Published papers

Abstract Myopia, or near-sightedness, is a growing global concern as its incidence rate continues to dramatically rise. It has been linked to significant ocular morbidity and reduced quality of life. Despite this, much is still largely unknown about the development of and the mechanisms driving the pathogenesis of myopia. As such, myopia prevention and myopia mitigation treatment strategies are occasionally ineffective, can be difficult to adhere to, and have diminishing returns over time. Recently, non-visual opsins (OPN3, OPN4, and OPN5) have emerged as potentially impacting myopia regulation. This narrative review aims to summarize the current understanding of the non-visual opsins and how they might influence myopia. In addition, this review explores how utilizing this knowledge can help develop promising future treatment strategies to reduce the incidence and severity of myopia.

Purpose We report a case of ocular siderosis caused by a subretinal iron foreign body. Observations A 30-year-old male construction worker injured by a small piece of shrapnel while working visited an eye clinic for decreased vision in left eye on day X, and was subsequently referred to our hospital with a diagnosis of vitreous hemorrhage on day X+1. Although a penetrating foreign body was suspected, no obvious wound or intraocular foreign body was found even after the hemorrhage subsided. On X+3 months, a rhegmatogenous retinal detachment was found and a lens-sparing vitrectomy was performed. A black elevated subretinal lesion was noted intraoperatively but not removed because it was considered to be a blood clot. The postoperative course was stable with best corrected visual acuity (BCVA) recovering to 20/16. However, the BCVA decreased to 20/30 on X+11 months with the subretinal lesion turning reddish brown. The electroretinogram also showed a significant attenuation of all stimuli. Siderosis was considered to have developed due to the subretinal foreign body. On X+14 months, we performed a combined phaco-vitrectomy to remove the foreign body. Analysis revealed iron as the main component of the foreign body. However, the postoperative electroretinogram remained unchanged, and the BCVA was 20/63 without improvement. Conclusions and importance We experienced a case of a subretinal iron foreign body being mistaken for a blood clot. Even if the vision stays stable, ocular siderosis may occur over the long term if a subretinal iron foreign body remains. Therefore, surgical removal should be actively considered when a subretinal iron foreign body is suspected.

Objectives Since the COVID-19 pandemic started, an increasing number of individuals use online resources to obtain health-related information, including myopia management. We aimed to obtain the search interest of global public health on myopia and prevention/treatment methods before and after the outbreak of COVID-19. Methods Google Trends was used to assess the global search interest in myopia and related terms. Data spanning from 2019 to 2023 were collected and segmented into three periods: prepandemic (2019), pandemic year (2020) and postpandemic (2021-2023). Each average search volume index was used to examine public awareness with the Kruskal-Wallis test. Results Among commonly used search keywords, Myopia is preferred over more colloquial terms (Nearsighted and Shortsighted). During the pandemic, searches for Myopia remained stable, while postpandemic, interest in Myopia surged (31.54%, p<0.0001). Myopia prevention/treatment awareness from 2019 to 2023 indicated notable shifts. In 2020, searches for Contact lenses and Spectacles decreased (-14.09% and -21.97%, respectively, both p<0.0001). These trends persisted postpandemic, with declining searches for Orthokeratology (-41.38%, p<0.01). Public interest for Light therapy (43.00%, p<0.0001) and Atropine (27.42%, p<0.0001) increased. Discussion The research highlights significant increases in global online awareness of myopia during the COVID-19 pandemic. The extended period of remote work during the pandemic may alter lifestyle habits and affect public perception of treatment options. Those findings could offer valuable perspectives on global interest patterns related to myopia, which supports subsequent myopia studies and is further useful to develop relevant public health policies.

