ヒト網膜色素上皮はヒドロキノンと最終糖化産物の共刺激により、VEGF遺伝子の発現上昇を伴って増殖する

Although recent research showed that advanced glycation endproduct (AGE) and hydroquinone (HQ) are related to the pathogenesis of age-related macular degeneration (AMD), the mechanism how AGE and HQ induce or accelerate AMD remains elusive. In the present study, we examined the effects of AGE and HQ on changes of human retinal pigment epithelial (RPE) cell numbers and found that the viable cell numbers were markedly reduced by HQ by apoptosis and that AGE prevented the decreases of HQ-treated cell numbers by increased replicative DNA synthesis of RPE cells without changing apoptosis. Real-time RT-PCR revealed that vascular endothelial growth factor (VEGF)-A mRNA was increased by HQ treatment and the addition of HQ+AGE resulted in a further increment. The increase of VEGF secretion was confirmed by ELISA, and inhibition of VEGF signaling by chemical inhibitors and small interfering RNA decreased the HQ+AGE-induced increases in RPE cell numbers. The deletion analysis demonstrated that −102 to −43 region was essential for the VEGF-A promoter activation. Site-directed mutaions of specificity protein 1 (SP1) binding sequences in the VEGF-A promoter and RNA interference of SP1 revealed that SP1 is an essential transcription factor for VEGF-A expression. These results indicate that HQ induces RPE cell apoptosis, leading to dry AMD, and suggest that AGE stimulation in addition to HQ enhances VEGF-A transcription via the AGE-receptor for AGE pathway in HQ-damaged cells. As a result, the secreted VEGF acts as an autocrine/paracrine growth factor for RPE and/or adjacent vascular cells, causing wet AMD.博士（医学）・甲第640号・平成27年11月27日Copyright © 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

シェーグレン症候群の新規自己抗原であるREG 蛋白の唾液導管細胞における発現誘導にはIL-6/STAT 経路が重要である

The regenerating gene, Reg, was originally isolated from a rat regenerating islet cDNA library, and its human homolog was named REG Iα. Recently, we reported that REG Iα mRNA as well as its product were overexpressed in ductal epithelial cells in the minor salivary glands of Sjögren׳s syndrome (SS) patients. This study was undertaken to elucidate the role of cytokines and the subsequent intracellular mechanism for induction of REG Iα in the salivary glands of SS patients. We prepared a reporter plasmid containing REG Iα promoter (−1190/+26) upstream of a luciferase reporter gene. The promoter plasmid was introduced by lipofection into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with interleukin (IL)-6, IL-8, and a combination of the two. Thereafter transcriptional activity of REG Iα was measured by luciferase assay. We found that IL-6 stimulation, but not IL-8, significantly enhanced the REG Iα promoter activity in salivary ductal cells. Deletion analysis revealed that the region of −141 to −117 of the REG Iα gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transduction and activation of transcription (STAT). The introduction of siRNA for human STAT3 abolished IL-6-induced REG Iα transcription. These results showed that IL-6 stimulation induced REG Iα transcription through STAT3 activation and binding to the consensus sequence of REG Iα promoter in salivary ductal cells. This IL-6/STAT dependent REG Iα induction might play a role in the pathogenesis of SS.博士（医学）・甲第641号・平成27年11月27日Copyright © 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Real-world management of treatment-naïve diabetic macular oedema : 2-year visual outcome focusing on the starting year of intervention from STREAT-DMO study

Background/aims To investigate the yearly change of real-world outcomes for best corrected visual acuity (BCVA) after 2-year clinical intervention for treatment-naïve diabetic macular oedema (DMO). Methods Retrospective analysis of aggregated, longitudinal medical records obtained from 27 retina specialised institutions in Japan from Survey of Treatment for DMO database. A total of 2049 treatment-naïve centre involving DMO eyes of which the initial intervention started between 2010 and 2015, and had been followed for 2 years, were eligible. As interventions, antivascular endothelial growth factor (VEGF) agents, local corticosteroids, macular photocoagulation and vitrectomy were defined. In each eye, baseline and final BCVA, the number of each intervention for 2 years was extracted. Each eye was classified by starting year of interventional treatment. Results Although baseline BCVA did not change by year, 2-year improvement of BCVA had been increased, and reached to +6.5 letters in the latest term. There is little difference among starting year about proportions of eyes which BCVA gained >15 letters, in contrast to those which lost >15 letters were decreased by year. The proportion of eyes receiving anti-VEGF therapy was dramatically increased, while those receiving the other therapies were gradually decreased. The proportion of eyes which maintained socially good vision of BCVA>20/40 has been increased and reached to 59.0% in the latest term. Conclusion For recent years, treatment patterns for DMO have been gradually but certainly changed; as a result, better visual gain, suppression of worsened eyes and better final BCVA have been obtained. Anti-VEGF therapy has become the first-line therapy and its injection frequency has been increasing

