論文 - 栗原　俊英

Retinal diseases regulated by hypoxia—basic and clinical perspectives: A comprehensive review

Shinojima A., Lee D., Tsubota K., Negishi K., Kurihara T.

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 23 ） 5496 2021年12月

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In recent years, the number of patients with age-related macular degeneration (AMD) is increasing worldwide along with increased life expectancy. Currently, the standard treatment for wet-AMD is intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs. The upstream of VEGF is hypoxia-inducible factor (HIF), a master regulator of hypoxia-responsive genes responsive to acute and chronic hypoxia. HIF activation induces various pathological pro-angiogenic gene expressions including VEGF under retinal hypoxia, ultimately leading to the development of ocular ischemic neovascular diseases. In this regard, HIF is considered as a promising therapeutic target in ocular ischemic diseases. In clinical ophthalmology, abnormal hypofluorescent areas have been detected in the late-phase of indocyanine green angiography, which are thought to be lipid deposits at the level of Bruch’s membrane to choriocapillaris in vitreoretinal diseases. These deposits may interfere with the oxygen and nutrients that should be supplied to the retinal pigment epithelium, and that HIF/VEGF is highly suspected to be expressed in the hypoxic retinal pigment epithelium, leading to neovascularization. In this review, we comprehensively summarize pathophysiology of AMD-related ocular diseases with the HIF/VEGF pathway from basic and clinic researches with recent findings.

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Association between ocular axial length and anthropometrics of Asian adults

Shinojima A., Kurihara T., Mori K., Iwai Y., Hanyuda A., Negishi K., Torii H., Tsubota K.

BMC Research Notes （BMC Research Notes）  14 （ 1 ） 328 - 328 2021年12月

査読有り

　概要を見る

Objective: The purpose of this study is to analyze axial length, body height, hand length, and foot length to find new factors that predict myopia and to identify gender differences as one of the factors of high myopia. A cross-sectional study was conducted as a single observation. Body height, hand length, and foot length were measured according to standard anthropometric methods. Axial length, retinal thickness, and choroidal thickness were measured using the IOL Master 700 and the Heidelberg Spectralis-OCT. To account for body height differences among participants, foot length/body height and hand length/body height were analyzed using a mixed-effects model. Results: A total of 80 eyes (men, n = 20, 40 eyes; women, n = 20, 40 eyes) were analyzed. The mean age was 33.5 years (range 21–59 years, SD: 9.6). For choroidal thickness, there was a significant association with axial length in men (p < 0.001) and a trend toward an association in women (p = 0.072). There was also a significant association between foot length/body height and axial length in men (p = 0.015), but not in women (p = 0.58). These results suggest that factors that determine body height and foot length may be related to axial length, although they vary by gender.

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Pparα modulation-based therapy in central nervous system diseases

Lee D., Tomita Y., Allen W., Tsubota K., Negishi K., Kurihara T.

Life （Life）  11 （ 11 ）  2021年11月

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The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.

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Effect of violet light-transmitting eyeglasses on axial elongation in myopic children: A randomized controlled trial

Mori K., Torii H., Hara Y., Hara M., Yotsukura E., Hanyuda A., Negishi K., Kurihara T., Tsubota K.

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 22 ） 5462 2021年11月

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The fact that outdoor light environment is an important suppressive factor against myopia led us to invent violet light-transmitting eyeglasses (VL glasses) which can transmit violet light (VL), 360–400 nm in wavelength, for the suppression of myopia, and can meanwhile block harmful ultra-violet waves from sunlight. The current study is a double-blinded randomized clinical trial to investigate the myopia-suppressive effect of VL glasses compared to conventional eyeglasses (placebo glasses) that do not transmit VL. The subjects were children aged from 6 to 12 years old, the population in which myopia progression is generally accelerated, and the myopia suppressive effect was followed up for two years in a city in Japan. Periodical ophthalmic examinations, interviews, and measurements of reflection and axial length under mydriasis were performed at the initial visit (the baseline) and at 1, 6, 12, 18, and 24 months. The mean change in axial length in the VL glasses group was significantly smaller than in the placebo glasses group when time for near-work was less than 180 min and when the subjects were limited to those who had never used eyeglasses before this trial (p < 0.01); however, this change was not significant without subgrouping. The suppressive rate for axial elongation in the VL glasses group was 21.4% for two years.

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Updates on the current treatments for diabetic retinopathy and possibility of future oral therapy

Tomita Y., Lee D., Tsubota K., Negishi K., Kurihara T.

