI can develop from a condition in which no apparent abnormal findings exist on FA/IA. Together with the fact that angiographic signs observed in this case were not severe enough to induce retinal artery occlusion, potent and prolonged vascular endothelial growth factor inhibition by brolucizumab IVI might have caused severe damage to retinal vascular endothelial cells. Then, the damage subsequently led to retinal vascular occlusions and enhanced immune reaction to brolucizumab. The latter would be enhanced through the migration of immune cells towards vitreous cavity being allowed by disrupted inner blood retinal barrier.2022年06月, American journal of ophthalmology case reports, 26, 101521 - 101521, 英語, 国際誌
- PURPOSE: To identify susceptibility genes for macular neovascularization (MNV) development in central serous chorioretinopathy (CSC). DESIGN: Genome-wide survival analysis using a longitudinal cohort study. PARTICIPANTS: We included 402 and 137 patients with CSC but without MNV at their first visit from the Kyoto CSC Cohort and Kobe CSC dataset, respectively. All patients underwent detailed ophthalmologic examinations, including multimodal imaging, such as fundus autofluorescence, spectral-domain optical coherence tomography, and fluorescein angiography/indocyanine green angiography and/or optimal coherence tomography angiography. METHODS: We conducted a genome-wide survival analysis using the Kyoto CSC Cohort. We applied the Cox proportional hazard model to adjust for age, sex, and the first principal component. Single nucleotide polymorphisms (SNPs) with P-values <1.0×10-5 were carried forward to the replication in the Kobe CSC dataset. Moreover, we evaluated the contribution of previously-reported age-related macular degeneration (AMD) susceptibility loci. We used FUMA and ToppFun for the functional enrichment analysis. MAIN OUTCOME MEASURES: The association between SNPs and MNV development in patients with CSC. RESULTS: Rs370974631 near ARMS2 displayed a genome-wide significant association in the meta-analysis of discovery and replication result (hazard ratio [HR]meta = 3.63; Pmeta = 5.76×10-9). Among previously-reported AMD susceptibility loci, we additionally identified CFH rs800292 (HR = 0.39, P = 2.55×10-4), COL4A3 rs4276018 (HR = 0.26, P = 1.56×10-3), and B3GALTL rs9564692 (HR = 0.56, P = 8.30×10-3) as susceptibility loci for MNV development in CSC. The functional enrichment analysis revealed significant enrichment of eight pathways (GO:0051561, GO:0036444, GO:0008282, GO:1990246, GO:0015272, GO:0030955, GO:0031420, and GO:0005242) related to ion transport. CONCLUSIONS: ARMS2, CFH, COL4A3, and B3GALTL were identified as susceptibility genes for MNV development in CSC. The aforementioned four genes are known as susceptibility genes for AMD, whereas COL4A3 and B3GALTL were previously reported to be polypoidal choroidal vasculopathy (PCV)-specific susceptibility genes. Our findings revealed the shared genetic susceptibility between PCV and MNV secondary to CSC.2022年04月, Ophthalmology, 129(9) (9), 1034 - 1042, 英語, 国際誌研究論文（学術雑誌）
- OBJECTIVE: To identify the risk factors and characteristics of central serous chorioretinopathy (CSC) with subsequent macular neovascularisation (MNV) detected on optical coherence tomography angiography (OCTA). METHODS AND ANALYSIS: We included patients from six institutions who were initially diagnosed with CSC and subsequently did or did not develop MNV detected by OCTA. Potential influencing factors were identified by evaluating the patients' baseline demographics, multimodal fundus imaging, treatment options, recurrence and outcomes in both groups. RESULTS: We enrolled 176 eyes in 152 patients (112 men, 40 women; mean age: 52.1±10.4 years) with a mean follow-up of 30.4±16.3 months. Secondary MNV was present in 23 eyes (13.1%), and non-MNV was observed in 153 eyes (86.9%) by OCTA. Multivariate analysis revealed that older age (OR 1.06; 95% CI 1.01 to 1.11; p=0.014), chronic CSC (OR 3.05; 95% CI 1.12 to 8.30; p=0.029), leakage sites within the fovea on fluorescein angiography (OR 7.60; 95% CI, 1.89 to 30.48; p=0.004) and recurrent fluid within the first year (OR 5.12; 95% CI 1.66 to 15.77; p=0.012) were risk factors for subsequent MNV. Moreover, eyes with CSC complicated with MNV were characterised by poor visual acuity and low complete fluid resolution rates. CONCLUSION: The factors associated with MNV secondary to CSC were older age, higher rates of chronic CSC and recurrence, and foveal leakage points on fluorescein angiography.2022年04月, BMJ open ophthalmology, 7(1) (1), 英語, 国際誌研究論文（学術雑誌）
- To investigate the incidence and risk of advanced age-related macular degeneration (AMD), including geographic atrophy (GA) and macular neovascularization (MNV), in eyes with drusenoid pigment epithelial detachment (PED). Eighty-five eyes with drusenoid PED from 85 patients (77.2 ± 7.0 years, male/female: 44/41) were included in this study. Patients were followed up every 1-3 months via spectral-domain optical coherence tomography (SD-OCT) and color fundus photography. If exudation was observed on SD-OCT, fluorescein and indocyanine green angiography were performed to confirm the MNV subtype accordingly. The maximum follow-up period was 60 months. During the study period, GA developed in 8 eyes while MNV also developed in 8 eyes. The Kaplan-Meier estimator revealed that the cumulative incidence for 60 months was 17.9% and 12.2% for GA and MNV, respectively. In eyes developing MNV, retinal angiomatous proliferation was the most common. Cox regression analysis revealed that baseline PED width was the only factor associated with advanced AMD. (p = 0.0026, Cox regression analysis). The 5-year cumulative incidence of advanced AMD, including GA and MNV, was approximately 30% in eyes with drusenoid PED among the Japanese elderly. A larger baseline PED width was the only risk factor for advanced AMD.2022年03月, Scientific reports, 12(1) (1), 4715 - 4715, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: To investigate the clinical features, treatment options, and visual outcomes of submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (nAMD). DESIGN: A retrospective, observational case series. METHODS: Setting: Multicenter institutional setting. Patient Population: A total of 127 patients (127 eyes; 88 men, 39 women; (mean age, 74.2 years)) diagnosed with AMD-associated SMHs exceeding 2 disc diameters involving the fovea. Observation: The AMD types, previous treatments, treatment options, anatomic findings, and best-corrected visual acuity (BCVA) were assessed. Main Outcome Measures: Clinical features, treatment options, and visual outcomes of SMHs secondary to nAMD. RESULTS: Thirty-two eyes had typical AMD, 94 eyes polypoidal choroidal vasculopathy (PCV), and one eye retinal angiomatous proliferation. Eighty-five eyes were treatment-naïve; 42 eyes were treated previously: anti-vascular endothelial growth factor (VEGF) therapy (n = 26), photodynamic therapy (n = 3), and combined therapy (n = 13). Treatment of SMHs included vitrectomy (36 eyes), pneumatic displacement (49 eyes), and anti-VEGF monotherapy (42 eyes). The final BCVA improved significantly in treatment-naïve cases from 0.86 to 0.62 logarithm of the minimal angle of resolution (logMAR) unit (Snellen equivalent from 20/145 to 20/83) and from 0.80 to 0.56 (Snellen equivalent from 20/126 to 20/73) in PCV cases. Meanwhile, the BCVA logMAR values improved from 1.15 to 0.75 (Snellen equivalent from 20/283 to 20/112) and from 0.87 to 0.63 (Snellen equivalent from 20/148 to 20/85) in eyes that underwent vitrectomy or pneumatic displacement, respectively. In eyes with BCVAs between 20/133 to 20/40 at SMH onset, the final VA in the pneumatic displacement group was better than in the anti-VEGF monotherapy group. One eye had a retinal detachment and 1 eye had a macular hole in the vitrectomy group, and 5 eyes had a vitreous hemorrhage in the pneumatic displacement group. CONCLUSIONS: The recommended treatment for SMHs secondary to nAMD exceeding 2 disc area and with BCVA below 20/40 is vitrectomy or pneumatic displacement for visual improvement.2022年, PloS one, 17(7) (7), e0271447, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: To evaluate the clinical characteristics, treatment trends, and visual prognosis of submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (nAMD) and retinal arterial macroaneurysm (RAM). METHODS: This retrospective study enrolled 187 Japanese patients with SMH at 10 institutions from 2015 to 2018. Medical records including SMH etiology, best-corrected visual acuity (BCVA), fundus photographs, optical coherence tomography images, and selected treatments were analyzed. RESULTS: Major causes of SMH were typical nAMD (tnAMD) (18%), polypoidal choroidal vasculopathy (PCV) (50%) and RAM (29%). Age, male/female ratio, baseline BCVA, central retinal thickness, and involved retinal layers were significantly different between etiologies (all P<0.0001). Treatment with anti-vascular endothelial growth factor drugs with and without intravitreal gas injection was chosen for half of eyes in the tnAMD and PCV groups, whereas vitrectomy was performed in 83.7% of eyes with RAM. The final BCVA improved significantly from baseline in the PCV and RAM groups (P = 0.0009, P<0.0001) and final BCVA was significantly better in the PCV group at a level similar to the other groups (P = 0.0007, P = 0.0008). BCVA improvement from baseline was significantly greater in the RAM group compared with the tnAMD (P = 0.0152) and PCV (P = 0.017) groups. Multivariate analysis revealed better final BCVA was significantly associated with younger age (P = 0.0054), better baseline BCVA (P = 0.0021), RAM subtype (P = 0.0446), and no tnAMD (P = 0.001). CONCLUSIONS: The characteristics of, and treatment strategy for, SMH were different between the underlying diseases. Anti-vascular endothelial growth factor treatment with or without expansile gas was mainly chosen for SMH in tnAMD and PCV, whereas vitrectomy with gas was the most common treatment for RAM, and the higher rate for vitrectomy might result in the greater BCVA improvement in the RAM group than in the other groups. Final BCVA was better in PCV, RAM, and tnAMD, in that order, because patients with PCV were younger and had better baseline BCVA.2022年, PloS one, 17(9) (9), e0274508, 英語, 国際誌研究論文（学術雑誌）
- To demonstrate the long-term effect of cystotomy with or without fibrinogen clot removal for treatment-resistant cystoid macular edema (CME) secondary to branch retinal vein occlusion (BRVO). Retrospective clinical study. We retrospectively analyzed medical records of 22 eyes of 22 patients with treatment-resistant CME secondary to BRVO with 12 months observation after cystotomy with or without fibrinogen clot removal. Patients included 11 women and 11 men. The mean ± SD age was 72.7 ± 10.2 years. LogMAR-converted best corrected visual acuity (BCVA) was statistically better at 12 months after surgery (0.30 ± 0.30) than preoperative BCVA (0.39 ± 0.27) (p = 0.01). The central sensitivity of microperimetry (dB) was maintained during follow-up (preoperative sensitivity: 25.4 ± 4.1, postoperative sensitivity at 12 months after the surgery: 25.9 ± 4.2, p = 0.69). Twelve months after surgery, there was a significant improvement in the central retinal thickness (CRT) on optical coherence tomography (OCT) (303.7 ± 80.1) (μm) compared with the preoperative CRT (524.2 ± 114.8) (p < 0.01). In 12 months, CME recurred in 3 of 22 eyes. The preoperative reflectivity in cystoid cavity on OCT was significantly higher in patients with fibrinogen clot removal (n = 5) than in patients without fibrinogen clot removal (n = 17) (p < 0.01). For treatment-resistant CME secondary to BRVO, Cystotomy with or without fibrinogen clot removal may be one of the treatment options.2021年04月, Scientific reports, 11(1) (1), 8460 - 8460, 英語, 国際誌研究論文（学術雑誌）
- Few studies report drusenoid pigment epithelial detachment (DPED) in Asians. In this multicenter study, we report the clinical and genetic characteristics of 76 patients with DPED, and, for comparison, 861 patients with exudative age-related macular degeneration (AMD) were included. On the initial presentation, the mean best-corrected visual acuity was 0.087 ± 0.17 (logMAR unit), and mean DPED height and width were 210 ± 132 and 1633 ± 1114 µm, respectively. Fifty-one (67%) patients showed macular neovascularization in the contralateral eye. The risk allele frequency of both ARMS2 A69S and CFH I62V was significantly higher in DPED than in typical AMD and polypoidal choroidal vasculopathy (PCV) (ARMS2 A69S risk allele frequency: DPED 77% vs. typical AMD 66% vs. PCV 57%, CFH I62V risk allele frequency: DPED 87% vs. typical AMD 73% vs. PCV 73%), although the risk allele frequency of both genes was similar between the DPED group and retinal angiomatous proliferation (RAP) group (ARMS2 A69S: p = 0.32, CFH I62V, p = 0.11). The prevalence of reticular pseudodrusen (RPD) was highest in RAP (60%), followed by DPED (22%), typical AMD (20%), and PCV (2%). Although the prevalence of RPD differs between DPED and RAP, these entities share a similar genetic background in terms of ARMS2 and CFH genes.2021年04月, International journal of molecular sciences, 22(8) (8), 英語, 国際誌研究論文（学術雑誌）
- Specific postoperative complications, such as tube exposure and conjunctival erosion, have occurred despite the favorable surgical outcomes of tube shunt surgeries for refractory glaucoma. The new autologous scleral pocket technique is performed by inserting the tube into the vitreous cavity without using a donor scleral patch. The purpose of this study was to evaluate the surgical results of Ahmed glaucoma valve (AGV) implantation using this technique for neovascular glaucoma (NVG), which is one of the representative refractory types of glaucoma. This observational retrospective case series included 15 consecutive eyes of 15 patients with NVG who had undergone AGV implantation at Kobe University between January 2018 and December 2019. The mean preoperative intraocular pressure (IOP) was 37.2 ± 13.8 mmHg and the glaucoma drug score was 4.2 ± 2.2. The mean IOP and glaucoma drug score at 1 year postoperatively decreased to 15.0 ± 4.6 mmHg and 1.3 ± 2.0, respectively (p < 0.001). No significant change in the corneal endothelial cell density following surgery was observed (p = 0.09); however, one patient required an additional trabeculectomy at 7 months postoperatively. No cases of tube exposure or conjunctival erosion were observed at 1 year postoperatively. These results indicated the effectiveness and safety of this technique in patients with NVG.2021年04月, Journal of clinical medicine, 10(8) (8), 英語, 国際誌研究論文（学術雑誌）
- This retrospective study was conducted to investigate the clinical factors associated with low-contrast visual acuity after reduced-fluence photodynamic therapy (RFPDT) in patients with resolved central serous chorioretinopathy (CSC) and good baseline visual acuity. A total of 45 eyes of 45 patients with resolved CSC at post-RFPDT and best-corrected visual acuity of >1.0 (logarithm of the minimal angle of resolution [logMAR], 0) at baseline were examined. Visual acuities of both eyes were measured at four contrast levels (100%, 25%, 12%, and 6%) at post-RFPDT. The low-contrast visual acuity (6%, 12%, and 25%) was significantly lower than the 100% contrast visual acuity in the affected eyes. Visual acuities of affected eyes were significantly worse than those of fellow eyes at any contrast levels. The degree of changes in 6% and 100% contrast visual acuities was significantly greater in affected eyes than that in fellow eyes (p < 0.05). The 6% contrast visual acuities in affected eyes at post-RFPDT were significantly associated with the symptom duration (p < 0.05). Patients with a long duration of symptoms might have disturbed low-contrast visual acuities at post-RFPDT even if their baseline visual acuities were good.2021年03月, Pharmaceuticals (Basel, Switzerland), 14(4) (4), 英語, 国際誌研究論文（学術雑誌）
