研究者詳細 - 栗原　俊英

論文 - 栗原　俊英

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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

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

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

査読有り

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

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

査読有り

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

© 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

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

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

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

© 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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Relationship between nerve fiber layer defect and the presence of epiretinal membrane in a Japanese population: The JPHC-NEXT Eye Study

Uchida A., Sasaki M., Motomura K., Yuki K., Kurihara T., Tomita Y., Ozawa Y., Yamagishi K., Kawasaki R., Hanyuda A., Sawada N., Tsubota K., Tsugane S., Iso H.

Scientific Reports （Scientific Reports） 10 （ 1 ） 779 - 779 2020年12月

査読有り

© 2020, The Author(s). The study subjects were residents of Chikusei city, Japan, aged 40 years or older who attended annual health check-up programs and participated in the JPHC-NEXT Eye Study which performed non-mydriatic fundus photography of both eyes. The relationship of glaucomatous fundus changes such as optic disc cupping (cup to disc ratio ≥ 0.7) and retinal nerve fiber layer defect (NFLD) with the presence of epiretinal membrane (ERM) were examined cross-sectionally. A total of 1990 persons gave consent to participate in this study in 2013. The overall prevalence of ERM was 12.9%. Of these, 1755 had fundus photographs of sufficient quality and no history of intraocular surgery (mean age: 62.3 ± 10.0 years). After adjusting for age, sex and refractive error, NFLD was positively associated with the presence of ERM (odds ratio [OR]: 2.48; 95% confidence interval [CI]: 1.24, 4.96; P = 0.010), but optic disc cupping was not (OR: 1.33; CI: 0.71, 2.48; P = 0.37). The results did not necessarily suggest an association between glaucoma and ERM, but indicated an association between NFLD and ERM.

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Genetic Spectrum of EYS-associated Retinal Disease in a Large Japanese Cohort: Identification of Disease-associated Variants with Relatively High Allele Frequency

Yang L., Fujinami K., Ueno S., Kuniyoshi K., Hayashi T., Kondo M., Mizota A., Naoi N., Shinoda K., Kameya S., Fujinami-Yokokawa Y., Liu X., Arno G., Pontikos N., Kominami T., Terasaki H., Sakuramoto H., Katagiri S., Mizobuchi K., Nakamura N., Mawatari G., Kurihara T., Tsubota K., Miyake Y., Yoshitake K., Iwata T., Tsunoda 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., Kondo H., 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.

Scientific Reports （Scientific Reports） 10 （ 1 ） 5497 - 5497 2020年12月

査読有り

© 2020, The Author(s). Biallelic variants in the EYS gene are a major cause of autosomal recessive inherited retinal disease (IRD), with a high prevalence in the Asian population. The purpose of this study was to identify pathogenic EYS variants, to determine the clinical/genetic spectrum of EYS-associated retinal disease (EYS-RD), and to discover disease-associated variants with relatively high allele frequency (1%-10%) in a nationwide Japanese cohort. Sixty-six affected subjects from 61 families with biallelic or multiple pathogenic/disease-associated EYS variants were ascertained by whole-exome sequencing. Three phenotype groups were identified in EYS-RD: retinitis pigmentosa (RP; 85.94%), cone-rod dystrophy (CORD; 10.94%), and Leber congenital amaurosis (LCA; 3.12%). Twenty-six pathogenic/disease-associated EYS variants were identified, including seven novel variants. The two most prevalent variants, p.(Gly843Glu) and p.(Thr2465Ser) were found in 26 and twelve families (42.6%, 19.7%), respectively, for which the allele frequency (AF) in the Japanese population was 2.2% and 3.0%, respectively. These results expand the phenotypic and genotypic spectrum of EYS-RD, accounting for a high proportion of EYS-RD both in autosomal recessive RP (23.4%) and autosomal recessive CORD (9.9%) in the Japanese population. The presence of EYS variants with relatively high AF highlights the importance of considering the pathogenicity of non-rare variants in relatively prevalent Mendelian disorders.

