Researcher Profile and Settings

Affiliation

• Faculty of Medicine　Specialized Medicine　Sensory Organ Medicine

Job Title

• Professor

URL

http://kaken.nii.ac.jp/d/r/10245558.ja.html

J-Global ID

• 201301044129759818

Research Interests

• 血管新生   網膜   加齢黄斑変性   血管内皮増殖因子   糖尿病網膜症   カロテノイド   免疫   Vascular Endothelial Growth Factor   NF-кB   眼科学   光障害   Matrix Metalloproteinase   脈絡膜新生血管   線維血管増殖   サイトカイン   NF-κB   接着分子   炎症   グリア細胞   眼内レンズ   ルテイン   加齢性黄斑変性   神経保護   眼内ケンズ   血液網膜関門   低酸素   claudin-5   アデノウイルス角結膜炎   遺伝子   感覚器   

Research Areas

• Life sciences / Ophthalmology
• Life sciences / Human pathology
• Life sciences / Hygiene and public health (non-laboratory)
• Life sciences / Hygiene and public health (laboratory)
• Life sciences / Healthcare management, medical sociology

Educational Organization

•  Bachelor's degree program　Departments of Medicine, School of Medicine
•  Master's degree program　Graduate School of Medicine
•  Doctoral (PhD) degree program　Graduate School of Medicine

Academic & Professional Experience

• 2009/04 - Today Hokkaido University Graduate School of Medicine

Research Activities

Published Papers

• Phosphorylation of αB-Crystallin Involves Interleukin-1β-Mediated Intracellular Retention in Retinal Müller Cells: A New Mechanism Underlying Fibrovascular Membrane Formation.

  Taku Yamamoto, Satoru Kase, Akihiro Shinkai, Miyuki Murata, Kasumi Kikuchi, Di Wu, Yasushi Kageyama, Masami Shinohara, Tomohiko Sasase, Susumu Ishida

  Investigative ophthalmology & visual science 64 (10) 20 - 20 2023/07/03 

  PURPOSE: Chronic inflammation plays a pivotal role in the pathology of proliferative diabetic retinopathy (PDR), in which biological alterations of retinal glial cells are one of the key elements. The phosphorylation of αB-crystallin/CRYAB modulates its molecular dynamics and chaperone activity, and attenuates αB-crystallin secretion via exosomes. In this study, we investigated the effect of phosphorylated αB-crystallin in retinal Müller cells on diabetic mimicking conditions, including interleukin (IL)-1β stimuli. METHODS: Human retinal Müller cells (MIO-M1) were used to examine gene and protein expressions with real-time quantitative PCR, enzyme linked immunosorbent assay (ELISA), and immunoblot analyses. Cell apoptosis was assessed by Caspase-3/7 assay and TdT-mediated dUTP nick-end labeling staining. Retinal tissues isolated from the Spontaneously Diabetic Torii (SDT) fatty rat, a type 2 diabetic animal model with obesity, and fibrovascular membranes from patients with PDR were examined by double-staining immunofluorescence. RESULTS: CRYAB mRNA was downregulated in MIO-M1 cells with the addition of 10 ng/mL IL-1β; however, intracellular αB-crystallin protein levels were maintained. The αB-crystallin serine 59 (Ser59) residue was phosphorylated with IL-1β application in MIO-M1 cells. Cell apoptosis in MIO-M1 cells was induced by CRYAB knockdown. Immunoreactivity for Ser59-phosphorylated αB-crystallin and glial fibrillary acidic protein was colocalized in glial cells of SDT fatty rats and fibrovascular membranes. CONCLUSIONS: The Ser59 phosphorylation of αB-crystallin was modulated by IL-1β in Müller cells under diabetic mimicking inflammatory conditions, suggesting that αB-crystallin contributes to the pathogenesis of PDR through an anti-apoptotic effect.
• Relationship between Brachial-Ankle Pulse Wave Velocity and Fundus Arteriolar Area Calculated Using a Deep-Learning Algorithm.

  Kanae Fukutsu, Michiyuki Saito, Kousuke Noda, Miyuki Murata, Satoru Kase, Ryosuke Shiba, Naoki Isogai, Yoshikazu Asano, Nagisa Hanawa, Mitsuru Dohke, Manabu Kase, Susumu Ishida

  Current eye research 47 (11) 1534 - 1537 2022/11 

  PURPOSE: Retinal vessels reflect alterations related to hypertension and arteriosclerosis in the physical status. Previously, we had reported a deep-learning algorithm for automatically detecting retinal vessels and measuring the total retinal vascular area in fundus photographs (VAFP). Herein, we investigated the relationship between VAFP and brachial-ankle pulse wave velocity (baPWV), which is the gold standard for arterial stiffness assessment in clinical practice. METHODS: Retinal photographs (n = 696) obtained from 372 individuals who visited the Keijinkai Maruyama Clinic for regular health checkups were used to analyze VAFP. Additionally, the baPWV was measured for each patient. Automatic retinal-vessel segmentation was performed using our deep-learning algorithm, and the total arteriolar area (AA) and total venular area (VA) were measured. Correlations between baPWV and several parameters, including AA and VA, were assessed. RESULTS: The baPWV was negatively correlated with AA (R = -0.40, n = 696, P < 2.2e-16) and VA (R = -0.36, n = 696, P < 2.2e-16). Independent variables (AA, sex, age, and systolic blood pressure) selected using the stepwise method showed a significant correlation with baPWV. The estimated baPWV, calculated using a regression equation with variables including AA, showed a better correlation with the measured baPWV (R = 0.70, n = 696, P < 2.2e-16) than the estimated value without AA (R = 0.68, n = 696, P < 2.2e-16). CONCLUSIONS: AA and VA were significantly correlated with baPWV. Moreover, baPWV estimated using AA correlated well with the actual baPWV. VAFP may serve as an alternative biomarker for evaluating systemic arterial stiffness.
• Surgical outcomes of partial ciliary body direct suturing under the scleral flap for traumatic cyclodialysis cleft: A five-case series.

  Riki Kijima, Yasuhiro Shinmei, Akihiro Shinkai, Rina Kanaya, Shinki Chin, Susumu Ishida

  European journal of ophthalmology 32 (6) 3712 - 3719 2022/11 

  BACKGROUND: Cyclodialysis cleft is an uncommon finding due to blunt ocular trauma. A larger and more chronic cyclodialysis requires surgical repair. The aim of this study was to introduce a minimally invasive suturing technique for the lens-sparing repair of traumatic cyclodialysis cleft and evaluate outcomes. METHODS: This study was a retrospective case series. The medical and surgical records of five patients with traumatic cyclodialysis cleft who underwent this surgery were reviewed. The surgeon (Y.S.) dissected a fornix-based conjunctival flap and created a 90° circumferential and limbal-based scleral flap. Several small incisions parallel to the limbus were made within the scleral bed 1.5 and 3 mm posterior to the limbus. After suprachoroidal fluid drainage, tiny bumps in the ciliary body were exposed from the incisions and sewn directly onto the scleral bed with 10-0 nylon sutures. RESULTS: The mean age of the patients was 37.8 ± 1.3 years. The mean duration from injury to surgery was 14.8 ± 16.7 months. Mean best-corrected visual acuity (BCVA) was 0.56 ± 0.70 and intraocular pressure (IOP) was 5.2 ± 1.9 mmHg. In all patients, IOP normalized and BCVA then returned to baseline following this procedure. Mean postoperative BCVA was 1.17 ± 0.86 and IOP was 17.8 ± 1.3 mmHg. Mean IOP and BCVA recovery times were 82.0 ± 139.6 and 294.3 ± 284.3 days, respectively. CONCLUSIONS: Partial ciliary body direct suturing under the scleral flap is a less invasive surgical option without lensectomy and considered safe and effective as a primary surgical repair for traumatic cyclodialysis cleft.
• Reduction of Intraocular Pressure and Aqueous Outflow Resistance after Modified 360-degree Suture Trabeculotomy.

  Kayo Suzuki, Yasuhiro Shinmei, Kiriko Hirooka, Rina Kanaya, Akihiro Shinkai, Riki Kijima, Shinki Chin, Yoichi M Ito, Susumu Ishida

  Journal of glaucoma 2022/10/12 

  PRCIS: Decreasing aqueous outflow resistance at trabecular meshwork is the main mechanism of modified 360-degree suture trabeculotomy, and the preoperative C-value, which shows aqueous outflow resistance, is likely to be useful for predicting IOP reduction. PURPOSE: To clarify the mechanism of intraocular pressure (IOP) reduction and the preoperative prognostic predictor of modified 360-degree suture trabeculotomy (ST). PATIENTS AND METHODS: Forty-three eyes of 32 patients with glaucoma who underwent ST at Hokkaido University Hospital between April 2017 and February 2020 were enrolled. The records of postoperative IOP and coefficient of aqueous outflow (C-value) after ST were reviewed from clinical charts retrospectively. Preoperative IOP and C-values were also reviewed and considered as the baseline. RESULTS: Although the differences were not significant, IOP decreased to 15.4±3.3 mmHg at 3 months (P=0.10) and 16.1±3.8 mmHg at 6 months (P=0.21). In addition, there were significant decreases in anti-glaucoma medication scores at both 3 and 6 months after surgery (P<0.01). The C-value increased significantly to 0.24±0.11 µl/min/mmHg at 3 months (P<0.01) and increased significantly to 0.27±0.14 µl/min/mmHg at 6 months (P<0.01). The rates of change in IOP were negatively correlated with that in the C-value at 3 months (r=-0.49 and P<0.01) and 6 months (r=-0.46 and P<0.01). The success rate (IOP<21 mmHg, IOP reduction>20%) was greater in the low baseline C-value group (≤0.17) than high baseline C-value group (>0.17) (P<0.05), and the baseline IOP and C-values were statistically significant in association with the success (P<0.05) at 6 months. CONCLUSIONS: Increased conventional outflow by elimination of the aqueous outflow resistance at the trabecular meshwork is the main mechanism of IOP reduction after ST. Preoperative examination of tonographic outflow facility may be useful for predicting the IOP reduction and outcome of ST.
• Diffuse large b-cell lymphoma of the ocular adnexa with flow cytometry analysis and review of the literature.

  Mizuho Mitamura, Satoru Kase, Yasuo Suzuki, Takatoshi Sakaguchi, Yuka Suimon, Toshiya Sinohara, A I Shimizu, Yoshihiro Matsuno, Hajime Sakai, Manabu Kase, Susumu Ishida

  European journal of ophthalmology 11206721221127053 - 11206721221127053 2022/09/16 

  PURPOSE: The aim of this study was to evaluate the clinicopathological features and flow cytometry (FCM) of tumor tissues in ocular adnexal diffuse large B-cell lymphoma (DLBCL). METHODS: This retrospective, multicenter case study was designed to evaluate the clinical and immunohistochemical features of tumors. DLBCL was diagnosed based on histopathology, immunoglobulin (Ig) heavy chain gene rearrangement, and FCM in all surgically removed periocular tumor tissues. This study involved assessing percentages (%) of B-cell/T-cell markers, a natural killer cell marker, and cell-surface Ig kappa/lambda (κ/λ) expression measured by FCM analysis in tumor tissues. RESULTS: Eleven DLBCL patients (4 men and 7 women) with 11 tumors were enrolled in this study. The median age at the time of initial presentation was 73 years. The tumor cells were immunohistochemically positive for cluster of differentiation (CD) 20, while CD5 was negative in all 8 cases tested. At the time of ophthalmic diagnosis, two cases already showed systemic dissemination of DLBCL throughout the body. FCM of tumor tissues detected a high percentage of B-cell markers including CD19 and CD20 in all 11 tumors. One case with high CD10 levels in FCM was histologic transformation from follicular lymphoma. One case with a relatively low CD20 population involved a history of systemic treatments including intravenous rituximab. CONCLUSION: Although caution should be exercised when interpreting the data, FCM is useful for not only supportive diagnosis complementary to immunohistochemistry, but also facilitates a better understanding of immunopathology including histologic transformation of follicular lymphoma to DLBCL in the ocular adnexa.
• Placental growth factor stabilizes VEGF receptor-2 protein in retinal pigment epithelial cells by downregulating glycogen synthase kinase 3 activity.

  Miyuki Murata, Kousuke Noda, Satoru Kase, Keitaro Hase, Di Wu, Ryo Ando, Susumu Ishida

  The Journal of biological chemistry 298 (9) 102378 - 102378 2022/09 

  Placental growth factor (PlGF) belongs to the vascular endothelial growth factor (VEGF) family of proteins that participate in angiogenesis and vasculogenesis. Anti-VEGF therapy has become the standard treatment for ocular angiogenic disorders in ophthalmological practice. However, there is emerging evidence that anti-VEGF treatment may increase the risk of atrophy of the retinal pigment epithelium (RPE), which is important for the homeostasis of retinal tissue. Whereas the cytoprotective role of VEGF family molecules, particularly that of VEGF A (VEGFA) through its receptor VEGF receptor-2 (VEGFR-2), has been recognized, the physiological role of PlGF in the retina is still unknown. In this study, we explored the role of PlGF in the RPE using PlGF-knockdown RPE cells generated by retrovirus-based PlGF-shRNA transduction. We show that VEGFA reduced apoptosis induced by serum starvation in RPE cells, whereas the antiapoptotic effect of VEGFA was abrogated by VEGFR-2 knockdown. Furthermore, PlGF knockdown increased serum starvation-induced cell apoptosis and unexpectedly reduced the protein level of VEGFR-2 in the RPE. The antiapoptotic effect of VEGFA was also diminished in PlGF-knockdown RPE cells. In addition, we found that glycogen synthase kinase 3 activity was involved in proteasomal degradation of VEGFR-2 in RPE cells and inactivated by PlGF via AKT phosphorylation. Overall, the present data demonstrate that PlGF is crucial for RPE cell viability and that PlGF supports VEGFA/VEGFR-2 signaling by stabilizing the VEGFR-2 protein levels through glycogen synthase kinase 3 inactivation.
• Long-term Outcomes of Modified 360-Degree Suture Trabeculotomy for Uveitic Glaucoma Compared With Primary Open Angle Glaucoma.

  Riki Kijima, Yasuhiro Shinmei, Shinki Chin, Rina Kanaya, Akihiro Shinkai, Takeshi Ohguchi, Kenichi Namba, Susumu Ishida

  Journal of glaucoma 31 (8) 682 - 688 2022/08/01 

  PRCIS: A Kaplan-Meier survival curve analysis showed no significant differences in success rates between uveitic glaucoma (UG) and primary open angle glaucoma (POAG) 120 months after modified 360-degree suture trabeculotomy, which was effective for both groups in the long term. PURPOSE: The aim of this study was to examine the outcomes of modified 360-degree suture trabeculotomy in patients with UG as compared with those with POAG. PATIENTS AND METHODS: This was a retrospective, nonrandomized, and comparative case series study. Modified 360-degree trabeculotomy using a 5-0 nylon suture (S-LOT) was performed on 51 eyes of 51 patients (54.4±13.4 y) with UG between October 2005 and January 2012 at Hokkaido University Hospital. Age-matched patients with POAG who underwent S-LOT during the same period were enrolled as controls. Written informed consent was obtained from all patients enrolled in the present study. Surgical success was defined as an intraocular pressure (IOP) <18 mm Hg with similar or lower doses of antiglaucoma medications. Kaplan-Meier survival curves of surgical failure were analyzed and compared between UG and POAG. RESULTS: The mean follow-up periods (±SD) for UG and POAG were 104.8±44.0 and 98.1±36.3 months ( P =0.23), respectively. Mean preoperative IOP in UG and POAG were 34.9±11.0 and 25.3±9.4 mm Hg ( P <0.001), respectively. After surgery, mean IOP in UG and POAG decreased to 12.0±4.1 and 13.8±3.2 mm Hg, respectively, at 60 months, and 12.1±5.6 and 12.4±1.8 mm Hg ( P =0.86), respectively, at 120 months. The Kaplan-Meier survival curve analysis showed no significant differences in success rates between UG and POAG at the end of the follow-up (Log-rank test, P =0.13). Success rates in UG and POAG were 70.0 and 62.5% at 60 months, and 67.5 and 41.2% at 120 months, respectively. CONCLUSION: These results suggest that S-LOT is effective for UG and POAG alike.
• 人を惹きつける魅力的なプレゼンをめざそう!

  石田 晋, 小沢 洋子, 近藤 峰生, 園田 康平, 中澤 徹, 安川 力, 山城 健児

  Retina Medicine (株)先端医学社 11 (1) 1 - 8 2187-2384 2022/04
• Serum advanced glycation end-products and αB-crystallin in diabetic retinopathy patients.

  Taku Yamamoto, Satoru Kase, Miyuki Murata, Susumu Ishida

  Biomedical reports 16 (4) 28 - 28 2022/04 

  αB-crystallin, one of the small heat shock proteins, which is also known as HSPB5, has cytoprotective effects under inflammatory conditions. Advanced glycation end-products (AGE) are produced through non-enzymatic glycation under conditions of hyperglycemia and they contribute to angiogenesis and inflammation. The aim of this study was to examine the levels of serum αB-crystallin and AGE concentrations in blood samples collected from proliferative diabetic retinopathy (PDR) patients. Blood samples were collected from seven diabetic patients with PDR and eight patients without diabetes mellitus who underwent vitrectomy due to PDR and idiopathic macular diseases, respectively, in a single center. The levels of serum αB-crystallin and AGE were measured by ELISA and correlations were assessed statistically. The serum levels (mean ± SEM) of AGE were significantly higher in PDR patients (28.41±0.46 µg/ml) than in patients with non-diabetic macular diseases (25.76±0.60 µg/ml; P=0.015), whereas there was no significant difference in serum αB-crystallin levels. There was one patient with an extremely high level of αB-crystallin, who was treated with systemic corticosteroid due to chronic autoimmune inflammatory diseases. The current prospective study showed that serum AGE levels were significantly higher in PDR patients; however, no correlations between serum AGE and αB-crystallin levels were identified.
• Downregulation of AlphaB-crystallin in Retinal Pigment Epithelial Cells Exposed to Diabetes-related Stimuli In Vivo and In Vitro.

  D I Wu, Satoru Kase, Y E Liu, Atsuhiro Kanda, Miyuki Murata, Susumu Ishida

  In vivo (Athens, Greece) 36 (1) 132 - 139 2022 

  BACKGROUND/AIM: AlphaB-crystallin plays a pivotal role in many diseases. However, the involvement of alphaB-crystallin in retinal pigment epithelial (RPE) cells with diabetes stimuli remains unknown. The aim of this study is to examine the alterations of RPE cells and alphaB-crystallin expression in diabetic models in vivo and in vitro. MATERIALS AND METHODS: Diabetic conditions in mice were induced by streptozotocin (STZ). The thickness of the RPE/choroid complex was measured by optical coherence tomography (OCT). Periodic acid-Schiff (PAS) staining was used to investigate the choriocapillaris in histological sections of murine eyeballs and oxidative stress was evaluated using immunofluorescence with anti-4-hydroxynonenal (HNE) antibody. AlphaB-crystallin expression was examined in the RPE/choroid complex using ELISA. Real-Time PCR was performed to evaluate the alphaB-crystallin expression in cultured human RPE cells with high glucose or following advanced glycation end-products (AGE) stimulation. RESULTS: In diabetic mice, OCT-based RPE/choroidal layers were thickened 2 months after STZ stimulation, where PAS-positive dilated choriocapillaris was noted. Immunoreactivity of 4-HNE was strongly observed in the RPE layer, from which a significant number of RPE cells was lost. Meanwhile, alphaB-crystallin expression in 2-month STZ mice was significantly lower compared to controls. In accordance with these results, in vitro data showed that the alphaB-crystallin expression was also significantly lower in RPE cells with high glucose or following AGE stimulation compared to untreated cells. CONCLUSION: In both types of diabetic models the expression of alphaB-crystallin was found to be downregulated in RPE cells and was associated with increased levels of oxidative stress.
• Imbalanced choroidal circulation in eyes with asymmetric dilated vortex vein

  Kiriko Hirooka, Michiyuki Saito, Yui Yamashita, Yuki Hashimoto, Nobuhiro Terao, Hideki Koizumi, Kousuke Noda, Susumu Ishida

  Japanese Journal of Ophthalmology 0021-5155 2021/12/03
• Recent Clinical Features of Intraocular Inflammation in Hokkaido, Japan - Comparison with the Previous Decade.

  Daiju Iwata, Kenichi Namba, Taku Yamamoto, Kazuomi Mizuuchi, Wataru Saito, Shigeaki Ohno, Nobuyoshi Kitaichi, Susumu Ishida

  Ocular immunology and inflammation 1 - 7 2021/02/11 

  PURPOSE: This study aimed to investigate the clinical features of intraocular inflammation (uveitis) in Hokkaido and to assess the etiology trends in comparison with those of our previous survey. METHODS: We retrospectively reviewed the medical records of 1,616 new referral uveitis patients (1,020 females and 596 males) in Hokkaido University Hospital between 2004 and 2014. RESULTS: Sarcoidosis was the most frequent etiology (17.4%), followed by Vogt-Koyanagi-Harada disease (8.1%), Behçet's disease (4.5%), and human leukocyte antigen B27 -associated uveitis (2.5%). The etiologies in 48.7% of the patients were unclassified. Compared to the previous survey between 1994 and 2003, the rate of Behçet's disease decreased and that of sarcoidosis increased. The rates of infectious uveitis and vitreoretinal lymphoma increased. CONCLUSION: Although the order of the top four etiologies was the same in the two surveys, the rate of sarcoidosis increased and that of Behçet's disease decreased.
• Hypoxia Induces Galectin-1 Expression Via Autoinduction of Placental Growth Factor in Retinal Pigment Epithelium Cells.

  Taku Yamamoto, Atsuhiro Kanda, Satoru Kase, Susumu Ishida

  Investigative ophthalmology & visual science 62 (2) 22 - 22 2021/02/01 

  Purpose: Galectin-1/LGALS1, a β-galactoside-binding protein, contributes to angiogenesis and fibrosis in various ocular diseases. Hypoxia-dependent and -independent pathways upregulate galectin-1/LGALS1 expression in Müller glial cells. Here, we present novel findings on the galectin-1/LGALS1 regulatory system in human retinal pigment epithelium (RPE) cells, the major cellular participant in the pathogenesis of neovascular age-related macular degeneration (nAMD). Methods: Human RPE cells were used to evaluate changes in gene and protein expression with real-time quantitative PCR and immunoblot analyses, respectively. The promoter and enhancer regions of LGALS1 were analyzed by reporter assay and chromatin immunoprecipitation. Immunofluorescence analysis of nAMD patient specimens was used to confirm the in vitro findings. Results: Hypoxia induced galectin-1/LGALS1 expression via binding of hypoxia-inducible factor 1α (HIF-1α) to hypoxia-responsive elements in the LGALS1 promoter region. Blockade of vascular endothelial growth factor receptor 1 (VEGFR1) partially decreased hypoxia-induced galectin-1/LGALS1 expression. Among several VEGFR1 ligands induced by hypoxia, placental growth factor (PlGF)/PGF alone upregulated galectin-1/LGALS1 expression via phosphorylation of activator protein 1 (AP-1) subunits following AKT and p38 mitogen-activated protein kinase (MAPK) activation. An AP-1 site in the LGALS1 enhancer region was required for PlGF-induced galectin-1/LGALS1 expression in RPE cells. PlGF application upregulated PGF expression via extracellular signal-regulated kinase 1 and 2, AKT, and p38 MAPK pathways. nAMD patient specimens demonstrated co-localization of galectin-1 with HIF-1α, PlGF, and VEGFR1 in RPE cells. Conclusions: Our present findings implicate the significance of hypoxia as a key inducer of galectin-1/LGALS1 in RPE cells and the autoinduction of hypoxia-induced PlGF as a vicious cycle amplifying the pathogenesis of nAMD.
• A Novel Deep Learning Architecture for Vascular Area Measurement in Fundus Images

  Kanae Fukutsu, Michiyuki Saito, Kousuke Noda, Miyuki Murata, Satoru Kase, Ryosuke Shiba, Naoki Isogai, Yoshikazu Asano, Nagisa Hanawa, Mitsuru Dohke, Manabu Kase, Susumu Ishida

  Ophthalmology Science 100004 - 100004 2666-9145 2021/02
• ROCK1 Mediates Retinal Glial Cell Migration Promoted by Acrolein.

  Kanae Fukutsu, Miyuki Murata, Kasumi Kikuchi, Shiho Yoshida, Kousuke Noda, Susumu Ishida

  Frontiers in medicine 8 717602 - 717602 2021 

  Objective: Acrolein is a highly reactive aldehyde that covalently binds to cellular macromolecules and subsequently modulates cellular function. Our previous study demonstrated that acrolein induces glial cell migration, a pathological hallmark of diabetic retinopathy; however, the detailed cellular mechanism remains unclear. The purpose of this study was to investigate the role of acrolein in retinal glial cell migration by focusing on rho-associated coiled-coil-containing protein kinases (ROCKs). Methods: Immunofluorescence staining for ROCK isoforms was performed using sections of fibrovascular tissue obtained from the eyes of patients with proliferative diabetic retinopathy (PDR). Rat retinal Müller glial cell line, TR-MUL5, was stimulated with acrolein and the levels of ROCK1 were evaluated using real-time PCR and western blotting. Phosphorylation of the myosin-binding subunit of myosin light chain phosphatase [myosin phosphatase target subunit 1, (MYPT1)] and myosin light chain 2 (MLC2) was assessed. The cell migration rate of TR-MUL5 cells exposed to acrolein and/or ripasudil, a non-selective ROCK inhibitor, was measured using the Oris cell migration assay. Results: ROCK isoforms, ROCK1 and ROCK2, were positively stained in the cytosol of glial cells in fibrovascular tissues. In TR-MUL5 cells, the mRNA expression level of Rock1, but not Rock2, was increased following acrolein stimulation. In line with the PCR data, western blotting showed increase in ROCK1 and cleaved ROCK1 protein in TR-MUL5 cells stimulated with acrolein. N-acetylcysteine (NAC) suppressed acrolein-associated Rock1 upregulation in TR-MUL5 cells. Acrolein augmented the phosphorylation of MYPT1 and MLC2 and increased the cell migration rate of TR-MUL5 cells, both of which were abrogated by ripasudil. Conclusions: Our study demonstrated that ROCK1 mediates the migration of retinal glial cells promoted by the unsaturated aldehyde acrolein.
• Surgical Outcomes of Trabeculectomy in Uveitic Glaucoma: A Long-Term, Single-Center, Retrospective Case-Control Study.

  Rina Kanaya, Riki Kijima, Yasuhiro Shinmei, Akihiro Shinkai, Takeshi Ohguchi, Kenichi Namba, Shinki Chin, Susumu Ishida

  Journal of ophthalmology 2021 5550776 - 5550776 2021 

  PURPOSE: To evaluate the long-term outcomes of trabeculectomy with mitomycin C (MMC-TLE) in patients with uveitic glaucoma (UG). Patients and Methods. This was a retrospective, nonrandomized case series study. MMC-TLE was performed on 50 eyes with UG between February 2001 and January 2015 at Hokkaido University Hospital. Age- and sex-matched patients with primary open angle glaucoma (POAG) who underwent MMC-TLE were matched by age and sex and enrolled as controls. Surgical success was defined as an intraocular pressure (IOP) less than 18 or 15 mmHg. The Kaplan-Meier survival curves for surgical failure were analyzed. RESULTS: The mean preoperative IOP in UG and POAG was 27.6 ± 10.6 and 18.0 ± 4.5 mmHg, respectively. After the surgery, the mean IOP in UG and POAG was reduced to 11.7 ± 4.2 and 12.2 ± 3.8 mmHg at 12 months, 11.9 ± 7.0 and 12.1 ± 3.1 mmHg at 36 months, and 13.0 ± 5.2 and 10.6 ± 1.2 mmHg at 120 months, respectively. The success rates (IOP <18 mmHg, IOP reduction >20%) in UG and POAG were 91.7% and 88.0% at 12 months, 82.2% and 75.6% at 36 months, and 66.5% and 61.8% at 120 months, respectively. The success rates (IOP <15 mmHg) in UG and POAG were 64.0% and 58.0% at 12 months, 55.1% and 45.5% at 36 months, and 47.9% and 37.8% at 120 months, respectively. There was no significant difference in the success rate between UG and POAG at 120 months after surgery by either definition of surgical success. CONCLUSIONS: MMC-TLE effectively reduced IOP in both UG and POAG. There was no significant difference in the success rate between UG and POAG. Following sufficient inflammation suppression, surgical outcomes of UG may be comparable with those of POAG.
• Involvement of Müller Glial Autoinduction of TGF-β in Diabetic Fibrovascular Proliferation Via Glial-Mesenchymal Transition.

  Di Wu, Atsuhiro Kanda, Ye Liu, Kousuke Noda, Miyuki Murata, Susumu Ishida

  Investigative ophthalmology & visual science 61 (14) 29 - 29 2020/12/01 

  Purpose: Müller glial-mesenchymal transition (GMT) is reported as the fibrogenic mechanism promoted by TGF-β-SNAIL axis in Müller cells transdifferentiated into myofibroblasts. Here we show the multifaceted involvement of TGF-β in diabetic fibrovascular proliferation via Müller GMT and VEGF-A production. Methods: Surgically excised fibrovascular tissues from the eyes of patients with proliferative diabetic retinopathy were processed for immunofluorescence analyses of TGF-β downstream molecules. Human Müller glial cells were used to evaluate changes in gene and protein expression with real-time quantitative PCR and ELISA, respectively. Immunoblot analyses were performed to detect TGF-β signal activation. Results: Müller glial cells in patient fibrovascular tissues were immunopositive for GMT-related molecular markers, including SNAIL and smooth muscle protein 22, together with colocalization of VEGF-A and TGF-β receptors. In vitro administration of TGF-β1/2 upregulated TGFB1 and TGFB2, both of which were suppressed by inhibitors for nuclear factor-κB, glycogen synthase kinase-3, and p38 mitogen-activated protein kinase. Of the various profibrotic cytokines, TGF-β1/2 application exclusively induced Müller glial VEGFA mRNA expression, which was decreased by pretreatment with small interfering RNA for SMAD2 and inhibitors for p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase. Supporting these findings, TGF-β1/2 stimulation to Müller cells increased the phosphorylation of these intracellular signaling molecules, all of which were also activated in Müller glial cells in patient fibrovascular tissues. Conclusions: This study underscored the significance of Müller glial autoinduction of TGF-β as a pathogenic cue to facilitate diabetic fibrovascular proliferation via TGF-β-driven GMT and VEGF-A-driven angiogenesis.
• Acute unilateral inner retinal dysfunction with photophobia: importance of electrodiagnosis.

  Toshiaki Hirakata, Kaoru Fujinami, Wataru Saito, Atsuhiro Kanda, Akito Hirakata, Susumu Ishida, Akira Murakami, Kazushige Tsunoda, Yozo Miyake

  Japanese journal of ophthalmology 65 (1) 42 - 53 2020/11/12 

  PURPOSE: To establish with negative electroretinogram (ERG) the clinical entity of eight patients with unilateral severe photophobia, essentially normal fundus, good visual acuity, and severe cone and rod dysfunction. STUDY DESIGN: Multicenter retrospective observation case series. METHODS: Comprehensive ophthalmologic examinations were performed, including best-corrected visual acuity (BCVA), full-field ERGs and multifocal ERGs (mfERGs), fundus photographs, and OCT. Systemic and genetic examinations were performed. RESULTS: The mean (± SD) age at the onset was 60.0 ± 8.4 years, and the six patients noticed severe photophobia in the affected eye in spite of almost normal fundus appearance and good BCVA. The dark-adapted bright flash ERGs in the affected eye had relatively well-preserved a-waves and depressed b-waves, i.e., a negative ERG. Cone ERGs and both b- and d-waves of the photopic long-duration ERGs were almost undetectable. Rod ERGs were severely reduced; however, only two patients complained of night blindness. In five patients, the mfERGs were extinguished in the periphery but preserved in the central retina, resulting in good BCVA. Electrophysiological findings indicated a severe diffuse dysfunction of the inner retina affecting bipolar cells of both ON- and OFF-pathways, and in five patients there was a reduction in the thickness of the inner nuclear layer. In seven patients the retinal arteries were attenuated. Anti-retinal antibodies were detected in the serum of two patients. No genetic causes were found. CONCLUSIONS: The common features in the eight patients with unilateral negative ERGs suggest a new disease entity of unilateral acute inner retinal layer dysfunction. In most patients, the only subjective complain was photophobia.
• Morphological features of macular telangiectasia type 2 in Japanese patients.

  Akihiro Shinkai, Wataru Saito, Yuki Hashimoto, Michiyuki Saito, Satoru Kase, Kousuke Noda, Susumu Ishida

  Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 2020/11/04 

  PURPOSE: This study aimed to demonstrate the clinical course of Japanese patients with macular telangiectasia type 2 (MacTel-2). METHODS: This retrospective observational case series included 16 eyes of 8 Japanese patients (3 men and 5 women) with MacTel-2. The mean age and follow-up duration was 66.9 years and 42.8 months, respectively. Differences in best-corrected visual acuity (BCVA), funduscopic macular findings, central macular thickness (CMT), and the length of macular ellipsoid zone (EZ) loss were compared between the initial/baseline and final visits. Optical coherence tomographic changes in CMT by ≥ 20% and in EZ loss by ≥ 20% or ≥ 100 μm were defined as improved or worsened. RESULTS: Numerical changes in BCVA and EZ loss during follow-up were not statistically significant. However, the mean CMT at baseline, which was lower than that of healthy control eyes (P < 0.001), significantly increased during follow-up (P = 0.041). A certain proportion of eyes showed improvement in several parameters: funduscopic findings (both parafoveal retinal graying and foveal retinal pigment epithelium depigmentation) in 29% of eyes, CMT in 21% of eyes, and EZ loss in 43% of eyes. CONCLUSIONS: The non-negligible proportion of eyes with improved parameters, marked especially by macular EZ loss, suggests that Japanese patients with MacTel-2 have milder clinical features than Caucasian patients reported in the literature.
• 硝子体内鉄片異物を経前房的に摘出した3例

  長谷川 綾華, 清水 啓史, 野田 航介, 廣岡 季里子, 柴田 有紀子, 石田 晋

  臨床眼科 (株)医学書院 74 (12) 1449 - 1454 0370-5579 2020/11 

  ＜文献概要＞目的:硝子体内鉄片異物に対して,術前に画像検査を用いてその径を計測し,強角膜創から経前房的に摘出した3症例を経験したので報告する。症例:症例は43〜74歳。全例男性で,左眼球内に鉄片が飛入して受傷していた。症例1と2は前医受診時に結膜裂創は確認されないものの硝子体出血を認めており,その後に硝子体出血が吸収されてから眼球内の鉄片が確認されて当科へ紹介となった。症例3は受傷同日に結膜裂創と眼内組織の脱出に対して前医で強膜縫合術が施行されたが,網膜剥離が疑われたため受傷3日後に当科へ紹介となった。所見:受傷眼の初診時矯正視力は,症例1は0.4,症例2は1.2,症例3は手動弁。鉄片サイズは光干渉断層計を用いて計測した症例1と2では約2×2mm,CTを用いた症例3では長径が約10mmであった。3症例とも経毛様体扁平部硝子体切除術を施行し,水晶体再建術を併施した。症例1と2は水晶体再建術で作成した強角膜切開創,症例3は鉄片サイズが大きかったため作成したフラウン切開創(8mm)を使用して,計画的後嚢切開部から経前房的に鉄片を摘出した。術後矯正視力は,0.8〜1.2と良好であった。結論:眼内鉄片異物症例に対して,異物の大きさを術前に計測して適切な強角膜創を作成することで低侵襲な眼内鉄片摘出が可能であった。
• 硝子体内鉄片異物を経前房的に摘出した3例

  長谷川 綾華, 清水 啓史, 柴田 有紀子, 品川 真有子, 齋藤 理幸, 加瀬 諭, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 13 (11) 739 - 739 1882-5176 2020/11
• 脈絡膜瘢痕病巣を生じた急性特発性黄斑症の1例

  大田 翔一郎, 齋藤 理幸, 鈴木 智浩, 清水 啓史, 橋本 勇希, 加瀬 諭, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 13 (11) 743 - 743 1882-5176 2020/11
• Pachychoroid関連疾患と鑑別を要したchoroidal macrovesselの1例

  片岡 慶次, 加瀬 諭, 長谷川 綾華, 柴田 有紀子, 品川 真有子, 清水 啓史, 齋藤 理幸, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 13 (11) 749 - 749 1882-5176 2020/11
• ポリープ状脈絡膜血管症に対するphotodynamic therapyトリプル療法におけるpachychoroidの有無での治療成績の比較

  柴田 有紀子, 安藤 亮, 野田 航介, 廣岡 季里子, 長谷川 綾華, 品川 真有子, 清水 啓史, 齋藤 理幸, 加瀬 諭, 齋藤 航, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 13 (11) 752 - 752 1882-5176 2020/11
• 増殖糖尿病網膜症患者の硝子体中アクロレイン結合蛋白と単球走化性因子

  村田 美幸, 福津 佳苗, 野田 航介, 吉田 志帆, 神田 敦宏, 石田 晋

  糖尿病合併症 (一社)日本糖尿病合併症学会 34 (Suppl.1) 262 - 262 2020/11
• Laser Speckle Flowgraphy Findings in a Patient with Choroidal Macrovessel.

  Keiji Kataoka, Satoru Kase, Kousuke Noda, Susumu Ishida

  Ophthalmology. Retina 4 (11) 1123 - 1124 2020/11
• 機械学習によって自動算出された網膜動静脈面積と血圧脈波の関係

  福津 佳苗, 齋藤 理幸, 野田 航介, 村田 美幸, 加瀬 諭, 柴 涼介, 磯貝 直己, 道家 充, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 13 (10) 683 - 684 1882-5176 2020/10
• 黄斑部毛細血管拡張症type 2患者の黄斑部脈絡膜厚評価

  新海 晃弘, 齋藤 航, 橋本 勇希, 齋藤 理幸, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 13 (10) 684 - 684 1882-5176 2020/10
• 抗carbonic anhydrase II抗体陽性自己免疫性網膜症の臨床像

  安藤 亮, 齋藤 航, 平形 寿彬, 藤波 芳, 角田 和繁, 加瀬 諭, 野田 航介, 神田 敦宏, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 13 (10) 684 - 684 1882-5176 2020/10
• Choroidal Thickness in Diabetic Patients Without Diabetic Retinopathy: A Meta-analysis.

  Hiroaki Endo, Satoru Kase, Michiyuki Saito, Masahiko Yokoi, Mitsuo Takahashi, Susumu Ishida, Manabu Kase

  American journal of ophthalmology 218 68 - 77 2020/10 

  PURPOSE: To evaluate the relationship between diabetic eyes without diabetic retinopathy and healthy eyes in subfoveal choroidal thickness. DESIGN: Systematic review and meta-analysis. METHODS: An independent retrospective or prospective clinical study comparing diabetic eyes without diabetic retinopathy and healthy control eyes in the subfoveal choroidal thickness was selected. This study compiled data from publications in PubMed and Web of Science between January 1, 2008, and November 15, 2019. Heterogeneity was statistically quantified by I2 statistics, and meta-analysis was performed using a random-effects model. RESULTS: Seventeen related studies were identified, including a total of 4,213 eyes, which consisted of 1,197 diabetic eyes without diabetic retinopathy and 3,016 healthy eyes. Meta-analysis clearly showed that the subfoveal choroidal thickness of diabetic eyes without retinopathy was significantly thinner than that of healthy control eyes (weighted mean difference = -14.34 μm; 95% confidence interval: -24.37 to -4.32 μm; P < .005). Similar results were obtained in sub-analysis based on the adjustment of the axial length. CONCLUSIONS: This study suggests that the subfoveal choroidal thickness was thin in diabetic eyes without retinopathy compared to healthy eyes. Subfoveal choroidal thickness might be an important parameter for the development of diabetic retinopathy in diabetic eyes without retinopathy.
• 機械学習によるFA画像からの網膜静脈分枝閉塞症の視力予後の推量

  品川 真有子, 齋藤 理幸, 高橋 光生, 伊藤 有希, 遠藤 弘毅, 加瀬 諭, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 13 (9) 638 - 638 1882-5176 2020/09
• Outer Retinal Abnormalities in a Patient with Danon Disease.

  Ayaka Hasegawa, Kousuke Noda, Akio Fujiya, Kiriko Hirooka, Toshihisa Anzai, Susumu Ishida

  Retinal cases & brief reports 2020/08/31 

  PURPOSE: To report outer retinal abnormalities evaluated using high-resolution imaging modalities in a patient with Danon disease. METHODS: Case report. RESULTS: A 26-year-old woman, diagnosed with Danon disease based on genetic testing, was referred to our department for further evaluation of ocular findings. Her best-corrected visual acuity was 20/20, and color vision was normal. Fundus examination revealed pigmentary changes consisting of mottled depigmentation and pigmentation in the peripheral retina of both eyes. Spectral-domain optical coherence tomography (SD-OCT) revealed disruptions of the ellipsoid and interdigitation zones, irregularity of the retinal pigment epithelium (RPE), and hyperreflectivity of the outer nuclear layer. In addition, an adaptive optics retinal camera demonstrated the ambiguous macular cone mosaic pattern. CONCLUSION: Danon disease is caused by a primary deficiency in lysosomal associated membrane protein 2 (LAMP-2), an important constituent of the lysosomal membrane that plays a crucial role in the process of autophagy. It is possible that the findings of SD-OCT and adaptive optics retinal camera are early changes associated with the accumulation of autophagosomes and/or phagosomes due to LAMP-2 dysfunction in the photoreceptors, eventually followed by outer retinal degeneration, such as thinning of both the photoreceptor and RPE layers at the fovea.
• Receptor-Associated Prorenin System in the Trabecular Meshwork of Patients with Primary Open-Angle Glaucoma and Neovascular Glaucoma.

  Erdal Tan Ishizuka, Atsuhiro Kanda, Yasuhiro Shinmei, Takeshi Ohguchi, Yoshiaki Tagawa, Keitaro Hase, Taku Yamamoto, Kousuke Noda, Shinki Chin, Susumu Ishida

  Journal of clinical medicine 9 (8) 2020/07/22 

  The receptor-associated prorenin system (RAPS) is associated with several pathologic conditions, including diabetic retinopathy, age-related macular degeneration, and uveitis. Here, we show the involvement of RAPS in the trabecular meshwork (TM) from patients with primary open-angle glaucoma (POAG) and neovascular glaucoma (NVG) due to proliferative diabetic retinopathy. Anterior chamber (AC) levels of prorenin significantly increased in both POAG and NVG, as did those of angiotensin II in NVG alone, compared to cataract. In surgically excised TM tissues, (pro)renin receptor ((P)RR) and angiotensin II type 1 receptor (AT1R) co-localized with prorenin and angiotensinogen, respectively. In screening for various genes related to glaucoma, prorenin stimulation to human TM cells exclusively upregulated cell junction constituents connexin 43 and zona occludens 1, while downregulating an extracellular matrix-degrading enzyme tissue plasminogen activator, all of which were reversed by (P)RR blockade. In contrast, angiotensin II application upregulated a pro-angiogenic factor placental growth factor alone, which was abolished by AT1R blockade. Consistently, (P)RR and AT1R co-localized with these corresponding proteins in patient TM tissues. Oxidative stress, a known etiology for glaucoma, induced the expression of prorenin and angiotensinogen in human TM cells. These data suggest the contribution of RAPS to the molecular pathogenesis of POAG and NVG through TM tissue remodeling and AC angle angiogenesis.
• Blockade of Platelet-Derived Growth Factor Signaling Inhibits Choroidal Neovascularization and Subretinal Fibrosis in Mice.

  Ye Liu, Kousuke Noda, Miyuki Murata, Di Wu, Atsuhiro Kanda, Susumu Ishida

  Journal of clinical medicine 9 (7) 2020/07/15 

  Neovascular age related macular degeneration (nAMD) leads to severe vision loss worldwide and is characterized by the formation of choroidal neovascularization (CNV) and fibrosis. In the current study, we aimed to investigate the effect of blockade for platelet derived growth factor receptor-β (PDGFR-β) on the formation of choroidal neovascularization and fibrosis in the laser-induced CNV model in mice. Firstly, the presence of PDGFR-β in CNV lesions were confirmed. Intravitreal injection of PDGFR-β neutralizing antibody significantly reduced the size of CNV and subretinal fibrosis. Additionally, subretinal hyperreflective material (SHRM), a landmark feature on OCT as a risk factor for subretinal fibrosis formation in nAMD patients was also suppressed by PDGFR-β blockade. Furthermore, pericytes were abundantly recruited to the CNV lesions during CNV formation, however, blockade of PDGFR-β significantly reduced pericyte recruitment. In addition, PDGF-BB stimulation increased the migration of the rat retinal pericyte cell line, R-rPCT1, which was abrogated by the neutralization of PDGFR-β. These results indicate that blockade of PDGFR-β attenuates laser-induced CNV and fibrosis through the inhibition of pericyte migration.
• A Case of IgG4-Related Ophthalmic Disease With Coronary Arteritis.

  Yuka Suimon, Satoru Kase, Shuhei Shimoyama, Susumu Ishida

  Ophthalmic plastic and reconstructive surgery 2020/07/13 

  IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition characterized by lymphoplasmacytic infiltrates rich in IgG4-positive plasma cells, often with elevated serum IgG4. Multiple organs may be affected. Coronary arteritis may be one form of fatal involvement in IgG4-RD. IgG4-RD can manifest as periocular lesions, called IgG4-related ophthalmic disease (IgG4-ROD). Here, the authors describe a patient with asymptomatic coronary arteritis detected after the diagnosis of IgG4-ROD. A 58-year-old male complained of eyelid swelling and diplopia without systemic symptoms. Swelling of bilateral lacrimal glands and infraorbital nerves, high serum IgG4 levels, and histopathology of lacrimal gland tissue fulfilled diagnostic criteria for IgG4-ROD. After diagnosis, systemic and coronary CT showed coronary lesions and coronary artery stenosis. After prednisolone at 40 mg/day was administered, swelling of the lacrimal glands, diplopia, and coronary lesions improved. This case emphasizes the importance of systemic screening, even if initial symptoms are solely associated with periocular regions.
• Multimodal imaging in sclerochoroidal calcification: a case report and literature review.

  Mizuho Mitamura, Satoru Kase, Susumu Ishida

  BMC ophthalmology 20 (1) 248 - 248 2020/06/22 

  BACKGROUND: Sclerochoroidal calcification (SCC), a rare condition found in elderly people, is idiopathic or occasionally secondary to disorders affecting calcium metabolism. Findings of multimodal imaging including choroidal circulation are, however, largely unknown. We present a patient of SCC with systemic background, who underwent multimodal imaging evaluations. CASE PRESENTATION: A 70-year-old Japanese man was referred to our clinic because of bilateral fundus lesions. He had a history of chronic kidney disease (CKD) and secondary hyperparathyroidism. Fundus photography showed a cluster of choroidal folds in the superotemporal extra-macular region OS. Swept-source optical coherence tomography demonstrated ellipsoid zone disruption OD, retinal pigment epithelium undulation OS, dilated Haller layer veins OU, and central choroidal thickening OU and thinning of the overlying choroid due to scleral elevation OS. Fluorescein angiography detected macular hyperfluorescence OD. Indocyanine green angiography demonstrated choroidal vascular hyperpermeability together with numerous scattered hypofluorescent lesions OU. Fundus autofluorescence showed multiple hypoautofluorescent spots surrounded by hyperautofluorescent areas OD. Laser speckle flowgraphy exhibited choroidal blood flow reduction represented by a cold color pattern OU. B-mode echography displayed hyperechoic solid lesions with acoustic shadowing and orbital computed tomography revealed high density areas in the sclera, both of which were consistent with calcification. The patient was diagnosed with SCC, and these imaging findings remained unchanged 7 months after the diagnosis. CONCLUSIONS: We reported a case of SCC with the background of CKD. Our detailed multimodal observations indicated choroidal hypoperfusion possibly caused by mechanical compression due to calcium deposition in the sclera.
• Regulation of Spermine Oxidase through Hypoxia-Inducible Factor-1α Signaling in Retinal Glial Cells under Hypoxic Conditions.

  Di Wu, Kousuke Noda, Miyuki Murata, Ye Liu, Atsuhiro Kanda, Susumu Ishida

  Investigative ophthalmology & visual science 61 (6) 52 - 52 2020/06/03 

  Purpose: Acrolein, a highly reactive unsaturated aldehyde, is known to facilitate glial cell migration, one of the pathological hallmarks in diabetic retinopathy. However, cellular mechanisms of acrolein generation in retinal glial cells remains elusive. In the present study, we investigated the role and regulation of spermine oxidase (SMOX), one of the enzymes related to acrolein generation, in retinal glial cells under hypoxic condition. Methods: Immunofluorescence staining for SMOX was performed using sections of fibrovascular tissues obtained from patients with proliferative diabetic retinopathy. Expression levels of polyamine oxidation enzymes including SMOX were analyzed in rat retinal Müller cell line 5 (TR-MUL5) cells under either normoxic or hypoxic conditions. The transcriptional activity of Smox in TR-MUL5 cells was evaluated using the luciferase assay. Levels of acrolein-conjugated protein, Nε-(3-formyl-3,4-dehydropiperidino) lysine adduct (FDP-Lys), and hydrogen peroxide were measured. Results: SMOX was localized in glial cells in fibrovascular tissues. Hypoxia induced SMOX production in TR-MUL5 cells, which was suppressed by silencing of hypoxia-inducible factor-1α (Hif1a), but not Hif2a. Transcriptional activity of Smox was regulated through HIF-1 binding to hypoxia response elements 2, 3, and 4 sites in the promoter region of Smox. Generation of FDP-Lys and hydrogen peroxide increased in TR-MUL5 cells under hypoxic condition, which was abrogated by SMOX inhibitor MDL72527. Conclusions: The current data demonstrated that hypoxia regulates production of SMOX, which plays a role in the generation of oxidative stress inducers, through HIF-1α signaling in Müller glial cells under hypoxic condition.
• 小児と成人のacute macular neuroretinopathyにおける網脈絡膜形態の比較

  橋本 勇希, 齋藤 航, 長谷川 裕香, 滝田 亜かり, 野田 航介, 吉冨 健志, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 13 (6) 431 - 432 1882-5176 2020/06
• Alteration of choroidal vascular structure in diabetic macular edema.

  Satoru Kase, Hiroaki Endo, Mitsuo Takahashi, Yuki Ito, Michiyuki Saito, Masahiko Yokoi, Satoshi Katsuta, Shozo Sonoda, Taiji Sakamoto, Susumu Ishida, Manabu Kase

  Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 258 (5) 971 - 977 2020/05 

  PURPOSE: The aim of this study was to analyze choroidal structures in healthy subjects and patients with/without diabetic macular edema (DME). METHODS: This was a retrospective observation case control study. Four hundred and two eyes of patients with diabetes mellitus (DM), and 124 age-matched eyes of healthy subjects were enrolled in this study. DM patients were divided into 3 groups: presence of central-involved (CI) DME (n = 81) and nonCI-DME/non-DME (n = 321), based on OCT findings. Central choroidal thickness (CCT) and total choroidal, luminal, and stromal areas were determined using EDI-OCT and a binarization method, respectively. The luminal area expressed as a ratio of the total choroidal area was defined as the L/C ratio. RESULTS: DM eyes showed a significantly lower L/C ratio than control eyes, whereas there was no significant difference in CCT or total choroidal, luminal, or stromal areas. There was no significant difference between CI-DME and non-DME groups in HbA1c, blood pressure, dyslipidemia, or renal function. CCT and total choroidal, luminal, and stromal areas were significantly greater in the CI-DME group than non-DME group (each P < 0.05). CONCLUSIONS: These results suggest that CCT was thickened in the presence of DME, associated with both increased luminal and stromal areas, which might be related to the pathology of DME.
• Glucocorticoid-transactivated TSC22D3 attenuates hypoxia- and diabetes-induced Müller glial galectin-1 expression via HIF-1α destabilization.

  Atsuhiro Kanda, Ikuyo Hirose, Kousuke Noda, Miyuki Murata, Susumu Ishida

  Journal of cellular and molecular medicine 24 (8) 4589 - 4599 2020/04 

  Galectin-1/LGALS1, a newly recognized angiogenic factor, contributes to the pathogenesis of diabetic retinopathy (DR). Recently, we demonstrated that glucocorticoids suppressed an interleukin-1β-driven inflammatory pathway for galectin-1 expression in vitro and in vivo. Here, we show glucocorticoid-mediated inhibitory mechanism against hypoxia-inducible factor (HIF)-1α-involved galectin-1 expression in human Müller glial cells and the retina of diabetic mice. Hypoxia-induced increases in galectin-1/LGALS1 expression and promoter activity were attenuated by dexamethasone and triamcinolone acetonide in vitro. Glucocorticoid application to hypoxia-stimulated cells decreased HIF-1α protein, but not mRNA, together with its DNA-binding activity, while transactivating TSC22 domain family member (TSC22D)3 mRNA and protein expression. Co-immunoprecipitation revealed that glucocorticoid-transactivated TSC22D3 interacted with HIF-1α, leading to degradation of hypoxia-stabilized HIF-1α via the ubiquitin-proteasome pathway. Silencing TSC22D3 reversed glucocorticoid-mediated ubiquitination of HIF-1α and subsequent down-regulation of HIF-1α and galectin-1/LGALS1 levels. Glucocorticoid treatment to mice significantly alleviated diabetes-induced retinal HIF-1α and galectin-1/Lgals1 levels, while increasing TSC22D3 expression. Fibrovascular tissues from patients with proliferative DR demonstrated co-localization of galectin-1 and HIF-1α in glial cells partially positive for TSC22D3. These results indicate that glucocorticoid-transactivated TSC22D3 attenuates hypoxia- and diabetes-induced retinal glial galectin-1/LGALS1 expression via HIF-1α destabilization, highlighting therapeutic implications for DR in the era of anti-vascular endothelial growth factor treatment.
• Alteration of Cell Surface Markers CD38 and CD138 in Lymphoproliferative Disorders in the Ocular Adnexa.

  Yuka Suimon, Satoru Kase, Ichiro Miura, Kan Ishijima, Susumu Ishida

  Anticancer research 40 (4) 2019 - 2023 2020/04 

  BACKGROUND/AIM: CD38 is a cell surface marker commonly present in plasma cells and activated T cells, while CD138 is a representative plasma cell marker. The aim of this study was to describe the expression of cell surface markers including CD38 and CD138, in the tumors of patients with IgG4-related ophthalmic disease (IgG4-ROD) and extranodal marginal zone B-cell lymphoma (EMZL) of the ocular adnexa. MATERIALS AND METHODS: Twenty-four consecutive patients of whom 12 had IgG4-ROD and 12 EMZL were enrolled in this study. Medical records were reviewed for flow cytometry (FCM) results on conventional T-cell markers, B-cell markers, CD38 and CD138. RESULTS: Positive rates of T-cell markers, CD38 and CD138 were significantly higher in IgG4-ROD than in EMZL (p<0.01 and p<0.05, respectively). CONCLUSION: Our FCM results on CD38 and CD138 showed that the lymphocyte populations were different between IgG4-ROD and EMZL, which may reflect the different pathophysiology of the two diseases.
• Pseudo-inflammatory manifestations of choroidal lymphoma resembling Vogt-Koyanagi-Harada disease: case report based on multimodal imaging.

  Kanae Fukutsu, Kenichi Namba, Daiju Iwata, Kazuomi Mizuuchi, Satoru Kase, Kayo Suzuki, Hiroshi Shimizu, Yukiko Shibata, Fumihiko Yamawaki, Masahiro Onozawa, Susumu Ishida

  BMC ophthalmology 20 (1) 94 - 94 2020/03/10 

  BACKGROUND: Hematologic malignancies occasionally cause serous retinal detachment (SRD); however, its pathogenesis remains unclear. Here we present the imaging characteristics of metastatic choroidal lymphoma masquerading as Vogt-Koyanagi-Harada (VKH) disease. CASE PRESENTATION: A 45-year-old Japanese woman was referred to our clinic because of bilateral SRD with blurred vision. Fluorescein angiography revealed multiple pinpoint leakage followed by pooling OU. Enhanced depth imaging optical coherence tomography showed marked choroidal thickening OU. Laser speckle flowgraphy detected choroidal circulation impairment OU. Although these results totally agreed with the inflammatory manifestations of acute VKH disease, indocyanine green angiography demonstrated various sizes of sharply marginated hypofluorescent lesions that seemed atypical for the finding of VKH disease, i.e., vaguely marginated hypofluorescent small dots. Cerebrospinal fluid pleocytosis was not detected. Blood tests revealed leukocytosis together with elevation of lactate dehydrogenase and soluble interleukin-2 receptor levels. Corticosteroid pulse therapy did not improve any ocular findings. Bone marrow biopsy was then performed, leading to a definite diagnosis of diffuse large B-cell lymphoma. After starting systemic chemotherapy, both SRD and choroidal thickening resolved rapidly with visual recovery. However, choroidal hypoperfusion persisted, which contrasted distinctly with the inflammatory pattern of VKH disease, i.e., the restoration of choroidal blood flow in parallel with normalization of choroidal thickness. CONCLUSIONS: Our detailed multimodal observations highlighted the differential imaging features of choroidal lymphoma despite close resemblance to VKH disease especially at the initial stage. Impaired circulation in the thickened choroid marked the pseudo-inflammatory pathogenesis of SRD due to choroidal involvement with neoplastic, but not inflammatory cells.
• Waardenburg症候群と網膜芽細胞腫を合併した13番染色体長腕部分欠失の1例

  赤岡 さくら, 安藤 亮, 加瀬 諭, 外木 秀文, 長 祐子, 藤井 史彦, 太田 亨, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 124 (臨増) 231 - 231 0029-0203 2020/03
• SDT fattyラット水晶体におけるポリオール経路と酸化ストレスの継時的解析

  菊地 香澄, 村田 美幸, 野田 航介, 神田 敦宏, 加瀬 諭, 影山 靖, 篠原 雅巳, 笹瀬 智彦, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 124 (臨増) 242 - 242 0029-0203 2020/03
• アクロレインによる網膜ミュラーグリア細胞の遊走作用とROCK1の関与

  福津 佳苗, 村田 美幸, 野田 航介, 吉田 志帆, 神田 敦宏, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 124 (臨増) 275 - 275 0029-0203 2020/03
• Alteration of choroidal vascular structure in diabetic retinopathy.

  Satoru Kase, Hiroaki Endo, Mitsuo Takahashi, Michiyuki Saito, Masahiko Yokoi, Yuki Ito, Satoshi Katsuta, Shozo Sonoda, Taiji Sakamoto, Susumu Ishida, Manabu Kase

  The British journal of ophthalmology 104 (3) 417 - 421 2020/03 

  PURPOSE: The aim of this study was to analyse choroidal structures in normal patients and patients with diabetes with various severities of diabetic retinopathy (DR). METHODS: This is a retrospective observation case control study. Three hundred and forty-two diabetic eyes, and age-matched 112 eyes without diabetes mellitus (DM) were enrolled in this study. Patients with DM were classified into no DR, mild/moderate non-proliferative DR (mNPDR), severe NPDR and proliferative DR (PDR). Patients with DM were further divided into two groups based on information regarding systemic DM treatment situation: DM-treated and untreated groups. Central choroidal thickness (CCT), and total choroidal area (TCA), luminal area (LA) and stromal area (SA) were determined using enhanced depth imaging optical coherence tomography and a binarisation method, respectively. The ratio of LA in the TCA was defined as L/C ratio. RESULTS: The haemoglobin A1c (HbA1c) value was significantly higher in the DM-untreated than in the DM-treated subjects. L/C ratio was significantly lower in all the diabetic eyes than control eyes (p<0.05). TCA, LA, L/C ratio and CCT were significantly greater in the DM-untreated than treated group (each p<0.05). In the DM-untreated group, TCA and LAs (p<0.05) and L/C ratio (p<0.01) were significantly lower in mNPDR subjects than normal controls (p<0.05). PDR in the DM-untreated group showed significantly larger SA and LA, and greater CCT than normal controls (each p<0.05). CONCLUSIONS: These results suggest that choroidal vasculature was initially involved at an early DR, whereas thickened LA and SA were noted in advanced DR.
• Waardenburg症候群と網膜芽細胞腫を合併した13番染色体長腕部分欠失の1例

  赤岡 さくら, 安藤 亮, 加瀬 諭, 外木 秀文, 長 祐子, 藤井 史彦, 太田 亨, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 124 (臨増) 231 - 231 0029-0203 2020/03
• Supplemental Restraint Systemエアバッグによる網膜再剥離と気胸を発症した1例

  新海 晃弘, 加瀬 諭, 山下 優, 森 祥平, 安藤 亮, 藤谷 顕雄, 鈴木 智浩, 野田 航介, 石田 晋

  あたらしい眼科 (株)メディカル葵出版 37 (2) 230 - 234 0910-1810 2020/02 

  背景:運転席用supplemental restraint system(SRS)エアバッグは、最高時速約300kmで運転手に向かって展開し、それに伴う臓器障害は多岐にわたる。本稿では、SRSエアバッグ展開に伴い網膜再剥離と気胸を発症した症例の臨床経過を報告する。症例:73歳、男性。北海道大学病院眼科で左眼裂孔原性網膜剥離(RRD)に対する水晶体再建術、硝子体手術および輪状締結術後の経過観察中に、展開するSRSエアバッグで受傷した。受傷2週間後に再診し、左眼のRRDの再発があり、硝子体手術およびシリコーンオイルタンポナーデを施行した。術後8日目に、突然の胸痛と動悸を発症した。右気胸と診断され、治療された。受傷後12ヵ月の現在、全身状態は安定しており、網膜再剥離はない。結論:SRSエアバッグ作動に伴う外傷は、網膜再剥離のリスクになると同時に、全身合併症を伴うこともあるため注意が必要である。(著者抄録)
• Increased choroidal blood flow and choroidal thickness in patients with hypertensive chorioretinopathy.

  Michiyuki Saito, Kousuke Noda, Wataru Saito, Kiriko Hirooka, Yuki Hashimoto, Susumu Ishida

  Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 258 (2) 233 - 240 2020/02 

  PURPOSE: To investigate the alterations of central choroidal thickness (CCT) and macular choroidal blood flow in patients with hypertensive chorioretinopathy treated with antihypertensive agents. METHODS: In retrospective observational case series, ten eyes of 9 patients with hypertensive chorioretinopathy were enrolled (5 men and 4 women; 43.1 ± 19.6 years of age). CCT and mean blur rate (MBR) had been observed during follow-up using enhanced depth imaging optical coherence tomography and laser speckle flowgraphy, respectively. RESULTS: With the medication for hypertension, serous retinal detachment (SRD) disappeared in all the eyes (mean period, 57.8 ± 50.4 days), and the mean blood pressure decreased (122.7 ± 13.0 mmHg and 93.4 ± 13.2 mmHg at the initial visit and at the day of subretinal fluid absorption, respectively; P < 0.01). The mean logMAR value of best corrected visual acuity showed a tendency toward improvement with the resolution of SRD (0.15 ± 0.30 and 0.08 ± 0.28, P = 0.15). The average MBR significantly decreased when SRD was absorbed (11.4 ± 4.5 and 7.7 ± 2.2, P < 0.01). Similarly, the mean values of CCT decreased (473.2 ± 218.0 μm and 325.7 ± 112.0 μm, P < 0.01). The changing rates of CCT and MBR showed a significant positive correlation (P < 0.01, R = 0.88). CONCLUSION: The current study demonstrated a novel finding that choroidal blood flow velocity and thickness concurrently increased in the acute phase of hypertensive chorioretinopathy, suggesting the role of choroidal hyperperfusion in the pathogenesis of hypertensive chorioretinopathy.
• Supplemental Restraint Systemエアバッグによる網膜再剥離と気胸を発症した1例

  新海 晃弘, 加瀬 諭, 山下 優, 森 祥平, 安藤 亮, 藤谷 顕雄, 鈴木 智浩, 野田 航介, 石田 晋

  あたらしい眼科 (株)メディカル葵出版 37 (2) 230 - 234 0910-1810 2020/02 [Refereed][Not invited]
   

  背景:運転席用supplemental restraint system(SRS)エアバッグは、最高時速約300kmで運転手に向かって展開し、それに伴う臓器障害は多岐にわたる。本稿では、SRSエアバッグ展開に伴い網膜再剥離と気胸を発症した症例の臨床経過を報告する。症例:73歳、男性。北海道大学病院眼科で左眼裂孔原性網膜剥離(RRD)に対する水晶体再建術、硝子体手術および輪状締結術後の経過観察中に、展開するSRSエアバッグで受傷した。受傷2週間後に再診し、左眼のRRDの再発があり、硝子体手術およびシリコーンオイルタンポナーデを施行した。術後8日目に、突然の胸痛と動悸を発症した。右気胸と診断され、治療された。受傷後12ヵ月の現在、全身状態は安定しており、網膜再剥離はない。結論:SRSエアバッグ作動に伴う外傷は、網膜再剥離のリスクになると同時に、全身合併症を伴うこともあるため注意が必要である。(著者抄録)
• Pathological Role of Unsaturated Aldehyde Acrolein in Diabetic Retinopathy.

  Miyuki Murata, Kousuke Noda, Susumu Ishida

  Frontiers in immunology 11 589531 - 589531 2020 

  With increasing prevalence of diabetes and a progressively aging society, diabetic retinopathy is emerging as one of the global leading causes of blindness. Recent studies have shown that vascular endothelial growth factor (VEGF) plays a central role in the pathogenesis of diabetic retinopathy and anti-VEGF agents have become the first-line therapy for the vision-threatening disease. However, recent studies have also demonstrated that diabetic retinopathy is a multifactorial disease and that VEGF-independent mechanism(s) also underlie much of the pathological changes in diabetic retinopathy. Acrolein is a highly reactive unsaturated aldehyde and is implicated in protein dysfunction. As acrolein is common in air pollutants, previous studies have focused on it as an exogenous causative factor, for instance, in the development of respiratory diseases. However, it has been discovered that acrolein is also endogenously produced and induces cell toxicity and oxidative stress in the body. In addition, accumulating evidence suggests that acrolein and/or acrolein-conjugated proteins are associated with the molecular mechanisms in diabetic retinopathy. This review summarizes the pathological roles and mechanisms of endogenous acrolein production in the pathogenesis of diabetic retinopathy.
• Cytoprotective Effect of Astaxanthin in a Model of Normal Intraocular Pressure Glaucoma.

  Kasumi Kikuchi, Zhenyu Dong, Yasuhiro Shinmei, Miyuki Murata, Atsuhiro Kanda, Kosuke Noda, Takayuki Harada, Susumu Ishida

  Journal of ophthalmology 2020 9539681 - 9539681 2020 

  Glaucoma is characterized by axonal degeneration of retinal ganglion cells (RGCs) and apoptotic death of their cell bodies. Lowering intraocular pressure is currently the only way to treat glaucoma, but it is often insufficient to inhibit the progression of the disease. Glaucoma is a multifactorial disease, and the involvement of oxidative stress has recently received much attention. In the present study, we investigated the cytoprotective effect of astaxanthin (AST) on RGC degeneration using a normal-tension glaucoma (NTG) mouse model, which lacks the glutamate/aspartate transporter (Glast) and demonstrates spontaneous RGC and optic nerve degeneration without elevated intraocular pressure. Three-week-old Glast± mice were given intraperitoneal injections of AST at 10, 30, or 60 mg/kg/day or vehicle alone, and littermate control mice were given vehicle alone for 14 days, respectively. Five weeks after birth, the number of RGCs was counted in paraffin sections of retinal tissues stained with hematoxylin and eosin. We also used a retrograde labeling technique to quantify the number of RGCs. Additionally, the phosphorylated (p) IκB/total IκB ratio and the 4-hydroxynonenal (HNE) were measured in retinal tissues. The number of RGCs in Glast± mice was significantly decreased compared with that in control mice. RGC loss was suppressed by the administration of AST at 60 mg/kg/day, compared with vehicle alone. Following AST administration, the concentration of 4-HNE in the retina was also suppressed, but the pIκB/IκB ratio did not change. Our study revealed that the antioxidative stress effects of AST inhibit RGC degeneration in the retina and may be useful in the treatment of NTG.
• Relationship between diabetic macular edema and choroidal layer thickness.

  Hiroaki Endo, Satoru Kase, Mitsuo Takahashi, Michiyuki Saito, Masahiko Yokoi, Chisato Sugawara, Satoshi Katsuta, Susumu Ishida, Manabu Kase

  PloS one 15 (1) e0226630  2020 

  PURPOSE: To investigate the relationship between diabetic macular edema (DME) and the choroidal layer thickness in diabetic patients. METHODS: This is a retrospective observation study. Three hundred eighteen eyes of 159 diabetes mellitus (DM) patients and age-matched 100 eyes of 79 healthy controls were enrolled. DME was defined as over 300 μm in the central retinal subfield of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid sector. The central choroidal thickness (CCT), as well as inner and outer layers were determined based on enhanced depth imaging (EDI)-OCT. Diabetic patients with/without systemic diabetic treatments (DT) at the start of this study was defined as DT+ and DT-, respectively. The number of eyes examined was 62 and 256 eyes in DME+and DME-groups, respectively. DM patients were further subdivided into 4 groups with/without DME and DT; DME+DT+(35 eyes), DME-DT+(159 eyes), DME+DT-(27 eyes), and DME-DT-group (97 eyes). Multiple comparisons on CCT layers including control and each DM group were statistically examined. RESULTS: The total CCT layer was 254±83, 283±88, and 251±70 μm in the control, DME+, and DME-group, respectively. A total CCT layer in DME+was significantly thicker than the DME-group (P < 0.05). The outer CCT layer was 195±75, 222±83, and 193±63 μm in the control, DME+, and DME-group, respectively. The outer CCT layer in DME+ was significantly thicker than the DME-group (P < 0.05). In the subdivided groups, the total CCT layers in the control, DME+DT+, DME-DT+, DME+DT-and DME-DT-groups were 254±83, 274±88, 247±66, 290±84 and 258±75 μm, respectively. The outer CCT layers in each group were 195±75, 214±83, 189±58, 228±77, and 201±70 μm, respectively. Total CCT and the outer layer in DME+DT-was significantly thicker than the DME-DT+group (each P < 0.05). In contrast, there was no significant difference in inner layer between the groups. CONCLUSIONS: The total and outer CCT layers of diabetic eyes were significantly thickened in the DME+DT-as compared with the DME-DT+group, suggesting that CCT may be related to the pathology of DME.
• Histological observation of trabecular meshwork in a patient with Axenfeld-Rieger syndrome-a new theory for the mechanism of ectropion uvea in congenital glaucoma.

  Satoru Kase, Shinki Chin, Teruhiko Hamanaka, Yasuhiro Shinmei, Takeshi Ohguchi, Susumu Ishida

  International journal of ophthalmology 13 (7) 1167 - 1169 2020
• Diabetic Cataract in Spontaneously Diabetic Torii Fatty Rats.

  Kasumi Kikuchi, Miyuki Murata, Kousuke Noda, Satoru Kase, Yoshiaki Tagawa, Yasushi Kageyama, Masami Shinohara, Tomohiko Sasase, Susumu Ishida

  Journal of diabetes research 2020 3058547 - 3058547 2020 

  Spontaneously Diabetic Torii (SDT) fatty rat is a novel animal model of type 2 diabetes with obesity. SDT fatty rats develop hyperglycemia, dyslipidemia, and other diabetic complications including ocular disorders; however, diabetic cataract formation in SDT fatty rats has not been fully investigated. The aim of the current study was to investigate the characteristics of cataract in the SDT fatty rats. The mean body weight of SDT fatty rats is larger than that of age-matched Sprague-Dawley (SD) rats and control animals until 8 weeks of age, and thereafter the growing speed decreased until the end of observation at 16 weeks of age. Blood glucose levels in SDT fatty rats were significantly higher than those in SD rats throughout the observational period. Slit-lamp examination revealed that no rats showed cataract formation at 5 weeks of age; however, SDT fatty rats gradually developed cortical cataract and posterior subcapsular cataract, both of which are the common types of cataract in patients with type 2 diabetes. The levels of glucose, sorbitol, and fructose were higher in the lens tissues of SDT fatty rats in comparison with that of SD rats. Furthermore, the level of 4-hydroxynonenal (4-HNE) was higher in the lens of SDT fatty rats than in that of SD rats. By contrast, total glutathione (GSH) concentration was lower in the lens of SDT fatty rats than in that of SD rats. The present study demonstrated that the cataractogenesis in SDT fatty rats resembled human diabetic cataract formation, indicating that SDT fatty rats serve as a potential animal model in researches on human cataract associated with type 2 diabetes and obesity.
• Sudden bilateral vision loss due to third ventricular cavernous angioma with intratumoral hemorrhage - case report.