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 20 ） 4666 2021年10月

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Diabetic retinopathy (DR) is a complication of diabetes and one of the leading causes of vision loss worldwide. Despite extensive efforts to reduce visual impairment, the prevalence of DR is still increasing. The initial pathophysiology of DR includes damage to vascular endothelial cells and loss of pericytes. Ensuing hypoxic responses trigger the expression of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors. At present, the most effective treatment for DR and diabetic macular edema (DME) is the control of blood glucose levels. More advanced cases require laser, anti-VEGF therapy, steroid, and vitrectomy. Pan-retinal photocoagulation for non-proliferative diabetic retinopathy (NPDR) is well established and has demonstrated promising outcomes for preventing the progressive stage of DR. Furthermore, the efficacy of laser therapies such as grid and subthreshold diode laser micropulse photocoagulation (SDM) for DME has been re-ported. Vitrectomy has been performed for vitreous hemorrhage and tractional retinal detachment for patients with PDR. In addition, anti-VEGF treatment has been widely used for DME, and re-cently its potential to prevent the progression of PDR has been remarked. Even with these treat-ments, many patients with DR lose their vision and suffer from potential side effects. Thus, we need alternative treatments to address these limitations. In recent years, the relationship between DR, lipid metabolism, and inflammation has been featured. Research in diabetic animal models points to peroxisome proliferator-activated receptor alpha (PPARα) activation in cellular metabolism and inflammation by oral fenofibrate and/or pemafibrate as a promising target for DR. In this paper, we review the status of existing therapies, summarize PPARα activation therapies for DR, and discuss their potentials as promising DR treatments.

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Shorter axial length is a risk factor for proliferative vitreoretinopathy grade C in eyes unmodified by surgical invasion

Minami S., Uchida A., Nagai N., Shinoda H., Kurihara T., Ban N., Terasaki H., Takagi H., Tsubota K., Sakamoto T., Ozawa Y.

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 17 ） 3944 2021年09月

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Purpose: To investigate the risk factors for the development of proliferative vitreoretinopathy grade C (PVR-C), independent of prior surgical invasion. Methods: Patients who underwent surgery for rhegmatogenous retinal detachment were prospectively registered with the Japan-Retinal Detachment Registry, organized by the Japanese Retina and Vitreous Society, between February 2016 and March 2017. Data obtained from general ophthalmic examinations performed before and at 1, 3, and 6 months after surgery were analyzed. Results: We included 2013 eyes of 2013 patients (men, 1326 (65.9%); mean age, 55.2 ± 15.2 years) from amongst 3446 registered patients. Preoperative PVR-C was observed in 3.6% of patients. Propensity score matching revealed that a shorter axial length (AL) was a risk factor for preoperative PVR-C (OR (Odds Ratio), 0.81; 95%CI (Confidence Interval), 0.69 to 0.96; p = 0.015), which was a risk factor for surgical failure (OR, 4.22; 95%CI, 1.12 to 15.93; p = 0.034); the association was particularly significant for eyes with an AL < 25.0 mm (p = 0.016), while it was insignificant for eyes with an AL ≥ 25.0 mm. Conclusions: A shorter AL was related to the development of PVR-C before surgical invasion. Our results will help elucidate the fundamental pathogenesis of PVR and caution clinicians to meticulously examine eyes with a shorter AL to detect retinal detachment before PVR development.

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Pemafibrate prevents retinal dysfunction in a mouse model of unilateral common carotid artery occlusion

Lee D., Tomita Y., Jeong H., Miwa Y., Tsubota K., Negishi K., Kurihara T.

International Journal of Molecular Sciences （International Journal of Molecular Sciences）  22 （ 17 ） 9408 - 9408 2021年09月