Acute retinal necrosis in a patient on immunosuppressive treatment for COVID-19 pneumonia: a case report

Abstract Background Patients with coronavirus disease 2019 (COVID-19) occasionally develop ocular complications. We report a case of acute retinal necrosis (ARN) caused by Epstein–Barr Virus (EBV) that developed in a patient who had severe acute respiratory syndrome due to SARS-CoV-2 infection. Case presentation A 68-year-old woman complained of floaters and blurred vision in her right eye as she was receiving systemic prednisolone for COVID-19 pneumonia under isolation in our hospital. The patient visited an ophthalmologist following her discharge from the hospital and after the 2 weeks of isolation had ended. At the initial examination, her best-corrected visual acuity (BCVA) was 20/100 in the right eye, and the eye showed moderate anterior segment inflammation and vitreous opacities. Treatment was initiated with topical 0.1% betamethasone and 1.5% levofloxacin. After 1 month, the inflammation in the right eye decreased and her BCVA improved to 20/40. However, on day 48 from her initial visit, the inflammation in her right eye worsened and her BCVA decreased to 20/2000 by day 80. Pars plana vitrectomy with silicone oil tamponade was performed to remove the vitreous opacities, and expanded white exudates peripherally and retinal vessels with white sheathing suggestive of acute retinal necrosis (ARN) were seen intraoperatively. Analysis of the vitreous sample revealed EBV positivity on polymerase chain reaction. The patient was diagnosed with EBV-associated ARN and treated with systemic steroids and valaciclovir. The ocular inflammation gradually decreased, and she was discharged from the hospital. However, a week later, the inflammation in the right eye markedly worsened. Despite another course of steroids, the inflammation worsened, resulting in total retinal detachment and absolute glaucoma. Because of the severe pain, the right eye was enucleated. Conclusions Clinicians should be aware that COVID-19 and immunosuppressive treatment can reactivate EBV in the eye

ポリープ状脈絡膜血管症における脈絡膜拡張血管の臨床的検討

Background: Polypoidal choroidal vasculopathy (PCV) is one of the disorders within the pachychoroid spectrum diseases. The presence of pachyvessels is one of the characteristics of pachychoroid disorders. However, the relationship between the presence of pachyvessels and the clinical characteristics of PCV eyes has not been determined. The purpose of this study was to determine the relationship between the presence of choroidal pachyvessels and the clinical characteristics of eyes with PCV. Methods: The medical records of patients who were diagnosed with PCV and were treatment-naïve were reviewed. Fluorescein and indocyanine green angiography, fundus photography, spectral domain optical coherence tomography (SD-OCT), and enhanced depth imaging OCT (EDI-OCT) were used to obtain images of the choroid. The presence of pathologically dilated outer choroidal vessels, pachyvessels, was determined by ICGA images. These pachyvessels were confirmed to correspond with the large choroidal vessels in the EDI OCT images. The PCV eyes were divided into two groups based on the presence or absence of pachyvessels and clinical features and subfoveal choroidal thickness (SFCT) were evaluated between the two groups. Results: Eighty-six eyes of 84 patients with PCV were evaluated. Pachyvessels were detected in 48 eyes (55.8%). The mean SFCT was 203.9 ± 83.9 μm in all 86 eyes, and it was significantly thinner in eyes with pachyvessels (+) than without pachyvessels (-) (183.2 ± 58.4 μm vs 230.2 ± 103.1 μm; P = 0.01). The differences in the incidence of subretinal fluid, pigment epithelial detachments, and hemorrhages between the two groups were not significant. However, the PCV eyes in pachyvessels (+) group with hemorrhage had the thinnest choroid (P = 0.047). The choroidal features of the fellow eyes were similar to those of the PCV affected eyes, that is, the fellow eyes in pachyvessels (+) group had pachyvessels and the fellow eyes in pachyvessels (-) group did not have pachyvessels. Conclusions: Pachyvessels were presented 55.8% in eyes with PCV, and these eyes had the thin SFCT. The presence of pachyvessels and attenuation of the inner choroid were probably due to the pathological changes in the eyes with PCV.博士（医学）・乙第1486号・令和2年12月24日Copyright © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data