  Kan Ishijima, Yasuhiro Shinmei, Mayo Nozaki, Shigeru Yamaguchi, Shinki Chin, Susumu Ishida

  BMC ophthalmology 19 (1) 259 - 259 2019/12/16 [Refereed][Not invited]
   

  BACKGROUND: We report a rare case of sudden bilateral vision loss due to third ventricular cavernous angioma with intratumoral hemorrhage. CASE PRESENTATION: A 45-year-old woman presented decreased visual acuity in both eyes. Her best corrected visual acuity was 0.1 in the right eye and 0.15 in the left eye. Goldmann perimetry showed bilateral central scotomas and bitemporal visual field defects. MRI demonstrated a lesion with mixed hypo- and hyperintensity at the optic chiasm, which was thought to be an intratumoral hemorrhage. The patient underwent bifrontal craniotomy. The tumor was exposed via an anterior interhemispheric approach, and histological evaluation of the mass led to a diagnosis of cavernous angioma. Six months after the surgery, her best corrected visual acuity was 0.9 in the right eye and 0.9 in the left, with slight bitemporal visual field defects. CONCLUSION: Third ventricular cavernous angioma is considered in the differential diagnosis of chiasmal syndrome. Contrast-enhanced MRI and FDG-PET might be useful for differential diagnosis of cavernous angioma from other chiasmal tumors including glioblastoma.
• ポリープ状脈絡膜血管症に対する光線力学的療法トリプル療法の5年成績

  安藤 亮, 野田 航介, 廣岡 季里子, 柴田 有紀子, 橋本 勇希, 鈴木 智浩, 清水 啓史, 藤谷 顕雄, 董 震宇, 加瀬 諭, 吉澤 史子, 齋藤 航, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 12 (11) 832 - 832 1882-5176 2019/11
• 網膜色素上皮細胞における胎盤成長因子のアポトーシス抑制効果

  村田 美幸, 野田 航介, 長谷 敬太郎, 神田 敦宏, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 12 (11) 850 - 850 1882-5176 2019/11
• 網膜変性を認めたDanon病の1例

  長谷川 綾華, 藤谷 顕雄, 柴田 有紀子, 鈴木 智浩, 清水 啓史, 董 震宇, 加瀬 諭, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 12 (11) 854 - 854 1882-5176 2019/11
• 術後細菌性眼内炎との鑑別を要した水晶体起因性眼内炎の1例

  清水 啓史, 加瀬 諭, 柴田 有紀子, 鈴木 智浩, 董 震宇, 藤谷 顕雄, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 12 (11) 856 - 856 1882-5176 2019/11
• 妊娠後期に発症した中心性漿液性脈絡網膜症の1例における脈絡膜循環動態と形態の変化

  金子 悠菜, 橋本 勇希, 齋藤 理幸, 山下 結衣, 廣岡 季里子, 野田 航介, 石田 晋

  日本視能矯正学会プログラム抄録集 日本視能矯正学会 60回 88 - 88 2019/11
• 妊娠に伴う高血圧脈絡膜症の1例における脈絡膜循環動態と形態の変化

  山下 結衣, 橋本 勇希, 齋藤 理幸, 金子 悠菜, 廣岡 季理子, 野田 航介, 石田 晋

  日本視能矯正学会プログラム抄録集 日本視能矯正学会 60回 88 - 88 2019/11
• Changes in Intraocular Pressure in Single Ventricle Patients After the Glenn or Fontan Procedure

  Riki Kijima, Osamu Sasaki, Yasuhiro Shinmei, Takeshi Ohguchi, Atsuhito Takeda, Shinki Chin, Susumu Ishida

  JOURNAL OF GLAUCOMA 28 (11) 1012 - 1014 1057-0829 2019/11 [Refereed][Not invited]
   

  Precis: A positive correlation was observed between intraocular pressure (IOP) and central venous pressure (CVP) in patients with single ventricle (SV) during the perioperative period. IOP needs to be carefully monitored in the postoperative period after the Glenn and Fontan procedures, particularly the Glenn procedure. Purpose: SV is a cardiac malformation characterized by the existence of only 1 functional ventricle and is treated using the Glenn and Fontan procedures. Significant changes occur in CVP after these procedures. IOP has been reported to differ in the same individual when measured in a seated or supine position, which may be related to CVP. In the present study, we examined the relationship between CVP and IOP before and after surgery for SV. Patients and Methods: This study was a prospective, nonrandomized case series. All patients had SV and this study excluded those with eye diseases associated with ocular hypertension. We measured IOP before and after the Glenn or Fontan procedure. CVP was concurrently monitored. Results: Twenty-eight eyes of 14 patients with SV who underwent the Glenn (N=8) or Fontan (N=6) procedure were examined. Mean ages (+/- SD) were 2.6 +/- 0.7 months for the Glenn procedure and 24.0 +/- 2.7 months for the Fontan procedure. A correlation was observed between CVP and IOP in the perioperative period. IOP and CVP were both significantly higher after than before the Glenn and/or Fontan procedures. However, no relationship was noted between changes in IOP and CVP after the Glenn and/or Fontan procedures. Conclusions: Elevations in CVP significantly increased IOP in patients with SV who underwent the Glenn or Fontan procedure. IOP needs to be carefully monitored in the postoperative period after both procedures.
• 黄斑部毛細血管拡張症type 2の視力と視細胞形態の推移

  新海 晃弘, 齋藤 航, 橋本 勇希, 齋藤 理幸, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 12 (10) 791 - 791 1882-5176 2019/10
• Glucocorticoid receptor inhibits Müller glial galectin-1 expression via DUSP1-dependent and -independent deactivation of AP-1 signalling.

  Ikuyo Hirose, Atsuhiro Kanda, Kousuke Noda, Susumu Ishida

  Journal of cellular and molecular medicine 23 (10) 6785 - 6796 2019/10 

  Galectin-1/LGALS1 is a hypoxia-induced angiogenic factor associated with diabetic retinopathy (DR). Recently, we elucidated a hypoxia-independent pathway to produce galectin-1 in Müller glial cells stimulated by interleukin (IL)-1β. Here we revealed glucocorticoid receptor (GR)-mediated inhibitory mechanisms for Müller glial galectin-1/LGALS1 expression. Activator protein (AP)-1 site in the LGALS1 enhancer region, to which activating transcription factor2, c-Fos and c-Jun bind, was shown to be essential for IL-1β-induced galectin-1/LGALS1 expression in Müller cells. Ligand (dexamethasone or triamcinolone acetonide)-activated GR induced dual specificity phosphatase (DUSP)1 expression via the glucocorticoid response element and attenuated IL-1β-induced galectin-1/LGALS1 expression by reducing phosphorylation of these AP-1 subunits following AKT and extracellular signal-regulated kinase (ERK)1/2 deactivation. Moreover, activated GR also caused DUSP1-independent down-regulation of IL-1β-induced LGALS1 expression via its binding to AP-1. Administration of glucocorticoids to mice attenuated diabetes-induced retinal galectin-1/Lgals1 expression together with AKT/AP-1 and ERK/AP-1 pathways. Supporting these in vitro and in vivo findings, immunofluorescence analyses showed co-localization of galectin-1 with GR and phosphorylated AP-1 in DUSP1-positive glial cells in fibrovascular tissues from patients with DR. Our present data demonstrated the inhibitory effects of glucocorticoids on glial galectin-1 expression via DUSP1-dependent and -independent deactivation of AP-1 signalling (transactivation and transrepression), highlighting therapeutic implications for DR.
• Unsaturated Aldehyde Acrolein Promotes Retinal Glial Cell Migration.

  Miyuki Murata, Kousuke Noda, Shiho Yoshida, Michiyuki Saito, Akio Fujiya, Atsuhiro Kanda, Susumu Ishida

  Investigative ophthalmology & visual science 60 (13) 4425 - 4435 2019/10/01 

  Purpose: To investigate the effect of the unsaturated aldehyde acrolein on retinal glial cell migration. Methods: Müller glial cell markers expression in TR-MUL5 were confirmed by RT-PCR and immunostaining. Cell viability and migration rate of TR-MUL5 cells were assessed after the stimulation with acrolein. DNA microarray analysis was performed to analyze changes in the expression levels of migration-related genes in Müller glial cells stimulated with acrolein. Real-time PCR and ELISA were performed to validate DNA microarray analysis results. Inhibitors of C-X-C motif chemokine ligand 1 (CXCL1), one of the genes highly upregulated after the exposure to acrolein, and blockers of its receptor, CXCR2, were used to investigate the role of the CXCL1-CXCR2 axis on glial cell migration. CXCL1 concentration was measured in vitreous fluid samples obtained from proliferative diabetic retinopathy (PDR) and nondiabetic control eyes. CXCL1 and CXCR2 expression in glial cells of fibrovascular tissues obtained from PDR patients was examined by immunostaining. Results: At a high concentration, acrolein (100 μM) significantly decreased cell viability. However, in moderate, sublethal concentrations (25-50 μM), acrolein induced cell migration and substantially increased the production of CXCL1 in TR-MUL5 cells. CXCL1 concentration was significantly elevated in vitreous fluids of PDR patients, and CXCL1 and CXCR2 were present in glial cells in fibrovascular tissues of PDR patients. CXCL1 stimulation increased glial cell migration in a dose-dependent manner, which was abrogated by the neutralization of the CXCL1-CXCR2 axis. Conclusions: Our data demonstrate that acrolein promotes retinal Müller glial cell migration by enhancing CXCL1 production.
• Suppression of Choroidal Neovascularization and Fibrosis by a Novel RNAi Therapeutic Agent against (Pro)renin Receptor.

  Ye Liu, Atsuhiro Kanda, Di Wu, Erdal Tan Ishizuka, Satoru Kase, Kousuke Noda, Atsuhiro Ichihara, Susumu Ishida

  Molecular therapy. Nucleic acids 17 113 - 125 2019/09/06 

  The receptor-associated prorenin system refers to the pathogenic mechanism whereby prorenin binding to (pro)renin receptor [(P)RR] dually activates the tissue renin-angiotensin system (RAS) and RAS-independent signaling, and its activation contributes to the molecular pathogenesis of various ocular diseases. We recently developed a new single-stranded RNAi agent targeting both human and mouse (P)RR ((P)RR-proline-modified short hairpin RNA [(P)RR-PshRNA]), and confirmed its therapeutic effect on murine models of ocular inflammation. Here, we investigated the efficacy of (P)RR-PshRNA against laser-induced choroidal neovascularization (CNV) and subretinal fibrosis, both of which are involved in the pathogenesis of age-related macular degeneration (AMD). Administration of (P)RR-PshRNA in mice significantly reduced CNV formation, together with the expression of inflammatory molecules, macrophage infiltration, and extracellular signal-regulated kinase (ERK) 1/2 activation. In addition, (P)RR-PshRNA attenuated subretinal fibrosis, together with epithelial-mesenchymal transition (EMT)-related markers including phosphorylated SMAD2. The suppressive effect of (P)RR-PshRNA is comparable with aflibercept, an anti-vascular endothelial growth factor drug widely used for AMD therapy. AMD patient specimens demonstrated (P)RR co-localization with phosphorylated ERK1/2 in neovascular endothelial cells and retinal pigment epithelial cells. These results indicate that (P)RR contributes to the ocular pathogenesis of both inflammation-related angiogenesis and EMT-driven fibrosis, and that (P)RR-PshRNA is a promising therapeutic agent for AMD.
• 網膜上下の増殖組織が連続していた黄斑円孔網膜剥離併発の増殖糖尿病網膜症の1例

  柴田 有紀子, 清水 啓史, 長谷川 綾華, 品川 真有子, 齋藤 理幸, 加瀬 諭, 野田 航介, 石田 晋

  糖尿病合併症 (一社)日本糖尿病合併症学会 33 (Suppl.1) 266 - 266 2019/09
• Spontaneously Diabetic Torii fattyラット網膜における炎症性サイトカインの発現解析

  菊地 香澄, 野田 航介, 村田 美幸, 神田 敦宏, 加瀬 諭, 影山 靖, 篠原 雅巳, 笹瀬 智彦, 石田 晋

  糖尿病合併症 (一社)日本糖尿病合併症学会 33 (Suppl.1) 271 - 271 2019/09
• 網膜色素上皮細胞における胎盤成長因子による血管内皮増殖因子受容体 2の安定化機序

  村田 美幸, 野田 航介, 長谷 敬太郎, Di Wu, 神田 敦宏, 石田 晋

  糖尿病合併症 (一社)日本糖尿病合併症学会 33 (Suppl.1) 271 - 271 2019/09
• Comparison of clinical characteristics in patients with Vogt-Koyanagi-Harada disease with and without anti-retinal antibodies.

  Yuki Hashimoto, Wataru Saito, Kenichi Namba, Kazuomi Mizuuchi, Daiju Iwata, Kousuke Noda, Atsuhiro Kanda, Susumu Ishida

  Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 257 (8) 1751 - 1758 2019/08 

  PURPOSE: To compare the clinical characteristics of Vogt-Koyanagi-Harada (VKH) disease patients with and without anti-retinal antibodies (ARAs) that are frequently detected in autoimmune retinopathy. METHODS: Using immunoblot analyses, serum autoantibodies for recoverin, carbonic anhydrase II, and α-enolase were examined in 20 treatment-naïve patients with VKH disease. Clinical factors before and after systemic corticosteroid therapy, including best-corrected visual acuity (BCVA) and macular outer retinal morphology, were statistically compared between patients with VKH disease with and without ARAs. RESULTS: Serum ARAs were detected in 50.0% of patients with VKH disease. There were no significant differences in clinical factors between the two groups, including final BCVA, frequency of uveitis recurrence, and recovery of the macular ellipsoid zone after systemic corticosteroid therapy. CONCLUSIONS: Our results suggest that the detected ARAs did not influence visual outcomes, the chronicity of uveitis, or outer retinal morphology in patients with VKH disease.
• 抗α-enolase抗体陽性自己免疫性網膜症の網膜電図所見

  安藤 亮, 齋藤 航, 神田 敦宏, 加瀬 諭, 藤波 芳, 菅原 道孝, 中村 洋介, 江口 秀一郎, 野田 航介, 篠田 啓, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 12 (8) 642 - 643 1882-5176 2019/08 [Refereed][Not invited]
  
• Relationship between choroidal structure and duration of diabetes.

  Hiroaki Endo, Satoru Kase, Yuki Ito, Mitsuo Takahashi, Masahiko Yokoi, Satoshi Katsuta, Shozo Sonoda, Taiji Sakamoto, Susumu Ishida, Manabu Kase

  Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 257 (6) 1133 - 1140 2019/06 

  BACKGROUND: The aim of this study was to evaluate the relationship between the choroidal structure of diabetic patients without diabetic retinopathy (DR) and duration of diabetes. METHODS: This study is a retrospective observational study in diabetic patients without DR. Eyes with diabetes mellitus (DM) (n = 105) were divided into two groups based on the duration: long duration group (over 10 years, n = 31) and short duration group (less than 10 years, n = 74). One hundred seventeen eyes of non-diabetic patients were used as control group. All patients underwent enhanced depth imaging optical coherence tomography, and the choroidal structure was analyzed using a binarization method. RESULTS: There was no significant difference in areas of total choroid and lumina/stroma or central choroidal thickness (CCT) between control and DM groups. In contrast, lumina/total choroidal (L/C) ratio was significantly lower in diabetic eyes than in control eyes (P = 0.02). Although there was no significant difference in the areas or CCT between short and long duration groups, L/C ratio was significantly lower in the long duration group than in the short duration group (P = 0.03). CONCLUSIONS: The current study suggests that choroidal vasculature is involved in the diabetic eyes and that the choroidal structure has changed with duration of diabetes. Our study points out that L/C ratio is a new potential biomarker in monitoring choroidal vascular disorders in diabetic eyes without DR.
• Cyclosporine and prednisolone combination therapy as a potential therapeutic strategy for relentless placoid chorioretinitis.

  Takehiko Uraki, Kenichi Namba, Kazuomi Mizuuchi, Daiju Iwata, Shigeaki Ohno, Nobuyoshi Kitaichi, Susumu Ishida

  American journal of ophthalmology case reports 14 87 - 91 2019/06 [Refereed][Not invited]
   

  Purpose: Relentless placoid chorioretinitis (RPC) is a new disease concept that was proposed by Jones et al. in 2000. Some cases of RPC have been reported; however, a treatment strategy has not yet been established. We report herein four cases of patients diagnosed with RPC. Observations: We experienced four cases of RPC in patients aged 24-51 years. All patients exhibited retinal lesions similar to that seen in acute posterior multifocal placoid pigment epitheliopathy or serpiginous choroiditis from the posterior pole to the surrounding region. Although patients underwent systemic prednisolone (PSL) therapy, recurrence was observed and the retinal scar formation was progressive; they were then diagnosed with RPC. In all cases, cyclosporine (CyA) was administered in addition to PSL, no recurrence was observed thereafter. Conclusions and Importance: RPC is a rare disease, and a treatment strategy has not yet been established. CyA and PSL combination therapy is considered to be effective in the treatment of RPC.
• Photocoagulation for juxtapapillary retinal hemangioma in a young girl: A case report.

  Satoru Kase, Susumu Ishida

  Molecular and clinical oncology 10 (5) 521 - 523 2019/05 

  von Hippel Lindau (VHL) disease is caused by inactivation of the VHL tumor suppressor gene, resulting in formation of multiple systemic tumors. Juxtapapillary retinal capillary hemangioma (JRCH) is one of the major manifestations in VHL disease; however, treatments are challenging, especially in children. The present study reports the case of a 6-year-old girl with suspected VHL disease presenting with JRCH. Fluorescein angiography demonstrated marked dye leakage from the tumor. Retinal hemorrhage occurred around the tumor 7 months later. Laser photocoagulation of the tumor tissue was safely and successfully conducted without general anesthesia. The hemorrhage diminished after laser photocoagulation. Optical coherence tomography demonstrated mild resolution of an elevated lesion in JRCH with contraction of the vitreoretinal interface over the tumor. Laser photocoagulation may be considered the first-line treatment for young patients with JRCH, although the primary physicians must have the necessary skills and be able to establish good doctor-patient relationships, even with children.
• Involvement of circulatory disturbance in optic disk melanocytoma with visual dysfunction.

  Iku Kikuchi, Satoru Kase, Yuki Hashimoto, Kiriko Hirooka, Susumu Ishida

  Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 257 (4) 835 - 841 2019/04 

  PURPOSE: This study aims to examine the relationship between ocular circulation changes and visual field defects in optic disk melanocytoma (ODM). METHODS: Five eyes of five patients were enrolled in this study. All patients were diagnosed with ODM in the Department of Ophthalmology, Hokkaido University Hospital from March 2009 to November 2017. Ophthalmological data including optical coherence tomography angiography (OCTA) and laser speckle flowgraphy (LSFG) findings were retrospectively analyzed. RESULTS: The five ODM cases consisted of two females and three males. Ages of the patients ranged from 47 to 82 years (mean 54 years). Follow-up periods were from 4 to 105 months. Fluorescein angiography showed hypo-fluorescence throughout the examination in all four eyes examined with this modality. OCTA detected dense blood vessel networks in the tumor in two out of the five eyes. Nasal visual field defects were found in two other eyes, which were correlated with locations of tumors free of vessel networks. One ODM eye without marked visual field defects and pigmentations showed lower mean blur rates determined by LSFG in optic disk vessels and tissue circulations than those in the contralateral eye. During follow-up, there was no tumor enlargement in any case. CONCLUSIONS: This study showed the relationship between the deficit of blood vessel networks and visual field defects in ODM patients. LSFG demonstrated reduced blood flow in the tumor, suggesting that circulatory disorder caused by the optic disk tumor might be correlated with visual field defect.
• 機能的単心室症におけるグレン手術およびフォンタン手術前後の眼圧の変化

  木嶋 理紀, 佐々木 理, 新明 康弘, 大口 剛司, 武田 充人, 陳 進輝, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 123 (臨増) 158 - 158 0029-0203 2019/03
• 人工多能性幹細胞由来マクロファージ様免疫抑制細胞を用いたぶどう膜炎モデルの軽症化

  長谷 敬太郎, 南場 研一, 北市 伸義, 岩田 大樹, 辻 飛雄馬, 和田 はるか, 清野 研一郎, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 123 (臨増) 226 - 226 0029-0203 2019/03
• Spontaneously Diabetic Torii fattyラットにおける糖尿病白内障の検討

  菊地 香澄, 野田 航介, 村田 美幸, 田川 義晃, 神田 敦宏, 加瀬 諭, 影山 靖, 篠原 雅巳, 笹瀬 智彦, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 123 (臨増) 166 - 166 0029-0203 2019/03
• トレミフェン内服中止後に視機能が改善した黄斑部毛細血管拡張症type 2の1例

  新海 晃弘, 齋藤 航, 橋本 勇希, 野田 航介, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 123 (臨増) 289 - 289 0029-0203 2019/03
• Galectin-1 promotes choroidal neovascularization and subretinal fibrosis mediated via epithelial-mesenchymal transition

  Di W, Kanda A, Ye L, Kase S, Noda, K, Ishida S

  FASEB J 2019/02 [Refereed][Not invited]
  
• TGF-β-SNAIL axis induces Müller glial-mesenchymal transition in the pathogenesis of idiopathic epiretinal membrane.

  Atsuhiro Kanda, Kousuke Noda, Ikuyo Hirose, Susumu Ishida

  Scientific reports 9 (1) 673 - 673 2019/01/24 

  The epithelial-mesenchymal transition (EMT) is a key process in fibrogenic diseases where transdifferentiated myofibroblasts produce excessive amounts of extracellular matrix, resulting in organ dysfunction. Idiopathic epiretinal membrane (iERM) is a vision-threatening disorder characterized by fibrocellular proliferation and contraction on the central retina. Müller glial cells, which regulate retinal physiology and structure, are the major cellular components in the iERM tissue; however, the pathological role of this cell type remains incompletely understood. Here we revealed the involvement of Müller glial-mesenchymal transition (GMT), as an alternative to EMT, in the pathogenesis of iERM lacking epithelial contribution in nature. Of various pro-fibrotic cytokines, transforming growth factor (TGF)-β1 stimulation to human Müller glial cells exclusively increased mRNA and protein levels of several EMT-related molecular markers, together with the transcription factor SNAIL but not SLUG or TWIST. TGF-β1-stimulated Müller cells also exhibited EMT-related cell motility, while reducing the expression of glutamine synthetase (GS), a Müller glial marker. Notably, all of these TGF-β-induced EMT features were reversed by SNAI1 knockdown in Müller cells. iERM patient specimens demonstrated co-immunolocalization of SNAIL with TGF-β1, GS, and smooth muscle protein 22. Our data implicated a critical role of the TGF-β-SNAIL axis in Müller GMT to promote iERM formation.
• Corneal hyperalgesia in patients with short tear film break-up time dry eye.

  Yoshiaki Tagawa, Kousuke Noda, Takeshi Ohguchi, Yoshitsugu Tagawa, Susumu Ishida, Nobuyoshi Kitaichi

  The ocular surface 17 (1) 55 - 59 1542-0124 2019/01 [Refereed][Not invited]
   

  PURPOSE: To evaluate corneal tactile and pain sensations in patients with short tear film break-up time dry eye (sBUT DE). METHODS: This study enrolled 60 patients with sBUT DE and 46 healthy volunteers from Japan. We evaluated corneal tactile and pain sensations using a modified method with the Cochet-Bonnet corneal esthesiometer. RESULTS: Patients with sBUT DE had higher corneal pain sensitivity (26.3 ± 23.1 mm) than healthy subjects (6.9 ± 16.4 mm), but similar corneal tactile sensation (52.0 ± 15.5 mm and 52.9 ± 14.9 mm, respectively). In patients with sBUT DE and corneal hyperalgesia (n = 22, 36.7%), defined as a pain sensitivity ≥40 mm (i.e., the cutoff value at the 95th percentile of corneal pain sensitivity in healthy subjects), a strong significant correlation was found between the subjective pain score and objective corneal pain sensation (R = 0.79). However, for the entire cohort, we found a weak positive correlation between the subjective pain score and objective corneal pain sensation. CONCLUSIONS: Patients with sBUT DE were hypersensitive to corneal pain, which suggested that corneal hyperalgesia partly accounted for subjective symptoms in patients with sBUT DE.
• Increased plasma galectin-1 correlates with advanced glycation end products and interleukin-1β in patients with proliferative diabetic retinopathy.

  Keitaro Hase, Atsuhiro Kanda, Kousuke Noda, Susumu Ishida

  International journal of ophthalmology 12 (4) 692 - 694 2019
• Involvement of Inner Choroidal Layer in Choroidal Thinning during Regression of Multiple Evanescent White Dot Syndrome.

  Yuki Hashimoto, Wataru Saito, Yuka Hasegawa, Kousuke Noda, Susumu Ishida

  Journal of ophthalmology 2019 6816925 - 6816925 2019 

  Purpose: To investigate relationships between total thickness and the thickness of inner and outer layers in the choroid during regression in patients with multiple evanescent white dot syndrome (MEWDS). Methods: This retrospective observational case series included 15 unilaterally affected eyes and 13 unaffected fellow eyes from 15 MEWDS patients (4 men and 11 women; mean age, 37.6 ± 17.6 years). Using enhanced depth imaging optical coherence tomography, whole, inner, and outer choroidal layer thicknesses at the fovea and perifovea were manually measured at the initial visit and at 1 and 3 months after the initial visit. The mean thickness values of the layers were compared at each stage. Results: With regression of MEWDS, the mean subfoveal whole and inner choroidal layer thicknesses significantly decreased at 1 and 3 months compared to baseline values in MEWDS eyes (P=0.01 and P < 0.0001, respectively), but not in fellow eyes. The outer layer in MEWDS eyes tended to thin. Changes in the inner and outer layers at the perifovea in MEWDS eyes also showed the same trends. Simple linear regression analysis revealed significant positive correlations in choroidal thickness changes between the whole and inner layers (R = 0.53, P=0.04) and between the whole and outer layers (R = 0.91, P < 0.0001) from baseline to 3 months. Multiple linear regression analysis revealed that choroidal thickness changes in the whole layer were significantly correlated with those in the inner (β = 0.51, P < 0.0001) and outer (β = 0.73, P < 0.0001) layers. Conclusion: The inner choroidal layer significantly thinned with regression of MEWDS, correlating with the thinning of total choroidal thickness. These results suggest that MEWDS lesions in the choroid are likely to lie mainly in the inner layer.
• A case of nodular posterior scleritis simulating intraocular tumor.

  Yukiko Shibata, Satoru Kase, Kenichi Namba, Susumu Ishida

  International journal of ophthalmology 12 (4) 685 - 688 2019
• Changes in blood flow velocity and thickness of the choroid in a patient with leukemic retinopathy.

  Takita A, Hashimoto Y, Saito W, Kase S, Ishida S

  American journal of ophthalmology case reports 12 68 - 72 2018/12 [Refereed][Not invited]
  
• Acute macular neuroretinopathyにおける脈絡膜層別厚の経時変化

  橋本 勇希, 齋藤 航, 滝田 亜かり, 長谷川 裕香, 鈴木 智浩, 安藤 亮, 藤谷 顕雄, 森 祥平, 加瀬 諭, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 11 (11) 836 - 837 1882-5176 2018/11
• MPO-ANCA陽性を示したparacentral acute middle maculopathyの1例

  福津 佳苗, 安藤 亮, 新明 康弘, 鈴木 智浩, 藤谷 顕雄, 森 祥平, 加瀬 諭, 阿部 早和子, 齋藤 航, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 11 (11) 837 - 837 1882-5176 2018/11
• エアバッグによる網膜再剥離と気胸を発症した1例

  新海 晃弘, 加瀬 諭, 森 祥平, 安藤 亮, 藤谷 顕雄, 鈴木 智浩, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 11 (11) 846 - 846 1882-5176 2018/11
• 血管径自動解析プログラムによる網膜動静脈比と血圧脈波の相関

  齋藤 理幸, 野田 航介, 星川 靖裕, 小林 正彦, 道家 充, 村田 美幸, 齋藤 航, 加瀬 学, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 11 (11) 850 - 851 1882-5176 2018/11
• Immunohistochemical and Immunocytochemical Analyses in Patients with Vitreoretinal Lymphoma.

  Kase S, Namba K, Kanno-Okada H, Onozawa M, Hidaka D, Iwata D, Mizuuchi K, Fukuhara T, Fukuhara J, Kitaichi N, Matsuno Y, Ishida S

  Ocular immunology and inflammation 1 - 9 0927-3948 2018/10 [Refereed][Not invited]
  
• Clinical features of Japanese patients with anti-α-enolase antibody-positive autoimmune retinopathy: Novel subtype of multiple drusen.

  Ando R, Saito W, Kanda A, Kase S, Fujinami K, Sugahara M, Nakamura Y, Eguchi S, Mori S, Noda K, Shinoda K, Ishida S

  American journal of ophthalmology 196 181 - 196 0002-9394 2018/09 [Refereed][Not invited]
   

  PURPOSE: To evaluate clinical features of Japanese patients with anti-α-enolase antibody-positive autoimmune retinopathy (anti-enolase AIR). DESIGN: Multicenter retrospective observational case series. METHODS: Forty-nine eyes of 25 Japanese anti-enolase AIR patients (16 female and 9 male; mean age at first visit, 60.8 years) were included. Fundus characteristics, perimetry, spectral-domain optical coherence tomography (SD-OCT), electroretinography (ERG), best-corrected visual acuity (BCVA), and complicating systemic tumors were assessed. Protein localization of α-enolase was examined by immunohistochemistry in an enucleated eye of 1 patient. RESULTS: Patients were classified into 3 groups: multiple drusen (48%), retinal degeneration (36%), and normal fundus (16%). Drusen varied in size from small deposits to vitelliform-like lesions. Images on SD-OCT revealed dome-shaped hyperreflectivity beneath the retinal pigment epithelium (RPE), corresponding to drusen. Perimetry showed that ring scotoma was the most frequent (39%). Rod-system and/or single-flash cone responses revealed decreased responses in 81% of the eyes. Combined rod and cone system responses demonstrated significantly lower a-wave amplitudes in the degeneration group than in the drusen group (P = .005). BCVA was improved or maintained in 80% of the eyes during follow-up. Malignant or benign tumors were detected in 30% of patients. The RPE and photoreceptor layers were immunopositive for α-enolase. CONCLUSIONS: The drusen subtype, scarcely described in the literature, is suggested to characterize Japanese patients with anti-enolase AIR. The different funduscopic features with different functional severities may have resulted from antibody-mediated damage to RPE as well as photoreceptor cells.
• 糖尿病網膜症における血管新生因子ガレクチン-1による病態形成への関与

  石田 晋, 董 陽子, 野田 航介, 齋藤 航, 神田 敦宏

  日本糖尿病眼学会誌 日本糖尿病眼学会 22 132 - 132 1881-753X 2018/09
• 糖尿病網膜症におけるポリアミン代謝の病態関与

  野田 航介, 村田 美幸, 神田 敦宏, 石田 晋

  日本糖尿病眼学会誌 日本糖尿病眼学会 22 132 - 132 1881-753X 2018/09
• 糖尿病網膜症の増殖組織における分子シャペロンαB-クリスタリンのリン酸化

  加瀬 諭, 董 陽子, 神田 敦宏, 野田 航介, 石田 晋

  日本糖尿病眼学会誌 日本糖尿病眼学会 22 133 - 133 1881-753X 2018/09
• 視機能と網膜機能が良好であった中心窩温存黄色斑眼底の1例

  新海 晃弘, 齋藤 航, 廣岡 季里子, 藤波 芳, 篠田 啓, 野田 航介, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 11 (7) 552 - 552 1882-5176 2018/07
• Two cases of cytomegalovirus panuveitis in immunocompetent patients

  Masato Sakai, Hiroshi Takase, Kenichi Namba, Kazuomi Mizuuchi, Daiju Iwata, Susumu Ishida

  American Journal of Ophthalmology Case Reports 10 189 - 191 2451-9936 2018/06/01 [Refereed][Not invited]
   

  Purpose: To report two cases of panuveitis in immunocompetent patients in which cytomegalovirus was involved. Observation: Case 1 was a 46-year-old man who had a history of recurrent anterior chamber inflammations in his left eye. After Nd:YAG laser posterior capsulotomy, he developed panuveitis with vitreous haze and periphlebitis. Polymerase chain reaction (PCR) examination revealed the presence of cytomegalovirus (CMV) DNA in the anterior chamber (AC). He responded well to a series of intravitreal injections of ganciclovir (GCV). Case 2 was a 63-year-old woman who had a history of recurrent anterior uveitis in her left eye. Two years after cataract surgery, AC inflammation, diffuse vitreous haze, and periphlebitis had developed. CMV DNA was detected in the AC. Intravitreal injections of GCV and oral valganciclovir were administered, and ocular inflammation finally improved. Conclusions: and importance: We experienced two cases of CMV panuveitis in immunocompetent adults, both of which responded well to anti-viral therapies.
• The clinical features of radiation cataract in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma

  Kanae Fukutsu, Satoru Kase, Kan Ishijima, Rumiko Kinoshita, Susumu Ishida

  Radiation Oncology 13 (1) 95  1748-717X 2018/05/16 [Refereed][Not invited]
   

  Background: To examine the clinical features of radiation cataract in patients with ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma. Methods: Twenty-one patients with 26 eyes diagnosed with ocular adnexal MALT lymphoma (26 eyes), who were treated in Hokkaido University Hospital, were retrospectively reviewed based on medical records. Results: Out of the 21 patients, 16 patients (21 eyes) received radiation therapy (RT) with a total dose of 30 Gy. All cases eventually achieved complete remission. Eight of these patients (11 eyes: 52.3%) required cataract surgery after RT. The mean age at surgery was 56.8 (40-70) years. The mean latency between RT and the indication for surgery was 43.3 months. The percentage of females was significantly higher in patients who required surgery (P < 0.01), compared with those without surgery. The eyes of patients who received bolus technique on radiation treatment developed cataract more frequently (P < 0.05). In contrast, none of the patients without RT required cataract surgery. Conclusions: Patients with ocular adnexal MALT lymphoma who underwent surgery for radiation cataract were seen more often in relatively young, female patients, and surgery was required about 3 years after RT. A long-term observation may be needed for patients after RT for a tumor. A female sex and the bolus technique may be risk factors for radiation cataract.
• Proteolytic cleavage of vascular adhesion protein-1 induced by vascular endothelial growth factor in retinal capillary endothelial cells

  Shiho Yoshida, Miyuki Murata, Kousuke Noda, Takashi Matsuda, Michiyuki Saito, Wataru Saito, Atsuhiro Kanda, Susumu Ishida

  Japanese Journal of Ophthalmology 62 (2) 256 - 264 1613-2246 2018/03/01 [Refereed][Not invited]
   

  Purpose: To investigate the mechanism of soluble vascular adhesion protein-1 (sVAP-1) accumulation induced by vascular endothelial growth factor (VEGF) in the vitreous of patients with diabetic retinopathy (DR). Study design: Experimental. Methods: Protein levels of sVAP-1 and N epsilon-(hexanoyl)lysine (HEL), an oxidative stress marker, in the vitreous samples from patients with proliferative diabetic retinopathy (PDR) with or without intravitreal bevacizumab (IVB) injection were determined by ELISA. The effect of VEGF on both mRNA expression of Vap-1 and secretion of sVAP-1 in rat retinal capillary endothelial cells (TR-iBRB2) was analyzed by real-time PCR and western blotting, respectively. In addition, the impact of VEGF on production and activation ratios of matrix metalloproteinase (MMP)-2 and MMP-9 was examined by gelatin zymography. Hydrogen peroxide production and reactive oxygen species (ROS) levels were assessed in the supernatants of TR-iBRB2 cells treated with VEGF. Results: IVB injection decreased vitreous levels of sVAP-1 and HEL in patients with PDR. VEGF stimulation released sVAP-1 protein from TR-iBRB2 cells as a consequence of membrane-anchored VAP-1 shedding by MMP-2 and MMP-9. In addition, VEGF increased hydrogen peroxide generation and ROS augmentation through spermine oxidation by sVAP-1 as semicarbazide-sensitive amine oxidase (SSAO) in the supernatant of cultured endothelial cells. Conclusions: The current data demonstrate that proangiogenic factor VEGF induces sVAP-1 release from retinal capillary endothelial cells and facilitates hydrogen peroxide generation via enzymatic property of sVAP-1, followed by the increase of oxidative stress, one of the crucial factors in the pathogenesis of DR.
• (Pro)renin receptor: Involvement in diabetic retinopathy and development of molecular targeted therapy.

  Kanda A, Ishida S

  Journal of diabetes investigation 2040-1116 2018/03 [Refereed][Not invited]
  
• CHOROIDAL THICKNESS CHANGES IN A PATIENT DIAGNOSED WITH CENTRAL SEROUS CHORIORETINOPATHY DURING FOLLOW-UP FOR PACHYCHOROID PIGMENT EPITHELIOPATHY.

  Saito W, Hashimoto Y, Hirooka K, Ishida S

  Retinal cases & brief reports 1935-1089 2018/02 [Refereed][Not invited]
  
• Relationship between choroidal blood flow velocity and choroidal thickness in patients with regression of acute central serous chorioretinopathy

  Michiyuki Saito, Kousuke Noda, Wataru Saito, Susumu Ishida

  Graefe's Archive for Clinical and Experimental Ophthalmology 256 (1) 227 - 229 1435-702X 2018/01/01 [Refereed][Not invited]
  
• Anterior proliferative vitreoretinopathy in a patient with Coats disease

  Satoru Kase, Shohei Mori, Kousuke Noda, Susumu Ishida

  International Journal of Ophthalmology 11 (2) 343 - 345 2227-4898 2018 [Refereed][Not invited]
  
• Role of the Epipapillary Membrane in Maculopathy Associated with Cavitary Optic Disc Anomalies: Morphology, Surgical Outcomes, and Histopathology.

  Tanaka A, Saito W, Kase S, Ishijima K, Noda K, Ishida S

  Journal of ophthalmology 2018 5680503 - 5680503 2090-004X 2018 [Refereed][Not invited]
   

  Purpose: To evaluate the surgical outcomes of pars plana vitrectomy (PPV) with epipapillary membrane removal in patients with maculopathy associated with cavitary optic disc anomalies. Methods: Eight patients (8 eyes) with cavitary optic disc anomaly-associated maculopathy who underwent PPV with epipapillary membrane removal were retrospectively reviewed. The best-corrected visual acuity (BCVA) and macular and papillary morphologies using enhanced depth imaging optical coherence tomography (EDI-OCT) were evaluated before and after treatment. Immunohistochemistry for an intraoperatively excised epipapillary membrane tissue was also performed. Results: Before surgery, EDI-OCT revealed that epipapillary membrane was observed in all patients. Retinoschisis was resolved with no recurrence in all patients following vitrectomy regardless of a disease type or the presence or absence of preoperative posterior vitreous detachment. The mean final BCVA and central retinal thickness significantly improved compared with pretreatment values (P = 0.008 and 0.004, resp.). Immunoreactivity for S100 protein and glial fibrillary acidic protein, markers of astrocytes, was positive in the resected membrane tissues. Conclusions: These results suggest that epipapillary membrane is involved in the pathogenesis of some patients with cavitary optic disc anomaly-associated maculopathy as well as posterior hyaloid membrane. PPV with epipapillary membrane removal may be a useful treatment option for this maculopathy. This trial is registered with UMIN000011123.
• Soluble Vascular Adhesion Protein-1 Mediates Spermine Oxidation as Semicarbazide-Sensitive Amine Oxidase: Possible Role in Proliferative Diabetic Retinopathy

  Miyuki Murata, Kousuke Noda, Akiko Kawasaki, Shiho Yoshida, Yoko Dong, Michiyuki Saito, Zhenyu Dong, Ryo Ando, Shohei Mori, Wataru Saito, Atsuhiro Kanda, Susumu Ishida

  Current Eye Research 42 (12) 1674 - 1683 1460-2202 2017/12/02 [Refereed][Not invited]
   

  Purpose/Aim of the study: To explore the possible role of vascular adhesion protein-1 (VAP-1) via its enzymatic function as a semicarbazide-sensitive amine oxidase (SSAO) in the pathogenesis of proliferative diabetic retinopathy (PDR). Materials and Methods: The levels of soluble VAP-1/SSAO and the unsaturated aldehyde acrolein (ACR)-conjugated protein, Nε-(3-formyl-3, 4-dehydropiperidino) lysine adduct (FDP-Lys), were measured in vitreous fluid samples of PDR and non-diabetic patients using ELISA. Recombinant human VAP-1/SSAO (rhVAP-1/SSAO) was incubated with spermine, with or without semicarbazide or RTU-1096 (a specific inhibitor for VAP-1/SSAO). Immunofluorescence assays were performed to assess the localization of VAP-1/SSAO and FDP-Lys in fibrovascular tissues from patients with PDR. The impact of ACR on cultured retinal capillary endothelial cells was assessed using a cell viability assay and total glutathione (GSH) measurements. Results: The levels of sVAP-1/SSAO and FDP-Lys were elevated in the vitreous fluid of patients with PDR. Incubation of rhVAP-1 with spermine resulted in the generation of hydrogen peroxide and FDP-Lys and the production was inhibited by semicarbazide and RTU-1096. In fibrovascular tissues, FDP-Lys and VAP-1/SSAO were present in endothelial cells. ACR stimulation reduced GSH levels in the cultured endothelial cells in a dose-dependent manner and caused cellular toxicity. Conclusions: Our results indicate the pathological role of sVAP-1/SSAO to generate hydrogen peroxide and toxic aldehyde ACR, both of which are associated with oxidative stress, as a consequence of spermine oxidation in eyes with PDR.
• Usefulness of PET/CT for early detection of internal malignancies in patients with Muir-Torre syndrome: report of two cases.

  Yui Ishiguro, Shigenori Homma, Tadashi Yoshida, Yosuke Ohno, Nobuki Ichikawa, Hideki Kawamura, Hiroo Hata, Satoru Kase, Susumu Ishida, Hiromi Okada-Kanno, Kanako C Hatanaka, Akinobu Taketomi

  Surgical case reports 3 (1) 71 - 71 2017/12 [Refereed][Not invited]
   

  BACKGROUND: Muir-Torre syndrome (MTS) is a rare autosomal dominant genodermatosis caused by mutations in mismatch repair genes. It is characterized by the presence of at least one sebaceous skin tumor associated with internal malignancies. Whether positron emission tomography/computed tomography (PET/CT) is useful for the detection of malignancies in patients with MTS has not been determined. We herein report two cases in which PET/CT was useful for the diagnosis and follow-up of internal malignancies in patients with MTS. CASE PRESENTATION: In case 1, a 57-year-old woman underwent excision of a sebaceous carcinoma on the left upper eyelid. She underwent follow-up PET/CT once yearly thereafter. Forty-two months after the eyelid surgery, PET/CT showed intense tracer uptake in the right lower abdomen. An ascending colon tumor was identified, and examination of a biopsy specimen showed adenocarcinoma. In case 2, a 77-year-old man presented for evaluation of three continuous papules with telangiectasia on his right cheek. Examination of a skin biopsy specimen of the cheek papule revealed a sebaceous carcinoma. He underwent PET/CT to detect other malignancies. PET/CT showed intense tracer uptake in the sigmoid colon. A sigmoid colon tumor was identified, and examination of a biopsy specimen showed adenocarcinoma. Both patients underwent resection of their tumors, and both were still free of recurrence of the sebaceous and colon carcinomas at the time of this writing. CONCLUSION: PET/CT is a reliable imaging modality for the detection of internal malignancies and is useful for the diagnosis and follow-up of MTS.
• Systemic factors related to soluble (pro)renin receptor in plasma of patients with proliferative diabetic retinopathy

  Keitaro Hase, Atsuhiro Kanda, Lkuyo Hirose, Kousuke Noda, Susumu Ishida

  PLOS ONE 12 (12) e0189696  1932-6203 2017/12 [Refereed][Not invited]
   

  (Pro)renin receptor [(P)RR], a new component of the tissue renin-angiotensin system (RAS), plays a crucial role in inflammation and angiogenesis in the eye, thus contributing to the development of proliferative diabetic retinopathy (PDR). In this study, we investigated systemic factors related to plasma levels of soluble form of (P) RR [s(P) RR] in patients with PDR. Twenty type II diabetic patients with PDR and 20 age-matched, non-diabetic patients with idiopathic macular diseases were enrolled, and plasma levels of various molecules were measured by enzyme-linked immunosorbent assays. Human retinal microvascular endothelial cells were stimulated with several diabetes-related conditions to evaluate changes in gene expression using real-time quantitative PCR. Of various systemic parameters examined, the PDR patients had significantly higher blood sugar and serum creatinine levels than non-diabetic controls. Protein levels of s(P) RR, prorenin, tumor necrosis factor (TNF)-alpha, complement factor D (CFD), and leucine-rich alpha-2-glycoprotein 1 (LRG1) significantly increased in the plasma of PDR subjects as compared to non-diabetes, with positive correlations detected between s(P)RR and these inflammatory molecules but not prorenin. Estimated glomerular filtration rate and serum creatinine were also correlated with plasma s (P)RR, but not prorenin, levels. Among the inflammatory molecules correlated with s(P)RR in the plasma, TNF-alpha, but not CFD or LRG1, application to retinal endothelial cells upregulated the mRNA expression of (P)RR but not prorenin, while stimulation with high glucose enhanced both (P)RR and prorenin expression. These findings suggested close relationships between plasma s(P)RR and diabetes-induced factors including chronic inflammation, renal dysfunction, and hyperglycemia in patients with PDR.
• 糖尿病網膜症における新規血管新生因子ガレクチン-1の発現調節メカニズム

  神田 敦宏, 野田 航介, 齋藤 航, 石田 晋

  生命科学系学会合同年次大会 生命科学系学会合同年次大会運営事務局 2017年度 [1P - 0023] 2017/12
• Long-term follow-up of conjunctival melanoma treated with topical interferon alpha-2b eye drops as adjunctive therapy following surgical resection

  Iku Kikuchi, Satoru Kase, Kan Ishijima, Susumu Ishida

  GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 255 (11) 2271 - 2276 0721-832X 2017/11 [Refereed][Not invited]
   

  The purpose of this study was to report the clinical outcomes of patients with conjunctival melanoma treated with interferon (IFN) alpha-2b eye drops following local tumor resection. Five eyes of five patients were enrolled in this study. All patients underwent the local resection of tumors, and topical IFN alpha-2b eye drops were subsequently administered 4 times/day until the complete disappearance of the pigmented lesions determined by slit-lamp examination. Ophthalmological findings, histopathological findings, and imaging modalities were retrospectively analyzed. The age of the patients ranged from 65 to 84 years (mean: 75.4 years). Locations of the tumor were the bulbar conjunctiva in three eyes, multiple palpebral conjunctivas in one eye, and palpebral conjunctiva and caruncle in one eye. All patients received topical IFN alpha-2b eye drop treatment for 6-10 months. Follow-up periods after resection ranged from 18 to 78 months. Histologically, all excised conjunctival tumors were diagnosed with malignant melanoma, where the surgical margins were completely negative in one patient. No patients had suffered from severe adverse effects related to IFN alpha-2b. Four out of five patients consequently achieved complete remission. Since one eye in one case showed resistance to the local chemotherapy containing IFN alpha-2b eye drops and the subconjunctival injection of IFN-beta, orbital exenteration was eventually required 12 months after local resection. Topical IFN alpha-2b eye drops may be safe and one of the useful adjunctive treatments following surgical resection for patients with conjunctival melanoma.
• Advanced glycation endproducts link inflammatory cues to upregulation of galectin-1 in diabetic retinopathy

  Atsuhiro Kanda, Yoko Dong, Kousuke Noda, Wataru Saito, Susumu Ishida

  SCIENTIFIC REPORTS 7 (1) 16168  2045-2322 2017/11 [Refereed][Not invited]
   

  Diabetic retinopathy (DR) is an inflammatory and progressive vaso-occlusive disease resulting in angiogenesis. Galectin-1 is a hypoxia-induced angiogenic factor associated with cancer and proliferative DR. Here we reveal a significant upregulation of galectin-1 in eyes of DR patients along with progression of clinical stages beginning from the pre-ischemic, inflammatory stage with diabetic macular edema, but not in eyes with non-diabetic retinal vascular occlusions. As for its regulatory mechanism unrelated to hypoxia but selective to DR, in vitro galectin-1/LGALS1 expression was shown to increase after application to Muller glial cells with interleukin (IL)-1 beta, which was induced in monocyte-derived macrophages and microglial cells via toll-like receptor (TLR) 4 signaling stimulated by advanced glycation endproducts (AGE). In vivo inhibition of AGE generation with aminoguanidine, macrophage depletion with clodronate liposomes, and antibody-based blockade of Il-1 beta and Tlr4 attenuated diabetes-induced retinal Lgals1 expression in mice. Fibrovascular tissues from proliferative DR eyes were immunoreactive for AGE, TRL4 and IL-1 beta in macrophages, and IL-1 beta receptor-positive glial cells expressed galectin-1. Therefore, diabetes-induced retinal AGE accumulation was suggested to activate IL-1 beta-related inflammatory cues in macrophages followed by Muller cells, linking to galectin-1 upregulation in human DR with time. Our data highlight AGE-triggered inflammation as the DR-selective inducer of galectin-1.
• Usefulness of Flow Cytometry in Diagnosis of IgG4-Related Ophthalmic Disease and Extranodal Marginal Zone B-Cell Lymphoma of the Ocular Adnexa

  Satoru Kase, Kan Ishijima, Takehiko Uraki, Yuka Suimon, Yasuo Suzuki, Manabu Kase, Susumu Ishida

  ANTICANCER RESEARCH 37 (9) 5001 - 5004 0250-7005 2017/09 [Refereed][Not invited]
   

  Background/Aim: Although flow cytometry (FCM) is used to evaluate cell surface markers of various leucocyte populations quantitatively, little is known about the usefulness of FCM in lymphoproliferative disorders of the ocular adnexa. The aim of this study was to disclose results of FCM, which were compared among IgG4-related ophthalmic disease (IgG4-ROD), idiopathic orbital inflammation (IOI), and extranodal marginal zone B-cell lymphoma (EMZL). Materials and Methods: This is a retrospective observational study. Sixty-nine tumors comprising of 16 IgG4-ROD, 24 IOI, and 29 EMZL were enrolled in the study. All tumors, surgically excised, were diagnosed based on histopathology, immunoglobulin (Ig) heavy chain gene rearrangement, and FCM. In FCM, the percentage of T-cell markers (CD2, CD3, CD4, CD5, CD7, CD8), B-cell markers (CD10, CD19, CD20, CD23), NK cell marker (CD56) and cell surface kappa/lambda was searched based on medical records. Ig light chain restriction was evaluated from results in kappa/lambda deviation by FCM. Results: The percentage of CD2, CD3, CD4, CD7, and CD10 was significantly higher in IgG4-ROD/IOI than EMZL (p<0.05 in every factor). In contrast, CD19 and CD20 percentages were significantly greater in EMZL than IgG4-ROD/IOI (p<0.01). There was no significant difference in any marker between IgG4-ROD and IOI. Kappa-positive cells were significantly greater in EMZL than IgG4-ROD/IOI (p<0.05). In kappa/lambda deviation, false-positive was noted in 3 (7.5%) benign IgG4-ROD/IOI and false-negative was observed in 10 (34.5%) EMZL cases. Sensitivity and specificity of Ig light chain restriction were 65.5 and 92.5%, respectively. Conclusion: Analyses of cell surface markers using FCM were useful in differentiating EMZL from IgG4-ROD/IOI. Sensitivity of Ig light chain restriction was relatively low in diagnosis of EMZL using FCM.
• A Novel Single-Strand RNAi Therapeutic Agent Targeting the (Pro)renin Receptor Suppresses Ocular Inflammation

  Atsuhiro Kanda, Erdal Tan Ishizuka, Atsushi Shibata, Takahiro Matsumoto, Hidekazu Toyofuku, Kousuke Noda, Kenichi Namba, Susumu Ishida

  MOLECULAR THERAPY-NUCLEIC ACIDS 7 116 - 126 2162-2531 2017/06 [Refereed][Not invited]
   

  The receptor-associated prorenin system (RAPS) refers to the pathogenic mechanism whereby prorenin binding to the (pro) renin receptor [(P) RR] dually activates the tissue reninangiotensin system (RAS) and RAS-independent intracellular signaling. Here we revealed significant upregulation of prorenin and soluble (P) RR levels in the vitreous fluid of patients with uveitis compared to non-inflammatory controls, together with a positive correlation between these RAPS components and monocyte chemotactic protein-1 among several upregulated cytokines. Moreover, we developed a novel single-strand RNAi agent, proline-modified short hairpin RNA directed against human and mouse (P) RR [(P) RR-PshRNA], and we determined its safety and efficacy in vitro and in vivo. Application of (P) RR-PshRNA in mice caused significant amelioration of acute (uveitic) and chronic (diabetic) models of ocular inflammation with no apparent adverse effects. Our findings demonstrate the significant implication of RAPS in the pathogenesis of human uveitis and the potential usefulness of (P) RR-PshRNA as a therapeutic agent to reduce ocular inflammation.
• Vascular Adhesion Protein-1 Blockade Suppresses Ocular Inflammation After Retinal Laser Photocoagulation in Mice

  Takashi Matsuda, Kousuke Noda, Miyuki Murata, Akiko Kawasaki, Atsuhiro Kanda, Yukihiko Mashima, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 58 (7) 3254 - 3261 0146-0404 2017/06 [Refereed][Not invited]
   

  PURPOSE. To investigate the effect of the vascular adhesion protein-1 (VAP-1) inhibitor RTU-1096 on retinal morphologic changes and ocular inflammation after retinal laser photocoagulation in mice. METHODS. C57BL/6JJcl mice were fed a diet containing RTU-1096, a specific inhibitor for VAP-1, or a control diet ad libitum for 7 days. Laser photocoagulation was performed on the peripheral retina of the animals. The semicarbazide sensitive amine oxidase (SSAO) activities in plasma and chorioretinal tissues were measured. Optical coherence tomography (OCT) images were acquired before and at 1, 3, and 7 days after laser photocoagulation, and thickness of the individual retinal layers was measured. Intravitreal leukocyte infiltration was assessed by histologic analysis. The expression level of intercellular adhesion molecule-1 (ICAM-1) in retinal tissues were examined by quantitative real-time PCR. RESULTS. One day after laser photocoagulation, the thickness of the outer nuclear layer (ONL) increased in the laser group compared with in the control group, and RTU-1096 administration abrogated the ONL thickening. Histologic analysis and OCT observation revealed that laser photocoagulation caused infiltration of inflammatory cells and the appearance of hyperreflective foci at the vitreoretinal surface, both of which were suppressed by RTU-1096 administration. In addition, systemic administration of RTU-1096 reduced upregulation of the leukocyte adhesion molecules ICAM-1 in the retina. CONCLUSIONS. The current data indicate that VAP-1/SSAO inhibition may be a potential therapeutic strategy for the prevention of macular edema secondary to scatter laser photocoagulation in patients with ischemic retinal diseases such as diabetic retinopathy.
• Effect of topical rebamipide on goblet cells in the lid wiper of human conjunctiva

  Satoru Kase, Toshiya Shinohara, Manabu Kase, Susumu Ishida

  EXPERIMENTAL AND THERAPEUTIC MEDICINE 13 (6) 3516 - 3522 1792-0981 2017/06 [Refereed][Not invited]
   

  It has been demonstrated that topical administration of rebamipide, which is an antiulcer agent, increases the mucin level of the tear film and ameliorates ocular surface conditions such as lid wiper epitheliopathy. The aim of the present study was to analyze the changes in goblet cell number, cell proliferation, and epidermal growth factor receptor (EGFR) induced by topical rebamipide addition to the lid wiper of humans. A total of 30 eyelid tissue samples were obtained during involutional entropion surgeries, fixed in paraformaldehyde, embedded in paraffin and divided into two groups: Rebamipide or non-rebamipide. The tissues in the rebamipide group were obtained from patients who had a medical history of topical rebamipide use prior to surgery. The number of goblet cells was counted under light microscopy. A total of 22 eyelid tissue samples were further examined using immunohistochemistry with anti-Ki-67 and anti-EGFR antibodies to evaluate cell proliferation and EGFR expression, respectively. Histologically, the lid wiper and palpebral conjunctiva were clearly identified in the tissues. The number of goblet cells was significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0367). There was no significant difference in lid wiper cell proliferation between the rebamipide and non-rebamipide groups. Immunohistochemistry revealed that EGFR levels in the lid wiper epithelial cells were significantly higher in the rebamipide group compared with the non-rebamipide group (P=0.0237). These results suggest that topical rebamipide application increases the number of goblet cells in the lid wiper, which in turn upregulates the expression of EGFR. These findings may be clinically relevant and provide a therapeutic basis for the treatment of ocular disease such as dry eye and lid wiper epitheliopathy.
• Blood flow velocity and thickness of the choroid in a patient with chorioretinopathy associated with ocular blunt trauma

  Yuri Ishikawa, Yuki Hashimoto, Wataru Saito, Ryo Ando, Susumu Ishida

  BMC OPHTHALMOLOGY 17 (1) 86  1471-2415 2017/06 [Refereed][Not invited]
   

  Background: Choroidal circulation hemodynamics in eyes with ocular blunt trauma has not been quantitatively examined yet. We quantitatively examined changes in choroidal blood flow velocity and thickness at the lesion site using laser speckle flowgraphy (LSFG) and enhanced depth imaging optical coherence tomography (EDI-OCT) in a patient with chorioretinopathy associated with ocular blunt trauma. Case presentation: A 13-year-old boy developed a chorioretinal lesion with pigmentation extending from the optic disc to the superotemporal side in the right eye after ocular blunt trauma. The patient's best-corrected visual acuity (BCVA) was 0.2 in the right eye. Indocyanine green angiography showed hypofluorescence from the initial phase, with a decrease of mean blur rate (MBR) on LSFG color map, which corresponded to the chorioretinal lesion. The BCVA and foveal outer retinal morphologic abnormality spontaneously improved during follow-up. MBR and choroidal thickness increased by 23-31% and 13-17 mu m at the lesion site and by 11-22% and 33-42 ae m at the fovea, respectively, during the 6-month follow-up period after baseline measurements in the affected eye. In contrast, these parameters showed little or no changes at the normal retinal site in the affected eye and the fovea in the fellow eye. Conclusions: Current data revealed that both blood flow velocity and thickness in the choroid at the lesion site decreased in the acute stage and subsequently increased together with improvements in visual function and outer retinal morphology. These results suggest that LSFG and EDI-OCT may be useful indices that can noninvasively evaluate activity of choroidal involvement in ocular blunt trauma-associated chorioretinopathy.
• Catastrophic Thermal Corneoscleral Injury Treated with Transplantation of Donor Scleral Graft

  Satoru Kase, Takeshi Ohguchi, Susumu Ishida

  Case Reports in Ophthalmology 8 (2) 349 - 352 1663-2699 2017/05/08 [Refereed][Not invited]
   

  Background: The aim of this study is to report a patient with senile cataract developing severe thermal corneoscleral injury during phacoemulsification, which was treated with a donor scleral graft. Case: Severe thermal corneoscleral injury occurred during phacoemulsification in the right eye of a 74-year-old male. His medical history was prostate hypertrophy. Visual acuity was hand motion and the intraocular pressure was 3 mm Hg OD. There was heavy corneal stromal opacity with intraocular fluid leakage. The patient underwent transplantation of a donor scleral graft to the burn site. Histologically, the injured sclera showed coagulation necrosis without inflammatory cell infiltration. An intraocular lens was eventually fixed in the ciliary sulcus 7 months later. His visual acuity remains at 2/20 OD. Conclusions: Transplantation of the donor scleral grafts is useful to close the wound in catastrophic thermal injury.
• Histological findings in the trabecular meshwork of a patient with atopic glaucoma

  Satoru Kase, Shiki Chin, Teruhiko Hamanaka, Yasuhiro Shinmei, Takeshi Ohguchi, Riki Kijima, Akira Matsuda, Susumu Ishida

  Open Ophthalmology Journal 11 103 - 106 1874-3641 2017/05/01 [Refereed][Not invited]
   

  Purpose: The aim of this study was to report a case of atopic dermatitis showing elevated intraocular pressure (IOP) beyond the baseline levels followed by a modified 360-degree suture trabeculotomy, and to analyze the histological findings in the trabecular meshwork. Methods: A 40-year-old male suffered from blurred vision in the right eye (OD). He had a medical history of severe atopic dermatitis and intraocular lens implantation OU due to atopic cataract. At the initial presentation, the visual acuity was 0.03, and IOP was 35 mmHg OD. Slit-lamp examination demonstrated corneal epithelial edema OD. Increased IOP was refractory to several topical medications. The patient underwent a modified 360-degree suture trabeculotomy. The visual field defect, however, deteriorated with persistently high IOP. The patient underwent trabeculectomy together with drainage implant surgery. In the outflow routes, although there seemed to be an opening of Schlemm’s canal into the anterior chamber, there was no endothelium of the canal in the region of its opening. The fibrotic changes were conspicuous around Schlemm’s canal. Conclusion: The histological results indicated that trabeculotomy might not be an appropriate treatment for patients with atopic glaucoma, possibly because of excessive repair to the newly created uveoscleral outflow in addition to the increased postoperative fibrosis in the trabecular meshwork and Schlemm’s canal.
• Evaluating the efficacy of epinastine ophthalmic solution using a conjunctivitis allergen challenge model in patients with birch pollen allergic conjunctivitis

  Yoshiaki Tagawa, Kenichi Namba, Yumi Nakazono, Daiju Iwata, Susumu Ishida

  ALLERGOLOGY INTERNATIONAL 66 (2) 338 - 343 1323-8930 2017/04 [Refereed][Not invited]
   

  Background: The efficacy of epinastine 0.05% ophthalmic solution for pollen allergic conjunctivitis has already been shown in a conjunctival allergen challenge (CAC) test using cedar pollen as a challenge. The present study investigated the efficacy of this solution against birch pollen conjunctivitis in a CAC test. Methods: Ten adult subjects (eight males and two females) with asymptomatic birch pollen conjunctivitis were enrolled in this study. The average age of the subjects was 41.1 years. This study was conducted during a period without birch pollen dispersion. In each subject, the epinastine 0.05% ophthalmic solution was instilled in one eye, and an artificial tear fluid was instilled in the fellow eye in a double-blind manner. Five minutes or 4 h after the drug instillation, both eyes were challenged with an optimal concentration of birch pollen, and ocular itching and conjunctival hyperemia were then graded. Tears were collected before the drug instillation and 20 min after the pollen challenge, and the histamine level was measured. Results: The ocular itching scores and palpebral conjunctival hyperemia scores of the epinastine-treated eyes were significantly lower than those of the contralateral control eyes when the eyes were pretreated with the drug 4 h before the CAC. There was a significant correlation between the tear histamine level and mean ocular itching score of three time points (3, 5 and 10 min) following the CAC in the control eyes but not the epinastine-treated eyes. Conclusions: Epinastine is effective in suppressing ocular itching and conjunctival hyperemia in birch pollen conjunctivitis. Copyright (C) 2017, Japanese Society of Allergology. Production and hosting by Elsevier B.V.
• Improvements of visual function and outer retinal morphology following spontaneous regression of cancer in anti-recoverin cancer-associated retinopathy

  Yuka Suimon, Wataru Saito, Kiriko Hirooka, Atsuhiro Kanda, Hidenori Kitai, Jun Sakakibara-Konishi, Susumu Ishida

  American Journal of Ophthalmology Case Reports 5 137 - 140 2451-9936 2017/04/01 [Refereed][Not invited]
   

  Purpose To report an anti-recoverin antibody-positive cancer-associated retinopathy (anti-recoverin CAR) patient with remarkable improvements of visual function and outer retinal morphology following spontaneous regression of cancer. Observations A 65-year-old woman with small cell lung carcinoma developed progressive, bilateral vision loss with diffuse loss of the ellipsoid zone at the macula on optical coherence tomography and marked reduced responses of a- and b-waves on electroretinography. Western blot analysis led to a diagnosis of anti-recoverin CAR. The visual function and outer retinal morphology gradually improved following spontaneous regression of the cancer and the initiation of systemic corticosteroid. Subsequent intermittent chemotherapy and continuation of corticosteroid maintained reduction of the cancer and prevented the recurrence of CAR, with preservation of improvements of the visual function and macular outer retinal morphology. Conclusions and importance These results suggest that requirement for obtaining good visual prognosis in CAR patients is to make the cancer regress prior to falling into photoreceptor apotosis.
• Vascular anomaly in the levator aponeurosis of neurofibromatosis type 1

  Satoru Kase, Toshiya Shinohara, Mika Noda, Susumu Ishida, Manabu Kase

  INTERNATIONAL JOURNAL OF OPHTHALMOLOGY 10 (4) 656 - 657 2222-3959 2017/04 [Refereed][Not invited]
  
• Pathologic Roles of Receptor-Associated Prorenin System in Idiopathic Epiretinal Membrane

  Yoko Dong, Atsuhiro Kanda, Kousuke Noda, Wataru Saito, Susumu Ishida

  SCIENTIFIC REPORTS 7 44266  2045-2322 2017/03 [Refereed][Not invited]
   

  Receptor-associated prorenin system (RAPS) refers to the pathogenic mechanism whereby prorenin binding to (pro) renin receptor [(P) RR] dually activates tissue renin-angiotensin system (RAS) and RASindependent signaling via (P) RR. The aim of this study is to determine the association of RAPS with idiopathic epiretinal membrane (iERM). Reverse transcription-PCR indicated the expression of RAPS components, including (P) RR and Ang II type 1 receptor (AT1R), in iERM tissues and human Muller glial cell line. Double-labeling analyses demonstrated that (P) RR and AT1R were detected in cells positive for glial fibrillary acidic protein, a marker for glial cells, and co-localized with prorenin and angiotensinogen, respectively. Administration of prorenin to Muller glial cells enhanced mRNA expression of fibroblast growth factor 2, while Ang II application stimulated the expression of glial cell line-derived neurotrophic factor, nerve growth factor, and transforming growth factor-alpha 1. These expression levels induced by prorenin or Ang II were reversed by (P) RR or AT1R blockade, respectively. Immunofluorescence revealed tissue co-localization of (P) RR and AT1R with the products of the upregulated genes in vitro. The present findings suggest the involvement of RAPS in the pathogenesis of iERM.
• Early post-treatment choroidal thickness to alert sunset glow fundus in patients with Vogt-Koyanagi- Harada disease treated with systemic corticosteroids

  Kiriko Hirooka, Wataru Saito, Kenichi Namba, Kazuomi Mizuuchi, Daiju Iwata, Yuki Hashimoto, Susumu Ishida

  PLOS ONE 12 (2) e0172612  1932-6203 2017/02 [Refereed][Not invited]
   

  Purpose To determine if early post-treatment central choroidal thickness (CCT) changes can predict sunset glow fundus (SGF) development in patients with Vogt-Koyanagi-Harada (VKH) disease treated using systemic corticosteroids. Methods This retrospective case series included 39 eyes of 21 treatment-naive patients with acute VKH disease who could be followed up for more than 12 months after systemic corticosteroid therapy. The eyes were divided into two groups according to whether SGF was present or absent at 12 months (9 eyes of 5 patients versus 30 eyes of 16 patients, respectively). Using enhanced depth imaging optical coherence tomography, CCT values were measured before treatment, then at 1 week and 1 and 3 months after treatment in both groups and compared between the two groups. Results Development of SGF was found 4-11 months after treatment. Mean post-treatment CCT decreased significantly at all examinations compared with baseline in both groups, along with resolution of serous retinal detachment. One week after treatment, mean CCT was significantly higher in eyes with SGF than in those without (P = 0.024). SGF was present at 12 months in 9 of 22 eyes with CCT values > 410 mu m at 1 week after starting treatment, in contrast with none of 17 eyes with CCT <= 410 mu m at this time (P = 0.003). Conclusions The current study suggested the potential validity of early post-treatment CCT as a feasible index to alert future progression to SGF in patients with VKH disease treated using systemic corticosteroids.
• HLA-B51 Carriers are Susceptible to Ocular Symptoms of Behcet Disease and the Association between the Two Becomes Stronger towards the East along the Silk Road: A Literature Survey

  Yukihiro Horie, Akira Meguro, Tohru Ohta, Eun Bong Lee, Kenichi Namba, Kazuomi Mizuuchi, Daiju Iwata, Nobuhisa Mizuki, Masao Ota, Hidetoshi Inoko, Susumu Ishida, Shigeaki Ohno, Nobuyoshi Kitaichi

  OCULAR IMMUNOLOGY AND INFLAMMATION 25 (1) 37 - 40 0927-3948 2017 [Refereed][Not invited]
   

  Purpose: Behcet disease (BD) is predominantly found between East Asia and the Mediterranean basin along the historic Silk Road. HLA-B51 is known to be strongly associated with BD. We investigated the association between HLA-B51 and the ocular manifestations of BD among various ethnic groups. Methods: A literature survey was conducted, and 18 articles written in English were reviewed. Results: A strong correlation was found between HLA-B51 and ocular lesions in the entire cohort discussed in the reviewed articles (OR = 1.76, p = 0.000057). HLA-B51 was shown to have a strong association with ocular manifestations of BD patients in East-Eurasian (OR = 2.40, p = 0.0030) and Middle-Eurasian (OR = 1.87, p = 0.0045), but not in West-Eurasian (OR = 1.28, p = 0.35) areas. This correlation seemed to become stronger towards the east. Conclusions: A meta-analysis showed that the correlation became stronger towards the east along the Silk Road. The study results may facilitate understanding of the etiology and characteristics of BD.
• Localization of Acrolein-Lysine Adduct in Fibrovascular Tissues of Proliferative Diabetic Retinopathy

  Yoko Dong, Kousuke Noda, Miyuki Murata, Shiho Yoshida, Wataru Saito, Atsuhiro Kanda, Susumu Ishida

  CURRENT EYE RESEARCH 42 (1) 111 - 117 0271-3683 2017/01 [Refereed][Not invited]
   

  Purpose: To determine the presence of N-epsilon-(3-formyl-3,4-dehydropiperidino) lysine adduct (FDP-Lys), unsaturated aldehyde acrolein-derived lipoxidation end-product, in fibrovascular tissues obtained from patients with proliferative diabetic retinopathy (PDR).Methods: Fibrovascular tissues were collected from 11 eyes of 11 patients with PDR and paraffin-embedded tissue sections were prepared. Tissue localization of FDP-Lys was studied by immunohistochemistry. Signal intensity was quantified by two masked evaluators and graded into three discrete categories. The relationship between FDP-Lys staining and vascular density was analyzed. In addition, subcellular localization of FDP-Lys was studied by immunofluorescent microscopy. The impact of acrolein on cell viability and proliferation was assessed and the expression level of heme oxygenase-1 (HO-1) mRNA was quantified by real-time polymerase chain reaction (PCR) in cultured retinal microvascular endothelial cells.Results: In fibrovascular tissues, FDP-Lys staining was found in vascular components containing CD34-positive cells and alpha smooth muscle actin (-SMA)-positive cells, and clusters of rabbit anti-glial fibrillary acid protein (GFAP)-positive cells. Immunofluorescent staining depicted subcellular localization of FDP-Lys in the nucleus and cytoplasm of the cells. Morphological analysis revealed that fibrovascular tissues with FDP-Lys staining in vascular components showed high vascular density. Exposure of cultured endothelial cells to high concentration of acrolein resulted in the decrease of cell viability and proliferation, whereas lower concentration of acrolein increased cell viability and proliferation. Sublethal concentration of acrolein upregulated HO-1 mRNA expression in retinal microvascular endothelial cells.Conclusions: The current data demonstrated the presence of FDP-Lys in fibrovascular tissues and indicate its involvement in fibrovascular proliferation in PDR.
• Serial Frequencies and Clinical Features of Uveitis in Hokkaido, Japan

  Daiju Iwata, Kazuomi Mizuuchi, Koki Aoki, Yukihiro Horie, Satoru Kase, Kenichi Namba, Shigeaki Ohno, Susumu Ishida, Nobuyoshi Kitaichi

  OCULAR IMMUNOLOGY AND INFLAMMATION 25 (sup1) S15 - S18 0927-3948 2017 [Refereed][Not invited]
   

  Purpose: Environmental and lifestyle changes influence the clinical features of uveitis. This study reviewed the epidemiologic trends of uveitis in the Japanese population.Methods: A retrospective review of the past 80 years of reports from Hokkaido University Hospital.Results: In the 1930s, tuberculosis accounted for 46% and syphilitic uveitis for 31% of cases. The frequency of these diseases decreased to 12% in the 1950s; 8% in 1969; 0.6% in the 1990s; and 0.8% in the 2000s, while the rate of non-infectious uveitis increased. The three most common specific diagnoses were: sarcoidosis, Vogt-Koyanagi-Harada disease, and Behcet disease. Although Behcet disease was the most frequent non-infectious uveitis until the 1980s, sarcoidosis is now the most frequent cause of newly diagnosed non-infectious uveitis.Conclusions: The etiology of uveitis has changed with the times. Tubercular and syphilitic cases have greatly decreased, and sarcoidosis is the most frequent type of uveitis today.
• Clinical practice pattern in management of diabetic macular edema in Japan: survey results of Japanese retinal specialists

  Yuichiro Ogura, Fumio Shiraga, Hiroko Terasaki, Masahito Ohji, Susumu Ishida, Taiji Sakamoto, Akito Hirakata, Tatsuro Ishibashi

  JAPANESE JOURNAL OF OPHTHALMOLOGY 61 (1) 43 - 50 0021-5155 2017/01 [Refereed][Not invited]
   

  To elucidate the current clinical practice patterns of diabetic macular edema (DME) management by retinal specialists in Japan in the era of anti-vascular endothelial growth factor (VEGF) therapy. Forty-six retinal specialists were administered a survey regarding the pathology and clinical practice of DME. Nearly, half of the specialists (45.2 %) think that the main biochemical factor involved in DME development is the vascular permeability-potentiating action of VEGF-A. Most specialists (70.6 %) use three modalities for detecting DME: optical coherence tomography, fluorescein angiography, and fundus examination. For focal macular edema, focal laser is used as first-line therapy by 70.3 % of specialists, whereas 21.6 % use medical treatment in combination with focal/grid laser. For diffuse macular edema, anti-VEGF therapy is the first choice (72.5 %), irrespective of visual acuity, whereas 17.5 % select off-label sub-Tenon's steroid injections. Vitrectomy is often performed for vitreomacular traction (86.5 %) or when anti-VEGF agent/laser therapy is ineffective (73.2 %). For persistent DME after vitrectomy, anti-VEGF agents (46.3 %) or steroids (intravitreal injections, 14.6 %; sub-Tenon's injections, 36.6 %) are selected. When applying anti-VEGF treatment regimen, most specialists continue loading injections until central retinal thickness stabilized (51.4 %) or both visual acuity and central retinal thickness stabilized (24.3 %). In the maintenance phase, many specialists provide injections with pro re nata (76.3 %), whereas 50.0 % responded that the treat-and-extend regimen is ideal. Our survey presents the current views about the DME management and practice patterns of anti-VEGF therapy by one part of the retinal specialists in Japan, and highlights the differences or gaps between evidence and actual clinical practice.
• Relationship between Choroidal Thickness and Visual Field Impairment in Acute Zonal Occult Outer Retinopathy

  Yuki Hashimoto, Wataru Saito, Michiyuki Saito, Yuka Hasegawa, Akari Takita, Shohei Mori, Kousuke Noda, Susumu Ishida

  JOURNAL OF OPHTHALMOLOGY 2017 2371032  2090-004X 2017 [Refereed][Not invited]
   