査読有り,  ISSN  16616596

　概要を見る

Cardiovascular diseases lead to retinal ischemia, one of the leading causes of blindness. Retinal ischemia triggers pathological retinal glial responses and functional deficits. Therefore, maintaining retinal neuronal activities and modulating pathological gliosis may prevent loss of vi-sion. Previously, pemafibrate, a selective peroxisome proliferator-activated receptor alpha modu-lator, was nominated as a promising drug in retinal ischemia. However, a protective role of pem-afibrate remains untouched in cardiovascular diseases-mediated retinal ischemia. Therefore, we aimed to unravel systemic and retinal alterations by treating pemafibrate in a new murine model of retinal ischemia caused by cardiovascular diseases. Adult C57BL/6 mice were orally administered pemafibrate (0.5 mg/kg) for 4 days, followed by unilateral common carotid artery occlusion (UCCAO). After UCCAO, pemafibrate was continuously supplied to mice until the end of exper-iments. Retinal function (a-and b-waves and the oscillatory potentials) was measured using elec-troretinography on day 5 and 12 after UCCAO. Moreover, the retina, liver, and serum were sub-jected to qPCR, immunohistochemistry, or ELISA analysis. We found that pemafibrate enhanced liver function, elevated serum levels of fibroblast growth factor 21 (FGF21), one of the neuropro-tective molecules in the eye, and protected against UCCAO-induced retinal dysfunction, observed with modulation of retinal gliosis and preservation of oscillatory potentials. Our current data suggest a promising pemafibrate therapy for the suppression of retinal dysfunction in cardiovascular diseases.

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Glucose levels between the anterior chamber of the eye and blood are correlated based on blood glucose dynamics

Kurihara T., Lee D., Shinojima A., Kinoshita T., Nishizaki S., Arita Y., Hidaka Y., Nishi Y., Shirakawa Y., Kimura S., Tsuneyoshi Y., Torii H., Tsubota K., Negishi K.

PLoS ONE （PLoS ONE）  16 （ 9 September ） e0256986 2021年09月

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Glycemic control is essential to manage metabolic diseases such as diabetes. Frequent measurements of systemic glucose levels with prompt managements can prevent organ damages. The eye is a glucose highly demanding organ in our body, and the anterior chamber (AC) in the eye has been suggested for a noninvasive blood glucose monitoring site. However, calculating blood glucose levels from measuring glucose levels in AC has been difficult and unclear. In this study, we aimed to examine glucose levels from AC and find a correlation with blood glucose levels. A total of 30 patients with cataracts (men and women, study 1; 7 and 3, study 2; 9 and 11) who visited Keio University Hospital from 2015 to 2018 and agreed to participate in this study were recruited. Glucose levels from AC and the blood were examined by a UV-hexokinase or H2O2-electrode method before/during the cataract surgery. These values were analyzed with regression analyses depending on the groups (blood glucose-ascending and descending groups). In the blood glucose-descending group, glucose levels from AC were strongly correlated with blood glucose levels (a high R2 value, 0.8636). However, the relatively moderate correlation was seen in the blood glucose-ascending group (a low R2 value, 0.5228). Taken together, we showed different correlation ratios on glucose levels between AC and the blood, based on blood glucose dynamics. Stacking data regarding this issue would enable establishing noninvasive blood glucose monitoring from measuring glucose levels in AC more correctly, which will be helpful for proper and prompt managements for glucose-mediated complications.

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Inhibition of the HIF-1α/BNIP3 pathway has a retinal neuroprotective effect

Kunimi H., Lee D., Ibuki M., Katada Y., Negishi K., Tsubota K., Kurihara T.

FASEB Journal （FASEB Journal）  35 （ 8 ） e21829 2021年08月

査読有り,  ISSN  08926638

　概要を見る

Retinal ischemia is a leading cause of irreversible blindness worldwide. Inner retinal dysfunction including loss of retinal ganglion cells is encountered in a number of retinal ischemic disorders. We previously reported administration of two different hypoxia-inducible factor (HIF) inhibitors exerted neuroprotective effects in a murine model of retinal ischemia/reperfusion (I/R) which mimics these disorders, as inner retinal degeneration could be involved in pathological HIF induction. However, this notion needs further investigation. Therefore, in this study, we attempted to use retina-specific Hif-1α conditional knockout (cKO) mice to uncover this notion more clearly under the same condition. Hif-1α cKO mice showed inner retinal neurodegeneration to a lesser extent than control mice. Hif-1α depletion in a murine 661W retinal cell line reduced cell death under pseudohypoxic and hypoxic conditions. Among hypoxia-related genes, the expression of BCL2 19 kDa protein-interacting protein 3 (Bnip3) was substantially upregulated in the inner retinal layer after retinal I/R. In this regard, we further examined Bnip3 depletion in retinal neurons in vitro and in vivo and found the similar neuroprotective effects. Our results support the notion that the HIF-1α/BNIP3 pathway may have a critical role in inner retinal neurodegeneration, which can be linked with the development of new promising therapeutics for inner retinal ischemic disorders.

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Retinal dysfunction induced in a mouse model of unilateral common carotid artery occlusion

Lee D., Jeong H., Miwa Y., Shinojima A., Katada Y., Tsubota K., Kurihara T.