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Clinical and Genetic Characteristics of 18 Patients from 13 Japanese Families with CRX-associated retinal disorder: Identification of Genotype-phenotype Association

Fujinami-Yokokawa Y., Fujinami K., Kuniyoshi K., Hayashi T., Ueno S., Mizota A., Shinoda K., Arno G., Pontikos N., Yang L., Liu X., Sakuramoto H., Katagiri S., Mizobuchi K., Kominami T., Terasaki H., Nakamura N., Kameya S., Yoshitake K., Miyake Y., Kurihara T., Tsubota K., Miyata H., Iwata T., Tsunoda K., Nishimura T., Hayashizaki Y., Kondo M., Shimozawa N., Horiguchi M., Yamamoto S., Kuze M., Naoi N., Machida S., Shimada Y., Nakamura M., Fujikado T., Hotta Y., Takahashi M., Mochizuki K., Murakami A., Kondo H., 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., Teruyama Y., Yamamoto M., Minematsu N., Sanbe H., Mori D., Kijima Y., Mawatari G., Kurata K., Yamada N., Itoh M., Kawaji H., Murakawa Y.

Scientific Reports （Scientific Reports） 10 （ 1 ） 9531 - 9531 2020年12月

査読有り

© 2020, The Author(s). Inherited retinal disorder (IRD) is a leading cause of blindness, and CRX is one of a number of genes reported to harbour autosomal dominant (AD) and recessive (AR) causative variants. Eighteen patients from 13 families with CRX-associated retinal disorder (CRX-RD) were identified from 730 Japanese families with IRD. Ophthalmological examinations and phenotype subgroup classification were performed. The median age of onset/latest examination was 45.0/62.5 years (range, 15–77/25–94). The median visual acuity in the right/left eye was 0.52/0.40 (range, −0.08–2.00/−0.18–1.70) logarithm of the minimum angle of resolution (LogMAR) units. There was one family with macular dystrophy, nine with cone-rod dystrophy (CORD), and three with retinitis pigmentosa. In silico analysis of CRX variants was conducted for genotype subgroup classification based on inheritance and the presence of truncating variants. Eight pathogenic CRX variants were identified, including three novel heterozygous variants (p.R43H, p.P145Lfs*42, and p.P197Afs*22). A trend of a genotype-phenotype association was revealed between the phenotype and genotype subgroups. A considerably high proportion of CRX-RD in ADCORD was determined in the Japanese cohort (39.1%), often showing the mild phenotype (CORD) with late-onset disease (sixth decade). Frequently found heterozygous missense variants located within the homeodomain underlie this mild phenotype. This large cohort study delineates the disease spectrum of CRX-RD in the Japanese population.

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Oral bovine milk lactoferrin administration suppressed myopia development through matrix metalloproteinase 2 in a mouse model

Ikeda S.I., Kurihara T., Toda M., Jiang X., Torii H., Tsubota K.

Nutrients （Nutrients） 12 （ 12 ） 1 - 9 2020年12月

査読有り

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Recent studies have reported an association between myopia development and local ocular inflammation. Lactoferrin (LF) is an iron-binding protein present in saliva, tears, and mother’s milk. Furthermore, sequestering iron by LF can cause its antibacterial property. Moreover, LF has an anti-inflammatory effect. We aimed to determine the suppressive effect of LF against the development and progress of myopia using a murine lens-induced myopia (LIM) model. We divided male C57BL/6J mice (3 weeks old) into two groups. While the experimental group was orally administered LF (1600 mg/kg/day, from 3-weeks-old to 7-weeks-old), a similar volume of Ringer’s solution was administered to the control group. We subjected the 4-week-old mice to −30 diopter lenses and no lenses on the right and left eyes, respectively. We measured the refraction and the axial length at baseline and 3 weeks after using a refractometer and a spectral domain optical coherence tomography (SD-OCT) system in both eyes. Furthermore, we determined the matrix metalloproteinase-2 (MMP-2) activity, and the amount of interleukin-6 (IL-6), MMP-2, and collagen 1A1 in the choroid or sclera. The eyes with a minus lens showed a refractive error shift and an axial length elongation in the control group, thus indicating the successful induction of myopia. However, there were no significant differences in the aforementioned parameters in the LF group. While LIM increased IL-6 expression and MMP-2 activity, it decreased collagen 1A1 content. However, orally administered LF reversed these effects. Thus, oral administration of LF suppressed lens-induced myopia development by modifying the extracellular matrix remodeling through the IL-6–MMP-2 axis in mice.

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Efficacy of the newly invented eyelid clamper in ultra-widefield fundus imaging

Ozawa N., Mori K., Katada Y., Tsubota K., Kurihara T.