  Purpose. To evaluate sequential changes in choroidal thickness at the affected area in patients with acute zonal occult outer retinopathy (AZOOR). Methods. This retrospective observational case series included 14 affected eyes and 6 unaffected fellow eyes from 10 AZOOR patients with impaired macular area. Using enhanced depth imaging optical coherence tomography, choroidal thicknesses at the subfovea and at nasal and temporal sites 1000 mu m away from the fovea were manually measured at baseline and 3 and 6 months thereafter. Changes in the choroidal thicknesses and the average threshold at the affected area on Humphrey perimetry were compared during the 6-month follow-up. Results. In AZOOR eyes, the average threshold at the affected area significantly increased over time, while outer retinal structure ameliorated. The mean choroidal thicknesses at all the sites measured significantly decreased at 3 and 6 months compared with baseline values in AZOOR eyes, but not in fellow eyes. There was an inverse correlation between the changing rates of the average threshold and the subfoveal choroidal thickness at 6 months from baseline. Conclusion. The current data suggest that choroidal thickness at AZOOR-affected area significantly decreased with regression of AZOOR and this anatomical change correlated with the functional recovery.
• Clinical and histological evaluation of large macular hole surgery using the inverted internal limiting membrane flap technique

  Satoru Kase, Wataru Saito, Shohei Mori, Michiyuki Saito, Ryo Aando, Zhenyu Dong, Tomohiro Suzuki, Kousuke Noda, Susumu Ishida

  Clinical Ophthalmology 11 9 - 14 1177-5483 2017/01/01 [Refereed][Not invited]
   

  Purpose: The aims of this study were to analyze optical coherence tomography (OCT) imaging of large macular holes (MHs) treated with inverted internal limiting membrane (ILM) flap technique and to perform a histological examination of an ILM-like membrane tissue obtained during vitrectomy. Patients and methods: This is a retrospective observational case study. Nine patients, comprising of five males and four females, showing large and myopic MHs, underwent pars plana vitrectomy (PPV) with inverted ILM flap technique assisted by brilliant blue G (BBG) staining. Ophthalmological findings including visual acuity and OCT were investigated based on medical records. Formalin-fixed paraffin-embedded tissue section of an ILM-like membrane was submitted for immunohistochemistry with glial fibrillary acidic protein (GFAP). Results: ILM was clearly stained with BBG in eight patients, whereas the ILM in one case revealed no staining with BBG during PPV. Visual acuities improved to > 0.2 LogMAR in six patients. The complete closure of MH following PPV with inverted ILM technique was eventually achieved in all patients determined by OCT imaging (100%). Only one patient showed recovery of ellipsoid zone and interdigitation zone following the surgery. Elongation of outer nuclear layer was noted in three eyes. The ILM-like membrane not stained with BBG histologically revealed an amorphous structure admixed with GFAP-positive mononuclear cell infiltration. Conclusion: PPV with inverted ILM flap technique achieved 100% closure rates with favorable configuration at an initial surgery in large MHs. Our histopathological data also suggest that even BBG staining-negative membrane may be a useful material for autologous transplantation to the hole.
• Evaluation of the Safety and Tolerability of Conjunctival Ring for Posterior Segment of the Eye

  Satoshi Kinoshita, Takeshi Ohguchi, Kousuke Noda, Miyuki Murata, Shin-ichi Yasueda, Haruka Obata, Toru Matsunaga, Tsutomu Fukushima, Atsuhiro Kanda, Susumu Ishida

  CURRENT EYE RESEARCH 42 (8) 1149 - 1154 0271-3683 2017 [Refereed][Not invited]
   

  Purpose: To evaluate the safety and tolerability of conjunctival rings (CRs), a novel device for drug delivery to the posterior segment of the eye.Methods: In animal studies, CRs containing 5% dexamethasone sodium phosphate (DSP) or vehicle solution were placed on the right and left eyes of C57BL/6J mice, respectively. Contact lenses (CLs) containing vehicle solution were used as a control. Twenty-four hours after placement of the CRs, corneal fluorescein staining was graded based on the McDonald-Shadduck scoring system, ranging from 0 to 4. In humans, CRs containing vehicle solution were placed on the right eye of healthy volunteers for 9 hours. The corneal curvature, corneal thickness, intraocular pressure, visual acuity, tear production (Schirmer I test), tear film break-up time and fluorescein staining scores of the cornea (scores ranging from 0 to 3) and conjunctiva (scores ranging from 0 to 6) were assessed before and after wearing the CRs. The release characteristics of DSP from CRs were also evaluated.Results: In animal experiments, corneal fluorescein staining scores were 1 or less in all the groups, and there was no significant difference between the CR group and the CL group. In the preclinical safety evaluation of CR for humans, ophthalmic examination revealed that CR caused no significant changes in all the parameters investigated including corneal curvature (p = 0.77), corneal thickness (p = 0.96), intraocular pressure (p = 0.59), visual acuity (p = 0.14), Schirmer I test results (p = 0.76), tear film break-up time (p = 0.68), corneal fluorescein staining scores (p = 0.64), and conjunctival fluorescein staining scores (p = 0.52). The DSP release from CRs occurs within a few hours, which is similar to the drug-release property of medicated CL, as reported previously.Conclusions: The current data showed the safety and tolerability of CR as a drug delivery device for the treatment of posterior segment diseases.
• Relationship between choroidal thickness and visual impairment in multiple evanescent white dot syndrome

  Yuki Hashimoto, Wataru Saito, Michiyuki Saito, Yuka Hasegawa, Shohei Mori, Kousuke Noda, Susumu Ishida

  ACTA OPHTHALMOLOGICA 94 (8) E804 - E806 1755-375X 2016/12 [Refereed][Not invited]
  
• Invariant natural killer T cells play dual roles in the development of experimental autoimmune uveoretinitis

  Masashi Satoh, Ken-ichi Namba, Nobuyoshi Kitaichi, Noriko Endo, Hirokuni Kitamei, Daiju Iwata, Shigeaki Ohno, Susumu Ishida, Kazunori Onoe, Hiroshi Watarai, Masaru Taniguchi, Tatsuro Ishibashi, Joan Stein-Streilein, Koh-Hei Sonoda, Luc Van Kaer, Kazuya Iwabuchi

  EXPERIMENTAL EYE RESEARCH 153 79 - 89 0014-4835 2016/12 [Refereed][Not invited]
   

  Experimental autoimmune uveoretinitis (EAU) represents an experimental model for human endogenous uveitis, which is caused by Th1/Th17 cell-mediated inflammation. Natural killer T (NKT) cells recognize lipid antigens and produce large amounts of cytokines upon activation. To examine the role of NKT cells in the development of uveitis, EAU was elicited by immunization with a peptide from the human interphotoreceptor retinoid-binding protein (hIRBP(1-20)) in complete Freund's adjuvant and histopathology scores were evaluated in C57BL/6 (WT) and NKT cell-deficient mice. NKT cell-deficient mice developed more severe EAU pathology than WT mice. When WT mice were treated with ligands of the invariant subset of NKT cells (alpha-GalCer or RCAI-56), EAU was ameliorated in mice treated with RCAI-56 but not alpha-GalCer. IRBP-specific Thl/Th17 cytokines were reduced in RCAI-56-treated compared with vehicle-treated mice. Although the numbers of IRBP-specific T cells detected by hIRBP(3-13)/I-A(b) tetramers in the spleen and the draining lymph node were the same for vehicle and RCAI-56 treatment groups, ROR gamma t expression by tetramer-positive cells in RCAI-56-treated mice was lower than in control mice. Moreover, the eyes of RCAI-56-treated mice contained fewer IRBP-specific T cells compared with control mice. These results suggest that invariant NKT (iNKT) cells suppress the induction of Th17 cells and infiltration of IRBP-specific T cells into the eyes, thereby reducing ocular inflammation. However, in sharp contrast to the ameliorating effects of iNKT cell activation during the initiation phase of EAU, iNKT cell activation during the effector phase exacerbated disease pathology. Thus, we conclude that iNKT cells exhibit dual roles in the development of EAU. (C) 2016 Elsevier Ltd. All rights reserved.
• Choroidal circulation impairment during the anterior recurrence of Vogt-Koyanagi-Harada disease confirmed with indocyanine green angiography and laser speckle flowgraphy

  Yuko Takemoto, Kenichi Namba, Kazuomi Mizuuchi, Daiju Iwata, Tomoe Uno, Shigeaki Ohno, Kiriko Hirooka, Yuki Hashimoto, Wataru Saito, Kazuhisa Sugiyama, Susumu Ishida

  ACTA OPHTHALMOLOGICA 94 (7) E629 - E636 1755-375X 2016/11 [Refereed][Not invited]
   

  PurposeTo assess choroidal inflammation-related circulatory changes associated with the anterior recurrence of Vogt-Koyanagi-Harada (VKH) disease, using indocyanine green angiography (ICGA) and laser speckle flowgraphy (LSFG). MethodsThis retrospective case series included 17 eyes of 11 patients with VKH disease showing recurrent inflammatory findings in the anterior, but not posterior, segment (i.e. anterior recurrence). Indocyanine green angiography (ICGA) and LSFG were performed at the time of recurrence and one month after the initiation of corticosteroid therapy. The number and total area of hypofluorescent dark dots (HDDs) on ICGA were independently counted by three physicians and measured with ImageJ, respectively. Mean blur rate (MBR), a quantitative index of relative blood flow velocity, was calculated via the LSFG Analyzer software. ResultsHypofluorescent dark dots (HDDs) were identified on ICGA in 13 of 17 eyes (76%) with the anterior recurrence of VKH disease. The number and total area of HDDs significantly decreased from 203101 dots to 59 +/- 51 dots and from 48789 +/- 24251 pixels to 15664 +/- 13254 pixels, respectively. The change ratio of MBR significantly increased by 17.9 +/- 16.3% after the treatment. Importantly, there was no significant association between the change ratios of HDDs and MBR. ConclusionsThese findings on LSFG and ICGA clearly demonstrated subclinical involvement as well as post-treatment improvement of choroidal circulation impairment due to granulomatous inflammation in eyes with the anterior recurrence of VKH disease. The present data suggest the validity of using these two examinations, capable of detecting different circulatory changes, in the management of recurrent VKH disease.
• Modified 360-degree suture trabeculotomy combined with phacoemulsification and intraocular lens implantation for glaucoma and coexisting cataract

  Yasuhiro Shinmei, Riki Kijima, Takuya Nitta, Kan Ishijima, Takeshi Ohguchi, Shinki Chin, Susumu Ishida

  JOURNAL OF CATARACT AND REFRACTIVE SURGERY 42 (11) 1634 - 1641 0886-3350 2016/11 [Refereed][Not invited]
   

  PURPOSE: To assess the efficacy and safety of a modified 360-degree suture trabeculotomy combined with a cataract surgery technique in patients with glaucoma and coexisting cataract. SETTING: Hokkaido University Hospital, Sapporo, Japan. DESIGN: Retrospective case series. METHODS: Medical records of patients with glaucoma having a modified 360-degree trabeculotomy combined with cataract surgery (Group 1) were reviewed. Another group of patients who had the modified 360-degree suture trabeculotomy alone served as controls (Group 2). RESULTS: Both groups comprised 46 patients. In each group, eyes were diagnosed with primary angle-closure glaucoma in 2 eyes, primary open-angle glaucoma in 24 eyes, exfoliation glaucoma in 4 eyes, uveitic glaucoma in 15 eyes, and steroid glaucoma in 1 eye. The mean preoperative intraocular pressure (IOP) values were 27.2 mm Hg +/- 7.3 (SD) on 3.0 +/- 0.5 medications in Group 1 and 27.7 +/- 10.7 mm Hg on 2.9 +/- 0.6 medications in Group 2. Twelve months after surgery, the mean IOPs were 13.4 +/- 3.7 mm Hg on 0.8 +/- 1.1 medications in Group 1 and 13.9 +/- 4.1 mm Hg on 0.6 +/- 0.9 medications in Group 2. The success rate (<18 mm Hg) at 12 months was 89.1% and 93.5%, respectively. Major complications included transient IOP spikes (30.4% and 37.0%) and prolonged hyphema (10.9% and 6.5%) in Group 1 and Group 2, respectively. CONCLUSION: The data showed the equivalent effects of suture trabeculotomy combined with cataract surgery and suture trabeculotomy surgery alone on postoperative safety and efficacy.
• Effect of geranylgeranylacetone on the protection of retinal ganglion cells in a mouse model of normal tension glaucoma.

  Zhenyu Dong, Yasuhiro Shinmei, Yoko Dong, Saori Inafuku, Junichi Fukuhara, Ryo Ando, Nobuyoshi Kitaichi, Atsuhiro Kanda, Kohichi Tanaka, Kousuke Noda, Takayuki Harada, Shinki Chin, Susumu Ishida

  Heliyon 2 (10) e00191  2405-8440 2016/10 [Refereed][Not invited]
   

  Glaucoma is characterized by axonal degeneration of retinal ganglion cells (RGCs) and apoptotic death of their cell bodies, and lowering intraocular pressure is associated with an attenuation of progressive optic nerve damage. Nevertheless, intraocular pressure (IOP) reduction alone was not enough to inhibit the progression of disease, which suggests the contribution of other factors to the glaucoma pathogenesis. In this study, we investigated the cytoprotective effect of geranylgeranylacetone (GGA) on RGCs degeneration using a normal tension glaucoma (NTG) mouse model, which lacks glutamate/aspartate transporter (GLAST) and demonstrates spontaneous RGC and optic nerve degeneration without elevated intraocular pressure (IOP). Three-week-old GLAST+/- mice were given oral administration of GGA at 100, 300, or 600 mg/kg/day or vehicle alone, and littermate control mice were given vehicle alone for 14 days, respectively. At 5 weeks after birth, the number of RGCs was counted in paraffin sections of retinal tissues stained with hematoxylin and eosin. In addition, retrograde labeling technique was also used to quantify the number of RGC. Expression and localization of heat shock protein 70 (HSP70) in retinas were evaluated by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. Activities of caspase-9 and -3 in retinas were also assessed. The number of RGCs of GLAST+/- mice significantly decreased, as compared to that of control mice. RGC loss was significantly suppressed by administration of GGA at 600 mg/kg/day, compared with vehicle alone. Following GGA administration, HSP70 was significantly upregulated together with reduction in the activities of caspase-9 and -3. Our studies highlight HSP70 induction in the retina is available to suppress RGC degeneration, and thus GGA may be applicable for NTG as a promising therapy.
• Vitreous levels of vascular endothelial growth factor-B in proliferative diabetic retinopathy

  Satoshi Kinoshita, Kousuke Noda, Wataru Saito, Atsuhiro Kanda, Susumu Ishida

  ACTA OPHTHALMOLOGICA 94 (6) E521 - E523 1755-375X 2016/09 [Refereed][Not invited]
  
• Regulation of vascular endothelial growth factor-C by tumor necrosis factor- in the conjunctiva and pterygium

  Yoko Dong, Satoru Kase, Zhenyu Dong, Junichi Fukuhara, Yoshiaki Tagawa, Erdal Tan Ishizuka, Miyuki Murata, Yasuhiro Shinmei, Takeshi Ohguchi, Atsuhiro Kanda, Kousuke Noda, Susumu Ishida

  INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 38 (2) 545 - 550 1107-3756 2016/08 [Refereed][Not invited]
   

  Vascular endothelial growth factor C (VEGF-C) plays an important role in the development of a pterygium through lymphangiogenesis. We examined the association between VEGF-C and tumor necrosis factor- (TNF-) in the pathogenesis of pterygia. Cultured conjunctival epithelial cells were treated with TNF-, and the gene expression levels of VEGFC were evaluated by quantitative polymerase chain reaction (qPCR) and VEGF-C protein expression levels were measured using an enzyme-linked immunosorbent assay (ELISA). In addition, using ELISA, we evaluated the VEGF-C protein expression in the supernatants of cultured conjunctival epithelial cells, in which we neutralized TNF- using anti-TNF- antibody. The gene expression of tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), known as TNF receptor 1 (TNFR1), was confirmed using reverse transcription PCR in cultured conjunctival epithelial cells. Immunofluorescence microscopy was used to examine the localization of VEGF-C and TNFR1 in pterygium tissues and TNFR1 expression in cultured conjunctival epithelial cells. Immunohistochemistry was used to examine the localization of TNFR1 in pterygia and normal conjunctival tissues. VEGFC gene expression increased in cultured conjunctival epithelial cells 24 h after the addition of TNF-. The secretion of VEGF-C protein was significantly increased 48 h after the stimulation of cultured conjunctival epithelial cells with TNF-. Increased VEGF-C protein secretion stimulated by TNF- was significantly reduced by anti-TNF- neutralizing antibody treatment. In cultured conjunctival epithelial cells, TNFRSF1A and TNFR1 were expressed. TNFR1 was immunolocalized in normal conjunctival tissues and in human pterygium tissues as well as in VEGF-C-positive epithelial cells from human pterygia. Our data demonstrate that TNF- mediates VEGF-C expression, which plays a critical role in the pathogenesis of pterygia.
• Phosphorylation of alphaB-crystallin in epiretinal membrane of human proliferative diabetic retinopathy

  Yoko Dong, Zhenyu Dong, Satoru Kase, Ryo Ando, Junichi Fukuhara, Satoshi Kinoshita, Saori Inafuku, Yoshiaki Tagawa, Erdal Tan Ishizuka, Wataru Saito, Miyuki Murata, Atsuhiro Kanda, Kousuke Noda, Susumu Ishida

  INTERNATIONAL JOURNAL OF OPHTHALMOLOGY 9 (8) 1100 - 1105 2222-3959 2016/08 [Refereed][Not invited]
   

  AIM: To examine phosphorylation of alphaB-crystallin (p-alpha BC), a vascular endothelial growth factor (VEGF) chaperone, and immunohistochemically investigate relationship between p-alpha BC, VEGF and phosphorylated p38-mitogen-activated protein kinase (p-p38 MAPK) in the epiretinal membrane of human proliferative diabetic retinopathy (PDR). METHODS: Eleven epiretinal membranes of PDR surgically excised were included in this study. Two normal retinas were also collected from enucleation tissues due to choroidal melanoma. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with anti-p-alpha BC, VEGF, CD31, and p-p38 MAPK antibodies. RESULTS: Immunoreactivity for p-alpha BC was observed in all of the epiretinal membranes examined, where phosphorylation on serine (Ser) 59 showed strongest immunoreactivity in over 70% of the membranes. The immunolocalization of p-alpha BC was detected in the CD31-positive endothelial cells, and co-localized with VEGF and p-p38 MAPK in PDR membranes. Immunoreactivity for p-alpha BC, however, was undetectable in endothelial cells of the normal retinas, where p-p38 MAPK immunoreactivity was less marked than PDR membranes. CONCLUSION: Phosphorylation of alpha BC, in particular, phosphorylation on Ser59 by p-p38 MAPK may play a potential role as a molecular chaperon for VEGF in the pathogenesis of epiretinal membranes in PDR.
• Occult hypertensive choroidopathy: novel finding of suprachoroidal fluid

  Wataru Saito, Michiyuki Saito, Yuki Hashimoto, Susumu Ishida

  GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 254 (6) 1229 - 1231 0721-832X 2016/06 [Refereed][Not invited]
  
• Increased choroidal blood flow velocity with regression of acute posterior multifocal placoid pigment epitheliopathy

  Kiriko Hirooka, Wataru Saito, Michiyuki Saito, Yuki Hashimoto, Shohei Mori, Kousuke Noda, Susumu Ishida

  JAPANESE JOURNAL OF OPHTHALMOLOGY 60 (3) 172 - 178 0021-5155 2016/05 [Refereed][Not invited]
   

  Purpose To quantitatively examine changes in choroidal circulation hemodynamics in patients with acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Methods Retrospective observational case series. Five eyes of 3 APMPPE patients were included. In all APMPPE eyes, laser speckle flowgraphy was conducted to evaluate the mean blur rate (MBR), a quantitative index of relative blood flow velocity. The changes in MBR at the initial visit and after 3 and 6 months were statistically analyzed. In 2 eyes, enhanced depth imaging optical coherence tomography was used to measure central choroidal thickness. Results In all eyes, multiple subretinal placoid lesions spontaneously regressed with recovery of outer retinal morphology. The average MBR significantly increased at 3 and 6 months after baseline at the fovea by 49.6 and 54.2 % and at the lesion site by 65.2 and 70.8 %, respectively. These changes at both regions during the 6-month follow-up were statistically significant (P = 0.02 for each). The mean central choroidal thickness decreased with time (518.0 A mu m at baseline to 344.5 A mu m at 6 months). Conclusions Our data revealed the significant elevation of choroidal blood flow velocity and the substantial reduction of choroidal thickness with regression of APMPPE, suggesting that impaired choroidal circulation is involved in the pathogenesis of APMPPE.
• Continuous Intraocular Pressure Monitoring During Nocturnal Sleep in Patients With Obstructive Sleep Apnea Syndrome

  Yasuhiro Shinmei, Takuya Nitta, Hiroshi Saito, Takeshi Ohguchi, Riki Kijima, Shinki Chin, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 57 (6) 2824 - 2830 0146-0404 2016/05 [Refereed][Not invited]
   

  PURPOSE. To evaluate intraocular pressure (IOP) changes during nocturnal sleep in patients with obstructive sleep apnea syndrome (OSAS) using a contact lens sensor (CLS). METHODS. This was a prospective cohort study. Seven OSAS patients who had no ocular diseases except mild cataract were enrolled. Each subject underwent CLS-based continuous IOP monitoring on one eye simultaneously with overnight polysomnography. We classified the nocturnal IOP records into nonapnea IOP and apnea IOP, according to the duration of apnea events on polysomnography within each IOP measurement time of 30 seconds every 5 minutes. RESULTS. Differences between IOP levels during nonapnea and apnea phases were statistically analyzed. The mean apnea-hypopnea index, the total number of these events per hour of sleep, was 44.2 +/- 21.0, indicating the participants' severity of OSAS as moderate to severe. The mean range of IOP fluctuations during nocturnal sleep was 22.3 +/- 59.5 mV eq. All patients showed lower mean IOP levels during apnea events than during nonapnea phases, with statistically significant differences detected in four of the seven patients. On average, in all seven eyes, IOP values significantly decreased by 23.1 +/- 16.4 mV eq in association with apnea events. CONCLUSIONS. Obstructive apnea led to an immediate IOP decline during nocturnal sleep in patients with OSAS. Attention should be paid to IOP-independent etiology, such as episodic hypoxia, potentially linking OSAS and glaucoma.
• Choroidal thickening prior to anterior recurrence in patients with Vogt-Koyanagi-Harada disease

  Yoshiaki Tagawa, Kenichi Namba, Kazuomi Mizuuchi, Yuko Takemoto, Daiju Iwata, Tomoe Uno, Takako Fukuhara, Kiriko Hirooka, Nobuyoshi Kitaichi, Shigeaki Ohno, Susumu Ishida

  BRITISH JOURNAL OF OPHTHALMOLOGY 100 (4) 473 - 477 0007-1161 2016/04 [Refereed][Not invited]
   

  Aim To assess choroidal thickness changes associated with anterior segment recurrences in patients with Vogt-Koyanagi-Harada (VKH) disease using enhanced depth imaging optical coherence tomography (EDI-OCT). Methods EDI-OCT images were obtained periodically from 11 patients with VKH disease (22 eyes) who were followed-up due to anterior segment recurrences. Subfoveal choroidal thickness (SCT) values at the following stages were evaluated: (1) during the remission phase, (2) 1 month before detecting the anterior recurrence, (3) during the anterior recurrence and (4) after systemic prednisolone (PSL) treatment leading to remission. In comparison with SCT values in remission as baseline, the changing ratios of SCT were statistically analysed at subsequent three stages. Results The average of the SCT changing ratios compared with the remission phase significantly increased to 1.45 +/- 0.11 during anterior segment recurrences (p=0.00044) lacking any funduscopic signs of posterior involvement. Interestingly, the average SCT ratio 1 month before detecting the recurrence had already increased to 1.30 +/- 0.08 (p=0.002). After the PSL treatment, the ratio of SCT recovered to 0.95 +/- 0.03, which was equivalent to the remission level. However, in patients with their remission SCT values less than 240 mm, the SCT ratio did not increase significantly at any time points evaluated. Conclusions The choroid in eyes with VKH disease thickened in association with the anterior segment recurrence, and this thickening was observed prior to the recurrence. EDI-OCT may be useful for detecting latent choroidal inflammation in VKH disease, whereas it may not for patients with the relatively thin choroid.
• [Etiology of diabetic retinopathy].

  Noda K, Ishida S

  Nihon rinsho. Japanese journal of clinical medicine 74 Suppl 2 107 - 111 0047-1852 2016/04 [Refereed][Not invited]
  
• Diagnostic efficacy of cell block method for vitreoretinal lymphoma

  Satoru Kase, Kenichi Namba, Daiju Iwata, Kazuomi Mizuuchi, Nobuyoshi Kitaichi, Yoshiaki Tagawa, Hiromi Okada-Kanno, Yoshihiro Matsuno, Susumu Ishida

  DIAGNOSTIC PATHOLOGY 11 29  1746-1596 2016/03 [Refereed][Not invited]
   

  Background: Vitreoretinal lymphoma (VRL) is a life- and sight-threatening disorder. The aim of this study was to analyze the usefulness of the cell block method for diagnosis of VRL. Methods: Sixteen eyes in 12 patients with VRL, and 4 eyes in 4 patients with idiopathic uveitis presenting with vitreous opacity were enrolled in this study. Both undiluted vitreous and diluted fluids were isolated during micro-incision vitrectomy. Cell block specimens were prepared in 19 eyes from diluted fluid containing shredding vitreous. These specimens were then submitted for HE staining as well as immunocytological analyses with antibodies against the B-cell marker CD20, the T-cell marker CD3, and cell proliferation marker Ki67. Conventional smear cytology was applied in 14 eyes with VRL using undiluted vitreous samples. The diagnosis of VRL was made based on the results of cytology, concentrations of interleukin (IL)-10 and IL-6 in undiluted vitreous, and immunoglobulin heavy chain gene rearrangement analysis. Results: Atypical lymphoid cells were identified in 14 out of 15 cell block specimens of VRL (positive rate: 93.3 %), but in 5 out of 14 eyes in conventional smear cytology (positive rate: 35.7 %). Atypical lymphoid cells showed immunoreactivity for CD20 and Ki67. Seven cell block specimens were smear cytology-negative and cell block-positive. The cell block method showed no atypical lymphoid cells in any patient with idiopathic uveitis. Conclusions: Cell block specimens using diluted vitreous fluid demonstrated a high diagnostic sensitivity and a low pseudo-positive rate for the cytological diagnosis of VRL. The cell block method contributed to clear differentiation between VRL and idiopathic uveitis with vitreous opacity.
• Short Communication: Increase of Sialylated N-Glycansin Eyes with Neovascular Glaucoma Secondary to Proliferative Diabetic Retinopathy

  Saori Inafuku, Kousuke Noda, Maho Amano, Shin-Ichiro Nishimura, Susumu Ishida

  CURRENT EYE RESEARCH 41 (5) 721 - 724 0271-3683 2016 [Refereed][Not invited]
   

  Purpose: To investigate the alteration of N-glycans in the vitreous fluid of patients with neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy (PDR). Methods: Vitreous samples were collected from 18 patients with PDR (including 7 with NVG and 11 without NVG), and 17 patients without diabetes. Profiles of N-glycans were analyzed by glycoblotting-based high throughput protocol, which we recently developed. Protein levels of vascular endothelial growth factor (VEGF)-A were measured by ELISA. Results: The concentration of total N-glycans and the concentration of N-glycans with sialic acids were significantly higher in NVG group compared with those in non-NVG group or control group, whereas there was no significant difference in concentrations of high-mannose N-glycans among three groups. There was a moderate correlation between the concentrations of sialylated N-glycans and VEGF-A. Conclusions: Our data demonstrate the distinct changes of N-glycan profile and the increase of sialylated N-glycans in eyes with NVG secondary to PDR.
• A Case of Severe Panuveitis Associated with Psoriasis Vulgaris Successfully Treated with Infliximab

  Yuri Sakurai, Kenichi Namba, Kazuomi Mizuuchi, Toshihumi Nomura, Susumu Ishida

  Case Reports in Ophthalmology 7 (1) 191 - 194 1663-2699 2016 [Refereed][Not invited]
   

  Purpose: Uveitis associated with psoriasis vulgaris is usually seen as an anterior segment inflammation, and it is very rare that the inflammation extends to the posterior segment. We herein report a case of severe panuveitis associated with psoriasis vulgaris presenting as retinal neovascularization, leading to vitreous hemorrhages that were successfully treated with infliximab (IFX). Case Report: A 27-year-old male with psoriasis vulgaris was referred to our hospital due to prolonged severe uveitis OU. He showed a severe anterior chamber inflammation with fibrin formation and total posterior iris synechia OU. With topical corticosteroid treatment, these conditions were relieved for a short time however, the intraocular inflammation was exacerbated with vitreous hemorrhages caused by retinal neovascularization OS. After the administration of IFX therapy, the intraocular inflammation and retinal neovascularization was resolved, and so far, no severe recurrences have been seen for 3 years with the therapy. Conclusion: When we see patients with severe panuveitis associated with psoriasis extending to the posterior segment, IFX treatment may be a good therapeutic option.
• Receptor-associated prorenin system contributes to development of inflammation and angiogenesis in proliferative diabetic retinopathy.

  Kanda A, Ishida S

  Inflammation and regeneration 36 22  1880-9693 2016 [Refereed][Not invited]
  
• Ocular Behçet's disease is less complicated with allergic disorders. A nationwide survey in Japan

  Yukihiro Horie, Nobuyoshi Kitaichi, Kuniaki Hijioka, Koh-Hei Sonoda, Yoshitsugu Saishin, Takeshi Kezuka, Hiroshi Goto, Masaru Takeuchi, Satoshi Nakamura, Takashi Kimoto, Machiko Shimakawa, Mihori Kita, Sunao Sugita, Manabu Mochizuki, Junko Hori, Mitsuhiro Iwata, Jun Shoji, Masahide Fukuda, Toshikatsu Kaburaki, Jiro Numaga, Hidetoshi Kawashima, Astuki Fukushima, Takeshi Joko, Nanae Takai, Yoko Ozawa, Akira Meguro, Nobuhisa Mizuki, Kenichi Namba, Susumu Ishida, Shigeaki Ohno

  Clinical and Experimental Rheumatology 34 (6 Suppl 102) 111 - 114 1593-098X 2016 [Refereed][Not invited]
   

  Objective. Behçet's disease (BD) is a systemic inflammatory disorder polarised to the Th1 and Th17 immune systems. Allergic diseases are polarised to the Th2 immune system. The aim of the present study is to investigate the prevalence of allergic diseases in patients who have BD. Methods. The study involved a largescale interview survey of Japanese patients with BD at 21 institutes of ophthalmology 353 patients (255 males and 98 females) were recruited for this study. We analysed the history of allergic diseases such as atopic dermatitis (AD), allergic rhinitis (AR), bronchial asthma (BA) and drug/food allergies (FA). Results. Oral aphthous ulcers, ocular lesions, skin lesions, genital ulcers, arthritis, neurological lesions, intestinal lesions, deep vein thrombosis and epididymitis were reported in 95.8%, 98.6%, 72.5%, 44.8%, 13.9%, 6.8%, 6.2%, 3.7% and 1.4% of the patients, respectively. It was also reported that 73 patients (20.7%) had histories of allergic diseases: AD (5 cases, 1.4%), AR (36 cases, 10.2%), BA (19 cases, 5.4%) and FA (30 cases, 8.5%). This percentage was significantly lower than in a survey that Japan's Ministry of Health, Labour and Welfare conducted for healthy population (47.6%) (odds ratio = 0.29, 95% confidence interval = 0.22-0.38, p=4.9×10-22). Frequencies of posterior/pan-uveitis, relatively severe ocular findings, and visual prognosis were not affected by a history of allergic diseases in BD. Conclusion. Patients with BD had fewer complications from allergic diseases than did the entire population of Japan.
• A case of tuberculous endophthalmitis successfully treated with vitrectomy followed by antituberculous agents

  Keitaro Hase, Kenichi Namba, Wataru Saito, Shigeaki Ohno, Susumu Ishida

  Journal of Ophthalmic Inflammation and Infection 5 (1) 14  1869-5760 2015/12/01 [Refereed][Not invited]
   

  Background: Tuberculous endophthalmitis is very rare with only 18 reports published worldwide and only a few cases in Japan. We report a case of tuberculous endophthalmitis successfully treated with vitrectomy followed by antituberculous agents. Findings: An 81-year-old man was referred to us due to the exacerbation of vitreous opacity on his left eye(OS) after he had received the corticosteroid therapy. His best corrected visual acuity was light perception OS, and he had severe intraocular inflammation with fibrin formation in the anterior chamber and dense vitreous opacity. A chest CT showed miliary nodules indicating miliary tuberculosis, and pars plana vitrectomy was performed. Intraoperative observation showed that the vitreous cavity was filled by fibrin, and large elevated subretinal yellow-white lesions were present at the mid-periphery. The patient immediately received triple antituberculous agents orally, and Mycobacterium tuberculosis was detected in vitreous fluids. The intraocular inflammation gradually decreased, and the subretinal mass regressed within 2 weeks. Conclusions: We encountered a case of tuberculous endophthalmitis successfully treated with vitrectomy followed by antituberculous agents. If endophthalmitis is suspected in a patient with systemic tuberculosis infection, prompt vitrectomy along with the administration of antituberculous agents may be necessary.
• Aflibercept Traps Galectin-1, an Angiogenic Factor Associated with Diabetic Retinopathy

  Atsuhiro Kanda, Kousuke Noda, Wataru Saito, Susumu Ishida

  SCIENTIFIC REPORTS 5 17946  2045-2322 2015/12 [Refereed][Not invited]
   

  Vascular endothelial growth factor (VEGF)-A-driven angiogenesis contributes to various disorders including cancer and proliferative diabetic retinopathy (PDR). Among several VEGF-A blockers clinically used is aflibercept, a chimeric VEGFR1/VEGFR2-based decoy receptor fused to the Fc fragment of IgG1 (i.e., VEGFR1/VEGFR2-Fc). Here, we revealed a novel anti-angiogenic function for aflibercept beyond its antagonism against VEGF family members. Immunoprecipitation and mass spectrometry analyses identified galectin-1 as an aflibercept-interacting protein. Biolayer interferometry revealed aflibercept binding to galectin-1 with higher affinity than VEGFR1-Fc and VEGFR2-Fc, which was abolished by deglycosylation of aflibercept with peptide: N-glycosidase F. Retinal LGALS1/Galectin-1 mRNA expression was enhanced in vitro by hypoxic stimulation and in vivo by induction of diseases including diabetes. Galectin-1 immunoreactivity co-localized with VEGFR2 in neovascular tissues surgically excised from human eyes with PDR. Compared with non-diabetic controls, intravitreal galectin-1 protein levels were elevated in PDR eyes, showing no correlation with increased VEGF-A levels. Preoperative injection of bevacizumab, a monoclonal antibody to VEGF-A, reduced the VEGF-A, but not galectin-1, levels. Galectin-1 application to human retinal microvascular endothelial cells up-regulated VEGFR2 phosphorylation, which was eliminated by aflibercept. Our present findings demonstrated the neutralizing efficacy of aflibercept against galectin-1, an angiogenic factor associated with PDR independently of VEGF-A.
• Significant role of the choroidal outer layer during recovery from choroidal thickening in Vogt-Koyanagi-Harada disease patients treated with systemic corticosteroids

  Kiriko Hirooka, Wataru Saito, Kenichi Namba, Kazuomi Mizuuchi, Daiju Iwata, Yuki Hashimoto, Susumu Ishida

  BMC OPHTHALMOLOGY 15 181  1471-2415 2015/12 [Refereed][Not invited]
   

  Background: Which of the choroidal layers suffers the most extensive morphological changes during the course of Vogt-Koyanagi-Harada (VKH) disease is still unknown. The aim of this study was to investigate the relationship between total thickness and the thickness of inner or outer layers in the choroid during systemic corticosteroid therapy in patients with VKH disease. Methods: This retrospective case series included 15 eyes of 10 patients with treatment-naive VKH disease (4 men and 6 women; mean age, 41.4 +/- 14.7 years) received systemic corticosteroid therapy. Whole, inner, and outer choroidal thickness was measured manually at 1 week and at 1 and 3 months after initiation of systemic corticosteroid therapy using enhanced depth imaging optical coherence tomography. The mean thickness values of the layers were compared at each stage. Results: Compared with the 1-week baseline, the mean whole and outer choroidal layer thicknesses were significantly lower at 1 (P = 0.008 and 0.03, respectively) and 3 months (P = 0.008 and 0.02, respectively), whereas the inner layer did not significantly thin. Importantly, there was a significant positive correlation between the rates of change of whole and outer layer thickness from 1 week to 3 months (R = 0.9312, P < 0.0001), but not between the rates of whole and inner layer thickness changes. Conclusions: The thinning of total choroidal thickness observed after treatment with corticosteroids strongly correlated with outer layer thinning, suggesting that the choroidal outer layer is the primary target in acute-stage VKH disease.
• 多発消失性白点症候群における脈絡膜厚の経時的変化

  橋本 勇希, 齋藤 航, 齋藤 理幸, 廣岡 季里子, 森 祥平, 野田 航介, 石田 晋

  日本視能訓練士協会誌 (公社)日本視能訓練士協会 44 199 - 199 0387-5172 2015/12
• Measurement of interleukins in vitreous infusion fluid.

  Kase S, Yokoi M, Ishida S, Kase M

  Biomedical reports Spandidos Publications 3 (6) 818 - 820 2049-9434 2015/11 [Refereed][Not invited]
   

  Measurements of interleukin (IL)-6 and -10 concentrations in the vitreous can be used to differentiate intraocular lymphoma (IOL) from uveitis. This is the first study reporting the IL-6 and -10 concentrations in the undiluted vitreous fluid and vitreous infusion fluid, which were simultaneously examined in the patients. A total of 2 females presented with intraocular inflammation, and underwent pars plana vitrectomy. Undiluted anterior vitreous and vitreous infusion fluid were collected simultaneously. IL concentrations were determined by enzyme-linked immunosorbent assay systems. Vitreous infusion fluid of 20 ml was eventually collected following completion of core vitrectomy in the two patients. IL-6 concentrations of the first patient were 513 and 106 pg/ml in the undiluted vitreous and the infusion fluid, respectively, while those of the second patient were 263 and 29 pg/ml. By contrast, IL-10 was under the detectable levels in all the fluids. The IL-10/-6 ratio was <1 in both fluids in the patients. Cytological examination revealed the presence of reactive inflammatory cells in the vitreous fluid. The two patients were eventually diagnosed with uveitis. Measurements of IL concentrations in the vitreous infusion fluid provided significant evidence on the differential diagnosis between IOL and uveitis, when considering how vitreous infusion fluid was diluted. The present study highlighted a novel application of cytokine analyses using the vitreous infusion fluid, which may contribute to the development of future translational researches on uveitis/IOL patients.
• [Retinal Cell Biology and Molecular Targeting Therapy--Post-VEGF Era for Innovative Drug Development].

  Ishida S

  Nippon Ganka Gakkai zasshi 119 (11) 759 - 760 0029-0203 2015/11 [Refereed][Not invited]
  
• Pulse Waveform Changes in Macular Choroidal Hemodynamics With Regression of Acute Central Serous Chorioretinopathy

  Michiyuki Saito, Wataru Saito, Kiriko Hirooka, Yuki Hashimoto, Shohei Mori, Kousuke Noda, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 56 (11) 6515 - 6522 0146-0404 2015/10 [Refereed][Not invited]
   

  PURPOSE. To quantitatively evaluate the pulse waveform changes in macular choroidal blood flow by using laser speckle flowgraphy (LSFG) with regression of acute central serous chorioretinopathy (CSC). METHODS. This retrospective observational case series included 20 eyes of 20 patients with acute CSC. Laser speckle flowgraphy was performed at baseline and after 6 months. On the LSFG monochrome map, automatically divided 5 x 5 grid segments within the macula were classified into predominantly delayed filling (PDF) or minimally or no delayed filling (MDF) areas according to the degree of choroidal filling delay on early-phase indocyanine green angiography. The average mean blur rate (MBR) and the pulse waveform parameters, including the skew and blowout time (BOT), were compared between the total PDF and MDF areas during follow-up. RESULTS. The average MBR significantly decreased in both PDF (P = 0.005) and MDF (P < 0.001) areas during follow-up; in both areas, the skew decreased (P < 0.001 and P = 0.006, respectively) and BOT increased (P < 0.001 for each), showing significant reduction in vascular resistance at 6 months. The degree of the changes in the skew and BOT was significantly larger (P = 0.02 and P < 0.001, respectively) in the PDF area than in the MDF area. CONCLUSIONS. Changes in the skew and BOT, indices for vascular resistance, confirmed the involvement of circulatory disturbance at the acute stage of CSC. The present findings suggested that the pathogenesis of CSC stems from imbalanced distribution of choroidal blood flow due to augmented vascular resistance.
• Multiple evanescent white dot syndrome associated with retinal vasculitis

  Akihiro Takahashi, Wataru Saito, Yuki Hashimoto, Susumu Ishida

  International Medical Case Reports Journal 8 209 - 213 1179-142X 2015/09/21 [Refereed][Not invited]
   

  Purpose: A recent study revealed thickening of the inner retinal layers in acute stage of multiple evanescent white dot syndrome (MEWDS) however, the pathogenesis is still unknown. We report two cases with MEWDS whose funduscopy showed obvious retinal vasculitis. Methods: Case reports. Results: Healthy myopic 16- and 27-year-old women were the cases under study. In both cases, funduscopic examination revealed multiple, faint, small, subretinal white dots at the posterior pole to the midperiphery and macular granularity oculus dexter. Retinal vascular sheathing was also observed at midperiphery. Late-phase fluorescein angiography revealed leakages corresponding to the vascular sheathing. Enhanced depth imaging optical coherence tomography revealed the discontinuity of the ellipsoid zone corresponding to the white dots and increased macular choroidal thickness. One month later, these white dots and retinal sheathing spontaneously resolved in both cases. Three months later, impairments of the outer retinal morphology and the visual acuity were restored. Conclusion: These results suggest that retinal vasculitis possibly plays a role in the pathogenesis of thickened inner retinal layers in acute stage of MEWDS.
• Decreased choroidal blood flow velocity in the pathogenesis of multiple evanescent white dot syndrome

  Yuki Hashimoto, Wataru Saito, Michiyuki Saito, Kiriko Hirooka, Shohei Mori, Kousuke Noda, Susumu Ishida

  GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 253 (9) 1457 - 1464 0721-832X 2015/09 [Refereed][Not invited]
   

  On the basis of angiographic features, it is suggested that choroidal circulation disturbance may be involved in the pathogenesis of multiple evanescent white dot syndrome (MEWDS). The aim of this study is to quantitatively evaluate changes in choroidal circulation hemodynamics using laser speckle flowgraphy (LSFG) in patients with MEWDS. Twelve eyes of 12 patients with MEWDS and 12 unaffected fellow eyes as controls were included. The macular mean blur rate (MBR), a quantitative index of relative blood flow velocity in the choroid, was measured by LSFG. Sequential changes in the average MBR values at the macula with granular changes and the lesion area with white dots were analysed. Moreover, correlations between the MRR changing rate and initial visual functions were examined. Visual functions significantly improved 3 months after initial visit with accompanying improvements in outer retinal morphology. When compared with the baseline measurements, the MBR significantly increased at the macula of the affected eyes by 20.2 % and 13.0 % at 1 and 3 months respectively (P < 0.01 for both), while no significant change was detected in fellow eyes. Similarly, the MBR increased at the lesion area by 17.8 % and 12.0 % at 1 and 3 months respectively (P < 0.05 for both). Notably, the macular MBR elevation at 1 month was negatively correlated with both initial best-corrected visual acuity and the average threshold at the macula on Humphrey perimetry at baseline (R = -0.76, P = 0.003; R = -0.60, P = 0.03, respectively), suggesting a close link between initially reduced choroidal blood flow and functional abnormalities at the onset of MEWDS. These results, in concert with angiographic findings, are likely to reinforce the concept of choroidal circulation impairment as a predisposing factor for MEWDS.
• SRPK1/CK2阻害活性を有する新規血管新生阻害局所薬

  諸岡 諭, 伊藤 暢聡, 細谷 孝充, 野田 航介, 石田 晋, 萩原 正敏, 吉村 長久

  日本眼薬理学会プログラム・抄録集 日本眼薬理学会 35回 49 - 49 2015/09
• Identification of a Dual Inhibitor of SRPK1 and CK2 That Attenuates Pathological Angiogenesis of Macular Degeneration in Mice

  Satoshi Morooka, Mitsuteru Hoshina, Isao Kii, Takayoshi Okabe, Hirotatsu Kojima, Naoko Inoue, Yukiko Okuno, Masatsugu Denawa, Suguru Yoshida, Junichi Fukuhara, Kensuke Ninomiya, Teikichi Ikura, Toshio Furuya, Tetsuo Nagano, Kousuke Noda, Susumu Ishida, Takamitsu Hosoya, Nobutoshi Ito, Nagahisa Yoshimura, Masatoshi Hagiwara

  MOLECULAR PHARMACOLOGY 88 (2) 316 - 325 0026-895X 2015/08 [Refereed][Not invited]
   

  Excessive angiogenesis contributes to numerous diseases, including cancer and blinding retinopathy. Antibodies against vascular endothelial growth factor (VEGF) have been approved and are widely used in clinical treatment. Our previous studies using SRPIN340, a small molecule inhibitor of SRPK1 (serine-arginine protein kinase 1), demonstrated that SRPK1 is a potential target for the development of antiangiogenic drugs. In this study, we solved the structure of SRPK1 bound to SRPIN340 by X-ray crystallography. Using pharmacophore docking models followed by in vitro kinase assays, we screened a large-scale chemical library, and thus identified a new inhibitor of SRPK1. This inhibitor, SRPIN803, prevented VEGF production more effectively than SRPIN340 owing to the dual inhibition of SRPK1 and CK2 (casein kinase 2). In a mouse model of age-related macular degeneration, topical administration of eye ointment containing SRPIN803 significantly inhibited choroidal neovascularization, suggesting a clinical potential of SRPIN803 as a topical ointment for ocular neovascularization. Thus SRPIN803 merits further investigation as a novel inhibitor of VEGF.
• Alteration of N-Glycan Profiles in Diabetic Retinopathy

  Saori Inafuku, Kousuke Noda, Maho Amano, Tetsu Ohashi, Chikako Yoshizawa, Wataru Saito, Miyuki Murata, Atsuhiro Kanda, Shin-Ichiro Nishimura, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 56 (9) 5316 - 5322 0146-0404 2015/08 [Refereed][Not invited]
   

  PURPOSE. To investigate the alteration of vitreal N-glycans in patients with proliferative diabetic retinopathy (PDR). METHODS. Plasma and vitreous samples were collected from 17 patients (10 females and 7 males) with PDR (PDR group) and 17 nondiabetic patients (8 females and 9 males) with epiretinal membrane (ERM) and idiopathic macular hole (MH) (non-diabetes mellitus [DM] group). Profiles of N-glycans were analyzed by a glycoblotting-based high-throughput protocol that we recently developed. Human retinal microvascular endothelial cells (HRMECs) were cultivated with culture media containing either low glucose (5 mM) or high glucose (25 mM), and expression levels of sialyltransferases were analyzed by real-time PCR and ELISA. RESULTS. Amount of N-glycans in the vitreous fluid of the PDR group was significantly higher than that of the non-DM group (495.5 +/- 37.4 vs. 142.7 +/- 30.8 pmol/100 mu g protein, P < 0.005), whereas there was no significant difference in the plasma samples between the PDR and the non-DM group. In addition, profile analysis showed that N-glycans with sialic acids increased in the vitreous of the PDR group (328.4 +/- 25.8 pmol/100 mu g protein) compared to the non-DM group (92.1 +/- 21.2 pmol/100 mu g protein, P < 0.0005). Expression levels of sialyltransferases ST3GAL1 and ST3GAL4 were upregulated in the HRMECs after high-glucose stimulation. Consistent with the real-time PCR data, high-glucose stimulation elevated the protein levels of ST3GAL1 (117.4 +/- 14.9 pg/mg, P < 0.01) and ST3GAL4 (6.1 +/- 0.9 pg/mg, P < 0.05) in the HRMECs compared with the cells cultured with low-glucose culture media (ST3GAL1, 64.4 +/- 5.8 pg/mg; ST3GAL4, 3.8 +/- 0.3 pg/mg). CONCLUSIONS. Our data demonstrate distinct changes in the N-glycan profile and an increase in sialylated N-glycans in eyes with PDR.
• Changes in Inner and Outer Retinal Layer Thicknesses after Vitrectomy for Idiopathic Macular Hole: Implications for Visual Prognosis

  Yuki Hashimoto, Wataru Saito, Akio Fujiya, Chikako Yoshizawa, Kiriko Hirooka, Shohei Mori, Kousuke Noda, Susumu Ishida

  PLOS ONE 10 (8) e0135925  1932-6203 2015/08 [Refereed][Not invited]
   

  Purpose To investigate sequential post-operative thickness changes in inner and outer retinal layers in eyes with an idiopathic macular hole (MH). Methods Retrospective case series. Twenty-four eyes of 23 patients who had received pars plana vitrectomy (PPV) for the closure of MH were included in the study. Spectral domain optical coherence tomography C-scan was used to automatically measure the mean thickness of the inner and outer retinal layers pre-operatively and up to 6 months following surgery. The photoreceptor outer segment (PROS) length was measured manually and was used to assess its relationship with best-corrected visual acuity (BCVA). Results Compared with the pre-operative thickness, the inner layers significantly thinned during follow-up (P = 0.02), particularly in the parafoveal (P = 0.01), but not perifoveal, area. The post-operative inner layer thinning ranged from the ganglion cell layer to the inner plexiform layer (P = 0.002), whereas the nerve fiber layer was unaltered. Outer layer thickness was significantly greater post-operatively (P = 0.002), and especially the PROS lengthened not only in the fovea but also in the parafovea (P < 0.001). Six months after surgery, BCVA was significantly correlated exclusively with the elongated foveal PROS (R = 0.42, P = 0.03), but not with any of the other thickness parameters examined. Conclusions Following PPV for MH, retinal inner layers other than the nerve fiber layer thinned, suggestive of subclinical thickening in the inner layers where no cyst was evident pre-operatively. In contrast, retinal outer layer thickness significantly increased, potentially as a result of PROS elongation linking tightly with favorable visual prognosis in MH eyes.
• Increased choroidal blood flow velocity with regression of unilateral acute idiopathic maculopathy

  Yuki Hashimoto, Wataru Saito, Michiyuki Saito, Kiriko Hirooka, Shohei Mori, Kousuke Noda, Susumu Ishida

  JAPANESE JOURNAL OF OPHTHALMOLOGY 59 (4) 252 - 260 0021-5155 2015/07 [Refereed][Not invited]
   

  Purpose The pathogenesis of unilateral acute idiopathic maculopathy (UAIM) is unknown. The aim of this study was to quantitatively examine changes in choroidal circulation hemodynamics in patients with UAIM. Methods This was a retrospective observational case-series which included five eyes of four patients with UAIM. All UAIM eyes and the fellow eyes in remaining three patients were studied using laser speckle flowgraphy (LSFG) to evaluate the mean blur rate (MBR), a quantitative index of relative blood flow velocity. The changes in MBR between the initial visit and after 1 and 3 months were statistically analyzed. Subfoveal choroidal thickness was measured in three UAIM eyes by enhanced depth imaging optical coherence tomography. Results The mean logMAR value of best-corrected visual acuity in the UAIM eyes significantly improved (P = 0.04) with recovery of outer retinal morphology. The average MBR of the UAIM eyes significantly increased at 1 (+21.7 % baseline value; P = 0.003) and 3 months (+32.5 % baseline value; P = 0.001), whereas the fellow eyes did not show this tendency. The mean values of subfoveal choroidal thickness decreased with time (316.0 mu m at baseline, 186.6 mu m at 1 month, and 167.3 mu m at 3 months). Conclusions These results reveal that there is a significant elevation of choroidal blood flow velocity and substantial reduction of choroidal thickness with regression of UAIM, suggesting that impaired choroidal circulation may be involved in the pathogenesis of UAIM.
• Increased vascular endothelial growth factor level in the subretinal fluid of eye with vasoproliferative retinal tumors

  Akio Fujiya, Kousuke Noda, Shiho Yoshida, Wataru Saito, Susumu Ishida

  Retinal Cases and Brief Reports 9 (2) 154 - 156 1937-1578 2015/04/06 [Refereed][Not invited]
   

  Purpose: To describe a level of vascular endothelial growth factor (VEGF) in the subretinal fluid obtained from a case with vasoproliferative retinal tumors (VPRTs). Methods: A 30-year-old male patient presented with VPRTs subsequent to longstanding rhegmatogenous retinal detachment. Results: The patient was treated with encircling scleral buckling, cryopexy, and intravitreal bevacizumab injection. The protein level of VEGF in the subretinal fluid was measured and compared with those in the subretinal fluid obtained from patients with rhegmatogenous retinal detachment. Vascular endothelial growth factor level in the subretinal fluid from a patient with VPRTs was 12,997.9 pg/mL, whereas the mean VEGF concentration in the subretinal fluid from 4 patients with rhegmatogenous retinal detachment was 2.1 ± 2.8 pg/mL. Conclusion: The current data provide the evidence that VEGF production has increased in eyes with VPRTs and anti-VEGF therapy is theoretically effective for the treatment of VPRTs.
• Relationship between choroidal blood flow velocity and choroidal thickness during systemic corticosteroid therapy for Vogt-Koyanagi-Harada disease

  Kiriko Hirooka, Wataru Saito, Kenichi Namba, Yuko Takemoto, Kazuomi Mizuuchi, Tomoe Uno, Yoshiaki Tagawa, Yuki Hashimoto, Susumu Ishida

  GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 253 (4) 609 - 617 0721-832X 2015/04 [Refereed][Not invited]
   

  To investigate the relationship between circulation hemodynamics and morphology in the choroid during systemic corticosteroid therapy for patients with Vogt-Koyanagi-Harada (VKH) disease. This retrospective case series includes 18 eyes of nine patients with VKH disease (two men and seven women; average age, 40.8 years) who received systemic corticosteroid therapy. Laser speckle flowgraphy (LSFG) and enhanced-depth imaging optical coherence tomography (EDI-OCT) were performed before treatment and at 1 week and 1 and 3 months after treatment. The average values of the mean blur rate (MBR) at the macula and the central choroidal thickness (CCT) were compared at each stage. The changing rates of the average MBR significantly increased at all examinations after the start of treatment compared with the pre-treatment value with resolution of serous retinal detachment (SRD) (P = 0.0002 for all). The CCT decreased significantly at all examinations after the start of treatment compared with the pre-treatment value (P = 0.0002 for all). Changes in MBR and CCT during the 3-month follow-up period correlated significantly (R = -0.5913, P = 0.0097). The best-corrected visual acuity at pre-treatment correlated significantly with the changing rate of the MBR from 0 to 3 months (R = 0.5944, P = 0.0093) but not with CCT. Our data suggest that circulatory disturbances and increased thickness of the choroid relate to the pathogenesis of VKH disease with link mutually. LSFG is useful as an index for evaluating the choroiditis activity of VKH disease as well as EDI-OCT.
• ATP6AP2/(Pro)renin Receptor Contributes to Glucose Metabolism via Stabilizing the Pyruvate Dehydrogenase E1 beta Subunit

  Atsuhiro Kanda, Kousuke Noda, Susumu Ishida

  JOURNAL OF BIOLOGICAL CHEMISTRY 290 (15) 9690 - 9700 0021-9258 2015/04 [Refereed][Not invited]
   

  Aerobic glucose metabolism is indispensable for metabolically active cells; however, the regulatory mechanism of efficient energy generation in the highly evolved mammalian retina remains incompletely understood. Here, we revealed an unsuspected role for (pro)renin receptor, also known as ATP6AP2, in energy metabolism. Immunoprecipitation and mass spectrometry analyses identified the pyruvate dehydrogenase (PDH) complex as Atp6ap2-interacting proteins in the mouse retina. Yeast two-hybrid assays demonstrated direct molecular binding between ATP6A P2 and the PDH El 13 subunit (PDHB). Pdhb immunoreactivity co-localized with Atp6ap2 in multiple retinal layers including the retinal pigment epithelium (RPE). A TP6AP2 knockdown in RPE cells reduced PDH activity, showing a predilection to anaerobic glycolysis. ATP6AP2 protected PDHB from phosphorylation, thus controlling its protein stability. Down-regulated PDH activity due to ATP6AP2 knockdown inhibited glucose-stimulated oxidative stress in RPE cells. Our present data unraveled the novel function of ATP6AP2/(P)RR as a PDHB stabilizer, contributing to aerobic glucose metabolism together with oxidative stress.
• Acute Zonal Occult Outer Retinopathy in Japanese Patients: Clinical Features, Visual Function, and Factors Affecting Visual Function

  Saho Saito, Wataru Saito, Michiyuki Saito, Yuki Hashimoto, Shohei Mori, Kousuke Noda, Kenichi Namba, Susumu Ishida

  PLOS ONE 10 (4) e0125133  1932-6203 2015/04 [Refereed][Not invited]
   

  Purpose To evaluate the clinical features and investigate their relationship with visual function in Japanese patients with acute zonal occult outer retinopathy (AZOOR). Methods Fifty-two eyes of 38 Japanese AZOOR patients (31 female and 7 male patients; mean age at first visit, 35.0 years; median follow-up duration, 31 months) were retrospectively collected: 31 untreated eyes with good visual acuity and 21 systemic corticosteroid-treated eyes with progressive visual acuity loss. Variables affecting the logMAR values of best-corrected visual acuity (BCVA) and the mean deviation (MD) on Humphrey perimetry at initial and final visits were examined using multiple stepwise linear regression analysis. Results In untreated eyes, the mean MD at the final visit was significantly higher than that at the initial visit (P = 0.00002). In corticosteroid-treated eyes, the logMAR BCVA and MD at the final visit were significantly better than the initial values (P = 0.007 and P = 0.02, respectively). The final logMAR BCVA was 0.0 or less in 85% of patients. Variables affecting initial visual function were moderate anterior vitreous cells, myopia severity, and a-wave amplitudes on electroretinography; factors affecting final visual function were the initial MD values, female sex, moderate anterior vitreous cells, and retinal atrophy. Conclusions Our data indicated that visual functions in enrolled patients significantly improved spontaneously or after systemic corticosteroids therapy, suggesting that Japanese patients with AZOOR have good visual outcomes during the follow-up period of this study. Furthermore, initial visual field defects, gender, anterior vitreous cells, and retinal atrophy affected final visual functions in these patients.
• Macular thickness changes in a patient with Leber's hereditary optic neuropathy

  Ayako Mizoguchi, Yuki Hashimoto, Yasuhiro Shinmei, Mayo Nozaki, Kan Ishijima, Yoshiaki Tagawa, Susumu Ishida

  BMC OPHTHALMOLOGY 15 27  1471-2415 2015/03 [Refereed][Not invited]
   

  Background: Leber's hereditary optic neuropathy (LHON) refers to an optic nerve dysfunction due to mutations in the mitochondrial DNA, resulting in visual loss by apoptosis of retinal ganglion cells (RGC). In 20% of LHON cases, their fundus examination looks entirely normal at early stage. There are some reports regarding the circumpapillary retinal nerve fiber layer (cpRNFL) and the ganglion cell analysis around the macula in LHON patients and carriers by using optical coherence tomography. Case presentation: A 40-year-old female complained of acute visual loss in both eyes. Her best-corrected visual acuity was 0.3 in the right eye and 0.2 in the left eye at the initial visit. Goldmann perimetry revealed bilateral central scotomas. Fundus examination and fluorescein angiography findings were normal, but decreased retinal inner layer thickness was detected around the macular area on spectral domain optical coherence tomography (SD-OCT). One month later, her visual acuity deteriorated to counting fingers in both eyes, and the thinning area of retinal inner layer spread rapidly. Suspected progressive RGC loss led us to check the possibility of LHON, with which the patient was diagnosed due to a positive result for the mitochondrial DNA (mtDNA) 11778 mutation. The ganglion cell complex (GCC) and cpRNFL thicknesses were observed for 24 months by using SD-OCT. The GCC thickness plunged sharply within 3 months followed by gradual decline until 6 months, thereafter showing a plateau up to 24 months. On the cpRNFL map, the temporal quadrant also showed the earliest thinning as seen in the macular area of the GCC map. The thicknesses of the superior, nasal, and inferior quadrants decreased gradually, keeping their normal ranges up to 6 months. Conclusions: SD-OCT was a useful tool in the diagnosis and follow-up of LHON. The macular GCC thickness map may detect the earliest morphological changes in LHON, as well as the temporal area of cpRNFL, before funduscopic examination reveals optic nerve atrophy.
• Single center study on ethnic and clinical features of Behcet's disease in Moscow, Russia

  Anton Lennikov, Zemfira Alekberova, Regina Goloeva, Nobuyoshi Kitaichi, Lev Denisov, Kenichi Namba, Mitsuhiro Takeno, Yoshiaki Ishigatsubo, Nobuhisa Mizuki, Eugeny Nasonov, Susumu Ishida, Shigeaki Ohno

  CLINICAL RHEUMATOLOGY 34 (2) 321 - 327 0770-3198 2015/02 [Refereed][Not invited]
   

  For the purpose of investigating Behcet's disease (BD) in Russia, 250 consecutive patients (177 men and 73 women) diagnosed with BD between 1990 and 2010 at the Research Institute of Rheumatology, Russian Academy of Medical Sciences in Moscow were enrolled in this study. The ethnic backgrounds of the patients were reported as follows: 23.2 % (58 cases) from Russia, 12.8 % (32 cases) from Azerbaijan, 14.4 % (36 cases) from Armenia, 8.8 % (22 cases) from Chechnya, and 21.6 % (55 cases) from Dagestan. The remaining 19.2 % (48 cases) were from other regions or of unknown origin. More than half (57.6 %) of the Behcet's disease patients originated from Central Asia, specifically Azerbaijan, Armenia, Chechnya, and Dagestan. The mean age at disease onset was 31.5 +/- 9.38 (13-60) years old, and the most typical initial manifestations were oral aphthous ulcers. Patients aged 20-39 years old were more commonly affected and displayed a wide clinical spectrum of the disease, with varieties of severe internal organ involvement. The manifestations observed throughout the course of the disease included oral aphthous ulcers (100 %), various cutaneous lesions (88.8 %), genital ulcers (81.2 %), and ocular lesions (54.0 %). Besides these, many organs/systems were implicated in patient cases, namely joint (53.2 %), vascular (25.2 %), neurological (8.0 %), gastrointestinal (25.2 %), and cardiac (5.6 %) systems. Involvements of ocular (p < 0.01) and skin (p < 0.01) lesions were more frequent in men than in women. HLA-B51 and HLA-A26 typing was performed in 127 patients and 508 healthy controls. HLA-B51 was found in 63.0 % of BD patients compared to 20.7 % of the healthy control subjects (p < 0.001), and HLA-A26 was present in 11.3 % of BD patients and 18.9 % of the control group. This study shows the presence of BD in Russia, and it is suggested that its prevalence in Central Asian people is much higher than that in White Russian.
• Single center study on ethnic and clinical features of Behcet's disease in Moscow, Russia.

  Anton Lennikov, Zemfira Alekberova, Regina Goloeva, Nobuyoshi Kitaichi, Lev Denisov, Kenichi Namba, Mitsuhiro Takeno, Yoshiaki Ishigatsubo, Nobuhisa Mizuki, Eugeny Nasonov, Susumu Ishida, Shigeaki Ohno

  Clinical rheumatology 34 (2) 321 - 7 1434-9949 2015/02 [Refereed][Not invited]
   

  For the purpose of investigating Behcet's disease (BD) in Russia, 250 consecutive patients (177 men and 73 women) diagnosed with BD between 1990 and 2010 at the Research Institute of Rheumatology, Russian Academy of Medical Sciences in Moscow were enrolled in this study. The ethnic backgrounds of the patients were reported as follows: 23.2% (58 cases) from Russia, 12.8% (32 cases) from Azerbaijan, 14.4% (36 cases) from Armenia, 8.8% (22 cases) from Chechnya, and 21.6% (55 cases) from Dagestan. The remaining 19.2% (48 cases) were from other regions or of unknown origin. More than half (57.6%) of the Behcet's disease patients originated from Central Asia, specifically Azerbaijan, Armenia, Chechnya, and Dagestan. The mean age at disease onset was 31.5 ± 9.38 (13-60) years old, and the most typical initial manifestations were oral aphthous ulcers. Patients aged 20-39 years old were more commonly affected and displayed a wide clinical spectrum of the disease, with varieties of severe internal organ involvement. The manifestations observed throughout the course of the disease included oral aphthous ulcers (100%), various cutaneous lesions (88.8%), genital ulcers (81.2%), and ocular lesions (54.0%). Besides these, many organs/systems were implicated in patient cases, namely joint (53.2%), vascular (25.2%), neurological (8.0%), gastrointestinal (25.2%), and cardiac (5.6%) systems. Involvements of ocular (p < 0.01) and skin (p < 0.01) lesions were more frequent in men than in women. HLA-B51 and HLA-A26 typing was performed in 127 patients and 508 healthy controls. HLA-B51 was found in 63.0% of BD patients compared to 20.7% of the healthy control subjects (p < 0.001), and HLA-A26 was present in 11.3% of BD patients and 18.9% of the control group. This study shows the presence of BD in Russia, and it is suggested that its prevalence in Central Asian people is much higher than that in White Russian.
• Involvement of the Receptor-Associated Prorenin System in the Pathogenesis of Human Conjunctival Lymphoma

  Erdal Tan Ishizuka, Atsuhiro Kanda, Satoru Kase, Kousuke Noda, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 56 (1) 74 - 80 0146-0404 2015/01 [Refereed][Not invited]
   

  PURPOSE. Extranodal marginal zone B-cell lymphoma (EMZL) is the most common subtype of conjunctival lymphoma, though its molecular mechanisms of pathogenesis are largely unknown. We attempted to explore the association of the renin-angiotensin system (RAS) and (pro) renin receptor ([P] RR) in the pathogenesis of conjunctival lymphoma. METHODS. Surgically removed conjunctiva EMZL samples were used for gene expression, and immunohistochemical and immunofluorescence analyses of (P) RR and RAS components. Human B-lymphoblast IM-9 cells were treated with prorenin or angiotensin II (Ang II), and gene expression levels were analyzed using real-time quantitative PCR (qPCR). In addition, immunofluorescence analysis of EMZL samples was used to evaluate the in vivo expression of those components. RESULTS. Gene expression and immunohistochemical analyses revealed the expression of RAS components, including (P) RR and angiotensin II type 1 receptor (AT1R), in EMZL tissues. Double-labeling analyses demonstrated that (P) RR and AT1R were detected in cells positive for CD20, a marker for B-cells, where they colocalized with prorenin and angiotensinogen, respectively. Prorenin stimulation of human B-lymphoblast IM-9 cells increased mRNA expression levels of fibroblast growth factor 2 (FGF2), while angiotensin II treatment upregulated the expression levels of basigin (BSG), matrix metallopeptidase (MMP) 2, 9, and 14, which were abolished by (P) RR and AT1R blockades, respectively. Immunofluorescence analyses of clinical samples showed colocalizations of (P) RR and AT1R with the products of these upregulated genes. CONCLUSIONS. The present study suggests that activation of (P) RR and AT1R is associated with the pathogenesis of conjunctival EMZL by stimulating the production of FGF2 and MMPs.
• A case of mature natural killer-cell neoplasm manifesting multiple choroidal lesions: Primary intraocular natural killer-cell lymphoma

  Yoshiaki Tagawa, Reiki Ogasawara, Hiromi Kanno, Susumu Ishida, Kenichi Namba

  Case Reports in Ophthalmology 6 (3) 380 - 384 1663-2699 2015 [Refereed][Not invited]
   

  Purpose: Natural killer (NK) cell neoplasm is a rare disease that follows an acute course and has a poor prognosis. It usually emerges from the nose and appears in the ocular tissue as a metastasis. Herein, we describe a case of NK-cell neoplasm in which the eye was considered to be the primary organ. Case: A 50-year-old female displayed bilateral anterior chamber cells, vitreous opacity, bullous retinal detachment, and multiple white choroidal mass lesions. Although malignant lymphoma or metastatic tumor was suspected, various systemic examinations failed to detect any positive results. A vitrectomy was performed OS however, histo-cytological analyses from the vitreous sample showed no definite evidence of malignancy, and IL-10 concentration was low. Enlarged choroidal masses were fused together. Three weeks after the first visit, the patient suddenly developed an attack of fever, night sweat, and hepatic dysfunction, and 5 days later, she passed away due to multiple organ failure. Im-munohistochemisty and in situ hybridization revealed the presence of atypical cells positive for CD3, CD56, and Epstein-Barr virus-encoded RNAs, resulting in the diagnosis of NK-cell neoplasm. With the characteristic clinical course, we concluded that this neoplasm was a primary intraocular NK-cell lymphoma. Conclusions: This is the first report to describe primary intraocular NK-cell neoplasm. When we encounter atypical choroidal lesions, we should consider the possibility of NK-cell lymphoma, even though it is a rare disease.
• Enhanced-depth Imaging Optical Coherence Tomography and Laser Speckle Flowgraphy in a Patient with Acute Macular Neuroretinopathy

  Kiriko Hirooka, Wataru Saito, Kousuke Noda, Susumu Ishida

  OCULAR IMMUNOLOGY AND INFLAMMATION 22 (6) 485 - 489 0927-3948 2014/12 [Refereed][Not invited]
  
• Amelioration of experimental autoimmune uveoretinitis by inhibition of glyceraldehyde-derived advanced glycation end-product formation

  Zhenyu Dong, Daiju Iwata, Nobuyoshi Kitaichi, Masayoshi Takeuchi, Masashi Sato, Noriko Endo, Kazuya Iwabuchi, Ryo Ando, Junichi Fukuhara, Satoshi Kinoshita, Anton Lennikov, Mizuki Kitamura, Kazuomi Mizuuchi, Atsuhiro Kanda, Kousuke Noda, Kenichi Namba, Sho-Ichi Yamagishi, Shigeaki Ohno, Susumu Ishida

  JOURNAL OF LEUKOCYTE BIOLOGY 96 (6) 1077 - 1085 0741-5400 2014/12 [Refereed][Not invited]
   

  Formation of glyceraldehyde-derived advanced glycation endoproducts contributes to the pathogenesis of endogenous uvetitis in human and animals. AGEs are permanently modified macromolecule derivatives that form through nonenzymatic glycation of amino groups of proteins. Glycer-AGEs are highly toxic and play an important role in the pathogenesis of chronic inflammatory diseases. However, the contribution of glycer-AGEs to the pathogenesis of uveitis is unclear. In this study, we measured serum levels of glycer-AGEs in 100 patients with endogenous uveitis (22 with HLA-B27-associated uveitis, 20 with VKH disease, 14 with Behcet's disease, and 44 with sarcoidosis) and 33 healthy volunteers. We then examined the effect of the AGE inhibitor in a mouse model of human endogenous uveitis (EAU) by continuous oral administration of pyridoxamine at 200 or 400 mg/kg/day. Regardless of the etiology, serum glycer-AGE levels were significantly higher in patients with uveitis than in healthy subjects. Treatment with 400 mg/kg pyridoxamine significantly reduced the clinical and histological severity of EAU and was accompanied by a significant decrease in serum and retinal glycer-AGE levels and suppression of translocation of NF-B p65 into the nucleus of retinal cells. Serum glycer-AGE levels may therefore serve as a biomarker of human uveitis, as well as systemic inflammation, and may contribute to the progression of uveitis, including diabetic iritis, via the activation of NF-B.
• Retinal outer layer thickness increases with regression of multiple evanescent white dot syndrome and visual improvement positively correlates with photoreceptor outer segment length

  Yuki Hashimoto, Wataru Saito, Michiyuki Saito, Kiriko Hirooka, Chikako Yoshizawa, Kousuke Noda, Susumu Ishida

  ACTA OPHTHALMOLOGICA 92 (7) e591 - e592 1755-375X 2014/11 [Refereed][Not invited]
  
• Genistein attenuates choroidal neovascularization

  Satoshi Kinoshita, Kousuke Noda, Yoshiaki Tagawa, Saori Inafuku, Yoko Dong, Junichi Fukuhara, Zhenyu Dong, Ryo Ando, Atsuhiro Kanda, Susumu Ishida

  JOURNAL OF NUTRITIONAL BIOCHEMISTRY 25 (11) 1177 - 1182 0955-2863 2014/11 [Refereed][Not invited]
   

  Genistein is a dietary-derived flavonoid abundantly present in soybeans and known to possess various biological effects including anti-inflammation and anti-angiogenic activity. To investigate the effects of genistein on intraocular neovascularization, we used an animal model of laser-induced choroidal neovascularization (CNV). Male C57BL/6J mice were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. CNV was induced by laser photocoagulation. The animals were fed a mixture diet containing 0.5% genistein or a control diet ad libitum for 7 days before laser photocoagulation and the treatment was continued until the end of the study. Seven days after laser injury, the size of CNV lesions was quantified. Retinal pigment epithelium (RPE)-choroid complex was also harvested 1 or 3 days after laser injury and the level of monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and matrix metalloproteinase (MMP)-9 were measured by enzyme-linked immunosorbent assay. Expression levels of Ets-1 and F4/80 were examined by real-time PCR. A significant decrease in CNV size was observed in animals treated with genistein (15441.9+/-1511.8 mu m(2)) compared to control mice (21074.0+/-1940.7 mu m(2), P<.05). Genistein significantly reduced the protein level of MCP-1, ICAM-1, and MMP-9 in the RPE-choroid complex (P<.05). In addition, genistein suppressed the expression levels of Ets-1 and F4/80 (P<.05). The current data indicate the anti-angiogenic property of genistein during CNV formation. (C) 2014 Elsevier Inc. All rights reserved.
• Acquired focal choroidal excavation associated with multiple evanescent white dot syndrome: observations at onset and a pathogenic hypothesis

  Yuki Hashimoto, Wataru Saito, Kousuke Noda, Susumu Ishida

  BMC Ophthalmology 14 135  1471-2415 2014/11 [Refereed][Not invited]
   

  Background: The mechanism underlying focal choroidal excavation (FCE) remains largely unknown. We evaluated the sequential progression of FCE generation using enhanced depth imaging optical coherence tomography (EDI-OCT) in a patient with multiple evanescent white dot syndrome (MEWDS). Case presentation: A 37-year-old woman suffered MEWDS in the right eye. EDI-OCT showed the loss of photoreceptor inner segment/outer segment junction line, detachment between the retinal pigment epithelium (RPE) and Bruch's membrane, and dome-shaped, moderately reflective, focal photoreceptor-layer lesions corresponding to perifoveal white dots. The region with pigment epithelium detachment involved RPE/Bruch's membrane ruptures. After 1 month, almost all white dots spontaneously resolved together with improvements of the perifoveal OCT findings. Interestingly, perifoveal region developed a conforming-type FCE. An abnormal hyper-reflective lesion on OCT, regarded as fibrosis formation, simultaneously appeared within the choroid below the FCE and subsequently increased in size. Conclusions: These results suggest that the RPE/Bruch's membrane disruption due to chorioretinal abnormalities and subsequent intrachoroidal scar formation play a role in the pathogenesis on an acquired FCE.
• 多発消失性白点症候群における脈絡膜厚の経時的変化

  橋本 勇希, 齋藤 航, 齋藤 理幸, 廣岡 季里子, 森 祥平, 野田 航介, 石田 晋

  日本視能矯正学会プログラム抄録集 日本視能矯正学会 55回 46 - 46 2014/11
• Impaired Circulation in the Thickened Choroid of a Patient with Serpiginous Choroiditis

  Ai Takahashi, Wataru Saito, Yuki Hashimoto, Michiyuki Saito, Susumu Ishida

  OCULAR IMMUNOLOGY AND INFLAMMATION 22 (5) 409 - 413 0927-3948 2014/10 [Refereed][Not invited]
  
• [Japan phase 3 study of pegaptanib sodium in patients with diabetic macular edema].