PeerJ （PeerJ）  9   e11665 2021年06月

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Background. Retinal ischemic stresses are associated with the pathogenesis of various retinal vascular diseases. To investigate pathological mechanisms of retinal ischemia, reproducible, robust and clinically significant experimental rodent models are highly needed. Previously, we established a stable murine model of chronic hypoperfusion retinal injuries by permanent unilateral common carotid artery occlusion (UCCAO) and demonstrated chronic pathological processes in the ischemic retina after the occlusion; however, retinal functional deficits and other acute retinal ischemic injuries by UCCAO still remain obscure. In this study, we attempted to examine retinal functional changes as well as acute retinal ischemic alterations such as retinal thinning, gliosis and cell death after UCCAO. Methods. Adult mice (male C57BL/6, 6–8 weeks old) were subjected to UCCAO in the right side, and retinal function was primarily measured using electroretinography for 14 days after the surgery. Furthermore, retinal thinning, gliosis and cell death were investigated using optical coherence tomography, immunohistochemistry and TUNEL assay, respectively. Results. Functional deficits in the unilateral right retina started to be seen 7 days after the occlusion. Specifically, the amplitude of b-wave dramatically decreased while that of a-wave was slightly affected. 14 days after the occlusion, the amplitudes of both waves and oscillatory potentials were significantly detected decreased in the unilateral right retina. Even though a change in retinal thickness was not dramatically observed among all the eyes, retinal gliosis and cell death in the unilateral right retina were substantially observed after UCCAO. Conclusions. Along with previous retinal ischemic results in this model, UCCAO can stimulate retinal ischemia leading to functional, morphological and molecular changes in the retina. This model can be useful for the investigation of pathological mechanisms for human ischemic retinopathies and furthermore can be utilized to test new drugs for various ischemic ocular diseases.

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Iris metastasis as the initial presentation of metastatic esophageal cancer diagnosed by fine needle aspiration biopsy: A case report

Ozawa H., Usui Y., Takano Y., Horiuchi N., Kuribayashi T., Kurihara T., Smith L.E.H., Tsubota K., Tomita Y.

Medicine （Medicine）  100 （ 22 ） e26232 2021年06月

査読有り,  ISSN  00257974

　概要を見る

RATIONALE: Metastasis of neoplasms to the eye is quite uncommon. In this case report, we describe a patient where primary esophageal cancer was diagnosed by fine needle aspiration biopsy (FNAB) of an iris tumor. PATIENT CONCERNS: A 70-year-old male complained of redness and discomfort in the right eye. DIAGNOSIS AND INTERVENTIONS: The patient's right eye was diagnosed as idiopathic uveitis, and a topical steroid was administered. As vitreous opacities were observed even after topical therapy, oral prednisolone was administered. On slit-lamp examination of the right eye, an iris mass with neovascularization was seen in the anterior chamber. A metastatic tumor was suspected, and FNAB was performed. Histology revealed squamous cell carcinoma. Systemic workup revealed esophageal cancer with several metastases. Best-corrected visual acuity decreased to 20/400, and intraocular pressure was 40 mmHg in the right eye. Two iris tumors with neovascularization were present extending into the anterior chamber with posterior iris synechiae and 360 degree peripheral anterior synechiae. Intraocular pressure in the right eye was medically managed with hypotensive eye drops and oral acetazolamide. Iris metastases were treated with 40 Gray of radiation therapy and concurrent chemotherapy. OUTCOMES: The tumor regressed, but intraocular pressure was refractory to treatment because of 360 degree goniosynechial closure. The right eye lost light perception six months after treatment commenced, and the patient died 9 months after the onset of therapy due to multiple systemic metastases. LESSONS: This is a rare case of masquerade syndrome without systemic symptoms in which FNAB of an iris tumor led to a diagnosis of metastatic esophageal squamous cell carcinoma. Although the patient lost his sight due to uncontrollable ocular hypertension, systemic chemotherapy, and radiation therapy were initially effective in the treatment of the metastatic iris tumor. As the prognosis of patients with metastatic iris tumors is poor, it is important for ophthalmologists to consider such diagnoses and conduct systemic investigations when necessary.

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Violet light suppresses lens-induced myopia via neuropsin (OPN5) in mice

Jiang X., Pardue M.T., Mori K., Ikeda S.I., Torii H., D'Souza S., Lang R.A., Kurihara T., Tsubota K.