- Bacterial endophthalmitis is an intraocular infection that causes rapid vison loss. Pathogens can infect the intraocular space directly (exogenous endophthalmitis (ExE)) or indirectly (endogenous endophthalmitis (EnE)). To identify predictive factors for the visual prognosis of Japanese patients with bacterial endophthalmitis, we retrospectively examined the bacterial endophthalmitis characteristics of 314 Japanese patients and performed statistics using these clinical data. Older patients, with significantly more severe clinical symptoms, were prevalent in the ExE group compared with the EnE group. However, the final best-corrected visual acuity (BCVA) was not significantly different between the ExE and EnE groups. Bacteria isolated from patients were not associated with age, sex, or presence of eye symptoms. Genus Streptococcus, Streptococcus pneumoniae, and Enterococcus were more prevalent in ExE patients than EnE patients and contributed to poor final BCVA. The presence of eye pain, bacterial identification, and poor BCVA at baseline were risk factors for final visual impairment.2021年03月, Pathogens (Basel, Switzerland), 10(4) (4), 英語, 国際誌研究論文（学術雑誌）
- Multidrug resistance protein 4 (MRP4) is an energy-dependent membrane transporter responsible for cellular efflux of a broad range of xenobiotics and physiological substrates. In this trial, we aimed to investigate the coeffects of aging and MRP4 deficiency using gene expression microarray and morphological and electrophysiological analyses of mouse retinas. Mrp4-knockout (null) mice and wild-type (WT) mice were reared in the same conditions to 8-12 weeks (young) or 45-55 weeks (aged). Microarray analysis identified 186 differently expressed genes from the retinas of aged Mrp4-null mice as compared to aged WT mice, and subsequent gene ontology and KEGG pathway analyses showed that differently expressed genes were related to lens, eye development, vision and transcellular barrier functions that are involved in metabolic pathways or viral infection pathways. No significant change in thickness was observed for each retinal layer among young/aged WT mice and young/aged Mrp4-null mice. Moreover, immunohistochemical analyses of retinal cell type did not exhibit an overt change in the cellular morphology or distribution among the four age/genotype groups, and the electroretinogram responses showed no significant differences in the amplitude or the latency between aged WT mice and aged Mrp4-null mice. Aging would be an insufficient stress to cause some damage to the retina in the presence of MRP4 deficiency.2021年03月, Antioxidants (Basel, Switzerland), 10(3) (3), 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: To report the case of a patient with cystoid macular edema (CME) secondary to idiopathic macular telangiectasia (MacTel) type 1, which was successfully treated by cystotomy and en bloc removal of the fibrinogen-rich component of the cystoid lesion. PATIENTS: A 80-year-old man was referred to our department because of a visual defect in his right eye. His best corrected decimal visual acuity (BCVA) was 0.7 (Snellen equivalent [SE], 20/30). METHODS: A fundus examination revealed clustered temporal juxafoveal microaneurysms and foveal CME. The patient refused to undergo conventional treatments, including direct retinal photocoagulation for microaneurysms, intravitreal anti-vascular endothelial growth factor injection, and intravitreal triamcinolone injection. However, he provided consent to undergo cystotomy and en bloc removal of the fibrinogen-rich component of the cystoid lesion. RESULTS: His BCVA was 0.2 (SE, 20/100) just before the surgery. A 27-gauge vitrectomy with internal limiting membrane peeling was performed. Cystotomy was performed during the surgery, and the fibrinogen clot visible in the cystoid cavity was also removed. CME rapidly disappeared after the surgery. Three years postoperatively, the patient had BCVA of 0.5 (SE, 20/40) at the last medical examination, and the CME had not recurred. CONCLUSION: Cystotomy and en bloc removal of the fibrinogen-rich component of the cystoid lesion could be valid treatment options for CME secondary to MacTel type 1.2021年01月, Retinal cases & brief reports, Publish Ahead of Print, 英語, 国際誌研究論文（学術雑誌）
- PURPOSE: To investigate clinical factors contributing to metamorphopsia after 27-gauge pars plana vitrectomy (27GPPV) for primary rhegmatogenous retinal detachment (RRD) to reveal whether the proximity of the preoperative retinal detachment to the fovea is associated with postoperative metamorphopsia. METHODS: We retrospectively reviewed medical records of 77 eyes of 77 patients after 27GPPV for RRD. Patients were subdivided into three groups using optical coherence tomography findings: Group A, patients with RRD outside the vascular arcade; Group B, patients whose condition was present within the vascular arcade, but without foveal detachment; and Group C, patients with foveal detachment. RESULTS: The average metamorphopsia score (°) assessed with M-charts 12 months after surgery was 0.01 ± 0.04 in Group A (24 eyes), 0.08 ± 0.18 in Group B (20 eyes), and 0.49 ± 0.48 in Group C (33 eyes) (p<0.001). Logistic regression analysis revealed that metamorphopsia at 12 months after surgery significantly correlated with the proximity of the retinal detachment to the fovea (p = 0.007). CONCLUSION: Metamorphopsia after 27GPPV for RRD correlated with the proximity of the preoperative retinal detachment to the fovea. Attention should be paid to the possibility of postoperative metamorphopsia development when retinal detachment is present within a vascular arcade even if the fovea is not involved.2021年, PloS one, 16(10) (10), e0258775, 英語, 国際誌研究論文（学術雑誌）
- This multicenter retrospective study was conducted to evaluate the 1-year treatment outcome of photodynamic therapy (PDT) combined with anti-vascular endothelial growth factor (VEGF) therapy for pachychoroid neovasculopathy (PNV). A total of 42 eyes of 42 patients with treatment-naïve PNV who were treated with PDT combined with intravitreal injections of an anti-VEGF agent (ranibizumab or aflibercept) for 1 year. All eyes showed exudative and/or hemorrhagic changes that affected the fovea at baseline. After the initial combination therapy, subfoveal choroidal thickness (SCT) and central retinal thickness (CRT) were significantly reduced and were maintained as such for 12 months (P < 0.01 in SCT and CRT). The best-corrected visual acuity (BCVA) (0.19 ± 0.30 at baseline) significantly improved at 3 months (0.15 ± 0.29, P < 0.05) and further improved at 12 months (0.10 ± 0.30, P < 0.01) when compared to that at baseline. After the initial combination therapy, 32 eyes (76.2%) required no additional treatments for 12 months. The mean number of additional PDT and intravitreal injections of anti-VEGF agents was 0.1 ± 0.3 and 0.9 ± 1.9, respectively. Of the 42 eyes included in this study, 22 eyes (52.4%) had polypoidal lesions at baseline. No significant differences in SCT, CRT, or BCVA were observed at any time points between eyes with and without polypoidal lesions. Of 20 eyes without polypoidal lesions, only 1 eye (5.0%) needed additional treatments. PNV, especially without polypoidal lesions, can be treated effectively with PDT combined with anti-VEGF therapy with few sessions.2021年, PloS one, 16(3) (3), e0248760, 英語, 国際誌研究論文（学術雑誌）
- 2020年12月, Pediatrics and neonatology, 61(6) (6), 665 - 666, 英語, 国際誌[査読有り]
- PURPOSE: To show surgical results of the intraoperative three-dimensional fluorescein angiography (3D-FA)-guided pars plana vitrectomy (PPV) for branch retinal vein occlusion (BRVO) with vitreous hemorrhage (VH) and neovascularization elsewhere (NVE). METHODS: The NGENUITY 3D ® visualization system was used for the digital assisted vitrectomy (DAV). 3D-FA-guided PPV was performed in three patients with BRVO with VH and NVE. PATIENTS: 3 eyes with BRVO with VH and NVE RESULTS:: In all eyes, the scatter retinal photocoagulations for nonperfusion area (NPA), depicted as hypofluorescein, and the segmentation and delamination of perivascular fibrovascular proliferative membrane, depicted as hyperfluorescein, could be safely performed on the same screen while implementing intraoperative 3D-FA. CONCLUSIONS: 3D-FA-guided PPV, a novel approach that fully utilizes the advantages of DAV, can be one of useful techniques for the treatment of BRVO with VH and NVE.2020年11月, Retinal cases & brief reports, 16(6) (6), 802 - 805, 英語, 国際誌研究論文（学術雑誌）
- Aquaporin 9 (AQP9) is an aquaglyceroporin that can transport lactate. Accumulating evidence suggests that astrocyte-to-neuron lactate shuttle (ANLS) plays a critical role in energy metabolism in neurons, including retinal ganglion cells (RGCs). To test the hypothesis that AQP9, in concert with monocarboxylate transporters (MCTs), participates in ANLS to maintain function and survival of RGCs, Aqp9-null mice and wild-type (WT) littermates were subjected to optic nerve crush (ONC) with or without intravitreal injection of an MCT2 inhibitor. RGC density was similar between the Aqp9-null mice and WT mice without ONC, while ONC resulted in significantly more RGC density reduction in the Aqp9-null mice than in the WT mice at day 7. Positive scotopic threshold response (pSTR) amplitude values were similar between the two groups without ONC, but were significantly more reduced in the Aqp9-null mice than in the WT mice 7days after ONC. MCT2 inhibitor injection accelerated RGC death and pSTR amplitude reduction only in the WT mice with ONC. Immunolabeling revealed that both RGCs and astrocytes expressed AQP9, that ONC predominantly reduced astrocytic AQP9 expression, and that MCTs 1, 2, and 4 were co-localized with AQP9 at the ganglion cell layer. These retinal MCTs were also co-immunoprecipitated with AQP9 in the WT mice. ONC decreased the co-immunoprecipitation of MCTs 1 and 4, but did not impact co-immunoprecipitation of MCT2. Retinal glucose transporter 1 expression was increased in Aqp9-null mice. Aqp9 gene deletion reduced and increased the intraretinal L-lactate and D-glucose concentrations, respectively. Results suggest that AQP9 acts as the ANLS to maintain function and survival of RGCs.2020年11月, Molecular neurobiology, 57(11) (11), 4530 - 4548, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- BACKGROUND AND OBJECTIVES: This study aimed to compare the efficacy of fluorescein angiography (FA)-guided and indocyanine green angiography (ICGA)-guided half-time photodynamic therapy (PDT) for central serous chorioretinopathy (CSC). SUBJECTS AND METHODS: Medical records of 61 eyes of 61 CSC patients who underwent half-time PDT were retrospectively reviewed. The irradiation area was determined using information from FA or ICGA with physicians' discretion. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), subfoveal choroidal thickness (SCT), and resolution of subretinal fluid (SRF) were evaluated at baseline and 1, 3, 6, and 12 months after PDT. RESULTS: A total of 29 and 32 eyes received FA-guided PDT (irradiation area, 2898.3 ± 705.7 μm) and ICGA-guided PDT (irradiation area, 4993.8 ± 333.1 μm), respectively. A significant improvement in the mean BCVA was found at 1 month in the FA-guided group (P = 0.02), but not in the ICGA-guided group (P = 0.88). BCVA was significantly improved in both groups at 3, 6, and 12 months with no significant intergroup difference at any time points. CRT and SCT were significantly reduced in both groups at all time points with no significant intergroup differences. No significant intergroup differences were observed in the rate of recurrence and persistent SRF. However, there was a significant difference between groups in the rate of recurrence and/or persistent SRF (P = 0.04). Multivariate analysis revealed that choice of FA-guided was significantly associated with recurrence and/or persistent SRF (P = 0.04). CONCLUSION: Half-time PDT with ICGA-guided irradiation spot might be more effective than that with FA-guided in treating CSC patients in complete resolution of SRF.2020年09月, Photodiagnosis and photodynamic therapy, 31, 101955 - 101955, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: To show the long-term effect of the cystotomy with or without fibrinogen clot removal for the refractory cystoid macular edema (CME) secondary to diabetic retinopathy (DR). METHODS: Retrospective analyses of the medical records of 30 eyes of 30 patients with refractory CME secondary to DR who had followed-up for 12 months after the surgery were performed. RESULTS: There were 15 men and 15 women. The mean±SD age was 68.4±7.9 years. The best corrected visual acuity (BCVA) (logMAR) at 12 months after the surgery (0.33±0.25, Snellen equivalent (SE), 20/42) was statistically better than the preoperative BCVA (0.45±0.33, SE, 20/56) (p<0.01). The central sensitivity on microperimetry (dB) was not statistically changed between preoperatively (24.0±4.9) and 12 months after the surgery (24.1±4.0) (p=0.75). The central retinal thickness (CRT) on optical coherence tomography (OCT) (μm) at 12 months after the surgery (300.3±99.0) was statistically improved compared with the preoperative CRT (565.6±198.7) (p<0.01). During the follow-up period, CME relapsed in 7 of 30 eyes. The preoperative cystoid cavity reflectivity on OCT in patients with fibrinogen clot removal (n=16) was significantly higher compared with that in patients without fibrinogen clot removal (n=14) (p<0.04). CONCLUSION: The cystotomy with or without fibrinogen clot removal may be a promising treatment option for refractory CME secondary to DR.2020年07月, Retina (Philadelphia, Pa.), 41(4) (4), 844 - 851, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (公財)日本眼科学会, 2020年06月, 日本眼科学会雑誌, 124(6) (6), 465 - 471, 日本語治療維持期の視力不良な滲出型加齢黄斑変性患者の固視
- PURPOSE: To show the usefulness of the intraoperative three-dimensional fluorescein angiography (3D-FA)-guided pars plana vitrectomy. METHODS: The NGENUITY 3D visualization system was used for the digital assisted vitrectomy. Three-dimensional fluorescein angiography-guided pars plana vitrectomy was performed in three patients with vitreous hemorrhage secondary to proliferative diabetic retinopathy. We investigated both whether several angiographic findings can be successfully displayed on the screen during 3D-FA and whether pars plana vitrectomy can be performed simultaneously on the same screen while implementing 3D-FA. RESULTS: In all cases, the abnormal FA findings including hypofluorescence due to non-perfusion areas, and the hyperfluorescence due to macular edema and fibrovascular proliferative membrane were successfully displayed on the screen. The segmentation and delamination of fibrovascular proliferative membrane and panretinal photocoagulation for detected non-perfusion areas were able to be performed on the same screen while implementing 3D-FA. CONCLUSION: Three-dimensional fluorescein angiography-guided pars plana vitrectomy is a novel approach that fully utilizes the advantages of digital assisted vitrectomy and a promising option for the treatment of proliferative diabetic retinopathy.2020年04月, Retina (Philadelphia, Pa.), 英語, 国際誌[査読有り]研究論文（学術雑誌）