  Ishibashi T, Yuzawa M, Yoshimura N, Ohji M, Ishida S, Isogawa N, Esaka E

  Nippon Ganka Gakkai zasshi 118 (9) 773 - 782 0029-0203 2014/09 [Refereed][Not invited]
  
• Intertypic modular exchanges of genomic segments by homologous recombination at universally conserved segments in human adenovirus species D

  Gabriel Gonzalez, Kanako O. Koyanagi, Koki Aoki, Nobuyoshi Kitaichi, Shigeaki Ohno, Hisatoshi Kaneko, Susumu Ishida, Hidemi Watanabe

  GENE 547 (1) 10 - 17 0378-1119 2014/08 [Refereed][Not invited]
   

  Human adenovirus species D (HAdV-D), which is composed of clinically and epidemiologically important pathogens worldwide, contains more taxonomic "types" than any other species of the genus Mastadenovirus, although the mechanisms accounting for the high level of diversity remain to be disclosed. Recent studies of known and new types of HAdV-D have indicated that intertypic recombination between distant types contributes to the increasing diversity of the species. However, such findings raise the question as to how homologous recombination events occur between diversified types since homologous recombination is suppressed as nucleotide sequences diverge. In order to address this question, we investigated the distribution of the recombination boundaries in comparison with the landscape of intergenomic sequence conservation assessed according to the synonymous substitution rate (d(s)). The results revealed that specific genomic segments are conserved between even the most distantly related genomes; we call these segments "universally conserved segments" (UCSs). These findings suggest that UCSs facilitate homologous recombination, resulting in intergenomic segmental exchanges of UCS-flanking genomic regions as recombination modules. With the aid of such a mechanism, the haploid genomes of HAdV-Ds may have been reshuffled, resulting in chimeric genomes out of diversified repertoires in the HAdV-D population analogous to the MHC region reshuffled via crossing over in vertebrates. In addition, some HAdVs with chimeric genomes may have had the opportunity to avoid host immune responses thereby causing epidemics. (C) 2014 Elsevier B.V. All rights reserved.
• A comparison of N-glycan profiles in human plasma and vitreous fluid

  Saori Inafuku, Kousuke Noda, Maho Amano, Tetsu Ohashi, Chikako Yoshizawa, Wataru Saito, Atsuhiro Kanda, Shin-Ichiro Nishimura, Susumu Ishida

  GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 252 (8) 1235 - 1243 0721-832X 2014/08 [Refereed][Not invited]
   

  To investigate the concentration and composition of N-glycans in plasma and vitreous samples obtained from patients with non-proliferative vitreoretinal diseases. Plasma and vitreous samples were collected from 11 patients with idiopathic macular hole (MH) and 9 patients with epiretinal membrane (ERM). The samples were pretreated for enzymatic cleaving, and subsequently glycans released from proteins were captured on BlotGlyco H beads. Sialic acids were methyl-esterified. Processed glycans were tagged with aminooxy-functionalized peptide reagent (aoWR) and released from the beads, followed by detection by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). The concentration and composition of N-glycans in the samples were assessed. Concentration of N-glycans in vitreous samples (132 +/- 29 pmol/100 mu g protein) was significantly lower compared with those in plasma samples (714 +/- 29 pmol/100 mu g protein, p < 0.001). Predominant N-glycan in both plasma (39.7 +/- 1.1 %) and vitreous fluid (37.2 +/- 3.1 %) was identical, and the composition was presumed as [(Hex)2(HexNAc)2(NeuAc)2+ (Man)3(GlcNAc)2]. By contrast, the second-ranked N-glycan in vitreous samples (15.6 +/- 1.5 %) was the seventh in plasma (2.3 +/- 0.2 %). The current data provide useful information on N-glycan profile in the vitreous fluid, which is distinct from that in the plasma.
• Decreased proteasomal activity causes photoreceptor degeneration in mice

  Ryo Ando, Kousuke Noda, Utano Tomaru, Mamoru Kamoshita, Yoko Ozawa, Shoji Notomi, Toshio Hisatomi, Mika Noda, Atsuhiro Kanda, Tatsuro Ishibashi, Masanori Kasahara, Susumu Ishida

  Investigative Ophthalmology and Visual Science 55 (7) 4682 - 4690 1552-5783 2014/07/03 [Refereed][Not invited]
   

  Purpose: To study the retinal degeneration caused by decreased proteasomal activity in β5t transgenic (β5t-Tg) mice, an animal model of senescence acceleration. Methods: β5t-Tg mice and age-matched littermate control (WT) mice were used. Proteasomal activities and protein level of poly-ubiquitinated protein in retinal extracts were quantified. Fundus images of β5t-Tg mice were taken and their features were assessed. For histologic evaluation, the thicknesses of inner nuclear layer (INL), outer nuclear layer (ONL), and photoreceptor outer segment (OS) were measured. For functional analysis, ERG was recorded under scotopic and photopic illumination conditions. Immunofluorescence (IF) staining and TUNEL were performed to investigate the mechanism of photoreceptor degeneration. Results: Chymotrypsin-like activity was partially suppressed in retinal tissues of β5t-Tg mice. Retinal degenerative changes with arterial attenuation were present in β5t-Tg, but not in WT mice. Inner nuclear layer thickness showed no significant change between β5t-Tg and WT mice at 1, 3, 6, and 9 months of age. By contrast, thicknesses of ONL and OS in β5t-Tg mice were significantly decreased at 3, 6, and 9 months compared with those in WT mice. Electroretinograms showed decrease of scotopic a-wave amplitude in β5t-Tg mice. The number of TUNEL-positive cells in ONL were significantly increased in β5t-Tg mice and colocalized with apoptosis-inducing factor, but not with cleaved caspase-3 and -9, indicating that the photoreceptor cell death was induced via a caspase-independent pathway. Conclusions: The current data showed that impaired proteasomal function causes photoreceptor degeneration. © 2014 The Association for Research in Vision and Ophthalmology, Inc.
• Oxidative Stress in the Levator Aponeurosis in Asian Involutional Blepharoptosis

  Satoru Kase, Mika Noda, Hiroshi Yoshikawa, Teppei Yamamoto, Kan Ishijima, Susumu Ishida

  OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY 30 (4) 290 - 294 0740-9303 2014/07 [Refereed][Not invited]
   

  Purpose: To analyze the histopathology and expression of 8-hydroxydeoxyguanosine (OHdG), a marker of oxidative stress, in the levator aponeurosis tissues of involutional aponeurotic and congenital blepharoptosis patients, and adult subjects with no history of blepharoptosis. Methods: Fourteen and 4 levator aponeurosis tissues obtained from Asian patients with involutional and congenital blepharoptosis and 3 normal adult tissues were examined. All tissues were fixed in 4% paraformaldehyde, embedded in paraffin, and then submitted for hematoxylin and eosin staining and immunohistochemistry with anti-8-OHdG antibody. Results: The levator aponeurosis tissues contained spindle smooth muscle fibers and striated muscles. Nuclear immunoreactivity for 8-OHdG was noted in striated and smooth muscle cells in all the tissues. The 8-OHdG-positive rate was significantly lower in congenital blepharoptosis than involutional blepharoptosis (p < 0.05). Moreover, the number of 8-OHdG-positive striated muscle cells was significantly higher in the involutional blepharoptosis than normal tissues (p < 0.05). In contrast, there was a rare positive -8-OHdG-immunoreactivity of smooth muscle cells in the aponeurotic tissues of the involutional blepharoptosis patients. Conclusions: Levator aponeurosis in involutional aponeurotic blepharoptosis tissues showed oxidative stress in the muscle, indicating that oxidative stress plays a potential role in the pathologic study of the disease.
• Pars Plana Vitrectomy for Macular Schisis Associated With Peripapillary Intrachoroidal Cavitation

  Chikako Yoshizawa, Wataru Saito, Kousuke Noda, Susumu Ishida

  OPHTHALMIC SURGERY LASERS & IMAGING RETINA 45 (4) 350 - 353 2325-8160 2014/07 [Refereed][Not invited]
   

  A case of retinoschisis associated with peripapillary intrachoroidal cavitation (ICC) was successfully treated with pars plana vitrectomy. A 70-year-old woman developed macular elevation and peripapillary ICC in her right eye. Optical coherence tomography revealed retinoschisis with retinal detachment in the macula. A microhole was observed within the myopic conus. A narrow passage was observed linking the ICC with the schisis cavity, complicated by a peripapillary epiretinal membrane tissue adjacent to the passage. The patient underwent vitrectomy with removal of the membrane tissue. Complete regression of the retinoschisis was observed, with closure of the connection channel between the ICC and schisis cavity. These findings suggest that the communication channel between the vitreous and schisis cavities was formed due to the traction exerted by the membrane tissue on the ICC that had generated a connecting path to the schisis cavity.
• [A review 59 molecular mechanisms in and medical treatments for diabetic retinopathy].

  Ishida S

  Nippon Ganka Gakkai zasshi 118 (7) 607 - 618 0029-0203 2014/07 [Refereed][Not invited]
  
• Expression of Vascular Endothelial Growth Factor in Human Ocular Adnexal Lymphoma

  Satoshi Kinoshita, Satoru Kase, Ryo Ando, Zhenyu Dong, Junichi Fukuhara, Yoko Dong, Saori Inafuku, Kousuke Noda, Mika Noda, Atsuhiro Kanda, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 55 (6) 3461 - 3467 0146-0404 2014/06 [Refereed][Not invited]
   

  PURPOSE. To examine the expression of VEGF in extranodal marginal zone B-cell lymphoma (EMZL) and reactive lymphoid hyperplasia (RLH) of human ocular adnexa, and analyze the correlation with the intratumoral microvessel density (MVD). METHODS. Twenty-two EMZL and 16 RLH tissues were examined in this study. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with antibodies against VEGF and CD20. Vascular endothelial growth factor expression was analyzed using the ELISA and RT-PCR in the EMZL tissues. Microvessel density was determined based on the immunoreactivity for anti-CD34 antibody. RESULTS. Vascular endothelial growth factor immunoreactivity was detected in the cytoplasm of lymphoid cells in EMZL and RLH. ELISA and RT-PCR confirmed VEGF protein and mRNA expressions in the EMZL tissue, respectively. Vascular endothelial growth factor-immunopositive rate in B-cells was significantly higher in 12 conjunctival EMZLs than four RLHs (P < 0.01) and 10 orbital EMZLs than 12 RLHs (P < 0.05). The MVD showed a significant positive correlation with the VEGF-immunopositive rate in conjunctival and orbital EMZLs. CONCLUSIONS. This study demonstrated increased VEGF expression in human conjunctival and orbital EMZL compared with that in RLH, suggesting that VEGF plays a significant role in the pathogenesis and tumor angiogenesis of ocular adnexal lymphoma.
• Adenosquamous carcinoma of the conjunctiva: A case report

  Satoru Kase, Hiroshi Yoshikawa, Yutaka Nakajima, Mika Noda, Susumu Ishida

  ONCOLOGY LETTERS 7 (6) 1941 - 1943 1792-1074 2014/06 [Refereed][Not invited]
   

  Adenosquamous carcinoma (ASC) is a rare form of malignancy which consists of two types of cell, including squamous cells and glandular-like cells. The current report presents the first known case of ASC in the conjunctiva and analyzes the histological findings. A 76-year-old female presented with right eyelid swelling in 2001. A right conjunctival tumor was noted and a biopsy was performed. Histologically, the tumor was diagnosed as a squamous cell carcinoma. The patient underwent radiotherapy, but the tumor rapidly relapsed. Subsequently, the patient underwent orbital exenteration. Histologically, the conjunctival tissues had been replaced with invasive tumor cells. A number of tumor cells demonstrated squamous differentiation with a keratinizing tendency, while other tumor cells exhibited mucin-producing activity with glandular formation. The conjunctival tumor was diagnosed as an ASC. At the time of writing, the patient is well without local recurrence or distant metastases. ASC typically exhibits aggressive biological behavior, and is associated with worse prognosis than conventional adenocarcinoma. Therefore, complete surgical excision is considered a key treatment for ASC of the conjunctiva.
• Aqueous humour levels of placental growth factor in diabetic retinopathy

  Ryo Ando, Kousuke Noda, Shiho Namba, Wataru Saito, Atsuhiro Kanda, Susumu Ishida

  ACTA OPHTHALMOLOGICA 92 (3) E245 - E246 1755-375X 2014/05 [Refereed][Not invited]
  
• Increased macular choroidal blood flow velocity and decreased choroidal thickness with regression of punctate inner choroidopathy

  Kiriko Hirooka, Wataru Saito, Yuki Hashimoto, Michiyuki Saito, Susumu Ishida

  BMC OPHTHALMOLOGY 14 73  1471-2415 2014/05 [Refereed][Not invited]
   

  Background: Changes in choroidal circulation hemodynamics during the course of punctate inner choroidopathy (PIC) remain unknown. The aim of this study was to quantitatively evaluate changes in choroidal blood flow velocity by using laser speckle flowgraphy (LSFG) in patients with PIC. Case presentation: This PIC patient was initially treated with systemic corticosteroids for 4 months. LSFG measurements were taken 10 consecutive times before treatment and at 1, 3, 12, 20 and 23 months after the initiation of therapy. The mean blur rate (MBR), a quantitative index of relative blood flow velocity, was calculated using LSFG in three regions: Circles 1, 2 and 3 were set at the fovea, a lesion site, and an area of normal-appearing retina, respectively. The PIC lesions scarred after treatment along with improvements in visual function and outer retinal morphology. When the changing rate of macular flow over the 12-month follow-up period was compared with the MBR before treatment (100%), an increase of 16-37%, 24-49% and 15-18% was detected in Circles 1, 2 and 3, respectively. At the time of PIC recurrence after 20 months, the MBR decreased temporarily but subsequently increased after retreatment with systemic corticosteroids. This trend was accompanied by a decrease in choroidal thickness at the lesion site after retreatment. Conclusions: Macular choroidal blood flow velocity increased and choroidal thickness decreased concurrently with regression of PIC. The present findings suggest that inflammation-related impairments in choroidal circulation may relate to the pathogenesis of PIC, extending over a wider area in the posterior pole than the PIC lesions per se.
• Roles of the retinal pigment epithelium in neuroprotection

  Atsuhiro Kanda, Susumu Ishida

  Neuroprotection and Neuroregeneration for Retinal Diseases 227 - 238 2014/05/01 [Refereed][Not invited]
   

  The retinal pigment epithelium (RPE), located between the photoreceptors and Bruch's membrane, is a vital tissue for the maintenance of photoreceptor functions. Numerous proteins expressed in the RPE regulate the transport of nutrients and waste products to and from the photoreceptors, which contributes to phagocytosis of shed photoreceptor outer segments and protects from the excessive light and oxygen reactive species to maintain retinal homeostasis. During aging, the RPE is observed to undergo characteristic changes including cell loss, loss of intact melanin granules, metabolic changes, and the intracellular accumulation of lipofuscin. Those changes adversely affect the RPE functions and associate with various diseases of the neural retina and the choroid. Given a number of studies reporting the RPE functions which serve for the retina and the choroid, it is essential to understand the physiological functions of the RPE in order to decipher disease- and age-related changes in vision.
• Correlation between decreased choroidal blood flow velocity and the pathogenesis of acute zonal occult outer retinopathy

  Michiyuki Saito, Wataru Saito, Yuki Hashimoto, Chikako Yoshizawa, Yasuhiro Shinmei, Kousuke Noda, Susumu Ishida

  CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 42 (2) 139 - 150 1442-6404 2014/03 [Refereed][Not invited]
   

  BackgroundTo evaluate changes of choroidal circulation quantitatively using laser speckle flowgraphy in patients with acute zonal occult outer retinopathy. DesignRetrospective observational case series. ParticipantsSixteen eyes of 11 acute zonal occult outer retinopathy patients: seven non-treated eyes with good visual acuity and nine systemic corticosteroid-treated eyes with progressive visual acuity loss. Six eyes with thyroid-associated ophthalmopathy receiving systemic corticosteroid therapy served as controls. MethodsThe mean blur rate, an index of quantitative relative blood flow velocity, in the affected area was measured by laser speckle flowgraphy. The changes of mean blur rate, best-corrected visual acuity and the average threshold at the affected area on Humphrey perimetry during 24-week follow up were analysed. Main Outcome MeasuresMean blur rate, best-corrected visual acuity, and the average threshold. ResultsIn non-treated eyes, the average mean blur rate significantly increased at 24 weeks, with a significant increase of the average threshold. In corticosteroid-treated eyes, the mean blur rates at 1, 4, 12 and 24 weeks were significantly higher than the pretreatment value, with significant improvement of best-corrected visual acuity and the average threshold. The increase in mean blur rate at 4 weeks in corticosteroid-treated acute zonal occult outer retinopathy eyes was significantly higher than that in corticosteroid-treated control eyes. ConclusionsIn eyes with acute zonal occult outer retinopathy, the mean blur rate at the affected area significantly increases along with improvement of visual functions. These results suggest that impaired choroidal circulation is involved in the pathogenesis of acute zonal occult outer retinopathy.
• Retinal outer layer thickness increases after vitrectomy for epiretinal membrane, and visual improvement positively correlates with photoreceptor outer segment length

  Yuki Hashimoto, Wataru Saito, Michiyuki Saito, Kiriko Hirooka, Akio Fujiya, Chikako Yoshizawa, Kousuke Noda, Susumu Ishida

  GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 252 (2) 219 - 226 0721-832X 2014/02 [Refereed][Not invited]
   

  To investigate postoperative thickness changes in the retinal layers in eyes with epiretinal membrane (ERM). Correlations between these changes and visual outcomes were also examined. Retrospective review of 25 eyes (24 patients) that had undergone pars plana vitrectomy for ERM and had a postoperative follow-up period a parts per thousand yen6 months. Optical coherence tomography (6 x 6 mm macular thickness map) was used to measure mean thickness of the inner and outer retinal layers 1 week and 1, 3, and 6 months following surgery. Photoreceptor outer segment (PROS) length was evaluated manually, and used to assess the association between best-corrected visual acuity (BCVA) and retinal layer thickness at the fovea. At 1 week and 1, 3, and 6 months, retinal layer thickness was 388, 377, 362, and 352 mu m for the whole layer; 133, 115, 107, and 101 mu m for the inner layer; 138, 145, 147, and 148 mu m for the outer layer; and 28, 35, 36, and 40 mu m for the PROS length, respectively. In comparison to 1-week data, the inner layers were significantly thinner at 1 month and later, as was the thickness of the entire retina. Outer layer thickness and PROS length were also significantly thicker at these time points. Six months following surgery, BCVA was significantly correlated with an elongated PROS length (R = 0.49, P = 0.01). Retinal outer layer thickness significantly increased following pars plana vitrectomy for ERM. Visual improvement was positively correlated with PROS length recovery.
• Amelioration of endotoxin-induced uveitis treated with the sea urchin pigment echinochrome in rats

  Anton Lennikov, Nobuyoshi Kitaichi, Kousuke Noda, Kazuomi Mizuuchi, Ryo Ando, Zhenyu Dong, Junichi Fukuhara, Satoshi Kinoshita, Kenichi Namba, Shigeaki Ohno, Susumu Ishida

  MOLECULAR VISION 20 171 - 177 1090-0535 2014/02 [Refereed][Not invited]
   

  Purpose: Echinochrome is a pigment present in the shells and spines of sea urchins. It has been reported to have several biologic protective effects, including in experimental models of myocardial ischemia/reperfusion injury, for which the proposed mechanisms are scavenging reactive oxygen species (ROS) and chelating iron. Endotoxin-induced uveitis (EIU) is an animal model of acute anterior segment intraocular inflammation that is induced by the injection of lipopolysaccharide (LPS). In this study, the therapeutic effect of echinochrome was examined in uveitis using the EIU model. Methods: EIU was induced in Lewis rats via 200 mu g subcutaneous injections of LPS from Escherichia coli. Echinochrome was administered intravenously in 10, 1, or 0.1 mg/kg doses suspended in PBS (controls were injected with PBS only). Twenty-four hours after LPS injection, the number of infiltrating cells and the protein concentration in aqueous humor were determined. Aqueous tumor necrosis factor alpha (TNF-alpha) concentration was quantified with enzyme-linked immunosorbent assay, eyes were stained with nuclear factor (NF) kappa B antibodies, and ROS production was determined by dihydroethidium staining in fresh frozen samples. Results: The number of inflammatory aqueous cells and protein levels were lower in the groups treated with 10 and 1 mg/kg of echinochrome than in the untreated LPS group (p<0.01). Treatment with 10 and 1 mg/kg of echinochrome significantly reduced TNF-alpha concentrations in aqueous humor (p<0.01). The numbers of NF kappa B-positive cells and ROS signals were also reduced by echinochrome administration (p<0.05). Conclusions: Echinochrome ameliorated intraocular inflammation caused by EIU by reducing ROS production, thereby also decreasing the expression of NF kappa B and TNF-alpha. As a natural pigment, echinochrome may therefore be a promising candidate for the safe treatment of intraocular inflammation. The use of sea urchin shells and spines in health foods and medical products is thus both economically and environmentally meaningful.
• Increase of lysosomal phospholipase A2 in aqueous humor by uveitis

  Miki Hiraoka, Akira Abe, Anton Lennikov, Nobuyoshi Kitaichi, Susumu Ishida, Hiroshi Ohguro

  EXPERIMENTAL EYE RESEARCH 118 13 - 19 0014-4835 2014/01 [Refereed][Not invited]
   

  This study was conducted to elucidate pathophysiological roles of the lysosomal phospholipase A2 (LPLA2), a phospholipid-degrading enzyme, of the aqueous humor (AH) in uveitis using an animal model and clinical specimens. Endotoxin-induced uveitis (EIU) was induced by subcutaneous injections of lipopolysaccharide from Escherichia coli to seven-week-old male Lewis rats. Inflammation of the anterior chamber (AC) was evaluated by measurement of the protein concentration of rat AH. The LPLA2 activity in the AH, serum and cerebrospinal fluid obtained from EIU rats was detected using liposomes consisting of 1,2-dioleoylphosphatidylglycerol/N-acetylsphingosine as the substrate under acidic conditions. Immunohistochemical analysis was performed using antibodies against CD11b and LPLA2. Sixty-five human AH specimens, in which 11 eyes had a history of chronic uveitis, were collected during patient cataract surgeries and used to determine LPLA2 activity. The LPLA2 activity in rat AH was significantly increased by EIU induction, and was correlated to the extent of inflammation in the AC. By contrast, the LPLA2 activity in rat serum or cerebrospinal fluid was not influenced by EIU induction. According to the immunohistochemistry, LPLA2 was found in CD11b positive cells in the AC of the EIU rats. In the clinical specimens, the AH obtained from the patients with a history of uveitis possessed significantly higher LPLA2 activity than that from the senile patients with cataract but without other ocular diseases. These results demonstrate that the LPLA2 activity in the AH is augmented with the inflammation in the AC and suggest that the LPLA2 in the AH participates in the inflammation process in the AC. (C) 2013 Published by Elsevier Ltd.
• A case of paraneoplastic optic neuropathy and outer retinitis positive for autoantibodies against collapsin response mediator protein-5, recoverin, and alpha-enolase

  Michiyuki Saito, Wataru Saito, Atsuhiro Kanda, Hiroshi Ohguro, Susumu Ishida

  BMC OPHTHALMOLOGY 14 5  1471-2415 2014/01 [Refereed][Not invited]
   

  Background: Specific cross-reacting autoimmunity against recoverin or collapsin response mediator protein (CRMP)-5 is known to cause cancer-associated retinopathy or paraneoplastic optic neuropathy, respectively. We report a rare case with small cell lung carcinoma developing bilateral neuroretinitis and unilateral focal outer retinitis positive for these antibodies. Case presentation: A 67-year-old man developed bilateral neuroretinitis and foveal exudation in the right eye. Optical coherence tomography showed a dome-shaped hyperreflective lesion extending from inner nuclear layer to the photoreceptor layer at the fovea in the right eye. Single-flash electroretinography showed normal a-waves in both eyes and slightly reduced b-wave in the left eye. Results of serological screening tests for infection were within normal limits. The patient's optic disc swelling and macular exudation rapidly improved after oral administration of prednisolone. Systemic screening detected lung small cell carcinoma and systemic chemotherapy was initiated. Immunoblot analyses using the patient's serum detected autoantibodies against recoverin, CRMP-5, and a-enolase, but not carbonic anhydrase II. Neuroretinitis once resolved after almost remission of carcinoma on imaging but it recurred following the recurrence of carcinoma. Conclusions: The development of neuroretinitis in this cancer patient with anti-retinal and anti-optic nerve antibodies depended largely on the cancer activity, suggesting the possible involvement of paraneoplastic mechanisms. Patients with paraneoplastic optic neuropathy and retinopathy are likely to develop autoimmune responses against several antigens, thus leading to various ophthalmic involvements.
• Atp6ap2/(Pro)renin Receptor Interacts with Par3 as a Cell Polarity Determinant Required for Laminar Formation during Retinal Development in Mice

  Atsuhiro Kanda, Kousuke Noda, Kenya Yuki, Yoko Ozawa, Takahisa Furukawa, Atsuhiro Ichihara, Susumu Ishida

  JOURNAL OF NEUROSCIENCE 33 (49) 19341 - 19351 0270-6474 2013/12 [Refereed][Not invited]
   

  (Pro) renin receptor [(P)RR], also known as Atp6ap2, has attracted growing attention as a key molecule for tissue renin-angiotensin system (RAS). In addition to its role in tissue RAS activation, A tp6ap2/(P)RR was originally identified as an accessory subunit for vacuolar H+-ATPase (v-ATPase), which is a multisubunit proton pump involved in diverse and fundamental cellular physiology. In this study, to elucidate the physiological function of Atp6ap2/(P) RR during retinal development in mammals, we used Cre-LoxP system to generate photoreceptor-specific conditional knock-out (CKO) mice, and revealed a critical role of Atp6ap2/(P) RR in photoreceptor development. Deletion of photoreceptor Atp6ap2/(P) RR did not affect retinal cell differentiation, but led to laminar disorganization around the outer nuclear layer together with severe dysfunction of photoreceptor cells. In the CKO mice, cell adhesion and polarity molecules, some of which were colocalized with Atp6ap2/(P) RR at the apical edge of the wild-type developing retina, were substantially dispersed together with mislocalization of retinal progenitor cells apart from the apical surface. Among theses molecules, coimmunoprecipitation using retinal homogenates and ATP6AP2/(P) RR-transfected cells showed that Atp6ap2/(P) RR interacted with partitioning defective 3 homolog (PAR3) protein, which is known to function in the Par-atypical protein kinase C (aPKC) system. Furthermore, yeast two-hybrid assays demonstrated direct molecular interaction between ATP6AP2/(P) RR and PAR3. Our present data revealed the novel function of Atp6ap2/(P) RR required for laminar formation during retinal development. We propose that this cellular activity associated with the Par-aPKC system, in addition to the v-ATPase function and tissue RAS activation, is the third biological role of Atp6ap2/(P) RR.
• 網膜中心静脈閉塞症を合併したacute macular neuroretinopathyの1例

  廣岡 季里子, 齋藤 航, 橋本 勇希, 齋藤 理幸, 吉澤 史子, 野田 航介, 石田 晋

  日本視能訓練士協会誌 (公社)日本視能訓練士協会 42 228 - 229 0387-5172 2013/12
• The Effects of 2% Rebamipide Ophthalmic Solution on the Tear Functions and Ocular Surface of the Superoxide Dismutase-1 (Sod1) Knockout Mice

  Takeshi Ohguchi, Takashi Kojima, Osama M. Ibrahim, Taeko Nagata, Takahiko Shimizu, Takuji Shirasawa, Tetsuya Kawakita, Yoshiyuki Satake, Kazuo Tsubota, Jun Shimazaki, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 54 (12) 7793 - 7802 0146-0404 2013/11 [Refereed][Not invited]
   

  PURPOSE. To investigate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status of the superoxide dismutase-1(Sod1(-/-)) mice. METHODS. Two percent Rebamipide ophthalmic solution was applied to 40-week-old male Sod1(-/-) and wild-type (WT) mice four times a day for 2 weeks. We examined the cytokine concentrations in the tear fluid (by CytoBead assay), tear film break-up time, amount of tear production, and expressions of mucins 1, 4, and 5AC, by RT-PCR. We also performed vital staining of the ocular surface, PAS staining for muc5AC, and immunohistochemical stainings for 4-hydroxy-2-nonenal (4-HNE), 8-hydroxy-2'-deoxyguanosine (8-OHdG), in the conjunctiva to compare the results before and after rebamipide instillations. RESULTS. The tear functions and ocular surface epithelial damage scores were significantly worse in the Sod1(-/-) than in the WT mice. Application of 2% rebamipide for 2 weeks significantly improved the tear film break-up time, the amount of tear production, and the corneal epithelial damage scores, which also significantly increased the conjunctival goblet cell density and muc5 mRNA expression, in the Sod1(-/-) mice. The mean IL-6, IL-17, TNF-alpha, and IFN-gamma levels in the tear fluid were reduced significantly along with a significant decrease in the density of cells positive for 4-HNE and 8-OHdG in the conjunctiva. CONCLUSIONS. Two percent Rebamipide ophthalmic solution significantly improved the tear stability and corneal epithelial damage, and enhanced the expression of muc5 mRNA on the ocular surface. We also observed anti-inflammatory effects in the tear film together with antioxidative effects in the conjunctiva, suggesting the efficacy of rebamipide in age-related dry eye disease attributable to SOD1 knockout.
• Expression of vascular endothelial growth factor and intravitreal anti-VEGF therapy with bevacizumab in vasoproliferative retinal tumors.

  Saito W, Kase S, Fujiya A, Dong Z, Noda K, Ishida S

  Retina (Philadelphia, Pa.) 33 (9) 1959 - 1967 0275-004X 2013/10 [Refereed][Not invited]
  
• Spontaneous regression of IgG4-related dacryoadenitis

  Satoru Kase, Teppei Yamamoto, Kan Ishijima, Mika Noda, Susumu Ishida

  Modern Rheumatology 23 (5) 1018 - 1021 1439-7595 2013/09 [Refereed][Not invited]
   

  This is the first report showing the clinical course of a patient with bilateral IgG4-related dacryoadenitis, which spontaneously regressed after excision of the left lacrimal gland. A 65-year-old female had been aware of bilateral eyelid swelling without pain for 5 years. Magnetic resonance imaging revealed enlargement of bilateral lacrimal gland. Laboratory tests showed high IgG4 concentrations, measuring 394 mg/dl. The biopsied specimen of the left lacrimal gland revealed marked lymphoplasmacytic infiltration with mild fibrosis. Marked IgG and IgG4-positive plasma cells surrounded the lymphoid follicles. Although the patient did not wish to undergo any treatments, lacrimal gland lesions showed gradual remission. This case highlights the potential of spontaneous improvement in IgG4-related dacryoadenitis, indicating that careful observation may be one of the therapeutic options for such patients. © 2012 Japan College of Rheumatology.
• Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease

  Yun Jong Lee, Yukihiro Horie, Graham R. Wallace, Yong Seok Choi, Ji Ah Park, Ji Yong Choi, Ran Song, Young-Mo Kang, Seong Wook Kang, Han Joo Baek, Nobuyoshi Kitaichi, Akira Meguro, Nobuhisa Mizuki, Kenichi Namba, Susumu Ishida, Jinhyun Kim, Edyta Niemczyk, Eun Young Lee, Yeong Wook Song, Shigeaki Ohno, Eun Bong Lee

  ANNALS OF THE RHEUMATIC DISEASES 72 (9) 1510 - 1516 0003-4967 2013/09 [Refereed][Not invited]
   

  Objectives To identify non-major histocompatibility complex susceptible genes that might contribute to Behcet's disease (BD). Methods We performed a genome-wide association study using DNA samples from a Korean population consisting of 379 BD patients and 800 controls. A replication study was performed in a Japanese population (363 BD patients and 272 controls). To evaluate the functional implication of the target single nucleotide polymorphisms (SNP), gene expression levels in peripheral T cells, allele-specific modulation of promoter activity and biological effect of mRNA knockdown were investigated. Results We found a novel association of BD to the GIMAP locus, mapped to chromosome 7q36.1 (rs1608157, p=6.01x10(-8) in a minor allele dominant model; rs11769828, allele based p=1.60x10(-6)). A fine mapping study identified an association with four additional SNP: rs1522596 (OR=1.45, p=7.70x10(-6)) in GIMAP4; rs10266069 (OR=1.32, p=2.67x10(-4)) and rs10256482 (OR=1.27, p=5.27x10(-4)) in GIMAP2; and rs2286900 (OR=1.61, p=3.53x10(-5)) in GIMAP1 areas. Replication study using DNA samples from the Japanese population validated the significant association between BD and the GIMAP locus. The GIMAP4 promoter construct plasmid with the minor allele of rs1608157 displayed significantly lower activity than one with the major allele. Moreover, CD4 T cells from BD patients showed a lower level of GIMAP4 mRNA, and GIMAP4 knockdown was protective against Fas-mediated apoptosis. Conclusions These results suggest that a GIMAP cluster is a novel susceptibility locus for BD, which is involved in T-cell survival, and T-cell aberration can contribute to the development of BD.
• Expression of alpha B-Crystallin and Vascular Endothelial Growth Factor in Conjunctival Squamous Cell Carcinoma

  Zhenyu Dong, Satoru Kase, Ryo Ando, Junichi Fukuhara, Satoshi Kinoshita, Yoko Dong, Saori Takashina, Atsuhiro Kanda, Mika Noda, Kousuke Noda, Susumu Ishida

  ANTICANCER RESEARCH 33 (9) 3745 - 3751 0250-7005 2013/09 [Refereed][Not invited]
   

  Aim: To examine the expression of alpha B-crystallin and vascular endothelial growth factor (VEGF) in conjunctival squamous cell carcinoma (CSCC). Materials and Methods: Seven CSCCs and three normal conjunctivas that were surgically excised were studied. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with antibodies against alpha B-crystallin, its phosphorylated forms, and VEGF. In vitro experiments were conducted to investigate the effects of mitomycin C (MMC) treatment on the expression of alpha B-crystallin and VEGF secretion. Results: alpha B-Crystallin and VEGF were strongly expressed in CSCCs compared to normal conjunctivas. alpha B-Crystallin immunoreactivity was co-localized with that for VEGF in CSCCs, whereas these signals were reduced in CSCC tissues treated with MMC before excision. MMC treatment suppressed the alpha B-crystallin expression and VEGF secretion in cultured conjunctival cells in a dose-dependent manner. Conclusion: This study demonstrated alpha B-crystallin and VEGF expressions in human CSCCs, which may play a role in the pathogenesis. alpha B-Crystallin expression, and VEGF secretion were reduced by MMC, indicating a novel therapeutic mechanism in MMC treatment for human CSCC.
• [Bioinformatics on new human adenoviruses causing nosocomial infection].

  Koki Aoki, Hisatoshi Kaneko, Nobuyoshi Kitaichi, Hidemi Watanabe, Susumu Ishida, Shigeaki Ohno

  Nippon Ganka Gakkai zasshi 117 (9) 721 - 6 0029-0203 2013/09 [Refereed][Not invited]
   

  Human adenovirus (HAdV) causing epidemic keratoconjunctivitis is limited to D and E species. Recent progress in bioinformatics revealed that these viruses attach to the host with fibers, infiltrate the host cells via RGD (Arg-Gly-Asp) motif of penton base, and reveal their serological reaction by hexons. Loops 1 and 2 are the variable regions of each hexon. The possibility that a novel adenovirus later named HAdV-52 was transmitted over the wall of species' from monkeys to humans was reported. The recombination of the above three hot spots introduces novel types such as HAdV-53, -54, and -56. Boinformatics may provide rapid genotyping in nosocomial infection, predicting future epidemics, and an estimate of the therapeutic target molecules in the near future.
• エキノクロームによるラットEIUの軽症化

  アントン・レニコフ, 北市 伸義, 野田 航介, 南場 研一, 石田 晋, 大野 重昭, 大黒 浩

  日本眼薬理学会プログラム・抄録集 日本眼薬理学会 33回 44 - 44 2013/09
• Authors' response to 'Choroidal blood flow measurement with laser speckle flowgraphy in macular disease'.

  Saito M, Saito W, Ishida S

  The British journal of ophthalmology 97 (8) 1083 - 1084 0007-1161 2013/08 [Refereed][Not invited]
  
• Blockade for vascular adhesion protein-1 suppresses pathological neovascularization in oxygen-induced retinopathy

  Nami Yoshikawa, Kousuke Noda, Yoko Ozawa, Yukihiko Mashima, Susumu Ishida

  ACTA OPHTHALMOLOGICA 91 (5) E409 - E410 1755-375X 2013/08 [Refereed][Not invited]
  
• A patient with acute macular neuroretinopathy and central retinal vein occlusion

  Kiriko Hirooka, Wataru Saito, Kousuke Noda, Susumu Ishida

  Clinical Ophthalmology 7 1447 - 1450 1177-5467 2013/07/12 [Refereed][Not invited]
   

  Purpose: The precise mechanism causing acute macular neuroretinopathy (AMN) is still unknown. A recent report suggested that choroidal circulation impairment correlates with its pathogenesis. We report a rare case with simultaneous onset of AMN and central retinal vein occlusion (CRVO), which is a retinal circulation disorder. Methods: Case report. Results: A 44-year-old woman complained of central visual loss of the left eye for the previous 2 weeks. The patient's visual acuity was 0.5 in the left eye (OS). Fundoscopic examination revealed a wedge-shaped, dark reddish-brown lesion at the macula, and CRVO-like retinal hemorrhages OS. Fluorescein angiography revealed retinal vasculitis and hypofluorescence corresponding to the macular lesion. The patient's scanning laser ophthalmoscopy infrared imaging result led to a diagnosis of AMN. Two weeks after corticosteroid pulse therapy, her visual acuity improved to 1.2 OS, with improvement of macular findings and Humphrey perimetry. When the dose of oral corticosteroid was decreased, the AMN lesion worsened, with recurrence of retinal hemorrhages. Visual functions improved again after an increased dose of corticosteroid. Conclusion: These results suggest that circulatory disorders almost simultaneously occurred in choroidal and retinal vessels, resulting in the onset of both AMN and CRVO. © 2013 Hirooka et al, publisher and licensee Dove Medical Press Ltd.
• Improvement of visual acuity after transcorneal electrical stimulation in case of Best vitelliform macular dystrophy

  Naoki Ozeki, Kei Shinoda, Hisao Ohde, Susumu Ishida, Kazuo Tsubota

  Graefe's Archive for Clinical and Experimental Ophthalmology 251 (7) 1867 - 1870 0721-832X 2013/07 [Refereed][Not invited]
   

  Purpose: To report an improvement of the visual acuity after transcorneal electrical stimulation (TES) in a case of Best vitelliform macular dystrophy (BVMD). Patient and methods: A 26-year-old woman diagnosed with BVMD presented with reduced vision. Her best corrected visual acuity (BCVA) was reduced to 20/200 in the right eye, and TES was performed once a month for two sessions. The current of the biphasic pulses (anodic first duration, 10 msec frequency, 20 Hz) was delivered using a DTL-electrode, and the duration of the TES was 30 min. Results: The BCVA in the right eye slowly improved after the TES, and 6 months later the BCVA was 20/25. The results of Humphrey visual field tests (VF) and multifocal ERGs (mfERGs) were only slightly changed. Two years later, the BCVA decreased, and it was improved again after another session of TES with the same parameters of the electrical pulses. Conclusion: The improvement of the visual acuity in our case of BVMD indicates that TES should be tried in other cases of retinal dystrophy. Further clinical and laboratory studies on TES are needed. © 2013 Springer-Verlag Berlin Heidelberg.
• Clinical features of human T lymphotropic virus type 1-associated uveitis in Hokkaido, Japan

  Satoru Kase, Kenichi Namba, Nobuyoshi Kitaichi, Daiju Iwata, Shigeaki Ohno, Susumu Ishida

  JAPANESE JOURNAL OF OPHTHALMOLOGY 57 (4) 379 - 384 0021-5155 2013/07 [Refereed][Not invited]
   

  To clarify the clinical features of human lymphotropic virus type 1 (HTLV-1)-associated uveitis (HAU) in patients of Hokkaido University Hospital, Hokkaido, northern Japan. We reviewed the records of a consecutive series of 21 patients with HAU who were followed up for more than 12 months at Hokkaido University Hospital. Of the 21 patients enrolled in this study, 19 as well as their parents (90.5 %) were born in Hokkaido. One patient was a member of the Ainu ethnic group. Unilateral involvement was found in 16 cases (76 %). In the ophthalmological examinations, vitreous opacity was most frequently followed by keratic precipitate, iris/gonio nodules, and posterior synechiae, while hypopyon, retinal vasculitis, and neovascularization were rarely observed. Intraocular inflammation was controlled by topical treatment, while systemic corticosteroids were required in less than one-fourth of patients. Visual acuity improved in 15 patients, remained unchanged in four patients, and deteriorated in two patients. HAU was observed in two patients with adult T-cell leukemia/lymphoma (ATLL). Three out of the four patients (75 %) for whom HLA typing was available had HLA-A26. A number of clinical features were unique to Hokkaido, namely, predominant unilateral involvement, as well as two HAU patients with ATLL. The phylogenetic difference of HTLV-1 and HLA typing may correlate with different clinical manifestations in HAU.
• TNF-alpha Decreases VEGF Secretion in Highly Polarized RPE Cells but Increases It in Non-Polarized RPE Cells Related to Crosstalk between JNK and NF-kappa B Pathways

  Hiroto Terasaki, Satoru Kase, Makoto Shirasawa, Hiroki Otsuka, Toshio Hisatomi, Shozo Sonoda, Susumu Ishida, Tatsuro Ishibashi, Taiji Sakamoto

  PLOS ONE 8 (7) e69994  1932-6203 2013/07 [Refereed][Not invited]
   

  Asymmetrical secretion of vascular endothelial growth factor (VEGF) by retinal pigment epithelial (RPE) cells in situ is critical for maintaining the homeostasis of the retina and choroid. VEGF is also involved in the development and progression of age-related macular degeneration (AMD). We studied the effect of tumor necrosis factor-alpha (TNF-alpha) on the secretion of VEGF in polarized and non-polarized RPE cells (P-RPE cells and N-RPE cells, respectively) in culture and in situ in rats. A subretinal injection of TNF-alpha caused a decrease in VEGF expression and choroidal atrophy. Porcine RPE cells were seeded on Transwell (TM) filters, and their maturation and polarization were confirmed by the asymmetrical VEGF secretion and trans electrical resistance. Exposure to TNF-alpha decreased the VEGF secretion in P-RPE cells but increased it in N-RPE cells in culture. TNF-alpha inactivated JNK in P-RPE cells but activated it in N-RPE cells, and TNF-alpha activated NF-kappa B in P-RPE cells but not in N-RPE cells. Inhibition of NF-kappa B activated JNK in both types of RPE cells indicating crosstalk between JNK and NF-kappa B. TNF-alpha induced the inhibitory effects of NF-kappa B on JNK in P-RPE cells because NF-kappa B is continuously inactivated. In N-RPE cells, however, it was not evident because NF-kappa B was already activated. The basic activation pattern of JNK and NF-kappa B and their crosstalk led to opposing responses of RPE cells to TNF-alpha. These results suggest that VEGF secretion under inflammatory conditions depends on cellular polarization, and the TNF-alpha-induced VEGF down-regulation may result in choroidal atrophy in polarized physiological RPE cells. TNF-alpha-induced VEGF up-regulation may cause neovascularization by non-polarized or non-physiological RPE cells.
• Macular choroidal blood flow velocity decreases with regression of acute central serous chorioretinopathy

  Michiyuki Saito, Wataru Saito, Yuki Hashimoto, Chikako Yoshizawa, Akio Fujiya, Kousuke Noda, Susumu Ishida

  BRITISH JOURNAL OF OPHTHALMOLOGY 97 (6) 775 - 780 0007-1161 2013/06 [Refereed][Not invited]
   

  Aim To quantitatively evaluate the time course of macular choroidal blood flow velocity in acute central serous chorioretinopathy (CSC). Methods This retrospective observational case series included 21 eyes of 20 patients (17 men, 3 women; mean age, 53.0 years) with treatment-naive acute CSC. Laser speckle flowgraphy was performed to calculate macular mean blur rate (MBR), an indicator of relative blood flow velocity at the first visit, 3 and 6 months thereafter. Changes in average MBR values were compared with visual improvement at 6 months. Results Subretinal fluid completely resolved in all eyes within 6 months, while best-corrected visual acuity (BCVA) significantly improved at 6 months compared to the initial BCVA. During the follow-up period, the average MBR significantly decreased to 92.8% and 82.3% at 3 and 6 months, respectively, against baseline (100%). Importantly, there was a negative correlation between the BCVA recovery and the MBR decrease, showing the possible association of MBR increase with poor visual prognosis. Multiple regression analysis demonstrated no significant correlation between MBR and ocular perfusion pressure. Conclusions These results indicate that macular choroidal blood flow velocity decreases concurrently with regression of CSC, suggesting a validity of choroidal blood flow elevation in the pathogenesis of acute CSC.
• IgG4-related Inflammation of the Orbit Simulating Malignant Lymphoma

  Satoru Kase, Mika Noda, Kan Ishijima, Teppei Yamamoto, Kanako Hatanaka, Susumu Ishida

  ANTICANCER RESEARCH 33 (6) 2779 - 2783 0250-7005 2013/06 [Refereed][Not invited]
   

  Immuno globulin (IgG) 4-related disease is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. We report a case of IgG4-related inflammation of the orbit simulating extranodal marginal zone B-cell lymphoma (EMZL). A 72-year-old female complained of bilateral eyelid swelling for three years. A MRI scan demonstrated two kinds of lesions, tumor 1, presenting with a predominantly low density, and tumor 2, of relatively high density. Laboratory tests showed high serum IgG4 concentrations, measuring 991 mg/dl. Partial resection of each tumor was conducted in September 2011. Based on the clinicopathological findings, tumors 1 and 2 were diagnosed as IgG4-related inflammation and EMZL, respectively. The patient initially received oral prednisolone at 30 mg/per day, followed by irradiation with a total dosage of 30 Gy to both eyes. The bilateral tumors consequently diminished, and she is currently well with no recurrence or systemic involvement. In conclusion, EMZL can arise from massive IgG4-related orbital inflammation. Since IgG4-related inflammation can represent multiple nodular lesions, biopsies from multiple sites within the lesion are required to make a correct diagnosis in selected cases. Oral prednisolone combined with radiotherapy is an effective treatment for patients with IgG4-related ophthalmic disease simulating EMZL.
• Angiotensin II Type 1 Receptor Antagonist Attenuates Lacrimal Gland, Lung, and Liver Fibrosis in a Murine Model of Chronic Graft-Versus-Host Disease

  Saori Yaguchi, Yoko Ogawa, Shigeto Shimmura, Tetsuya Kawakita, Shin Hatou, Shingo Satofuka, Shigeru Nakamura, Toshihiro Imada, Hideyuki Miyashita, Satoru Yoshida, Tomonori Yaguchi, Yoko Ozawa, Takehiko Mori, Shinichiro Okamoto, Yutaka Kawakami, Susumu Ishida, Kazuo Tsubota

  PLOS ONE 8 (6) e64724  1932-6203 2013/06 [Refereed][Not invited]
   

  Chronic graft-versus-host disease (cGVHD), a serious complication following allogeneic HSCT (hematopoietic stem cell transplantation), is characterized by systemic fibrosis. The tissue renin-angiotensin system (RAS) is involved in the fibrotic pathogenesis, and an angiotensin II type 1 receptor (AT1R) antagonist can attenuate fibrosis. Tissue RAS is present in the lacrimal gland, lung, and liver, and is known to be involved in the fibrotic pathogenesis of the lung and liver. This study aimed to determine whether RAS is involved in fibrotic pathogenesis in the lacrimal gland and to assess the effect of an AT1R antagonist on preventing lacrimal gland, lung, and liver fibrosis in cGVHD model mice. We used the B10.D2-->BALB/c (H-2(d)) MHC-compatible, multiple minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD. First, we examined the localization and expression of RAS components in the lacrimal glands using immunohistochemistry and quantitative real-time polymerase chain reaction (PCR). Next, we administered an AT1R antagonist (valsartan; 10 mg/kg) or angiotensin II type 2 receptor (AT2R) antagonist (PD123319; 10 mg/kg) intraperitoneally into cGVHD model mice and assessed the fibrotic change in the lacrimal gland, lung, and liver. We demonstrated that fibroblasts expressed angiotensin II, AT1R, and AT2R, and that the mRNA expression of angiotensinogen was greater in the lacrimal glands of cGVHD model mice than in controls generated by syngeneic-HSCT. The inhibition experiment revealed that fibrosis of the lacrimal gland, lung, and liver was suppressed in mice treated with the AT1R antagonist, but not the AT2R antagonist. We conclude that RAS is involved in fibrotic pathogenesis in the lacrimal gland and that AT1R antagonist has a therapeutic effect on lacrimal gland, lung, and liver fibrosis in cGVHD model mice. Our findings point to AT1R antagonist as a possible target for therapeutic intervention in cGVHD.
• Membrane tissue on the optic disc may cause macular schisis associated with a glaucomatous optic disc without optic disc pits

  S. Saori, W. Wataru, Kousuke Noda, Maki Katai, Susumu Ishida

  Clinical Ophthalmology 7 883 - 887 1177-5467 2013/05/10 [Refereed][Not invited]
   

  This article reports a case of possible involvement of membrane tissue on the optic disc with macular schisis formation associated with glaucomatous optic disc without optic disc pits. A 78-year-old man presented with loss of central visual acuity of the left eye. He had a medical history of primary open-angle glaucoma. Visual acuity was 0.6 in his left eye, and funduscopy revealed macular schisis and a glaucomatous optic disc without optic disc pits. Optical coherence tomography (OCT) revealed membrane tissue on the optic disc and a tunnellike hyporefective lesion connecting the schisis cavity and a site near the tissue, but no obvious optic disc pit. He underwent pars plana vitrectomy during which the membrane tissue on the disc and internal limiting membrane were removed. Posterior vitreous detachment was observed intraoperatively. Thereafter, the tunnel-like lesion observed on OCT was rapidly obscured and the macular schisis gradually reduced. Eighteen months after surgery, his visual acuity had improved to 0.9 with almost complete regression of the macular schisis. No optic disc pit was visualized after surgery. The changes in OCT findings described here suggest an etiology for macular schisis without optic disc pits in an eye with a glaucomatous optic disc with posterior vitreous detachment. A connection between the schisis cavity and the vitreous cavity may have appeared via the tunnel-like structure due to the membrane tissue exerting traction on the optic disc. © 2013 Takashina et al, publisher and licensee Dove Medical Press Ltd.
• Trabecular meshwork depigmentation in Vogt-Koyanagi-Harada disease.

  Kazuomi Mizuuchi, Nobuyoshi Kitaichi, Kenichi Namba, Yukihiro Horie, Susumu Ishida, Shigeaki Ohno

  Japanese journal of ophthalmology 57 (3) 245 - 51 0021-5155 2013/05 [Refereed][Not invited]
   

  PURPOSE: Since some patients develop depigmentation of the trabecular meshwork in the course of Vogt-Koyanagi-Harada (VKH) disease, we examined the incidence of trabecular depigmentation and its correlation with other ocular findings and systemic symptoms. METHODS: We retrospectively reviewed the clinical charts of 53 Japanese patients diagnosed with VKH disease. The scores of trabecular and limbal pigmentation of all patients were recorded. We then examined the correlation between trabecular pigmentation and the presence of sunset glow fundus or skin lesions. RESULTS: Trabecular pigmentation was significantly lower in the patients with sunset glow fundus than in those without it (P = 0.022), whereas limbal pigmentation showed no significance. However, there were no significant differences in trabecular and limbal pigmentation between the patients with and those without skin lesions. Furthermore, there was no correlation between trabecular and limbal pigmentation. CONCLUSIONS: Depigmentation of the trabecular meshwork develops in some patients in the course of VKH disease. This depigmentation is significantly correlated with sunset glow fundus, but not with limbal depigmentation or skin lesions.
• Vitreous renin activity correlates with vascular endothelial growth factor in proliferative diabetic retinopathy

  Atsuhiro Kanda, Kousuke Noda, Wataru Saito, Susumu Ishida

  BRITISH JOURNAL OF OPHTHALMOLOGY 97 (5) 666 - 668 0007-1161 2013/05 [Refereed][Not invited]
  
• Serum Vascular Adhesion Protein-1 correlates with vascular endothelial growth factor in patients with type II diabetes

  Nami Yoshikawa, Kousuke Noda, Hajime Shinoda, Atsuro Uchida, Yoko Ozawa, Kazuo Tsubota, Yukihiko Mashima, Susumu Ishida

  JOURNAL OF DIABETES AND ITS COMPLICATIONS 27 (2) 162 - 166 1056-8727 2013/03 [Refereed][Not invited]
   

  Aims: To study serum levels of soluble vascular adhesion protein (sVAP)-1 in type II diabetic patients with retinopathy. Methods: Serum samples were obtained from 53 consecutive patients, including 14 cases with non-angiogenic ocular diseases, i.e., epiretinal membrane (ERM) and idiopathic macular hole (MH), 19 cases with age-related macular degeneration (AMD), and 20 cases with diabetic retinopathy (DR). Protein levels of sVAP-1, intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and vascular endothelial growth factor (VEGF) were determined by enzyme-linked immunosorbent assay. Enzymatic activity of semicarbazide-sensitive amine oxidase (SSAO) was also measured. Results: Serum level of sVAP-1 showed a moderate correlation with SSAO activity in all cases. Patients with DR had higher levels of serum sVAP-1 than subjects with ERM and MH, or those with AMD; however, severity of DR is not related to the serum levels of sVAP-1. Serum sVAP-1 correlated positively with VEGF in patients with DR, but not in those with ERM and MH, or those with AMD. Neither soluble ICAM-1 nor VCAM-1 correlated with VEGF, even in subjects with DR. Conclusion: The current data demonstrate the elevated serum levels of sVAP-1 and correlation between sVAP-1 and VEGF in patients with type II diabetes. (C) 2013 Elsevier Inc. All rights reserved.
• Specific inhibition of serine/arginine-rich protein kinase attenuates choroidal neovascularization

  Zhenyu Dong, Kousuke Noda, Atsuhiro Kanda, Junichi Fukuhara, Ryo Ando, Miyuki Murata, Wataru Saito, Masatoshi Hagiwara, Susumu Ishida

  MOLECULAR VISION 19 536 - 543 1090-0535 2013/03 [Refereed][Not invited]
   

  Purpose: To investigate the applicability of serine/arginine-rich protein kinase (SRPK)-specific inhibitor, SRPIN340, for attenuation of choroidal neovascularization (CNV) formation using a mouse model. Methods: Laser photocoagulation was performed to induce CNV in C57BL/'6J mice, followed by intravitreal injection of SRPIN340 or vehicle. Seven days after the treatment, the CNV size was evaluated using a flatmount technique. Protein levels of vascular endothelial growth factor (VEGF) and inflammation-associated molecules, such as monocyte chemoattractant protein (MCP)-1 and intercellular adhesion molecule (ICAM)-1, in the retinal pigment epithelium-choroid complex were measured with enzyme-linked immunosorbent assay. Expression levels of total Vegf, exon 8a-containing Vegf isoforms, and F4/80 (a specific marker for macrophage) were assessed using real-time PCR. Results: SRPIN340 inhibited CNV formation in a dose-dependent manner. Compared with the vehicle, SRPIN340 significantly decreased the protein levels of VEGF, MCP-1, ICAM-1, and consequently inhibited macrophage infiltration. Furthermore, SRPIN340 suppressed the gene expression levels of total Vegf and exon 8a-containing Vegf isoforms. Conclusions: SRPIN340, a specific inhibitor of SRPK, suppressed Vegf expression and attenuated CNV formation. Our data suggest the possibility that SRPIN340 is applicable for neovascular age-related macular degeneration as a novel chemical therapeutics.
• Expression of vascular endothelial growth factor C in human pterygium

  Junichi Fukuhara, Satoru Kase, Tsutomu Ohashi, Ryo Ando, Zhenyu Dong, Kousuke Noda, Takeshi Ohguchi, Atsuhiro Kanda, Susumu Ishida

  Histochemistry and Cell Biology 139 (2) 381 - 389 0948-6143 2013/02 [Refereed][Not invited]
   

  Vascular endothelial growth factor C (VEGF-C) and its receptor VEGFR-3 mediate lymphangiogenesis. In this study, we analyzed the expression of VEGF-C and VEGFR-3 as well as lymphatic vessels in the pterygium and normal conjunctiva of humans. Fifteen primary nasal pterygia and three normal bulbar conjunctivas, surgically removed, were examined in this study. The lymphatic vessel density (LVD) and blood vessel density were determined by the immunolabeling of D2-40 and CD31, markers for lymphatic and blood vessels, respectively. VEGF-C and VEGFR-3 expression in pterygial and conjunctival tissue proteins was detected by Western blotting and were evaluated using immunohistochemistry. The LVD was significantly higher in the pterygium than normal conjunctiva (p < 0.05). Western blot demonstrated high-level expression of VEGF-C and VEGFR-3 in the pterygium compared with normal conjunctiva. VEGF-C immunoreactivity was detected in the cytoplasm of pterygial and normal conjunctival epithelial cells. The number of VEGF-C-immunopositive cells in pterygial epithelial cells was significantly higher than in normal conjunctival cells (p < 0.05). VEGFR-3 immunoreactivity was localized in the D2-40-positive lymphatic endothelial cells. The present findings suggest the potential role of VEGF-C in the pathogenesis and development of a pterygium through lymphangiogenesis and the VEGF-C/VEGFR-3 pathway as a novel therapeutic target for the human pterygium. © 2012 Springer-Verlag.
• Induction of heat shock protein 70 ameliorates ultraviolet-induced photokeratitis in mice.

  Anton Lennikov, Nobuyoshi Kitaichi, Satoru Kase, Kousuke Noda, Yukihiro Horie, Akira Nakai, Shigeaki Ohno, Susumu Ishida

  International journal of molecular sciences 14 (1) 2175 - 89 2013/01/22 [Refereed][Not invited]
   

  Acute ultraviolet (UV) B exposure causes photokeratitis and induces apoptosis in corneal cells. Geranylgeranylacetone (GGA) is an acyclic polyisoprenoid that induces expression of heat shock protein (HSP)70, a soluble intracellular chaperone protein expressed in various tissues, protecting cells against stress conditions. We examined whether induction of HSP70 has therapeutic effects on UV-photokeratitis in mice. C57 BL/6 mice were divided into four groups, GGA-treated (500 mg/kg/mouse) and UVB-exposed (400 mJ/cm2), GGA-untreated UVB-exposed (400 mJ/cm2), GGA-treated (500 mg/kg/mouse) but not exposed and naive controls. Eyeballs were collected 24 h after irradiation, and corneas were stained with hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). HSP70, reactive oxygen species (ROS) production, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and protein kinase B (Akt) expression were also evaluated. Irradiated corneal epithelium was significantly thicker in the eyes of mice treated with GGA compared with those given the vehicle alone (p < 0.01). Significantly fewer TUNEL-positive cells were observed in the eyes of GGA-treated mice than controls after irradiation (p < 0.01). Corneal HSP70 levels were significantly elevated in corneas of mice treated with GGA (p < 0.05). ROS signal was not affected by GGA. NF-κB activation was reduced but phospho-(Ser/Ther) Akt substrate expression was increased in corneas after irradiation when treated with GGA. GGA-treatment induced HSP70 expression and ameliorated UV-induced corneal damage through the reduced NF-κB activation and possibly increased Akt phosphorilation.
• Autoimmune retinopathy associated with colonic adenoma

  Wataru Saito, Satoru Kase, Hiroshi Ohguro, Susumu Ishida

  Graefe's Archive for Clinical and Experimental Ophthalmology 251 (5) 1447 - 1449 0721-832X 2013 [Refereed][Not invited]
  
• Photodynamic therapy combined with intravitreal bevacizumab and sub-tenon triamcinolone acetonide injections for age-related macular degeneration

  Chikako Yoshizawa, Wataru Saito, Shigeki Hirose, Hirokuni Kitamei, Kousuke Noda, Susumu Ishida

  Japanese Journal of Ophthalmology 57 (1) 68 - 73 0021-5155 2013/01 [Refereed][Not invited]
   

  Purpose: To report the results of triple therapy with photodynamic therapy (PDT) (PDT combined with intravitreal injection of bevacizumab (IVB) and sub-tenon injection of triamcinolone acetonide (STTA)) for the treatment of age-related macular degeneration (AMD) in Japanese patients. Methods: This retrospective case series included 38 eyes of 38 patients with exudative AMD treated with PDT combined with IVB (1.25 mg) and STTA (40 mg). Retreatment was performed in the same manner with intervals of at least 3 months. All patients had been treatment naïve, with a follow-up period of 12 months. Best-corrected visual acuity (BCVA), macular retinal thickness (MRT) on optical coherence tomography, and the number of treatments were analyzed. Results: The mean logarithm of the minimum angle of resolution BCVA in patients treated with PDT triple therapy was 0.86 ± 0.55 at baseline and 0.62 ± 0.55 at 12 months (p < 0.001). The mean MRT was 554.0 ± 202.6 μm at baseline and 205.1 ± 78.6 μm at 12 months (p < 0.001). During the 1-year follow-up, the average number of PDT triple therapy (treatments per patient) was 1.1. No complications, for example increase in intraocular pressure, cataract, or endophthalmitis, were observed. Conclusions: In AMD patients, PDT triple therapy significantly improved visual acuity with a minimum number of treatments and a low risk of complications during the 1-year follow-up. © 2012 Japanese Ophthalmological Society.
• Identification of contamination in the American type culture collection stock of human adenovirus type 8 by whole-genome sequencing.

  Shotaro Yamane, Amanda Wei Ling Lee, Nozomu Hanaoka, Gabriel Gonzalez, Hisatoshi Kaneko, Susumu Ishida, Nobuyoshi Kitaichi, Shigeaki Ohno, Kanako O Koyanagi, Koki Aoki, Tsuguto Fujimoto, Nobuyo Yawata, Hidemi Watanabe

  Journal of virology 87 (2) 1285 - 6 0022-538X 2013/01 [Refereed][Not invited]
  
• Expression of Vascular Endothelial Growth Factor in Eyes with Coats' Disease

  Satoru Kase, Narsing A. Rao, Hiroshi Yoshikawa, Junichi Fukuhara, Kousuke Noda, Atsuhiro Kanda, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 54 (1) 57 - 62 0146-0404 2013/01 [Refereed][Not invited]
   

  PURPOSE. To examine the expression of vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR)-2 in enucleated eyes with Coats' disease. METHODS. Formalin-fixed, paraffin-embedded tissue sections from nine globes with Coats' disease were submitted for hematoxylin and eosin staining and immunohistochemistry with anti-VEGF and VEGFR antibodies. RESULTS. Histologically, the enucleated eyes demonstrated the presence of macrophage infiltration and cholesterol clefts in the subretinal space. There were marked retinal vascular abnormalities, including dilated vessels with hyalinized vessel walls in six globes. Exudative retinal detachment was noted in all globes. VEGF immunoreactivity was observed in macrophages infiltrating the subretinal space, and in the detached retina including several blood vessels. VEGF-positivity in macrophages was significantly higher in cases containing retinal vessel abnormalities than those without the abnormalities (P < 0.01). VEGFR-2 immunoreactivity was detected in endothelial cells lining the abnormal retinal vessels, where VEGFR-1 or VEGFR-3 was not expressed. CONCLUSIONS. Immunoreactivity for VEGF and VEGFR-2 was detected in macrophages and endothelia of abnormal vessels in eyes with Coats' disease. These results suggest that anti-VEGF approach is a promising therapy for patients with Coats' disease. (Invest Ophthalmol Vis Sci. 2013; 54: 57-62) DOI: 10.1167/iovs.12-10613
• Tissue Kallikrein Attenuates Choroidal Neovascularization via Cleavage of Vascular Endothelial Growth Factor

  Junichi Fukuhara, Kousuke Noda, Miyuki Murata, Shiho Namba, Satoshi Kinoshita, Zhenyu Dong, Ryo Ando, Anton Lennikov, Atsuhiro Kanda, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 54 (1) 274 - 279 0146-0404 2013/01 [Refereed][Not invited]
   

  PURPOSE. To investigate the antiangiogenic properties of tissue kallikrein in a murine model of laser-induced choroidal neovascularization (CNV). METHODS. CNV was induced in male C57BL/6J mice by laser photocoagulation. The animals received daily subcutaneous injections of tissue kallikrein (50 lg/kg) or vehicle control for 2 days before the laser photocoagulation, and this treatment continued until sample collection. Seven days after laser injury, the CNV size was quantified. The levels of monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and interleukin (IL)-6 were assessed by enzyme-linked immunosorbent assay 3 days after laser injury. Cleavage of mouse VEGF with tissue kallikrein was assessed in vivo and in vitro. The protein levels of bradykinin were assessed in the RPE-choroid complexes and hearts. RESULTS. A significant decrease in CNV size was observed in animals treated with tissue kallikrein (27,168.3 +/- 2432.2 mu m(2)) compared with vehicle-treated controls (36,374.6 +/- 3204.1 mu m(2), P < 0.05). Tissue kallikrein treatment significantly reduced MCP-1, ICAM-1, and IL-6 levels in RPE-choroid complexes. Furthermore, immunoblotting showed the bands, presumably corresponding to the fragmented VEGF(164) protein, in the samples of both mouse VEGF preincubated with tissue kallikrein and RPE-choroid complexes obtained from animals treated with tissue kallikrein. In addition, bradykinin was unchanged in the RPE-choroid complexes of animals treated with tissue kallikrein, whereas the level of bradykinin was increased in the heart obtained from these experimental animals. CONCLUSIONS. The current data indicate that kallikrein exhibits antiangiogenic properties by cleaving VEGF164 in a laser-induced CNV model. (Invest Ophthalmol Vis Sci. 2013; 54: 274279) DOI: 10.1167/iovs.12-10512
• Two cases of subfoveal choroidal neovascularization with tubulointerstitial nephritis and uveitis syndrome

  Yuko Takemoto, Kenichi Namba, Kazuomi Mizuuchi, Shigeaki Ohno, Susumu Ishida

  European Journal of Ophthalmology 23 (2) 255 - 257 1120-6721 2013 [Refereed][Not invited]
   

  Purpose. Tubulointerstitial nephritis and uveitis (TINU) syndrome usually shows anterior segment intraocular inflammation, but severe posterior segment intraocular inflammation is rarely observed. We report 2 children with TINU syndrome complicated by subfoveal choroidal neovascularization (CNV). Methods. Case reports. Results. Patients were a 12-year-old girl and a 12-year-old boy diagnosed with probable TINU syndrome on the basis of typical ocular findings and high value of urinary β2 microglobulin even though renal biopsy was not performed. The girl showed development of CNV with subretinal macular hemorrhage along with the exacerbation of anterior chamber inflammation in her left eye. Subretinal macular hemorrhage recurred frequently even with oral prednisolone therefore, intravitreal injection of bevacizumab (IVB) was performed. After IVB, the subretinal proliferative tissue shrunk and subretinal hemorrhage has not recurred for 5 years. The boy showed subretinal hemorrhage from CNV with severe anterior chamber inflammation in his left eye. With oral prednisolone, anterior chamber inflammation and subretinal hemorrhage disappeared, but shrunken subretinal fibrosis in the macula remained. Final visual acuity was poor due to residual subretinal fibrosis in both cases. Conclusions. Tubulointerstitial nephritis and uveitis syndrome has a potential to develop CNV that leads to severe visual loss therefore, prompt anti-inflammatory therapy is required, and IVB should be regarded as a potential choice of treatment. © 2013 Wichtig Editore.
• Bacterial endophthalmitis caused by an intraocular cilium in a patient under treatment with infliximab

  Xue-Hai Jin, Kenichi Namba, Wataru Saito, Daiju Iwata, Susumu Ishida

  Journal of Ophthalmic Inflammation and Infection 3 (1) 1 - 3 1869-5760 2013 [Refereed][Not invited]
   

  Background: We report a case of bacterial endophthalmitis caused by an intraocular cilium in a patient without any history of trauma or ocular surgery. Findings: A 32-year-old Caucasian male showed symptoms of orbital myositis and scleritis, with no intraocular inflammation in the right eye. The patient had been treated with infliximab for Crohn's disease. Three weeks after initiation of oral prednisolone therapy, he developed bacterial endophthalmitis. During pars plana vitrectomy, a cilium in the massive vitreous opacity was found. A focal scleral necrosis was detected just outside where the cilium was intraoperatively observed. Vitreous culture showed the presence of Staphylococcus aureus. Conclusions: The intraocular cilium seemed to be the aetiology of the endophthalmitis in this case, which suggests that anti-tumour necrosis factor-α therapy may play a role in the migration of cilia into the globe and the occurrence of endophthalmitis. © 2013 Jin et al.
• Angiopoietin-like protein 2 mediates endotoxin-induced acute inflammation in the eye

  Atsuhiro Kanda, Kousuke Noda, Yuichi Oike, Susumu Ishida

  LABORATORY INVESTIGATION 92 (11) 1553 - 1563 0023-6837 2012/11 [Refereed][Not invited]
   

  Angiopoietin-like protein (Angptl) 2 is a key mediator linking obesity to chronic adipose-tissue inflammation and systemic insulin resistance, and increasing evidence has shown that Angptl2 is associated with various chronic inflammatory diseases such as cancer and dermatomyositis; however, it remains unclear that Angptl2 functions in acute inflammation. In this study, we investigate whether Angptl2 has a role in acute inflammation in the eye with endotoxin-induced uveitis (EIU). Angptl2 was widely expressed in the normal mouse retina, while Angptl2(-/-) mice did not exhibit any changes in retinal cell marker expression and morphological analyses. Treatment with lipopolysaccharide (LPS) stimulated retinal Angptl2 mRNA expression in vivo and in vitro. We generated EIU in wild-type (C57BL/6) and Angptl2(-/-) mice by injecting LPS intraperitoneally. Compared with wild-type animals, Angptl2(-/-) mice significantly reduced various EIU-associated cellular and molecular parameters including leukocyte adhesion to the retinal vessels and infiltration into the vitreous cavity and retinal mRNA expression levels of monocyte chemotactic protein-1, intercellular adhesion molecule-1, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha, together with nuclear translocation of nuclear factor (NF)-kappa B p65 subunit. In vitro, antibody-based inhibition of alpha 5 beta 1 integrin, a receptor for Angptl2, significantly repressed LPS-induced expression of IL-6 and TNF-alpha, both of which are the major inflammatory cytokines derived from macrophages. The present findings indicate that Angptl2 mediates endotoxin-induced retinal inflammation through the activation of NF-kappa B signaling pathway and suggest a potential validity of Angptl2 as a new molecular target for the treatment of acute inflammation. Laboratory Investigation (2012) 92, 1553-1563; doi:10.1038/labinvest.2012.111; published online 6 August 2012
• 正常眼における中心窩の錐体外節端(COST)形態と視細胞外節(PROS)長の年代別検討

  橋本 勇希, 齋藤 航, 齋藤 理幸, 高橋 亜衣, 藤谷 顕雄, 吉澤 史子, 野田 航介, 石田 晋

  日本視能矯正学会プログラム抄録集 日本視能矯正学会 53回 46 - 46 2012/11
• 網膜中心静脈閉塞症を合併したacute macular neuroretinopathyの1例

  廣岡 季里子, 齋藤 航, 橋本 勇希, 齋藤 理幸, 吉澤 史子, 野田 航介, 石田 晋

  日本視能矯正学会プログラム抄録集 日本視能矯正学会 53回 55 - 55 2012/11
• 健常成人における錐体外節端(COST)ラインの範囲

  高橋 亜衣, 齋藤 航, 橋本 勇希, 齋藤 理幸, 藤谷 顕雄, 吉澤 史子, 野田 航介, 石田 晋

  日本視能矯正学会プログラム抄録集 日本視能矯正学会 53回 67 - 67 2012/11
• (Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

  A. Kanda, K. Noda, W. Saito, S. Ishida

  DIABETOLOGIA 55 (11) 3104 - 3113 0012-186X 2012/11 [Refereed][Not invited]
   

  The renin-angiotensin system (RAS) potentially has a role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor for diabetic retinopathy. We have recently shown significant involvement of (pro)renin receptor ([P]RR) in retinal inflammation in a rodent model of early diabetes. In this study we aim to elucidate the (P)RR-associated pathogenesis of fibrovascular proliferation, a late-stage angiogenic complication in human diabetic retinopathy. Vitreous fluids from 23 eyes of patients with proliferative diabetic retinopathy (PDR) and 16 eyes of controls with non-diabetic, idiopathic macular diseases (macular hole and epiretinal membrane) were collected. Protein levels of soluble (P)RR were measured by ELISA, and immunofluorescence was performed to assess the localisation of (P)RR and related molecules in fibrovascular tissues from PDR eyes. (P)RR immunoreactivity was detected in neovascular endothelial cells, colocalised with prorenin, phosphorylated extracellular signal-regulated kinase (ERK) and vascular endothelial growth factor (VEGF). Prorenin application to human retinal microvascular endothelial cells significantly upregulated mRNA expression of VEGF, especially the VEGF165 isoform, which was abolished by (P)RR or ERK signalling blockade. Proteases known to cleave (P)RR, including furin, were positive in endothelial cells in fibrovascular tissues. Protein levels of soluble (P)RR in vitreous fluids were higher in PDR eyes than in non-diabetic control eyes, and correlated significantly with vitreous prorenin and VEGF levels and the vascular density of fibrovascular tissues. Our data using human samples provide the first evidence that (P)RR is associated with angiogenic activity in PDR.
• Increased macular choroidal blood flow velocity during systemic corticosteroid therapy in a patient with acute macular neuroretinopathy

  Yuki Hashimoto, Wataru Saito, Shohei Mori, Michiyuki Saito, Susumu Ishida

  Clinical Ophthalmology 6 (1) 1645 - 1649 1177-5467 2012/10/08 [Refereed][Not invited]
   

  Purpose: The precise mechanism causing outer retinal damage in acute macular neuroretinopathy (AMN) remains unclear. In this study, choroidal blood flow velocity was quantitatively evaluated using laser speckle flowgraphy (LSFG) in a patient with AMN who received systemic corticosteroid therapy. Methods: Corticosteroids were systemically administrated across 4 months for an AMN patient. LSFG measurements were taken ten consecutive times before treatment and at 1 week and 1, 3, and 10 months after the onset of therapy. The square blur rate, a quantitative index of relative blood flow velocity, was calculated using LSFG in three regions: Square 1, the macular lesion with findings of severe multifocal electroretinography amplitude reduction, and Squares 2 and 3, funduscopically normal-appearing retinal areas with findings of moderate and mild multifocal electroretinography amplitude reduction, respectively. Results: The AMN lesion gradually decreased after treatment and improved results were detected on the Amsler chart, as well as on optical coherence tomography and scanning laser ophthalmoscopy. When the changing rates of the macular flow were compared with the mean square blur rate level before treatment (100%), 14.6%, 24.5%, 12.9%, and 16.3% increases were detected in Square 1 (macular lesion) at 1 week and 1, 3, and 10 months after treatment, respectively. Similarly, in Square 2 (normal-appearing area next to the lesion), 12.6%, 18.6%, 6.7%, and 8.3% increases were also noted at 1 week and 1, 3, and 10 months after treatment, respectively. In Square 3 (normal-appearing area apart from the lesion), 16.0%, 15.1%, 19.1%, and 3.8% increases were measured at 1 week and 1, 3, and 10 months after treatment, respectively. Conclusion: In a patient with AMN, choroidal blood flow velocity at the lesion site, which was examined with LSFG, sequentially increased during systemic corticosteroid therapy, together with improvement of visual function. The present findings suggest that choroidal circulation impairment relates to the pathogenesis of AMN, extending over a wider area in the posterior pole than the site of an AMN lesion per se. © 2012 Hashimoto et al, publisher and licensee Dove Medical Press Ltd.
• Amelioration of endotoxin-induced uveitis treated with an I kappa B kinase beta inhibitor in rats

  Anton Lennikov, Nobuyoshi Kitaichi, Kousuke Noda, Ryo Ando, Zhenyu Dong, Junichi Fukuhara, Satoshi Kinoshita, Kenichi Namba, Miho Mizutani, Tomoyuki Fujikawa, Akiko Itai, Shigeaki Ohno, Susumu Ishida

  MOLECULAR VISION 18 (267-70) 2586 - 2597 1090-0535 2012/10 [Refereed][Not invited]
   

  Purpose: Endotoxin-induced uveitis (EIU) is an animal model for acute ocular inflammation. Several substances play major roles in the development of inflammatory changes in EIU, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, and IL-6. These inflammatory cytokines trigger the degradation of I kappa B by activating I kappa B kinases (IKKs). Released nuclear factor kappaB (NF kappa B) subsequently translocates to the nucleus, where NF kappa B expresses its proinflammatory function. IMD-0354, N-(3,5-Bis-trifluoromethylphenyl)-5-chloro-2-hydroxybenzamide, selectively inhibits IKK beta, particularly when induced by proinflammatory cytokines, such as TNF-alpha and IL-1 beta. In the present study, we examined whether IKK beta inhibition has therapeutic effects on EIU by using IMD-0354 and its prodrug IMD-1041. Methods: Six-week-old male Lewis rats were used. EIU was induced with subcutaneous injections of 200 mu g of lipopolysaccharide (LPS) from Escherichia coli that had been diluted in 0.1 ml of phosphate-buffered saline. IMD-0354 was administered intraperitoneally at 30, 10, 3, or 0 mg/kg, suspended in 1.0 ml of 0.5% carboxymethyl cellulose sodium. The prodrug IMD-1041 (100 mg/kg) was also administered orally. The rats were euthanized 24 h after LPS injection, and EIU severity was evaluated histologically. The number of infiltrating cells and the protein, TNF-alpha, and monocyte chemoattractant protein-1 (MCP-1) concentrations in the aqueous humor were determined. TNF-alpha and MCP-1 concentrations were quantified with enzyme-linked immunosorbent assay. Eye sections were also stained with anti-NF kappa B and phosphorylated I-kappa B alpha antibodies. Results: The number of infiltrating cells in aqueous humor was 53.6 +/- 9.8x10(5), 72.5 +/- 17.0x10(5), 127.25 +/- 32.0x10(5), and 132.0 +/- 25.0x10(5) cells/ml in rats treated with 30, 10, 3, or 0 mg/kg of IMD-0354, respectively. The total protein concentrations of aqueous humor were 92.6 +/- 3.1 mg/ml, 101.5 +/- 6.8 mg/ml, 112.6 +/- 1.9 mg/ml, and 117.33 +/- 1.8 mg/ml in rats treated with 30, 10, 3, and 0 mg/kg of IMD-0354, respectively. Infiltrating cells and protein concentrations were significantly decreased by treatment with IMD-0354 (p < 0.01). IMD-0354 treatment significantly reduced the concentration of TNF-alpha (p < 0.05) and MCP-1 (p < 0.01) in aqueous humor. The number of NF kappa B positive nuclei was reduced when treated with IMD-0354. Furthermore, IMD-0354-treated EIU rats showed only background levels of phosphorylated I-kappa B alpha; however, it was strongly expressed in the iris-ciliary body cell cytoplasm of the IMD-0354 untreated EIU rats. Oral administration of IMD-1041 also decreased the cell number (p < 0.01) and protein concentration (p < 0.05) of aqueous humor in EIU. Conclusions: Acute uveitis was ameliorated by inhibition of IKK beta in rats. IMD-0354 and its prodrug IMD-1041 seem to be promising candidates for treating intraocular inflammation/uveitis.
• Clinical Features of Central Retinal Vein Occlusion With Inflammatory Etiology.