Proceedings of the National Academy of Sciences of the United States of America （Proceedings of the National Academy of Sciences of the United States of America）  118 （ 22 ） e2018840118 2021年06月

査読有り,  ISSN  00278424

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Myopia has become a major public health concern, particularly across much of Asia. It has been shown in multiple studies that outdoor activity has a protective effect on myopia. Recent reports have shown that short-wavelength visible violet light is the component of sunlight that appears to play an important role in preventing myopia progression in mice, chicks, and humans. The mechanism underlying this effect has not been understood. Here, we show that violet light prevents lens defocus-induced myopia in mice. This violet light effect was dependent on both time of day and retinal expression of the violet light sensitive atypical opsin, neuropsin (OPN5). These findings identify Opn5-expressing retinal ganglion cells as crucial for emmetropization in mice and suggest a strategy for myopia prevention in humans.

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Assessment of hypofluorescent foci on late-phase indocyanine green angiography in central serous chorioretinopathy

Shinojima A., Ozawa Y., Uchida A., Nagai N., Shinoda H., Kurihara T., Suzuki M., Minami S., Negishi K., Tsubota K.

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 10 ） 2178 2021年05月

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To assess the hypofluorescent foci (HFF) on late-phase indocyanine green angiography (ICGA) in central serous chorioretinopathy (CSC) using short-wavelength fundus autofluorescence (SW-FAF), near-infrared autofluorescence (NIR-AF), and fluorescein angiography (FA). The HFF area on late-phase ICGA for at least 20 min was compared with the area of abnormal foci on SW-FAF, NIR-AF, and FA. In 14 consecutive patients (12 men, including 1 with bilateral CSC; and 2 women with unilateral CSC), four kinds of images of 27 eyes were acquired. The mean age ± standard deviation (range) was 46 ± 9.2 years (31–69 years). The HFF on late-phase ICGA were found in 23 eyes (in all 15 CSC eyes and the contralateral 8 eyes). From the results of simple regression analysis, we obtained the following three formulas. The HFF area on ICGA = 1.058 × [abnormal SW-FAF area] + 0.135, the HFF area on ICGA = 1.001 × [abnormal NIR-AF area] + 0.015, and the HFF area on ICGA = 1.089 × [abnormal FA area] + 0.135. Compared to SW-FAF and FA, NIR-AF was found to be the easiest method to detect the HFF on late-phase ICGA, which may indicate melanin abnormalities, especially a decrease, in the retinal pigment epithelium.

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Efficacy and safety of 0.01% atropine for prevention of childhood myopia in a 2-year randomized placebo-controlled study

Hieda O., Hiraoka T., Fujikado T., Ishiko S., Hasebe S., Torii H., Takahashi H., Nakamura Y., Sotozono C., Oshika T., Morimoto T., Nishida K., Nishikawa N., Song Y.S., Tokutake T., Nishi Y., Shigeno Y., Kurihara T., Negishi K., Tsubota K., Ono M., Nakai T., Tan D., Tanaka S., Kinoshita S.

Japanese Journal of Ophthalmology （Japanese Journal of Ophthalmology）  65 （ 3 ） 315 - 325 2021年05月

査読有り,  ISSN  00215155

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Purpose: Atropine eye drops prevent the progression of myopia, but their use has not been tested in the Japanese schoolchildren population. Here, we evaluate the efficacy and safety of 0.01% atropine eye drops for myopia control in Japanese children. Study design: Multicenter (7 university hospitals), randomized, double-masked, placebo-controlled trial. Methods: Participants were 171 Japanese schoolchildren aged 6 to 12 years, with progressive myopia, spherical equivalence (SE) of −1.00 to −6.00 diopters (D), and astigmatism of ≤1.5 D. They were randomized to receive either 0.01% atropine (n=85) or placebo (n=86) eye drops once nightly OU for 24 months. Primary and secondary efficacy endpoints were changes in SE and axial length (AL), respectively, from baseline to month 24. Results: Data from 168 subjects were analyzed. At month 24, compliance was similar in both groups (atropine: 83.3%; placebo: 85.7%). The least squares mean change in SE and AL from baseline were, respectively, −1.26 D (95% confidence interval [CI]: −1.35, −1.17) and 0.63 mm (0.59, 0.67) for atropine and −1.48 D (− 1.57, −1.39) and 0.77 mm (0.73, 0.81) for placebo. Inter-group differences were 0.22 D (95% CI: 0.09, 0.35; P < 0.001) for SE and − 0.14 mm (−0.20, −0.08; P < 0.001) for AL. Three patients experienced mild allergic conjunctivitis side effects, with no inter-group difference in incidence (atropine: 2.4%; 2/84 patients; placebo: 1.4%; 1/84 patients). Conclusion: With good compliance, 0.01% atropine is effective and safe for preventing the progression of childhood myopia.