- OBJECTIVE: To evaluate the usefulness of en face slab optical coherence tomography (OCT) imaging for monitoring diabetic retinal neurodegeneration with supporting animal experimental data. RESEARCH DESIGN AND METHODS: We retrospectively examined 72 diabetic eyes over 3 years using Cirrus-HD OCT. Two-dimensional en face slab OCT images of the innermost retina were reconstructed and graded according to the ratio of dark area to total area, and relative red, green, and blue color area ratios were calculated and used as indexes for each en face slab OCT image. Values from en face OCT images were used for statistical analyses. To obtain insight into the pathogenesis of diabetic retinal neurodegeneration, we used the InsPr-Cre;Pdk1flox/flox diabetic mouse model. RESULTS: Both OCT grade and relative red color area ratio significantly increased with the advancing stage of diabetic retinopathy (p=0.018 and 0.006, respectively). After a mean follow-up period of 4.6 years, the trend was unchanged in the analyses of 42 untreated eyes (p<0.001 and 0.001, respectively). Visual acuity showed a weak but significant negative correlation with the red color ratio on en face slab OCT images, but central retinal thickness did not exhibit a clinically meaningful correlation with values obtained from en face slab OCT images. Immunohistochemical analyses of InsPr-Cre;Pdk1flox/flox diabetic mice demonstrated the loss of ganglion axon bundles and thinning of laminin without apparent retinal vascular change at the age of 20 weeks. CONCLUSIONS: En face slab OCT imaging would be a novel useful modality for the assessment of diabetic retinal neurodegeneration as it could detect subtle optical changes occurring in the innermost retina in diabetic eyes. Our animal experimental data suggest that dark areas observed on en face slab OCT images might be the impairment of the extracellular matrix as well as neurons.2020年03月, BMJ open diabetes research & care, 8(1) (1), 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: To retrospectively investigate the sensitivity and specificity of weight gain, insulin-like growth factor 1, and neonatal retinopathy of prematurity (WINROP) algorithm for the prediction of severe retinopathy of prematurity (ROP) in a Japanese population of preterm infants. The WINROP algorithm is a tool based on postnatal weight gain. STUDY DESIGN: Retrospective cohort study. METHODS: The medical records of preterm infants born between January 2011 and March 2017 were retrospectively reviewed. Infants born after 33 weeks of gestation were excluded based on the indications of the WINROP algorithm. Postnatal weight was recorded weekly on the WINROP system until postmenstrual week 36. The sensitivity and specificity of the WINROP algorithm were analyzed. RESULTS: In total, 278 infants were included in this study. Based on the WINROP algorithm 110 of these infants were predicted to be at low risk for developing severe ROP and 105 did not develop severe ROP. Based on the WINROP algorithm 168 infants were predicted to be at high risk for developing severe ROP and 27 developed severe ROP. Thus, the sensitivity of the WINROP algorithm was 84.4% and the specificity 42.7%. CONCLUSION: The WINROP algorithm could be used for preterm infants (gestational age of <28 weeks) without a complicated hospital course. Modification of the algorithm will improve its sensitivity and specificity for the Japanese population.2020年03月, Japanese journal of ophthalmology, 64(2) (2), 223 - 227, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- OBJECTIVES: To compare the surgical results between air and 20% sulfur hexafluoride (SF6) tamponade in 27-gauge pars plana vitrectomy (27GPPV) for rhegmatogenous retinal detachment (RRD). METHODS: A retrospective, observational, and consecutive study. All patients underwent 27GPPV for RRD were divided into two groups. Group A comprised patients who underwent 20% SF6 gas tamponade. Group B comprised patients who underwent air tamponade. The anatomical success rate, visual outcome, and the type and frequency of complications were investigated and compared between the groups. All patients were followed-up for 12 months after surgery. RESULTS: Seventy eyes were enrolled (Group A: 35 eyes, Group B: 35 eyes). Seventeen eyes in Group A and 13 eyes in Group B had RRD with superior retinal breaks, while 14 eyes in Group A and 19 eyes in Group B had RRD with inferior retinal breaks. There was no statistically difference in preoperative demographic date between the groups. The initial and final anatomical success rates were 97.1% and 100% in Group A and 94.3% and 100% in Group B, respectively. The success rates between the groups were not statistically different (p = 1). The best corrected visual acuity (BCVA) (logMAR) at 12 months after surgery was -0.02 ± 0.14 in Group A and -0.03 ± 0.27 in Group B. The BCVA between the groups was not statistically different (p = 0.27). CONCLUSIONS: The surgical results of air tamponade were not inferior to 20% SF6 tamponade in 27GPPV for RRD irrespective of retinal break locations in the present cohort.2020年02月, Eye (London, England), 34(2) (2), 299 - 306, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- This retrospective study was conducted to investigate the predictive factors associated with metamorphopsia after reduced-fluence photodynamic therapy (RFPDT) in patients with central serous chorioretinopathy (CSC) with good baseline visual acuity. A total of 36 eyes of 36 consecutive patients with resolved CSC after RFPDT and best-corrected visual acuity (BCVA) better than 1.0 (logarithm of the minimal angle of resolution (logMAR) 0) at baseline were examined. Metamorphopsia was measured using M-CHARTS at 12 months after RFPDT. An average of the horizontal and vertical M-CHARTS scores was applied for defining the extent of metamorphopsia. The association between M-CHARTS score at 12 months after RFPDT and clinical parameters (age, sex, duration of symptoms, BCVA, and findings of optical coherence tomography (OCT)) was investigated at baseline or 12 months after RFPDT. The M-CHARTS score at 12 months correlated significantly with duration of symptoms (P = 0.005), baseline outer nuclear layer (ONL) thickness (P = 0.009), central foveal thickness (CFT) (P = 0.001) at 12 months, and ONL thickness (P = 0.001) at 12 months after RFPDT. In the multivariate analysis of baseline-related factors, thinner ONL thickness before RFPDT (P = 0.010) was significantly associated with large metamorphopsia at 12 months after RFPDT in CSC patients with good baseline BCVA. Baseline ONL thickness may be a useful predictive factor of metamorphopsia after RFPDT in CSC patients with good baseline BCVA.2020年, PloS one, 15(10) (10), e0240557, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Genetic factors associated with treatment response to reduced-fluence photodynamic therapy for chronic central serous chorioretinopathy.Purpose: Reduced-fluence photodynamic therapy (RFPDT) has proven effective for some patients with chronic central serous chorioretinopathy (cCSC). Several clinicodemographic factors influencing treatment response have been identified, but associations with genetic factors have not been examined. Therefore, we investigated the associations of single nucleotide polymorphisms (SNPs) implicated in cCSC pathogenesis with clinical outcome following RFPDT. Methods: This was a retrospective study of 87 eyes from 87 patients with cCSC who underwent RFPDT and were followed up for more than 12 months. Patients were divided into a good response group (53 patients) and a poor response group (34 patients) based on either persistence or recurrence of subretinal fluid detected with spectral domain optical coherence tomography after the first application of RFPDT. SNPs in the genes encoding age-related maculopathy susceptibility protein 2 (ARMS2, SNP rs10490924) and complement factor H (CFH, SNP rs800292) were genotyped using TaqMan technology. Results: There were no statistically significant differences in the baseline characteristics between the response groups except the degree of hyperfluorescence on indocyanine green angiography (ICGA; p = 0.011). The minor (T) allele frequency of ARMS2 (rs10490924) were statistically significantly lower in the good response group than in the poor response group (24.0% versus 41.0%, p = 0.021). Further, the good response frequency was statistically significantly lower in patients with at least one minor allele (GT or TT) compared to the homozygous major allele group (GG; p<0.05). The baseline best-corrected visual acuity (BCVA) at 12 months after RFPDT was statistically significantly better in the GG carriers than in the GT or TT carriers (p<0.01). Logistic regression analysis showed less intense hyperfluorescence on ICGA, and the T allele of ARMS2 (rs10490924) was statistically significantly associated with poor response to PDT treatment (p = 0.012, p = 0.039, respectively). Conclusions: Carriers of the ARMS2 rs10490924 minor allele (GT or TT) demonstrated a higher subretinal fluid persistence or recurrence rate and poorer visual outcome following RFPDT. In addition to the ICGA findings, genotyping of ARMS2 (rs10490924) may assist in the selection of patients with cCSC most likely to benefit from RFPDT.2020年, Molecular vision, 26, 505 - 509, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- BACKGROUND/PURPOSE: To present a case report of retinal metastasis of laryngeal squamous cell carcinoma that was diagnosed by a histopathologic finding from the surgically extracted tumor tissue. METHODS: A 66-year-old man, who was suffered from the treatment-resistant laryngeal carcinoma, was referred to our department because of visual field defect in his right eye. A fundus examination revealed a parafoveal white retinal lesion, which rapidly expanded to the central fovea and decreased the visual acuity. A tissue extraction by 27G pars plana vitrectomy was performed to confirm the diagnosis. RESULTS: The abnormal retinal tissue was extracted en block through 10-mm sclerocorneal tunnel during pars plana vitrectomy. The histopathologic findings revealed that the retinal lesion was retinal metastasis of laryngeal carcinoma. CONCLUSION: We must keep in mind that retinal metastasis can be one of the differential diagnoses for white retinal lesions of unknown cause.2020年, Retinal cases & brief reports, 14(2) (2), 127 - 130, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: To introduce the methodology and outcomes of en bloc removal of the component of cystoid lesion during pars plana vitrectomy as a novel approach for the treatment of cystoid macular edema and show evidence that the component is an aggregation of fibrinogen by mass spectrometry analysis. METHODS: The surgical en bloc extraction of the component of cystoid lesion was performed for cystoid macular edemas secondary to diabetic retinopathy and retinal vein occlusion. Perioperative change of best-corrected decimal visual acuity, and the central retinal thickness and the continuity of subfoveal ellipsoid zone and external limiting membrane on optical coherence tomography were evaluated. Mass spectrometry was performed for the identification of protein constituting the component. RESULTS: Six eyes from six patients were included in the study. In all cases, central retinal thickness was improved after the surgery and remained stable during the follow-up period. Best-corrected decimal visual acuity and the continuity of ellipsoid zone and external limiting membrane were kept in all cases during the follow-up period. The mass spectrometry analysis disclosed that the component was composed of fibrinogen. CONCLUSION: The en block removal of the component of cystoid lesion combined with pars plana vitrectomy may be a promising option for treatment of cystoid macular edema. The component of cystoid lesion is presumably a fibrinogen aggregate.2020年01月, Retina (Philadelphia, Pa.), 40(1) (1), 154 - 159, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 眼科臨床紀要会, 2019年11月, 眼科臨床紀要, 12(11) (11), 834 - 834, 日本語滲出型加齢黄斑変性の固視に関する検討[査読有り]
- PURPOSE: To investigate the clinical characteristics of eyes with cuticular drusen in Japanese individuals, while paying special attention to large colloid drusen (LCD). STUDY DESIGN: Retrospective case series. METHODS: Eyes with cuticular drusen, from patients of 4 medical institutes in Japan, were investigated. Multimodal imaging findings were used to diagnose cuticular drusen. LCD was defined as cuticular drusen > 200 µm. RESULTS: Twenty-four eyes from 12 patients (8 women, 4 men) were diagnosed with cuticular drusen. The mean age of all patients (n = 12) was 60.8 years. The mean age of patients without additional macular pathology (n = 5) was 55.4 years. Of the 7 patients with additional macular pathology, 6 (85.7%) exhibited age-related macular degeneration-associated macular pathology, including drusenoid pigment epithelial detachment (PED) (8 eyes from 4 patients), geographic atrophy (2 eyes from 1 patient), and occult choroidal neovascularization (1 eye). LCD were found in 6 eyes of 3 patients (25%), those with LCD were on average 53.7 ± 8.7 years old and those without 69.9 ± 14.1 years of age (P = 0.064, Mann-Whitney U test). CONCLUSIONS: Cuticular drusen were predominantly seen in females, and drusenoid PED was most frequently seen in eyes with additional macular pathology. LCD were seen in 25% of eyes with cuticular drusen.2019年11月, Japanese journal of ophthalmology, 63(6) (6), 448 - 456, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- PURPOSE: To determine the association of age-related maculopathy susceptibility 2 (ARMS2) gene polymorphisms with the 12-month outcomes of intravitreal aflibercept combined with photodynamic therapy (IVA+PDT) in polypoidal choroidal vasculopathy (PCV). STUDY DESIGN: Interventional cohort study. METHODS: This was a retrospective study of 48 consecutive treatment-naïve PCV patients. The patients underwent IVA+PDT as the initial therapy and were followed up for more than 12 months under a pro re nata regimen. The single nucleotide polymorphism (SNP) at rs10490924 in the ARMS2 gene was genotyped using the TaqMan assay. The clinical characteristics and outcomes of IVA+PDT were compared among the 3 genotypes at rs10490924. Multivariate regression analysis was performed to evaluate the influence of the clinical cofactors on the association of rs10490924 with the visual outcome at 12 months after the first IVA+PDT. RESULTS: No significant difference was found in the baseline characteristics among the 3 genotypes (n = 9, 23, and 16 for the GG, GT, and TT genotypes, respectively). All the patients, regardless of genotype, showed a significant improvement in vision, central retinal thickness, and subfoveal choroidal thickness at all time points measured after the initial IVA+PDT. The number of treatments was significantly smaller in the patients with the GG genotype than in those with the GT or the TT genotype. On multivariate logistic regression analysis, the number of the T allele at rs10490924 was significantly associated with the chance of retreatment after the initial IVA+PDT. CONCLUSION: The presence of the G allele at rs10490924 in the ARMS2 gene is likely associated with a lower chance of retreatment after IVA+PDT in patients with PCV.2019年09月, Japanese journal of ophthalmology, 63(5) (5), 389 - 395, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- PURPOSE: To investigate the perioperative clinical factors, which contribute to the postsurgical aqueous flare intensity (AFI) following 27-gauge pars plana vitrectomy (27GPPV) for primary rhegmatogenous retinal detachment (RRD). STUDY DESIGN: Retrospective clinical study. METHODS: We performed retrospective analyses of the medical records of 47 eyes of 47 patients with primary RRD who had undergone 27GPPV with a wide-angle viewing system. AFI was measured preoperatively and 1 week, 1 month, 3 months, 6 months, and 12 months after the surgery. RESULTS: AFI was significantly increased 1 week after the surgery (p<0.01) and then decreased overtime. At 6 months after surgery it was still statistically significantly higher than preoperative AFI (p=0.03). There was no statistical difference between preoperative AFI and that at 12 months following surgery. Multiple regression analyses revealed that the number of retinal photocoagulations and the performance of scleral indentation had significant positive correlation with AFI at 1 week, 1 month, 3 months, and 6 months, and at 1 month and 3 months after the surgery, respectively. CONCLUSION: Intraoperative retinal photocoagulation and scleral indentation are probable causes of increased AFI after 27G PPV for RRD.2019年07月, Japanese journal of ophthalmology, 63(4) (4), 317 - 321, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- Purpose: To investigate the foveal avascular zone (FAZ) in the eyes of patients with a history of retinopathy of prematurity (ROP) using optical coherence tomography angiography (OCTA) and to identify associated clinical factors. Patients and methods: Overall, 14 children with a history of laser treatment for ROP, 17 children born prematurely without a history of ROP, and 41 age-matched children born at full-term (age range 7-14 years) were included. OCTA was conducted on an area measuring 3 × 3 mm in the central macula. The area of FAZ in the superficial layer was measured. Foveal thickness (FT), ganglion cell complex thickness, and the presence of inner retinal layer (IRL) at the fovea were evaluated. Results: There were significant differences in FT and FAZ size among patients (P < 0.001). The eyes of patients that had been treated for ROP showed the smallest FAZ and greatest FT. Univariate analyses demonstrated that the area of FAZ was not correlated with visual acuity (P=0.078) but with gestational age (GA) (P=0.001), birth weight (P=0.013), the presence of IRL (P < 0.001), and FT (P < 0.001). Multivariate regression analyses showed that the area of FAZ was significantly associated with GA, the presence of IRL, and FT (P=0.03, P=0.01, P < 0.001, respectively). Conclusion: The eyes of preterm children had small FAZ, and this reduction in area was associated with greater FT, the presence of IRL, and lower GA.2019年, Journal of ophthalmology, 2019, 8340729 - 