  Yoshizawa C, Saito W, Kase M, Ishida S

  Asia-Pacific journal of ophthalmology (Philadelphia, Pa.) 1 (5) 270 - 276 2012/09 [Refereed][Not invited]
  
• Conjunctival lymphoma arising from reactive lymphoid hyperplasia

  Junichi Fukuhara, Satoru Kase, Mika Noda, Kan Ishijima, Teppei Yamamoto, Susumu Ishida

  WORLD JOURNAL OF SURGICAL ONCOLOGY 10 194  1477-7819 2012/09 [Refereed][Not invited]
   

  Extra nodal marginal zone B-cell lymphoma (EMZL) of the conjunctiva typically arises in the marginal zone of mucosa-associated lymphoid tissue. The pathogenesis of conjunctival EMZL remains unknown. We describe an unusual case of EMZL arising from reactive lymphoid hyperplasia (RLH) of the conjunctiva. A 35-year-old woman had fleshy salmon-pink conjunctival tumors in both eyes, oculus uterque (OU). Specimens from conjunctival tumors in the right eye, oculus dexter (OD), revealed a collection of small lymphoid cells in the stroma. Immunohistochemically, immunoglobulin (Ig) light chain restriction was not detected. In contrast, diffuse atypical lymphoid cell infiltration was noted in the left eye, oculus sinister (OS), and positive for CD20, a marker for B cells OS. The tumors were histologically diagnosed as RLH OD, and EMZL OS. PCR analysis detected IgH gene rearrangement in the joining region (JH) region OU. After 11 months, a re-biopsy specimen demonstrated EMZL based on compatible pathological and genetic findings OD, arising from RLH. This case suggests that even if the diagnosis of the conjunctival lymphoproliferative lesions is histologically benign, confirmation of the B-cell clonality by checking IgH gene rearrangement should be useful to predict the incidence of malignancy.
• Reduction of Intraocular Pressure Using a Modified 360-degree Suture Trabeculotomy Technique in Primary and Secondary Open-Angle Glaucoma: A Pilot Study

  Shinki Chin, Takuya Nitta, Yasuhiro Shinmei, Maiko Aoyagi, Akari Nitta, Shigeaki Ohno, Susumu Ishida, Kazuhiko Yoshida

  JOURNAL OF GLAUCOMA 21 (6) 401 - 407 1057-0829 2012/08 [Refereed][Not invited]
   

  Purpose: To investigate the effects of a modified 360-degree suture trabeculotomy technique for primary and secondary open-angle glaucoma (POAG and SOAG). Methods: We modified the procedure for 360-degree trabeculotomy by using a 5-0 nylon suture, making a scleral flap to allow clear identification of Schlemm canal, and creating a corneal side port incision opposite to the scleral flap to retrieve the suture used to cannulate and cleave the canal. The modified 360-degree suture trabeculotomy (not combined with cataract surgery) was performed on 25 eyes with POAG and 18 eyes with SOAG, and the results were compared retrospectively with those of standard trabeculotomy with metal trabeculotomes (16 eyes with POAG and 19 eyes with SOAG). When the intraocular pressure (IOP) was reduced by 30% from the preoperative IOP and was also below 18 mm Hg at 3, 6, 9, 12, and 18 months after surgery and the patient was taking a similar number or fewer medications, the surgery was considered a "success." Results: Using this modified technique, Schlemm canal was appropriately incised without resistance. At 12 months after the modified 360-degree suture trabeculotomy and trabeculotomy with metal trabeculotomes, the mean postoperative IOP values were 13.1 and 15.2 mm Hg, respectively, and the mean numbers of antiglaucoma medications were 0.5 and 1.4, respectively. The success rates of POAG at 12 months for the modified 360-degree suture trabeculotomy and trabeculotomy with metal trabeculotomes were 84% and 31%, respectively, and those of SOAG were 89% and 50%, respectively. The complications included a transient elevation of the IOP above 30 mm Hg in 22 eyes (47%) treated with the 360-degree suture trabeculotomy and 17 eyes (49%) treated with trabeculotomy with metal trabeculotomes. There was no significant difference between preoperative visual acuity and postoperative visual acuity in either procedure. Conclusions: This modified 360-degree suture trabeculotomy is a feasible surgical option for POAG and SOAG.
• Presence and Physiologic Function of the Renin-Angiotensin System in Mouse Lacrimal Gland

  Saori Yaguchi, Yoko Ogawa, Shigeto Shimmura, Shin Hatou, Shigeru Nakamura, Takaaki Inaba, Toshihiro Imada, Yoko Ozawa, Yutaka Kawakami, Susumu Ishida, Kazuo Tsubota

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 53 (9) 5416 - 5425 0146-0404 2012/08 [Refereed][Not invited]
   

  PURPOSE. To investigate the expression, localization, and physiologic function of renin-angiotensin system (RAS) components in the mouse lacrimal gland. METHODS. Lacrimal glands and cultured lacrimal gland fibroblasts from wild-type (WT) BALB/c (H-2(d)) mice were used. Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry were used to determine the expression and localization of the RAS components, prorenin/renin, angiotensin-converting enzyme (ACE), angiotensin II, angiotensin II type 1 receptor (AT1R), and angiotensin II type 2 receptor (AT2R) in the normal mouse lacrimal gland. To examine the change in tear secretion, mice received ARB (AT1R blocker) or AT2R antagonist. Tear secretion was assessed by cotton thread test before and after drug administration. RESULTS. The mRNAs coding for angiotensinogen, prorenin, ACE, and both AT1R and AT2R were found in normal lacrimal gland tissue and cultured lacrimal gland fibroblasts. Prorenin/renin and ACE were identified in myoepithelial cells around ducts and acini and in blood vessels. Angiotensin II, AT1R, and AT2R were observed in the ducts and interstitial fibroblasts. AT1R and AT2R were also localized in blood vessels. All the cultured lacrimal gland fibroblasts expressed angiotensin II, AT1R, and AT2R. Tear secretion increased in mice that received ARB. CONCLUSIONS. The results are consistent with the hypothesis that a tissue-specific RAS is present in the lacrimal gland, and suggest that fibroblasts are one of the cell types playing a role in the tissue RAS. Tissue RAS might be involved in tissue function of regulating tear secretion in the lacrimal gland. (Invest Ophthalmol Vis Sci. 2012;53:5416-5425) DOI: 10.1167/iovs.12-9891
• Correlation between elevation of serum antinuclear antibody titer and decreased therapeutic efficacy in the treatment of Beh double dagger et's disease with infliximab

  Daiju Iwata, Kenichi Namba, Kazuomi Mizuuchi, Nobuyoshi Kitaichi, Satoru Kase, Yuko Takemoto, Shigeaki Ohno, Susumu Ishida

  GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 250 (7) 1081 - 1087 0721-832X 2012/07 [Refereed][Not invited]
   

  Infliximab, an anti-TNF-alpha monoclonal antibody, administered to Beh double dagger et's disease (BD) patients in Japan with refractory intraocular inflammation, has shown excellent clinical results. However, some patients demonstrate a decreased response to infliximab during the course of the treatment. In the present study, we investigated the correlation between this reduced therapeutic effect and elevation of the serum antinuclear antibody (ANA) titers in patients with BD who were undergoing infliximab therapy. Seventeen patients (14 males and three females) with uveitis in BD who were undergoing treatment with infliximab for 2 years or longer were enrolled. Their blood test results and clinical histories were obtained from medical records. One patient (5.9%) was ANA-positive prior to the initiation of infliximab, and 11 patients (64.7%) developed positive ANA during the therapy. The appearance of ANA was observed 6 months after the initiation of the infliximab therapy, and its titers gradually increased. None of the patients showed lupus symptoms. Five patients (29.4%) have suffered from ocular inflammatory attacks since the sixth month from the initiation of infliximab treatment and all of them were ANA-positive. In contrast, four patients (23.5%) who were ANA-negative experienced no ocular attacks during the follow-up period. Here we report the positive conversion and subsequent elevation of serum ANA titers in some patients with BD after the initiation of infliximab therapy. Since all recurrences of uveitis were shown only in the ANA-positive patients, serum ANA titer may be a helpful biomarker for predicting the recurrence of ocular attacks in BD patients treated with anti-TNF-alpha antibody therapies.
• [Etiology of diabetic retinopathy].

  Ishida S

  Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 5 343 - 348 0047-1852 2012/07 [Refereed][Not invited]
  
• Replication of a microsatellite genome-wide association study of Behcet's disease in a Korean population

  Yukihiro Horie, Akira Meguro, Nobuyoshi Kitaichi, Eun Bong Lee, Atsuhiro Kanda, Kousuke Noda, Yeong Wook Song, Kyung Sook Park, Kenichi Namba, Masao Ota, Hidetoshi Inoko, Nobuhisa Mizuki, Susumu Ishida, Shigeaki Ohno

  RHEUMATOLOGY 51 (6) 983 - 986 1462-0324 2012/06 [Refereed][Not invited]
   

  Objective. Behcet's disease is one of the major aetiologies of uveitis causing blindness in Asian countries. A genome-wide association study identified six microsatellite markers as disease susceptibility loci for Japanese patients with Behcet's disease. To confirm our recent results, these microsatellite markers were examined in a Korean population as a replication study. Methods. Study participants included 119 Behcet's disease patients and 141 controls. All were enrolled in Korea. Association between the six reported microsatellite markers (D3S0186i, D6S0014i, D6S0032i, 536G12A, D12S0645i and D22S0104i) and Behcet's disease was analysed. HLA-B was genotyped by sequence-based typing methods. Results. A microsatellite marker located near the HLA-B region demonstrated significant association with Behcet's disease (P = 0.028). The genotype and phenotype frequencies of the HLA-B*51 gene were significantly increased in patients (23.1 and 39.5%, respectively) compared with healthy controls (11.2 and 20.1%, respectively; P < 0.001). Conclusion. Microsatellite analysis revealed that the HLA-B*51 gene was strongly associated with Behcet's disease in a Korean population.
• ALPHAB-CRYSTALLIN EXPRESSION IN EPIRETINAL MEMBRANE OF HUMAN PROLIFERATIVE DIABETIC RETINOPATHY

  Zhenyu Dong, Satoru Kase, Ryo Ando, Junichi Fukuhara, Wataru Saito, Atsuhiro Kanda, Miyuki Murata, Kousuke Noda, Susumu Ishida

  RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES 32 (6) 1190 - 1196 0275-004X 2012/06 [Refereed][Not invited]
   

  Purpose: To examine the expression of alphaB-crystallin and its colocalization with vascular endothelial growth factor in the epiretinal membrane of human proliferative diabetic retinopathy. Methods: Ten epiretinal membranes of proliferative diabetic retinopathy and three normal retinas surgically excised were included in this study. Paraformaldehyde-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry with alphaB-crystallin, vascular endothelial growth factor, and CD31 antibodies. Results: AlphaB-crystallin was expressed in all epiretinal membranes examined. The immunolocalization of alphaB-crystallin was detected in the cytoplasm of CD31-positive endothelial cells, but not in normal retinal blood vessels. Furthermore, alphaB-crystallin immunoreactivity was colocalized in vascular endothelial growth factor-positive endothelial cells in proliferative diabetic retinopathy membranes. Conclusion: AlphaB-crystallin was expressed in proliferative diabetic retinopathy membranes, and colocalized with vascular endothelial growth factor-positive neovessels. AlphaB-crystallin may play a potential role in the pathogenesis of epiretinal membranes in proliferative diabetic retinopathy, together with vascular endothelial growth factor. RETINA 32:1190-1196, 2012
• Soluble Vascular Adhesion Protein-1 Accumulates in Proliferative Diabetic Retinopathy

  Miyuki Murata, Kousuke Noda, Junichi Fukuhara, Atsuhiro Kanda, Satoru Kase, Wataru Saito, Yoko Ozawa, Satsuki Mochizuki, Shioko Kimura, Yukihiko Mashima, Yasunori Okada, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 53 (7) 4055 - 4062 0146-0404 2012/06 [Refereed][Not invited]
   

  PURPOSE. Vascular adhesion protein (VAP)-1, a multifunctional molecule with adhesive and enzymatic properties, is expressed at the surface of vascular endothelial cells of mammals. It also exists as a soluble form (sVAP-1), which is implicated in oxidative stress via its enzymatic activity. This study explores a link between increased level of sVAP-1 and oxidative stress in proliferative diabetic retinopathy (PDR) with a focus on mechanistic components to form sVAP-1 by shedding from retinal endothelial cells. METHODS. Protein levels of sVAP-1 and N epsilon-(hexanoyl) lysine (HEL), an oxidative stress marker, in the vitreous samples from patients with PDR or non-PDR were measured by ELISA. The mechanism of VAP-1 shedding under diabetic condition, exposure to high glucose and/or inflammatory cytokines, was explored using cultured retinal capillary endothelial cells. RESULTS. Protein level of sVAP-1 was increased and correlated with HEL in the vitreous fluid of patients with PDR. Retinal capillary endothelial cells released sVAP-1 when stimulated with high glucose or inflammatory cytokines, such as TNF-alpha and IL-1 beta in vitro. Furthermore, matrix metalloproteinase-2 and -9, type IV collagenases, were the key molecules to mediate the protein cleavage of VAP-1 from retinal capillary endothelial cells. CONCLUSIONS. Our data for the first time provide evidence on the link between sVAP-1 and type IV collagenases in the pathogenesis of PDR. (Invest Ophthalmol Vis Sci. 2012;53:4055-4062) DOI:10.1167/iovs.12-9857
• Receptor-associated prorenin system in the pathogenesis of retinal diseases

  Shingo Satofuka, Atsuhiro Kanda, Susumu Ishida

  Frontiers in Bioscience - Scholar 4 (4) 1449 - 1460 1945-0516 2012/06/01 [Refereed][Not invited]
   

  Receptor-associated prorenin system (RAPS) refers to the pathogenic mechanisms whereby prorenin binding to (pro)renin receptor [(P)RR] dually activates tissue renin-angiotensin system (RAS) and RASindependent intracellular signaling through the receptor. Although we found significant involvement of angiotensin II type 1 receptor (AT1-R) in intraocular inflammation and neovascularization, central pathologies of age-related macular degeneration and diabetic retinopathy, the association of RAPS with these vision-threatening disorders has not been defined. (P)RR blockade to murine disease models led to significant suppression of laserinduced choroidal neovascularization and diabetes-induced retinal inflammation together with the upregulation of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1 and vascular endothelial growth factor (VEGF). Either the genetic ablation or the pharmacological blockade of AT1-R exhibited significant reduction of choroidal and retinal abnormalities, both of which were further suppressed by (P)RR blockade. (P)RR blockade inhibited ERK activation and the production of VEGF and MCP-1, but not ICAM-1, in AT1-R-deficient mice with retinal and choroidal disorders. These recent findings indicate significant contribution of RAPS to the pathogenesis of age-related macular degeneration and diabetic retinopathy.
• Biological role of lutein in the light-induced retinal degeneration

  Mariko Sasaki, Kenya Yuki, Toshihide Kurihara, Seiji Miyake, Kosuke Noda, Saori Kobayashi, Susumu Ishida, Kazuo Tsubota, Yoko Ozawa

  JOURNAL OF NUTRITIONAL BIOCHEMISTRY 23 (5) 423 - 429 0955-2863 2012/05 [Refereed][Not invited]
   

  Lutein, a xanthophyll of a carotenoid, is anticipated as a therapeutic product to prevent human eye diseases. However, its biological mechanism is still unclear. Here, we show the molecular mechanism of lutein's effect to reduce photodamage of the retina. We analyzed the light-exposed retinas of Balb/c mice given lutein-supplemented or normal diet. Visual function was measured by electroretinogram, and histological changes were observed. Immunohistochemical and immunoblot analyses were performed to analyze molecular mechanism. The reactive oxygen species induced in the retina was evaluated by fluorescent probes. In the mice after light exposure, reduction of a-wave and b-wave amplitudes in electroretinogram, indicating visual impairment, and thinning of the photoreceptor cell layer owing to apoptosis were both attenuated by lutein diet. Interestingly, gamma-H2AX, a marker for double-strand breaks (DSBs) in DNA, was up-regulated in the photoreceptor cells after light exposure, but this increase was attenuated by lutein diet, suggesting that DSBs caused by photodamage contributed to the photoreceptor cell death and that this change was suppressed by lutein. Moreover, the expression of eyes absent (EYA), which promotes DNA repair and cell survival, was significantly up-regulated with lutein diet in the light-exposed retina. Therefore, lutein induced EYA for DNA repair, which could suppress DNA damage and photoreceptor cell apoptosis. Lutein reduced light-induced oxidative stress in the retina, which might contribute to promote DNA repair. The lutein-supplemented diet attenuated light-induced visual impairment by protecting the photoreceptor cells' DNA. (C) 2012 Elsevier Inc. All rights reserved.
• Spontaneous Regression of Intraocular Lymphoma

  Satoru Kase, Kenichi Namba, Xue-Hai Jin, Kanako C. Kubota, Susumu Ishida

  OPHTHALMOLOGY 119 (5) 1083 - 1084 0161-6420 2012/05 [Refereed][Not invited]
  
• Chickenpox chorioretinitis with retinal exudates and periphlebitis.

  Hirokuni Kitamei, Kenichi Namba, Nobuyoshi Kitaichi, Akiko Wakayama, Shigeaki Ohno, Susumu Ishida

  Case reports in ophthalmology 3 (2) 180 - 4 2012/05 [Refereed][Not invited]
   

  BACKGROUND: Chickenpox is rarely associated with posterior segment inflammation. We report on a case of unilateral chickenpox chorioretinitis with retinal exudates and periphlebitis. CASE PRESENTATION: A 21-year-old healthy man, who suffered from chickenpox 2 weeks prior to symptom development, exhibited mild anterior chamber cells, vitreous opacity, sheathing of retinal veins, and yellow-white exudates in his right eye. Varicella zoster virus DNA was detected by polymerase chain reaction in the aqueous humor. He was treated with intravenous acyclovir followed by oral prednisolone and valaciclovir. Aqueous cells quickly disappeared and retinal exudates diminished within 1 month, leaving faint retinal scarring. Retinal arteritis had never been observed in this patient. CONCLUSIONS: ALTHOUGH THE OCULAR FINDINGS IN THIS CASE WERE SIMILAR TO ACUTE RETINAL NECROSIS (ARN), THE CLINICAL FEATURES DIFFERED FROM ARN IN THE FOLLOWING POINTS: (1) mild anterior chamber inflammation, (2) absence of retinal arteritis, and (3) prompt resolution of inflammatory findings. The distinctive clinical features indicated that chorioretinitis associated with chickenpox may not have the same pathological conditions as ARN.
• Blockade of vascular adhesion protein-1 attenuates choroidal neovascularization

  Nami Yoshikawa, Kousuke Noda, Yoko Ozawa, Kazuo Tsubota, Yukihiko Mashima, Susumu Ishida

  MOLECULAR VISION 18 (60-65) 593 - 600 1090-0535 2012/03 [Refereed][Not invited]
   

  Purpose: Vascular adhesion protein (VAP)-1 is an adhesion molecule elucidated as a mediator of the leukocyte recruitment cascade. The purpose of this study was to investigate the role of VAP-1 in ocular inflammatory neovascularization using a mouse laser-induced choroidal neovascularization (CNV) model. Methods: CNV was induced with 532 nm laser irradiation in C57BL/6 mice, and production of VAP-1 protein in the retinal pigment epithelium (RPE) choroid during CNV formation was examined. CNV animals were treated with the specific VAP-1 inhibitor U-V002 or vehicle solution, and the volume of CNV tissue was evaluated with volumetric measurements. Macrophage infiltration into the CNV lesions was evaluated using two different techniques, flatmount staining and real-time polymerase chain reaction (PCR) for F4/80. The protein levels of intercellular adhesion molecule (ICAM)-1, monocyte chemoattractant protein (MCP)-1, P-selectin, and vascular endothelial growth factor (VEGF) in the RPE-choroid were measured with enzyme-linked immunosorbent assay (ELISA). Results: VAP-1 inhibition significantly suppressed CNV formation in a dose-dependent manner and reduced macrophage infiltration into CNV lesions. Furthermore, VAP-1 blockade decreased the expression of ICAM-1 and MCP-1, both of which play a pivotal role in macrophage recruitment. Conclusions: Our data suggest VAP-1 has an important role during ocular inflammatory neovascularization through leukocyte recruitment. VAP-1 inhibition may be a novel and potent therapeutic strategy in treating CNV formation.
• Expression of alpha-crystallin in the retina of human sympathetic ophthalmia

  Satoru Kase, Beeran B. Meghpara, Susumu Ishida, Narsing A. Rao

  MOLECULAR MEDICINE REPORTS 5 (2) 395 - 399 1791-2997 2012/02 [Refereed][Not invited]
   

  Sympathetic ophthalmia (SO) is a bilateral, granulomatous, intraocular inflammation that occurs following a penetrating injury to one eye, and has the potential to cause blindness of both eyes. The aim of this study was to examine the expression of alpha-crystallin and to detect apoptotic cells in the retina of human eyes with SO. Five globes, including three with SO and two age-matched normal appearing retinae, were examined. Formal in-fixed, paraffin-embedded tissue sections were submitted to hematoxylin and eosin staining and immunohistochemistry with anti-alpha A and alpha B-crystallin antibodies. Apoptotic cells were detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) method, and double-staining immunohistochemistry was conducted together with the TUNEL reaction. In normal-appearing retina, alpha A-crystallin immunoreactivity was predominantly detected in the cytoplasm of photoreceptors, where alpha B-crystallin was less marked. In SO globes, granulomatous inflammation was noted in the choroid, whereas the retina and choriocapillaris were preserved. Immunoreactivity for alpha A-crystallin was detected in the retina, as well as in the cytoplasm and inner/outer photoreceptor segments. By contrast, alpha B-crystall in was weakly noted in the SO retina. Double-staining immunohistochemistry revealed no TUNEL-positive photoreceptors in the retina displaying high immunoreactivity for alpha A-crystallin, but photoreceptor apoptosis was noted where expression of alpha A-crystallin was relatively low. The present study demonstrated that alpha A-crystalin was up-regulated in the cytoplasm of photoreceptors in the SO retina. This may play a protective role in the suppression of photoreceptor apoptosis associated with intraocular inflammation.
• Astaxanthin increases choroidal blood flow velocity

  Michiyuki Saito, Kazuhiko Yoshida, Wataru Saito, Akio Fujiya, Kazuhiro Ohgami, Nobuyoshi Kitaichi, Hiroki Tsukahara, Susumu Ishida, Shigeaki Ohno

  GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 250 (2) 239 - 245 0721-832X 2012/02 [Refereed][Not invited]
   

  Previous studies have reported that astaxanthin (AXT) has antioxidative and anti-inflammatory effects in addition to its ability to shorten blood transit times. As laser speckle flowgraphy (LSFG) can noninvasively visualize the hemodynamics of the choroidal circulation, we used the technique to evaluate whether continuous ingestion of 12 mg of AXT per day could increase quantitative blood flow velocity. In this randomized, double-blind, placebo-controlled study, we examined 20 healthy volunteers who ingested 12 mg AXT or placebo capsules over a 4-week period. LSFG was measured in the right eyes of all subjects at pre-ingestion, and at 2 and 4 weeks after the treatment of AXT. LSFG values were used to calculate the square blur rate (SBR), which is a quantitative index of relative blood flow velocity. A significant increase of the macular SBR was seen 4 weeks after AXT ingestion when compared to the pre-ingestion values (Wilcoxon signed-rank test, P = 0.018). In contrast, no statistical difference in the macular SBR was detected in the placebo group (Friedman test, P = 0.598). No subjective or objective adverse events were found after the 12-mg AXT ingestion. Results suggest that administration of AXT over a 4-week period can elevate the choroidal blood flow velocity without any adverse effects.
• Leukocyte Adhesion Molecules in Diabetic Retinopathy

  Kousuke Noda, Shintaro Nakao, Susumu Ishida, Tatsuro Ishibashi

  JOURNAL OF OPHTHALMOLOGY 2012 279037  2090-004X 2012 [Refereed][Not invited]
   

  Diabetes is a systemic disease that causes a number of metabolic and physiologic abnormalities. One of the major microvascular complications of diabetes is diabetic retinopathy (DR), a leading cause of blindness in people over age 50. The mechanisms underlying the development of DR are not fully understood; however, extensive studies have recently implicated chronic, low-grade inflammation in the pathophysiology of DR. During inflammation leukocytes undergo sequential adhesive interactions with endothelial cells to migrate into the inflamed tissues, a process known as the "leukocyte recruitment cascade" which is orchestrated by precise adhesion molecule expression on the cell surface of leukocytes and the endothelium. This paper summarizes the recent clinical and preclinical works on the roles of leukocyte adhesion molecules in DR.
• Immunolocalization of Vascular Adhesion Protein-1 in Human Conjunctival Tumors

  Junichi Fukuhara, Satoru Kase, Kousuke Noda, Miyuki Murata, Mika Noda, Ryo Ando, Zhenyu Dong, Atsuhiro Kanda, Susumu Ishida

  OPHTHALMIC RESEARCH 48 (1) 33 - 37 0030-3747 2012 [Refereed][Not invited]
   

  Objective: We analyzed the expression and immunolocalization of vascular adhesion protein (VAP)-1 in conjunctival tumors and normal conjunctival tissue of humans. Methods: Nine conjunctival tumors, including pyogenic granuloma and extranodal marginal zone B-cell lymphoma (EMZL), and 2 normal conjunctivas were analyzed by immunohistochemistry for VAP-1 and CD31 expression. Results: Immunoreactivity for VAP-1 was detected in the lumen of microvessels in pyogenic granuloma and in EMZLs. In contrast, normal bulbar conjunctival tissues demonstrated weak cytoplasmic immunoreactivity for VAP-1 in the blood vessels. Conclusions: The immunolocalization of VAP-1 varied in the histopathology of the conjunctiva, involving the pathology of inflammatory conjunctival disorders. Copyright (c) 2012 S. Karger AG, Basel
• Amelioration of ultraviolet-induced photokeratitis in mice treated with astaxanthin eye drops.

  Lennikov A, Kitaichi N, Fukase R, Murata M, Noda K, Ando R, Ohguchi T, Kawakita T, Ohno S, Ishida S

  Molecular vision 18 455 - 464 2012 [Refereed][Not invited]
  
• Renin-angiotensin system hyperactivation can induce inflammation and retinal neural dysfunction

  Toshihide Kurihara, Yoko Ozawa, Susumu Ishida, Hideyuki Okano, Kazuo Tsubota

  International Journal of Inflammation 2012 581695  2090-8040 2012 [Refereed][Not invited]
   

  The renin-angiotensin system (RAS) is a hormone system that has been classically known as a blood pressure regulator but is becoming well recognized as a proinflammatory mediator. In many diverse tissues, RAS pathway elements are also produced intrinsically, making it possible for tissues to respond more dynamically to systemic or local cues. While RAS is important for controlling normal inflammatory responses, hyperactivation of the pathway can cause neural dysfunction by inducing accelerated degradation of some neuronal proteins such as synaptophysin and by activating pathological glial responses. Chronic inflammation and oxidative stress are risk factors for high incidence vision-threatening diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma. In fact, increasing evidence suggests that RAS inhibition may actually prevent progression of various ocular diseases including uveitis, DR, AMD, and glaucoma. Therefore, RAS inhibition may be a promising therapeutic approach to fine-tune inflammatory responses and to prevent or treat certain ocular and neurodegenerative diseases. © 2012 Toshihide Kurihara et al.
• Ectopic cilia: A histopathological study

  Keitaro Hase, Satoru Kase, Mika Noda, Tsutomu Ohashi, Satoru Shinkuma, Susumu Ishida

  Case Reports in Dermatology 4 (1) 37 - 40 1662-6567 2012/01 [Refereed][Not invited]
   

  Cilia are normally found at the eyelid margin, while ectopic cilia are one or more lash follicles appearing in an abnormal position within the eyelid. We herein report two cases of cilia located in the palpebral conjunctiva. A 31-year-old female and a 46-year-old male presented with ectopic cilia in the superior palpebral conjunctiva. Histopathological study of the excised ectopic cilia and related lesions showed the cilia-related lesion to be located in the epithelial pit that contains goblet cells, which is consistent with the crypts of Henle. The hair follicle was surrounded by granulation tissue, while a dermal papilla and a hair matrix, which are known to produce hair follicles, did not exist in the excised tissue. While anterior ectopic cilia are congenital, ectopic cilia in the palpebral conjunctiva may be acquired, and these aberrant cilia are associated with crypts of Henle and chronic inflammation. Copyright © 2012 S. Karger AG, Basel.
• Abnormalities of fundus autofluorescence in pigmented paravenous chorioretinal atrophy

  Yuki Hashimoto, Satoru Kase, Wataru Saito, Susumu Ishida

  Open Ophthalmology Journal 6 125 - 128 1874-3641 2012 [Refereed][Not invited]
   

  The aim of this study is to investigate fundus autofluorescence (FAF) as well as fluorescein angiography (FA), indocyanine green angiography (IA), and optical coherence tomography (OCT) in a patient with pigmented paravenous chorioretinal atrophy (PPCRA). A funduscopic examination revealed chorioretinal atrophy along the paravenous area in both eyes. A marked bone spicule pigment clumping together with the atrophy was noted left eye. FA and IA showed a window defect and hypofluorescence, respectively, which exclusively corresponds to the atrophic area along the retinal vein area and the optic disc both eyes. FAF revealed geographic hypofluorescence along the paravenous and supranasal retinal areas. Hyperfluorescence was noted, which comparatively surrounded the hypofluorescence in the peripheral paravenous distribution. Hypofluorescence detected by FAF corresponded to the areas of retinal thinning and atrophy detected by OCT and FA. FAF is a useful examination in PPCRA, which can noninvasively demonstrate the distribution of deficit and dysfunction of retinal pigment epithelium. © Hashimoto et al.
• Acute visual field defect following vitrectomy determined to originate from optic nerve by electrophysiological tests

  Atsuro Uchida, Kei Shinoda, Celso Soiti Matsumoto, Miho Kawai, Sayaka Kawai, Hisao Ohde, Yoko Ozawa, Susumu Ishida, Makoto Inoue, Atsushi Mizota, Kazuo Tsubota

  Case Reports in Ophthalmology 3 (3) 396 - 405 1663-2699 2012 [Refereed][Not invited]
   

  Purpose: To present our findings on the cause of an acute visual field defect (VFD) that developed in a patient on the day after vitrectomy for proliferative diabetic retinopathy. Case: A 50-year-old man complained of a blind area in the superior visual field that developed one day after vitrectomy. The patient had undergone uncomplicated vitrectomy for a long-duration vitreous hemorrhage associated with proliferative diabetic retinopathy. Residual vitreous hemorrhage hampered a clear view of the fundus. Goldmann perimetry showed a horizontal VFD in the superior field. The area corresponding to the VFD was examined by multifocal electroretinograms (mfERGs) and multifocal visual evoked potentials (mfVEPs). The amplitudes of the mfVEPs were reduced with prolonged implicit times especially when the superior hemifield was stimulated, while the amplitudes and implicit times were within the normal range when other parts of the visual field were stimulated. In addition, the full-field photopic ERGs and photopic negative responses were attenuated in the right eye. These findings suggested that the VFD did not originate from alterations in the retinal inner and middle layer but in the ganglion cells. The visual acuity improved to 1.2 but his optic disc became pale and the VFD remained unchanged more than 12 years after the surgery. Conclusion: We suggest that vitrectomy can cause ischemic optic neuropathy by interfering with the circulation associated with diabetes mellitus. Evaluations by mfERGs, mfVEPs, and full-field photopic ERGs were helpful in making the diagnosis. © 2012 S. Karger AG, Basel.
• Intravitreal injection of bevacizumab in a case of occlusive retinal vasculitis accompanied by syphilitic intraocular inflammation

  Kan Ishijima, Kenichi Namba, Shigeaki Ohno, Kiyofumi Mochizuki, Susumu Ishida

  Case Reports in Ophthalmology 3 (3) 434 - 437 1663-2699 2012 [Refereed][Not invited]
   

  Background: We report a rare case of syphilitic intraocular inflammation with occlusive retinal vasculitis treated with intravitreal injection of bevacizumab (IVB) in addition to conventional therapy for syphilis. Case: A 24-year-old woman who complained floaters in both her eyes showed occlusive retinal vasculitis OU. According to the high titer of the Treponema antigen and characteristic cutaneous eruption, she was diagnosed as secondary syphilis. Observation: She was treated with oral amoxicillin and retinal photocoagulation OU. Then, administration of prednisolone was required to the intraocular inflammations considered as Jarisch-Herxheimer reactions. IVB was also performed toward exacerbated retinal neovascularization and showed transient effects. Conclusion: We experienced a rare case of occlusive retinal vasculitis accompanied by syphilis intraocular inflammation. IVB was considered to be effective as an adjunctive therapy for inflammatory neovascularizations. © 2012 S. Karger AG, Basel.
• Preventive Medicine for Age-related Macular Degeneration

  ISHIDA Susumu

  tits Japan Science Support Foundation 17 (12) 12_80 - 12_85 1342-3363 2012
• Neuroprotective response after photodynamic therapy: Role of vascular endothelial growth factor

  Misa Suzuki, Yoko Ozawa, Shunsuke Kubota, Manabu Hirasawa, Seiji Miyake, Kousuke Noda, Kazuo Tsubota, Kazuaki Kadonosono, Susumu Ishida

  JOURNAL OF NEUROINFLAMMATION 8 176  1742-2094 2011/12 [Refereed][Not invited]
   

  Background: Anti-vascular endothelial growth factor (VEGF) drugs and/or photodynamic therapy (PDT) constitute current treatments targeting pathological vascular tissues in tumors and age-related macular degeneration. Concern that PDT might induce VEGF and exacerbate the disease has led us to current practice of using anti-VEGF drugs with PDT simultaneously. However, the underlying molecular mechanisms of these therapies are not well understood. Methods: We assessed VEGF levels after PDT of normal mouse retinal tissue, using a laser duration that did not cause obvious tissue damage. To determine the role of PDT-induced VEGF and its downstream signaling, we intravitreally injected a VEGF inhibitor, VEGFR1 Fc, or a PI3K/Akt inhibitor, LY294002, immediately after PDT. Then, histological and biochemical changes of the retinal tissue were analyzed by immunohistochemistry and immunoblot analyses, respectively. Results: At both the mRNA and protein levels, VEGF was upregulated immediately and transiently after PDT. VEGF suppression after PDT resulted in apoptotic destruction of the photoreceptor cell layer in only the irradiated area during PDT. Under these conditions, activation of the anti-apoptotic molecule Akt was suppressed in the irradiated area, and levels of the pro-apoptotic protein BAX were increased. Intravitreal injection of a PI3K/Akt inhibitor immediately after PDT increased BAX levels and photoreceptor cell apoptosis. Conclusion: Cytotoxic stress caused by PDT, at levels that do not cause overt tissue damage, induces VEGF and activates Akt to rescue the neural tissue, suppressing BAX. Thus, the immediate and transient induction of VEGF after PDT is neuroprotective.
• Intraocular neovascularization associated with choroidal ganglioneuroma in neurofibromatosis type 1

  Kan Ishijima, Satoru Kase, Mika Noda, Susumu Ishida

  EUROPEAN JOURNAL OF OPHTHALMOLOGY 21 (6) 837 - 840 1120-6721 2011/11 [Refereed][Not invited]
   

  PURPOSE. Neurofibromatosis type 1 (NF-1) complicates various tumors originating from the neural crest. The authors report a case of NF-1 presenting with globe enlargement and subretinal and choroidal neovascularization associated with choroidal ganglioneuroma. METHODS. A 7-year-old boy with NF-1 had severe ocular pain OS. He has a medical history of congenital glaucoma OS. Left eye showed increased intraocular pressure, buphthalmos, corneal opacity, hyphema, and vitreous hemorrhage. Magnetic resonance imaging indicated prominent vitreous hemorrhage and a choroidal tumor. Enucleation was consequently performed OS. RESULTS. Histopathologic diagnosis of the choroidal tumor was ganglioneuroma admixed with micro-vessels and melanocytes. There was a huge subretinal and choroidal fibrovascular membrane formation originating from the choroidal ganglioneuroma. CONCLUSIONS. Severe ocular pain in this patient was caused by intraocular neovascularization and subsequent increased eyeball content by vitreous hemorrhage associated with the choroidal tumor. In NF-1 with orbitofacial involvement, detection of intraocular tumor by imaging tests may predict tumor-associated severe ophthalmic complications.
• Roles of AMP-Activated Protein Kinase in Diabetes-Induced Retinal Inflammation

  Shunsuke Kubota, Yoko Ozawa, Toshihide Kurihara, Mariko Sasaki, Kenya Yuki, Seiji Miyake, Kousuke Noda, Susumu Ishida, Kazuo Tsubota

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 52 (12) 9142 - 9148 0146-0404 2011/11 [Refereed][Not invited]
   

  PURPOSE. AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. The purpose of the present study was to elucidate the roles of AMPK in the pathogenesis of diabetic retinopathy using the known AMPK activators resveratrol and AICAR (5-aminoimidazole-4-carboxamide ribonucleoside) in a mouse model. METHODS. C57BL/6 mice with streptozotocin-induced diabetes were treated with resveratrol orally at 50 mg/kg for 7 days or with AICAR intraperitoneally at 100 mg/kg 24 hours before death. Retinal protein levels of phosphorylated and total AMPK, phosphorylated nuclear factor (NF)-kappa B p65, intercellular adhesion molecule (ICAM)-1, and vascular endothelial growth factor (VEGF) were evaluated by Western blot analysis or enzyme-linked immunosorbent assay. Retinal activity of sirtuin (SIRT) 1 was measured by deacetylase fluorometric assay. Leukocyte adhesion to the retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique. RESULTS. Induction of diabetes in mice led to retinal AMPK dephosphorylation, which was significantly reversed by either resveratrol or AICAR. Either resveratrol or AICAR significantly reversed SIRT1 deactivation and NF-kappa B phosphorylation, both of which were induced in the diabetic retina. Administration of resveratrol to diabetic mice significantly reduced diabetes-induced retinal leukocyte adhesion, together with retinal expression of ICAM-1 and VEGF. CONCLUSIONS. The present findings reveal that diabetes-induced retinal inflammation stems from downregulation of the AMPK pathway, leading subsequently to SIRT1 deactivation and NF-kappa B activation. The data also suggest the potential use of the AMPK activator resveratrol as a therapeutic agent for diabetic retinopathy. (Invest Ophthalmol Vis Sci. 2011;52:9142-9148) DOI: 10.1167/iovs.11-8041
• Genome variability of human adenovirus type 8 causing epidemic keratoconjunctivitis during 1986-2003 in Japan

  Xue-Hai Jin, Koki Aoki, Nobuyoshi Kitaichi, Toshihide Ariga, Susumu Ishida, Shigeaki Ohno

  MOLECULAR VISION 17 (336-37) 3121 - 3127 1090-0535 2011/11 [Refereed][Not invited]
   

  Purpose: Epidemic keratoconjunctivitis (EKC) is a contagious acute conjunctivitis associated with community-acquired infection. Human adenovirus type 8 (HAdV-8) is one of the major serotypes isolated from patients with EKC. DNA restriction enzyme analyses were performed to investigate the genetic characteristics of the isolates and their chronological pattern. Methods: Viral samples were taken from 11 strains isolated from sporadic cases of EKC and identified as HAdV-8 by the neutralization method with type-specific antiserum against HAdV-8 between 1986 and 2003 in Japan. DNA restriction enzyme analysis included six restriction enzymes: BamHI, HindIII, PstI, SacI, SalI, and SmaI. Results: The restriction patterns revealed that the genome types were HAdV-8A and HAdV-8B in 1986, HAdV-8K in 1991, and HAdV-8E in 1996. HAdV-8K was a new genome type revealed with the enzyme SacI. Two strains isolated in 2003 exhibited identical restriction patterns as HAdV-54, which was described in 2008 and collected from Japanese patients in 2000. Conclusions: Genetic changes might occur chronologically in HAdV-8. HAdV-8 displays considerable variability. The investigations of these variants might be helpful for defining the evolutionary tendency and to predict future outbreaks of HAdV infection.
• [Two cases of conjunctival malignant melanoma treated with topical interferon alpha-2b drop as an adjuvant therapy].

  Kase S, Ishijima K, Noda M, Ishida S

  Nippon Ganka Gakkai zasshi 日本眼科学会 115 (11) 1043 - 1047 0029-0203 2011/11 [Refereed][Not invited]
  
• Increased expression of alpha A-crystallin in human diabetic eye

  Satoru Kase, Susumu Ishida, Narsing A. Rao

  INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE 28 (4) 505 - 511 1107-3756 2011/10 [Refereed][Not invited]
   

  We recently demonstrated that alpha A-crystallin, a molecular chaperone, protected photoreceptors from apoptotic signals in intraocular inflammation. Advanced glycation end product (AGE) plays an important role in the progression of diabetic retinopathy. The aim of this study was to examine the expression of alpha-crystallins and apoptosis in human diabetic retina, and to analyze alpha-crystallin up-regulation in murine eyes after AGE stimulation. Eight eye globes were obtained from postmortem donors. Six out of the eight had a medical history of diabetes mellitus, while two were without diabetes. Formalin-fixed, paraffin-embedded tissue sections were subjected to H&E staining and immunohistochemistry with anti-alpha A and alpha B-crystallins, anti-AGE and receptor for AGE (RAGE) antibodies. Apoptotic cells were detected by the TUNEL assay. Recombinant AGE protein was injected into the vitreous of adult murine eyes, and the posterior eyecups were excised 4 days after the administration. Western blot analyses and quantitative real-time PCR were performed to evaluate the alteration of alpha-crystallin expression. Histopathology revealed no remarkable differences between diabetic and non-diabetic retinas. Immunoreactivity for alpha A-crystallin was predominantly detected in the diabetic retina, whereas alpha B-crystallin expression was relatively low. AGE immunoreactivity was highly detected in diabetic retina and the vitreous, whilst immunoreactivity for RAGE was less marked. TUNEL-positive apoptotic cells were occasionally observed in photoreceptors of the diabetic retina, whereas cytoplasmic immunoreactivity for alpha A-crystallin was relatively low. alpha A-crystallin expression was up-regulated, and alpha B-crystallin was down-regulated in murine posterior eyecups exposed to AGE protein. The mRNA levels of alpha A-crystallin were significantly up-regulated, whereas those of alpha B-crystallin remained unchanged after AGE stimulation. Thus, alpha A-crystallin and AGE were highly expressed in human diabetic retina. alpha A-crystallin responded to AGE accumulation, which may contribute to the protection of photoreceptors against AGE-related retinal tissue injury.
• GEP100-Arf6-AMAP1-Cortactin Pathway Frequently Used in Cancer Invasion Is Activated by VEGFR2 to Promote Angiogenesis

  Ari Hashimoto, Shigeru Hashimoto, Ryo Ando, Kosuke Noda, Eiji Ogawa, Hirokazu Kotani, Mayumi Hirose, Toshi Menju, Masaki Morishige, Toshiaki Manabe, Yoshinobu Toda, Susumu Ishida, Hisataka Sabe

  PLOS ONE 6 (8) e23359  1932-6203 2011/08 [Refereed][Not invited]
   

  Angiogenesis and cancer invasiveness greatly contribute to cancer malignancy. Arf6 and its effector, AMAP1, are frequently overexpressed in breast cancer, and constitute a central pathway to induce the invasion and metastasis. In this pathway, Arf6 is activated by EGFR via GEP100. Arf6 is highly expressed also in human umbilical vein endothelial cells (HUVECs) and is implicated in angiogenesis. Here, we found that HUVECs also highly express AMAP1, and that vascular endothelial growth factor receptor-2 (VEGFR2) recruits GEP100 to activate Arf6. AMAP1 functions by binding to cortactin in cancer invasion and metastasis. We demonstrate that the same GEP100-Arf6-AMAP1-cortactin pathway is essential for angiogenesis activities, including cell migration and tubular formation, as well as for the enhancement of cell permeability and VE-cadherin endocytosis of VEGF-stimulated HUVECs. Components of this pathway are highly expressed in pathologic angiogenesis, and blocking of this pathway effectively inhibits VEGF-or tumor-induced angiogenesis and choroidal neovascularization. The GEP100-Arf6-AMAP1-cortactin pathway, activated by receptor tyrosine kinases, appears to be common in angiogenesis and cancer invasion and metastasis, and provides their new therapeutic targets.
• Recombination analysis of intermediate human adenovirus type 53 in Japan by complete genome sequence

  Hisatoshi Kaneko, Koki Aoki, Susumu Ishida, Shigeaki Ohno, Nobuyoshi Kitaichi, Hiroaki Ishiko, Tsuguto Fujimoto, Yoshifumi Ikeda, Masako Nakamura, Gabriel Gonzalez, Kanako O. Koyanagi, Hidemi Watanabe, Tatsuo Suzutani

  JOURNAL OF GENERAL VIROLOGY 92 (Pt 6) 1251 - 1259 0022-1317 2011/06 [Refereed][Not invited]
   

  Human adenovirus type 53 (HAdV-53) has commonly been detected in samples from epidemic keratoconjunctivitis (EKC) patients in Japan since 1996. HAdV-53 is an intermediate virus, containing hexon-chimeric, penton base and fiber structures similar to HAdV-22 and -37, HAdV-37 and HAdV-8, respectively. HAdV-53-like intermediate strains were first isolated from EKC samples in Japan in the 1980s. Here, the complete genome sequences of three such HAdV-53-like intermediate strains (870006C, 880249C and 890357C) and four HAdV-53 strains were determined, and their relationships were analysed. The seven HAdV strains were classified into three groups, 870006C/880249C, 890357C and the four HAdV-53 strains, on the basis of phylogenetic analyses of the partial and complete genome sequences. HAdV strains within the same group showed the highest nucleotide identities (99.87-100.00%). Like HAdV-53, the hexon loop 1 and 2 regions of 870006C, 8802490 and 890357C showed the highest identity with HAdV-22. However, these strains did not show a hexon-chimeric structure similar to HAdV-22 and -37, or a penton base similar to HAdV-37. The fiber genes of 8700060 and 880249C were identical to that of HAdV-37, but not HAdV-8. Thus, the three intermediate HAdVs isolated in the 1980s were similar to each other but not to HAdV-53. The recombination breakpoints were inferred by the Recombination Detection Program (RDP) using whole-genome sequences of these seven HAdV and of 12 HAdV-D strains from GenBank. HAdV-53 may have evolved from intermediate HAdVs circulating in the 1980s, and from HAdV-8, -22 and -37, by recombination of sections cut at the putative breakpoints.
• Retinal Ganglion Cell Loss in Superoxide Dismutase 1 Deficiency

  Kenya Yuki, Yoko Ozawa, Tetsu Yoshida, Toshihide Kurihara, Manabu Hirasawa, Naoki Ozeki, Daisuke Shiba, Kousuke Noda, Susumu Ishida, Kazuo Tsubota

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 52 (7) 4143 - 4150 0146-0404 2011/06 [Refereed][Not invited]
   

  PURPOSE. To investigate the influence of deficiency in superoxide dismutase (SOD) 1, a major antioxidative enzyme, on retinal ganglion cells (RGCs). METHODS. In the SOD1 total knockout (SOD1-deficient) mice, the level of superoxide anion was measured using dihydroethidium. The number of RGCs was counted in both the retinal sections and the flat-mount retinas after retrograde labeling. Thickness of nerve fiber layer (NFL) was measured in the sections, and the amount of neurofilament protein was measured by immunoblot analysis. Pattern electroretinogram (ERG), which reflects the function of retinal ganglion cells, dark-adapted ERG, and cone ERG were performed. The intraocular pressure (IOP) was measured with an induction-impact tonometer. The levels of SOD-1 and -2 were measured by ELISA, in the serum of 47 newly diagnosed consecutive normal tension glaucoma (NTG) patients and 44 consecutive control subjects. RESULTS. The level of superoxide anion in the RGC layer was significantly higher in 24-week-old SOD1-deficient mice than in wild-type mice. The RGC number was significantly reduced in 24-week-old SOD1-deficient mice, although they were not in 8-week-old mice. The NFL thickness and neurofilament protein were reduced in 24-week-old SOD1-deficient mice. The amplitude of pattern ERG was significantly reduced, although dark-adapted and cone ERGs showed no impairment, in 24-week-old SOD1-deficient mice. The IOP level was not changed in the SOD1-deficient mice. The serum level of SOD1, but not SOD2, was significantly lower in the NTG patients than in the healthy controls. CONCLUSIONS. SOD1 deficiency causes RGC vulnerability, which may be involved in the underlying condition of NTG. (Invest Ophthalmol Vis Sci. 2011;52:4143-4150) DOI:10.1167/iovs.106294
• Incidence of Increased Intraocular Pressure after Subtenon Injection of Triamcinolone Acetonide

  Ryosuke Kawamura, Makoto Inoue, Hajime Shinoda, Kei Shinoda, Yuji Itoh, Susumu Ishida, Kazuo Tsubota

  JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS 27 (3) 299 - 304 1080-7683 2011/06 [Refereed][Not invited]
   

  Purpose: To determine the incidence of eyes that have an increase in the intraocular pressure (IOP) after subtenon injections of triamcinolone acetonide (TA). Methods: The medical records of 147 patients treated with single or multiple subtenon injections of TA (10 mg) were reviewed. The incidence of an IOP elevation (Delta IOP) >= 5mmHg or an IOP of > 21mmHg was determined. The peak Delta IOP, defined as the difference in the IOP at the peak to the baseline IOP, was also evaluated. Multivariate analyses were used to evaluate the relation between the IOP elevation and the age, gender, refractive error, and lens status. Results: A Delta IOP >= 5mmHg was found in 75 eyes (46%), and an IOP > 21mmHg was found in 48 eyes (30%) after a single injection of TA. The IOP increased within 3 months in 39 eyes (81%) and after 4 months in 9 eyes (19%). The IOP began to increase significantly from 2 weeks up to 5 months (P < 0.05) and returned to the baseline IOP in 10 months. The incidence of Delta IOP >= 5mmHg or an IOP of > 21mmHg after multiple subtenon injections of TA was significantly higher than after a single injection (62%; P= 0.027, 47%; P= 0.013, respectively). The incidence of IOP > 21mmHg and the peak Delta IOP were significantly related with younger age (P= 0.002, P= 0.021, Forward stepwise regression analysis). A weak but significant negative correlation was found between the peak Delta IOP and the age (r= -0.216, P = 0.006, Pearson's correlation coefficient test), and the peak Delta IOP and the refractive error (r= -0.198; P = 0.018). Conclusion: Repeated injections of TAs and injection of younger patients or myopic eyes increase the incidence of an IOP elevation.
• Repair of blowout orbital floor fracture by periosteal suturing

  Mika Noda, Kousuke Noda, Shinji Ideta, Yasuhisa Nakamura, Susumu Ishida, Makoto Inoue, Kazuo Tsubota

  CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 39 (4) 364 - 369 1442-6404 2011/05 [Refereed][Not invited]
   

  P>The study objective was to evaluate the outcome of a periosteal suturing technique in eyes with orbital blowout fractures. Fifteen orbital floor fractures were classified into: type 1, linear fracture; type 2, middle fracture; and type 3, posterior fracture extending two-thirds into the orbit. The feasibility of periosteal suturing without silicone plates or one of minimal size was determined. The improvement of ocular movements and surgical complications were evaluated. A complete suture of the torn periosteum without implanting a silicone plate was achieved in 2/2 (100%) type 1 cases, 5/7 (71%) type 2 cases and 0/6 (0%) type 3 cases. A partial fixation was achieved in 3/6 (50%) type 3 cases with an implantation of a silicone plate of approximate one-third of the usual size in one case. Conventional surgery with silicone plates after failed periosteal suture was required in 2/7 (29%) type 2 cases and 3/6 (50%) type 3 cases. Eye movements were improved postoperatively in all eyes, and a complete range of eye movements was achieved in 6/7 (86%) cases with complete periosteal closure, 1/3 (33%) of cases with partial closure and 2/5 (40%) cases without closure. In conclusion, periosteal suturing can minimize the need for silicone plates especially for anterior or middle orbital floor factures.
• Extranodal marginal zone B-cell lymphoma involving superior rectus muscle: A clinicopathological case report

  Junichi Fukuhara, Satoru Kase, Mika Noda, Kan Ishijima, Susumu Ishida

  ONCOLOGY LETTERS 2 (3) 489 - 491 1792-1074 2011/05 [Refereed][Not invited]
   

  A 66-year-old female had suffered from proptosis in the left eye (OS) and double vision for 1 month due to abnormality of the superior rectus muscle. Visual acuity was noted as 20/20 in both eyes (OU). Eye movement showed limited OS supraduction. Magnetic resonance imaging revealed an indistinct mass in the orbit involving the superior rectus muscle. A biopsy specimen of the orbital tumor led to the histological diagnosis of extranodal marginal zone B-cell lymphoma. Radiotherapy with a total dosage of 30 Gy was administered, which subsequently resolved the tumor. However, the supraduction limitation of ocular movement remained unchanged. Supraduction limitation is due to muscular contraction disorder of the superior rectus muscle, caused by direct lymphoma cell invasion.
• Transcriptional factors associated with epithelial-mesenchymal transition in choroidal neovascularization

  Manabu Hirasawa, Kousuke Noda, Setsuko Noda, Misa Suzuki, Yoko Ozawa, Kei Shinoda, Makoto Inoue, Yoko Ogawa, Kazuo Tsubota, Susumu Ishida

  MOLECULAR VISION 17 (137) 1222 - 1230 1090-0535 2011/05 [Refereed][Not invited]
   

  Purpose: To investigate the transcriptional factors associated with epithelial-mesenchymal transition (EMT) in choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Methods: Paraffin sections of CNV obtained from patients with AMD (n = 12) were stained for transcriptional factors related to EMT, i.e., Snail, Slug, SIP1, and Twist. As a control, postmortem sections of ocular normal tissue were used. Furthermore, using a human retinal pigment epithelial (RPE) cell line (ARPE-19), reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence microscopy were performed to explore the cellular localization and expression levels of EMT-associated transcriptional factors upon cytokine stimulation. Results: Of 12 specimens, 11 CNV tissues (91.6%) showed staining for Snail localized in cellular nuclei, particularly in those of RPE cells. Snail was strongly co-localized with a-smooth muscle antigen (SMA) in RPE cells. In contrast, postmortem human retina showed no Snail staining in RPE cells. Other transcriptional factors, Slug, Twist and SIP1 were not detected in CNV or normal human retina. In ARPE-19 cells, RT-PCR and immunofluorescence microscopy showed that Snail mRNA was upregulated by transforming growth factor (TGF)-beta and VEGF stimulation. Furthermore, TGF-beta induced relocalization of Snail to the nucleus in RPE cells. Conclusions: The current data indicate that Snail is a major transcriptional factor for EMT changes of RPE cells in human CNV.
• Detection of human adenovirus hexon antigen using carbon nanotube sensors

  Xue-Hai Jin, Atsushi Ishii, Koki Aoki, Susumu Ishida, Koichi Mukasa, Shigeaki Ohno

  JOURNAL OF VIROLOGICAL METHODS 171 (2) 405 - 407 0166-0934 2011/02 [Refereed][Not invited]
   

  Human adenoviruses (HAdVs) have been implicated in a wide range of diseases affecting primarily the respiratory, ocular and gastrointestinal systems. A rapid and efficient method for the detection of HAdV hexon antigen is described using carbon nanotube (CNT) sensors. Anti-HAdV antibody was immobilised on the reverse surface of a CNT sensor. As a control, non-specific mouse IgG was immobilised on another CNT sensor. I-V(gate) curves were measured after incubation of various concentrations of recombinant HAdVs hexon antigen with anti-HAdVs antibody-immobilised or non-specific mouse IgG-immobilised sensors. The curves showed a positive shift that was dependent on the hexon antigen concentration in the anti-HAdV antibody-immobilised sensor, whereas no such shift was observed in the non-specific mouse IgG-immobilised sensor. The sensitivity of the CNT sensor method was greater than that of enzyme-linked immunosorbent assay. Hence, this method offers a new tool for HAdV detection by analysing antigen-antibody interactions. (C) 2010 Elsevier B.V. All rights reserved.
• Conjunctival lymphoproliferative disorder.

  Fukuhara J, Kase S, Ishijima K, Noda M, Ishida S

  Ophthalmology 118 (2) 423.e1 - 2 0161-6420 2011/02 [Refereed][Not invited]
  
• Epidemiological and virological features of epidemic keratoconjunctivitis due to new human adenovirus type 54 in Japan

  Hisatoshi Kaneko, Tatsuo Suzutani, Koki Aoki, Nobuyoshi Kitaichi, Susumu Ishida, Hiroaki Ishiko, Tsutomu Ohashi, Shigeki Okamoto, Hisashi Nakagawa, Rikutaro Hinokuma, Yoshimori Asato, Shinobu Oniki, Teiko Hashimoto, Tomohiro Iida, Shigeaki Ohno

  BRITISH JOURNAL OF OPHTHALMOLOGY 95 (1) 32 - 36 0007-1161 2011/01 [Refereed][Not invited]
   

  Background/aims New human adenovirus (HAdV)-54 causes epidemic keratoconjunctivitis (EKC) and is virologically close to and has occasionally been detected as HAdV-8. Taking HAdV-54 into account, we re-determined HAdV type in EKC samples to determine its epidemiology in Japan, and examined the virological features of HAdV-54. Methods HAdV type was re-determined in 776 conjunctival swabs from Japan and 174 from six other countries, obtained between 2000 and 2009. Using 115 HAdV strains obtained before 1999, trends regarding HAdV-8 and HAdV-54 were also determined. In addition, immunochromatography (IC) kit features, DNA copy numbers and viral isolation of HAdV-54 in samples were evaluated. Results Recently, HAdV-37 and HAdV-54 have been the major causative types of EKC in Japan. HAdV-54 has been isolated each year since 1995, whereas HAdV-8 has become less common since 1997, although it remains the most common cause of EKC in the six other countries investigated where HAdV-54 is yet to be detected. HAdV-54 is comparable to other EKC-related HAdV types in terms of IC kit sensitivity and DNA copy numbers, although HAdV-54 grows more slowly on viral isolation. Conclusions EKC due to HAdV-54 can result in epidemics; therefore, it should be accurately diagnosed and monitored as an emerging infection worldwide.
• Choroidal neovascularization in a patient with blunt trauma-caused traumatic retinopathy without choroidal rupture

  Mitsuo Takahashi, Satoshi Kinoshita, Wataru Saito, Manabu Kase, Susumu Ishida

  GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 249 (1) 137 - 140 0721-832X 2011/01 [Refereed][Not invited]
   

  To report a case of choroidal neovascularization (CNV) following blunt trauma without choroidal rupture, with past history of central serous chorioretinopathy (CSC). A 43-year-old man with a nonperforating injury caused by a baseball that hit his right eye exhibited traumatic retinopathy. The damage was localized to the outer layer of the retina at the macula and there was no choroidal rupture. Five years prior to the accident, the patient suffered from a CSC attack with retinal pigment epithelium detachment. Two weeks after the blunt trauma, fundus examination revealed CNV extending into the subfoveal space, which led to an abrupt development of retinal hemorrhage and serous retinal detachment at the macula. Intravitreal injection of bevacizumab led to the resolution of retinal detachment 15 days later, with complete absorption of retinal hemorrhage 41 days later. Fluorescein angiography performed 2 months later revealed hyperfluorescent points with no leakage. CNV following blunt trauma in this case occurred in traumatic retinopathy, with the damage localized in the outer layer of the retina. This suggests that the retinal pigment epithelium-Bruch's membrane complex developed susceptibility to anteroposterior forces, which is subsequent to the spontaneous healing of CSC. Bevacizumab treatment also reduced exudation from CNV.
• Hydrogen and N-Acetyl-L-Cysteine Rescue Oxidative Stress-Induced Angiogenesis in a Mouse Corneal Alkali-Burn Model

  Miyuki Kubota, Shigeto Shimmura, Shunsuke Kubota, Hideyuki Miyashita, Naoko Kato, Kousuke Noda, Yoko Ozawa, Tomohiko Usui, Susumu Ishida, Kazuo Umezawa, Toshihide Kurihara, Kazuo Tsubota

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 52 (1) 427 - 433 0146-0404 2011/01 [Refereed][Not invited]
   

  PURPOSE. To investigate the role of reactive oxygen species (ROS) as the prime initiators of the angiogenic response after alkali injury of the cornea and observe the effects of antioxidants in preventing angiogenesis. METHODS. The corneal epithelia of SOD-1-deficient mice or wild-type (WT) mice were removed after application of 0.15 N NaOH to establish the animal model of alkali burn. ROS production was semiquantitatively measured by dihydroethidium (DHE) fluorescence. Angiogenesis was visualized by CD31 immunohistochemistry. The effects of the specific NF-kappa B inhibitor DHMEQ, the antioxidant N-acetyl-L-cysteine (NAC), and hydrogen (H(2)) solution were observed. RESULTS. ROS production in the cornea was enhanced immediately after alkali injury, as shown by increased DHE fluorescence (P < 0.01). NF-kappa B activation and the upregulation of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) were significantly enhanced (P < 0.01), leading to a significantly larger area of angiogenesis. Angiogenesis in SOD-1(-/-) mice corneas were significantly higher in WT mice (P < 0.01), confirming the role of ROS. Pretreatment with the specific NF-kappa B inhibitor DHMEQ or the antioxidant NAC significantly reduced corneal angiogenesis by downregulating the NF-kappa B pathway (P < 0.01) in both WT and SOD-1(-/-) mice. Furthermore, we showed that irrigation of the cornea with hydrogen (H 2) solution significantly reduced angiogenesis after alkali-burn injury (P < 0.01). CONCLUSIONS. Immediate antioxidant therapy with H(2)-enriched irrigation solution is a new potent treatment of angiogenesis in cornea to prevent blindness caused by alkali burn. (Invest Ophthalmol Vis Sci. 2011;52:427-433) DOI:10.1167/iovs.106167
• Tissue factor expression in human pterygium

  Ryo Ando, Satoru Kase, Tsutomu Ohashi, Zhenyu Dong, Junichi Fukuhara, Atsuhiro Kanda, Miyuki Murata, Kousuke Noda, Nobuyoshi Kitaichi, Susumu Ishida

  MOLECULAR VISION 17 (8-10) 63 - 69 1090-0535 2011/01 [Refereed][Not invited]
   

  Purpose: A pterygium shows tumor-like characteristics, such as proliferation, invasion, and epithelial-mesenchymal transition (EMT). Previous reports suggest that tissue factor (TF) expression is closely related to the EMT of tumor cells, and subsequent tumor development. In this study, we analyzed the expression and immunolocalization of TF in pterygial and normal conjunctival tissues of humans. Methods: Eight pterygia and three normal bulbar conjunctivas, surgically removed, were used in this study. Formalin-fixed, paraffin-embedded tissues were submitted for immunohistochemical analysis with anti-TF antibody. Double staining immunohistochemistry was performed to assess TF and alpha-smooth muscle actin (alpha-SMA) or epidermal growth factor receptor (EGFR) expression in the pterygia. Results: Immunoreactivity for TF was detected in all pterygial tissues examined. TF immunoreactivity was localized in the cytoplasm of basal, suprabasal, and superficial epithelial cells. The number of TF-immunopositive cells in pterygial epithelial cells was significantly higher than in normal conjunctival epithelial cells (p<0.001). TF immunoreactivity was detected in alpha-SMA-positive or -negative pterygial epithelial cells. EGFR immunoreactivity was detected in pterygial epithelium, which was colocalized with TF. Conclusions: These results suggest that TF plays a potential role in the pathogenesis and development of a pterygium, and that TF expression might be involved through EMT-dependent and -independent pathways.
• Evaluation of NLRP1 gene polymorphisms in Vogt-Koyanagi-Harada disease

  Yukihiro Horie, Wataru Saito, Nobuyoshi Kitaichi, Toshie Miura, Susumu Ishida, Shigeaki Ohno

  JAPANESE JOURNAL OF OPHTHALMOLOGY 55 (1) 57 - 61 0021-5155 2011/01 [Refereed][Not invited]
   

  Polymorphisms of the NACHT [neuronal apoptosis inhibitory protein (NAIP), CIITA, HET-E, TP1] and leucine-rich repeat protein 1 (NLRP1) gene are reported to be associated with susceptibility to vitiligo and several autoimmune diseases. Vogt-Koyanagi-Harada (VKH) disease is an autoimmune disorder affecting melanocytes in the skin, eyes, inner ear, and meninges. In this study, genetic associations between VKH disease and single-nucleotide polymorphisms (SNPs) surrounding the NLRP1 gene were investigated. Six SNPs (rs6502867, rs925597, rs3926687, rs2733359, rs878329, and rs4790796) near the NLRP1 gene, including noncoding regions, were sequenced by a direct method to genotype 167 Japanese patients with VKH disease and 187 healthy Japanese volunteers. None of the six SNPs in the NLRP1 region were significantly associated with disease susceptibility or the ocular, neurological, and dermatological manifestations of VKH. Although skin manifestations are clinically similar between vitiligo and VKH disease, the genetic and immunological mechanisms of these two diseases may be different.
• Diffuse infiltrating retinoblastoma invading subarachnoid space

  Satoru Kase, Kazuhiko Yoshida, Shigenobu Suzuki, Koh-Ichi Ohshima, Shigeaki Ohno, Susumu Ishida

  Clinical Ophthalmology 5 (1) 861 - 863 1177-5467 2011 [Refereed][Not invited]
   

  We report herein an unusual case of diffuse infiltrating retinoblastoma involving the brain, which caused a patient's death 27 months after enucleation. An eight-year-old boy complained of blurred vision in his right eye (OD) in October 2006. Funduscopic examination showed optic disc swelling, dense whitish vitreous opacity, and an orange-colored subretinal elevated lesion adjacent to the optic disc. Fluorescein angiography revealed hyperfluorescence in the peripapillary region at an early-phase OD. Because the size of the subretinal lesion and vitreous opacity gradually increased, he was referred to us. His visual acuity was 20/1000 OD on June 20, 2007. Slit-lamp biomicroscopy showed a dense anterior vitreous opacity. Ophthalmoscopically, the subretinal orange-colored area spread out until reaching the mid peripheral region. A B-mode sonogram and computed tomography showed a thick homogeneous lesion without calcification. Gadolinium-enhanced magnetic resonance imaging showed a markedly enhanced appearance of the underlying posterior retina. Enucleation of the right eye was performed nine months after the initial presentation. Histopathology demonstrated retinal detachment and a huge choroidal mass invading the optic nerve head. The tumor was consistent with diffuse infiltrating retinoblastoma. The patient died due to brain involvement 27 months after enucleation. Ophthalmologists should be aware that diffuse infiltrating retinoblastoma may show an unfavorable course if its diagnosis is delayed. © 2011 Kase et al, publisher and licensee Dove Medical Press Ltd.
• Calcium Channel Blocker Nilvadipine, but Not Diltiazem, Inhibits Ocular Inflammation in Endotoxin-Induced Uveitis

  Susumu Ishida, Takashi Koto, Norihiro Nagai, Yuichi Oike

  JAPANESE JOURNAL OF OPHTHALMOLOGY 54 (6) 594 - 601 0021-5155 2010/11 [Refereed][Not invited]
   

  Purpose: Calcium channel blockers (CCBs), widely used for hypertensive patients, have recently been shown to inhibit atherosclerosis by their antioxidative action. The aim of the present study was to examine whether the CCBs nilvadipine and diltiazem reduce ocular inflammation in endotoxin-induced uveitis (EIU). Methods: EIU was induced in male C57/B6 mice with a single intraperitoneal injection of lipopolysaccharide (LPS). The animals received intraperitoneal injections of either nilvadipine, diltiazem, or vehicle for 5 days before the LPS application. Twenty-four hours after EIU induction, adherent leukocytes to the retinal vasculature were counted with a concanavalin A lectin perfusion-labeling technique. The protein concentration in the aqueous humor was measured to assess blood-ocular barrier breakdown. Retinal levels of intercellular adhesion molecule (ICAM)-1 and monocyte chemotactic protein (MCP)-1 were analyzed by enzyme-linked immunosorbent assay. LPS-stimulated generation of superoxide in murine microvascular endothelial cells was examined with a nitroblue tetrazolium assay. Results: Compared to vehicle treatment, application of nilvadipine, but not diltiazem, led to significant suppression of EIU-associated retinal leukocyte adhesion, together with anterior-chamber protein leakage, retinal expression of ICAM-1 and MCP-1, and LPS-induced superoxide generation in vitro. Conclusions: The CCB nilvadipine exercises an inhibitory effect on the pathogenesis of ocular inflammation through the suppression of inflammation-related molecules. Jpn J Ophthalmol 2010;54:594-601 (C) Japanese Ophthalmological Society 2010
• [VEGF blockers].