The study goals were measurement of the choroidal thickness (CT) and investigation of related factors among children. Third-grade students at an elementary school in Tokyo participated in this study. A total of 119 schoolchildren underwent measurements of the axial length (AL), non-cycloplegic objective refraction (SE), and CT. The CT was divided into nine regions: the subfoveal area with a diameter of 1 mm (C0), a 5-mm-diameter circle-C0 (C1), and a 9-mm-diameter circle (C2); each was further divided into four quadrants. The SE, AL, and C0 CT were, respectively, - 1.57 ± 1.56 diopters, 23.39 ± 0.80 mm, and 297.73 ± 57.88 μm. Multiple regression analysis showed that the time spent using a computer was associated significantly with the CT in the C0 and the inferior C2 (C0: β = -0.728, P = 0.028; inferior C2: β = -0.527, P = 0.048), and the reading distance was associated significantly with the CT in the superior and nasal C2 (superior, β = 1.664, P = 0.007; nasal, β = 1.128, P = 0.015). In addition, time spent using smartphones, tablets, or handheld gaming devices was associated significantly with the CT in the superior and inferior C2 (superior C2: β = 0.259, P = 0.018; inferior C2: β = 0.262, P = 0.013). In conclusion, reading distance and time spent on digital devices may be associated with choroid thickness in children.

PURPOSE: Mast cells (MCs), key immune regulators, contribute to inflammatory responses through their degranulation. Choroidal thinning is a hallmark of myopia, and MC degranulation has been shown to induce choroidal thinning in a rat model of geographical atrophy. However, the role of choroidal MCs in myopia remains poorly understood. This study aimed to demonstrate that an increased number and proportion of degranulated MCs in the choroid are important determinants of choroidal thinning and myopia development. METHODS: Lens-induced myopia (LIM) was induced by monocular -30 diopter (D) lens wearing in C57BL/6 mice, MC-deficient mice (Mcpt5/Cma1DTR/+), and MC-deficient mice receiving suprachoroidal injection of peritoneal MCs (PMCs). Cromolyn sodium (cromolyn) and pemirolast potassium (pemirolast), reagents that inhibit degranulation by stabilizing MC membranes, were topically applied in LIM mice. Ocular parameters including refraction, axial length, and choroidal thickness were measured before and after LIM. Choroidal MC degranulation was evaluated by choroidal flatmount staining. RESULTS: LIM was successfully induced in wild-type mice but was significantly suppressed in MC-deficient mice. Suprachoroidal injection of PMCs into MC-deficient mice restored myopia progression, as evidenced by axial elongation and choroidal thinning. MC degranulation was significantly increased by -30 D lens wearing, whereas topical administration of cromolyn and pemirolast effectively inhibited both MC degranulation and myopia progression. CONCLUSIONS: Choroidal MC degranulation plays a critical role in LIM by promoting choroidal thinning and axial elongation. These findings enhance our understanding of the role of choroidal MC degranulation in myopia, suggesting a potential therapeutic target for myopia treatment.

Objective or Purpose: To investigate the effect of anti-VEGF therapy on wide-field retinal and choroidal thickness in patients with macular edema secondary to RVO, and to identify how these effects vary based on clinical characteristics such as occlusion location and patient sex. Design: Retrospective observational study. Subjects, Participants, and/or Controls: Thirty-eight patients (38 eyes) with RVO treated at Keio University Hospital (26 males, 12 females; mean age, 67.7 ± 8.5 years). Seventeen fellow eyes without injection served as internal controls. Methods, Intervention, or Testing: We analyzed 38 eyes with RVO who received intravitreal injections of aflibercept (n = 31) or ranibizumab (n = 7). Wide-field optical coherence tomography (OCT) was performed at baseline (within 7 days before the injection) and at the follow-up visit (30 ± 14 days after the injection). Changes in retinal and choroidal thickness were analyzed across nine predefined regions: a central 5-mm subfield (C0) and eight surrounding peripheral sectors: temporal (L1), superior-temporal (L2), superior (L3), superior-nasal (L4), nasal (L5), inferior-nasal (L6), inferior (L7), and inferior-temporal (L8). Statistical analysis was performed using the Wilcoxon signed-rank test and Bonferroni correction for nine regions. Main Outcome Measures: Changes in regional retinal and choroidal thickness Results: Post-injection, retinal thickness significantly decreased in all regions except L4 and L6 (p < 0.0056). Choroidal thickness showed a significant reduction in L2, L5, and L8 (p < 0.0056). Subgroup analyses revealed no significant changes in choroidal thickness in either the superior RVO group (n = 9) or the inferior RVO group (n = 17). A clear sex-based difference was also observed: male patients (n = 26) exhibited choroidal thinning in L4, L5, L6, and L8 (p < 0.0056), whereas female patients (n = 12) showed no significant changes in any region. Conclusion: Anti-VEGF therapy reduced retinal and choroidal thickness in specific regions in eyes with RVO. No significant differences were observed between eyes with superior and inferior occlusions. In male patients, significant thinning was observed in multiple peripheral regions, whereas no significant changes were noted in female patients. These findings suggest that the choroidal response to anti-VEGF therapy is complex and warrants further investigation.