8340729, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- BACKGROUND: Surgical intervention for dense vitreous hemorrhage (DVH) with unclear etiology is often delayed in favor of conservative follow-up despite possible disease progression and the availability of safe minimally invasive vitrectomy. OBJECTIVES: The aim of this study is to investigate the efficacy of early surgical intervention for DVH with unknown etiology. METHODS: Eighty-eight cases (88 eyes) of DVH with unknown origin were retrospectively reviewed. Inclusion criteria were as follows: (1) measured visual acuity (VA) of 20/200 or worse and (2) fundus invisibility requiring B-scan ultrasonography. Eyes with a history of diabetic retinopathy, recent trauma, or likely retinal detachment (RD) as revealed by B-scan ultrasonography were excluded. Outcome measures were a cause of vitreous hemorrhage and final VA following early (≤2 weeks after symptom onset) or delayed vitrectomy. RESULTS: The most frequently occurring causes of DVH were central or branch retinal vein occlusion (30 eyes, 34%) and retinal tear or RD (29 eyes, 33%). logMAR VA significantly improved after treatment (p < 0.001). Final VA was significantly higher for eyes treated within 2 weeks compared with eyes treated later than 2 weeks after symptom onset (p = 0.020). CONCLUSIONS: Surgical intervention within 2 weeks after symptom onset may prevent a lower visual outcome.2019年, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde, 242(4) (4), 234 - 238, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- The recently emerged pachychoroid concept has changed the understanding of age-related macular degeneration (AMD), which is a major cause of blindness; recent studies attributed AMD in part to pachychoroid disease central serous chorioretinopathy (CSC), suggesting the importance of elucidating the CSC pathogenesis. Our large genome-wide association study followed by validation studies in three independent Japanese and European cohorts, consisting of 1546 CSC samples and 13,029 controls, identified two novel CSC susceptibility loci: TNFRSF10A-LOC389641 and near GATA5 (rs13278062, odds ratio = 1.35, P = 1.26 × 10-13; rs6061548, odds ratio = 1.63, P = 5.36 × 10-15). A T allele at TNFRSF10A-LOC389641 rs13278062, a risk allele for CSC, is known to be a risk allele for AMD. This study not only identified new susceptibility genes for CSC, but also improves the understanding of the pathogenesis of AMD.2019年, Communications biology, 2, 468 - 468, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: This study was prospectively carried out to clarify the effectiveness of visual and anatomical outcomes under combination therapy of intravitreal aflibercept (IVA) and verteporfin photodynamic therapy (vPDT) in over 24 months. STUDY DESIGN: A single-arm prospective exploratory study. METHODS: Twenty-six eyes of 26 treatment naïve PCV patients were enrolled in this study. The primary outcome measures were the changes in best corrected visual acuity (BCVA) and the complete polyp regression rate. The secondary outcome measures included central retinal thickness assessed by optical coherence tomography. RESULTS: The patients showed significant improvement in BCVA by 0.14 logMAR units at 12 months and 0.11 logMAR units at 24 months from baseline (both p < 0.01). The mean central retinal thickness also significantly decreased at 12 months (p < 0.001) and at 24 months (p = 0.001). Complete regression of polypoidal lesions was achieved by 15 out of 20 eyes (75%) at 12 months and 11 out of 20 eyes (55%) at 24 months. The mean treatment number was 2.9 courses of IVA and 1.5 courses of vPDT and the mean retreatment free interval after initial therapy was 12.8 months during follow up of 24 months. The complete data from all predetermined examinations were observed in 17 out of 26 enrolled patients (65%) in this study. CONCLUSION: In this study, combination therapy of IVA and vPDT yielded visual and anatomical improvements in treatment-naïve PCV patients over a 24-month follow-up period.2019年01月, Japanese journal of ophthalmology, 63(1) (1), 100 - 108, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- Purpose: Central serous chorioretinopathy (CSC) is a retinal disorder that often affects the vision of middle-aged people yet the molecular mechanisms of CSC remain unknown. This study was conducted to identify genetic factors influencing individual differences in susceptibility to CSC. Methods: A two-stage genome-wide association study (GWAS) was conducted with a total of 320 unrelated Japanese idiopathic CSC cases and 3245 population-based controls. In a discovery stage, 137 unrelated Japanese idiopathic CSC cases and 1174 population-based controls were subjected to GWAS, followed by a replication study using an additional 183 individuals with idiopathic CSC and 2071 population-based volunteers. The results of the discovery and replication stages were combined to conduct a meta-analysis. Results: In the two-stage GWAS, rs11865049 located at SLC7A5 in chromosome 16q24.2 was identified as a novel disease susceptibility locus for CSC, as evident from the discovery and replication results using meta-analysis (combined P = 9.71 × 10-9, odds ratio = 2.10). Conclusions: The results of the present study demonstrated that SLC7A5 might be the potential candidate gene associated with CSC, indicating a previously unidentified molecular mechanism of CSC.2018年11月, Investigative ophthalmology & visual science, 59(13) (13), 5542 - 5547, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Purpose: To report a rare case of bilateral periphlebitis associated with a pineal germinoma. Observations: A 17-year-old male teenager presented at a local clinic complaining of blurred vision in both eyes. The treating physician identified bilateral uveitis, and prescribed the patient with a local steroid treatment. However, the inflammatory findings did not improve with the treatment, and the patient was referred to our hospital for further examination. At the first visit, his best-corrected visual acuities were 0.3 for the right eye and 0.06 for the left eye; we found no inflammation in the anterior ocular segment, but observed bilateral retinal periphlebitis and a proliferative membrane from the papilla to the macula in the ocular fundus. In addition, we found a tractional serous retinal detachment in the macula. We suspected tuberculous uveitis clinically and initiated treatment with an antituberculous drug. However, the condition of the patient did not improve. Two months after our initial examination, left optic neuritis appeared, and we initiated a steroid pulse therapy. Although the periphlebitis remained, the left optic nerve findings and the visual acuity of both eyes improved. Thus, we reduced the oral steroid dose gradually. However, two months after initiating the dose reduction, the patient suffered a consciousness disturbance, and we detected a pineal tumor by magnetic resonance imaging (MRI). The patient was diagnosed as having a germ cell tumor by pathological examination and underwent radiation and chemotherapy. We noted marked improvements in both the periphlebitis findings and in the visual acuity following the treatment for the pineal tumor. Conclusions and importance: Cases of pineal tumor accompanied with retinal periphlebitis have been reported rarely. Because juvenile retinal vasculitis cases of unknown cause can be associated with pineal germinomas, we recommend brain MRI examinations for such cases.2018年09月, American journal of ophthalmology case reports, 11, 142 - 145, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2018年07月, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 59(9) (9)The association of age-related maculopathy susceptibility 2 gene polymorphisms with the 12 months outcomes of combination therapy with intravitreal aflibercept and verteporfin photodynamic therapy for polypoidal choroidal vasculopathy[査読有り]研究論文（学術雑誌）
- Central serous chorioretinopathy (CSC) is a common disease affecting younger people and may lead to vision loss. CSC shares phenotypic overlap with age-related macular degeneration (AMD). As recent studies have revealed a characteristic increase of choroidal thickness in CSC, we conducted a genome-wide association study on choroidal thickness in 3,418 individuals followed by TaqMan assays in 2,692 subjects, and we identified two susceptibility loci: CFH rs800292, an established AMD susceptibility polymorphism, and VIPR2 rs3793217 (P = 2.05 × 10-10 and 6.75 × 10-8, respectively). Case-control studies using patients with CSC confirmed associations between both polymorphisms and CSC (P = 5.27 × 10-5 and 5.14 × 10-5, respectively). The CFH rs800292 G allele is reportedly a risk allele for AMD, whereas the A allele conferred risk for thicker choroid and CSC development. This study not only shows that susceptibility genes for CSC could be discovered using choroidal thickness as a defining variable but also, deepens the understanding of differences between CSC and AMD pathophysiology.2018年06月, Proceedings of the National Academy of Sciences of the United States of America, 115(24) (24), 6261 - 6266, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Purpose: To report a case of temporary bilateral corneal denting in a patient who underwent cardiovascular surgery under general anesthesia. Observations: A 71-year-old male with no history of ophthalmological disease experienced bilateral corneal denting immediately after undergoing surgery for aneurysm of the thoracic aorta under general anesthesia. Anesthesia was induced with propofol and maintained with rocuronium bromide and remifentanil hydrochloride. The initial examination revealed significant denting on the surface of both the corneas and ocular hypotension. Visual evaluation could not be performed due to the patient's low level of consciousness resulting from delayed emergence from anesthesia. After applying tropicamide and phenylephrine ophthalmic solution for fundus examination, the ocular morphology improved. Ocular pressure was normal on the day after surgery, and creasing on the surface of the corneas had disappeared. Conclusions: and Importance: We experienced a patient with bilateral corneal denting following a cardiovascular surgery under general anesthesia. The dents could be attributed to augmentation of ocular hypotension using several types of anesthesia at relatively high doses.2018年06月, American journal of ophthalmology case reports, 10, 290 - 292, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: To compare the postoperative anatomic success rates and the frequency of complications between prone or supine postoperative positioning after transconjunctival sutureless vitrectomy (TSV) for rhegmatogenous retinal detachment (RRD). METHODS: All patients underwent primary 27-gauge TSV for the treatment of primary RRD. Patients were divided into two groups as follows: group A was patients instructed to keep strict postoperative prone positioning for a minimum of 8 days. Group B was patients instructed to keep the prone positioning on the day of the surgery followed by supine positioning for minimum of 7 days from the day after surgery. RESULT: Sixty-two eyes were enrolled (group A: 32, group B: 30). There was no significant difference in baseline data between two groups. The initial and final anatomical success rates were 93.8% and 100% in group A and 93.3% and 100% in group B, respectively (p = 1, p = 1, respectively). Posterior synechia of the iris occurred in one eye in group A and in two eyes in group B (p = 0.61). Macular pucker and retinal fold did not occur in either group. Preoperative intraocular pressure (IOP; mmHg) was 14.5 ± 2.9 in group A and 14.5 ± 2.6 in group B (p = 0.92). Intraocular pressure (IOP) was not statistically different between the groups during the follow-up period (p = 0.36, p = 0.07, respectively). CONCLUSION: Supine positioning may be an option as a postoperative positioning after TSV and gas tamponade for the treatment of RRD.2018年03月, Acta ophthalmologica, 96(2) (2), e189-e194, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- S. Karger AG, 2018年01月, Case Reports in Ophthalmology, 9(1) (1), 113 - 119, 英語[査読有り]研究論文（学術雑誌）
- Aim: To compare the anatomic and visual outcomes of 25-gauge (25G), and 27-gauge (27G) transconjunctival sutureless pars plana vitrectomy (TSV) for the management of primary rhegmatogeneous retinal detachment (RRD). Design: A retrospective nonrandomized clinical trial. Methods: A retrospective comparative analysis of 62 consecutive eyes from 62 patients with 6 months of follow-up was performed. Results: Thirty-two patients underwent 25G TSV, and 30 patients underwent 27G TSV for the treatment of primary RRD. There was no significant difference in baseline demographic and preoperative ocular characteristics between the two groups. The initial and final anatomical success rates were 93.8% and 100% in 25G TSV and 96.7% and 100% in 27G TSV, respectively (p=1 and p=1, resp.). Preoperative best-corrected visual acuity (BCVA) (logMAR) was 0.44 ± 0.69 and 0.38 ± 0.61 for 25G and 27G TSV, respectively (p=0.73). The final follow-up BCVA was 0.07 ± 0.25 and -0.02 ± 0.17 for 25G and 27G TSV, respectively (p=0.16). The final BCVA was significantly better than the preoperative BCVA in both groups (p=0.02 and p=0.002, resp.). Preoperative intraocular pressure (IOP) (mmHg) was 13.0 ± 3.5 in 25G TSV and 14.3 ± 2.8 in 27G TSV (p=0.11). IOP did not statistically significantly change in both groups during the follow-up period (p=0.63 and p=0.21, resp.). Conclusion: The 27G TSV system is safe and useful for RRD treatment as 25G TSV.2018年, Journal of ophthalmology, 2018, 7643174 - 7643174, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: The aim of this study was to investigate the clinical implications of required retreatment after 3-monthly intravitreal ranibizumab (IVR) injections followed by as-needed reinjections up to 5 years in eyes with exudative age-related macular degeneration (AMD). METHODS: A retrospective cohort study was conducted for 165 treatment-naïve eyes from 165 patients with exudative AMD. Visual changes were investigated in terms of the required retreatments. RESULTS: Retreatment-free proportions were 37.0, 23.7, 16.6, 12.1, and 10.5% at 12, 24, 36, 48, and 60 months, respectively. Visual changes were significantly better in eyes which did not require retreatment at every yearly checkpoint within the 5 years. A multivariate logistic regression analysis revealed that requirement of additional IVR treatments in the first 12-24 months was associated with the T allele (risk allele) of ARMS2 A69S (p = 0.010 and 0.015, respectively). Cox regression analysis revealed that older age (p = 0.046) and the T allele of ARMS2 A69S (p = 0.036) were associated with required retreatment within the 5-year follow-up period. CONCLUSIONS: Age and the T allele of ARMS2 A69S are the risk factors requiring retreatments, leading to poor visual change in eyes with exudative AMD following the initial 3-monthly IVR.2018年, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde, 239(1) (1), 52 - 59, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: This study evaluates optical coherence tomography (OCT) findings of the macula in patients with a history of retinopathy of prematurity (ROP). METHODS: We enrolled 112 patients (age: 6-15 years) and categorized them into 3 groups: gestational age (GA) < 36 weeks with or without a history of ROP (ROP group, preterm group) and GA ≥37 weeks. We included 1 eye of each patient and measured the retinal thickness of the macula by OCT. RESULTS: The ROP group demonstrated the worst VA and the shallowest foveal depression. Furthermore, foveal depression significantly correlated with birth weight, GA, ganglion cell layer/inner plexiform layer (GCL-IPL) thickness, and a history of ROP. CONCLUSIONS: This study established a correlation of fovea formation with premature birth, damage of GCL-IPL, and a history of ROP. The retention of the inner retina possibly contributes to abnormal foveal morphology in patients with a history of ROP.2018年, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde, 240(2) (2), 106 - 110, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Polypoidal Choroidal Vasculopathy Associated with Optic Disc Coloboma.Purpose:2018年01月, Case Rep Ophthalmol., 英語
To report a case of polypoidal choroidal vasculopathy associated with optic disc coloboma.
Methods:
Case report.