  Ishida S

  Nihon rinsho. Japanese journal of clinical medicine 68 Suppl 9 304 - 309 0047-1852 2010/11 [Refereed][Not invited]
  
• [Renin-angiotensin system].

  Ishida S

  Nihon rinsho. Japanese journal of clinical medicine 68 Suppl 9 255 - 261 0047-1852 2010/11 [Refereed][Not invited]
  
• Resveratrol Prevents Light-Induced Retinal Degeneration via Suppressing Activator Protein-1 Activation

  Shunsuke Kubota, Toshihide Kurihara, Mari Ebinuma, Miyuki Kubota, Kenya Yuki, Mariko Sasaki, Kousuke Noda, Yoko Ozawa, Yuichi Oike, Susumu Ishida, Kazuo Tsubota

  AMERICAN JOURNAL OF PATHOLOGY 177 (4) 1725 - 1731 0002-9440 2010/10 [Refereed][Not invited]
   

  Light damage to the retina accelerates retinal degeneration in human diseases and rodent models. Recently, the polyphenolic phytoalexin resveratrol has been shown to exert various bioactivities in addition to its classical antioxidant property. In the present study, we investigated the effect of resveratrol on light-induced retinal degeneration together with its underlying molecular mechanisms. BALB/c mice with light exposure (5000-lux white light for 3 hours) were orally pretreated with resveratrol at a dose of 50 mg/kg for 5 days. Retinal damage was evaluated by TdT-mediated dUTP nick-end labeling, outer nuclear layer morphometry, and electroretinography. Administration of resveratrol to mice with light exposure led to a significant suppression of light-induced pathological parameters, including TdT-mediated dUTP nick-end labeling-positive retinal cells, outer nuclear layer thinning, and electroretinography changes. To clarify the underlying molecular mechanisms, the nuclear translocation of activator protein-1 subunit c-fos was evaluated by enzyme-linked immunosorbent assay, and the retinal activity of sirtuin 1 was measured by deacetylase fluorometric assay. Retinal activator protein-1 activation, up-regulated following light exposure, was significantly reduced by application of resveratrol. In parallel, retinal sirtuin 1 activity, reduced in animals with light damage, was significantly augmented by resveratrol treatment. Our data suggest the potential use of resveratrol as a therapeutic agent to prevent retinal degeneration related to light damage. (Am J Pathol 2010, 1 77:1725-1731; DOI: 10.2353/ajpath.2010.100098)
• Molecular epidemiology of adenoviral keratoconjunctivitis in Saudi Arabia

  Khalid F. Tabbara, Nazri Omar, Ehab Hammouda, Masataka Akanuma, Takeshi Ohguchi, Toshihide Ariga, Yoshitsugu Tagawa, Nobuyoshi Kitaichi, Susumu Ishida, Koki Aoki, Hiroaki Ishiko, Shigeaki Ohno

  MOLECULAR VISION 16 (228) 2132 - 2136 1090-0535 2010/10 [Refereed][Not invited]
   

  Purpose: Adenoviral keratoconjunctivitis is a major cause of ocular morbidity and may lead to visual loss. Adenovirus types 8, 19, and 37 may cause epidemic keratoconjunctivitis. The main objective of this study was to determine the types of adenoviruses causing keratoconjunctivitis in Saudi Arabia. Methods: We conducted a non-interventional observational clinical study. Seventy three eyes from 65 patients who presented to The Eye Center in Riyadh, Saudi Arabia with clinical features of acute adenoviral keratoconjunctivitis were included. Each patient underwent complete clinical examination and features such as membranous reaction, conjunctival hemorrhage, subepithelial corneal infiltrates, and preauricular lymph node enlargement were recorded. Conjunctival swabs were obtained from patients with presumed acute viral conjunctivitis. Immunochromatography (IC) and restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) were performed on the conjunctival swabs obtained from each eye. Serotype identification was performed using direct sequencing technique. Results: Forty-nine (67.1%) were adenovirus type 8, 8 (11.0%) were adenovirus type 3, 6 (8.2%) type 37, 5 (6.8%) were adenovirus type 4, and 2 (2.3%) type 19. The remaining 5 were types 14, 19, and 22. The prevalence of membranous conjunctivitis was highest (83%) among eyes with adenovirus type 37 while subepithelial corneal opacities were most commonly seen among eyes with adenovirus type 8 (47%). Immunochromatography tests were positive for adenovirus in 48 (65.7%) out of 73 eyes. Conclusions: This study determined the types of adenoviruses causing keratoconjunctivitis at one center in Saudi Arabia. Direct sequencing techniques is an efficient, accurate, and rapid means of diagnosing adenoviral keratoconjunctivitis. The most common causes of adenoviral keratoconjunctivitis in Saudi Arabia were adenovirus types 8, 3, and 37. Membranous conjunctivitis and subepithelial opacities had the highest frequency of adenovirus types 37 and 8, respectively. Lymph nodes enlargement was least likely in adenovirus type 4.
• Eicosapentaenoic acid suppresses ocular inflammation in endotoxin-induced uveitis

  Misa Suzuki, Kousuke Noda, Shunsuke Kubota, Manabu Hirasawa, Yoko Ozawa, Kazuo Tsubota, Nobuhisa Mizuki, Susumu Ishida

  MOLECULAR VISION 16 (151-52) 1382 - 1388 1090-0535 2010/07 [Refereed][Not invited]
   

  Purpose: To investigate the effect of eicosapentaenoic acid (EPA) on acute ocular inflammation in an animal model of endotoxin-induced uveitis (EIU). Methods: C57Bl/6 mice (6-week-old males) were orally treated with EPA at a dose of 50 mg/kg/day for 5 days. EIU was then induced in the animals by intraperitoneal injection of 160 mu g lipopolysaccharide (LPS). Twenty-four hours after LPS injection, leukocyte adhesion to the retinal vasculature was evaluated by the concanavalin A lectin perfusion-labeling technique, and leukocyte infiltration into the vitreous cavity was quantified. Furthermore, the protein levels of monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, intercellular adhesion molecule-1 and phospholyrated nuclear factor (NF)-kappa B p65 in the retina and retinal pigment epithelium (RPE)-choroid complex were examined by enzyme-linked immunosorbent assay (ELISA). Results: At 24 h after LPS injection, the EIU animals treated with oral EPA administration showed a significant decrease in leukocyte adhesion to the retinal vessels by 43.4% (p< 0.01) and leukocyte infiltration into the vitreous cavity by 49.2% (p<0.05). In addition, EPA significantly reduced the protein levels of MCP-1 and IL-6 in the retina and the RPE-choroid complex. Furthermore, phosphorylation of NF-kappa B was suppressed by EPA treatment. Conclusions: Our data suggest that EPA inhibits multiple inflammatory molecules in vivo. EPA may become a novel strategy in the prevention and/or treatment of ocular inflammatory diseases.
• Secondary macular hole formation with presumed evulsion of foveal hard exudates in a patient with diabetic retinopathy

  Yohei Tomita, Kousuke Noda, Hajime Shinoda, Yoko Ozawa, Kazuo Tsubota, Susumu Ishida

  JAPANESE JOURNAL OF OPHTHALMOLOGY 54 (4) 366 - 368 0021-5155 2010/07 [Refereed][Not invited]
  
• CYCLO-OXYGENASE-2 EXPRESSION IN HUMAN IDIOPATHIC EPIRETINAL MEMBRANE

  Satoru Kase, Wataru Saito, Shigeaki Ohno, Susumu Ishida

  RETINA-THE JOURNAL OF RETINAL AND VITREOUS DISEASES 30 (5) 719 - 723 0275-004X 2010/05 [Refereed][Not invited]
   

  Purpose: The purpose of this study was to examine the expression of cyclo-oxygenase (COX)-2 in the idiopathic epiretinal membrane (IERM), inner limiting membrane (ILM), and proliferative diabetic retinopathy membrane. Methods: Twenty membranes, consisting of eight IERMs, four ILMs, and eight proliferative diabetic retinopathy membranes, were surgically removed. Formalin-fixed, paraffin-embedded tissue sections were processed for immunohistochemistry using anti-COX-2 antibody. The nuclear density showing the density of cells situated in IERM and ILM specimens was calculated under high-power fields using a light microscope. Results: The IERM comprised flattened cells with oval nuclei constituting a monolayer. The ILM contained a few cells with abundant collagenous tissues. Neither endothelial nor inflammatory cells were observed in the IERM and ILM. COX-2 immunoreactivity was markedly detected in cells located in the IERM. In contrast, COX-2 immunoreactivity was faintly detected in the ILM. The COX-2-positive rate was 65.4 +/- 15.5% and 34.3 +/- 20.3% in the IERM and ILM, respectively, being significantly higher in the former (P = 0.046). The nuclear density was 39.3 +/- 10.3 and 8.6 +/- 7.2 in the IERM and ILM, respectively, being significantly higher in the former (P = 0.0003). The proliferative diabetic retinopathy membranes consisted of many vascular endothelial and stromal cells. Cytoplasmic immunoreactivity for COX-2 was detected in endothelial and stromal cells in the proliferative diabetic retinopathy membranes. Conclusion: These results suggest that COX-2 plays a potential role in the formation of avascular and vascularized epiretinal membranes if an epiphenomenon of COX-2 expression within these epiretinal membranes has been ruled out in future studies. RETINA 30:719-723, 2010
• von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina

  Toshihide Kurihara, Yoshiaki Kubota, Yoko Ozawa, Keiyo Takubo, Kousuke Noda, M. Celeste Simon, Randall S. Johnson, Makoto Suematsu, Kazuo Tsubota, Susumu Ishida, Nobuhito Goda, Toshio Suda, Hideyuki Okano

  DEVELOPMENT 137 (9) 1563 - 1571 0950-1991 2010/05 [Refereed][Not invited]
   

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

  Daiju Iwata, Nobuyoshi Kitaichi, Akiko Miyazaki, Kazuya Iwabuchi, Kazuhiko Yoshida, Kenichi Namba, Michitaka Ozaki, Shigeaki Ohno, Kazuo Umezawa, Kenichiro Yamashita, Satoru Todo, Susumu Ishida, Kazunori Onoe

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 51 (4) 2077 - 2084 0146-0404 2010/04 [Refereed][Not invited]
   

  PURPOSE. Experimental autoimmune uveoretinitis (EAU), a Th1/Th17 cell-mediated autoimmune disease induced in mice, serves as a model of human endogenous uveitis. In this model, proinflammatory cytokines and various stimuli activate the transcriptional factor, nuclear factor-kappa B (NF-kappa B), in the retina. The therapeutic effect of the NF-kappa B inhibitor, dehydroxy methyl epoxyquinomicin (DHMEQ), was examined on EAU. METHODS. EAU was induced in B10.BR mice by K2 peptide immunization. DHMEQ (40 mg/kg/d) was administered daily by intraperitoneal injection. Clinical severity and histopathologic severity were assessed. Translocation of NF-kappa B p65 into the nucleus in EAU retina was assessed. T cells were collected from draining lymph nodes of the K2-immunized mice to examine antigen (Ag)-specific T-cell active responses and cytokine production in vitro. RESULTS. Disease onset was significantly delayed in DHMEQ-treated mice (15.6 days) compared with untreated mice (12.6 days; P < 0.01). Histologic severity was significantly milder in DHMEQ-treated mice (score, 1.13) than in controls (score, 2.33; P < 0.05). DHMEQ suppressed the Ag-specific T-cell active responses and downregulated the productions of Th-1 type cytokines in vitro in a dose-dependent manner. Alternation was not observed in Th-2 type cytokines. Pretreatment of primed T cells or Ag-presenting cells with DHMEQ reduced T-cell activation and Th1/Th17 cytokine production. DHMEQ treatment suppressed the translocation of the NF-kappa B p65 subunit into the nuclei. CONCLUSIONS. Systemic administration of DHMEQ suppressed NF-kappa B translocation in the retina, which might have reduced the inflammation of ocular tissues. DHMEQ-mediated regulation of NF-kappa B p65 could be a therapeutic target for the control of endogenous ocular inflammatory diseases. (Invest Ophthalmol Vis Sci. 2010; 51: 2077-2084) DOI:10.1167/iovs.09-4030
• Merkel cell carcinoma of the conjunctiva.

  Kase S, Ishijima K, Ishida S, Rao NA

  Ophthalmology 117 (3) 637.e1 - 2 0161-6420 2010/03 [Refereed][Not invited]
  
• Mechanism of Visual Sensations Experienced during Pars Plana Vitrectomy under Retrobulbar Anesthesia

  Eiko Sugisaka, Kei Shinoda, Ronaldo Yuiti Sano, Susumu Ishida, Yutaka Imamura, Yoko Ozawa, Hajime Shinoda, Kotaro Suzuki, Kazuo Tsubota, Makoto Inoue

  OPHTHALMOLOGICA 224 (2) 103 - 108 0030-3755 2010 [Refereed][Not invited]
   

  Purpose: To investigate the visual sensations experienced by patients during vitrectomy under retrobulbar anesthesia. Methods: 30 men and 45 women with a mean age of 65.3 +/- 10.6 years underwent vitrectomy under retrobulbar anesthesia for macular disease. 28 eyes had an idiopathic epiretinal membrane, 13 had an idiopathic macular hole, 32 had macular edema ( 17 diabetic retinopathy and 15 retinal vein occlusion), and 2 had submacular hemorrhage. 49 patients with nonmacular disease underwent similar vitrectomy procedures and were used for comparison. An interview was conducted with the patient about his/her visual sensations during and within 3 h of the vitrectomy. Results: 70 (93.3%) of the patients reported seeing lights, 53 (70.7%) reported seeing colors, and 48 (64.0%) reported seeing movements or moving objects. Of the patients who reported seeing movements or moving objects, 44 (58.7%) reported seeing surgical instruments, and 5 (6.7%) saw the surgeon's fingers or hands. Patients with macular diseases tended to report more visual sensations than patients with nonmacular diseases. The patients' description and drawings appeared to arise mainly from the shadows cast by the intravitreal objects, and some patients perceived highly accurate details including the movements and color of the objects. Conclusions: Visual sensations are experienced by approximately 90% of the patients, and there may be a common mechanism by which patients perceive the intravitreal objects that are not focused on by the retina through the eye's optical system. Copyright (C) 2009 S. Karger AG, Basel
• Prevention of experimental autoimmune uveoretinitis by blockade of osteopontin with small interfering RNA

  Daiju Iwata, Mizuki Kitamura, Nobuyoshi Kitaichi, Yoshinari Saito, Shigeyuki Kon, Kenichi Namba, Junko Morimoto, Akiko Ebihara, Hirokuni Kitamei, Kazuhiko Yoshida, Susumu Ishida, Shigeaki Ohno, Toshimitsu Uede, Kazunori Onoe, Kazuya Iwabuchi

  EXPERIMENTAL EYE RESEARCH 90 (1) 41 - 48 0014-4835 2010/01 [Refereed][Not invited]
   

  Osteopontin (OPN) is elevated during the progression of experimental autoimmune uveoretinitis (EAU) in C57BL/6 (B6) mice. Furthermore, EAU symptoms are ameliorated in OPN knockout mice or in B6 mice treated with anti-OPN antibody (M5). Recently, OPN has been shown to promote the Th1 response not only in the extracellular space as a secretory protein but also in cytosol as a signaling component. Thus, we attempted to reduce OPN in both compartments by using a small interfering RNA (siRNA) targeting the OPN coding sequence (OPN-siRNA). EAU was induced in B6 mice by immunization with human interphotoreceptor retinoid-binding protein (hIRBP) peptide sequence 1-20. The OPN- or control-siRNA was administered with hydrodynamic methods 24 h before and simultaneously with immunization (prevention regimen). When plasma OPN levels were quantified following siRNA administration with the prevention regimen, the level in the OPN-siRNA-treated group was significantly lower than that in the control-siRNA-treated group. Accordingly, the clinical and histopathological scores of EAU were significantly reduced in B6 mice when siRNA caused OPN blockade. Furthermore, TNF-alpha, IFN-gamma, IL-2, GM-CSFand IL-17 levels in the culture supernatants were markedly suppressed in the OPN-siRNA-treated group, whereas the proliferative responses of T lymphocytes from regional lymph nodes against immunogenic peptides was not significantly reduced. On the other hand, the protection was not significant if the mice received the OPN-siRNA treatment on day 7 and day 8 after immunization when the clinical symptoms appeared overt (reversal regimen). Our results Suggest that OPN blockade with OPN-siRNA can be an alternative choice for the usage of anti-OPN antibody and controlling uveoretinitis in the preventive regimen. (C) 2009 Elsevier Ltd. All rights reserved.
• Elevation of surfactant protein D, a pulmonary disease biomarker, in the sera of uveitis patients with sarcoidosis

  Nobuyoshi Kitaichi, Mizuki Kitamura, Kenichi Namba, Susumu Ishida, Shigeaki Ohno

  JAPANESE JOURNAL OF OPHTHALMOLOGY 54 (1) 81 - 84 0021-5155 2010/01 [Refereed][Not invited]
   

  Surfactant protein D (SP-D) is found in the epithelial cells of multiple mucosal surfaces. It is commonly used to diagnose and screen for pulmonary diseases. In the present study, serum levels of SP-D were measured in patients with uveitis to ascertain whether SP-D is a clinically useful laboratory parameter to diagnose sarcoidosis. Sera were obtained from 81 patients with sarcoidosis, 16 patients with Beh double dagger et disease, 40 patients with HLA-B27 associated uveitis, 50 patients with Vogt-Koyanagi-Harada (VKH) disease, and 33 healthy volunteers. Serum SP-D levels were quantified with an SP-D enzyme immunoassay kit. In the healthy control subjects, the average serum SP-D level was 39.70 ng/ml; in the uveitis patients with sarcoidosis, the mean serum SP-D level was 57.0 ng/ml, and in the uveitis patients with other etiologies the mean levels were 38.63 ng/ml for Beh double dagger et disease, 38.18 ng/ml for HLA-B27 associated uveitis, and 31.32 ng/ml for the VKH patients. The average serum SP-D levels of patients with sarcoidosis were significantly higher than those of patients with any other uveitis etiologies or healthy controls (P < 0.01). SP-D may be a less invasive and less expensive laboratory examination for sarcoidosis screening. SP-D should be considered as a new laboratory parameter for the diagnosis of uveitis and sarcoidosis.
• Combined vitreous and cataract surgeries in highly hyperopic eye

  Makoto Inoue, Kei Shinoda, Tomoko Matsuda-Yamamitsu, Ronaldo Yuiti Sano, Susumu Ishida

  Clinical Ophthalmology 4 (1) 1003 - 1005 1177-5467 2010 [Refereed][Not invited]
   

  We report a case of a patient with a highly hyperopic eye who underwent cataract surgery combined with vitreous surgery to create a posterior vitreous detachment (PVD) to prevent choroidal neovascularization (CNV). A 78-year-old man noticed a decrease in his vision due to a cataract in his right eye. The patient had a severe visual loss in his left eye because of a CNV 2 years after a cataract surgery. His visual acuities were 20/30 OD and 20/600 OS, and funduscopic examination showed an orange-colored lesion OD and degenerative subretinal fibrosis OS. The posterior vitreous was attached to the retina in both eyes. The axial length was 18.9 mm OD and 19.0 mm OS. Cataract surgery combined with vitreous surgery to create PVD was performed on the right eye, and the vision improved to 20/20 with no signs of developing CNV after 5 years. We conclude that cataract surgery combined with vitreous surgery to create a PVD may prevent the development of CNV in highly hyperopic eyes. © 2010 Inoue et al.
• Proliferative Diabetic Retinopathy with Lymphocyte-Rich Epiretinal Membrane Associated with Poor Visual Prognosis

  Satoru Kase, Wataru Saito, Shigeaki Ohno, Susumu Ishida

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 50 (12) 5909 - 5912 0146-0404 2009/12 [Refereed][Not invited]
   

  PURPOSE. The aim of this study was to analyze lymphocyte infiltration using immunohistochemistry in proliferative diabetic retinopathy (PDR) membranes. METHODS. Sixteen patients, 13 with PDR and 3 without diabetes, underwent pars plana vitrectomy, and the epiretinal membrane was peeled. Formalin-fixed, paraffin-embedded epiretinal membrane tissues were processed for immunohistochemistry with anti-leukocyte common antigen (LCA), CD3, and CD20 antibodies. Lymphocyte density was determined by direct counting at a high magnification under a light microscope, which was compared with the patients' visual prognoses. RESULTS. The lymphocyte density ranged from 1 to 52 (mean, 9.5) in high-power fields. Of 13 membranes, 5 showed a lymphocyte density of >5 cells, whereas the other 8 membranes showed a cell number of <2. The former type is defined as a lymphocyte-rich epiretinal membrane (LERM). Infiltrated lymphocytes were immunohistochemically positive for CD3, a T-cell marker, but not for CD20, a B-cell marker. All patients with LERM had poor visual prognosis after vitrectomy. In contrast, the visual prognosis in 7 patients with non-LERM improved or remained unchanged. A significant association was observed between high-level lymphocyte infiltration in the epiretinal membrane and poor visual prognosis (P < 0.001). LCA(+) mononuclear cells were not observed in epiretinal membranes in the absence of diabetes. CONCLUSIONS. These results suggest that the high-level infiltration of T lymphocytes into the PDR membrane is well correlated with poor visual prognosis. Histopathologic observation of the epiretinal membrane in patients with PDR may provide significant prognostic information. (Invest Ophthalmol Vis Sci. 2009;50:5909-5912) DOI:10.1167/iovs.09-3767
• Retinal phototoxicity in a novel murine model of intraocular lens implantation.

  Kurihara T, Omoto M, Noda K, Ebinuma M, Kubota S, Koizumi H, Yoshida S, Ozawa Y, Shimmura S, Ishida S, Tsubota K

  Molecular vision 15 2751 - 2761 2009/12 [Refereed][Not invited]
  
• Dehiscence of levator aponeurosis in ptosis after sub-Tenon injection of triamcinolone acetonide

  Shinji Ideta, Mika Noda, Ryosuke Kawamura, Kei Shinoda, Kotaro Suzuki, Susumu Ishida, Makoto Inoue

  CANADIAN JOURNAL OF OPHTHALMOLOGY-JOURNAL CANADIEN D OPHTALMOLOGIE 44 (6) 668 - 672 0008-4182 2009/12 [Refereed][Not invited]
   

  Objective:To report the incidence, intraoperative findings,and surgical outcome of secondary ptosis that developed after a sub-Tenon injection of triamcinolone acetonide (TA). Study Design: Retrospective, cross-sectional study. Participants: One hundred forty-seven cases with a total of 286 sub-Tenon TA injections. Methods: The medical records of 163 eyes of 147 cases treated with a sub-Tenon injection of 10 mg or 20 mg TA were reviewed. The incidence of secondary ptosis (palpebral fissure >2 mm narrower than that of the fellow eye) after a sub-Tenon TA injection was determined. The preoperative levator function and margin reflex distance (MRD) of the affected eyes, and the intraoperative findings in eyes that underwent reconstructive surgery, were evaluated. Results: Eight eyes (5%) developed secondary ptosis after the injection and 6 eyes were treated by reconstructive surgery. The preoperative levator function of the affected eyes did not differ from that of the fellow eyes. Intraoperatively, no septal disruption or fat herniation was noted, but an aponeurotic disinsertion was identified and repaired with an advancement of the leading edge to the anterior tarsal plate. The surgery led to satisfactory results, with improvement of the MRD from -1.3 (SD 1.5) mm preoperatively to 2.3 (SD 0.5) mm postoperatively (p = 0.027). Additional sub-Tenon TA injections were required in 2 eyes after eyelid surgery but the ptosis did not worsen. Conclusions: A sub-Tenon TA injection can occasionally cause ptosis by inducing a disinsertion of the levator aponeurosis. However, surgical reconstruction can lead to successful resolution of the ptosis.
• New retractor capable of aspirating fluids during scleral buckling surgery.

  Kurihara T, Suzuki K, Noda K, Kawamura R, Nagai N, Shinoda H, Shinoda K, Tsubota K, Ishida S, Inoue M

  Retina (Philadelphia, Pa.) 29 (10) 1542 - 1544 0275-004X 2009/11 [Refereed][Not invited]
  
• Inflammatory Corneal Neovascularization and Tissue Renin-Angiotensin System

  Tomohiko Usui, Susumu Ishida, Shiro Amano

  CORNEA 28 (9) S54 - S57 0277-3740 2009/10 [Refereed][Not invited]
   

  Corneal neovascularization (NV), a severe sight-threatening condition affecting transparency of the cornea, is usually associated with inflammation and mainly results from inflammatory disruption of an exquisitely balanced corneal immune homeostasis. Although the renin-angiotensin system is chiefly known as the major controller of blood pressure, there is also an increasing body of evidence documenting the involvement of angiotensin II in inflammatory angiogenesis. To investigate the involvement of renin-angiotensin system in corneal NV, the expression of angiotensin II, angiotensinogen, and angiotensin type I receptor was examined in mouse suture-induced corneal NV model. Furthermore, we analyzed the expression of angiotensinogen and angiotensin-converting enzyme under hypoxic conditions in cultured corneal epithelium in vitro. The efficacy of angiotensin type I receptor blocker against corneal NV is discussed.
• Involvement of Hyaluronan and Its Receptor CD44 with Choroidal Neovascularization

  Hiroshi Mochimaru, Eri Takahashi, Nobuo Tsukamoto, Junichiro Miyazaki, Tomonori Yaguchi, Takashi Koto, Toshihide Kurihara, Kousuke Noda, Yoko Ozawa, Takatsugu Ishimoto, Yutaka Kawakami, Hidenobu Tanihara, Hideyuki Saya, Susumu Ishida, Kazuo Tsubota

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 50 (9) 4410 - 4415 0146-0404 2009/09 [Refereed][Not invited]
   

  PURPOSE. CD44 is a cell-surface adhesion molecule and receptor for hyaluronan (HA), one of the major extracellular matrix components. The purpose of the present study was to clarify a role of HA and CD44 in the development of choroidal neovascularization (CNV). METHODS. Laser photocoagulation was used to induce CNV in C57BL/6 mice or CD44-deficient mice. The mRNA expression of CD44 and HA synthase (HAS)-2 in the retinal pigment epithelium (RPE)-choroid complex was evaluated by DNA microarray and real-time RT-PCR analyses 3 days after laser treatment. HA synthesis and CD44 expression were examined by immunohistochemistry 1 week after photocoagulation. Mice with laser-induced CNV were systemically administered the HA synthesis inhibitor 4-methylumbelliferone (MU) or an antiCD44-neutralizing antibody. The response of CNV was analyzed by volumetric measurements 1 week after photocoagulation. Macrophage infiltration into CNV lesions was evaluated by real-time RT-PCR for F4/80 3 days after laser-induced injury. RESULTS. The induction of CNV led to a significant increase in expression of CD44 and HAS2 mRNA. HA and CD44 were immunopositive in the CNV lesions. Compared with vehicle treatment, the systemic application of MU significantly attenuated CNV volume in a dose-dependent fashion, together with macrophage infiltration into the lesions. Consistently, antibody-based blockade of CD44 resulted in a significant reduction of CNV volume, compared with the isotype control. In contrast, genetic ablation of CD44 significantly augmented CNV formation together with HA accumulation and macrophage infiltration, compared with wild-type mice. CONCLUSIONS. These results indicate a significant role of HA and its receptor CD44 in the development of CNV. (Invest Ophthalmol Vis Sci. 2009;50:4410-4415) DOI: 10.1167/iovs.08-3044
• Prevention of Ocular Inflammation in Endotoxin-Induced Uveitis with Resveratrol by Inhibiting Oxidative Damage and Nuclear Factor-kappa B Activation

  Shunsuke Kubota, Toshihide Kurihara, Hiroshi Mochimaru, Shingo Satofuka, Kousuke Noda, Yoko Ozawa, Yuichi Oike, Susumu Ishida, Kazuo Tsubota

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 50 (7) 3512 - 3519 0146-0404 2009/07 [Refereed][Not invited]
   

  PURPOSE. Resveratrol is known as one of the antioxidant polyphenols contained in red wine and grape skin. The purpose of the present study was to investigate the role of resveratrol in ocular inflammation in endotoxin-induced uveitis (EIU). METHODS. EIU was induced in male C57/B6 mice at the age of 6 weeks by a single intraperitoneal injection of lipopolysaccharide (LPS). Animals had received oral supplementation of resveratrol at the doses of 5, 50, 100, or 200 mg/kg for 5 days until LPS injection. Twenty-four hours after LPS administration, leukocyte adhesion to the retinal vasculature was examined with a concanavalin A lectin perfusion-labeling technique. Retinal and retinal pigment epithelium (RPE)-choroidal levels of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear translocation of nuclear factor (NF)-kappa B p65 were evaluated by enzyme-linked immunosorbent assay. Retinal and RPE-choroidal activities of silent information regulator two ortholog (SIRT) 1 were measured by deacetylase fluorometric assay. RESULTS. Resveratrol pretreatment led to significant and dose-dependent suppression of leukocyte adhesion to retinal vessels of EIU mice compared with vehicle application. Protein levels of MCP-1 and ICAM-1 in the retina and the RPE-choroid of EIU animals were significantly reduced by resveratrol administration. Importantly, resveratrol-treated animals showed significant decline of retinal 8-OHdG generation and nuclear NF-kappa B P65 translocation, both of which were upregulated after EIU induction. RPE-choroidal SIRT1 activity, reduced in EIU animals, was significantly augmented by treatment with resveratrol. CONCLUSIONS. Resveratrol prevented EIU-associated cellular and molecular inflammatory responses by inhibiting oxidative damage and redox-sensitive NF-kappa B activation. (Invest Ophthalmol Vis Sci. 2009; 50: 3512-3519) DOI: 10.1167/iovs.08-2666
• (Pro)renin Receptor-Mediated Signal Transduction and Tissue Renin-Angiotensin System Contribute to Diabetes-Induced Retinal Inflammation

  Shingo Satofuka, Atsuhiro Ichihara, Norihiro Nagai, Kousuke Noda, Yoko Ozawa, Akiyoshi Fukamizu, Kazuo Tsubota, Hiroshi Itoh, Yuichi Oike, Susumu Ishida

  DIABETES 58 (7) 1625 - 1633 0012-1797 2009/07 [Refereed][Not invited]
   

  OBJECTIVE-The term "receptor-associated prorenin system" (RAPS) refers to the pathogenic mechanisms whereby prorenin binding to its receptor dually activates the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling via the receptor. The aim of the present study was to define the association of the RAPS with diabetes-induced retinal inflammation. RESEARCH DESIGN AND METHODS-Long-Evans rats, C57BL/6 mice, and angiotensin II type 1 receptor (AT1-R)deficient mice with streptozotocin-induced diabetes were treated with (pro)renin receptor blocker (PRRB). Retinal mRNA expression of prorenin and the (pro)renin receptor was examined by quantitative RT-PCR. Leukocyte adhesion to the retinal vasculature was evaluated with a concanavatin A lectin perfusion-labeling technique. Retinal protein levels of vascular endothelial growth factor (VEGF) and intercellular adhesion molecule (ICAM)-1 were examined by ELISA. Retinal extracellular signal-regulated kinase (ERK) activation was analyzed by Western blotting. RESULTS-Induction of diabetes led to significant increase in retinal expression of prorenin but not the (pro)renin receptor. Retinal adherent leukocytes were significantly suppressed with PRRB. Administration of PRRB inhibited diabetes-induced retinal expression of VEGF and ICAM-1. To clarify the role of signal transduction via the (pro)renin receptor in the diabetic retina, we used AT1-R-deficient mice in which the RAS was deactivated. Retinal adherent leukocytes in AT1-R-deficient diabetic mice were significantly suppressed with PRRB. PRRB suppressed the activation of ERK and the production of VEGF, but not ICAM-1, in AT1-R-deficient diabetic mice. CONCLUSIONS-These results indicate a significant contribution of the RAPS to the pathogenesis of diabetes-induced retinal inflammation, suggesting the possibility of the (pro)renin receptor as a novel molecular target for the treatment of diabetic retinopathy. Diabetes 58:1625-1633, 2009
• Evaluation of PTPN22 polymorphisms and Vogt-Koyanagi-Harada disease in Japanese patients

  Yukihiro Horie, Nobuyoshi Kitaichi, Yoshihiko Katsuyama, Kazuhiko Yoshida, Toshie Miura, Masao Ota, Yuri Asukata, Hidetoshi Inoko, Nobuhisa Mizuki, Susumu Ishida, Shigeaki Ohno

  MOLECULAR VISION 15 (118) 1115 - 1119 1090-0535 2009/06 [Refereed][Not invited]
   

  Purpose: Vogt-Koyanagi-Harada (VKH) disease is an autoimmune disorder against melanocytes. Polymorphisms of the protein tyrosine phosphatase non-receptor 22 gene (PTPN22) have recently been reported to be associated with susceptibility to several autoimmune diseases. In this study, genetic susceptibility to VKH disease was investigated by screening for single nucleotide polymorphisms (SNPs) of PTPN22. Methods: A total of 167 Japanese patients with VKH disease and 188 healthy Japanese controls were genotyped by direct sequencing methods for six SNPs (rs3811021, rs1217413, rs1237682, rs3761935, rs3789608, and rs2243471) of PTPN22 including the uncoding exons. Results: The six SNPs in PTPN22 showed no significant association with susceptibility to VKH disease or its ocular, neurologic, or dermatological manifestation. Conclusions: Further studies are needed to clarify the genetic mechanisms underlying VKH disease.
• Secondary macular hole associated with central retinal vein occlusion treated with corticosteroid injection

  Manabu Hirasawa, Kousuke Noda, Hajime Shinoda, Yoko Ozawa, Kazuo Tsubota, Susumu Ishida

  JAPANESE JOURNAL OF OPHTHALMOLOGY 53 (3) 279 - 281 0021-5155 2009/05 [Refereed][Not invited]
  
• Neuroprotective Effect of an Antioxidant, Lutein, during Retinal Inflammation

  Mariko Sasaki, Yoko Ozawa, Toshihide Kurihara, Kousuke Noda, Yutaka Imamura, Saori Kobayashi, Susumu Ishida, Kazuo Tsubota

  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 50 (3) 1433 - 1439 0146-0404 2009/03 [Refereed][Not invited]
   

  PURPOSE. Lutein has been the focus of recent study as a possible therapeutic approach for retinal diseases, but the molecular mechanism of its neuroprotective effect remains to be elucidated. The aim of this study was to investigate, with the use of a mouse endotoxin-induced uveitis (EIU) model, the neuroprotective effects of lutein against retinal neural damage caused by inflammation. METHODS. EIU was induced by intraperitoneal injection of lipopolysaccharide (LPS). Each animal was given a subcutaneous injection of lutein or vehicle three times: concurrently with and 3 hours before and after the LPS injection. Analysis was carried out 24 hours after EIU induction. Levels of rhodopsin protein and STAT3 activation were analyzed by immunoblotting. Lengths of the outer segments of the photoreceptor cells were measured. Dark-adapted full-field electroretinograms were recorded. Oxidative stress in the retina was analyzed by dihydroethidium and fluorescent probe. Expression of glial fibrillary acidic protein (GFAP) was shown immunohistochemically. RESULTS. The EIU-induced decrease in rhodopsin expression followed by shortening of the outer segments and reduction in a-wave amplitude were prevented by lutein treatment. Levels of STAT3 activation, downstream of inflammatory cytokine signals, and reactive oxygen species (ROS), which are both upregulated during EIU, were reduced by lutein. Pathologic change of Muller glial cells, represented by GFAP expression, was also prevented by lutein. CONCLUSIONS. The present data revealed that the antioxidant lutein was neuroprotective during EIU, suggesting a potential approach for suppressing retinal neural damage during inflammation. (Invest Ophthalmol Vis Sci. 2009; 50: 1433-1439) DOI: 10.1167/iovs.08-2493
• [Lifestyle-related diseases and anti-aging ophthalmology: suppression of retinal and choroidal pathologies by inhibiting renin-angiotensin system and inflammation].

  Ishida S

  Nippon Ganka Gakkai zasshi 113 (3) 403 - 22; discussion 423 0029-0203 2009/03 [Refereed][Not invited]
  
• 生活習慣病と眼 生活習慣病と抗加齢眼科学 レニン-アンジオテンシン系と炎症制御による網脈絡膜病態の是正

  石田 晋, 永井 紀博, 里深 信吾, 永井 香奈子, 栗原 俊英, 厚東 隆志, 持丸 博史, 久保田 俊介, 野田 航介, 小沢 洋子, 坪田 一男, 市原 淳弘, 伊藤 裕, 岡野 栄之, 須田 年生, 河上 裕, 梅澤 一夫, 尾池 雄一, 深水 昭吉, 大神 一浩, 大野 重昭

  日本眼科学会雑誌 (公財)日本眼科学会 113 (3) 403 - 423 0029-0203 2009/03 

  生活習慣病では,内臓肥満から長期の経過にわたって全身に血管症が起こり,脳・心・腎・眼などの主要臓器の障害により寿命が短縮する.生活習慣病により老化が加速する進行過程では,最上流の内臓肥満から最下流の臓器障害まで複数の病態に循環・組織レニン-アンジオテンシン系(RAS)が関与することが分かってきた.失明原因として重要な糖尿病網膜症や加齢黄斑変性は,生活習慣病が進行の危険因子であり,それぞれ網膜・脈絡膜血管新生を合併する血管症である.まず我々は,糖尿病網膜症や脈絡膜血管新生では,組織RASが活性化することによりアンジオテンシン1型受容体(AT1-R)シグナルを介してvascular endothelial growth factor(VEGF),intercellular adhesion molecule(ICAM)-1,monocyte chemotactic protein(MCP)-1などの炎症関連分子が血管病態に関与することを見出した.また,糖尿病網膜症において神経機能が低下するメカニズムとして,AT1-Rシグナルによりシナプス機能蛋白質の分解が亢進することを示した.さらに我々は,レニンの単なる不活性型前駆体と信じられていたプロレニンの受容体((プロ)レニン受容体)が眼に存在することを示した.(プロ)レニン受容体はプロレニンと結合すると細胞内シグナルと組織RASを同時に活性化させ,この新しい病態システムは受容体随伴プロレニン系(RAPS)と呼ばれる.我々は,脈絡膜血管新生がRAPSの制御を受けており,特にVEGFとMCP-1が(プロ)レニン受容体シグナルとAT1-Rシグナルによって二重に調節されることを発見した.次に,RASの下流で制御される炎症関連分子群と網脈絡膜病態が,自然界の食物成分により是正される可能性について報告した.緑黄色野菜に豊富なルテイン,魚油由来のω-3不飽和脂肪酸エイコサペンタエン酸,サケやエビの赤色成分アスタキサンチンを用いて網脈絡膜病態への影響を検討した.これらの機能性食品因子は,VEGF,ICAM-1,MCP-1などの炎症関連分子の発現抑制を介して抗血管新生作用や抗炎症作用を発揮することが明らかとなった.生活習慣病を背景因子とする眼科疾患,加齢黄斑変性と糖尿病網膜症に対する予防医学は,近年ますます重要視されている.本総説では,抗加齢眼科学的アプローチとしてRAS抑制薬や機能性食品因子による早期介入の妥当性について生物学的根拠を示した.(著者抄録)
• Simultaneous use of intravitreal viscoelastics and perfluorocarbon liquid during vitrectomy for severe globe rupture.

  Shigeyasu C, Imamura Y, Ishida S, Tsubota K, Inoue M

  Retinal cases & brief reports 3 (3) 305 - 307 1935-1089 2009 [Refereed][Not invited]
  
• 慶應義塾大学眼科におけるLASIK術後の網膜剥離・網膜裂孔の検討(第2報)

  谷口 沙織, 今村 裕, 内田 敦郎, 川村 亮介, 鈴木 浩太郎, 篠田 肇, 野田 航介, 小沢 洋子, 石田 晋

  眼科臨床紀要 眼科臨床紀要会 2 (1) 75 - 76 1882-5176 2009/01
• Gender-specific associations of vision and hearing impairments with adverse health outcomes in older Japanese: A population-based cohort study

  Takehiro Michikawa, Yuji Nishiwaki, Yuriko Kikuchi, Makiko Nakano, Satoko Iwasawa, Keiko Asakura, Ai Milojevic, Kunio Mizutari, Hideyuki Saito, Susumu Ishida, Tomonori Okamura, Toru Takebayashi

  BMC Geriatrics 9 (1) 1471-2318 2009 [Refereed][Not invited]
   

  Background. Several epidemiological studies have shown that self-reported vision and hearing impairments are associated with adverse health outcomes (AHOs) in older populations however, few studies have used objective sensory measurements or investigated the role of gender in this association. Therefore, we examined the association of vision and hearing impairments (as measured by objective methods) with AHOs (dependence in activities of daily living or death), and whether this association differed by gender. Methods. From 2005 to 2006, a total of 801 residents (337 men and 464 women) aged 65 years or older of Kurabuchi Town, Gunma, Japan, participated in a baseline examination that included vision and hearing assessments they were followed up through September 2008. Vision impairment was defined as a corrected visual acuity of worse than 0.5 (logMAR = 0.3) in the better eye, and hearing impairment was defined as a failure to hear a 30 dB hearing level signal at 1 kHz in the better ear. Information on outcomes was obtained from the town hall and through face-to-face home visit interviews. We calculated the risk ratios (RRs) of AHOs for vision and hearing impairments according to gender. Results. During a mean follow-up period of 3 years, 34 men (10.1%) and 52 women (11.3%) had AHOs. In both genders, vision impairment was related to an elevated risk of AHOs (multi-adjusted RR for men and women together = 1.60, 95% CI = 1.05-2.44), with no statistically significant interaction between the genders. In contrast, a significant association between hearing impairment and AHOs (multi-adjusted RR = 3.10, 95% CI = 1.43-6.72) was found only in the men. Conclusion. In this older Japanese population, sensory impairments were clearly associated with AHOs, and the association appeared to vary according to gender. Gender-specific associations between sensory impairments and AHOs warrant further investigation. © 2009 Michikawa et al licensee BioMed Central Ltd.
• (Pro)renin Receptor Promotes Choroidal Neovascularization by Activating Its Signal Transduction and Tissue Renin-Angiotensin System

  Shingo Satofuka, Atsuhiro Ichihara, Norihiro Nagai, Kousuke Noda, Yoko Ozawa, Akiyoshi Fukamizu, Kazuo Tsubota, Hiroshi Itoh, Yuichi Oike, Susumu Ishida

  AMERICAN JOURNAL OF PATHOLOGY 173 (6) 1911 - 1918 0002-9440 2008/12 [Refereed][Not invited]
   

  The receptor-associated prorenin system (RAPS) refers to pathogenic mechanisms whereby prorenin binding to its receptor activates both the tissue renin-angiotensin system (RAS) and RAS-independent intracellular signaling pathways. Although we found significant involvement of angiotensin H type 1 receptor (AT1-R)-mediated inflammation in choroidal neovascularization (CNV), a central abnormality of vision-threatening age-related macular degeneration, the association of RAPS with CNV has not been defined. Here, (pro)renin receptor blockade in a murine model of laser-induced CNV led to the significant suppression of CNV together with macrophage infiltration and the up-regulation of intercellular adhesion molecule (ICAM-1), monocyte chemotactic protein (MCP-1), vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2. To clarify the role of signal transduction via the (pro)renin receptor in CNV, we used mice in which renin-angiotensin system was deactivated by either the pharmacological blockade of AT1-R with losartan or the genetic ablation of AT1-R or angiotensinogen. Compared with wild type controls, these mice exhibited significant reduction of CNV and macrophage infiltration, both of which were further suppressed by (pro)renin receptor blockade. The (pro)renin receptor and phosphorylated extracellular signal-regulated kinases (ERK) were co-localized in vascular endothelial cells and macrophages in CNV. (Pro)renin receptor blockade suppressed ERK activation and the production of MCP-1 and VEGF, but not ICAM-1, VEGFR-1, or VEGFR-2, in AT1-R-deficient mice with CNV and in losartan-treated microvascular endothelial cells and macrophages. These results indicate the significant contribution of RAPS to CNV pathogenesis. (Am J Pathol, 2008, 173:1911-1918; DOI: 10.2353/ajpath.2008.080457)
• Suprachoroidal hemorrhage caused by breakage of a 25-gauge cannula.

  Chen CJ, Satofuka S, Inoue M, Ishida S, Shinoda K, Tsubota K

  Ophthalmic surgery, lasers & imaging : the official journal of the International Society for Imaging in the Eye 39 (4) 323 - 324 1542-8877 2008/07 [Refereed][Not invited]
  
• Vitrectomy combined with glial tissue removal at the optic pit in a patient with optic disc pit maculopathy: A case report

  Makoto Inoue, Kei Shinoda, Susumu Ishida

  Journal of Medical Case Reports 2 1752-1947 2008/04/07 [Refereed][Not invited]
   

  Introduction: We present a case of a man with optic disc pit maculopathy, whose vision improved after vitrectomy combined with glial tissue removal from the optic pit area, and without the use of photocoagulation. Case presentation: A 45-year-old man complained of blurred vision, and ophthalmoscopy revealed a retinal detachment and retinoschisis extending from an optic disc pit through the macula in his left eye. He was diagnosed with optic disc pit maculopathy, and vitrectomy was performed. A posterior vitreous detachment was created, glial tissue at the optic pit was removed, and octafluoropropane (C3F8) was injected as a gas tamponade. The retinal detachment and retinoschisis disappeared after six months, and vision improved to 20/20 without any visual field defects (Goldmann perimetry). A cataractous lens was extracted 2 years after the vitrectomy, and vision has remained 20/20 for 10 years without any recurrence. Conclusion: The removal of glial tissue during vitrectomy may be beneficial in patients with optic disc pit maculopathy. © 2008 Inoue et al licensee BioMed Central Ltd.
• アンジオテンシンII1型受容体阻害による糖尿病モデル網膜血管炎症の抑制

  永井 紀博, 厚東 隆志, 里深 信吾, 持丸 博史, 小澤 洋子, 坪田 一男, 井上 真, 石田 晋

  日本糖尿病眼学会誌 日本糖尿病眼学会 12 83 - 83 1881-753X 2008/04
• マウス脈絡膜新生血管モデルにおけるVAP-1阻害剤の血管新生抑制効果

  野田 航介, 吉川 奈美, 里深 信吾, 栗原 俊英, 真島 行彦, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 112 (臨増) 222 - 222 0029-0203 2008/03
• Jamming of 25-gauge instruments in the cannula during vitrectomy for vitreous haemorrhage

  Hajime Shinoda, Takeshi Nakajima, Kei Shinoda, Kotaro Suzuki, Susumu Ishida, Makoto Inoue

  ACTA OPHTHALMOLOGICA 86 (2) 160 - 164 1755-375X 2008/03 [Refereed][Not invited]
   

  Purpose: To report the jamming of 25-gauge instruments in the cannula during vitreous surgery for non-clearing vitreous haemorrhage. Methods: Forty-five eyes underwent vitrectomy with 25-gauge instruments for non-clearing vitreous haemorrhage (VH group). The incidence of 25-gauge instruments jamming in the cannula was determined retrospectively and compared with that in 112 eyes that underwent vitrectomy for epiretinal membrane (ERM group), also using 25-gauge instruments. Results: The 25-gauge vitreous cutter or light pipe became jammed in the cannula in three eyes (7%) in the VH group and the instrument locked inside the cannula had to be removed with the cannula. None of the 25-gauge instruments in the ERM group jammed (p = 0.022, Fisher's exact probability test). Two of three eyes developed giant retinal breaks near the sclerotomy but no retinal break related to the sclerotomy was detected in the ERM group. Examination of the cutter revealed blood trapped between the cutter and the cannula. Conclusions: Twenty-five gauge instruments may become jammed in the cannula in eyes with non-clearing vitreous haemorrhage. Clinicians should be aware of this surgical complication when 25-gauge instruments are used in vitreous haemorrhage.
• The current state and issues of medical treatment for age-related macular degeneration

  ISHIDA Susumu

  Folia Pharmacologica Japonica 公益社団法人 日本薬理学会 131 (1) 47 - 49 0015-5691 2008/01/01 

  滲出型加齢黄斑変性の中心的病態は，脈絡膜血管新生であり，新生血管の透過性亢進による滲出性変化が神経網膜を恒久的に傷害する．近年の細胞生物学の進歩は，これらの病態における複数の分子メカニズムを明らかにしてきたため，特定の分子を標的とした阻害薬が開発される時代になった．なかでも血管内皮増殖因子（VEGF）は，進行の鍵となる2つの病態，血管新生・血管透過性亢進を促進することが明らかにされ，その阻害薬の臨床応用が実現した．眼科領域で臨床応用されたVEGF阻害薬pegaptanib（Macugen^®），ranibizumab（Lucentis^®），bevacizumab（Avastin^®）は，黄斑浮腫・剥離や血管新生を軽減させ，少なくとも短期的には有効であることがわかった．しかし，至適な投与法，長期の安全性，既存の光線力学療法との併用についてなど，検討すべき課題が山積みされている．
  
• 【糖尿病網膜症の最新治療戦略】治療戦略を立てるための病態の細胞生物学的理解

  野田 航介, 石田 晋

  眼科手術 (公社)日本眼科手術学会 21 (1) 5 - 9 0914-6806 2008/01 

  疾患の治療戦略を立てるうえで重要なことは、その病態を惹起する因子を把握することである。現在、糖尿病網膜症に対する分子標的治療として抗VEGF療法が行われているが、この新しく登場した薬物治療と従来行われてきた硝子体手術や光凝固療法とを適切に併用していくためには、糖尿病網膜症に対する病態の細胞生物学的理解が必須と考えられる。本稿では、糖尿病網膜症の治療戦略を立てるうえで重要と考えられるその細胞生物学的知見について述べる。(著者抄録)
• Two-step oblique incision during 25-gauge vitrectomy reduces incidence of postoperative hypotony

  Makoto Inoue, Kei Shinoda, Hajime Shinoda, Ryosuke Kawamura, Kotaro Suzuki, Susumu Ishida

  CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 35 (8) 693 - 696 1442-6404 2007/11 [Refereed][Not invited]
   

  The efficacy of a two-step, oblique incision procedure during 25-gauge vitrectomy on postoperative hypotony was evaluated by a retrospective, case-control study. The transconjunctival incision during 25-gauge vitrectomy was made in two steps: penetration with a microvitreoretinal blade followed by a penetrater instrument of a blunt trocar. The two-step procedure was performed on 89 eyes and with the conventional incision on 68 eyes. The incidence of hypotony (intraocular pressure < 6 mmHg) on the first postoperative day and after 1 week and 1 month was compared. Hypotony was found in two eyes (2%) with the two-step method and 12 eyes (18%) with the conventional incision on the first postoperative day (P = 0.001, Fisher's exact probability test). The preoperative intraocular pressure was not significantly different in the two groups but was significantly higher in the two-step group than in the conventional method group on the first postoperative day (P = 0.001, Wilcoxon rank test). Twenty-five-gauge vitrectomy with two-step oblique incisions will reduce the incidence of postoperative hypotony on the first postoperative day.
• レニン・アンジオテンシン系とカリクレイン・キニン系の実験的脈絡膜血管新生への関与

  永井 紀博, 永井 香奈子, 厚東 隆志, 里深 信吾, 小澤 洋子, 井上 真, 石田 晋

  眼科臨床医報 眼科臨床医報会 101 (9) 946 - 946 0386-9601 2007/09
• エイコサペンタエン酸の摂取による実験的脈絡膜血管新生の抑制効果

  厚東 隆志, 永井 紀博, 篠田 肇, 里深 信吾, 栗原 俊英, 小澤 洋子, 井上 真, 石田 晋

  眼科臨床医報 眼科臨床医報会 101 (9) 946 - 946 0386-9601 2007/09
• プロレニンの非タンパク融解的活性化の阻害による網膜血管新生の抑制

  里深 信吾, 永井 紀博, 厚東 隆志, 小澤 洋子, 井上 真, 石田 晋

  眼科臨床医報 眼科臨床医報会 101 (9) 946 - 947 0386-9601 2007/09
• 25-Gauge cannula system with microvitreoretinal blade trocar

  Makoto Inoue, Kei Shinoda, Hajime Shinoda, Kotaro Suzuki, Ryosuke Kawamura, Susumu Ishida

  AMERICAN JOURNAL OF OPHTHALMOLOGY 144 (2) 302 - 304 0002-9394 2007/08 [Refereed][Not invited]
   

  PURPOSE: To report a 25-gauge trocar-cannula that en hances wound closure and reduces the incidence of postoperative hypotony. DESIGN: Development of surgical instruments. METHODS: A 25,gauge cannula with a microvitreoretinal (MVR) blade trocar was constructed. The resistance of inserting this trocar cannula was compared with that of the conventional 25-gauge trocar cannula (Alcon Labo ratories; Fort Worth, Texas, USA). Vitreous surgery was performed on 55 eyes with the trocar cannula with an oblique sclerotomy incision, and the results were compared with those from 68 eyes that underwent surgery with the conventional trocar cannula. RESULTS: The resistance of inserting the trocar cannula was less than that with the conventional trocar cannula. A temporary hypotony (intraocular pressure [IOP] < 6 mm Hg) was found in one eye (2%) with the trocar cannula and in 12 eyes (18%) with the conventional trocar cannula (P =.006, Fisher exact probability test). CONCLUSIONS: The trocar cannula with a MVR blade was effective in postoperative wound closure and prevention of postoperative hypotony.
• プロレニン受容体の阻害による脈絡膜血管新生の抑制

  里深 信吾, 市原 淳弘, 永井 紀博, 厚東 隆志, 小沢 洋子, 井上 真, 伊藤 裕, 坪田 一男, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 111 (臨増) 266 - 266 0029-0203 2007/03
• 眼と加齢 活性酸素・炎症 エイジング仮説

  坪田 一男, 今村 裕, 藤島 浩, 根岸 一乃, 井上 真, 榛村 重人, 石田 晋, 村戸 ドール, 小沢 洋子, 木村 至, 出田 真二, 結城 賢弥, 橋爪 公平, 永井 紀博, 里深 信吾, 平沢 学, 小川 由佳子, 栗原 俊英, 厚東 隆志, 深川 和己, 樋口 明弘, 海道 美奈子, 石田 玲子, 篠田 啓, 加藤 直子, 小川 葉子, 佐伯 めぐみ, 斎藤 一郎, 美島 健二, 井上 裕子, 後藤 英樹, 野田 節子, 水島 裕, 白澤 卓二, 清水 孝彦, 山口 美峰子, 内山 智, 吉田 悟, 比嘉 一成, 川北 哲也, 佐竹 良之, 田 聖花, 富田 真智子, 島崎 潤, 戸田 郁子, 堀 好子, 酒井 誓子, 河上 裕, 竹内 勤, 中村 滋, 渋谷 倫子, 中嶋 英雄, 久村 隆二, 増田 望, 佐々木 恭平

  日本眼科学会雑誌 (公財)日本眼科学会 111 (3) 193 - 206 0029-0203 2007/03 

  フリーラジカルに起因する酸化ストレスは癌,炎症,神経疾患など多くの慢性疾患の発症に深く関与している.また,加齢黄斑変性,白内障などのいくつかの眼疾患においても加齢や日光の過剰曝露による酸化ストレスが関与している.眼表面は,紫外線,大気中の酸素,瞬きによる酸素分圧変動の酸化ストレス発生原因に常にさらされている.ブランコモデルを使ったドライアイモデルを用いて,本モデルでは角膜上皮障害の発症とともに酸化ストレスの亢進が認められることを示した.瞬き減少型ドライアイにおける角膜上皮障害の発症に酸化ストレスが深く関与している可能性が示唆された.次にレーザー破壊による実験的脈絡膜新生血管モデルを用いて,アンジオテンシン受容体拮抗薬が,脈絡膜新生血管抑制効果があること,また網膜内での代表的なフリーラジカルスカベンジャーであるsuperoxide dismutase(SOD)の欠損マウスが,加齢黄斑変性の典型的な臨床所見を呈することを示した.現在,再生医療において幹細胞の維持が注目されているが,幹細胞の維持は,幹細胞自身の加齢(ステムセルエイジング)の制御に他ならないという最近の概念についても我々の見解を示した.(著者抄録)
• Detecting vitreomacular adhesions in eyes with asteroid hyalosis with triamcinolone acetonide

  Takefumi Yamaguchi, Makoto Inoue, Susumu Ishida, Kei Shinoda

  GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY 245 (2) 305 - 308 0721-832X 2007/02 [Refereed][Not invited]
   

  To report the incidence of posterior vitreous detachments (PVDs) and the surgical results of vitrectomy with intravitreal triamcinolone acetonide (TA) to detect vitreomacular adhesions in eyes with asteroid hyalosis (AH). Ten eyes of nine patients with AH underwent vitrectomy, six eyes with TA and four without TA. The presence of a PVD was determined preoperatively by ultrasound echography (USE) and intraoperatively by microscopic observations. The postoperative best-corrected visual acuities (BCVA) were evaluated. The BCVA was improved by > 2 Snellen lines in nine eyes and maintained at 20/20 with symptomatic improvements in the other eye. A vitreomacular adhesion was clearly seen during TA-assisted vitrectomy, and none was seen when TA was not used, even though preoperative USE showed an incomplete PVD in all eyes. The BCVA was not significantly better in eyes with TA-assisted vitrectomy than without TA-assisted vitrectomy. In one eye with vitrectomy without TA, a second surgery was required for a persistent cystoid macular edema and an epiretinal membrane. The BCVA and the edema in this eye improved after removing the epiretinal membrane. All (ten) of the eyes with AH were found to have a vitreomacular adhesion by preoperative USE and intraoperative microscopic observations. The residual vitreous over the macula is more easily detected and removed after intravitreally injected TA, but the visual acuities were not significantly different from eyes without TA.
• Current concept of the pathogenesis of age-related macular degeneration : the role of oxidative stress and inflammation

  IMAMURA Yutaka, ISHIDA Susumu, TSUBOTA Kazuo

  Inflammation and Regeneration 日本炎症・再生医学会 26 (6) 492 - 500 1880-9693 2006/11/25 

  Age-related macular degeneration (AMD) is a common disorder in the aged people that affects the central region of the retina, which is called macula. AMD is the leading cause of legal blindness in people older than 65 in the developed world. AMD is characterized by very typical retinal pathologies including drusen, retinal pigment epithelium dysfunction, retinal degeneration (geographic atrophy) and choroidal neovascu-larization. Recent studies reveal that oxidative stress and inflammation are significantly linked to the pathogenesis of AMD. Retina is especially susceptible to oxidative stress by following reasons: 1) photoreceptors contain polyunsaturated fatty acids, 2) retina is exposed continuously to light, 3) its oxygen consumption is high, 4) it contains chromopheres which react with light and produce reactive oxygen species (ROS). Moreover, ran-domized, prospective, placebo-controlled study in United States showed that high-dose supplementation of beta-caroten, vitamin C, vitamin E, copper, and zinc significantly slowed the progression of the disease and visual deterioration in patients with AMD. Mice deficient of Cu, Zn-superoxide dismutase showed typical features of human AMD, suggesting that oxidative stress scavenger may play a critical role in the prevention of age-related retinal degeneration. Obesity and inflammatory biomarkers are significantly associated with the risk of AMD, which possibly indicates that AMD is considered as a consequence of disturbance of homeo-stasis, such as metabolic syndrome. Recent genetic studies showed genes related to immune system via complement are associated with AMD, which revealed that inflammatory reactions are causally linked with the pathogenesis of AMD. Recently, the inhibitor of angiotensin II type 1 receptor reduced the volume of experimental CNV after laser burn, suggesting that angiotensin II type 1 receptor blockade be a novel therapeutic strategy as a preventive treatment for AMD. Further research is necessary to invent mechanism-based therapies forAMD.
• アンジオテンシンII1型受容体阻害による脈絡膜新生血管の抑制

  永井 紀博, 里深 信吾, 厚東 隆志, 篠田 肇, 栗原 俊英, 小沢 洋子, 井上 真, 石田 晋

  眼科臨床医報 眼科臨床医報会 100 (10) 808 - 808 0386-9601 2006/10
• Angiotensin II 1型受容体阻害による抗炎症を介した脈絡膜新生血管の抑制

  永井 紀博, 尾池 雄一, 永井 香奈子, 里深 信吾, 厚東 隆志, 小澤 洋子, 坪田 一男, 石田 晋

  日本抗加齢医学会総会プログラム・抄録集 (一社)日本抗加齢医学会 6回 139 - 139 2006/05
• 脈絡膜血管新生の抑制へのω-3脂肪酸の影響(Effects of ω-3 Fatty Acid on Suppression of Choroidal Neovascularization)

  厚東 隆志, 永井 紀博, 小澤 洋子, 井上 真, 坪田 一男, 石田 晋

  日本抗加齢医学会総会プログラム・抄録集 (一社)日本抗加齢医学会 6回 148 - 148 2006/05
• アンジオテンシンII1型受容体拮抗薬による脈絡膜新生血管の抑制

  永井 紀博, 里深 信吾, 厚東 隆志, 篠田 肇, 栗原 俊英, 小澤 洋子, 井上 真, 坪田 一男, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 110 (臨増) 198 - 198 0029-0203 2006/03
• 【糖尿病眼合併症の診療指針】Basic 網膜新生血管の硝子体内侵入と間質分解酵素MMP

  野田 航介, 石田 晋

  眼科プラクティス (株)文光堂 7 245 - 247 2006/01
• アンギオテンシンII1型レセプターのブロックによる炎症を介した網膜血管新生抑制

  永井 紀博, 野田 航介, 篠田 肇, 厚東 隆志, 篠田 啓, 井上 真, 石田 晋

  眼科臨床医報 眼科臨床医報会 99 (11) 905 - 905 0386-9601 2005/11
• 網膜静脈分枝閉塞症に伴う黄斑浮腫へのトリアムシノロンのテノン嚢下投与の有効性

  寺内 直毅, 永井 紀博, 篠田 肇, 野田 航介, 今村 裕, 石田 晋, 井上 真

  眼科 金原出版(株) 47 (12) 1847 - 1852 0016-4488 2005/11 

  黄斑浮腫を伴った網膜静脈分枝閉塞症に対し,トリアムシノロン(TA)のテノン嚢下注射を行って有効性を検討した.対象は網膜光凝固未施行の18例19眼で,最終的な後部硝子体剥離(PVD)の有無によってPVD+群7眼とPVD-群12眼に分け,TA注入前後の中心窩網膜厚を光干渉断層計によって測定した.更に視力の推移を比較した.1)中心窩網膜厚はPVD+群がPVD-群よりも有意に減少し,視力は2段階以上向上して,全例で0.8以上となった.PVD-群では5眼で視力向上した.2)経過中PVDが生じた1眼と,側副血行路が発育したPVD-群の2眼は,中心窩網膜厚が減少し,視力も向上した.3)PVD-群の4眼では視力が悪化したため再度TAを注入したが,2眼で浮腫の改善や視力の向上が認められず,硝子体手術を施行した.4)PVD-群では,注入後3ヵ月以上経過してもPVD発生や側副血行路の発育による黄斑浮腫の軽減が期待できない場合は,TA再注入か硝子体手術を適応とすべきである
• Intraocular lens implantation after atopic cataract surgery decreases incidence of postoperative retinal detachment

  Makoto Inoue, Kei Shinoda, Susumu Ishida, Atsuro Uchida, Daijiro Kurosaka, Hiroshi Katsura, Kazuo Tsubota

  Ophthalmology 112 (10) 1719 - 1724 0161-6420 2005/10 [Refereed][Not invited]
   

  Purpose: To investigate the efficacy of intraocular lens (IOL) implantation in reducing the incidence of postoperative retinal detachment after cataract surgery in patients with atopic dermatitis. Design: Retrospective review. Participants: One hundred sixty-nine eyes of 126 patients who underwent cataract surgery for atopic cataract were followed for more than 1 year. None of the eyes previously had a retinal detachment or retinal detachment surgery. Methods: The eyes were divided into 132 eyes of 95 patients with an IOL implantation (IOL group) and 37 eyes of 31 patients without an IOL implantation (aphakia group). The postoperative visual acuity and incidence of postoperative retinal detachment were compared between the 2 groups. The effects of the location of the causative retinal breaks, intraoperative posterior capsule rupture, and postoperative posterior capsulotomy on the incidence of retinal detachments were evaluated. Main Outcome Measures: The postoperative corrected visual acuity, incidence of postoperative retinal detachment, and influence of intraoperative posterior capsule rupture on the retinal detachment. Results: The final visual acuity was better than or equal to 20/20 in 128 eyes (97.0%) of the IOL group and in 29 eyes (78.4%) of the aphakia group (P = 0.0007). Retinal detachment after an uncomplicated cataract surgery occurred in 3 eyes (2.3%) of the IOL group and in 8 eyes (25.8%) of the aphakia group (P< 0.0001, Mantel-Cox). Two of 3 eyes (66.7%) in the IOL group and 1 of 8 eyes (16.7%) in the aphakia group that later developed a retinal detachment had an intraoperative posterior capsule rupture. Posterior capsulotomy by yttrium-aluminum-garnet laser did not seem to alter the incidence of postoperative retinal detachment in either the IOL (2.0%) or the aphakia group (25.0%). Conclusions: The rate of postoperative retinal detachment in eyes with IOL and no intraoperative posterior capsule rupture seems to be low. Intraocular lens implantation with capsular bag fixation may reduce the incidence of postoperative retinal detachment triggered by lens surgery for atopic cataract. © 2005 by the American Academy of Ophthalmology.
• アンギオテンシンII1型受容体阻害による抗炎症作用を介した網膜血管新生抑制

  里深 信吾, 永井 紀博, 篠田 肇, 厚東 隆志, 篠田 啓, 井上 真, 坪田 一男, 石田 晋

  炎症・再生 (一社)日本炎症・再生医学会 25 (4) 333 - 333 1346-8022 2005/07
• アンジオテンシンII1型受容体阻害による脈絡膜新生血管新生の抑制

  永井 紀博, 厚東 隆志, 里深 信吾, 小沢 洋子, 石田 晋, 坪田 一男

  炎症・再生 (一社)日本炎症・再生医学会 25 (4) 334 - 334 1346-8022 2005/07
• アンギオテンシンII1型受容体阻害による眼内炎症の抑制

  厚東 隆志, 永井 紀博, 里深 信吾, 小沢 洋子, 篠田 啓, 井上 真, 石田 晋, 坪田 一男

  炎症・再生 (一社)日本炎症・再生医学会 25 (4) 355 - 355 1346-8022 2005/07
• Adherence of intravitreally injected triamcinolone acetonide to the denuded retinal surface after internal limiting membrane peeling

  Shingo Satofuka, Makoto Inoue, Kei Shinoda, Susumu Ishida, Yutaka Imamura, Yasutaka Ando

  Retina 25 (5) 672 - 673 0275-004X 2005/07 [Refereed][Not invited]
  
• 炎症抑制による加齢黄斑変性の新しい治療法の開発

  石田 晋, 永井 紀博, 篠田 肇, 厚東 隆志, 坪田 一男

  日本抗加齢医学会総会プログラム・抄録集 (一社)日本抗加齢医学会 5回 92 - 92 2005/06
• 低酸素濃度環境下における血管内皮細胞barrier機能の破綻

  池田 栄二, 厚東 隆志, 石田 晋, 篠田 肇, 井上 真, 坪田 一男, 岡田 保典

  日本病理学会会誌 (一社)日本病理学会 94 (1) 213 - 213 0300-9181 2005/03
• 低酸素下の血管内皮細胞におけるclaudin-5発現動態と血液網膜関門破綻機構の解明

  厚東 隆志, 石田 晋, 篠田 肇, 井上 真, 坪田 一男, 岡田 保典, 池田 栄二

  日本眼科学会雑誌 (公財)日本眼科学会 109 (臨増) 146 - 146 0029-0203 2005/02
• アンギオテンシンII1型レセプターのブロックによる眼内炎症の抑制

  永井 紀博, 篠田 肇, 厚東 隆志, 小沢 洋子, 篠田 啓, 井上 真, 坪田 一男, 山城 健児, 石田 晋

  日本眼科学会雑誌 (公財)日本眼科学会 109 (臨増) 184 - 184 0029-0203 2005/02
• アンギオテンシンII 1型レセプター阻害による抗炎症作用を介した網膜血管新生抑制

  石田 晋, 永井 紀博, 野田 航介, 篠田 肇, 厚東 隆志, 篠田 啓, 井上 真, 坪田 一男

  日本眼科学会雑誌 (公財)日本眼科学会 109 (臨増) 212 - 212 0029-0203 2005/02
• 外傷性黄斑円孔に対する硝子体手術

  小森 景子, 野田 航介, 永井 紀博, 今村 裕, 石田 晋, 井上 真

  眼科臨床医報 眼科臨床医報会 99 (1) 8 - 12 0386-9601 2005/01 

  目的 外傷性黄斑円孔に対して硝子体手術を施行し,その術後成績を検討した.対象 対象は外傷性黄斑円孔に対して硝子体手術を施行した4例4眼で,性別は全て男性,年齢は16〜20歳であった.硝子体切除術およびSF6ガスタンポナーデを施行し,3例において内境界膜剥離を併用した.各症例における術前後の視力と網脈絡膜萎縮の位置との関係について検討した.結果 術前視力は,0.04〜0.5であり,円孔径が1/3乳頭径大以上が2眼,全例で後部硝子体は未剥離であった.全例で術後に黄斑円孔は閉鎖し,2段階以上の視力改善が得られた.術後視力0.5以上は3眼(75%)で得られたが,網脈絡膜萎縮が黄斑部におよんだ1眼では0.3であった.結論 外傷性黄斑円孔に対して硝子体手術は有効であり,その視力予後は黄斑部におよぶ網脈絡膜萎縮の有無により影響された(著者抄録)
• DORC社製25Gシステムの使用経験

  井上 真, 里深 信吾, 永井 紀博, 野田 航介, 今村 裕, 篠田 啓, 石田 晋

  眼科臨床医報 眼科臨床医報会 99 (1) 65 - 65 0386-9601 2005/01
• 【硝子体における眼疾患の病態】眼内血管新生

  石田 晋, 野田 航介

  眼科 金原出版(株) 46 (13) 1851 - 1855 0016-4488 2004/12
• 脈絡膜新生血管に対する黄斑下手術の術後成績

  川村 亮介, 永井 紀博, 野田 航介, 今村 裕, 石田 晋, 井上 真

  眼科臨床医報 眼科臨床医報会 98 (11) 1034 - 1034 0386-9601 2004/11
• 外傷性黄斑円孔に対する硝子体手術

  小森 景子, 野田 航介, 永井 紀博, 今村 裕, 石田 晋, 井上 真

  眼科臨床医報 眼科臨床医報会 98 (11) 1035 - 1035 0386-9601 2004/11
• 増殖糖尿病網膜症に併発した黄斑円孔に対する内境界膜剥離

  栗原 俊英, 野田 航介, 永井 紀博, 今村 裕, 石田 晋, 井上 真

  眼科臨床医報 眼科臨床医報会 98 (11) 1047 - 1047 0386-9601 2004/11
• 脈絡膜新生血管に対する黄斑下手術成績

  川村 亮介, 永井 紀博, 野田 航介, 今村 裕, 石田 晋, 井上 真

  眼科 金原出版(株) 46 (8) 1069 - 1076 0016-4488 2004/08 

  加齢性黄斑変性(ARMD)15例16眼とポリープ様脈絡膜血管症(PCV)5例5眼を対象に,脈絡膜新生血管(CNV)抜去術併用硝子体切除術を施行し,CNVを中心窩下,傍中心窩,中心窩外に分けて術前後視力を比較した.ARMDの中心窩下CNV7眼では,改善43%,不変14%,悪化43%であり,傍中心窩CNV5眼では,改善60%,悪化40%で,中心窩外CNV4眼では,改善75%,不変25%であった.PCV5眼においてCNVは3眼が中心窩下,2眼が傍中心窩に存在し,改善80%,不変20%であった.黄斑下手術は,ARMDの中心窩外,傍中心窩CNVに有効で,PCVではCNVの位置にかかわらず有効であった.また,ARMDによる中心窩下CNVの術後視力が不良であったが,原因は中心窩下に生じた網膜色素上皮欠損と術中に生じた黄斑円孔の発生が考えられた
• Treatment of cystoid macular edema with oral acetazolamide in a patient with best vitelliform macular dystrophy

  Kuniko Hori, Susumu Ishida, Makoto Inoue, Kei Shinoda, Shinichi Kawashima, Shizuaki Kitamura, Yoshihisa Oguchi

  Retina 24 (3) 481 - 482 0275-004X 2004/06 [Refereed][Not invited]
  
• 糖尿病網膜症の眼内血管新生病変形成における網膜虚血状態の関与

  池田 栄二, 野田 航介, 石田 晋, 篠田 肇, 厚東 隆志, 小口 芳久, 岡田 保典

  日本病理学会会誌 (一社)日本病理学会 93 (1) 247 - 247 0300-9181 2004/05
• VEGF164(165) as the Pathological Isoform: Differential Leukocyte and Endothelial Responses through VEGFR1 and VEGFR2

  Tomohiko Usui, Susumu Ishida, Kenji Yamashiro, Yuichi Kaji, Vasiliki Poulaki, Johnny Moore, Tara Moore, Shiro Amano, Yoshitaka Horikawa, Darlene Dartt, Matthew Golding, David T. Shima, Anthony P. Adamis

  Investigative Ophthalmology and Visual Science 45 (2) 368 - 374 0146-0404 2004/02 [Refereed][Not invited]
   