Life （Life） 10 （ 12 ） 1 - 7 2020年12月

査読有り

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Background: Ultra-widefield fundus imaging is widely used for obtaining wide angle images of the retina in one single image. Although it has a potential to obtain a wide area of retinal photographs, images are often obstructed by eyelashes or eye lids. In this study, we used a newly invented eyelid clamper, which can keep an eye open without touching conjunctiva or lid margin, to assess the efficacy in clinical use by comparing with conventional tape fixation. Methods: Ultra-widefield fundus images were captured with an ultra-widefield imaging system in 19 patients who visited to the outpatient clinic of Department of Ophthalmology, Keio University Hospital with the eyelid clamper or a conventional tape fixation. The area of imaged retinas was outlined and quantified with pixels. After obtaining images, patients answered a questionnaire. Results: The average number of pixels in total areas with the eyelid clamper or with tape fixation were 4.31 ± 0.35 and 4.32 ± 0.34 mega pixels, respectively, showing no significant difference between the groups (p = 0.889). The average face pain scale of the eyelid clamper was 1.13 on a scale of 0 to 5. The number of patients who did not feel any pain was nine (47.4%). Conclusions: The eyelid clamper can be applied in clinical setting and can better support obtaining sufficiently wide fundus images compared to a conventional tape fixation.

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Axial length shortening in a myopic child with anisometropic amblyopia after wearing violet light-transmitting eyeglasses for 2 years

Ofuji Y., Torii H., Yotsukura E., Mori K., Kurihara T., Negishi K., Tsubota K.

American Journal of Ophthalmology Case Reports （American Journal of Ophthalmology Case Reports） 20 101002 2020年12月

査読有り, ISSN 24519936

© 2020 The Authors Purpose: To report a case in which the axial length (AL) shortened and the choroid thickened due to the use of violet light-transmitting eyeglasses. Observations: A 4-year-old boy with high myopia was referred to Keio University Hospital. He was prescribed standard eyeglasses. Six months after the first visit, his best-corrected visual acuities were 1.2 and 0.4 in the right and left eyes, respectively, with the standard eyeglasses, and he was diagnosed with anisometropic amblyopia. The right eye then was patched for 6 hours daily during the daytime. Because of the availability of violet light-transmitting eyeglasses, we changed the eyeglasses and instructed his parents to have him engage in outdoor activities for over 2 hours daily to be exposed to sufficient violet light. As a result, the violet light entered his left eye and minimal violet light entered his right eye. The changes in the ALs, choroidal thicknesses, and cycloplegic objective refractions in the right and left eyes during 2 years of wearing violet light-transmitting eyeglasses were +0.85 and −0.20 mm, +4.9 and + 115.7 μm, and −1.02 and + 1.88 D, respectively. Conclusions and importance: We successfully described a case in which the myopia improved, the AL shortened, and the choroid thickened after using violet light-transmitting eyeglasses.

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Automatic screening for diabetic retinopathy in interracial fundus images using artificial intelligence

Katada Y., Ozawa N., Masayoshi K., Ofuji Y., Tsubota K., Kurihara T.

Intelligence-Based Medicine （Intelligence-Based Medicine） 3-4 100024 2020年12月

査読有り, ISSN 2666-5212

The development of deep learning technology and high-performance computers in recent years has enabled significant improvement in the accuracy of image recognition, and efforts are currently being made toward the development of ophthalmic artificial intelligence (AI). In this study, deep learning was applied to fundus image analysis. The fundus images were automatically classified by their severity index and the recognition accuracies for Japanese and American data were compared. We trained a deep convolutional neural network and a support vector machine using a data set consisting of 35,126 open-source American clinical fundus images, which were graded for diabetic retinopathy by licensed ophthalmologists. The grading accuracy of the trained AI model was evaluated by comparison with its performance for 200 Japanese fundus images obtained at Keio University Hospital. The trained AI model exhibited a sensitivity of 81.5% and specificity of 71.9% for the American validation data set, and a sensitivity of 90.8% and specificity of 80.0% for the Japanese data set. This indicates that the proposed AI program developed using American image data can be applied to fundus photographs of Japanese subjects and thus represents an interracial screening model. It can be used for screening tests and applied to telemedicine systems.

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A murine model of ischemic retinal injury induced by transient bilateral common carotid artery occlusion

Lee D., Miwa Y., Jeong H., Ikeda S.I., Katada Y., Tsubota K., Kurihara T.