Results:
A 50-year-old woman presented with optic disc coloboma and retinochoroidal coloboma associated with subretinal hemorrhage and serous retinal detachment (SRD) in her left eye. Optical coherence tomography (OCT) confirmed SRD at the macula and show[査読有り]研究論文（学術雑誌） - Association of Folia Ophthalmologica Japonica, 2017年10月, Folia Japonica de Ophthalmologica Clinica, 10(10) (10), 817 - 821, 中国語The analysis of preoperative factors associated with postoperative metamorphopsia after 27-gauge transconjunctival sutureless pars plana vitrectomy for idiopathic epiretinal membrane研究論文（学術雑誌）
- Igaku-Shoin Ltd, 2017年10月, Japanese Journal of Clinical Ophthalmology, 71(10) (10), 1505 - 1511, 日本語Photodynamic therapy and intravitreal bevacizumab resulted in prolonged improvement of visual acuity in a case of choroidal osteoma with choroidal neovascularization研究論文（学術雑誌）
- (株)医学書院, 2017年10月, 臨床眼科, 71(10) (10), 1505 - 1511, 日本語臨床報告 光線力学療法とベバシズマブ硝子体注射により長期間視力が改善した脈絡膜骨腫に続発した脈絡膜血管新生の1例
- We conducted a genome-wide association study (GWAS) on the outcome of anti-VEGF treatment for exudative age-related macular degeneration (AMD) in a prospective cohort. Four hundred and sixty-one treatment-naïve AMD patients were recruited at 13 clinical centers and all patients were treated with 3 monthly injections of ranibizumab followed by pro re nata regimen treatment for one year. Genomic DNA was collected from all patients for a 2-stage GWAS on achieving dry macula after the initial treatment, the requirement for an additional treatment, and visual acuity changes during the 12-month observation period. In addition, we evaluated 9 single-nucleotide polymorphisms (SNPs) in 8 previously reported AMD-related genes for their associations with treatment outcome. The discovery stage with 256 patients evaluated 8,480,849 SNPs, but no SNPs showed genome-wide level significance in association with treatment outcomes. Although SNPs with P-values of <5 × 10-6 were evaluated in replication samples of 205 patients, no SNP was significantly associated with treatment outcomes. Among AMD-susceptibility genes, rs10490924 in ARMS2/HTRA1 was significantly associated with additional treatment requirement in the discovery stage (P = 0.0023), and pooled analysis with the replication stage further confirmed this association (P = 0.0013). ARMS2/HTRA1 polymorphism might be able to predict the frequency of injection after initial ranibizumab treatment.2017年08月, Scientific reports, 7(1) (1), 9196 - 9196, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: Central serous chorioretinopathy (CSC) is a common choroidal disorder which often affects the vision of young adults. Although the molecular mechanisms associated with CSC remain unknown, correlations between steroid hormone use and CSC have been suspected. We investigated the choroidal status of CSC secondary to corticosteroid use. METHODS: The records of 25 eyes of 25 consecutive acute CSC cases secondary to corticosteroid use were reviewed retrospectively. Central choroidal thickness was measured by optical coherent tomography. Choroidal vessel dilation and choroidal vascular hyperpermeability were evaluated based on indocyanine green angiography findings. The parameters related to secondary CSC were compared with those of 25 eyes of 25 cases with acute idiopathic CSC. RESULTS: The mean central choroidal thickness of secondary CSC was 294.8 ± 95.0 μm, which was significantly thinner than that of idiopathic CSC (409.4 ± 124.7 μm, P = 0.00064). The proportion of the cases exhibiting choroidal vessel dilation was not significantly different between secondary CSC (52%) and idiopathic CSC (64%). The proportion of cases showing choroidal vascular hyperpermeability was significantly smaller in secondary CSC (62%) than idiopathic CSC (92%) (P = 0.028). CONCLUSION: The choroidal status in the acute phase of secondary CSC after corticosteroid use might be different from that of idiopathic CSC, which suggests a complex mechanism for CSC.2017年08月, Retina (Philadelphia, Pa.), 37(8) (8), 1562 - 1567, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- 2017年06月, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 58(8) (8)Association between CFH variants and choroidal thickness in central serous chorioretinopathy[査読有り]研究論文（学術雑誌）
- PURPOSE: The purpose of the study was to evaluate the 1-year visual and anatomical outcomes of combination therapy with intravitreal aflibercept (IVA) and verteporfin photodynamic therapy (vPDT) for polypoidal choroidal vasculopathy (PCV), and to determine the predictors of a good visual outcome. METHODS: This was a prospective case-series study. Twenty eyes from 20 treatment-naïve PCV patients were treated with combination therapy with IVA and vPDT. Best-corrected visual acuity (BCVA) and morphological parameters including polypoidal lesions in indocyanine green angiography (ICGA) were evaluated over 12 months of follow-up. RESULTS: The mean logMAR BCVA was significantly improved from 0.30 at baseline to 0.20 at 3 months and 0.18 at 12 months. The mean central retinal thickness was also significantly improved at 3 months and at 12 months. In ICGA, complete regression of polypoidal lesions was found in 14 out of 20 eyes (70 %) at 3 months and in 14 out of 18 eyes (78 %) at 12 months although no ICGA were done on two eyes. In the multivariate logistic regression analyses, the baseline greatest linear dimension was found as a significant predictive factor for good visual improvement (≧0.3 LogMAR units improvement from baseline) at 12 months. CONCLUSION: In this study, combination therapy with IVA and vPDT gave visual and anatomical improvements to treatment-naïve PCV patients over 12 months of follow-up period.2017年03月, Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 255(3) (3), 541 - 548, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (株)メディカル葵出版, 2017年02月, あたらしい眼科, 34(2) (2), 280 - 282, 日本語
- BACKGROUND: To compare the 12-month outcomes of intravitreal ranibizumab (IVR) between two angiographic subtypes of polypoidal choroidal vasculopathy (PCV). METHODS: This is a retrospective cohort study of 38 treatment-naïve PCV cases. Three consecutive IVR and retreatments as needed were performed. Subsequently, the PCV cases were classified into two phenotypes (18 type 1 and 20 type 2) according to the status of branching vascular network. The best-corrected visual acuity (BCVA) was evaluated in each PCV subtype up to 12 months after the initial IVR. RESULTS: The mean BCVA was significantly improved from baseline in type 1 PCV while not in type 2 PCV. In type 2 PCV, 3 cases showed severe visual loss after 6 months from the initial IVR. The mean retreatment number was 1.9 ± 1.7 in type 1 PCV and 1.2 ± 1.3 in type 2 PCV. CONCLUSIONS: The outcomes of IVR may be different between two angiographic subtypes of PCV.2017年, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde, 237(3) (3), 123 - 127, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- ARMS2 variants may predict the 3-year outcome of photodynamic therapy for wet age-related macular degeneration.PURPOSE: To determine the association of age-related maculopathy susceptibility2 (ARMS2) gene polymorphisms with the 3-year outcomes of photodynamic therapy (PDT) in wet age-related macular degeneration (wet AMD). METHODS: The single nucleotide polymorphism (SNP) at rs10490924 in the ARMS2 gene of 65 patients with wet AMD who underwent PDT was genotyped using the TaqMan assay. The clinical characteristics and the outcomes of PDT were compared among the three genotypes at rs10490924. A multivariate regression analysis was performed to evaluate the influence of the clinical cofactors on the association of rs10490924 with the visual outcome at 36 months after the first PDT. RESULTS: A significant difference was found among the genotypes in the age and the baseline lesion size. The patients with the GG genotype showed a significant improvement in vision, and the patients with the TT genotype showed a significant worsening of vision at all time points measured after the initial PDT. In the multivariate regression analysis, the number of the G allele at rs10490924 was associated with a significantly greater improvement in the baseline best-corrected visual acuity (BCVA) at 36 months after the first PDT. CONCLUSIONS: ARMS2 variants are likely associated with the 3-year outcomes of PDT in patients with wet AMD.2017年, Molecular vision, 23, 514 - 519, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Previous sequencing studies of AMD susceptibility genes have revealed the association of rare coding variants in CFH, CFI, C3 and C9 in European population; however, the impact of rare or low-frequency coding variants on AMD susceptibility in other populations is largely unknown. To identify the role of low-frequency coding variants on exudative AMD susceptibility in a Japanese population, we analysed the association of coding variants of 34 AMD candidate genes in the two-stage design by a multiplex PCR-based target sequencing method. We used a total of 2,886 (1st: 827, 2nd: 2,059) exudative AMD cases including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation and 9,337 (1st: 3,247 2nd: 6,090) controls. Gene-based analysis found a significant association of low-frequency variants (minor allele frequency (MAF) < 0.05) in CETP, C2 and CFB. The association of CETP remained after conditioned with all known genome-wide association study (GWAS) associated variants. In addition, when we included only disruptive variants, enrichment of rare variants (MAF < 0.01) was also observed after conditioned with all GWAS associated variants (P = 1.03 × 10−6, odds ratio (OR) = 2.48). Haplotype and conditional analysis of the C2-CFB-SKIV2L locus showed a low-frequency variant (R74H) in CFB would be individually associated with AMD susceptibility independent of the GWAS associated SNP. These findings highlight the importance of target sequencing to reveal the impact of rare or low-frequency coding variants on disease susceptibility in different ethnic populations.2016年11月, Human molecular genetics, 25(22) (22), 5027 - 5034, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Aquaporin 9 (AQP9), an aquaglyceroporin, is not only permeable to water but also to non-charged solutes, such as lactate. Lactate can be an energy source for retinal neurons. This study aimed to evaluate the effect of the downregulation of AQP9 expression on the survival rates and reactive oxygen species accumulation in RGC-5 cells cultured in a medium containing lactate. The Live/Dead assay revealed that the cell death rate of RGC-5 cells transfected with the control siRNA (siControl) was 3.65%±0.75% in the 5-mM glucose medium. The death rate was significantly increased by five-fold in the no glucose and 10-mM d-lactate media but not in the 10-mM l-lactate medium. In comparison, the death rate of cells transfected with siRNA targeting AQP9 (siAQP9) was 8.07%±1.01% in the 5-mM glucose medium, which was significantly increased by two-fold in the other medium conditions, indicating that the downregulation of AQP9 expression eliminated the prosurvival effect of l-lactate. Few RGC-5 cells transfected with siControl showed dichlorofluorescein (DCF) fluorescence when cultured in 5-mM glucose and 10-mM l-lactate media. However, approximately 70% of those showed DCF fluorescence when cultured in the no glucose and 10-mM d-lactate media. The downregulation of AQP9 significantly increased the DCF fluorescence rate to 50.44%±6.13% in the 10-mM l-lactate medium, whereas, it did not increase the rate in the other medium conditions. These results demonstrate that AQP9 expression is required for l-lactate to maintain retinal neuronal survival.2015年03月, Neuroscience letters, 589, 185 - 90, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- OBJECTIVE: To compare the association of elastin (ELN) gene variants between two different angiographic phenotypes of polypoidal choroidal vasculopathy (PCV). METHODS: We included 411 treatment-naïve PCV patients and 350 controls in the present study. PCV was classified into two phenotypes (152 Type 1 and 259 Type 2) according to the presence or absence of feeding vessels found in indocyanine-green angiography. Single nucleotide polymorphisms (SNPs) in the ELN region including rs868005, rs884843, rs2301995, rs13239907 and rs2856728 were genotyped using TaqMan Genotyping Assays. RESULTS: In the allelic association analyses, rs868005 showed the strongest association with Type 2 PCV (allelic odds ratio 1.56; p = 7.4x10(-6)), while no SNP was significantly associated with Type 1 PCV. Genotype association analyses revealed the significant association of rs868005 with Type 2 PCV in log additive model and predominant model (odds ratio 1.75; p = 1.5x10(-6) and odds ratio 1.60; p = 0.0044, respectively), but not with Type 1 PCV. These findings were further corroborated by another control group in the literature. CONCLUSIONS: There may be significantly different associations in genetic variants of elastin between two angiographic phenotypes of PCV.2015年, PloS one, 10(3) (3), e0120643, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: The effects of oxygen supplementation status and other clinical risk factors on the development of severe retinopathy of prematurity (ROP) were evaluated. METHODS: Clinical records of 143 newborn infants with a gestational age of 32 weeks or less were reviewed. Severe ROP was diagnosed when photocoagulation due to progression to stage 3 was identified or when 'plus disease' developed. The factors were evaluated with univariate and multivariate logistic regression analyses between the groups with severe (n = 24) and non-severe (n = 119) ROP. RESULTS: Gestational age, birth weight, duration of oxygen supplementation, duration of directional positive air pressure and maximum fraction of inspiratory oxygen (FiO2) were significantly associated with severe ROP in the univariate analyses. In the multivariate analysis, a longer duration of oxygen supplementation and a higher maximum FiO2 were revealed as significant risk factors associated with severe ROP. CONCLUSIONS: Duration of oxygen supplementation and maximum FiO2 required were important factors associated with severe ROP.2015年, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde, 234(3) (3), 135 - 8, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: To compare the response to ranibizumab between patients with typical neovascular age-related macular degeneration (tAMD) and those with polypoidal choroidal vasculopathy (PCV), and to determine the predictors for the outcomes. METHODS: Fifty-nine eyes from 59 consecutive patients (tAMD: 27 eyes, PCV: 32 eyes) were treated with three monthly ranibizumab injections followed by as-needed retreatment. Best-corrected visual acuity (BCVA) and morphological parameters were evaluated over 24 months of follow-up. RESULTS: The mean BCVA in tAMD and PCV patients was significantly improved at 3 months (-0.22 and -0.09 logMAR units, respectively). The improvement in BCVA was sustained up to 24 months in tAMD (p = 0.01) but not in PCV patients. The significant predictor for good response to ranibizumab in tAMD patients was the improvement of BCVA at 3 months, whereas that in PCV patients was the anatomical resolution at 3 months. CONCLUSIONS: Ranibizumab is an effective therapy for tAMD and PCV over 24 months. The predictors