Aims To compare the changes in ocular parameters after implantation of two types of intraocular lenses (IOLs) following cataract surgery. One IOL transmits violet light (VL), and the other does not. Methods A total of 402 patients were randomly assigned to receive either a VL-non-transmitting IOL or a VL-transmitting IOL. Ocular parameters were measured preoperatively and postoperatively, and participants completed a lifestyle questionnaire. The choroidal thickness (CT) was measured using the PLEX Elite 9000 (Carl Zeiss Meditec). The associations between changes in CT and age, sex, type of IOL, preoperative CT, time spent outdoors, time spent using a smartphone or tablet and time spent reading were examined using stepwise multiple regression analysis (SPSS V.28.0 for Windows, IBM-SPSS). Results The baseline mean spherical equivalents were −4.00±5.97 D and −2.19±4.73 D, the axial lengths were 24.84±1.82 mm and 24.19±1.65 mm, and the CTs were 213.78±102.93 µm and 239.20±104.98 µm for the VL-non-transmitting and VL-transmitting IOL groups, respectively. The mean changes in the CT from 3 to 12 months postoperatively were −0.30±18.32 µm for the VL-non-transmitting IOLs and 3.48±16.46 µm for the VL-transmitting IOLs (p=0.012). Multiple regression analysis identified significant choroidal thickening associated with female sex (p=0.004), VL-transmitting IOL implantation (p=0.049) and increased outdoor exposure (p=0.008). Conclusion The choroidal thickening after cataract surgery was associated with the VL-transmitting IOL and longer time spent outdoors with exposure to abundant VL. Despite these findings, this study has several limitations, including a relatively short follow-up period, and it did not assess postoperative lifestyle, VL exposure or actual peripheral defocus in the patients. Trial registration number UMIN000038961.

Scleral remodeling plays a crucial role in myopia development. Although ultrastructural collagen changes have been described, quantitative assessment at the fiber bundle level remains limited. This study quantitatively evaluated scleral collagen remodeling in a lens-induced myopia (LIM) mouse model using polarized light microscopy (PLM) combined with picrosirius red (PSR) staining. LIM was induced in C57BL/6J male mice by applying a monocular −30 D lens from postnatal week 3 to 6. Eyes wearing −30 D lenses showed myopic shifts in refraction (−8.42 ± 3.87 D vs. 4.42 ± 4.45 D; p = 0.002) and axial elongation (0.21 ± 0.04 mm vs. 0.18 ± 0.05 mm; p = 0.020) compared with contralateral controls. PLM revealed looser, more disorganized collagen bundles in myopic sclera. Quantitative analysis showed reduced bundle proportion (40.91 ± 6.58% vs. 48.36 ± 6.47%; p = 0.040) and mean size (147.11 ± 59.38 µm2 vs. 281.45 ± 101.00 µm2; p = 0.002). These results indicate that myopia development involves structural remodeling of the sclera and that PLM with PSR staining provides a practical approach for quantitative wide-field evaluation of collagen architecture in experimental myopia.

East Asia is facing a growing burden of myopia, with pronounced disparities in access to eye care between urban and rural populations. Digital health technologies present a scalable and cost-effective alternative to traditional myopia interventions that enhance early detection, risk stratification, behavioral modification, and public education. Artificial intelligence-assisted screening tools, wearable monitors, and mHealth initiatives, such as the World Health Organization-International Telecommunication Union MyopiaEd program, have demonstrated effectiveness in improving myopia prevention and health education accessibility. However, achieving a sustained impact requires rigorous validation, robust data governance, infrastructure investment, and integration with established clinical strategies. East Asia could be well-positioned to pioneer a comprehensive digital model for equitable myopia control.