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Fenofibrate protects against retinal dysfunction in a murine model of common carotid artery occlusion-induced ocular ischemia

Lee D., Tomita Y., Miwa Y., Jeong H., Mori K., Tsubota K., Kurihara T.

Pharmaceuticals （Pharmaceuticals）  14 （ 3 ） 223 2021年03月

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Ocular ischemia is a common cause of blindness and plays a detrimental role in various diseases such as diabetic retinopathy, occlusion of central retinal arteries, and ocular ischemic syndrome. Abnormalities of neuronal activities in the eye occur under ocular ischemic conditions. Therefore, protecting their activities may prevent vision loss. Previously, peroxisome proliferator-activated receptor alpha (PPARα) agonists were suggested as promising drugs in ocular ischemia. However, the potential therapeutic roles of PPARα agonists in ocular ischemia are still unknown. Thus, we attempted to unravel systemic and ocular changes by treatment of fenofibrate, a well-known PPARα agonist, in a new murine model of ocular ischemia. Adult mice were orally administered fenofibrate (60 mg/kg) for 4 days once a day, followed by induction of ocular ischemia by unilateral common carotid artery occlusion (UCCAO). After UCCAO, fenofibrate was continuously supplied to mice once every 2 days during the experiment period. Electroretinography was performed to measure retinal functional changes. Furthermore, samples from the retina, liver, and blood were subjected to qPCR, Western blot, or ELISA analysis. We found that fenofibrate boosted liver function, increased serum levels of fibroblast growth factor 21 (FGF21), one of the neuroprotective molecules in the central nervous system, and protected against UCCAO-induced retinal dysfunction. Our current data suggest a promising fenofibrate therapy in ischemic retinopathies.

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Spatial Functional Characteristics of East Asian Patients With Occult Macular Dystrophy (Miyake Disease); EAOMD Report No. 2

Yang L., Joo K., Tsunoda K., Kondo M., Fujinami-Yokokawa Y., Arno G., Pontikos N., Liu X., Nakamura N., Kurihara T., Tsubota K., Iwata T., Li H., Zou X., Wu S., Sun Z., Ahn S.J., Kim M.S., Mun Y.S., Park K.H., Robson A.G., Miyake Y., Woo S.J., Sui R., Fujinami K.

American Journal of Ophthalmology （American Journal of Ophthalmology）  221   169 - 180 2021年01月

査読有り,  ISSN  00029394

　概要を見る

© 2020 The Authors Purpose: To describe the functional phenotypic features of East Asian patients with RP1L1-associated occult macular dystrophy (ie, Miyake disease). Design: An international multicenter retrospective cohort study. Methods: Twenty-eight participants (53 eyes) with Miyake disease were enrolled at 3 centers (in Japan, China, and South Korea). Ophthalmologic examinations including spectral-domain optical coherence tomography (SDOCT) and multifocal electroretinogram (mfERG) were performed. Patients were classified into 3 functional groups based on mfERG: Group 1, paracentral dysfunction with relatively preserved central/peripheral function; Group 2, homogeneous central dysfunction with preserved peripheral function; and Group 3, widespread dysfunction over the recorded area. Three functional phenotypes were compared in clinical parameters and SDOCT morphologic classification (severe phenotype, blurred/flat ellipsoid zone and absence of the interdigitation zone; mild phenotype, preserved ellipsoid zone). Results: There were 8 eyes in Group 1, 40 eyes in Group 2, and 5 eyes in Group 3. The patients in Group 1 showed significantly later onset (P =.005) and shorter disease duration (P =.002), compared with those in Group 2. All 8 eyes in Group 1 showed the mild morphologic phenotype, while 43 of 45 eyes in Groups 2 and 3 presented the severe phenotype, which identified a significant association between the functional grouping and the morphologic classification (P <.001). Conclusions: A spectrum of functional phenotypes of Miyake disease was first documented with identification of 3 functional subtypes. Patients with paracentral dysfunction had the mildest phenotype, and those with homogeneous central or widespread dysfunction showed overlapping clinical findings with severe photoreceptor changes, suggesting various extents of visual impairment.