for good outcome might be different between tAMD and PCV.2015年, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde, 234(1) (1), 33 - 9, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- The impairment of mitochondrial function is an important pathogenic factor in glaucoma and other optic neuropathies in which retinal ganglion cell (RGC) death is the fundamental pathology. Syntaphilin was recently discovered as a docking protein that affects mitochondrial mobility. However, no reports have investigated the involvement of syntaphilin in the visual system. We investigated the expression of syntaphilin in the rat retina, optic nerve and brain. The expression of syntaphilin exhibited varying patterns in the visual system. Syntaphilin was expressed in retinal ganglion cells in the retina, in the cell bodies of neurons in the superior colliculus and was abundant in the astrocytes of rat optic nerves (similar to the findings that syntaphilin is expressed in human optic nerves). After optic nerve transection, which caused RGC death and axonal degeneration, quantitative real-time RT-PCR was used to assess changes in gene expression in the rat retina and optic nerve. Syntaphilin gene and protein expression in the optic nerve was downregulated 3 and 7 days after optic nerve transection. Our study suggests that syntaphilin expression in astrocytes at the optic nerve might be involved in axonal injury.2014年12月, Experimental eye research, 129, 38 - 47, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: To investigate whether complement factor H (CFH) gene DNA variants are associated with central serous chorioretinopathy (CSCR). DESIGN: Cross-sectional study. PARTICIPANTS: A case-control group of 140 CSCR subjects and 2 different control groups: 934 population-based controls and 335 hospital-based controls. METHODS: Five single-nucleotide polymorphisms (SNPs) in CFH (rs3753394, rs800292, rs2284664, rs1329428, and rs106548) were evaluated for association with CSCR in 2 separate association analyses comparing CSCR subjects with 2 different control groups. Genotyping was performed using TaqMan technology (Applied Biosystems, Foster City, CA). MAIN OUTCOME MEASURES: Allele and haplotype frequencies of the 5 variants in the CFH region. RESULTS: Highly statistically significant associations with CSCR were found for the 5 SNPs. The strongest association was observed with rs1329428 (allelic P = 6.44×10(-6); odds ratio, 1.79; 95% confidence interval [CI], 1.39-2.31, cases vs. population-based controls), which accounted for 35.5% of the population-attributable fraction for CSCR. Consistent with the analysis, rs1329428 showed the strongest disease association (allelic P = 1.00×10(-5); odds ratio, 1.89; 95% CI, 1.42-2.50) in comparing cases with hospital-based controls. The second most strongly associated SNP, rs1065489, was correlated highly with the most strongly associated SNP, rs1329428 (r(2) = 0.77), and their effects could not be distinguished statistically from each other. A conditional logistic regression analysis revealed that the 2 highly correlated SNPs, rs1329428 and rs1065489, account for the association signals detected at the CFH locus. CONCLUSIONS: We identified a novel association between CSCR and common CFH polymorphisms. Our findings support the involvement of CFH in the pathogenesis of CSCR; exploration of the role of CFH could yield important insights into the biological mechanisms underlying CSCR. Our identification of common CFH variants as susceptibility elements for CSCR will open new avenues for research, leading to a better understanding of CSCR pathogenesis and ultimately to the development of improved therapeutic approaches.2014年05月, Ophthalmology, 121(5) (5), 1067 - 72, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- AIM: This study was conducted to evaluate the possible clinical and genetic indicators for an early response to intravitreal ranibizumab (IVR) in exudative age-related macular degeneration (AMD). PATIENTS & METHODS: The records of 120 eyes from 120 Japanese patients with treatment-naive exudative AMD were retrospectively reviewed. Three consecutive IVR treatments were performed every month. Achievement of anatomical resolution was evaluated by ophthalmoscopy and optical coherence tomography. Multivariable logistic regression analysis was conducted by analyzing SNPs in the ARMS2 locus (A69S) and in the CFH gene (I62V and Y402H), in addition to clinical factors. RESULTS: The mean central retinal thickness of overall patients was significantly decreased (-120.1 ± 122.8 µm, p = 2.7 × 10(-19)) at 3 months after the initial treatment. In the logistic regression analysis, the poor anatomical resolution of the lesion at 3 months was associated with the combination of CFH I62V + CFH Y402H variants (p = 0.0021), and the polypoidal choroidal vasculopathy lesions (p = 0.044). CONCLUSION: The CFH variants and the polypoidal choroidal vasculopathy lesion may influence the early anatomical resolution with IVR in exudative AMD.2014年04月, Pharmacogenomics, 15(6) (6), 833 - 43, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- BACKGROUND: To compare the outcomes of photodynamic therapy (PDT) between two different angiographic subtypes of polypoidal choroidal vasculopathy (PCV). METHODS: Ninety-three consecutive cases of PCV were classified into two phenotypes (42 type 1 and 51 type 2) according to the presence or absence of feeding vessels found on indocyanine green angiography. Full-dose PDT and retreatments were performed every 3 months as needed based on the findings on angiography. The best-corrected visual acuity (BCVA) was compared as the main outcome between type 1 and type 2 PCV up to 12 months after the initial PDT. RESULTS: The baseline greatest linear dimension (GLD) was significantly larger in type 1 PCV than type 2 PCV. The mean BCVA was significantly improved from baseline in type 2 PCV, while no improvement was found in type 1 PCV. Analysis with matching the GLD between both PCV subtypes did not change the original results. CONCLUSIONS: There may be a significantly different response to PDT between two angiographic phenotypes of PCV.2014年, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde, 232(2) (2), 92 - 6, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Doxorubicin (DXR) and daunorubicin (DNR) inhibit hypoxia-inducible factor-1 (HIF-1) transcriptional activity by blocking its binding to DNA. Intraocular injections of DXR or DNR suppressed choroidal and retinal neovascularization (NV), but also perturbed retinal function as demonstrated by electroretinograms (ERGs). DXR was conjugated to novel copolymers of branched polyethylene glycol and poly(sebacic acid) (DXR-PSA-PEG3) and formulated into nanoparticles that when placed in aqueous buffer, slowly released small DXR-conjugates. Intraocular injection of DXR-PSA-PEG3 nanoparticles (1 or 10 μg DXR content) reduced HIF-1-responsive gene products, strongly suppressed choroidal and retinal NV, and did not cause retinal toxicity. In transgenic mice that express VEGF in photoreceptors, intraocular injection of DXR-PSA-PEG3 nanoparticles (10 μg DXR content) suppressed NV for at least 35 days. Intraocular injection of DXR-PSA-PEG3 nanoparticles (2.7 mg DXR content) in rabbits resulted in sustained DXR-conjugate release with detectable levels in aqueous humor and vitreous for at least 105 days. This study demonstrates a novel HIF-1-inhibitor-polymer conjugate formulated into controlled-release particles that maximizes efficacy and duration of activity, minimizes toxicity, and provides a promising new chemical entity for treatment of ocular NV.2013年12月, Journal of controlled release : official journal of the Controlled Release Society, 172(3) (3), 625 - 33, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Aberrant angiogenesis can cause or contribute to a number of diseases such as neovascular age-related macular degeneration (NVAMD). While current NVAMD treatments target angiogenesis, these treatments are not effective for all patients and also require frequent intravitreal injections. New agents and delivery systems to treat NVAMD could be beneficial to many patients. We have recently developed a serpin-derived peptide as an anti-angiogenic agent. Here, this peptide is investigated for activity in human retinal endothelial cells in vitro and for reducing angiogenesis in a laser-induced choroidal neovascularization mouse model of NVAMD in vivo. While frequent intravitreal injections can be tolerated clinically, reducing the number of injections can improve patient compliance, safety, and outcomes. To achieve this goal, and to maximize the in vivo activity of injected peptide, we have developed biodegradable polymers and controlled release particle formulations to extend anti-angiogenic therapy. To create these devices, the anionic peptides are first self-assembled into nanoparticles using a biodegradable cationic polymer and then as a second step, these nanoparticles are encapsulated into biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles. In situ, these particles show approximately zero-order, linear release of the anionic peptide over 200 days. These particles are made of safe, hydrolytically degradable polymers and have low endotoxin. Long-term in vivo experiments in the laser-induced neovascularization model for NVAMD show that these peptide-releasing particles decrease angiogenesis for at least fourteen weeks in vivo following a single particle dose and therefore are a promising treatment strategy for NVAMD.2013年10月, Biomaterials, 34(30) (30), 7544 - 51, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: To compare the association of age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) variants between two different angiographic phenotypes of polypoidal choroidal vasculopathy (PCV). METHODS: We included 175 Japanese patients with PCV and 150 age- and sex-matched controls. PCV was classified into two phenotypes (Type 1 and Type 2) according to the presence or absence of the feeding vessels found in indocyanine-green angiography. The single nucleotide polymorphism (SNP) at rs10490924 (A69S) in ARMS2 and rs800292 (I62V), rs1061170 (Y402H) in the CFH region were genotyped using the TaqMan assay. RESULTS: The minor allele frequency (MAF) of rs10490924 was significantly different between Type 1 PCV (n = 81) and control (p < 0.0001), while no difference was found between Type 2 PCV (n = 94) and control (p = 0.20). The MAF of rs800292 was significantly different between each type of PCV and control (p < 0.0001 and 0.0001 for Type 1 versus control and Type 2 versus control, respectively). The MAF of rs1061170 was not significantly different between either type of PCV and control (p = 0.084 and 0.15, respectively). CONCLUSIONS: There may be significantly different associations in the genetic variants of ARMS2 between two angiographic phenotypes of PCV.2013年09月, Ophthalmic genetics, 34(3) (3), 146 - 50, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (公財)臨床薬理研究振興財団, 2013年06月, 臨床薬理の進歩, (34) (34), 86 - 92, 日本語近視性脈絡膜血管新生に対するビスフォスフォネート薬内服の2年後効果の検討
- BACKGROUND: Choroidal neovascularisation is often associated with pathological myopia. Bisphosphonates (BP), the preferred drug for treatment of osteoporosis, are known to have anti-angiogenic effects. OBJECTIVE: To compare the therapeutic effects of oral BP with anti-vascular endothelial growth factor therapy (anti-VEGF) and photodynamic therapy (PDT) for myopic choroidal neovascularisation (mCNV) over 2 years of follow-up. METHODS: One hundred eyes of 96 consecutive patients with mCNV who underwent oral BP treatment (alendronate 5 mg/day or 35 mg/week), anti-VEGF therapy, PDT or observation only were followed up for 2 years. The best-corrected visual acuity (BCVA) and the central retinal thickness (CRT) in optical coherence tomography were compared among the treatment groups. RESULTS: The mean BCVA of the patients was maintained for up to 2 years in the BP and PDT groups. In the anti-VEGF group, the mean BCVA was significantly improved but was significantly worse in the no-treatment group. The visual outcomes were significantly better in the BP, PDT and anti-VEGF groups than the no-treatment group over 2 years of follow-up (-0.28, -0.26 and -0.39 logMAR units, p=0.032, 0.021 and 0.0004, respectively). The mean CRT was significantly decreased in all treatment groups (-84, -121 and -122 mm, p=0.0025, 0.017 and 0.000025, respectively). CONCLUSIONS: Oral BP should be investigated further as possible therapeutic and preventive drugs for mCNV.2013年06月, The British journal of ophthalmology, 97(6) (6), 770 - 4, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Aquaporin 9 (AQP9), an aquaglyceroporin belonging to the AQP water channel family, is permeable not only to water but also to noncharged solutes such as lactate. In neurons, lactate presumably acts as an energy substrate and as a source of NADH (the reduced form of nicotinamide adenine dinucleotide), a scavenger of reactive oxygen species (ROS). We previously reported that retinal ganglion cells (RGCs) express AQP9 and that elevated intraocular pressure reduces AQP9 expression and increases death of neurons in the retinal ganglion cell layer of rodents. In the present study, we investigated the association of AQP9 expression with serum deprivation-induced death of RGC-5 cells and with death of neurons in the rat retinal ganglion cell layer after optic nerve transection (ONT). The effect of AQP9 RNA interference on serum deprivation-induced apoptosis, ROS accumulation, and the NAD(+)/NADH ratio in RGC-5 cells was examined. Both serum deprivation and ONT significantly reduced AQP9 protein expression in RGCs and increased the rate of RGC death. Retinal AQP9 gene expression also declined after ONT. Down-regulation of AQP9 significantly increased apoptosis, ROS accumulation, and the NAD(+)/NADH ratio in the RGC-5 cells. These findings suggest that AQP9 loss adversely affects survival of RGCs, at least partly because of decreased transport of lactate as a substrate for energy and/or ROS scavenger.2013年05月, The American journal of pathology, 182(5) (5), 1727 - 39, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- PURPOSE: To evaluate the long-term effects of photodynamic therapy (PDT) on typical neovascular age-related macular degeneration (tAMD) and polypoidal choroidal vasculopathy (PCV). METHODS: This was a multicenter prospective study of 139 eyes from 136 patients (tAMD: 74 eyes; PCV: 65 eyes) who underwent PDT as the initial treatment. The change in best-corrected visual acuity (BCVA), predictive factors for the BCVA at 60 months, frequency of recurrence, and mean recurrence period were analyzed. RESULTS: The pre-PDT BCVA and greatest linear dimension (GLD) did not differ between the two groups. The mean BCVA (logMAR) was significantly improved at 6 months post-initial PDT (post-PDT) in the PCV group (-0.11, P = 0.0091). However, at 60 months post-PDT, the mean BCVA was significantly worse than baseline in the tAMD (+0.21, P = 0.0035) and PCV (+0.21, P = 0.0076) groups. Pre-PDT BCVA, age, and GLD were the factors significantly associated with the BCVA at 60 months post-PDT. Although the frequency of recurrence did not significantly differ between the two phenotype groups, the mean recurrence period was significantly longer in the PCV group than in the tAMD group (15.7 vs. 8.6 months, P = 0.0020). CONCLUSIONS: PDT may not have benefits for visual acuity in cases of tAMD and PCV over 5 years of follow-up.2013年05月, Japanese journal of ophthalmology, 57(3) (3), 301 - 7, 英語, 国内誌[査読有り]研究論文（学術雑誌）