  PURPOSE. Vascular endothelial growth factor (VEGF) induces angiogenesis and vascular permeability and is thought to be operative in several ocular vascular diseases. The VEGF isoforms are highly conserved among species however, little is known about their differential biological functions in adult tissue. In the current study, the inflammatory potential of two prevalent VEGF isoform splice variants, VEGF120(121) and VEGF164(165), was studied in the transparent and avascular adult mouse cornea. METHODS. Controlled-release pellets containing equimolar amounts of VEGF120 and VEGF164 were implanted in corneas. The mechanisms underlying this differential response of VEGF isoforms were explored. The response of VEGF in cultured endothelial cells was determined by Western blot analysis. The response of VEGF isoforms in leukocytes was also investigated. RESULTS. VEGF164 was found to be significantly more potent at inducing inflammation. In vivo blockade of VEGF receptor (VEGFR)-1 significantly suppressed VEGF164-induced corneal inflammation. In vitro, VEGF 165 more potently stimulated intracellular adhesion molecule (ICAM) -1 expression on endothelial cells, an effect that was mediated by VEGFR2. VEGF164 was also more potent at inducing the chemotaxis of monocytes, an effect that was mediated by VEGFR1. In an immortalized human leukocyte cell line, VEGF165 was found to induce tyrosine phosphorylation of VEGFR1 more efficiently. CONCLUSIONS. Taken together, these data identify VEGF 164(165) as a proinflammatory isoform and identify multiple mechanisms underlying its proinflammatory biology.
• Cerebral fat embolism diagnosed by magnetic resonance imaging at one, eight, and 50 days after hip arthroplasty: A case report

  Nobuko Sasano, Susumu Ishida, Shinichiro Tetsu, Hiroe Takasu, Kiyoshi Ishikawa, Hiroshi Sasano, Hirotada Katsuya

  Canadian Journal of Anesthesia 51 (9) 875 - 879 0832-610X 2004 [Refereed][Not invited]
   

  Purpose: To describe cardiovascular collapse during a cemented hip hemiarthroplasty in a patient who, despite a successful cardiopulmonary resuscitation, remained in a persistent vegetative state due to cerebral fat embolism diagnosed by magnetic resonance imaging (MRI). Clinical features: A 75-yr-old woman with no medical history underwent cemented hip hemiarthroplasty under spinal anesthesia for a right femoral neck fracture. Shortly after insertion of the prosthesis, a sudden oxygen desaturation, hypotension, bradycardia, and cardiac arrest occurred. The patient was successfully resuscitated, but did not regain consciousness. The patient developed high-grade fever, thrombocytopenia, anemia, and oliguria. MRI scans of the brain revealed multiple high intensity signals throughout the white matter, the basal ganglia, the cerebellum, and the brain stem. The diagnosis of fat embolism was made on the basis of clinical findings and MRI images. Although her cardiorespiratory status improved over the next week, the patient remained in a persistent vegetative state. Conclusion: When fat embolism is suspected, serial MRI scans of the brain should be performed to diagnose the etiology of cerebral embolism as well as to evaluate the severity of brain damage.
• Novel 473-bp deletion in XLRS1 gene in a Japanese family with X-linked juvenile retinoschisis

  Kei Shinoda, Hisao Ohde, Susumu Ishida, Makoto Inoue, Yoshihisa Oguchi, Yukihiko Mashima

  Graefe's Archive for Clinical and Experimental Ophthalmology 242 (7) 561 - 565 0721-832X 2004 [Refereed][Not invited]
   

  Purpose: To present the clinical features of two brothers with molecularly confirmed X-linked juvenile retinoschisis (xlRS) but with non-characteristic electrophysiological findings. Methods: Comprehensive ophthalmological examinations were performed. The electroretinograms (ERGs) were recorded under ISCEV standards, and ERGs elicited by long-duration stimuli were also evaluated. Standard genetic analysis of peripheral blood leukocytes was performed. Results: Molecular testing revealed a novel 473-bp deletion including exon 4 in the XLRS1 gene in both siblings. This resulted in a frameshift mutation and a premature termination at codon 78. The scotopic and photopic ERGs were reduced, but the 'negative-type' ERG, characteristic of xlRS, was not observed. Flicker ERGs were also highly reduced. Long-duration stimuli elicited ERGs with a complete loss of the b-wave and a preservation of the off-response, i.e., negative-type ERG. The phenotype/genotype relationship was not determined. Conclusion: The consistency of the ERGs elicited by long-duration stimuli in xlRS patients suggests that this type of stimuli provides responses that are a better indicator for the progression or stage of the disease. © Springer-Verlag 2004.
• Retinal blood flow in the macular area before and after scleral buckling procedures for rhegmatogenous retinal detachment without macular involvement

  Tadahiko Eshita, Kei Shinoda, Itaru Kimura, Shizuaki Kitamura, Susumu Ishida, Makoto Inoue, Yukihiko Mashima, Hiroshi Katsura, Yoshihisa Oguchi

  Japanese Journal of Ophthalmology 48 (4) 358 - 363 0021-5155 2004 [Refereed][Not invited]
   

  Purpose: To investigate retinal microcirculation changes in patients with rhegmatogenous retinal detachment (RRD). Methods: The tissue blood flow in the macular area was measured in 28 patients with RRD without macular involvement by scanning laser Doppler flowmetry before and after scleral buckling procedures. The mean blood flow (MBF) was calculated by the automatic full-field analysis program. The MBF ratios of the affected eye to the fellow eye (a/f ratio) in patients were compared with those of the right eye to the left eye (R/L ratio) in the control subjects. Results: The mean preoperative a/f ratio in the patients (0.81 ± 0.11) was lower than the mean R/L ratio in the control subjects (1.02 ± 0.11, P < 0.0001) and correlated with the extent of RRD (P < 0.05). The mean a/f ratio tended to decrease 2 weeks after surgery (0.72 ± 0.09) and recovered to an almost normal level after 1 month (0.96 ± 0.09). The blood-flow change was not influenced by the type of buckling. Conclusions: The retinal microcirculation in the macular area was disturbed in RRD patients without macular involvement. It correlated with the extent of the RRD, and subsided 1 month after successful scleral buckling procedures. © Japanese Ophthalmological Society 2004.
• VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization

  Susumu Ishida, Tomohiko Usui, Kenji Yamashiro, Yuichi Kaji, Shiro Amano, Yuichiro Ogura, Tetsuo Hida, Yoshihisa Oguchi, Jayakrishna Ambati, Joan W. Miller, Evangelos S. Gragoudas, Yin-Shan Ng, Patricia A. D'Amore, David T. Shima, Anthony P. Adamis

  Journal of Experimental Medicine 198 (3) 483 - 489 0022-1007 2003/08/04 [Refereed][Not invited]
   

  Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF164-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF164-deficient (VEGF120/188) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF+/+) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte-mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.
• Platelets accumulate in the diabetic retinal vasculature following endothelial death and suppress blood-retinal barrier breakdown

  Kenji Yamashiro, Akitaka Tsujikawa, Susumu Ishida, Tomohiko Usui, Yuichi Kaji, Yoshihito Honda, Yuichiro Ogura, Anthony P. Adamis

  American Journal of Pathology 163 (1) 253 - 259 0002-9440 2003/07/01 [Refereed][Not invited]
   

  Platelet microthrombi are present in the diabetic retinal vasculature of humans and rodents however, the mechanisms and consequences of their presence have not been defined. The current study demonstrates that platelet containing microthrombi accumulate in the retinal vasculature of the rat within 2 weeks of experimental diabetes, a timepoint at which leukocyte-mediated endothelial cell injury and death are known to occur. Platelet accumulation increased with the duration of diabetes, and crossover experiments revealed that maximal platelet accumulation required both diabetic platelets and a diabetic endothelium. Platelet accumulation also coincided with the expression of Fas and FasL in the diabetic retina. When endothelial cell apoptosis was inhibited with an anti-FasL neutralizing antibody, platelet accumulation was effectively suppressed. When platelets were depleted from the systemic circulation with an anti-platelet antibody, blood-retinal barrier breakdown worsened in the diabetic animals. These findings suggest that platelet accumulation in the diabetic retinal vasculature is secondary to endothelial cell death and serves, in part, to suppress blood-retinal barrier breakdown.
• Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease

  Susumu Ishida, Kenji Yamashiro, Tomohiko Usui, Yuichi Kaji, Yuichiro Ogura, Tetsuo Hida, Yoshihito Honda, Yoshihisa Oguchi, Anthony P. Adamis

  Nature Medicine 9 (6) 781 - 788 1078-8956 2003/06/01 [Refereed][Not invited]
   

  Retinal ischemia can cause vision-threatening pathological neovascularization. The mechanisms of retinal ischemia are not fully understood, however. Here we have shown that leukocytes prune the retinal vasculature during normal development and obliterate it in disease. Beginning at postnatal day 5 (P5) in the normal rat, vascular pruning began centrally and extended peripherally, leaving behind a less dense, smaller-caliber vasculature. The pruning was correlated with retinal vascular expression of intercellular adhesion molecule-1 (ICAM-1) and coincided with an outward-moving wave of adherent leukocytes composed in part of cytotoxic T lymphocytes. The leukocytes adhered to the vasculature through CD18 and remodeled it through Fas ligand (FasL)-mediated endothelial cell apoptosis. In a model of oxygen-induced ischemic retinopathy, this process was exaggerated. Leukocytes used CD18 and FasL to obliterate the retinal vasculature, leaving behind large areas of ischemic retina. In vitro, T lymphocytes isolated from oxygen-exposed neonates induced a FasL-mediated apoptosis of hyperoxygenated endothelial cells. Targeting these pathways may prove useful in the treatment of retinal ischemia, a leading cause of vision loss and blindness.
• VEGF164 is proinflammatory in the diabetic retina

  Susumu Ishida, Tomohiko Usui, Kenji Yamashiro, Yuichi Kaji, Ednan Ahmed, Karen G. Carrasquillo, Shiro Amano, Tetsuo Hida, Yoshihisa Oguchi, Anthony P. Adamis

  Investigative Ophthalmology and Visual Science 44 (5) 2155 - 2162 0146-0404 2003/05/01 [Refereed][Not invited]
   

  PURPOSE. The objectives of this study were to characterize the differential potency of two major VEGF isoforms, VEGF120 and VEGF164, for inducing leukocyte stasis (leukostasis) within the retinal vasculature and blood-retinal barrier (BRB) breakdown and to determine whether endogenous VEGF164 mediates retinal leukostasis and BRB breakdown in early and established diabetes. METHODS. Retinal leukostasis and BRB breakdown were simultaneously quantified by combining concanavalin A lectin (ConA) perfusion labeling with a fluorophotometric dextran leakage assay. CD45 immunohistochemistry was performed to confirm that ConA-stained cells within the vasculature were leukocytes. Retinal leukostasis and BRB breakdown were compared in nondiabetic rats receiving intravitreous injections of VEGF120 or VEGF164. Retinal intercellular adhesion molecule (ICAM)-1 and VEGF protein levels were studied by Western blot and ELISA, respectively. An anti-VEGF164(165) aptamer (EYE001) was administered by intravitreous injection to 2-week and 3-month diabetic rats, and the effect on retinal leukostasis and BRB breakdown was quantified. RESULTS. Compared with VEGF120, VEGF164 more potently increased retinal ICAM-1 levels (2.2-fold), leukostasis (1.9-fold), and BRB breakdown (2.1-fold, P < 0.01 for all), despite negligible differences in vitreoretinal VEGF levels at the time of evaluation (P > 0.05). Retinal leukostasis and leakage increased with the duration of diabetes (P < 0.01) and correlated closely (P < 0.01, r = 0.889). The isoform-specific blockade of endogenous VEGF164 with EYE001 resulted in a significant suppression of retinal leukostasis and BRB breakdown in both early (72.4% and 82.6%, respectively) and established (48.5% and 55.0%, respectively) diabetes (P < 0.01). CONCLUSIONS. On an equimolar basis, VEGF164 is at least twice as potent as VEGF120 at inducing ICAM-1-mediated retinal leukostasis and BRB breakdown in vivo. The inhibition of diabetic retinal leukostasis and BRB breakdown with EYE001 in early and established diabetes indicates that VEGF164 is an important isoform in the pathogenesis of early diabetic retinopathy.
• 増殖糖尿病網膜症における硝子体液中のmatrix metalloproteinaseについての検討

  野田 航介, 池田 栄二, 石田 晋, 井上 真, 小幡 賢一, 岡田 保典, 小口 芳久

  日本眼科学会雑誌 (公財)日本眼科学会 107 (臨増) 212 - 212 0029-0203 2003/03
• Expression and function of receptors for advanced glycation end products in bovine corneal endothelial cells

  Yuichi Kaji, Shiro Amano, Tomohiko Usui, Tetsuro Oshika, Kenji Yamashiro, Susumu Ishida, Kaori Suzuki, Sumiyoshi Tanaka, Anthony P. Adamis, Ryoji Nagai, Seiko Horiuchi

  Investigative Ophthalmology and Visual Science 44 (2) 521 - 528 0146-0404 2003/02/01 [Refereed][Not invited]
   

  PURPOSE. The corneal endothelium is a target of the aging process. This study was undertaken to reveal the relationship between corneal endothelial cell (CEC) death and the accumulation of advanced glycation end products (AGEs), by investigating the possible mechanism of accumulation of AGE in CECs and its effects on CEC death. METHODS. First, the in vivo expression of the receptor was investigated for AGE (RAGE) and galectin-3, both receptors for AGE, at both the mRNA and protein levels. Second, AGEs were added to the culture media of the cultured CECs, and the uptake of AGEs, the generation of reactive oxygen species, and the induction of apoptosis were investigated. RESULTS. Immunohistochemistry and RT-PCR demonstrated that both RAGE and galectin-3 were expressed in bovine CECs. After administration of AGE-modified bovine serum albumin to the culture medium, uptake of AGE was observed in the cytoplasm of the cultured bovine CECs. In addition, with increasing concentration of AGEs, the generation of reactive oxygen and the number of apoptotic cells also increased. CONCLUSIONS. These results show that the accumulation of AGEs in CECs induced apoptosis, in part, by increasing cellular oxidative stress. The accumulation of AGEs in the CECs of elderly patients may be involved in the loss of CECs during the aging process.
• Indocyanine green can distinguish posterior vitreous cortex from internal limiting membrane during vitrectomy with removal of epiretinal membrane

  Tadahiko Eshita, Susumu Ishida, Kei Shinoda, Shizuaki Kitamura, Makoto Inoue, Yoshihisa Oguchi, Kazuto Yamazaki

  Retina 22 (1) 104 - 106 0275-004X 2002/02 [Refereed][Not invited]
  
• ON-pathway disturbance in two siblings

  Kei Shinoda, Hisao Ohde, Rikako Inoue, Susumu Ishida, Yukihiko Mashima, Yoshihisa Oguchi

  Acta Ophthalmologica Scandinavica 80 (2) 219 - 223 1395-3907 2002 [Refereed][Not invited]
   

  Purpose: To present two clinical cases diagnosed with predominant cone dystrophy and demonstrating early disturbance in the on-centre bipolar cells (ON-pathway). Methods: Electrophysiological findings are presented in two siblings with predominant cone dystrophy. The subjects showed no remarkable ophthalmoscopic or fluorescein angiographic retinal changes, but demonstrated progressive visual disturbance during their 20s. Results: The electroretinograms (ERGs) showed reduced dark-adapted responses but the positive component of the photopic ERG was absent. Response to 30 Hz flicker was severely reduced. Electroretinograms elicited by long-duration stimuli showed a loss of the b-wave, and the off-response was slightly reduced. In both patients, multifocal ERGs (m-ERGs) were more reduced within the central 10°, where the ON-pathway is normally a major contributor. Conclusion: We conclude that these patients may be affected by an abnormality of the synapses of the cone receptors and that their decrease in vision might, at least initially, be due to selective ON-pathway dysfunction.
• Posterior synechia of the iris after combined pars plana vitrectomy, phacoemulsification, and intraocular lens implantation

  Kei Shinoda, Aya O'hira, Susumu Ishida, Mika Hoshide, Liliana Sayuri Ogawa, Yoko Ozawa, Kenichi Nagasaki, Makoto Inoue, Hiroshi Katsura

  Japanese Journal of Ophthalmology 45 (3) 276 - 280 0021-5155 2001/05 [Refereed][Not invited]
   

  Purpose: Combined pars plana vitrectomy, phacoemulsification, and intraocular lens implantation has become a widely accepted treatment for cataracts in patients with vitreoretinal diseases. We examined factors influencing the development of posterior synechia after this triple procedure. Methods: One hundred and three patients (107 eyes) were evaluated. The frequency of postoperative posterior synechia, the preoperative diagnosis, whether gas tamponade was used, and the type of lens implanted were reviewed. Results: Twenty-one eyes (19.6%) developed posterior synechia, and the highest rate (12/39 eyes, 30.8%) was in patients with proliferative diabetic retinopathy. Posterior synechia was more frequent after gas tamponade (28.1%) than in eyes without tamponade (10.1%). In proliferative diabetic retinopathy (PDR) patients, fibrin deposition and the amount of retinal photocoagulation were causative factors for posterior synechia. Conclusions: Factors promoting postoperative synechia after the triple procedure included (1) the existence of PDR, (2) expanding gas tamponade, (3) fibrin deposition in PDR, and (4) the amount of photocoagulation in PDR. Copyright © 2001 Japanese Ophthalmological Society.
• A new method for quantification of metamorphopsia in patients with epiretinal membrane

  Kei Shinoda, Susumu Ishida, Shinichi Kawashima, Tadayuki Matsuzaki, Kyoko Yamada, Hiroshi Katsura

  Japanese Journal of Ophthalmology 44 (4) 424 - 427 0021-5155 2000/07 [Refereed][Not invited]
   

  Purpose: A new method for quantification of metamorphopsia was applied to study distorted vision in patients with epiretinal membrane. Method: Sixty-three patients with unilateral epiretinal membrane in the macula were examined. A modified Amsler chart (a grid of black lines on a white background measuring 12 x 12 cm with grid squares of 2 x 2 cm) was prepared. If patients saw any of the grid lines as irregular or curved, they were asked to trace these on the chart. The length of all lines drawn by the patients was measured, except those on the outer border. The length of the grid is 1200 mm, but it should be drawn longer by patients with metamorphopsia. The severity of metamorphopsia was also scored subjectively and the relationship of grid length to the subjective score and the visual acuity was analyzed. Results: The grid length ranged from 1200 to 1259 mm (mean = 1223.3 mm) and was correlated significantly with the subjective score (P < .01, ρ = .387). Conclusion: This method might be applicable for evaluating the severity of metamorphopsia and the surgical outcome in patients with epiretinal membrane. (C) 2000 Japanese Ophthalmological Society.
• Macular hole retinal detachment in highly myopic eyes: Ultrastructure of surgically removed epiretinal membrane and clinicopathologic correlation

  Susumu Ishida, Kazuto Yamazaki, Kei Shinoda, Shinichi Kawashima, Yoshihisa Oguchi

  Retina 20 (2) 176 - 183 0275-004X 2000 [Refereed][Not invited]
   

  Purpose: To elucidate the pathogenesis of macular hole retinal detachment (RD) in highly myopic eyes by investigating the ultrastructure of surgically removed epiretinal membranes (ERM). Methods: Five consecutive Japanese patients with macular hole RD in highly myopic eyes underwent vitrectomy with attempted removal of the ERM around the hole. The surgical specimens were examined by light microscopy and by scanning and transmission electron microscopy. Results: Extremely thin, translucent sheets of epiretinal tissue were harvested from all patients during surgery, resulting in successful retinal reattachment. Ultrastructural examination revealed that the ERM consisted of cortical vitreous and various cellular components. Fibrous astrocytes were the major cell population and extended cytoplasmic processes with membrane-associated vesicles onto the cortical vitreous. Gap junctions were observed between the interdigitating processes of fibrous astrocytes. The cortical vitreous contained abundant newly formed collagen, including fibrous long-spacing collagen, surrounded by sparsely distributed native vitreous collagen. Conclusions: Active synthesis of new collagen may be regulated by fibrous astrocytes by means of transmission of metabolic substances through gap junctions and cytoplasmic vesicles. The frequent occurrence of newly formed collagen aggregates may subsequently lead to a diffusely condensed posterior cortical vitreous that exerts tangential traction on the posterior retina, causing macular hole RD.
• Coexpression of VEGF receptors VEGF-R2 and neuropilin-1 in proliferative diabetic retinopathy

  Susumu Ishida, Kei Shinoda, Shinichi Kawashima, Yoshihisa Oguchi, Yasunori Okada, Eiji Ikeda

  Investigative Ophthalmology and Visual Science 41 (7) 1649 - 1656 0146-0404 2000 [Refereed][Not invited]
   

  PURPOSE. To elucidate vascular endothelial growth factor (VEGF)-mediated pathogenesis of fibrovascular proliferation in diabetic retinopathy. METHODS. Fibrovascular tissues were obtained at vitrectomy from 22 cases with proliferative diabetic retinopathy. The half-divided tissues were processed for reverse transcription-polymerase chain reaction (RT-PCR) analysis to examine the expression of VEGF isoforms and their receptors. Paraffin sections of the other half were used for immunohistochemistry for CD34, glial fibrillary acidic protein and VEGF, and in situ hybridization for VEGF. RESULTS. RT-PCR analysis demonstrated the expression of VEGF receptors VEGF- R1, VEGF-R2, and neuropilin-1 in 12, 14, and 14 of 22 cases, respectively. Notably, VEGF-R2 and neuropilin-1 were simultaneously expressed in the identical 14 tissues. The isoform VEGF121 was constitutively expressed in all the tissues examined, whereas the expression of VEGF165 was confined to the 7 tissues that also expressed VEGF-R2 and neuropilin-1. The vascular density of fibrovascular tissues evaluated by immunohistochemistry for CD34 was significantly higher in the cases with the expression of VEGF-R2 and neuropilin-1 than in those without their expression (P < 0.01), whereas VEGF- R1 expression had no such relationship with the vascular density. The fibrovascular tissues that expressed VEGF165 together with VEGF-R2 and neuropilin-1 were found in significantly younger patients (P < 0.01). In situ hybridization and immunohistochemical studies demonstrated that glial cells in the fibrovascular tissues express and produce VEGF. CONCLUSIONS. Coexpression of VEGF-R2 and neuropilin-1 is suggested to facilitate fibrovascular proliferation in diabetic retinopathy.
• A new technique for separation of posterior vitreous in vitreous surgery

  Kei Shinoda, Makoto Inoue, Hiroshi Katsura, Susumu Ishida

  Ophthalmic Surgery and Lasers 30 (7) 588 - 590 1082-3069 1999/07 [Refereed][Not invited]
   

  To describe a new effective technique, hydroseparation, for use in detaching the posterior cortical vitreous from the retina by the simple injection of fluid into the subhyaloid space. This technique was used in 7 eyes of 6 patients with diabetic retinopathy who had limited posterior vitreous detachment. Following core vitrectomy, a 32 gauge cannula was inserted into the subhyaloid space a balanced salt solution (BSS) was injected. The injected fluid spread easily to the periphery, causing the vitreous cortex to be smoothly separated, except for areas with firm vitreoretinal adhesion. In those areas, we also used microscissors to separate the tissue. No iatrogenic retinal break occurred in any case. This simple technique, which exerts minimal traction force on the retina, was safe useful for inducing posterior vitreous detachment in patients with diabetes.
• Severe juvenile retinoschisis associated with a 33-bps deletion in XLRS1 gene

  Kei Shinoda, Yukihiko Mashima, Susumu Ishida, Yoshihisa Oguchi

  Ophthalmic Genetics 20 (1) 57 - 61 0167-6784 1999 [Refereed][Not invited]
   

  X-linked juvenile retinoschisis is a form of vitreoretinal dystrophy that is characterized by foveal and peripheral splitting of the retinal nerve fiber layer. Pathognomonic of this disorder is a microcystic radiate appearance in the fovea. We encountered a 10-year-old, mildly retarded, Japanese boy, who exhibited a widely extended macular retinoschisis bilaterally. A break in the inner layer of the left eye mimicked a lamellar macular hole, which is a rare manifestation of the disease. Peripheral retinoschisis was absent. Only a few reports have described marked bilateral macular retinoschisis that involved the entire posterior pole, while various other macular findings have been reported. This patient with a severe form of retinoschisis was found to harbor the deletion of 33 base pairs, including the boundary region of exon 3 and intron 3 in the XLRS1 gene.
• Comparison of the levels of hepatocyte growth factor and vascular endothelial growth factor in aqueous fluid and serum with grades of retinopathy in patients with diabetes mellitus

  Kei Shinoda, Susumu Ishida, Shinichi Kawashima, Toshiko Wakabayashi, Tadayuki Matsuzaki, Michiyo Takayama, Ken Shinmura, Masakazu Yamada

  British Journal of Ophthalmology 83 (7) 834 - 837 0007-1161 1999 [Refereed][Not invited]
   

  Aims - To determine the relation between the stages of diabetic retinopathy (DR) and the levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) in aqueous fluid and serum. Methods - Levels of HGF and VEGF in serum and aqueous humour obtained during ocular surgery were measured by enzyme linked immunosorbent assay in 58 diabetic patients with 32 non-diabetic patients (NDM) as controls. The patients with diabetes were classified into three groups according to the stage of DR: no DR (NDR 15 cases), non-proliferative DR (NPDR six cases), and proliferative DR (PDR 37 cases). Results - No significant differences were found between any of the groups in serum concentrations of HGF or VEGF. The aqueous HGF levels increased with the stage of DR: NDM, median 397 pg/ml, range 133-930 pg/ml NDR, 371 pg/ml, 142-1536 pg/ml NPDR, 455 pg/ml, 162-1007 pg/ml and PDR, 638 pg/ml, 187-2222 pg/ml. The aqueous VEGF levels in PDR (median 212 pg/ml, range 14-1216 pg/ml) were significantly higher than in NDM (105 pg/ml, 9-203 pg/ml), but aqueous HGF concentrations were unrelated to those of VEGF. Conclusion - The results of the present study suggest that both HGF and VEGF present in the ocular tissues may play important roles in the progression of DR.

Conference Activities & Talks

• Advanced gycation endoproducts link inflammatory cues to upregulation of Galectin-1 in diabetic retinopathy  [Not invited]

  Susumu Ishida

  The 31st Meeting of the Club Jules Gonin  2018/07
• Two types of choroidal thickening : pachychoroid and choroiditis. What is the difference in choroidal circulation hemodynamics?  [Invited]

  Susumu Ishida

  5th Annual Meeting Asia Pacific Retinal Imaging Society (APRIS) 2018  2018/07
• PshRNA against (pro)renin receptor as innovative drug development for diabetic retinopathy. Symposium: New dawn of ophthalmic pharmacologic therapy.  [Invited]

  Susumu Ishida

  36th World Ophthalmology Congress (WOC) 2018  2018/06
• Unusual case masquerading as Vogt-Koyanagi-Harada Disease  [Not invited]

  Susumu Ishida

  The 25th Anniversary Meeting of the Retina Center at Pali Momi Medical Center International Vitreoretinal Symposium  2018/04
• An unusual case masquerading as Vogt-Koyanagi-Harada disease: What is different?  [Not invited]

  Susumu Ishida

  Macula Society 41th Annual Meeting  2018/02
• Receptor-associated prorenin system in diabetic retinopathy. Ocular inflammation and diabetic retinopathy: The unplanned marriage.  [Invited]

  Susumu Ishida

  13th IOIS  2015/09
• Choroidal circulatory distur. Ocular inflammation and diabetic retinopathy: The unplanned marriage.  [Invited]

  Susumu Ishida

  13th IOIS  2015/09
• Role of VEG as a pro-inflammatory cytokine in diabetic macular edema.  [Invited]

  Susumu Ishida

  Asia-ARVO 2015  2015/02
• Receptor-associated prorenin system in the pathogenesis of diabetic retinopathy. Plenary session: Recent advances in retinal basic research.  [Invited]

  Susumu Ishida

  Asia-ARVO 2015  2015/02
• Choroidal thickening with impaired circulateon in acute idiopathic maculopathy.  [Invited]

  Susumu Ishida

  2015 Meeting with Hokkaido University in Taipei  2015/01

MISC

• 人を惹きつける魅力的なプレゼンをめざそう!

  石田 晋, 小沢 洋子, 近藤 峰生, 園田 康平, 中澤 徹, 安川 力, 山城 健児  Retina Medicine  11-  (1)  1  -8  2022/04
• Attenuation of experimental autoimmune uveoretinitis in mice by IKKβ inhibitor IMD-0354.

  Ye Liu, Nobuyoshi Kitaichi, Di Wu, Keitaro Hase, Masashi Satoh, Daiju Iwata, Kenichi Namba, Atsuhiro Kanda, Kousuke Noda, Akiko Itai, Kazuya Iwabuchi, Susumu Ishida  Biochemical and biophysical research communications  525-  (3)  589  -594  2020/02/27  [Not refereed][Not invited]
   

  Uveitis is a sight-threatening intraocular inflammatory disease that accounts for almost 10% of blindness worldwide. NF-κB signaling plays pivotal roles in inflammatory diseases. We have reported that IMD-0354, which inhibits NF-κB signaling via selective blockade of IKK-β, suppresses inflammation in several ocular disease models. Here, we examined the therapeutic effect of IMD-0354 in an experimental autoimmune uveoretinitis (EAU) model, a well-established animal model for endogenous uveitis in humans. Systemic administration of IMD-0354 significantly suppressed the clinical and histological severity, inflammatory edema, and the translocation of NF-κB p65 into the nucleus of retinas in EAU mice. Furthermore, IMD-0354 treatment significantly inhibited the levels of several Th1/Th17-mediated pro-inflammatory cytokines in vitro. Our current data demonstrate that inhibition of IKKβ with IMD-0354 ameliorates inflammatory responses in the mouse EAU model, suggesting that IMD-0354 may be a promising therapeutic agent for human endogenous uveitis.
• 慢性眼痛を有する症例の安静的機能的MRIによる検討

  田川義晃, 大口剛司, 杉森博行, KHIN Tha Khin, 木嶋理紀, 岩田大樹, 田川義継, 石田晋  日本眼科学会雑誌  123-  2019
• ニューラルネットワークによる眼底写真の網膜動静脈検出

  福津佳苗, 齋藤理幸, 野田航介, 村田美幸, 加瀬諭, 柴涼介, 磯貝直己, 道家充, 石田晋  日本眼循環学会講演抄録集  36th-  2019
• 眼痛を有する患者の安静時機能的MRIによる検討

  田川 義晃, 杉森 博行, Tha Khin Khin, 石田 晋  PAIN RESEARCH  33-  (2)  146  -146  2018/06  [Not refereed][Not invited]
  
• 生涯アカデミック宣言!

  石田 晋, 小沢 洋子, 尾花 明, 栗山 晶治, 近藤 峰生, 園田 康平, 中澤 徹, 安川 力, 山城 健児  Retina Medicine  7-  (1)  1  -8  2018/04  [Not refereed][Not invited]
  
• 弱視治療をおこなった広汎な網膜有髄神経線維の4例

  福津 佳苗, 安藤 亮, 野崎 真世, 溝口 亜矢子, 石田 晋  眼科臨床紀要  11-  (4)  300  -300  2018/04  [Not refereed][Not invited]
  
• 眼科のトランスレーショナルリサーチ 多機能蛋白質に着目した糖尿病網膜症に対する創薬研究

  野田 航介, 村田 美幸, 稲福 沙織, 松田 剛, 吉田 志帆, 董 陽子, 木下 哲志, 安藤 亮, 藤谷 顕雄, 齋藤 理幸, 董 震宇, 森 祥平, 加瀬 諭, 吉澤 史子, 齋藤 航, 神田 敦宏, 石田 晋, 眞島 行彦, 笹瀬 智彦, 天野 麻穂, 大橋 哲, 西村 伸一郎, 今川 貴仁, 白仁田 明生  日本眼科学会雑誌  122-  (3)  223  -248  2018/03  [Not refereed][Not invited]
   

  近年の基礎研究は、血管内皮増殖因子(vascular endothelial growth factor:VEGF)が糖尿病網膜症の病態形成に主要な役割を演じることを明らかとした。そして、同分子群に対する阻害薬の臨床応用は糖尿病網膜症の治療予後を劇的に改善し、現在我々はanti-VEGF eraと呼ばれるこの時代において同疾患の治療体系が刻々と変貌するのを目の当たりにしている。かつては光凝固と硝子体手術のみが進行した糖尿病網膜症に対する治療手段であったことを考えると隔世の感がある。しかしながらその一方で、情報システムの革新と研究技術の進歩を背景に蓄積される基礎および臨床研究の成果は、網膜症病態の複雑さ、VEGF単独阻害による治療の限界、そしてその弊害の可能性なども浮き彫りにした。そして、その必然としてVEGF以外の病態責任分子を標的とした糖尿病網膜症に対する創薬研究が全世界で現在行われ、複数の分子標的製剤が糖尿病網膜症の治療オプションとなるpost anti-VEGF eraが目前に迫ってきている。糖尿病網膜症の発症および進展には、慢性炎症、そして酸化ストレスの関与が知られている。本研究においては、糖鎖など新規標的分子の探索的研究を行うとともに、この二つの病態に関わる分子としてvascular adhesion protein-1(VAP-1)/semicarbazide sensitive amine oxidase(SSAO)の糖尿病網膜症病態における役割についての検討を主に行った。VAP-1/SSAOは血管内皮細胞に発現する白血球接着分子だが、その一方で酵素活性も持つ多機能蛋白質"moonlighting protein"であり、慢性炎症と酸化ストレスの双方に関わる重要な分子の一つである。本研究ではVAP-1/SSAOが糖尿病網膜症の病態形成に白血球接着分子として関与する一方、遊離型蛋白質としてその眼内に蓄積すること、そしてその機序にVEGFや蛋白質分解酵素matrix metalloproteinasesが関与することを明らかにした。また、VAP-1/SSAOは酵素として過酸化水素および不飽和アルデヒドの一種アクロレインを産生し、血管内皮細胞における酸化ストレス亢進に寄与することとその機序を見出した。以上の検討結果に基づいて、本稿では糖尿病網膜症におけるVAP-1/SSAO阻害剤による治療可能性について述べたい。(著者抄録)
• ドライアイ症状を有する患者の安静時機能的MRIによる検討

  田川 義晃, 大口 剛司, 杉森 博行, タ・キンキン, 木嶋 理紀, 岩田 大樹, 田川 義継, 石田 晋  日本眼科学会雑誌  122-  (臨増)  156  -156  2018/03  [Not refereed][Not invited]
  
• 眼サルコイドーシスの診断における血液検査・画像検査の有用性

  鈴木 佳代, 南場 研一, 水内 一臣, 岩田 大樹, 福原 崇子, 長谷 敬太郎, 濱田 怜, 大野 重昭, 北市 伸義, 石田 晋  日本眼科学会雑誌  122-  (臨増)  191  -191  2018/03  [Not refereed][Not invited]
  
• 多発消失性白点症候群における脈絡膜構造の層別解析

  廣岡 季里子, 齋藤 航, 江川 麻理子, 三田村 佳典, 橋本 勇希, 野田 航介, 園田 祥三, 坂本 泰二, 石田 晋  日本眼科学会雑誌  122-  (臨増)  235  -235  2018/03  [Not refereed][Not invited]
  
• 増殖糖尿病網膜症患者における血漿ガレクチン-1と炎症関連分子との相関解析

  長谷 敬太郎, 神田 敦宏, 野田 航介, 石田 晋  日本眼科学会雑誌  122-  (臨増)  237  -237  2018/03  [Not refereed][Not invited]
  
• 視神経乳頭黒色細胞腫のOCT angiography所見

  菊地 郁, 加瀬 諭, 石田 晋  日本眼科学会雑誌  122-  (臨増)  279  -279  2018/03  [Not refereed][Not invited]
  
• 【免疫疾患と眼炎症】 眼炎症研究の最前線

  北市 伸義, 石田 晋  炎症と免疫  26-  (2)  128  -132  2018/02  [Not refereed][Not invited]
   

  ベーチェット病は、その多発地域が日本を含むユーラシア大陸/北アフリカ大陸のシルクロード地域に偏在し、中央アジアやカスピ海・カフカス地方の諸民族でも患者が確認された。Th1/Th17に免疫状態が偏倚していると考えられており、日本人ベーチェット病患者でTh2関連アレルギー疾患の合併率が健常者より低かった。眼の調節機能の酷使による眼精疲労に対して、二重盲検臨床試験で抗酸化食品因子のアスタキサンチン、アントシアニンが自覚的にも他覚的にも有効性を示した。(著者抄録)
• 糖尿病網膜症における新規血管新生因子ガレクチン-1の発現調節メカニズム

  神田 敦宏, 野田 航介, 齋藤 航, 石田 晋  日本眼科学会雑誌  122-  (2)  132  -133  2018/02  [Not refereed][Not invited]
  
• フォークト・小柳・原田病の発症年齢における脈絡膜形態および循環動態の検討

  橋本 勇希, 南場 研一, 廣岡 季里子, 水内 一臣, 岩田 大樹, 石田 晋  日本視能訓練士協会誌  46-  309  -309  2017/12  [Not refereed][Not invited]
  
• 糖尿病網膜症における新規血管新生因子ガレクチン-1の発現調節メカニズム

  神田 敦宏, 野田 航介, 齋藤 航, 石田 晋  生命科学系学会合同年次大会  2017年度-  [1P  -0023]  2017/12  [Not refereed][Not invited]
  
• ステロイド治療と卵巣腫瘍摘出により視機能改善を示した癌関連網膜症の1例

  山田 梨佳, 山添 克弥, 久須見 有美, 神田 敦宏, 齋藤 航, 石田 晋, 堀田 一樹  眼科臨床紀要  10-  (11)  913  -917  2017/11  [Not refereed][Not invited]
   

  背景:発症1年後に卵巣癌の存在が明らかになった癌関連網膜症cancer-associated retinopathy(CAR)の1例を報告する。症例:39歳女性、左視力低下を主訴に受診、視力は右(1.5)、左(0.7)で、検眼鏡的に明らかな眼底異常はみられなかった。2ヵ月後に左視力が(0.2)に低下し、両眼に網膜静脈周囲炎、硝子体混濁が出現した。網膜電図は両眼とも錐体・桿体反応が著明に減弱していた。ぶどう膜炎精査およびCARを疑った全身検索を行ったが、悪性腫瘍は認めず、CAR関連自己抗体も陰性であった。ステロイド内服にて治療を開始し、いったん視力・所見の改善が得られたが、漸減過程で再燃した。ステロイドパルス療法を施行し、再度視力・所見の改善が得られ、その漸減過程で卵巣癌が判明した。腫瘍摘出および化学療法を行い、その後はステロイド漸減後も再燃はみられていない。結論:CARを疑う場合は、悪性腫瘍を認めず自己抗体陰性でも、早期治療と全身検索を繰り返すことが重要である。(著者抄録)
• 増殖糖尿病網膜症患者の硝子体中アクロレイン結合蛋白FDP-lysine濃度

  森 祥平, 村田 美幸, 野田 航介, 鈴木 智浩, 齋藤 理幸, 安藤 亮, 加瀬 諭, 齋藤 航, 神田 敦宏, 石田 晋  眼科臨床紀要  10-  (11)  920  -921  2017/11  [Not refereed][Not invited]
  
• PDTトリプル療法を行った加齢黄斑変性における治療2年後視力の規定因子

  安藤 亮, 野田 航介, 廣岡 季里子, 橋本 勇希, 鈴木 智浩, 森 祥平, 齋藤 理幸, 吉澤 史子, 加瀬 諭, 齋藤 航, 石田 晋  眼科臨床紀要  10-  (11)  940  -940  2017/11  [Not refereed][Not invited]
  
• ステロイドパルス療法が著効した脈絡膜新生血管とAZOORを伴った点状脈絡膜内層症の1例

  鈴木 智浩, 加瀬 諭, 森 祥平, 安藤 亮, 齋藤 理幸, 野田 航介, 石田 晋  眼科臨床紀要  10-  (11)  949  -950  2017/11  [Not refereed][Not invited]
  
• 朝顔様視神経乳頭眼に発症した急性帯状潜在性網膜外層症の1例

  橋本 勇希, 齋藤 航, 齋藤 理幸, 野田 航介, 石田 晋  眼科臨床紀要  10-  (11)  950  -950  2017/11  [Not refereed][Not invited]
  
• 【臓器炎症からみた糖尿病および糖尿病性合併症】 慢性炎症と糖尿病網膜症

  神田 敦宏, 石田 晋  糖尿病診療マスター  15-  (10)  851  -855  2017/10  [Not refereed][Not invited]
   

  ＜POINT＞糖尿病網膜症の危険因子として高血糖,高血圧,脂質異常,喫煙,妊娠などが古くから指摘されており,これらの危険因子を軽減することが重要である.生活習慣病により老化が加速する進行過程では,複数の病態に慢性炎症と循環・組織レニン-アンジオテンシン系が関与する.(著者抄録)
• 北海道大学眼科における全層角膜移植術の成績

  山本 拓, 大口 剛司, 田川 義晃, 木嶋 理紀, 水内 一臣, 岩田 大樹, 田川 義継, 石田 晋  眼科手術  30-  (4)  707  -709  2017/10  [Not refereed][Not invited]
   

  目的:北海道大学眼科(以下、当科)における全層角膜移植術(PKP)の成績を検討した。方法:2011年9月〜2015年5月に同一術者にてPKPを施行した28例30眼につき、診療録から後ろ向きに検討した。結果:男性14例15眼、女性14例15眼、平均年齢63.4歳、術後平均観察期間は479.7日であった。原因疾患は、水疱性角膜症11眼、移植後内皮機能不全8眼、円錐角膜5眼、角膜白斑5眼、角膜ジストロフィ1眼であった。術後最終観察時に角膜透明治癒が得られたのは29眼(96.7%)であった。術中合併症として眼内レンズおよび硝子体脱出が1眼にみられた。術後合併症は高眼圧が5眼(16.7%)にみられ、そのうち1眼は手術治療を要した。Primary graft failureが1眼にみられたが、拒絶反応を生じた症例はなかった。内皮細胞密度減少率は術後1ヵ月で14.3%、1年で17.4%であった。結論:当科のPKP後の角膜透明治癒率は今のところ良好だが、今後さらなる経過の観察が必要である。また、PKP後の高眼圧が16.7%にみられており、術後の眼圧管理が重要であると考えられた。(著者抄録)
• 難治性黄斑円孔に対する内境界膜自家移植変法

  柴田 有紀子, 齋藤 理幸, 藤谷 顕雄, 鈴木 智浩, 安藤 亮, 森 祥平, 加瀬 諭, 野田 航介, 石田 晋  眼科臨床紀要  10-  (10)  843  -843  2017/10  [Not refereed][Not invited]
  
• Pachychoroid pigment epitheliopathyの臨床像

  廣岡 季里子, 齋藤 航, 齋藤 理幸, 森 祥平, 安藤 亮, 橋本 勇希, 加瀬 諭, 野田 航介, 石田 晋  眼科臨床紀要  10-  (10)  860  -860  2017/10  [Not refereed][Not invited]
  
• 挙筋整復術を契機に発見された眼球運動制限を伴う眼窩内転移性乳がんの一例

  鈴木 佳代, 新明 康弘, 和田 莉奈, 石嶋 漢, 新田 卓也, 陳 進輝, 石田 晋  神経眼科  34-  (増補1)  58  -58  2017/10  [Not refereed][Not invited]
  
• 日内変動を伴う眼瞼下垂と複視を呈し、重症筋無力症との鑑別を要した脳脊髄液減少症の一例

  和田 莉奈, 新明 康弘, 鈴木 佳代, 石嶋 漢, 中村 佳代子, 高橋 明弘, 陳 進輝, 石田 晋  神経眼科  34-  (増補1)  94  -94  2017/10  [Not refereed][Not invited]
  
• 糖尿病眼における熱ショック蛋白α-クリスタリンと最終糖化産物の発現

  加瀬 諭, 石田 晋  糖尿病合併症  31-  (Suppl.1)  341  -341  2017/10  [Not refereed][Not invited]
  
• 糖尿病網膜症における新規血管新生因子ガレクチン-1の発現調節メカニズム

  神田 敦宏, 野田 航介, 齋藤 航, 石田 晋  糖尿病合併症  31-  (Suppl.1)  342  -342  2017/10  [Not refereed][Not invited]
  
• 網膜グリア細胞に対するアクロレインの作用

  野田 航介, 村田 美幸, 吉田 志帆, 神田 敦宏, 石田 晋  糖尿病合併症  31-  (Suppl.1)  347  -347  2017/10  [Not refereed][Not invited]
  
• 瞼板内角質嚢胞との鑑別を要した眼瞼結膜嚢胞性病変の1例

  水門 由佳, 加瀬 諭, 石嶋 漢, 高桑 恵美, 石田 晋  日本眼腫瘍学会誌  6-  1  -4  2017/09  [Not refereed][Not invited]
   

  【緒言】瞼板内角質嚢胞は、瞼板内に発生する腫瘤性病変において代表的な嚢胞性疾患である。今回我々は、瞼板内角質嚢胞と鑑別を要し、眼瞼結膜に発生した嚢胞性病変の1例を経験したので報告する。【症例】62歳女性。6年前から右上眼瞼の腫脹と自然排膿があり、前医にて経過観察を行ってきた。腫瘤が増大傾向を示したため、眼瞼脂腺癌などの悪性疾患が疑われ、当科紹介となった。初診時、右眼の上眼瞼結膜側に突出する黄色腫瘤がみられた。同日、眼瞼結膜から腫瘤の切除生検を行った。腫瘤の本体は瞼板内にみられ、病理組織検査では、一部に顆粒層を有する異型に乏しい重層扁平上皮が嚢胞状構造を形成しており、眼瞼結膜に隣接していた。嚢胞内腔には層板状の角化物が見られ、病理組織学的には表皮嚢胞を考える所見であった。【結論】上眼瞼の代表的な嚢胞性疾患として、表皮嚢胞、瞼板内角質嚢胞が挙げられる。本症例は、臨床的に開口部が結膜と考えられること、嚢胞壁に顆粒層を有することから表皮嚢胞、瞼板内角質嚢胞とは異なる結膜嚢胞性病変である。(著者抄録)
• 眼皮膚白皮症に角膜内血腫を合併した1例

  菊地 郁, 大口 剛司, 田川 義晃, 木嶋 理紀, 水内 一臣, 岩田 大樹, 田川 義継, 石田 晋  臨床眼科  71-  (8)  1227  -1231  2017/08  [Not refereed][Not invited]
   

  目的:眼皮膚白皮症に角膜内血腫を合併した症例の報告。症例:66歳,男性。生来最高矯正視力は両眼0.1。左眼視力低下にて当院を紹介された。初診時,矯正視力は右0.1,左0.02,両眼の虹彩血管と右眼脈絡膜血管が透見され,全身の皮膚と毛髪に色素脱失がみられたため,眼皮膚白皮症と診断した。左眼角膜実質内の2/3の範囲に血腫を認めた。血腫の吸収に伴い実質内に血管侵入がみられ,強角膜炎に続発した病変と考えてステロイド点眼薬を追加した。2ヵ月後に角膜内血腫は吸収され,新生血管も消退した。結論:眼皮膚白皮症に角膜内血腫を合併した稀な症例を経験した。(著者抄録)
• 視細胞形態に異常を示さなかった急性帯状潜在性網膜外層症の1例

  廣岡 季里子, 齋藤 航, 神田 敦宏, 石田 晋  眼科臨床紀要  10-  (7)  590  -590  2017/07  [Not refereed][Not invited]
  
• Rosai-Dorfman病に合併した続発緑内障に対し360.suture trabeculotomy変法が奏効した1例

  菊地 香澄, 木嶋 理紀, 新明 康弘, 大口 剛司, 陳 進輝, 南場 研一, 齋藤 航, 石田 晋  眼科手術  30-  (3)  514  -517  2017/07  [Not refereed][Not invited]
   

  背景:Rosai-Dorfman病(RDD)は1969年にRosaiとDorfmanによって報告された非腫瘍性組織球増殖性疾患であり、無痛性の頸部リンパ節腫脹で発症することが多く、約半数に節外病変を生じる。節外病変としてぶどう膜炎の報告が17例あるが、その続発緑内障に対しtrabeculotomy(LOT)を施行した報告はない。今回、筆者らはRDDに合併したぶどう膜炎治療中に続発緑内障をきたし、半年以上眼圧の改善がみられなかった症例に対し、360.suture trabeculotomy変法(S-LOT)を施行し、良好な眼圧コントロールが得られた1例を経験したので報告する。症例:63歳、女性。ぶどう膜炎精査加療目的で近医より紹介。所見:両眼に汎ぶどう膜炎を認め、精査にても確定診断には至らなかった。ステロイドの内服と点眼、Tenon嚢下注射にて加療し、眼圧は正常範囲内で経過していた。初診から7年後に腎腫瘍・骨腫瘍を指摘され、生検の結果RDDと診断された。初診から10年後に両眼圧は右眼46mmHg、左眼32mmHgと上昇し、前房に炎症所見はなく、緑内障点眼やアセタゾラミドナトリウム内服にてもコントロール不良であったため、両眼にS-LOTを施行した。術後2年間にわたり、眼圧は右眼10〜16mmHg、左眼9〜13mmHgと良好であった。結論:RDDに合併したぶどう膜炎治療中に発症した続発緑内障に対し、S-LOTが有効である可能性が示唆された。(著者抄録)
• Mechanism in suppression of CCK pathway by rebamipide in trigeminal neurons.

  Yoshiaki Tagawa, Kousuke Noda, Ken-ichi Otsuguro, Erdal Tan Ishizuka, Atsuhiro Kanda, Susumu Ishida  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE  58-  (8)  2017/06  

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• 【糖尿病網膜症】 糖尿病網膜症の病態研究と進歩

  神田 敦宏, 石田 晋  Diabetes Frontier  28-  (3)  273  -276  2017/06  [Not refereed][Not invited]
  
• 多発消失性白点症候群における年代別の網脈絡膜形態の比較

  森 なみ, 橋本 勇希, 長谷川 裕香, 齋藤 航, 石田 晋  眼科臨床紀要  10-  (6)  513  -513  2017/06  [Not refereed][Not invited]
  
• Laser speckle flowgraphyを施行した小児発症のフォークト・小柳・原田病の1例

  橋本 勇希, 南場 研一, 廣岡 季里子, 水内 一臣, 岩田 大樹, 齋藤 航, 石田 晋  眼科臨床紀要  10-  (6)  514  -514  2017/06  [Not refereed][Not invited]
  
• 非典型的所見を呈した片眼性網膜芽細胞腫の1例

  安藤 亮, 加瀬 諭, 野崎 真世, 石田 晋  眼科臨床紀要  10-  (6)  517  -517  2017/06  [Not refereed][Not invited]
  
• (プロ)レニン受容体特異的一本鎖RNA干渉による眼炎症病態の抑制

  神田 敦宏, 石塚 タンエルダル, 劉 野, 野田 航介, 石田 晋  日本抗加齢医学会総会プログラム・抄録集  17回-  173  -173  2017/06  [Not refereed][Not invited]
  
• 【アンチエイジング研究-世界の趨勢と日本】各領域におけるアンチエイジング研究 感覚器のアンチエイジング研究 眼科領域の食品因子研究の現状

  北市 伸義, 石田 晋  医学のあゆみ  261-  (6)  613  -618  2017/05  [Not refereed][Not invited]
   

  眼科領域のアンチエイジング研究は、食品因子の効果が臨床試験で科学的に検証されていることが大きな特色のひとつである。加齢黄斑変性に対するビタミンやルテイン、調節性眼精疲労に対する抗酸化物質、アスタキサンチンやアントシアニンなどが代表的である。海外での大規模臨床試験だけでなく、日本でも疫学調査や臨床試験での好成績が報告されている。(著者抄録)
• 臨床報告Selected 求心性視野狭窄を呈した交通外傷後脳脊髄液減少症

  鈴木 佳代, 高橋 明弘, 新明 康弘, 田川 義晃, 野崎 真世, 石嶋 漢, 陳 進輝, 石田 晋  臨床眼科  71-  (3)  301  -307  2017/03  [Not refereed][Not invited]
   

  目的:交通事故による頭頸部打撲後に視力と視野障害が生じ,脳脊髄液減少症と診断された症例の報告。症例:28歳男性が自家用車を運転中に樹木に衝突し,右頭頸部を打撲した。翌日に視力低下を自覚した。矯正視力は右0.4,左1.2で,エアバッグによる角膜混濁と診断された。1ヵ月後に視力が悪化して当科を受診した。所見と経過:視力は右手動弁,左0.07で,両眼に求心性の視野狭窄と左眼に中心暗点があった。眼底に異常はなく,MRIでは脳と眼窩に異常はなかった。以後7ヵ月間に視力と視野に変化はなかったが,補液により起立性頭痛と視機能が著明に改善した。脳脊髄圧は正常で,脳槽シンチグラフィで髄液漏出像はなく,RIクリアランスが亢進していた。外傷後の脳脊髄液減少症と診断した。硬膜外自家血注入で,視力は右0.8,左1.0に改善し,視野障害も回復した。結論:頭頸部への鈍性外傷後に生じた視力障害と視野狭窄は,脳脊髄液減少症によると推定され,硬膜外自家血注入が有効であった。(著者抄録)
• 臨床報告 春季カタルにおけるタクロリムス点眼薬の長期使用成績

  品川 真有子, 南場 研一, 北市 伸義, 石田 晋  臨床眼科  71-  (3)  343  -348  2017/03  [Not refereed][Not invited]
   

  目的:春季カタルに対する0.1%タクロリムス点眼薬の長期使用効果の報告。対象と方法:1年以上タクロリムス点眼薬で加療した春季カタル16例30眼を対象とした。全例でシクロスポリン点眼薬がそれ以前に使用され,効果不十分であった。年齢は6〜19歳,平均15歳で,26眼が眼瞼型,4眼が眼瞼輪部混合型であった。14例にアトピー性皮膚炎,5例に喘息,3例にアレルギー性鼻炎の合併があった。9眼でステロイド点眼薬,8眼でステロイド内服薬を併用していた。結果:春季カタルの他覚的所見は全例で改善した。タクロリムス点眼薬の回数は,多くの症例で当初の1日2回から1日1回になり,ステロイド点眼薬の併用は開始時30%から1年後10%,ステロイド内服薬の併用は開始時25%から1年後6%に減少した。タクロリムス点眼薬を1年以上使用した30眼中16眼で一過性の増悪があり,その多くは5月と7〜9月に生じた。1眼でタクロリムス点眼薬の使用開始から38ヵ月後に上皮性単純ヘルペス角膜炎が発症し,加療により治癒した。結論:シクロスポリン点眼薬が奏効しない春季カタルに対し,1年以上のタクロリムス点眼薬の使用で,他覚的所見と症状の改善がみられた。(著者抄録)
• 【世界のトップを走る日本のドライアイ最前線】 痛みをターゲットとしたドライアイ治療

  田川 義晃, 石田 晋  あたらしい眼科  34-  (3)  341  -346  2017/03  [Not refereed][Not invited]
  
• 創薬に必要な眼科のドラッグデリバリーシステム(DDS) 後眼部疾患の治療を目的としたドラッグデリバリーシステム「結膜リング」の開発(Drug delivery system(DDS) for innovation of ophthalmic drugs Development of the Conjunctival Ring for Treating Posterior-Segment Eye Diseases)

  石田 晋  日本眼科学会雑誌  121-  (臨増)  34  -34  2017/03  [Not refereed][Not invited]
  
• 糖尿病網膜症における新規血管新生因子ガレクチン-1の発現調節メカニズム

  神田 敦宏, 董 陽子, 野田 航介, 齋藤 航, 石田 晋  日本眼科学会雑誌  121-  (臨増)  176  -176  2017/03  [Not refereed][Not invited]
  
• 眼付属器MALTリンパ腫の診断におけるフローサイトメトリの有用性

  加瀬 諭, 石嶋 漢, 浦木 健彦, 鈴木 康夫, 石田 晋  日本眼科学会雑誌  121-  (臨増)  201  -201  2017/03  [Not refereed][Not invited]
  
• 多発消失性白点症候群における脈絡膜層別厚の経時変化

  橋本 勇希, 齋藤 航, 長谷川 裕香, 齋藤 理幸, 安藤 亮, 森 祥平, 加瀬 諭, 野田 航介, 石田 晋  日本眼科学会雑誌  121-  (臨増)  218  -218  2017/03  [Not refereed][Not invited]
  
• 三叉神経節細胞におけるレバミピドのコレシストキニン経路抑制機序の検討

  田川 義晃, 野田 航介, 宮本 亮, 乙黒 兼一, 石塚 タンエルダル, 神田 敦宏, 石田 晋  日本眼科学会雑誌  121-  (臨増)  221  -221  2017/03  [Not refereed][Not invited]
  
• RPE特異的なAtp6ap2コンディショナルノックアウトマウスにおける眼の表現型の分析(Analysis of ocular phenotype in RPE-specific Atp6ap2 conditional knockout mice)

  石塚 タンエルダル, 神田 敦宏, 野田 航介, 市原 淳弘, 石田 晋  日本眼科学会雑誌  121-  (臨増)  229  -229  2017/03  [Not refereed][Not invited]
  
• 両眼の外転神経麻痺を合併した仙骨軟骨肉腫の一例

  石嶋 漢, 新明 康弘, 高宮 宗一郎, 関 俊隆, 新田 卓也, 野崎 真世, 中村 佳代, 石田 晋  日本眼科学会雑誌  121-  (臨増)  317  -317  2017/03  [Not refereed][Not invited]
  
• 腫瘍性病変が疑われた結節性後部強膜炎の1例

  柴田 有紀子, 加瀬 諭, 南場 研一, 石田 晋  日本眼科学会雑誌  121-  (臨増)  329  -329  2017/03  [Not refereed][Not invited]
  
• 著者インタビュー Guest 杉田直先生 (日本人のヒット論文 : 本音で語る苦労話(第11回))

  杉田 直, 石田 晋, 小沢 洋子  Retina medicine : journal of retina medeicine : 網膜・硝子体領域を中心とした医学情報誌  6-  (2)  140  -144  2017
• 切腱しない筋移動術を行ったDouble Elevator Palsy

  白枝 友子, 安藤 亮, 野崎 真世, 新明 康弘, 溝口 亜矢子, 阿部 朋子, 石田 晋  眼科手術  30-  (1)  174  -177  2017/01  [Not refereed][Not invited]
   

  背景:外転神経麻痺に対する術式として、切腱を伴わない垂直筋移動術(西田法)が報告されている。今回、筆者らはdouble elevator palsy(DEP)の症例に対して、その術式を水平筋に応用し施行したので報告する。症例:0歳4ヵ月、女児。生下時からの眼位異常の精査目的に北海道大学病院眼科へ紹介となった。初診時、Hirschberg 15°の左下斜視があり、左眼では著明な上転制限と眼瞼下垂を認めた。MRIにて頭蓋内病変は否定され、Bell現象陽性であることから、核上性DEPと診断した。5歳時、35Δの左下斜視に対し、患眼に切腱を伴わない水平筋上方移動術を施行した。術中、外直筋が通常よりも半筋腹下方に付着していたため、移動量は予定よりも少なくなった。術後の斜視角は16Δの左下斜視に改善した。初回手術の6ヵ月後に左下直筋後転術(4mm)を追加し、術後は5Δの左下斜視となった。所見:本症例に対する水平筋上方移動術の手術効果は19Δであった。この結果は西田法本来の眼位矯正効果よりも低矯正であったが、これは外直筋の付着異常により水平筋を十分に上方へ移動できなかったことが一因と考えられた。結論:DEPに対して切腱を伴わない水平筋上方移動術は有効な術式であると考えられた。(著者抄録)
• 睫毛乱生に対するラジオ波メス睫毛根焼灼の治療効果

  浦木 健彦, 加瀬 諭, 木下 哲志, 石嶋 漢, 石田 晋  眼科手術  30-  (1)  187  -190  2017/01  [Not refereed][Not invited]
   

  目的:睫毛乱生に対するラジオ波メスを用いた睫毛根焼灼の治療成績を報告する。方法:2015年3〜12月に帯広協会病院にてラジオ波メスを用いた睫毛根焼灼を施行し睫毛乱生13例21側を対象とした。機器はサージトロンEMC(Ellman社)を使用し、焼灼条件は止血・凝固モード、パワーは2W、焼灼時間は1秒とした。焼灼後56日間で再発がみられない場合に寛解と定義した。結果:初回治療では151本中111本が寛解した(寛解率:73.5%)。再発した40本に対し2回目の治療を施行し、32本が寛解した(寛解率:80%)。再度、再発した8本に3回目の治療を施行し、結果的に100%の寛解率を得た。治療回数が多い眼瞼では、有意に睫毛数が増加していた。合併症では21側中2側(9.5%)に軽微な色素沈着や陥凹瘢痕がみられた。結論:本研究により、睫毛乱生に対するラジオ波焼灼は、有用な治療法の一つであることが示された。(著者抄録)
• 受容体結合プロレニン系を標的とした新規阻害薬の開発

  石田晋  北海道大学研究シーズ集  4-  (54)  2017  [Not refereed][Not invited]
  
• 三角症候群の1例における脈絡膜循環動態と形態の経時変化

  石川 由梨, 橋本 勇希, 齋藤 航, 安藤 亮, 溝口 亜矢子, 石田 晋  日本視能訓練士協会誌  45-  356  -357  2016/12  [Not refereed][Not invited]
  
• フォークト・小柳・原田病のステロイド薬全身投与後における眼底自発蛍光

  橋本 勇希, 水内 一臣, 廣岡 季里子, 南場 研一, 石田 晋  日本視能訓練士協会誌  45-  335  -335  2016/12  [Not refereed][Not invited]
  
• 360°Suture Trabeculotomy変法とTrabeculotomyの術後眼圧下降効果の比較検討

  木嶋 理紀, 陳 進輝, 新明 康弘, 大口 剛司, 新田 朱里, 新田 卓也, 石田 晋  あたらしい眼科  33-  (12)  1779  -1783  2016/12  [Not refereed][Not invited]
   

  目的:同一症例での360°suture trabeculotomy(S-LOT)変法、金属ロトームによる120°trabeculotomy(LOT)の術後経過の比較。対象および方法:2005年8月〜2008年3月に、同一症例において片眼にS-LOT変法、他眼にLOTを施行し、2年以上経過観察できた7例14眼を対象に、診療録をもとに後ろ向きに検討を行った。結果:7例中4例でS-LOT眼の眼圧下降効果がLOT眼に比べて大きく、そのうち2例でLOT眼のみでは眼圧下降が不十分であったため、緑内障追加手術を必要とした。7例中3例は両眼の比較で術後眼圧に統計学的な有意差がなかった。S-LOT眼では経過観察中に緑内障追加手術を必要とした症例はなかった。全例の平均眼圧でみると、術後6、9、12、24、48ヵ月の時点でS-LOT眼のほうがLOT眼に比較して統計学的に有意に眼圧が低かった。結論:S-LOT変法はLOTに比べ、より強い眼圧下降効果が得られる可能性がある。(著者抄録)
• ビルベリーエキス含有食品摂取による眼精疲労改善効果 ランダム化二重盲検プラセボ対照試験

  堀江 幸弘, 片山 詩野, 所 茉利奈, 董 震宇, 小齊平 麻里衣, 大野 重昭, 石田 晋, 北市 伸義  あたらしい眼科  33-  (12)  1795  -1800  2016/12  [Not refereed][Not invited]
   

  アントシアニンはブルーベリーなどに豊富に含まれ、古来眼症状への好影響が伝承されている。今回筆者らは機器を用いて眼疲労を他覚的に評価するとともに、Visual Analog Scale(VAS)スコアを用いた自覚的検査で標準ビルベリー抽出物ミルトアルゴスの眼疲労抑制効果を検討した。健康成人男女31名を参加者とし、無作為にプラセボ群、ビルベリーエキス160mg摂取群、3倍量ビルベリーエキス480mg摂取群の3群に分けて評価した。その結果、ビルベリー群では2群とも経口摂取1時間後に血漿中アントシアニン濃度が上昇した。摂取群では他覚検査トライイリスにて瞳孔緊張率が有意に改善し(p<0.05)、VASスコアでも自覚症状が有意に改善した(p<0.05)。標準ビルベリー抽出物はVDT作業や近見作業などによる眼の調節改善と疲労感軽減への有用性が期待された。(著者抄録)
• PDTトリプル療法を行ったポリープ状脈絡膜血管症における治療1年後視力の規定因子

  安藤 亮, 齋藤 航, 廣岡 季里子, 鈴木 智浩, 吉澤 史子, 齋藤 理幸, 加瀬 諭, 森 祥平, 野田 航介, 石田 晋  眼科臨床紀要  9-  (11)  930  -930  2016/11  [Not refereed][Not invited]
  
• アフリベルセプト併用PDTトリプル療法1年後の治療成績

  鈴木 智浩, 齋藤 航, 森 祥平, 齋藤 理幸, 安藤 亮, 加瀬 諭, 廣岡 季里子, 吉澤 史子, 野田 航介, 石田 晋  眼科臨床紀要  9-  (11)  931  -931  2016/11  [Not refereed][Not invited]
  
• 2型脈絡膜新生血管を伴った加齢黄斑変性に対するPDTトリプル療法の治療成績

  森 祥平, 齋藤 航, 齋藤 理幸, 安藤 亮, 廣岡 季里子, 吉澤 史子, 野田 航介, 石田 晋  眼科臨床紀要  9-  (11)  932  -933  2016/11  [Not refereed][Not invited]
  
• ベバシズマブ硝子体内注射が奏効した血管増殖性網膜腫瘍の3例

  川向 友子, 齋藤 航, 加瀬 諭, 石田 晋  眼科臨床紀要  9-  (11)  934  -934  2016/11  [Not refereed][Not invited]
  
• フォークト・小柳・原田病の発症年齢における脈絡膜形態および循環動態の検討

  橋本 勇希, 南場 研一, 廣岡 季里子, 水内 一臣, 岩田 大樹, 石田 晋  日本視能矯正学会プログラム抄録集  57回-  88  -88  2016/10  [Not refereed][Not invited]
  
• 【眼科検査の最新情報】 ぶどう膜炎 Laser speckle flowgraphyでみるぶどう膜疾患

  橋本 勇希, 南場 研一, 石田 晋  眼科  58-  (11)  1200  -1206  2016/10  [Not refereed][Not invited]
  
• Vogt・小柳・原田病の再発の有無によるステロイド全身投与後の脈絡膜循環動態の比較

  廣岡 季里子, 齋藤 航, 南場 研一, 水内 一臣, 岩田 大樹, 橋本 勇希, 齋藤 理幸, 石田 晋  眼科臨床紀要  9-  (10)  842  -843  2016/10  [Not refereed][Not invited]
  
• 多発消失性白点症候群におけるlaser speckle flowgraphyを用いた波形解析

  橋本 勇希, 齋藤 航, 齋藤 理幸, 廣岡 季里子, 野田 航介, 石田 晋  眼科臨床紀要  9-  (10)  855  -855  2016/10  [Not refereed][Not invited]
  
• 意識障害を伴う頭部外傷の7年後に診断された外傷性脳脊髄液減少症の一例

  野崎 真世, 新明 康弘, 金 学海, 高橋 明弘, 山本 哲平, 石嶋 漢, 陳 進輝, 石田 晋  神経眼科  33-  (増補1)  120  -120  2016/10  [Not refereed][Not invited]
  
• 両眼の眼瞼延長術と瞼板縫合術が必要となった甲状腺眼症の一例

  石嶋 漢, 新明 康弘, 野崎 真世, 陳 進輝, 石田 晋  神経眼科  33-  (増補1)  150  -150  2016/10  [Not refereed][Not invited]
  
• Effect of Conjunctival Ring with Dexamethasone Sodium Phosphate on Rabbit VEGF-induced Blood-Retinal Barrier Breakdown

  Hiroaki Takahashi, Wakiko Asayama, Haruka Obata, Toru Matsunaga, Atsuhiro Kanda, Kousuke Noda, Susumu Ishida  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE  57-  (12)  2016/09  [Not refereed][Not invited]
  
• Galectin-1 is an Angiogenic Factor Associated with Proliferative Diabetic Retinopathy: Novel Target for Aflibeccept

  Atsuhiro Kanda, Kousuke Noda, Wataru Saito, Susumu Ishida  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE  57-  (12)  2016/09  [Not refereed][Not invited]
  
• Suppression of Cholecystokinin Response by Rebamipide in Trigeminal Ganglion Cells

  Yoshiaki Tagawa, Kousuke Noda, Ryo Miyamoto, Ken-ichi Otsuguro, Erdal Tan Ishizuka, Takeshi Ohguchi, Atsuhiro Kanda, Susumu Ishida  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE  57-  (12)  2016/09  [Not refereed][Not invited]
  
• Alterations of Choroidal Thickness and Circulation in Patients with Hypertensive Choroidopathy

  Michiyuki Saito, Kousuke Noda, Yuki Hashimoto, Kiriko Hirooka, Zhenyu Don, Ryo Ando, Shohei Mori, Satoru Kase, Wataru Saito, Susumu Ishida  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE  57-  (12)  2016/09  [Not refereed][Not invited]
  
• 糖尿病網膜症における血管新生因子ガレクチン-1による病態形成への関与

  石田 晋, 董 陽子, 野田 航介, 齋藤 航, 神田 敦宏  糖尿病合併症  30-  (Suppl.1)  247  -247  2016/09  [Not refereed][Not invited]
  
• 糖尿病網膜症におけるポリアミン代謝の病態関与

  野田 航介, 村田 美幸, 神田 敦宏, 石田 晋  糖尿病合併症  30-  (Suppl.1)  248  -248  2016/09  [Not refereed][Not invited]
  
• 糖尿病網膜症の増殖組織における分子シャペロンαB-クリスタリンのリン酸化

  加瀬 諭, 董 陽子, 神田 敦宏, 野田 航介, 石田 晋  糖尿病合併症  30-  (Suppl.1)  249  -249  2016/09  [Not refereed][Not invited]
  
• 【眼疾患の治療】 糖尿病網膜症

  野田 航介, 石田 晋  医学と薬学  73-  (9)  1135  -1142  2016/08  [Not refereed][Not invited]
  
• 慢性に進行した急性帯状潜在性網膜外層症の1例

  加藤 理絵子, 今村 裕, 齋藤 航, 神田 敦宏, 松本 惣一, 篠田 啓, 石田 政弘, 石田 晋, 溝田 淳, 三宅 養三  眼科臨床紀要  9-  (8)  671  -671  2016/08  [Not refereed][Not invited]
  
• 抗α-enolase抗体陽性の両眼性網脈絡膜変性の1例

  浜野 茂樹, 菅原 道孝, 齋藤 航, 神田 敦宏, 比嘉 利沙子, 松本 惣一, 篠田 啓, 石田 晋, 溝田 淳, 三宅 養三  眼科臨床紀要  9-  (8)  672  -672  2016/08  [Not refereed][Not invited]
  
• 抗α-enolase抗体が陽性となった黄斑浮腫合併網膜色素変性の1例

  橋本 勇希, 齋藤 航, 神田 敦宏, 安藤 亮, 石田 晋  眼科臨床紀要  9-  (8)  672  -672  2016/08  [Not refereed][Not invited]
  
• 【エイジングと加齢眼疾患】 エイジングからみた糖尿病網膜症

  神田 敦宏, 石田 晋  眼科  58-  (6)  643  -649  2016/06  [Not refereed][Not invited]
  
• 涙液中O型糖鎖の定量法

  田川 義晃, 野田 航介, 大口 剛司, 平 敏夫, 山口 さより, 山口 昭博, 牧 与志幸, 神田 敦宏, 石田 晋  日本眼科学会雑誌  120-  (6)  455  -455  2016/06  [Not refereed][Not invited]
  
• 【新時代の臨床糖尿病学(下)-より良い血糖管理をめざして-】 糖尿病合併症の病態・診断・治療 慢性合併症 糖尿病に起因する眼疾患 糖尿病網膜症の成因

  野田 航介, 石田 晋  日本臨床  74-  (増刊2 新時代の臨床糖尿病学(下))  107  -111  2016/04  [Not refereed][Not invited]
  
• 眼科医はじめの5年・10年にしておくべきこと

  石田 晋, 小沢 洋子, 近藤 峰生, 園田 康平, 中澤 徹, 安川 力, 山城 健児  Retina Medicine  5-  (1)  1  -7  2016/04  [Not refereed][Not invited]
  
• 後天性滑車神経麻痺に対する垂直筋水平移動術の手術効果

  石垣 さやか, 新明 康弘, 安藤 亮, 野崎 真世, 溝口 亜矢子, 阿部 朋子, 陳 進輝, 石田 晋  眼科臨床紀要  9-  (4)  323  -327  2016/04  [Not refereed][Not invited]
   

  目的:後天性滑車神経麻痺に対して患眼の垂直筋水平移動術を行い、その手術効果について検討した。対象および方法:対象は2003〜2013年までに北海道大学病院眼科を受診し、後天性滑車神経麻痺と診断され患眼の垂直筋水平移動術を行った5例である。回旋斜視と上斜視に対して患眼の下直筋鼻側移動術と短縮術を3例、上直筋耳側移動術と後転術を1例、下直筋鼻側移動術のみを1例に行った。また、垂直筋の短縮または後転術を行った麻痺性斜視患者10例をコントロール群とした。結果:外方回旋斜視に対する垂直筋水平移動術の手術効果は、1筋腹あたり4.7±1.7°であった。上下偏位に対する垂直筋短縮後転術の手術効果は1mmあたり0.4±1.0°であったのに対して、コントロール群における上下偏位に対する手術効果は1mmあたり1.5±1.1°であった(P=0.14)。結論:後天性滑車神経麻痺による外方回旋斜視に対する患眼の垂直筋水平移動術は、有効な術式と考えられた。(著者抄録)
• 小児高血圧性脈絡膜症の1例における脈絡膜循環動態と形態の経時変化

  橋本 勇希, 齋藤 航, 齋藤 理幸, 滝田 亜かり, 石田 晋  眼科臨床紀要  9-  (4)  368  -368  2016/04  [Not refereed][Not invited]
  
• 当科における先天性眼瞼下垂に伴った屈折異常と弱視の検討

  野崎 真世, 安藤 亮, 溝口 亜矢子, 石嶋 漢, 野田 実香, 吉田 和彦, 石田 晋  眼科臨床紀要  9-  (4)  372  -372  2016/04  [Not refereed][Not invited]
  
• 小児白血病網膜症の1例における脈絡膜の循環動態と形態の経時変化

  滝田 亜かり, 橋本 勇希, 清水 啓史, 齋藤 航, 石田 晋  眼科臨床紀要  9-  (4)  374  -374  2016/04  [Not refereed][Not invited]
  