Abstract Background Opn3 is a non-visual blue light-sensitive opsin that has recently been reported to have an expansive repertoire of biological functions. To investigate the function of Opn3-expressing cells, we aimed to generate a system in which Opn3-expressing cells can be targeted by site-specific gene recombination. Methods Opn3-phiC31o knock-in (KI) mice were generated using the CRISPR-Cas9 method. The phiC31o-poly(A) cassette was inserted into the translation start site in exon 1. Opn3 mRNA and phiC31o mRNA were visualized by in situ hybridization (ISH). 5' rapid amplification of cDNA end (5' RACE) analysis was performed using RNAs from wild-type mouse cerebral cortex and cerebellum to identify the transcription start site of Chml, predicted to be shared with the transcription start site of Opn3. Cold-induced decrease in body temperature was monitored with a telemetric probe to confirm the phenotype of Opn3 knockout. To examine the phiC31o integrase-mediated recombination, Opn3-phiC31o mice were crossed with the ROSA26 MultiFPsΔPuro reporter and cyan fluorescent protein, mCerulean, expression was labeled by immunohistochemistry. Results The expression pattern of phiC31o mRNA was consistent with that of Opn3 mRNA in Opn3-phiC31o heterozygous mouse brains, indicating that phiC31o mRNA is expressed under the control of the Opn3 promoter. Based on the public database, the transcription start site of exon 1 of Opn3 is identical to that of Chml, suggesting that phiC31o KI disrupts Chml expression. However, Opn3-phiC31o homozygous mice sustained Chml expression, and the transcription start site of Chml was confirmed to be located 112 bp upstream of the predicted second exon. Opn3-phiC31o homozygous mice showed a larger decrease in body temperature under cold exposure compared to wild-type controls. In addition, these mice also exhibited a refractive myopia phenotype. These findings confirmed the functional knockout of Opn3. Double transgenic mice of Opn3-phiC31o and ROSA26 MultiFPsΔPuro reporter showed mCerulean expression mainly in the olfactory bulb, cerebral cortex, thalamus, and cerebellum. The recombination efficiency was 30% to 44% in the cerebellum. Conclusions Opn3-phiC31o KI mice were successfully generated. We can generate Opn3 null mice that does not disrupt Chml by preparing homozygotes of Opn3-phiC31o. We have deposited the sequences including the newly found transcription start site of Chml.

Diabetic retinopathy (DR) is a serious complication of diabetes, leading to vision loss worldwide. The prevalence of DR has increased in recent decades. To understand the pathophysiology of DR, various experimental models have been developed and used. In this review article, we first outline what is currently known of the general pathology of DR, including the mechanisms involved in hyperglycemia, vascular dysfunction, retinal ischemia, retinal inflammation, and retinal degeneration. We next summarize various pathologies detected in experimental models in vivo, such as in chemically and genetically induced murine, rat, and monkey models, surgical methods in larger animals like cats, and a novel murine DR model using occlusion of the carotid artery under early diabetic conditions. A general overview of the in vitro models, including cell monocultures, co-cultures, and 3D models, is also provided. This current summary enables further research to obtain a more thorough understanding of DR pathogenesis and develop appropriate treatment measures.

The global pandemic of myopia has become an urgent public health concern in recent years. Although the mechanism remains largely unclear, the importance of outdoor light exposure on myopia prevention is widely recognized. Outdoor light is more intense and has a different spectral composition compared to indoor lighting, which are believed to contribute to the suppression of myopia. However, due to modern lifestyles, even children find it difficult to spend time outdoors. To receive outdoor light efficiently is important, yet previous reports showed inconsistent findings on optimal thresholds for outdoor light exposure. One reason may be the lack of a standardized protocol for measuring light reaching the eye surface. In this study, we developed a novel measurement device using a 3D-printed mannequin head with a light sensor probe embedded at the eye position to mimic the human eye. We assessed the proportion of light that reached the mannequin’s eye surface from different directions at various time points on a sunny day and evaluated the influence of different eyeglasses and lenses.

The posterior ocular circulatory system comprises choroidal vasculature and central retinal and posterior ciliary arteries (PCAs) that are fundamental for ocular tissue maintenance. Much is known about the development of the retinal vascular system, but that of the posterior ocular circulation system remain obscure. Therefore, we aimed to clarify the development of the intraocular vasculature involved in the posterior ocular circulation system. Choriocapillaris and hyaloid capillaries are formed in situ and de novo through the endothelial differentiation of hemangioblasts. The intraocular segments of the hyaloid artery penetrate the retina before extraocular segments appear. The intraocular segments of PCAs arise from the hyaloid artery before the extraocular segments reach the eye. The posterior ocular circulation system apparently synchronizes with events throughout the entire process of ocular development. The intraocular vasculature notably formed before the extraocular segments reached the eyes. Our findings provide a novel perspective on ocular development and might facilitate understanding of eye diseases in humans.