- Difference between age-related macular degeneration and polypoidal choroidal vasculopathy in the hereditary contribution of the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2).PURPOSE: To investigate whether the A69S variant of the age-related maculopathy susceptibility 2 gene (ARMS2) has a different hereditary contribution in neovascular age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS: We initially conducted a comparative genetic analysis of neovascular AMD and PCV, genotyping the ARMS2 A69S variant in 181 subjects with neovascular AMD, 198 subjects with PCV, and 203 controls in a Japanese population. Genotyping was conducted using TaqMan technology. Results were then integrated into a meta-analysis of previous studies representing an assessment of the association between the ARMS2 A69S variant and neovascular AMD and/or PCV, comprising a total of 3,828 subjects of Asian descent. The Q-statistic test was used to assess between-study heterogeneity. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a fixed effects model. RESULTS: The genetic effect of the A69S variant was stronger in neovascular AMD (allelic summary OR=3.09 [95% CI, 2.71-3.51], fixed effects p<0.001) than in PCV (allelic summary OR=2.13 [95% CI, 1.91-2.38], fixed effects p<0.001). The pooled risk allele frequency was significantly higher in neovascular AMD (64.7%) than in PCV (55.6%). The population attributable risks for the variant allele were estimated to be 43.9% (95% CI, 39.0%-48.4%) and 29.7% (95% CI, 25.4%-34.0%) for neovascular AMD and PCV, respectively. No significant between-study heterogeneity was observed in any statistical analysis in this meta-analysis. CONCLUSIONS: Our meta-analysis provides substantial evidence that the ARMS2 A69S variant confers a significantly higher risk of neovascular AMD than PCV. Furthermore, there is compelling evidence that the risk attributable to the A69S variant differs between geographic atrophy and neovascular AMD. Together with defining the molecular basis of susceptibility, understanding the relationships between this genomic region and disease subtypes will yield important insights, elucidating the biologic architecture of this phenotypically heterogeneous disorder.2011年, Molecular vision, 17, 3574 - 82, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- BACKGROUND: Genetic variants in the complement component 3 gene (C3) have been shown to be associated with age-related macular degeneration (AMD) in Caucasian populations of European descent. In particular, a nonsynonymous coding variant, rs2230199 (R102G), is presumed to be the most likely causal variant in the C3 locus based on strong statistical evidence for disease association and mechanistic functional evidence. However, the risk allele is absent or rare (<1%) in Japanese and Chinese populations, and the association of R102G with AMD has not been reported in Asian populations. Genetic heterogeneity of disease-associated variants among different ethnicities is common in complex diseases. Here, we sought to examine whether other common variants in C3 are associated with wet AMD, a common advanced-stage manifestation of AMD, in a Japanese population. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped 13 tag single nucleotide polymorphisms (SNPs) that capture the majority of common variations in the C3 locus and tested for associations between these SNPs and wet AMD in a Japanese population comprising 420 case subjects and 197 controls. A noncoding variant in C3 (rs2241394) exhibited statistically significant evidence of association (allelic P = 8.32 × 10(-4); odds ratio = 0.48 [95% CI = 0.31-0.74] for the rs2241394 C allele). Multilocus logistic regression analysis confirmed that the effect of rs2241394 was independent of the previously described loci at ARMS2 and CFH, and that the model including variants in ARMS2 and CFH plus C3 rs2241394 provided a better fit than the model without rs2241394. We found no evidence of epistasis between variants in C3 and CFH, despite the fact that they are involved in the same biological pathway. CONCLUSIONS: Our study provides evidence that C3 is a common AMD-associated locus that transcends racial boundaries and provides an impetus for more detailed genetic characterization of the C3 locus in Asian populations.2011年, PloS one, 6(12) (12), e28847, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- It has recently been reported that relatively short-term inhibition of vascular endothelial growth factor (VEGF) signaling can cause photoreceptor cell death, a potentially clinically important finding since VEGF blockade has become an important modality of treatment of ocular neovascularization and macular edema. However, in a set of studies in which we achieved extended and complete blockage of VEGF-induced vascular leakage through retinal expression of a VEGF binding protein, we did not observe any toxicity to retinal neurons. To follow-up on these apparently discrepant findings, we designed a set of experiments with the kinase inhibitor SU4312, which blocks phosphorylation of VEGF receptors, to look directly for evidence of VEGF inhibition-related retinal toxicity. Using transgenic mice with sustained expression of VEGF in photoreceptors, we determined that periocular injection of 3 microg of SU4312 every 5 days markedly suppressed subretinal neovascularization, indicating effective blockade of VEGF signaling. Wild-type mice given periocular injections of 5 microg of SU4312 every 5 days for up to 12 weeks showed normal scotopic and photopic electroretinograms (ERGs), no TUNEL stained cells in the retina, and no reduction in outer nuclear layer thickness. Incubation of cultured ganglion cells or retinal cultures containing photoreceptors with high doses of SU4312 did not reduce cell viability. These data suggest that blocking VEGF signaling in the retina for up to 12 weeks does not damage photoreceptors nor alter ERG function and should reassure patients who are receiving frequent injections of VEGF antagonists for choroidal and retinal vascular diseases.2010年07月, Journal of cellular physiology, 224(1) (1), 262 - 72, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- OBJECTIVE: This study compared the effects of intraocular injections of ranibizumab (RBZ) and bevacizumab (BVZ) in transgenic mouse models in which human vascular endothelial growth factor (VEGF) causes subretinal neovascularization (NV) or exudative retinal detachment. DESIGN: Randomized trials in animal models. PARTICIPANTS: Transgenic mice in which the rhodopsin promoter drives expression of human VEGF in photoreceptors (rho/VEGF mice) and double transgenic mice with doxycycline-inducible expression of human VEGF in photoreceptors (Tet/opsin/VEGF mice). METHODS: Rho/VEGF mice received intraocular injections of RBZ, BVZ, or vehicle, and after various time periods the area of subretinal NV was measured. Tet/opsin/VEGF mice were given an intraocular injection of RBZ, BVZ, or vehicle, and after 5 days of doxycycline treatment the presence or absence of retinal detachment was determined. MAIN OUTCOME MEASURES: Area of subretinal NV per retina in rho/VEGF mice and the occurrence of retinal detachment in Tet/opsin/VEGF mice. RESULTS: In rho/VEGF mice, intraocular injections of RBZ or BVZ strongly suppressed subretinal NV, but the duration of effect was greater for BVZ. Three injections of 10 microg of BVZ over the course of 2 weeks not only suppressed subretinal NV in the injected eye but also caused significant suppression in the fellow eye, indicating a systemic effect. In doxycycline-treated Tet/opsin/VEGF mice, intraocular injection of 10 microg of BVZ significantly reduced the incidence of exudative retinal detachment compared with injection of 10 microg of RBZ. Injection of 25 microg of BVZ reduced the incidence of retinal detachment in both eyes. CONCLUSIONS: Intraocular injections of RBZ and BVZ had similar efficacy in rho/VEGF mice, but the duration of effect was greater for BVZ. In Tet/opsin/VEGF mice, in which expression levels of human VEGF are very high and the phenotype is severe, BVZ showed greater efficacy than RBZ. In both models, higher doses or repeated injections of BVZ, but not RBZ, resulted in a systemic effect. These data suggest that BVZ is not inferior to RBZ for treatment of subretinal NV in mice and is superior in a severe model. The systemic effects of BVZ after intraocular injection deserve further study and consideration of their potential consequences. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.2009年09月, Ophthalmology, 116(9) (9), 1748 - 54, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- Retinitis pigmentosa (RP) is a collection of diseases in which rod photoreceptors die from a variety of mutations. After rods die, the level of tissue oxygen in the outer retina becomes elevated and there is progressive oxidative damage to cones that ultimately triggers apoptosis. In this study, we investigated the hypothesis that NADPH oxidase (Nox) and/or xanthine oxidase serve as critical intermediaries between increased tissue oxygen and the generation of excessive reactive oxygen species that cause oxidative damage to cones. Apocynin, a blocker of Nox, but not allopurinol, a blocker of xanthine oxidase, markedly reduced the superoxide radicals visualized by hydroethidine in the outer retina in the retinal degeneration-1 (rd1(+/+)) model of RP. Compared to rd1(+/+) mice treated with vehicle, those treated with apocynin, but not those treated with allopurinol, had significantly less oxidative damage in the retina measured by ELISA for carbonyl adducts. Apocynin-treated, but not allopurinol-treated, rd1(+/+) mice had preservation of cone cell density, increased mRNA levels for m- and s-cone opsin, and increased mean photopic b-wave amplitude. In Q344ter mice, a model of dominant RP in which mutant rhodopsin is expressed, apocynin treatment preserved photopic electroretinogram b-wave amplitude compared to vehicle-treated controls. These data indicate that Nox, but not xanthine oxidase, plays a critical role in generation of the oxidative stress that leads to cone cell death in RP and inhibition of Nox provides a new treatment strategy.2009年08月, Journal of neurochemistry, 110(3) (3), 1028 - 37, 英語, 国際誌[査読有り]研究論文（学術雑誌）
- (公財)日本眼科学会, 2023年03月, 日本眼科学会雑誌, 127(臨増) (臨増), 231 - 231, 日本語未熟児網膜症既往症例の学童期視機能と眼球構造の多施設研究(J-CREST study)
- (公社)日本眼科手術学会, 2022年12月, 眼科手術, 36(臨増) (臨増), 172 - 172, 日本語Heads-Up Surgeryにおける無彩色映像下での内境界膜の視認性
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- 眼科臨床紀要会, 2022年10月, 眼科臨床紀要, 15(10) (10), 688 - 688, 日本語ブロルシズマブ硝子体内注射後の眼内炎症の頻度と特徴
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- (公財)日本眼科学会, 2022年03月, 日本眼科学会雑誌, 126(臨増) (臨増), 276 - 276, 日本語滲出型加齢黄斑変性に対するブロルシズマブへの切り替え効果についての検討
- 眼科臨床紀要会, 2021年11月, 眼科臨床紀要, 14(11) (11), 757 - 757, 日本語黄斑部毛細血管拡張に伴う嚢胞様黄斑浮腫に嚢胞様腔内壁切開術が奏効した1例
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- 眼科臨床紀要会, 2021年10月, 眼科臨床紀要, 14(10) (10), 680 - 680, 日本語未熟児網膜症に対するベバシズマブ併用治療の効果に関する多施設研究(J-CREST study)
- 眼科臨床紀要会, 2021年10月, 眼科臨床紀要, 14(10) (10), 684 - 685, 日本語裂孔原性網膜剥離に対する硝子体手術後の歪視量に寄与する周術期因子の検討
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- (一社)日本糖尿病合併症学会, 2021年09月, 糖尿病合併症, 35(Suppl.1) (Suppl.1), 252 - 252, 日本語糖尿病黄斑浮腫におけるen face slab OCT imagingと長期視力予後
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- (公財)日本眼科学会, 2019年03月, 日本眼科学会雑誌, 123(臨増) (臨増), 267 - 267, 日本語ポリープ状脈絡膜血管症へのaflibercept併用光線力学的療法と異常血管網の進展
- (公財)日本眼科学会, 2019年03月, 日本眼科学会雑誌, 123(臨増) (臨増), 289 - 289, 日本語視力良好な中心性漿液性脈絡網膜症における治療後歪視の予測因子についての検討
- (公社)日本視能訓練士協会, 2018年12月, 日本視能訓練士協会誌, 47, 293 - 293, 日本語
- 日本糖尿病眼学会, 2018年09月, 日本糖尿病眼学会誌, 22, 134 - 134, 日本語実臨床における糖尿病黄斑浮腫に対するラニビズマブ硝子体注射の12ヵ月治療成績
- (株)メディカ出版, 2018年02月, 眼科ケア, 20(2) (2), 130 - 135, 日本語【検査も手術もまるわかり!写真&イラストで最強レクチャー 黄斑疾患の病態と治療】写真・イラストでわかる 黄斑疾患の病態&治療 加齢黄斑変性
- (株)メディカル葵出版, 2017年12月, あたらしい眼科, 34(12) (12), 1741 - 1742, 日本語抗VEGF治療セミナー 加齢黄斑変性 光線力学的治療併用のタイミング
- 2015年06月, INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 56(7) (7), 英語The OCT findings of macula and associated factors in patients with a history of retinopathy of prematurity研究発表ペーパー・要旨（国際会議）
- 2015年, 日本眼科学会雑誌, 119ポリープ状脈絡膜血管症に対するアフリベルセプト併用光線力学療法の12ケ月成績
- 2015年, 日本眼科学会雑誌, 119中心性漿液性脈絡網膜症に対する時間短縮光線力学的療法における照射径設定法の比較
- 2014年, 日本網膜硝子体学会総会プログラム・講演抄録集, 53rdポリープ状脈絡膜血管症に対するアフリベルセプト併用光線力学的療法の6ケ月成績
- 2013年, 日本眼科学会雑誌, 117(3) (3)視神経疾患の新しい展開
- 2012年, 日本眼科学会雑誌, 116近視性脈絡膜血管新生に対するビスフォスフォネート薬内服の中期効果
- 2012年, 日本網膜硝子体学会総会プログラム・講演抄録集, 51stポリープ状脈絡膜血管症の血管造影に基づくサブタイプと光線力学療法の治療効果の検討
- 2012年, 日本網膜硝子体学会総会プログラム・講演抄録集, 51st中心性漿液性脈絡網膜症に対する低照射エネルギーPDTの短期成績
- 中山書店, 2023年10月眼科診療エクレール/最新 眼科画像診断パワーアップ－検査の基本から最新機器の撮影法まで/PCV
- 総合医学社, 2021年05月, 日本語, ISBN: 9784883786893眼と全身病アトラス/薬物中毒・副作用等 1)副腎皮質ステロイド（薬）
- 総合医学社, 2021年05月, 日本語, ISBN: 9784883786893眼と全身病アトラス/心・循環疾患/1)高血圧症(3)妊娠高血圧症候群
- 2021年02月日本医事新報/未熟児網膜症の診断と治療/未熟児網膜症に対する抗VEGF薬硝子体内注射の新たな治療選択肢の可能性
- 医学書院, 2020年臨床眼科/特集 すべて見せます！ 患者説明・同意書マニュアル/13.AMD/PDT
- メディカ出版, 2018年眼科ケア/2.写真・イラストでわかる 黄斑疾患の病態＆治療/1加齢黄斑変性
- 2017年12月あたらしい眼科/抗VEGF治療：加齢黄斑変性：光線力学的治療併用のタイミング
- 第58回日本網膜硝子体学会, 2019年12月, 日本語視力良好な中心性漿液性脈絡網膜症における治療後不等像視の関連因子についての検討ポスター発表
- 第58回日本網膜硝子体学会, 2019年12月, 日本語視力良好なポリープ状脈絡膜血管症に対する硝子体注射併用光線力学的療法の1年経過ポスター発表
- 13th Asia-Pacific Vitreo-retina Society Congress, 2019年11月, 英語, 国際会議Clinical factors associated with aniseikonia after reduced-fluence photodynamic therapy in central serous chorioretinopathy patients with good visual acuity.口頭発表（一般）
- 第73回日本臨床眼科学会, 2019年10月, 日本語中心性漿液性脈絡網膜症に対する低照射エネルギー光線力学療法の長期治療成績ポスター発表
- 第73回日本臨床眼科学会, 2019年10月, 英語, 国内会議今だから知っておきたい、最新PDT事情 VITRA PDTの使用経験公開講演，セミナー，チュートリアル，講習，講義等
- 第73回日本臨床眼科学会, 2019年10月, 日本語卵黄様黄斑症を伴う眼内リンパ腫の臨床的特徴の検討口頭発表（一般）
- 19th Euretina Congress, 2019年09月, 英語, 国際会議Effectiveness of the intentional lamellar macular hole formation for the treatment of refractory cystoid macular edema.口頭発表（一般）
- 19th Euretina Congress, 2019年09月, 英語, 国際会議The comparison of reduced fluence photodynamic therapy with modified or conventional irradiation area for central serous chorioretinopathy.口頭発表（一般）
- Global Ocular Inflammation Workshop 2019, 2019年06月, 英語, 国内会議Optical coherence tomography in vitreoretinal lymphoma with or without vitelliform submaculopathy.ポスター発表
- The Association for Research in Vision and Ophthalmology, 2019年04月, 英語, 国際会議Deletion of Aqp9 in mice enhances retinal ganglion cell death after optic nerve injury. Sotaro Mori, Takuji Kurimoto, Akiko Miki, Sentaro Kusuhara, Makoto Nakamura Predictive factors for metamorphopsia after reduced-fluence photodynamic therapy.口頭発表（一般）
- The Association for Research in Vision and Ophthalmology, 2019年04月, 英語, 国際会議The association of the branching vascular network area progression with the outcomes of combination therapy with intravitreal aflibercept and verteporfin photodynamic therapy for polypoidal choroidal vasculopathy口頭発表（一般）
- 第123回日本眼科学会総会, 2019年04月, 日本語ポリープ状脈絡膜血管症へのaflibercept併用光線力学的療法と異常血管網の進展ポスター発表
- 第123回日本眼科学会総会, 2019年04月, 日本語視力良好な中心性漿液性脈絡網膜症における治療後歪視の予測因子についての検討ポスター発表
- 第123回日本眼科学会総会, 2019年04月, 日本語難治性黄斑浮腫に対する嚢胞内壁穿破術の有効性口頭発表（一般）
- The Association for Research in Vision and Ophthalmology, 2019年04月Genetic factors associated with the treatment response to reduced-flurence photodynamic therapy for chronic central serous chorioretinopathy.