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Axial length and prevalence of myopia among schoolchildren in the equatorial region of brazil

Yotsukura E., Torii H., Ozawa H., Hida R.Y., Shiraishi T., Corso Teixeira I., Rautha Y.V.B.L., Moraes Do Nascimento C.F., Mori K., Uchino M., Kurihara T., Negishi K., Tsubota K.

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 1 ） 1 - 11 2021年01月

査読有り

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The prevalence of myopia is increasing globally, and the outdoor light environment is considered as a possible factor that can retard myopia. The aim of this study was to evaluate the prevalence of myopia and the light environment in Aracati, equatorial Brazil. We surveyed 421 children (421 right eyes; mean age, 10.6 years) and performed ocular examinations that in- cluded non-cycloplegic refraction and axial length (AL). Multiple regression analyses were performed to identify factors affecting myopia such as time spent outdoors and in near work. We measured illuminance and violet light irradiance in Aracati. The mean spherical equivalent (SE) and AL were-0.44 ± 1.38 diopters (D) and 22.98 ± 0.87 mm, respectively. The prevalence of myopia (SE≤-0.75 D) and high myopia (SE ≤-6.0 D/AL≥26.0 mm) was 20.4 and 1.4/0.48%, respectively. Multiple regression analyses showed that myopia was not associated with lifestyle factors. The average illuminance in Aracati was about 100,000 lux from morning to evening. The current results reflect the ALs and the prevalence of myopia among Brazilian schoolchildren. There is a possibility that the light environment in addition to other confounding factors including racial differences affects the ALs and refractive errors.

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Prediction of causative genes in inherited retinal disorder from fundus photography and autofluorescence imaging using deep learning techniques

Fujinami-Yokokawa Y., Ninomiya H., Liu X., Yang L., Pontikos N., Yoshitake K., Iwata T., Sato Y., Hashimoto T., Tsunoda K., Miyata H., Fujinami K., Iwata T., Fujinami K., Ueno S., Kuniyoshi K., Hayashi T., Kondo M., Mizota A., Naoi N., Shinoda K., Kameya S., Kondo H., Kominami T., Terasaki H., Sakuramoto H., Katagiri S., Mizobuchi K., Nakamura N., Mawatari G., Kurihara T., Tsubota K., Miyake Y., Yoshitake K., Nishimura T., Hayashizaki Y., Shimozawa N., Horiguchi M., Yamamoto S., Kuze M., MacHida S., Shimada Y., Nakamura M., Fujikado T., Hotta Y., Takahashi M., Mochizuki K., Murakami A., Ishida S., Nakazawa M., Hatase T., Matsunaga T., Maeda A., Noda K., Tanikawa A., Yamamoto S., Yamamoto H., Araie M., Aihara M., Nakazawa T., Sekiryu T., Kashiwagi K., Kosaki K., Piero C., Fukuchi T., Hayashi A., Hosono K., Mori K., Tanaka K., Furuya K., Suzuki K., Kohata R., Yanagi Y., Minegishi Y., Iejima D., Suga A., Rossmiller B.P., Pan Y., Oshima T., Nakayama M., Yamamoto M., Minematsu N., Mori D., Kijima Y., Kurata K., Yamada N., Itoh M., Kawaji H., Murakawa Y., Ando R., Saito W., Murakami Y., Miyata H., Yang L., Liu X., Arno G.

British Journal of Ophthalmology （British Journal of Ophthalmology）     bjophthalmol-2020-318544 2021年

査読有り,  ISSN  00071161

　概要を見る

Background/Aims: To investigate the utility of a data-driven deep learning approach in patients with inherited retinal disorder (IRD) and to predict the causative genes based on fundus photography and fundus autofluorescence (FAF) imaging. Methods: Clinical and genetic data from 1302 subjects from 729 genetically confirmed families with IRD registered with the Japan Eye Genetics Consortium were reviewed. Three categories of genetic diagnosis were selected, based on the high prevalence of their causative genes: Stargardt disease (ABCA4), retinitis pigmentosa (EYS) and occult macular dystrophy (RP1L1). Fundus photographs and FAF images were cropped in a standardised manner with a macro algorithm. Images for training/testing were selected using a randomised, fourfold cross-validation method. The application program interface was established to reach the learning accuracy of concordance (target: >80%) between the genetic diagnosis and the machine diagnosis (ABCA4, EYS, RP1L1 and normal). Results: A total of 417 images from 156 Japanese subjects were examined, including 115 genetically confirmed patients caused by the three prevalent causative genes and 41 normal subjects. The mean overall test accuracy for fundus photographs and FAF images was 88.2% and 81.3%, respectively. The mean overall sensitivity/specificity values for fundus photographs and FAF images were 88.3%/97.4% and 81.8%/95.5%, respectively. Conclusion: A novel application of deep neural networks in the prediction of the causative IRD genes from fundus photographs and FAF, with a high prediction accuracy of over 80%, was highlighted. These achievements will extensively promote the quality of medical care by facilitating early diagnosis, especially by non-specialists, access to care, reducing the cost of referrals, and preventing unnecessary clinical and genetic testing.