PURPOSE. The prevalence of myopia has increased worldwide in recent decades, shifting the focus in research from genetic to environmental factors. The roles of diet in the development of myopia may be directly associated with gut microbiota composition. Therefore this study evaluated the effects of antibiotic-induced gut dysbiosis on the development of negative lens-induced myopia. METHODS. We administered several antibiotics (ampicillin, vancomycin, neomycin, or a mixture) to induce gut dysbiosis in male C57BL/6J mice with negative lens-induced myopia. Gut microbiome profiles were analyzed by 16 S rRNA gene sequencing. RESULTS. Mice administered vancomycin, neomycin, and a mixture of three antibiotics exhibited resistance to lens-induced myopia, unlike control or ampicillin-administered mice. Further analyses revealed no specific trend in the gut microbiota composition and diversity related to myopia resistance, except for an increase in the abundance of Clostridiaceae. CONCLUSIONS. These findings demonstrate the potential role of the gut microbiome, particularly Clostridiaceae family, in myopia susceptibility. This study offers new insights into the preventive strategies and therapeutic interventions to mitigate myopia development.

PURPOSE. This study aimed to evaluate the efficacy of photoimmunotherapy (PIT) targeting VEGFR2 for the treatment of neovascular AMD and to investigate its potential as a novel therapeutic strategy. METHODS. DC101-IR700, a conjugate of the anti-mouse VEGFR2 monoclonal antibody DC101 and the photosensitizer IR700, was investigated both in vitro and in vivo. VEGFR2 expression in endothelial cells was confirmed via qPCR and immunocytochemistry. Laser-induced choroidal neovascularization (CNV) was established in C57BL/6J mice. Localization of DC101-IR700 within CNV lesions was assessed by immunofluorescence. After PIT was performed using either a 690 nm near-infrared manual laser or a slit lamp laser, CNV volumes were quantified through confocal microscopy. Cell viability post PIT was measured using MTT assay and cell death in CNV lesions was evaluated using TUNEL staining. RESULTS. DC101-IR700 localized specifically to VEGFR2-positive cells in CNV lesions, and PIT induced significant VEGFR2-dependent cytotoxicity in vitro. In vivo, both PIT and directional PIT using slit lamp laser significantly reduced CNV volumes compared with controls. TUNEL staining confirmed VEGFR2-specific cell death in treated CNV lesions. Directional PIT achieved similar efficacy to PIT, demonstrating its potential as a clinically viable alternative. CONCLUSIONS. PIT targeting VEGFR2 selectively induced cell death in pathological neovascular tissues, significantly reducing CNV volume in an AMD model. These findings suggest that VEGFR2-specific PIT represents a promising and targeted approach for treating neovascular AMD, offering advantages over conventional anti-VEGF therapies by potentially decreasing treatment frequency and improving efficacy.

Background: Myopia, characterized by excessive axial elongation of the eyeball, has become a significant global public health issue, particularly in Asia. Severe myopia increases the risk of ocular complications, including retinal degeneration and glaucoma. Recent studies have identified the role of scleral extracellular matrix remodeling and endoplasmic reticulum (ER) stress in myopia pathogenesis. Our previous study identified scleral ER stress as a critical factor in myopia development. This study aimed to investigate the therapeutic potential of 4-phenylbutyric acid (4-PBA), a chemical chaperone, in mitigating scleral ER stress and its effects on myopia progression in a mouse myopia model under masked condition. Methods: A lens-induced myopia (LIM) mouse model was utilized to evaluate the effects of 4-PBA administered as eye drops. Mice received varying concentrations of 4-PBA or phosphate-buffered saline (PBS) as a control. Changes in refractive error and axial length were measured to assess myopia progression. In addition, further experiments were also conducted under masked conditions, where the experimenter was unaware of the treatment was being applied, for the three conditions of 2%, 0.5% 4-PBA eye drops or vehicle treatment of LIM mice. Results: Administration of 4-PBA at concentrations of 0.5% and higher significantly suppressed the myopic shift in refraction and axial elongation associated with myopia compared to mice in the PBS control group. In a blinded, masked experiment, 2% and 0.5% 4-PBA eye drops also suppressed the progression of myopia in a dose-dependent manner. Conclusions: This study demonstrated that 4-PBA effectively mitigated myopia progression in a mouse model by targeting scleral ER stress. The dose-dependent suppression of myopic shifts and axial elongation under masked experimental condtion highlights the potential of 4-PBA as a therapeutic agent for managing myopia. These findings pave the way for further research and potential clinical applications in myopia treatment.