- 第57回日本網膜硝子体学会総会, 2018年12月, 日本語, 京都, 国内会議滲出型加齢黄斑変性の固視に関する検討口頭発表（一般）
- 第57回日本網膜硝子体学会総会, 2018年12月, 日本語, 京都, 国内会議ポリープ状脈絡膜血管症へのaflibercept単独療法とaflibercept併用光線力学的療法との2年経過の比較口頭発表（一般）
- 第72回日本臨床眼科学会, 2018年10月, 日本語, 東京, 国内会議裂孔原性網膜剥離に対する27ゲージ硝子体手術後の歪視量に寄与する周術期因子の検討口頭発表（一般）
- 第72回日本臨床眼科学会, 2018年10月, 日本語, 東京, 国内会議原因不明の硝子体出血眼に対する早期硝子体手術の効果口頭発表（一般）
- 第72回日本臨床眼科学会, 2018年10月, 日本語, 東京, 国内会議ポリープ状脈絡膜血管症に対するaflibercept併用光線力学的療法の3年経過口頭発表（一般）
- WOC, 2018年06月, 英語, バルセロナ, 国際会議Time Course of Changes in Aqueous Flare Intensity after 27-gauge pars plana Vitrectomy for Primary Rhegmatogenous Retinal Detachment口頭発表（一般）
- WOC, 2018年06月, 英語, バルセロナ, 国際会議Prediction of severe retinopathy of prematurity with WINROP algorithm in a Japanese poplulation of preterm infants口頭発表（一般）
- 第122回日本眼科学会総会, 2018年04月, 日本語, 大阪, 国内会議裂孔原性網膜剥離に対する27G硝子体手術後の前房フレア値に寄与する周術期因子の検討口頭発表（一般）
- 第122回日本眼科学会総会, 2018年04月, 日本語, 大阪, 国内会議未熟児網膜症既往眼における中心窩無血管領域と固視点安定性の関連口頭発表（一般）
- 第122回日本眼科学会総会, 2018年04月, 日本語, 大阪, 国内会議ポリープ状脈絡膜血管症へのアフリベルセプト併用光線力学療法後の網膜色素上皮萎縮口頭発表（一般）
- 第122回日本眼科学会総会, 2018年04月, 日本語, 大阪, 国内会議ポリープ状脈絡膜血管症に対する光線力学的療法及びaflibercept併用療法と脈絡膜変化口頭発表（一般）
- 第122回日本眼科学会総会, 2018年04月, 日本語, 大阪, 国内会議アクアポリン9 遺伝子欠損マウスにおける視神経挫滅後の網膜神経節細胞死口頭発表（一般）
- ARVO, 2018年04月, 英語, ホノルル, 国際会議The relationship between foveal avascular zone and fixation stability in patients with a history of retinopathy of prematurity.口頭発表（一般）
- ARVO, 2018年04月, 英語, ホノルル, 国際会議The impact of early vitrectomy for dense vitreous hemorrhage without a history of diabetic retinopathy口頭発表（一般）
- ARVO, 2018年04月, 英語, ホノルル, 国際会議The association of age-related maculopathy susceptibility 2 gene polymorphisms with the 12 months outcomes of combination therapy with intravitreal aflibercept and verteporfin photodynamic therapy for polypoidal choroidal vasculopathy.口頭発表（一般）
- 第87回福祉情報工学研究会, 2016年12月, 日本語, 電子情報通信学会 福祉情報工学研究会, 東京, 国内会議視機能異常に対応した病院内設備とカラーユニバーサルデザイン口頭発表（一般）
- 第17回日本クリニカルパス学会, 2016年11月, 日本語, 日本クリニカルパス学会, 金沢, 国内会議患者用パスの色覚異常への配慮の調査と作成ガイドラインの提案口頭発表（一般）
- The 8th Congress of Asia Pacific Vitreo-retina Society (APVRS), 2013年12月, 英語, 日本網膜硝子体学会, 名古屋, 国際会議The Short Term Outcomes of a Single Intravitreal Injection of Aflibercept Combined With Photodynamic Therapy for Polypoidal Choroidal Vasculopathy口頭発表（一般）
- The 8th Congress of Asia Pacific Vitreo-retina Society (APVRS), 2013年12月, 英語, 日本網膜硝子体学会, 名古屋, 国際会議The natural course and response to treatments in the cases with peripapillary polypoidal choroidal vasculopathy,口頭発表（一般）
- The 8th Congress of Asia Pacific Vitreo-retina Society (APVRS), 2013年12月, 英語, 日本網膜硝子体学会, 名古屋, 国際会議The early response to aflibercept in the recurrent neovascular age-related macular degeneration after ranibizumab treatment.口頭発表（一般）
- 第67回日本臨床眼科学会, 2013年10月, 日本語, 日本眼科学会, 横浜, 国内会議網膜中心静脈閉塞症合併黄斑浮腫にBevacizumab硝子体内注射後無還流領域を来たした症例口頭発表（一般）
- 第67回日本臨床眼科学会, 2013年10月, 日本語, 日本眼科学会, 横浜, 国内会議黄斑浮腫を伴う網膜中心静脈閉塞症に対するBevacizumab治療の6カ月成績と予後予測因子口頭発表（一般）
- 第67回日本臨床眼科学会, 2013年10月, 日本語, 日本眼科学会, 横浜, 国内会議ポリープ状脈絡膜血管症に対する光線力学療法の治療効果に関連する因子の検討口頭発表（一般）
- 第67回日本臨床眼科学会, 2013年10月, 日本語, 日本眼科学会, 横浜, 国内会議AMDに対するranibizumab硝子体注射の導入期治療の成績に関与する遺伝的因子討口頭発表（一般）
- 第47回日本眼炎症学会, 2013年07月, 日本語, 日本眼炎症学会, 大阪, 国内会議両眼性網膜血管炎を伴う松果体部胚細胞腫の一例口頭発表（一般）
- フォーサム2013大阪, 2013年07月, 日本語, 日本眼炎症学会, 大阪, 国内会議MPPEに組織プラスミノーゲン活性化因子硝子体注射を施工した1例口頭発表（一般）
- ARVO2012, 2013年05月, 英語, The Association For Research in Vision and Ophthalmology, Seattle, USA, 国際会議The association of elastin gene variants with two angiographic subtypes of polypoidal choroidal vasculopathy.口頭発表（一般）
- ARVO2012, 2013年05月, 英語, The Association For Research in Vision and Ophthalmology, Seattle, USA, 国際会議Syntaphilin is expressed in astrocytes in optic nerve and is down regulated in optic nerve after axonal injury口頭発表（一般）
- 第117回日本眼科学会総会, 2013年04月, 日本語, 日本眼科学会, 東京, 国内会議日本人の成人発症卵黄状黄斑ジストロフィーにおけるRDS遺伝子多型の検討口頭発表（一般）
- 第117回日本眼科学会総会, 2013年04月, 日本語, 日本眼科学会, 東京, 国内会議ポリープ状脈絡膜血管症のインドシアニングリーン蛍光造影所見とエラスチン遺伝子多型口頭発表（一般）
- 第51回日本網膜硝子体学会, 2012年11月, 日本語, 日本網膜硝子体学会, 甲府, 国内会議絡膜血管症の血管造影に基づくサブタイプと光線力学療法の治療効果の検討口頭発表（一般）
- 第51回日本網膜硝子体学会, 2012年11月, 日本語, 日本網膜硝子体学会, 甲府, 国内会議中心性網脈絡膜症に対する低照射エネルギーPDTの短期成績口頭発表（一般）
- 第51回日本網膜硝子体学会, 2012年11月, 日本語, 日本網膜硝子体学会, 甲府, 国内会議加齢黄斑変性に対するranibizumab硝子体注射の24ヶ月成績口頭発表（一般）
- 第66回日本臨床眼科学会, 2012年10月, 日本語, 日本眼科学会, 京都, 国内会議両眼にポリープ状脈絡膜血管症を生じた一卵性双生児の症例口頭発表（一般）
- 第66回日本臨床眼科学会, 2012年10月, 日本語, 日本眼科学会, 京都, 国内会議中心性漿液性脈絡網膜症に対する光線力学療法のレーザー照射径と治療効果に関する検討口頭発表（一般）
- 第66回日本臨床眼科学会, 2012年10月, 日本語, 日本眼科学会, 京都, 国内会議ポリープ状脈絡膜血管症における脳動脈瘤および腹部大動脈瘤関連遺伝子多型口頭発表（一般）
- 第23回日本緑内障学会, 2012年09月, 日本語, 日本緑内障学会, 金沢, 国内会議視神経切断モデルにおけるsyntaphilinの変化口頭発表（一般）
- 第46回日本眼炎症学会, 2012年07月, 日本語, 日本眼炎症学会, 横浜, 国内会議結核性ぶどう膜炎に組織プラスミノーゲン活性化因子硝子体注射を施行した2例口頭発表（一般）
- 第46回日本眼炎症学会, 2012年07月, 日本語, 日本眼炎症学会, 横浜, 国内会議クリオグロブリン血症に伴う血管炎から網膜静脈分枝閉塞症を発症した1症例口頭発表（一般）
- 第68回日本弱視斜視学会総会, 2012年06月, 日本語, 日本弱視斜視学会, 名古屋, 国内会議長期経過において形態変化を認めた網膜つた状血管腫の一例口頭発表（一般）
- ARVO2012, 2012年05月, 英語, The Association For Research in Vision and Ophthalmology, Florida,USA, 国際会議The association of altered aquaporin 9 expression with apoptosis of retinal ganglion cells.口頭発表（一般）
- 第116回日本眼科学会総会, 2012年04月, 日本語, 日本眼科学会, 東京, 国内会議近視性脈絡膜血管新生に対するビスフォスフォネート薬内服の中期効果口頭発表（一般）
- 第116回日本眼科学会総会, 2012年04月, 日本語, 日本眼科学会, 東京, 国内会議ranibizumab硝子体内投与後のAMD再発例における臨床的及び遺伝的関連因子の検討口頭発表（一般）
- 第50回日本網膜硝子体学会総会, 2011年12月, 日本語, 日本網膜硝子体学会, 東京, 国内会議日本人PCVにおけるインドシアニングリーン蛍光造影所見とARMS2遺伝子およびCFH遺伝子との関連の検討口頭発表（一般）
- 第50回日本網膜硝子体学会総会, 2011年12月, 日本語, 日本網膜硝子体学会, 東京, 国内会議在胎38週出生の胎児仮死に対する高濃度酸素管理後に重度の未熟児網膜症を呈した1例口頭発表（一般）
- 第65回日本臨床眼科学会, 2011年10月, 日本語, 日本大学, 東京, 国内会議広義滲出型加齢黄斑変性に対する光線力学療法の兵庫県下多施設研究～5年成績報告～口頭発表（一般）
- 第65回日本臨床眼科学会, 2011年10月, 日本語, 日本大学, 東京, 国内会議狭義加齢黄斑変性とポリープ状脈絡膜血管症に対するranibizumab 硝子体注射の治療成績口頭発表（一般）
- 第65回日本臨床眼科学会, 2011年10月, 日本語, 日本大学, 東京, 国内会議狭義加齢黄斑変性とポリープ状脈絡膜血管症におけるCD36遺伝子多型口頭発表（一般）
- 第22回日本緑内障学会, 2011年09月, 日本語, 日本緑内障学会, 秋田, 国内会議ラット網膜神経節細胞死とアクアポリン9の発現変化の関連口頭発表（一般）
■ 共同研究・競争的資金等の研究課題
- 日本学術振興会, 科学研究費助成事業, 基盤研究(C), 神戸大学, 2021年04月01日 - 2024年03月31日網膜内に析出するフィブリノーゲンに着目した糖尿病黄斑浮腫の病態解明本研究の目的は、難治糖尿病黄斑浮腫(DME)の病態に、網膜内に滲出する血漿成分、とくにフィブリノーゲン(Fb)がどのように関与するのかを検討することである。そのため、In vitro実験としてrMC-1（ラットミュラー細胞株）、HMREC（ヒト網膜血管内皮細胞株）を用いて、Fbによる細胞傷害性の有無、HMRECにおいては血管透過性への影響の有無、さらにはそれらの傷害性を調整する経路について検討する計画である。さらにIn vivo実験として正常マウス、さらには糖尿病疾患モデルマウスを用いて、生体におけるFbによる各種網膜細胞への細胞傷害性の有無、および疾患の病態への関与の有無を検討する計画である。 本年は、MTT assayの結果、HMRECにおいてはFb濃度依存性に細胞傷害性が増加する結果を得た。またHMRECを上層に単相培養するTransWell実験において、Fb濃度依存性に血管透過性が亢進する結果を得た。さらに正常マウスの硝子体内にFbを投与することで網膜電図においてa波、b波、およびop波の各振幅が減弱すること、しかしPhNRは低下しない結果を得た。そして、これらのFbによる各種網膜細胞への傷害性の作用は、In vitroおよびIn vivoの両実験ともに、細胞間接着分子1(ICAM1)中和抗体の投与によって一部中和される結果を得た。これらの結果は、高濃度Fbは各種網膜細胞に傷害性に作用し、その作用はICAM1を介した細胞内シグナルによって調整されている可能性を示す。
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2018年04月 - 2021年03月2010～2017年に血液浄化療法を行った抗アクアポリン4抗体陽性視神経炎患者連続9例15眼の視機能予後を後ろ向きに検討した。いずれもステロイドパルス療法に抵抗性であった。12眼(80%)においてlogMAR換算で0.3以上の視力改善を見た。その大半が1年後にも良好な視力を保ち、早期の血液浄化療法が視神経脊髄炎患者の視機能回復に有効であることを報告した(Mori S, Nakamura M, et al.Jpn J Ophthalmol. 2018;62(4):525-530)。 AQP9 knowkout (KO) マウスにおいて、視神経挫滅後の網膜神経節細胞死が野生型マウスに比べて、有意に多かった。また、免疫沈降とWestern blottingにより、野生型マウスにおいては、網膜や視神経にmonocarboxylate transporter (MCT)4がAQP9と共発現していること、一方、AQP9 KOマウスや視神経挫滅後にはMCT4の発現が代償性に増加することを見出した。網膜においてエネルギー基質である乳酸の輸送を司る二つのtransporter（AQP9とMCT4）が、網膜神経節細胞において共発現していること、ならびにどちらかの一方のみ発現している場合、naiveな網膜神経節細胞の生存は維持できるが、視神経挫滅のようなストレス下では、代償機転は働くものの、生存を維持できない可能性が示唆された。競争的資金
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 2016年04月01日 - 2019年03月31日中心性漿液性脈絡網膜症(CSC)に対するゲノムワイド関連解析(GWAS)を行い、16番染色体の一塩基多型(SNP)がCSCと有意に関連することを明らかにした。同SNPはSLC7A5遺伝子に存在し、SLC7A5は網膜色素上皮細胞やミュラー細胞などに発現するアミノ酸トランスポーターであるLAT1をコードする事から、同分子がCSCの病態に関わる可能性がある。また、脈絡膜厚に関連するGWASでは補体H因子のSNPとの有意な関連を認めたが、SLC7A5遺伝子のSNPは脈絡膜厚との関連はなかったことから、CSCは脈絡膜厚に関連する病態と、そうでない病態が独立あるいは共存して発症する事が推察される。競争的資金
- 日本学術振興会, 科学研究費助成事業 基盤研究(C), 基盤研究(C), 神戸大学, 2014年04月01日 - 2017年03月31日ラット視神経に抗アクアポリン4(AQP4)抗体陽性視神経炎患者の血清を暴露することで、実験的視神経脊髄炎（NMO）モデルを構築し、ヒト免疫グロブリン投与が網膜神経節細胞(RGC)死を有意に抑制できる事を示した。抗AQP4抗体陽性ならびに陰性視神経炎患者では網膜神経組織への障害様式が異なる事を示した。アクアポリン9チャンネルによる乳酸輸送がRGCの生存にとって重要であることを示した。競争的資金