Journal of Visualized Experiments （Journal of Visualized Experiments） 2020 （ 165 ） 1 - 19 2020年11月

査読有り, ISSN 1940087X

© 2020 JoVE Journal of Visualized Experiments. Diverse vascular diseases such as diabetic retinopathy, occlusion of retinal veins or arteries and ocular ischemic syndrome can lead to retinal ischemia. To investigate pathological mechanisms of retinal ischemia, relevant experimental models need to be developed. Anatomically, a main retinal blood supplying vessel is the ophthalmic artery (OpA) and OpA originates from the internal carotid artery of the common carotid artery (CCA). Thus, disruption of CCA could effectively cause retinal ischemia. Here, we established a mouse model of retinal ischemia by transient bilateral common carotid artery occlusion (tBCCAO) to tie the right CCA with 6-0 silk sutures and to occlude the left CCA transiently for 2 seconds via a clamp, and showed that tBCCAO could induce acute retinal ischemia leading to retinal dysfunction. The current method reduces reliance on surgical instruments by only using surgical needles and a clamp, shortens occlusion time to minimize unexpected animal death, which is often seen in mouse models of middle cerebral artery occlusion, and maintains reproducibility of common retinal ischemic findings. The model can be utilized to investigate the pathophysiology of ischemic retinopathies in mice and further can be used for in vivo drug screening.

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PPARα agonist oral therapy in diabetic retinopathy

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

Biomedicines （Biomedicines） 8 （ 10 ） 1 - 18 2020年10月

査読有り

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Diabetic retinopathy (DR) is an eye condition that develops after chronically poorly-managed diabetes, and is presently the main cause for blindness on a global scale. Current treatments for DR such as laser photocoagulation, topical injection of corticosteroids, intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents and vitreoretinal surgery are only applicable at the late stages of DR and there are possibilities of significant adverse effects. Moreover, the forms of treatment available for DR are highly invasive to the eyes. Safer and more effective pharmacological treatments are required for DR treatment, in particular at an early stage. In this review, we cover recently investigated promising oral pharmacotherapies, the methods of which are safer, easier to use, patient-friendly and pain-free, in clinical studies. We especially focus on peroxisome proliferator-activator receptor alpha (PPARα) agonists in which experimental evidence suggests PPARα activation may be closely related to the attenuation of vascular damages, including lipid-induced toxicity, inflammation, an excess of free radical generation, endothelial dysfunction and angiogenesis. Furthermore, oral administration of selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) agonists may induce hepatic fibroblast growth factor 21 expression, indirectly resulting in retinal protection in animal studies. Our review will enable more comprehensive approaches for understanding protective roles of PPARα for the prevention of DR development.

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A fairy chemical suppresses retinal angiogenesis as a HIF inhibitor

Lee D., Miwa Y., Wu J., Shoda C., Jeong H., Kawagishi H., Tsubota K., Kurihara T.

Biomolecules （Biomolecules） 10 （ 10 ） 1 - 14 2020年10月

査読有り

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. Neovascular retinal degeneration is a leading cause of blindness in advanced countries. Anti-vascular endothelial growth factor (VEGF) drugs have been used for neovascular retinal diseases; however, anti-VEGF drugs may cause the development of chorioretinal atrophy in chronic therapy as they affect the physiological amount of VEGF needed for retinal homeostasis. Hypoxia-inducible factor (HIF) is a transcription factor inducing VEGF expression under hypoxic and other stress conditions. Previously, we demonstrated that HIF was involved with pathological retinal angiogenesis in murine models of oxygen-induced retinopathy (OIR), and pharmacological HIF inhibition prevented retinal neovascularization by reducing an ectopic amount of VEGF. Along with this, we attempted to find novel effective HIF inhibitors. Compounds originally isolated from mushroom-forming fungi were screened for prospective HIF inhibitors utilizing cell lines of 3T3, ARPE-19 and 661W. A murine OIR model was used to examine the anti-angiogenic effects of the compounds. As a result, 2-azahypoxanthine (AHX) showed an inhibitory effect on HIF activation and suppressed Vegf mRNA upregulation under CoCl2-induced pseudo-hypoxic conditions. Oral administration of AHX significantly suppressed retinal neovascular tufts in the OIR model. These data suggest that AHX could be a promising anti-angiogenic agent in retinal neovascularization by inhibiting HIF activation.

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