In early neonates, the fetal circulatory system undergoes dramatic transition to the adult circulatory system. Normally, embryonic connecting vessels, such as the ductus arteriosus and the foramen ovale, close and regress. In the neonatal retina, hyaloid vessels maintaining blood flow in the embryonic retina regress, and retinal vessels take over to form the adult-type circulatory system. This process is regulated by a programmed cell death switch mediated by macrophages via Wnt and angiopoietin 2 pathways. In this study, we seek other mechanisms that regulate this process, and focus on the dramatic change in oxygen environment at the point of birth. The von Hippel-Lindau tumor suppressor protein (pVHL) is a substrate recognition component of an E3-ubiquitin ligase that rapidly destabilizes hypoxia-inducible factor alpha s (HIF-alpha s) under normoxic, but not hypoxic, conditions. To examine the role of oxygen-sensing mechanisms in retinal circulatory system transition, we generated retina-specific conditional-knockout mice for VHL (Vhl(alpha-CreKO) mice). These mice exhibit arrested transition from the fetal to the adult circulatory system, persistence of hyaloid vessels and poorly formed retinal vessels. These defects are suppressed by intraocular injection of FLT1-Fc protein [a vascular endothelial growth factor (VEGF) receptor-1 (FLT1)/Fc chimeric protein that can bind VEGF and inhibit its activity], or by inactivating the HIF-1 alpha gene. Our results suggest that not only macrophages but also tissue oxygen-sensing mechanisms regulate the transition from the fetal to the adult circulatory system in the retina.

Wide-angle viewing systems (WAVSs) were originally established for pars plana vitrectomy. However, their application to scleral buckling surgery was recently reported. In this study, we compared the outcomes of scleral buckling using a noncontact WAVS with that of scleral buckling using conventional indirect ophthalmoscopy for rhegmatogenous retinal detachment. The clinical records of 39 eyes (39 patients) with rhegmatogenous retinal detachment primarily treated between November 2012 and June 2014 at the Vitreo-Retina Surgical Division Clinic at the Department of Ophthalmology, Keio University Hospital were retrospectively reviewed. Scleral bucking was performed using WAVS with surgical placement of an endoilluminator in 16 eyes and indirect ophthalmoscopy in 23 eyes. The patients in these groups were consecutive over different intervals. The preoperative demographics, success rate of retinal reattachment, intraoperative findings, and postoperative complications were evaluated. There were no significant differences in pre- or postoperative conditions between groups, and similar surgical outcomes were achieved with the WAVS and conventional procedures. However, compared with the conventional procedure, the WAVS procedure resulted in fewer intraoperative corneal epithelial disorders (p = 0.049) and decreased the surgical duration of segmental buckling (p = 0.02); therefore, it may be suggested as an effective alternative procedure.

Myopia is increasing worldwide. Although the exact etiology of myopia is unknown, outdoor activity is one of the most important environmental factors for myopia control. We previously reported that violet light (VL, 360-400 nm wavelength), which is abundant in the outdoor environment, suppressed myopia progression for individuals under 20 years of age. However, whether VL is also effective for adult high myopia, which can be sight-threatening, has remained unknown. To investigate the influence of VL for adult myopia, we retrospectively compared the myopic progression and the axial length elongation over five years in adult high myopic patients over 25 years of age after two types (non-VL transmitting and VL transmitting) of phakic intraocular lens (pIOL) implantation. We found that high myopic patients with the non-VL transmitting pIOLs implanted are almost two times more myopic in the change of refraction and four times longer in the change of axial length, compared to those implanted with the VL transmitting pIOLs. This result indicated that the VL transmitting pIOL suppressed myopia progression and axial length elongation compared with the non-VL transmitting one. In conclusion, our study showed the VL possibly has an anti-myopia effect for human adults with high myopia.