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Retinal Degeneration in a Murine Model of Retinal Ischemia by Unilateral Common Carotid Artery Occlusion

Lee D., Nakai A., Miwa Y., Tomita Y., Serizawa N., Katada Y., Hatanaka Y., Tsubota K., Negishi K., Kurihara T.

BioMed Research International （BioMed Research International）  2021   7727648 2021年

査読有り,  ISSN  23146133

　概要を見る

Retinal degeneration is a progressive retinal damage in ocular vascular diseases. There are several reasons for this, such as occlusion of arteries or veins, diabetic retinopathy, or hereditary retinal diseases. To study pathological mechanisms of retinal degeneration, it is required to develop experimentally reproducible and clinically relevant models. In our previous studies, we developed a murine model of retinal hypoperfusion by unilateral common carotid artery occlusion (UCCAO) which mimics the pathophysiology of ocular ischemic syndrome (OIS) in humans, and described broad pathological mechanisms in the retina after UCCAO. However, there still remain missing pieces of the ocular pathologic process by UCCAO. In this study, we examined those unfound mechanisms. UCCAO was performed on adult mice. Ocular dysfunctions, histological deficits, and inflammation were examined after UCCAO, compared with sham-operated mice. Evaluation values were analyzed by electrophysiological, histological, and molecular biological methods. Eyelid drooping was permanently seen after UCCAO. Induction time point of acute reversible cataract under anesthesia was shortened. Retinal/visual dysfunctions were detected 2-4 weeks after UCCAO. Specifically, scotopic b-wave was more affected than a-wave, with the dysfunction of photopic b-wave. Impaired oscillatory potentials and visual evoked potential were constantly observed. Pathological Müller gliosis/inflammation was featured with NeuN-positive cell loss in the ganglion cell layer. Axial length, intraocular pressure, pupillary light reflex, and retinal pigment epithelium/choroidal thickness were not changed by UCCAO. A murine model of retinal ischemia by UCCAO can be useful for studying a series of degenerative process in the ischemic retina.

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Rice bran and vitamin b6 suppress pathological neovascularization in a murine model of age‐related macular degeneration as novel hif inhibitors

Ibuki M., Lee D., Shinojima A., Miwa Y., Tsubota K., Kurihara T.

International Journal of Molecular Sciences （International Journal of Molecular Sciences）  21 （ 23 ） 1 - 24 2020年12月

査読有り,  ISSN  16616596

　概要を見る

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Pathological neovascularization in the eye is a leading cause of blindness in all age groups from retinopathy of prematurity (ROP) in children to age‐related macular degeneration (AMD) in the elderly. Inhibiting neovascularization via antivascular endothelial growth factor (VEGF) drugs has been used for the effective treatment. However, anti‐VEGF therapies may cause development of chorioretinal atrophy as they affect a physiological amount of VEGF essential for retinal homeostasis. Furthermore, anti‐VEGF therapies are still ineffective in some cases, especially in patients with AMD. Hypoxia‐inducible factor (HIF) is a strong regulator of VEGF induction under hypoxic and other stress conditions. Our previous reports have indicated that HIF is associated with pathological retinal neovascularization in murine models of ROP and AMD, and HIF inhibition suppresses neovascularization by reducing an abnormal increase in VEGF expression. Along with this, we attempted to find novel effective HIF inhibitors from natural foods of our daily lives. Food ingredients were screened for prospective HIF inhibitors in ocular cell lines of 661W and ARPE‐19, and a murine AMD model was utilized for examining suppressive effects of the ingredients on retinal neovascularization. As a result, rice bran and its component, vitamin B6 showed inhibitory effects on HIF activation and suppressed VEGF mRNA induction under a CoCl2‐induced pseudo-hypoxic condition. Dietary supplement of these significantly suppressed retinal neovascularization in the AMD model. These data suggest that rice bran could have promising therapeutic values in the management of pathological ocular neovascularization.

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