• 眼所見から診断されたStevens-Johnson症候群の1例

  鈴木 智浩, 大口 剛司, 北尾 仁奈, 木嶋 理紀, 岩田 大樹, 水内 一臣, 野村 友希子, 田川 義継, 石田 晋  あたらしい眼科  33-  (3)  451  -454  2016/03  [Not refereed][Not invited]
   

  目的:皮膚病変を伴わず眼所見を中心に粘膜病変のみを呈したStevens-Johnson症候群(SJS)の1例について報告する。症例:20歳、女性。当院初診の10日前、発熱と両眼の充血、眼脂を自覚し総合感冒薬を内服。3日後内科を受診し、咽頭結膜熱の診断でアセトアミノフェン内服処方された。同日眼科を受診し、アデノウイルス結膜炎の診断で点眼処方されるも炎症所見が徐々に増悪したため当院紹介となった。両眼瞼結膜に偽膜形成、瞼球癒着、角膜びらんがみられ、SJSが疑われた。皮膚科を受診し、口腔内に粘膜疹を認めたが皮膚病変はみられなかった。しかし、発熱・粘膜病変および眼所見よりSJSと診断し、即日ステロイドパルス療法が開始された。その後徐々に充血、偽膜、瞼球癒着、角膜びらんは改善した。結論:SJSは皮膚病変を伴わず、眼症状を含めた粘膜病変のみを呈することがあり、十分な注意が必要である。(著者抄録)
• 血管新生緑内障の線維柱帯における受容体結合プロレニン系の病態関与

  石塚 タンエルダル, 神田 敦宏, 新明 康弘, 田川 義晃, 野田 航介, 石田 晋  日本眼科学会雑誌  120-  (臨増)  168  -168  2016/03  [Not refereed][Not invited]
  
• 中心性漿液性脈絡網膜症における中心窩脈絡膜厚と黄斑部脈絡膜血流の変化

  齋藤 理幸, 野田 航介, 橋本 勇希, 廣岡 季里子, 安藤 亮, 森 祥平, 加瀬 諭, 齋藤 航, 石田 晋  日本眼科学会雑誌  120-  (臨増)  188  -188  2016/03  [Not refereed][Not invited]
  
• 血管新生因子ガレクチン-1のアフリベルセプトによる阻害と糖尿病網膜症における関与

  神田 敦宏, 野田 航介, 齋藤 航, 石田 晋  日本眼科学会雑誌  120-  (臨増)  219  -219  2016/03  [Not refereed][Not invited]
  
• レバミピドは三叉神経節細胞におけるコレシストキニン応答を抑制する

  田川 義晃, 野田 航介, 宮本 亮, 乙黒 兼一, 石塚 タンエルダル, 神田 敦宏, 石田 晋  日本眼科学会雑誌  120-  (臨増)  232  -232  2016/03  [Not refereed][Not invited]
  
• 慢性中心性漿液性脈絡網膜症における脈絡膜循環と形態の経時変化

  廣岡 季里子, 齋藤 航, 齋藤 理幸, 橋本 勇希, 森 祥平, 加瀬 諭, 安藤 亮, 野田 航介, 石田 晋  日本眼科学会雑誌  120-  (臨増)  242  -242  2016/03  [Not refereed][Not invited]
  
• Acute macular neuroretinopathyにおける脈絡膜厚の経時変化

  橋本 勇希, 齋藤 航, 廣岡 季里子, 森 祥平, 野田 航介, 石田 晋  日本眼科学会雑誌  120-  (臨増)  273  -273  2016/03  [Not refereed][Not invited]
  
• PIC、AMN、強膜炎を併発し頻回に再発した急性帯状潜在性網膜外層症の1例

  菊地 郁, 齋藤 航, 廣岡 季里子, 橋本 勇希, 石田 晋  日本眼科学会雑誌  120-  (臨増)  309  -309  2016/03  [Not refereed][Not invited]
  
• むちうち外傷後の視神経症と脳脊髄液減少症の診断と臨床症状の検討

  野崎 真世, 新明 康弘, 金 学海, 高橋 明弘, 石嶋 漢, 田川 義晃, 石田 晋  日本眼科学会雑誌  120-  (臨増)  321  -321  2016/03  [Not refereed][Not invited]
  
• 増殖糖尿病網膜症における硝子体中VEGF-B濃度の検討

  木下 哲志, 野田 航介, 田川 義晃, 石塚 タンエルダル, 稲福 沙織, 董 陽子, 齋藤 航, 神田 敦宏, 石田 晋  日本糖尿病眼学会誌  20-  113  -113  2016/03  [Not refereed][Not invited]
  
• 糖尿病網膜症の硝子体および血漿におけるN型糖鎖プロファイル

  稲福 沙織, 野田 航介, 天野 麻穂, 大橋 哲, 齋藤 航, 村田 美幸, 神田 敦宏, 西村 紳一郎, 石田 晋  日本糖尿病眼学会誌  20-  114  -114  2016/03  [Not refereed][Not invited]
  
• SRPK1/CK2阻害活性を有する新規血管新生阻害局所薬

  諸岡 諭, 伊藤 暢聡, 細谷 孝充, 野田 航介, 石田 晋, 萩原 正敏, 吉村 長久  日本眼科学会雑誌  119-  (12)  882  -883  2015/12  [Not refereed][Not invited]
  
• 中心性漿液性脈絡網膜症患者に対する寒冷刺激試験後の脈絡膜循環変化

  齋藤 理幸, 齋藤 航, 橋本 勇希, 廣岡 季里子, 安藤 亮, 森 祥平, 野田 航介, 石田 晋  眼科臨床紀要  8-  (11)  825  -826  2015/11  [Not refereed][Not invited]
  
• 近視性黄斑分離に対する内境界膜剥離併用硝子体手術成績

  森 祥平, 齋藤 航, 齋藤 理幸, 安藤 亮, 廣岡 季里子, 野田 航介, 石田 晋  眼科臨床紀要  8-  (11)  834  -835  2015/11  [Not refereed][Not invited]
  
• フォークト・小柳・原田病のステロイド全身投与前後におけるLSFGを用いた波形解析

  廣岡 季里子, 齋藤 航, 南場 研一, 水内 一臣, 宇野 友絵, 田川 義晃, 齋藤 理幸, 野田 航介, 石田 晋  眼科臨床紀要  8-  (11)  850  -851  2015/11  [Not refereed][Not invited]
  
• 網膜細胞生物学と分子標的療法 ポストVEGF創薬の時代

  石田 晋  日本眼科学会雑誌  119-  (11)  759  -760  2015/11  [Not refereed][Not invited]
  
• 三角症候群の1例における脈絡膜循環動態と形態の経時変化

  石川 由梨, 橋本 勇希, 齋藤 航, 安藤 亮, 溝口 亜矢子, 石田 晋  日本視能矯正学会プログラム抄録集  56回-  81  -81  2015/10  [Not refereed][Not invited]
  
• フォークト・小柳・原田病のステロイド薬全身投与後における眼底自発蛍光

  橋本 勇希, 水内 一臣, 廣岡 季里子, 南場 研一, 石田 晋  日本視能矯正学会プログラム抄録集  56回-  50  -50  2015/10  [Not refereed][Not invited]
  
• カラー臨床報告 硝子体浸潤を伴った脈絡膜悪性黒色腫の1例

  横山 英恵, 加瀬 諭, 鈴木 康夫, 勝田 聡, 高橋 光生, 篠原 敏也, 石田 晋, 加瀬 学  臨床眼科  69-  (10)  1545  -1550  2015/10  [Not refereed][Not invited]
   

  背景:硝子体浸潤を伴う脈絡膜悪性黒色腫はわが国では稀である。目的:硝子体浸潤を伴う脈絡膜悪性黒色腫の1例の報告。症例:73歳の男性が左眼の眼底の隆起性病変で紹介受診した。2年前から左眼の飛蚊症を自覚していた。所見と経過:矯正視力は左右眼とも0.6であった。左眼には前部硝子体に色素細胞が浮遊し,眼底耳側に3乳頭径大の茶褐色隆起性病変があり,その頂点に黒褐色病巣があった。この隆起性病変は,フルオレセイン蛍光眼底造影の後期で色素漏出,インドシアニングリーン蛍光造影で過蛍光であり,黒褐色病巣は終始低蛍光であった。悪性黒色腫と診断し,左眼を摘出した。病理学的に,類上皮型の脈絡膜悪性黒色腫であり,腫瘍の大きさは8mm×8mm×5mmで,腫瘤の頂点で腫瘍細胞が網膜を穿破して硝子体腔に浸潤していた。結論:本症例はわが国では稀な,硝子体浸潤を伴う脈絡膜悪性黒色腫であった。(著者抄録)
• 萎縮型加齢黄斑変性の診断基準

  高橋 寛二, 白神 史雄, 石田 晋, 瓶井 資弘, 柳 靖雄, 吉村 長久, 厚生労働省網膜脈絡膜, 視神経萎縮症調査研究班萎縮型加齢黄斑変性診療ガイドライン作成ワーキンググループ  日本眼科学会雑誌  119-  (10)  671  -677  2015/10  [Not refereed][Not invited]
   

  視力,眼底所見,画像所見,除外規定,重症度分類からなる萎縮型加齢黄斑変性の診断基準を作成した.診断に重要な「地図状萎縮」の必須所見として,(1)直径250μm以上,(2)円形,卵円形,房状または地図状の形態,(3)境界鮮明,(4)網膜色素上皮の低色素または脱色素変化,(5)脈絡膜中大血管が明瞭に透見可能,のすべてを満たすものとした.重症度分類は,地図状萎縮と中心窩の位置関係および随伴所見によって軽症,中等症,重症に分類した.(著者抄録)
• 360°suture trabeculotomy変法とtrabeculotomyの術後眼圧降下効果の比較検討

  木嶋 理紀, 陳 進輝, 大口 剛司, 新明 康弘, 新田 朱里, 新田 卓也, 石田 晋  日本緑内障学会抄録集  26回-  146  -146  2015/09  [Not refereed][Not invited]
  
• 【Medical Retina】 網膜疾患におけるVEGFの生物活性とVEGF阻害薬の特色

  石田 晋  日本の眼科  86-  (8)  1088  -1094  2015/08  [Not refereed][Not invited]
   

  血管内皮増殖因子(VEGF)遺伝子ファミリーには、VEGF(VEGF-A)、VEGF-B、VEGF-C、VEGF-D、胎盤成長因子が含まれる。これらの受容体として、3つの受容体型チロシンキナーゼ(VEGFR-1、VEGFR-2、VEGFR-3)は、それぞれ炎症細胞、血管内皮細胞、リンパ管内皮細胞に発現し、炎症・血管新生・リンパ管新生を惹起する。VEGFR-1とVEGFR-2に結合するVEGFは炎症と血管新生を促進することで、血管新生病態のみならず、浮腫性・滲出性病態にも関与する。したがって、VEGF阻害薬は、抗炎症・抗血管新生作用により有益な効果をもたらすと考えられる。(著者抄録)
• 【抗VEGF薬による治療】 抗VEGF薬の治療 種々の眼疾患、眼腫瘍への応用

  加瀬 諭, 石田 晋  あたらしい眼科  32-  (8)  1075  -1081  2015/08  [Not refereed][Not invited]
  
• 治療に苦慮した乾癬ぶどう膜炎による続発緑内障の1例

  田川 小百合, 陳 進輝, 田川 義晃, 新明 康弘, 大口 剛司, 木嶋 理紀, 宇野 友絵, 石嶋 漢, 新田 卓也, 南場 研一, 石田 晋  あたらしい眼科  32-  (8)  1201  -1204  2015/08  [Not refereed][Not invited]
   

  症例は45歳の男性で、10数年前より乾癬の診断を受け、数年前から両眼にぶどう膜炎による発作を繰り返し、プレドニゾロン内服とステロイド点眼治療を受けていた。繰り返す発作と眼圧上昇のため、北海道大学病院眼科を受診、左眼眼圧のコントロール不良に対し、左マイトマイシンC併用線維柱帯切除術を施行した。術後数ヵ月間にわたる遷延性の低眼圧が持続したため、毛様体機能不全による房水産生能低下を考え、左強膜弁縫合術を行った。その後、左眼眼圧は落ち着いたが、半年後に右眼の続発緑内障をきたし、さらに左眼眼圧の再上昇をきたしたため、前回の経過を踏まえ、右眼に360° suture trabeculotomy変法、左眼に240° trabeculotomy変法を施行した。右眼の眼圧は良好だったが、3ヵ月後に左眼眼圧が再上昇したため、左眼濾過胞再建術を追加した。その後は両眼とも眼圧が10mmHg前後と落ち着いている。(著者抄録)
• 後天性滑車神経麻痺に対する上下直筋水平移動術の手術効果

  石垣 さやか, 新明 康弘, 安藤 亮, 野崎 真世, 溝口 亜矢子, 阿部 朋子, 清水 啓史, 横山 千秋, 陳 進輝, 石田 晋  眼科臨床紀要  8-  (7)  510  -511  2015/07  [Not refereed][Not invited]
  
• Role of the Receptor Associated Prorenin System in Trabecular Meshwork of Glaucoma

  Erdal Tan Ishizuka, Atsuhiro Kanda, Yasuhiro Shinmei, Yoko Dong, Saori Inafuku, Yoshiaki Tagawa, Kousuke Noda, Susumu Ishida  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE  56-  (7)  2015/06  [Not refereed][Not invited]
  
• Alteration of N-glycan Profiles in Diabetic Retinopathy

  Saori Inafuku, Kousuke Noda, Maho Amano, Miyuki Murata, Wataru Saito, Tetsu Ohashi, Atsuhiro Kanda, Shin-Ichiro Nishimura, Susumu Ishida  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE  56-  (7)  2015/06  [Not refereed][Not invited]
  
• Rebamipide Reduces the Response to Capsaicin in Sensory Ganglion Cells

  Yoshiaki Tagawa, Kousuke Noda, Ryo Miyamoto, Ken-ichi Otsuguro, Erdal Tan Ishizuka, Saori Inafuku, Takeshi Ohguchi, Atsuhiro Kanda, Susumu Ishida  INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE  56-  (7)  2015/06  [Not refereed][Not invited]
  
• 【感覚とその異常】 感覚の基礎知識 視覚

  神田 敦宏, 石田 晋  Clinical Neuroscience  33-  (5)  504  -506  2015/05  [Not refereed][Not invited]
  
• 【現代社会と眼-視覚情報社会、超高齢社会の与える眼への影響】 現代社会の環境因子からとらえた加齢黄斑変性

  神田 敦宏, 石田 晋  医学のあゆみ  253-  (2)  162  -165  2015/04  [Not refereed][Not invited]
   

  わが国はかつてない高齢化社会を迎えており、健康長寿という言葉に代表されるように、いかにQOL(quality of life)を低下させずに寿命を全うするかは大きな関心となっている。このような状況のなかで、QOLに大きな影響をもつ感覚器の健康を維持するために眼科学のもつ役割は大きいと考えられる。加齢黄斑変性(agerelated macular degeneration:AMD)は、欧米では失明原因の主因となる疾患であり、わが国でも高齢化社会・食生活の欧米化に伴い失明原因として増加中の眼底疾患である。本稿では、AMDを理解するための基礎知識をオーバービューするとともに、近年の分子遺伝学的研究や臨床疫学的研究により、AMDは単なる老年病ではなく、生活習慣病として介入可能な疾患概念へと変遷してきた流れを概説する。(著者抄録)
• 網膜研究・診療の未来予想図

  石田 晋, 小沢 洋子, 近藤 峰生, 中澤 徹, 平見 恭彦, 藤波 芳, 安川 力, 山城 健児  Retina Medicine  4-  (1)  1  -9  2015/04  [Not refereed][Not invited]
  
• 診断の困難な症例・電気生理学的に興味深い症例 多発消失性白点症候群発症後にchoroidal excavationを形成した1例

  橋本 勇希, 齋藤 航, 野田 航介, 石田 晋  眼科臨床紀要  8-  (4)  245  -245  2015/04  [Not refereed][Not invited]
  
• 糖尿病網膜症の硝子体および血漿におけるN型糖鎖の網羅的解析

  稲福 沙織, 野田 航介, 天野 麻穂, 大橋 哲, 吉澤 史子, 齋藤 航, 村田 美幸, 神田 敦宏, 西村 紳一郎, 石田 晋  日本眼科学会雑誌  119-  (臨増)  160  -160  2015/03  [Not refereed][Not invited]
  
• 若年性慢性虹彩毛様体炎の臨床像の検討

  宇野 友絵, 南場 研一, 水内 一臣, 岩田 大樹, 北市 伸義, 大野 重昭, 石田 晋  日本眼科学会雑誌  119-  (臨増)  162  -162  2015/03  [Not refereed][Not invited]
  
• SRPK1およびCK2阻害活性を有する新規血管新生阻害薬の開発

  諸岡 諭, 喜井 勲, 奥野 友紀子, 吉田 優, 福原 淳一, 野田 航介, 伊藤 暢聡, 石田 晋, 細谷 孝充, 萩原 正敏, 吉村 長久  日本眼科学会雑誌  119-  (臨増)  178  -178  2015/03  [Not refereed][Not invited]
  
• 結膜節外辺縁帯B細胞性リンパ腫におけるレニン・アンジオテンシン系の病態への関与

  石塚 タンエルダル, 神田 敦宏, 加瀬 諭, 安藤 亮, 董 陽子, 稲福 沙織, 田川 義晃, 野田 航介, 石田 晋  日本眼科学会雑誌  119-  (臨増)  180  -180  2015/03  [Not refereed][Not invited]
  
• 急性帯状潜在性網膜外層症における視機能を規定する因子

  齋藤 航, 齊藤 沙宝, 齋藤 理幸, 橋本 勇希, 森 祥平, 安藤 亮, 野田 航介, 南場 研一, 石田 晋  日本眼科学会雑誌  119-  (臨増)  182  -182  2015/03  [Not refereed][Not invited]
  
• Vogt-小柳-原田病再発例に対するシクロスポリン併用療法の検討

  水内 一臣, 南場 研一, 岩田 大樹, 宇野 友絵, 北市 伸義, 大野 重昭, 石田 晋  日本眼科学会雑誌  119-  (臨増)  187  -187  2015/03  [Not refereed][Not invited]
  
• 糖負荷刺激によるシアル酸転移酵素の誘導

  稲福 沙織, 野田 航介, 天野 麻穂, 大橋 哲, 齋藤 航, 村田 美幸, 神田 敦宏, 西村 紳一郎, 石田 晋  日本眼科学会雑誌  119-  (臨増)  199  -199  2015/03  [Not refereed][Not invited]
  
• Triggerfishによる睡眠時無呼吸症候群患者の睡眠中の眼圧測定

  新明 康弘, 新田 卓也, 齋藤 拓志, 大口 剛司, 宇野 友絵, 陳 進輝, 石田 晋  日本眼科学会雑誌  119-  (臨増)  224  -224  2015/03  [Not refereed][Not invited]
  
• 特発性黄斑円孔手術前後における網膜内層厚層別解析

  橋本 勇希, 齋藤 航, 廣岡 季里子, 森 祥平, 齋藤 理幸, 安藤 亮, 野田 航平, 石田 晋  日本眼科学会雑誌  119-  (臨増)  233  -233  2015/03  [Not refereed][Not invited]
  
• 流行性角結膜炎の起因ヒトアデノウイルス遺伝子解析

  青木 功喜, 大野 重昭, 北市 伸義, 日隈 陸太郎, 金子 久俊, 石田 晋  日本眼科学会雑誌  119-  (臨増)  250  -250  2015/03  [Not refereed][Not invited]
  
• BUT短縮型ドライアイ患者のfunctionalMRIによる脳機能解析を施行した1例

  田川 義晃, 大口 剛司, Tha Khin Khin, 藤間 憲幸, 敦賀 健吉, 加藤 類, 木嶋 理紀, 岩田 大樹, 水内 一臣, 田川 義継, 石田 晋  日本眼科学会雑誌  119-  (臨増)  266  -266  2015/03  [Not refereed][Not invited]
  
• 急性後部多発性斑状色素上皮症における脈絡膜形態と循環動態の経時的変化

  廣岡 季里子, 齋藤 航, 齋藤 理幸, 石田 晋  日本眼科学会雑誌  119-  (臨増)  287  -287  2015/03  [Not refereed][Not invited]
  
• 糖尿病網膜症における炎症と血管新生の分子病態

  石田 晋  日本糖尿病眼学会誌  19-  56  -60  2015/03  [Not refereed][Not invited]
  
• 黄斑浮腫に対する抗VEGF療法 理論と実際

  石田 晋  眼科臨床紀要  7-  (12)  954  -955  2014/12  [Not refereed][Not invited]
  
• 発症5年後に網膜静脈に沿った網膜変性が出現した急性帯状潜在性網膜外層症の1例

  長谷川 裕香, 齋藤 航, 橋本 勇希, 齋藤 沙宝, 石田 晋  日本視能訓練士協会誌  43-  326  -326  2014/12  [Not refereed][Not invited]
  
• 多発消失性白点症候群における視野異常所見

  橋本 勇希, 齋藤 航, 齋藤 沙宝, 長谷川 裕香, 石田 晋  日本視能訓練士協会誌  43-  330  -330  2014/12  [Not refereed][Not invited]
  
• 間歇性外斜視の手術後に過矯正となった症例の検討

  阿部 朋子, 安藤 亮, 溝口 亜矢子, 石垣 さやか, 山口 淑子, 野崎 真世, 石田 晋  日本視能訓練士協会誌  43-  338  -338  2014/12  [Not refereed][Not invited]
  
• 正常眼と急性帯状潜在性網膜外層症眼におけるハンフリー視野の中心窩閾値と視力の関連

  齊藤 沙宝, 齋藤 航, 橋本 勇希, 石田 晋  日本視能訓練士協会誌  43-  346  -346  2014/12  [Not refereed][Not invited]
  
• 増殖糖尿病網膜症における硝子体レニン-アンジオテンシン系(Vitreous renin-angiotensin system in proliferative diabetic retinopathy)

  石田 晋  眼科臨床紀要  7-  (11)  844  -846  2014/11  [Not refereed][Not invited]
  
• 【超高齢社会におけるアンチエイジングとRAS】 糖尿病網膜症とRAS

  神田 敦宏, 石田 晋  Angiotensin Research  11-  (4)  190  -193  2014/10  [Not refereed][Not invited]
   

  生活習慣病では、内臓肥満から長期の経過にわたって全身に血管症などが起こり、眼を含めたさまざまな臓器に障害がおきる。さらに生活習慣病によって老化が加速・進行する過程では、最上流の内臓肥満から最下流の臓器障害までの複数の病態形成に慢性炎症と循環・組織レニン・アンジオテンシン系が関与することがわかってきた。わが国における主要な失明原因である糖尿病網膜症や加齢黄斑変性、また網膜静脈閉塞症といった眼底疾患は、生活習慣病が発症・進行の危険因子である血管症である。これら眼の血管症にも慢性炎症とレニン・アンジオテンシン系が関与する。(著者抄録)
• 眼のアンチエイジング 眼の健康と栄養の関係

  北市 伸義, 石田 晋  臨床栄養  125-  (3)  254  -255  2014/09  [Not refereed][Not invited]
  
• 糖尿病黄斑浮腫患者を対象としたペガプタニブナトリウムの国内第III相臨床試験

  石橋 達朗, 湯澤 美都子, 吉村 長久, 大路 正人, 石田 晋, 五十川 直樹, 江坂 悦子  日本眼科学会雑誌  118-  (9)  773  -782  2014/09  [Not refereed][Not invited]
   

  目的:糖尿病黄斑浮腫患者に対するペガプタニブナトリウムの有効性と安全性を評価する.対象と方法:糖尿病黄斑浮腫患者243例に,二重盲検期(24週まで)はペガプタニブナトリウムの硝子体内投与もしくはsham投与を6週ごとに1回,計4回行った.非盲検期(24週から54週まで)はペガプタニブナトリウムの硝子体内投与を6週ごとに1回,計5回行った.有効性の主要評価は24週時点,安全性評価は54週までとした.結果と結論:Early Treatment Diabetic Retinopathy Study(ETDRS)視力表を用いた視力が10文字以上改善した被験者の割合は,ペガプタニブナトリウム群で20.3%,sham群で5.0%であり,有意な差が認められた(p=0.0003).二重盲検期において治験薬との因果関係を否定できない有害事象の発現率は,両群で同程度(ペガプタニブナトリウム群で10.6%,sham群で10.0%)であり,報告された主な有害事象は,軽度または中等度の投与手技に起因すると判断された眼に関する事象であった.54週までの非盲検期において,二重盲検期と比較して新たな安全性の問題は認められなかった.ただし,盲検性維持に関するプロセス上の問題を考慮すると,本治験は完全な二重盲検試験ではなかった.(著者抄録)
• 【高齢者の感覚器障害】 眼疾患 眼科領域のアンチエイジング

  北市 伸義, 石田 晋  臨牀と研究  91-  (9)  1169  -1173  2014/09  [Not refereed][Not invited]
  
• 糖尿病網膜症の分子病態と薬物治療

  石田 晋  日本眼科学会雑誌  118-  (7)  607  -618  2014/07  [Not refereed][Not invited]
   

  糖尿病網膜症のマネージメントについて全身管理を含めた薬物療法をサマリーし、特に最近になって導入された抗血管内皮増殖因子(VEGF)療法について述べた。分子病態との関連が明らかにされた治療戦略は、現在のところ抗VEGF療法・副腎皮質ステロイド療法・レニン-アンジオテンシン抑制のみである。また、糖尿病網膜症は慢性疾患であるため、網膜症に対する抗VEGF療法はいつまで続けるべきか、硝子体手術やレーザー治療といかに組合せてゆくか、といった至適な治療プロトコールを検討してゆく必要がある。
• 発症5年後に網膜静脈に沿った網膜変性が出現した急性帯状潜在性網膜外層症の1例

  長谷川 裕香, 齋藤 航, 橋本 勇希, 齊藤 沙宝, 石田 晋  眼科臨床紀要  7-  (7)  531  -535  2014/07  [Not refereed][Not invited]
   

  背景:発症5年後に色素性傍静脈網脈絡膜萎縮(PPCRA)に似た網膜変性所見が出現した急性帯状潜在性網膜外層症(AZOOR)の1例を経験したので報告する。症例:35歳、女性。矯正視力は右1.5、左2.0。右眼は検眼鏡的に網膜に異常所見はなかったが、視野検査では弓状暗点を示し、多局所網膜電図で視野異常に一致して振幅の低下を示したことからAZOORと診断された。ステロイドパルス療法開始後視野所見は改善した。発症5年後に、初診時にはなかった網膜静脈に沿った帯状の網膜色素上皮レベルの変性が出現した。結論:網膜変性所見を合併するAZOORは、PPCRAなどの網膜変性疾患との鑑別が必要になると考えられた。(著者抄録)
• 平滑筋肉腫に合併した腫瘍随伴網膜症が疑われた1例

  高橋 明裕, 齋藤 航, 齋藤 理幸, 岩田 大樹, 神田 敦宏, 石田 晋  臨床眼科  68-  (6)  819  -824  2014/06  [Not refereed][Not invited]
   

  目的:網膜症の発症から18ヵ月後に平滑筋肉腫が発見され,腫瘍随伴網膜症であることが疑われた症例の報告。症例:79歳女性が1ヵ月前からの左眼の霧視で受診した。高血圧以外には全身疾患はなかった。所見:矯正視力は右1.2,左0.8で,左眼に乳頭の腫脹と周辺部に雪玉様の硝子体混濁があった。蛍光眼底造影で乳頭と周辺部の網膜血管からの色素漏出があった。光干渉断層計で,視細胞内外節接合部の不連続化が両眼にあった。2週間後に左眼視力が0.2に低下した。多局所網膜電図での応答が両眼で低下していた。全身検査でサルコイドーシスは否定され,Gaシンチグラフィと胸腹部CTを含む諸検査で悪性腫瘍は発見されなかった。プレドニゾロンの経口投与で左眼視力は0.6に改善した。初診から18ヵ月後に背部に皮下腫瘍が発見され,切除により平滑筋肉腫と診断された。初診から37ヵ月後の現在まで,格別の変化はない。結論:本症例での網膜症は,腫瘍随伴網膜症であった可能性がある。(著者抄録)
• 日本における視覚障害の原因と現状

  若生 里奈, 安川 力, 加藤 亜紀, 大森 豊緑, 石田 晋, 石橋 達朗, 小椋 祐一郎  日本眼科学会雑誌  118-  (6)  495  -501  2014/06  [Not refereed][Not invited]
   

  目的:日本における視覚障害の原因を調査する.対象と方法:全国を7ブロックに分け,1ブロックから1自治体を無作為に抽出し,2007年4月〜2010年3月に身体障害者診断書・意見書に基づいて新規に視覚障害認定を受けた18歳以上の4,852名について検討した.結果:原因の1位は緑内障で21.0%であった.2位は糖尿病網膜症15.6%,3位は網膜色素変性12.0%,4位は黄斑変性9.5%,5位は脈絡網膜萎縮8.4%であった.緑内障は70代以降の主因で,1,2級で61%を占めた.糖尿病網膜症は50,60代の主因で,40代以下の主因は網膜色素変性であった.黄斑変性は80代以降で多かった.結論:2001年〜2004年の調査と比べ上位の順位に違いはなかった.さらに増加が見込まれる視覚障害者に対する予防や早期治療対策を立て,実態調査のために原因疾患や障害状態を解析できるデータ集約システムの構築が求められる.(著者抄録)
• 加齢黄斑変性 臨床の疑問(疑問3) VEGF阻害薬によって薬理作用の強さは異なるのか?

  石田 晋  眼科  56-  (7)  883  -890  2014/06  [Not refereed][Not invited]
  
• 【内科疾患 最新の治療 明日への指針】(第10章)代謝・内分泌 糖尿病網膜症

  野田 航介, 石田 晋  内科  113-  (6)  1544  -1545  2014/06  [Not refereed][Not invited]
  
• 視機能とロコモティブシンドローム レニン-アンジオテンシン系と糖尿病網膜症

  石田 晋  日本抗加齢医学会総会プログラム・抄録集  14回-  130  -130  2014/06  [Not refereed][Not invited]
  
• 小児における網脈絡膜形態の検討

  橋本 勇希, 齋藤 航, 廣岡 季里子, 齋藤 理幸, 安藤 亮, 吉澤 史子, 野田 航介, 石田 晋  眼科臨床紀要  7-  (5)  386  -387  2014/05  [Not refereed][Not invited]
  
• AREDS2総括と考察

  石田 晋  眼科  56-  (5)  615  -621  2014/04  [Not refereed][Not invited]
   

  米国の国立眼研究所の主導により、Age-Related Eye Disease Study(AREDS)の結果が2001年に報告され、2012年にはわが国の加齢黄斑変性の治療指針に「AREDSに基づくサプリメント摂取」が加えられた。さらに2013年、AREDS2の結果が発表され、AREDS処方に変更を加えることが推奨された。黄斑色素とω-3不飽和脂肪酸は、いずれも単独の効果ではなく、既存のAREDS処方に追加した場合の上乗せ効果があるかどうかが検討された。本試験の前提となるAREDSを紹介したうえで、AREDS2の結果を総括し、考察を加えた。
• 糖尿病網膜症と心血管病発症および死亡との関連 久山町研究

  福原 崇子, 安田 美穂, 橋本 左和子, 田原 朋子, 荒川 聡, 清原 裕, 石田 晋, 石橋 達朗  日本眼科学会雑誌  118-  (4)  393  -394  2014/04  [Not refereed][Not invited]
  
• 英語で発表しよう、留学に行こう

  石田 晋, 小沢 洋子, 近藤 峰生, 園田 康平, 中澤 徹, 安川 力, 山城 健児  Retina Medicine  3-  (1)  1  -7  2014/04  [Not refereed][Not invited]
  
• 【先端的眼科治療(角膜と網膜の新しい治療法)】 血管内皮増殖因子阻害薬による加齢黄斑変性治療

  吉澤 史子, 石田 晋  Medical Science Digest  40-  (3)  124  -127  2014/03  [Not refereed][Not invited]
   

  高齢化社会に伴い、わが国では加齢黄斑変性(Age-related Macular Degeneration:AMD)の患者数が急速に増加している。その治療の中心は、血管内皮増殖因子(Vascular Endothelial Growth Factor:VEGF)阻害薬である。これまで治療の大きな位置を占めていたのが、ラニビズマブであるが、最近、耐性例や無効例が報告されるようになった。その時期に登場したのが、昨年末から使用可能となったアフリベルセプトである。既存薬との違いは、血管新生や炎症に関与する因子をより幅広く抑制すること、そして効果持続期間が長くなったことである。二つの大規模な第III相試験で、ラニビズマブ4週毎投与とアフリベルセプト8週間毎投与は、ほぼ同等の効果・安全性を示した。またラニビズマブ耐性・無効例に効果を示す報告が相次いでおり、長期継続投与の有効性・安全性の結果が待たれる。(著者抄録)
• 【「眼疾患メカニズムの新しい理解」をより理解するために 加齢黄斑変性:新知見によるパラダイムシフト】 加齢黄斑変性 新知見によるパラダイムシフト

  柳 靖雄, 石田 晋  日本の眼科  85-  (3)  285  -287  2014/03  [Not refereed][Not invited]
   

  加齢黄斑変性(AMD)の診療は、血管内皮増殖因子(VEGF)阻害薬の導入や光干渉断層計をはじめとする診断機器の改良により、この数年で格段に進歩した。しかしながら、抗VEGF療法は一定の成功を収めているものの限界も見えて来ており、新たな治療戦略の確立は急務である。さらに、診療技術の向上による詳細な観察はAMD病態の本質について新たな疑問を投げかけている。当講演では、これら未解決の諸問題にチャレンジする。まず、病態概念として典型AMDとポリープ状脈絡膜血管症の異同を浮き彫りにした上で、脈絡膜血管透過性に着目したAMDの新分類を提唱する。さらに、ポストVEGF時代の到来を視野に入れた新規治療ターゲットとして、マクロファージ遊走に関与する炎症性サイトカインの制御について紹介する。このように、当講演がAMDの新知見を提供することにより、パラダイムシフトを来すことを期待したい。(著者抄録)
• 糖尿病網膜症における前房水中PIGF濃度の検討

  安藤 亮, 野田 航介, 難波 志帆, 石嶋 漢, 藤谷 顕雄, 吉沢 史子, 新明 康弘, 齋藤 航, 神田 敦宏, 石田 晋  日本眼科学会雑誌  118-  (臨増)  265  -265  2014/03  [Not refereed][Not invited]
  
• 診断に苦慮した毛様体平滑筋腫の一例

  石嶋 漢, 加瀬 諭, 吉川 洋, 鈴木 茂伸, 新明 康弘, 南場 研一, 山本 哲平, 野崎 真世, 野田 実香, 石田 晋  日本眼科学会雑誌  118-  (臨増)  304  -304  2014/03  [Not refereed][Not invited]
  
• ドライアイ患者の自覚症状と角膜知覚および痛覚についての検討

  田川 義晃, 大口 剛司, 山本 哲平, 水内 一臣, 田川 義継, 北市 伸義, 石田 晋  日本眼科学会雑誌  118-  (臨増)  312  -312  2014/03  [Not refereed][Not invited]
  
• ステロイド含有結膜リングの安全性評価

  木下 哲志, 野田 航介, 田川 義晃, 石塚 タンエルダル, 高階 沙織, 董 陽子, 厚見 育代, 小畑 晴香, 松永 透, 大口 剛司, 神田 敦宏, 石田 晋  日本眼科学会雑誌  118-  (臨増)  314  -314  2014/03  [Not refereed][Not invited]
  
• ヒト結膜リングのオキュラーサーフェスにおける安全性の検討

  大口 剛司, 野田 航介, 木下 哲志, 神田 敦宏, 安枝 真一, 福島 努, 石田 晋  日本眼科学会雑誌  118-  (臨増)  314  -314  2014/03  [Not refereed][Not invited]
  
• 心因性視覚障害との鑑別に難渋した高次脳機能障害を伴う詐病の1例

  石垣 さやか, 新明 康弘, 溝口 亜矢子, 陳 進輝, 石田 晋  神経眼科  31-  (1)  52  -56  2014/03  [Not refereed][Not invited]
   

  症例は交通事故により右眼が失明した43歳の男性。受傷から10年を経て左眼の視力低下を自覚。当初は離婚によるストレスを契機とした心因性視覚障害と診断した。2年後に左眼の眼窩底骨折を起こし、再度左眼の視力低下を訴え、視覚障害者の認定を求めて来院。眼窩底骨折の原因は仕事中のトラブルであり、記銘力の低下や脳MRIでびまん性脳萎縮がみられたため、10年前の交通事故での頭部外傷による高次脳機能障害も疑われた。当初は心因性視覚障害と考えられたが、その後に詐病の要素が加わり、同時に高次脳機能障害の存在も疑われたため、診断を行う上で非常に苦慮した。(著者抄録)
• 原発開放隅角緑内障患者に対する0.03%ビマトプロスト切り替えによる眼圧下降効果と安全性の検討

  仲 昌彦, 山本 麻梨亜, 金 学海, 横山 千秋, 石島 漢, 北市 伸義, 大口 剛司, 新田 卓也, 新明 康弘, 陳 進輝, 石田 晋  臨床眼科  68-  (2)  219  -224  2014/02  [Not refereed][Not invited]
   

  目的:プロスタグランジン関連薬をビマトプロストへ変更した際の眼圧下降効果と安全性の報告。対象と方法:開放隅角緑内障患者33例57眼を対象とした。男性27眼,女性30眼で,平均年齢は67歳である。全例が,プロスタグランジン関連薬およびβ遮断薬を含む2種類以上の点眼薬で加療中であった。点眼を0.03%ビマトプロストに変更し,1ヵ月と3ヵ月に眼圧と副作用を評価した。結果:平均眼圧は,変更前15.1±3.5mmHg,1ヵ月後14.2±2.8mmHg,3ヵ月後14.0±2.9mmHgであり,変更後いずれも有意に低下した(p<0.01)。変更前の眼圧が15mmHg以上の症例のみで有意な眼圧低下があった(p<0.01)。有意な眼圧下降は,変更前にラタノプロストまたはタフルプロストを点眼中の症例のみにあった(p<0.01)。43例中8例(19%)に結膜充血が生じた。結論:他剤で点眼加療中の開放隅角緑内障に対し,ビマトプロスト点眼に切り替えた結果,1ヵ月と3ヵ月後に有意な眼圧下降が得られた。結膜充血が主な副作用であった。(著者抄録)
• 【生活習慣病が関連する眼疾患における炎症病態】 生活習慣病と慢性炎症におけるレニン-アンジオテンシン系の病態意義

  石田 晋, 神田 敦宏  日本の眼科  85-  (2)  130  -135  2014/02  [Not refereed][Not invited]
   

  生活習慣病では、内臓肥満から長期の経過にわたって全身に血管症が起こり、脳・心・腎・眼などの主要臓器の障害により寿命が短縮する。生活習慣病により老化が加速する進行過程では、最上流の内臓肥満から最下流の臓器障害まで複数の病態に慢性炎症と循環・組織レニン-アンジオテンシン系が関与することがわかってきた。失明原因として重要な糖尿病網膜症・加齢黄斑変性・網膜静脈閉塞症といった眼底疾患は、生活習慣病が発症・進行の危険因子である血管症である。これら眼の血管症にも慢性炎症とレニン-アンジオテンシン系が関与する。(著者抄録)
• 【新薬展望2014】 (第III部)治療における最近の新薬の位置付け<薬効別> 新薬の広場 眼科治療薬

  吉澤 史子, 石田 晋  医薬ジャーナル  50-  (増刊)  521  -531  2014/01  [Not refereed][Not invited]
   

  高齢化・欧米化社会に伴い、わが国では加齢黄斑変性(age-related macular degeneration:AMD)の患者数が急速に増加している。その治療の中心は、血管内皮増殖因子(vascular endothelial growth factor:VEGF)阻害薬である。これまで治療の大きな位置を占めていたのがラニビズマブであるが、最近、耐性例や無効例が報告されるようになった。その時期に登場したのが、昨年末から使用可能となったアフリベルセプトである。既存薬との違いは、血管新生や炎症に関与する因子をより幅広く抑制すること、そして効果持続期間がより長くなったことである。二つの大規模な第III相試験で、ラニビズマブ4週毎投与とアフリベルセプト8週間毎投与は、ほぼ同等の効果・安全性を示した。また、ラニビズマブ耐性・無効例に効果を示す報告が相次いでおり、今後長期継続投与の有効性・安全性の結果が待たれる。(著者抄録)
• 梅毒性網脈絡膜炎に合併した嚢胞様黄斑浮腫にステロイド局所投与が奏効した症例

  横山 英恵, 田川 義晃, 本田 仁, 横井 匡彦, 加瀬 学, 石田 晋  臨床眼科  67-  (13)  1995  -1999  2013/12  [Not refereed][Not invited]
   

  目的:梅毒性網脈絡膜炎に併発した嚢胞様黄斑浮腫にペニシリンと局所ステロイド投与が奏効した症例の報告。症例:59歳男性が9ヵ月前からの左眼視力低下で受診した。10歳代に梅毒に罹患し,加療した既往がある。所見:矯正視力は右1.0,左0.2で,左眼にびまん性硝子体混濁と嚢胞様黄斑浮腫があった。TPHAが高値で硝子体混濁とFAでの血管透過性亢進所見から,梅毒性網脈絡膜炎と診断した。ペニシリンGの大量点滴で2週後に左眼視力は0.6に改善した。残存した黄斑浮腫に対し,初診から68日後にトリアムシノロンのテノン嚢下注射を行い,左眼視力は0.9に改善した。初診から20ヵ月後の現在まで再発はない。結論:本症例でペニシリン投与後に残存した黄斑浮腫は,免疫性機序による炎症であったと解釈され,ステロイドの局所投与が奏効した。(著者抄録)
• 正常眼における中心窩の錐体外節端(COST)形態と視細胞外節(PROS)長の年代別検討

  橋本 勇希, 齋藤 航, 齋藤 理幸, 高橋 亜衣, 藤谷 顕雄, 吉澤 史子, 野田 航介, 石田 晋  日本視能訓練士協会誌  42-  225  -225  2013/12  [Not refereed][Not invited]
  
• 健常成人における錐体外節端(COST)ラインの範囲

  高橋 亜衣, 齋藤 航, 橋本 勇希, 齋藤 理幸, 藤谷 顕雄, 吉澤 史子, 野田 航介, 石田 晋  日本視能訓練士協会誌  42-  235  -235  2013/12  [Not refereed][Not invited]
  
• 単焦点眼鏡へ移行できた後に眼位変動を来した非屈折性調節性内斜視の長期経過

  溝口 亜矢子, 安藤 亮, 山口 淑子, 石垣 さやか, 石田 晋  日本視能訓練士協会誌  42-  239  -240  2013/12  [Not refereed][Not invited]
  
• 【抗VEGF薬をどう使う?】 抗VEGF療法の理論と加齢黄斑変性に対するアフリベルセプトの使い方

  吉澤 史子, 石田 晋  臨床眼科  67-  (12)  1830  -1838  2013/11  [Not refereed][Not invited]
  
• 発症5年後に網膜静脈に沿った網膜変性が出現した急性帯状潜在性網膜外層症の1例

  長谷川 裕香, 齋藤 航, 橋本 勇希, 齋藤 沙宝, 石田 晋  日本視能矯正学会プログラム抄録集  54回-  61  -61  2013/11  [Not refereed][Not invited]
  
• 多発消失性白点症候群における視野異常所見

  橋本 勇希, 齋藤 航, 齋藤 沙宝, 長谷川 裕香, 石田 晋  日本視能矯正学会プログラム抄録集  54回-  67  -67  2013/11  [Not refereed][Not invited]
  
• 間歇性外斜視の手術後に過矯正となった症例の検討

  阿部 朋子, 安藤 亮, 溝口 亜矢子, 石垣 さやか, 山口 淑子, 野崎 真世, 石田 晋  日本視能矯正学会プログラム抄録集  54回-  79  -79  2013/11  [Not refereed][Not invited]
  
• 正常眼と急性帯状潜在性網膜外層症眼におけるハンフリー視野の中心窩閾値と視力の関連

  齊藤 沙宝, 齋藤 航, 橋本 勇希, 石田 晋  日本視能矯正学会プログラム抄録集  54回-  90  -90  2013/11  [Not refereed][Not invited]
  
• 【糖尿病網膜症の診療】 糖尿病網膜症の病態生理

  野田 航介, 石田 晋  OCULISTA  (8)  6  -11  2013/11  [Not refereed][Not invited]
   

  近年の生活環境や食習慣の変化によって、網膜症を有する糖尿病患者が今後増加することは自明であり、その病態生理の解明は一層重要となると考えられる。本症の病態には依然として不明な点も多いが、近年の研究成果は高血糖以外に酸化ストレスや慢性炎症などがその発症機序に関与することを徐々に明らかとしてきている。また、検査機器の進歩によって糖尿病による血管障害は網膜のみならず脈絡膜にも生じていることが分かってきている。本稿では、DRの病態生理に関する最近の知見について論じる。(著者抄録)
• 糖尿病網膜症の分子病態

  石田 晋  眼科臨床紀要  6-  (11)  919  -919  2013/11  [Not refereed][Not invited]
  
• 【加齢黄斑変性の新展開】 加齢・生活習慣病としての加齢黄斑変性

  石田 晋  Progress in Medicine  33-  (10)  2063  -2065  2013/10  [Not refereed][Not invited]
  
• 左眼の視力低下と眼球突出、右眼の内・外転制限を呈したIgG4関連眼疾患の一例

  石嶋 漢, 新明 康弘, 鈴木 佳代, 田川 義晃, 新田 卓也, 陳 進輝, 石田 晋  神経眼科  30-  (増補1)  50  -50  2013/10  [Not refereed][Not invited]
  
• トリアムシノロンアセトニド硝子体注射後に視神経炎を発症したサルコイドーシス性視神経炎と考えられた1例

  田川 義晃, 新明 康弘, 鈴木 佳代, 石嶋 漢, 新田 卓也, 陳 進輝, 石田 晋  神経眼科  30-  (増補1)  71  -71  2013/10  [Not refereed][Not invited]
  
• 交通外傷の1ヵ月後に両眼視野障害を呈した脳脊髄圧減少症の1例

  鈴木 佳代, 新明 康弘, 田川 義晃, 石嶋 漢, 新田 卓也, 陳 進輝, 高橋 明弘, 石田 晋  神経眼科  30-  (増補1)  76  -76  2013/10  [Not refereed][Not invited]
  
• 【加齢黄斑変性】 加齢黄斑変性に対する抗VEGF療法

  吉澤 史子, 石田 晋  眼科  55-  (10)  1133  -1144  2013/10  [Not refereed][Not invited]
  
• 癌関連網膜症の臨床像

  齋藤 理幸, 齋藤 航, 加瀬 諭, 野田 航介, 吉沢 史子, 藤谷 顕雄, 大黒 浩, 石田 晋  眼科臨床紀要  6-  (10)  808  -809  2013/10  [Not refereed][Not invited]
  
• 多発消失性白点症候群における網膜厚層別解析による経時的変化

  橋本 勇希, 齋藤 航, 齋藤 理幸, 藤谷 顕雄, 吉澤 史子, 野田 航介, 石田 晋  眼科臨床紀要  6-  (10)  821  -821  2013/10  [Not refereed][Not invited]
  
• 中心窩に多発性裂孔を呈した黄斑円孔の1例

  鈴木 智浩, 野田 航介, 齋藤 航, 齋藤 理幸, 加瀬 諭, 藤谷 顕雄, 吉澤 史子, 石田 晋  眼科臨床紀要  6-  (10)  830  -830  2013/10  [Not refereed][Not invited]
  
• ラニビズマブ併用PDTトリプル療法1年後の治療成績

  吉澤 史子, 齋藤 航, 加瀬 諭, 齋藤 理幸, 藤谷 顕雄, 橋本 勇希, 野田 航介, 石田 晋  眼科臨床紀要  6-  (10)  837  -838  2013/10  [Not refereed][Not invited]
  
• 線維柱帯切除術後に持続性の低眼圧に陥った乾癬ぶどう膜炎による続発緑内障の一例

  田川 義晃, 大口 剛司, 新明 康弘, 清水 啓史, 宇野 友絵, 石嶋 漢, 新田 卓也, 南場 研一, 陳 進輝, 石田 晋  日本緑内障学会抄録集  24回-  163  -163  2013/09  [Not refereed][Not invited]
  
• 抗VEGF療法の基礎と臨床 血管内皮増殖因子の基礎知識

  石田 晋  眼薬理  27-  (1)  30  -33  2013/09  [Not refereed][Not invited]
   

  血管内皮増殖因子(VEGF)遺伝子ファミリーには、VEGF(VEGF-A)、VEGF-B、VEGF-C、VEGF-D、胎盤成長因子が含まれる。これらの受容体として、3つの受容体型チロシンキナーゼ(VEGFR-1、VEGFR-2、VEGFR-3)は、それぞれ炎症細胞、血管内皮細胞、リンパ管内皮細胞に発現し、炎症・血管新生・リンパ管新生を惹起する。VEGFR-1とVEGFR-2に結合するVEGFは炎症と血管新生を促進することで、血管新生病態のみならず、浮腫性・滲出性病態にも関与する。したがって、VEGF阻害薬は、抗炎症・抗血管新生作用により有益な効果をもたらすと考えられる。(著者抄録)
• 院内感染を起こす新型ヒトアデノウイルスのバイオインフォマティクス

  青木 功喜, 金子 久俊, 北市 伸義, 渡邉 日出海, 石田 晋, 大野 重昭  日本眼科学会雑誌  117-  (9)  721  -726  2013/09  [Not refereed][Not invited]
   

  流行性角結膜炎を引き起こすヒトアデノウイルス(HAdV)はすべてD種かE種である.バイオインフォマティクスの進歩により,その病態は宿主の免疫応答に関与するearly transcription unit 3(E3),標的器官に接着するファイバー・ノブ,細胞に侵入するためのペントンベースにあるRGD(Arg-Gly-Asp)モチーフ,中和決定基のヘキソンとその可変領域であるループ1と2という構造が関与することが明らかになってきた.サルからヒトへ種の壁を超えた感染が起こった可能性が指摘され(HAdV-52型),さらに近年はゲノムの組換えによりHAdV-53,-54,-56型などの新型が次々に出現している.バイオインフォマティクスを用いた全ゲノム系統解析をアデノウイルス研究に応用し,臨床と遺伝子の相互関連の解明に取り組み,新しい型の命名法,院内感染の病原体の特定,遺伝子構造と進化,流行の予測と治療薬の標的推定への利用が期待される.(著者抄録)
• 【糖尿病性合併症を考慮した高血圧治療】 高血圧と糖尿病性合併症 糖尿病網膜症と高血圧 RA系阻害薬の可能性

  石田 晋, 神田 敦宏  月刊糖尿病  5-  (8)  65  -69  2013/08  [Not refereed][Not invited]
  
• 増殖糖尿病網膜症の硝子体手術後に診断された腫瘍随伴網膜症の1例

  清水 啓史, 齋藤 航, 齋藤 理幸, 大黒 浩, 石田 晋  臨床眼科  67-  (8)  1349  -1355  2013/08  [Not refereed][Not invited]
   

  目的:糖尿病網膜症に対する硝子体手術後に腫瘍随伴網膜症と診断された1症例の報告。症例:58歳,男性。右眼視力低下を主訴に初診。両眼の硝子体出血を伴う増殖糖尿病網膜症の診断で,両眼に硝子体手術が行われた。術中術後に合併症はなく,検眼鏡的に糖尿病網膜症は沈静化したようにみえたが,手術の1年後に視力低下,網膜電図のa波減弱および求心性視野狭窄が進行した。全身検索で直腸癌が発見され腫瘍随伴網膜症と診断された。結論:高齢者で眼内手術の術後に原因不明の視機能障害が生じた際には,腫瘍随伴網膜症も考え全身検索を行うべきである。(著者抄録)
• Goldmann動的視野検査がHumphrey静的視野検査(30-2)よりも早期発見に有効であった緑内障の3例

  石垣 さやか, 新明 康弘, 山口 淑子, 溝口 亜矢子, 阿部 朋子, 大口 剛司, 宇野 友絵, 辻野 奈緒子, 陳 進輝, 石田 晋  あたらしい眼科  30-  (8)  1160  -1164  2013/08  [Not refereed][Not invited]
   

  目的:緑内障の早期発見におけるGoldmann動的視野検査(GP)の有用性を検討する。対象および方法:Humphrey静的視野検査(HFA)中心30-2プログラムでは、緑内障の診断に至らなかったが、GPによって緑内障性視野変化が確認でき、緑内障の診断となった3症例について、GPとHFA中心30-2 SITA-Standardおよび中心10-2 SITA-Standardの結果を比較する。結論:緑内障の早期発見には、GPがHFA中心30-2プログラムよりも、緑内障性視野変化の早期発見に有効な場合がある。HFA中心30-2で緑内障の診断に迷ったときには、GPを行い、さらに中心10-2を追加するとよいと思われる。(著者抄録)
• 【黄斑疾患診療の最前線】 黄斑疾患の治療 薬物療法 VEGF阻害薬

  石田 晋  Pharma Medica  31-  (7)  41  -45  2013/07  [Not refereed][Not invited]
  
• 【アンチエイジング医学の最近の流れ】 アンチエイジング医学による疾病治療の可能性 アンチエイジング医学による加齢性眼疾患への介入

  北市 伸義, 石田 晋  Geriatric Medicine  51-  (7)  693  -696  2013/07  [Not refereed][Not invited]
   

  現在、日本人の中途失明原因の約6割は加齢が関係する疾患による。一方、眼科領域はアンチエイジング医学のエビデンス蓄積と、そのエビデンスに基づいた介入が最も先行している分野の1つである。抗酸化ビタミン、ルテインやアスタキサンチンなどのカロテノイド、あるいは白内障手術時に眼内に挿入する眼内レンズでも短波長可視光線を吸収する素材が普及し、網膜の加齢黄斑変性などに対する有効性が期待されている。今後さらに基礎的・臨床的エビデンスの蓄積が進むと考えられる。(著者抄録)
• The vitreous renin-angiotensin system is mediated by soluble (pro)renin receptor in diabetic retinopathy: A new implication of the receptor-associated prorenin system

  Atsuhiro Kanda, Susumu Ishida  Taiwan Journal of Ophthalmology  3-  (2)  51  -53  2013/06  [Not refereed][Not invited]
   

  The renin-angiotensin system (RAS) plays pivotal roles in homeostasis, but its abnormal activation has been proposed as a risk factor for several disorders including diabetes. Using animal models, we previously clarified the molecular mechanisms in which tissue RAS stimulates retinal angiogenesis and the critical roles of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction, i.e., the receptor-associated prorenin system (RAPS). Most recently, we have revealed that (P)RR is associated with vascular endothelial growth factor (VEGF)-driven angiogenic activity in human proliferative diabetic retinopathy (DR), and also showed a close relationship between vitreous renin activity and VEGF-induced pathogenesis of DR. These findings suggest that both vitreous RAS and retinal RAPS are tightly linked to the molecular pathogenesis of DR. © 2013.
• 眼の健康科学 食品のサイエンス

  北市 伸義, 石田 晋  眼科  55-  (6)  717  -722  2013/06  [Not refereed][Not invited]
  
• Laser speckle flowgraphyを施行した小児多発消失性白点症候群の1例

  橋本 勇希, 齋藤 航, 齋藤 理幸, 吉澤 史子, 野田 航介, 石田 晋  眼科臨床紀要  6-  (5)  405  -405  2013/05  [Not refereed][Not invited]
  
• 多発消失性白点症候群寛解後に中心窩に非典型的な網膜色素上皮症を生じた15歳男児

  廣岡 季里子, 齋藤 航, 橋本 勇希, 齋藤 理幸, 吉澤 史子, 野田 航介, 石田 晋  眼科臨床紀要  6-  (5)  408  -408  2013/05  [Not refereed][Not invited]
  
• 多発消失性白点症候群寛解後も中心窩に持続する非典型的な網膜色素上皮症の15歳男児

  廣岡 季里子, 齋藤 航, 橋本 勇希, 野田 航介, 堤 雅幸, 古館 直樹, 石田 晋  眼科臨床紀要  6-  (4)  278  -282  2013/04  [Not refereed][Not invited]
   

  背景:多発消失性白点症候群(MEWDS)寛解後も中心窩に持続した非典型的な網膜色素上皮症の小児例を報告する。症例:症例は15歳男児。右視力は矯正0.3、右眼底には白点が散在し、蛍光眼底造影所見から右MEWDSと診断された。黄斑部には黄白色病巣を伴っていたが、それは周辺部の白点の消失後も持続した。右視力は1.0に上昇したが、8ヵ月後0.4に低下した。右眼底には周辺部に白点はなかったが、中心窩病巣が拡大していた。インドシアニングリーン蛍光眼底造影では病巣部は低蛍光を示した。プレドニゾロン30mg/日の内服を開始し以後漸減したところ、病巣はやや縮小し右視力は0.7に上昇した。結論:MEWDS発症後も持続した網膜色素上皮症の原因として、中心窩に限局して網膜色素上皮から脈絡膜毛細血管板レベルに慢性の炎症が生じたことが示唆された。(著者抄録)
• ラボのマネージメントの実際を語る 魅力的なラボづくりに向けて

  石田 晋, 小沢 洋子, 近藤 峰生, 中澤 徹, 安川 力, 山城 健児  Retina Medicine  2-  (1)  1  -7  2013/04  [Not refereed][Not invited]
  
• 今さら聞けないQ&A(第2回) 人間ドックなどでKeith-Wagener分類など眼底所見の記載を求められることがありますが、あのように分類する意味は現在でもあるのでしょうか?

  石田 晋  Retina Medicine  2-  (1)  103  -106  2013/04  [Not refereed][Not invited]
  
• 今さら聞けないQ&A(第2回) (1)VEGF阻害薬の機序を考えると、VEGFが結合する受容体であるVEGFR-2阻害薬も効果があるように思われますが、そのような薬剤はあるのでしょうか?(2)新しいVEGF阻害薬アフリベルセプトは可溶型VEGF受容体(VEGFR-1とR-2の融合蛋白)ですので、VEGFR-1の作用はどう理解したらいいのでしょうか?

  石田 晋  Retina Medicine  2-  (1)  106  -107  2013/04  [Not refereed][Not invited]
  
• 黄斑円孔網膜剥離に対する硝子体手術成績 黄斑バックル使用の効果

  藤谷 顕雄, 齋藤 航, 齋藤 理幸, 吉沢 史子, 野田 航介, 加瀬 諭, 石田 晋  眼科手術  26-  (2)  279  -283  2013/04  [Not refereed][Not invited]
   

  目的:黄斑円孔網膜剥離(MHRD)に対する硝子体手術(PPV)成績を検討すること。対象および方法:2003年12月から2011年8月に北海道大学病院眼科でPPVを施行したMHRD20例20眼(男性3例、女性17例、平均年齢69.5歳)を対象とした。初回術式として15眼に内境界膜(ILM)剥離併用PPV(PPV群)、5眼に黄斑バックル(MB)併用PPV(MB群)が施行された。網膜復位率、視力の推移、黄斑円孔閉鎖率などについて、診療録より後ろ向きに検討した。結果:PPV群の初回網膜復位率は66.7%であり、MHが再開通した3眼にMB併用PPVを追加し、全例で網膜復位を得た。一方、MB群の初回網膜復位率は80%、最終網膜復位術は100%であった。最終的に19眼(95%)で網膜は復位した。最終平均視力は有意に改善し(p=0.0007)、最終的にMB併用群は、非併用群より良好な傾向があった(p=0.069)。黄斑円孔閉鎖率は、MB併用群、非併用群でそれぞれ71.4%、40.0%であった。結論:MHRDに対するPPVにおける、長眼軸長眼でもMBを併用することで良好な網膜腹位率と良好な黄斑円孔閉鎖率が得られた。(著者抄録)
• ステロイドパルス療法後に視機能が回復した点状脈絡膜内層症に合併した急性帯状潜在性網膜外層症の1例

  齊藤 沙宝, 齋藤 航, 橋本 勇希, 石田 晋  眼科臨床紀要  6-  (3)  190  -194  2013/03  [Not refereed][Not invited]
   

  背景:著明に視機能が低下した点状脈絡膜内層症(PIC)を合併した急性帯状潜在性網膜外層症(AZOOR)の1例に対して、ステロイドパルス療法を行ったのでその経過を報告する。症例:24歳、女性。矯正視力は右0.01。右眼後極部網膜に黄白色の点状病巣が多発し、蛍光眼底造影所見も併せてPICと診断された。光干渉断層計では、視細胞形態のびまん性の異常を、Goldmann視野では40×40°の中心暗点を、多局所網膜電図では全体的な振幅の低下を示したことからAZOORを合併していると診断した。ステロイドパルス療法の2クール投与後、プレドニゾロン全身投与が約5ヵ月間施行された。視力は治療開始1ヵ月後には0.3、8ヵ月後には1.0に改善し、中心暗点も消失した。結論:本症例の経過から、中心視力が低下したPIC合併AZOORに対する副腎皮質ステロイドの大量全身投与は有効である可能性がある。(著者抄録)
• Vogt-小柳-原田病の前眼部炎症再発時における脈絡膜循環障害

  竹本 裕子, 南場 研一, 水内 一臣, 橋本 勇希, 宇野 友絵, 北市 伸義, 大野 重昭, 石田 晋  日本眼科学会雑誌  117-  (臨増)  255  -255  2013/03  [Not refereed][Not invited]
  
• SRPK阻害薬による脈絡膜血管新生の抑制効果

  董 震宇, 野田 航介, 斉藤 航, 木下 哲志, 福原 淳一, 安藤 亮, 村田 美幸, 神田 敦宏, 萩原 正敏, 石田 晋  日本眼科学会雑誌  117-  (臨増)  289  -289  2013/03  [Not refereed][Not invited]
  
• マウス脈絡膜新生血管モデルにおけるゲニステインの抑制効果

  木下 哲志, 野田 航介, 高階 沙織, 董 陽子, 福原 淳一, 董 震宇, 安藤 亮, 神田 敦宏, 石田 晋  日本眼科学会雑誌  117-  (臨増)  289  -289  2013/03  [Not refereed][Not invited]
  
• マウス脈絡膜新生血管モデルにおけるケルセチンの抑制効果

  福原 淳一, 野田 航介, 高階 沙織, 董 陽子, 木下 哲志, 董 震宇, 安藤 亮, 神田 敦宏, 石田 晋  日本眼科学会雑誌  117-  (臨増)  289  -289  2013/03  [Not refereed][Not invited]
  
• 慢性移植片対宿主病モデルマウス涙腺の線維化病態の検討

  谷口 紗織, 小川 葉子, 榛村 重人, 羽藤 晋, 中村 滋, 稲葉 隆明, 今田 敏博, 小沢 洋子, 河上 裕, 石田 晋, 坪田 一男  日本眼科学会雑誌  117-  (臨増)  296  -296  2013/03  [Not refereed][Not invited]
  
• マウス網膜発生における(プロ)レニン受容体の生理的機能解析

  神田 敦宏, 野田 航介, 結城 賢弥, 小沢 洋子, 古川 貴久, 市原 淳弘, 石田 晋  日本眼科学会雑誌  117-  (臨増)  311  -311  2013/03  [Not refereed][Not invited]
  
• プロテアソーム機能不全による網膜変性

  安藤 亮, 野田 航介, 外丸 詩野, 野田 実香, 高階 沙織, 董 陽子, 木下 哲志, 福原 淳一, 董 震宇, 神田 敦宏, 石田 晋  日本眼科学会雑誌  117-  (臨増)  312  -312  2013/03  [Not refereed][Not invited]
  
• 眼内のリソゾームホスホリパーゼA2(LPLA2)活性化機序の検討

  平岡 美紀, 阿部 晃, 北市 伸義, アントン・レニコフ, 石田 晋, 大黒 浩  日本眼科学会雑誌  117-  (臨増)  314  -314  2013/03  [Not refereed][Not invited]
  
• ベーチェット病眼炎症発作とインフリキシマブトラフ値・サイトカイン血中濃度との相関

  水内 一臣, 竹本 裕子, 南場 研一, 宇野 友絵, 大野 重昭, 石田 晋  日本眼科学会雑誌  117-  (臨増)  317  -317  2013/03  [Not refereed][Not invited]
  
• ぶどう膜炎における網羅的糖鎖解析

  南場 研一, 北市 伸義, 安藤 亮, 竹本 裕子, 水内 一臣, 堀江 幸弘, 大野 重昭, 天野 麻穂, 西村 紳一郎, 石田 晋  日本眼科学会雑誌  117-  (臨増)  318  -318  2013/03  [Not refereed][Not invited]
  
• 周辺虹彩前癒着を伴うぶどう膜炎に続発した緑内障に対するsuture-trabeculotomyの成績

  大口 剛司, 新明 康弘, 新田 卓也, 山本 麻梨亜, 南場 研一, 大野 重昭, 陳 進輝, 石田 晋  日本眼科学会雑誌  117-  (臨増)  339  -339  2013/03  [Not refereed][Not invited]
  
• 硝子体手術後に初めて乳頭小窩が明らかになった視神経乳頭小窩黄斑症候群の2例

  田中 敦, 齋藤 航, 吉沢 史子, 野田 航介, 石田 晋  日本眼科学会雑誌  117-  (臨増)  345  -345  2013/03  [Not refereed][Not invited]
  
• 眼科医の目視と血管径自動解析プログラムによる網膜動静脈比判定の比較

  齋藤 理幸, 野田 航介, 星川 靖裕, 小林 正彦, 藤谷 顕雄, 吉澤 史子, 齋藤 航, 石田 晋  日本眼科学会雑誌  117-  (臨増)  354  -354  2013/03  [Not refereed][Not invited]
  
• 特発性黄斑円孔手術後における網膜厚層別解析による経時的変化

  橋本 勇希, 齋藤 航, 齋藤 理幸, 藤谷 顕雄, 吉澤 史子, 野田 航介, 石田 晋  日本眼科学会雑誌  117-  (臨増)  366  -366  2013/03  [Not refereed][Not invited]
  
• 増殖糖尿病網膜症における硝子体中可溶型VAP-1とプロレニン

  高階 沙織, 野田 航介, 難波 志帆, 木下 哲志, 福原 淳一, 董 震宇, 安藤 亮, 吉澤 史子, 斎藤 航, 神田 敦宏, 石田 晋  日本眼科学会雑誌  117-  (臨増)  366  -366  2013/03  [Not refereed][Not invited]
  
• 強膜内陥術後にみられた続発緑内障の1例

  山本 麻梨亜, 新明 康弘, 新田 卓也, 齋藤 航, 陳 進輝, 石田 晋  あたらしい眼科  30-  (3)  391  -395  2013/03  [Not refereed][Not invited]
   

  半年以上経過した陳旧性の裂孔原性網膜剥離の23歳、男性に対し、強膜内陥術を施行した。初回手術でエクソプラントを施行したが、術後再剥離がみられたため、再度輪状締結併用インプラントを行い、復位が得られた。しかし、初回手術直後から眼圧上昇をきたし、再手術により網膜が復位した後も高眼圧は続いた。抗緑内障薬を使用し、さらにステロイド薬を中止しても眼圧下降が得られず、初回手術から3週間にわたり高眼圧が持続した。線維柱帯切開術を施行したところ、十分な眼圧下降が得られ、有効であった。(著者抄録)
• 中心性漿液性脈絡網膜症 (特集 眼循環と網膜関連疾患の関与を探る)

  齋藤 航, 齋藤 理幸, 石田 晋  Retina medicine : journal of retina medeicine : 網膜・硝子体領域を中心とした医学情報誌  2-  (2)  182  -186,130  2013
• 多発消失性白点症候群における網膜厚層別解析

  橋本 勇希, 齋藤 航, 石田 晋  日本視能訓練士協会誌  41-  280  -280  2013/01  [Not refereed][Not invited]
  
• 【網膜硝子体疾患診療の進歩2012】 治療手技の進歩 加齢黄斑変性 加齢黄斑変性の予防治療

  石田 晋  あたらしい眼科  29-  (臨増)  113  -117  2012/12  [Not refereed][Not invited]
   

  1.加齢黄斑変性(AMD)に対する血管内皮増殖因子(VEGF)阻害薬が臨床応用された現在、より良い視機能の確保を目指して早期の介入による発症予防にも関心が集まっている。2.AMDの遺伝因子と環境因子(生活習慣)は独立した危険因子ではなく、これらの相乗作用によりAMD発症につながると考えられる。3.加齢黄斑変性の発症要因に酸化ストレスが関与することは、黄斑が光刺激に曝露されていることや食習慣との関連を調査した疫学研究から示唆されていた。4.AREDSでは、抗酸化ビタミンと微量ミネラルの摂取により加齢黄斑変性の発症リスクが低下することが実証された。5.現在、黄斑色素ルテインとオメガ3不飽和脂肪酸の効果を検証するためAREDS2が進行中である。(著者抄録)
• 【禁煙の推進と医師の役割】 喫煙と眼疾患

  石田 晋, 石橋 達朗  日本医師会雑誌  141-  (9)  1959  -1961  2012/12  [Not refereed][Not invited]
  
• 急性帯状潜在性網膜外層症を合併した多発消失性白点症候群の2例

  橋本 勇希, 齋藤 航, 齋藤 理幸, 吉澤 史子, 野田 航介, 石田 晋  眼科臨床紀要  5-  (12)  1117  -1123  2012/12  [Not refereed][Not invited]
   

  緒言:多発消失性白点症候群multiple evanescent white dot syndrome(MEWDS)に急性帯状潜在性網膜外層症(AZOOR)を合併した2例の臨床経過を報告する。症例:症例1は26歳、女性。左眼底に白点が多発し、蛍光眼底造影所見からMEWDSと診断された。初診3日後、白点が消失したにもかかわらず、視力と視野所見が悪化した。多局所網膜電図で視野異常部位に一致して振幅が低下していたことから、AZOORと診断された。ステロイド全身投与を開始したところ視力と視野は早期から改善した。症例2は33歳、女性。右MEWDSと診断された29ヵ月後に左MEWDSと診断された。その28ヵ月後に左眼にAZOORが発症した。経過観察で視機能は改善したが、次第に視野異常部位に一致して網膜萎縮病巣を示した。結論:MEWDSとAZOORが同時に発症、または同一眼に時期を変えて発症したことから、両疾患は共通の病因をもつことが示唆された。(著者抄録)
• 単焦点眼鏡へ移行できた後に眼位変動を来した非屈折性調節性内斜視の長期経過

  溝口 亜矢子, 安藤 亮, 山口 淑子, 石垣 さやか, 石田 晋  日本視能矯正学会プログラム抄録集  53回-  73  -73  2012/11  [Not refereed][Not invited]
  
• (Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

  神田 敦宏, 野田 航介, 齋藤 航, 石田 晋  北海道醫學雜誌 = Acta medica Hokkaidonensia  87-  (6)  263  -263  2012/11/01
• 【鮭】 鮭・イクラの色素、アスタキサンチン

  石田 晋  食生活  106-  (11)  32  -36  2012/11  [Not refereed][Not invited]
  
• 【炎症とRASのかかわりを探る】 糖尿病網膜症 炎症とRAS

  石田 晋, 尾池 雄一  Angiotensin Research  9-  (4)  225  -229  2012/10  [Not refereed][Not invited]
   

  近年の細胞生物学的研究の進歩は、糖尿病網膜症の分子細胞メカニズムとして血管内皮増殖因子(vascular endothelial growth factor:VEGF)や炎症細胞の関与を明らかにした。その結果、糖尿病網膜症は炎症性疾患と捉えられるようになり、従来のレーザー網膜光凝固術や硝子体手術に加えて、抗VEGF療法や抗炎症ステロイド薬が網膜症診療において未認可ながらも汎用されるようになった。さらに早期から積極的におこなえる安全かつ有効な治療戦略として、生活習慣病における臓器障害の鍵因子レニン・アンジオテンシン系(renin-angiotensin system:RAS)への介入が考えられる。網膜症の動物モデルにおいては、RAS活性化の下流でVEGFなどさまざまな炎症関連因子が誘導される分子病態が明らかにされた。実際、海外の複数の大規模臨床試験の結果から、RAS抑制薬の網膜症に対する有効性が示され、RAS関連分子を標的にした新しい治療戦略が有望視されている。(著者抄録)
• AMDに対するranibizumab硝子体内注射後の網脈絡膜循環と血管径変化

  齋藤 理幸, 齋藤 航, 橋本 勇希, 野田 航介, 石田 晋  眼科臨床紀要  5-  (10)  941  -942  2012/10  [Not refereed][Not invited]
  
• 網膜血管増殖性腫瘍に対する硝子体手術成績と血管内皮増殖因子の発現

  齋藤 航, 藤谷 顕雄, 加瀬 諭, 董 震宇, 石田 晋  眼科臨床紀要  5-  (10)  942  -942  2012/10  [Not refereed][Not invited]
  
• 多発消失性白点症候群における脈絡膜循環動態の経時的変化

  橋本 勇希, 齋藤 航, 齋藤 理幸, 石田 晋  眼科臨床紀要  5-  (10)  945  -945  2012/10  [Not refereed][Not invited]
  
• DNAメチル化阻害剤による脈絡膜血管内皮細胞の増殖抑制効果

  加瀬 諭, 園田 祥三, ヘー・シクン, ステファン・ライアン, ヒントン・デービット, 石田 晋  眼科臨床紀要  5-  (10)  954  -954  2012/10  [Not refereed][Not invited]
  
• 強度近視眼に発症したタモキシフェン網膜症の1例

  吉澤 史子, 加瀬 諭, 齋藤 航, 石田 晋  眼科臨床紀要  5-  (10)  971  -971  2012/10  [Not refereed][Not invited]
  
• 交通外傷による片眼の失明後に他眼の視力低下を訴えた1例

  石垣 さやか, 新明 康弘, 新田 卓也, 石嶋 漢, 陳 進輝, 石田 晋  神経眼科  29-  (増補1)  77  -77  2012/10  [Not refereed][Not invited]
  
• 隅角結節を伴う続発緑内障の臨床像

  竹本 裕子, 新田 卓也, 南場 研一, 水内 一臣, 宇野 友絵, 大口 剛司, 新明 康弘, 陳 進輝, 石田 晋  日本緑内障学会抄録集  23回-  133  -133  2012/09  [Not refereed][Not invited]
  
• 【眼科薬物療法】 AREDSサプリメント

  石田 晋  眼科  54-  (10)  1431  -1433  2012/09  [Not refereed][Not invited]
  
• 抗VEGF治療の基礎と臨床 今さら聞けないVEGFの基礎知識・研究史

  石田 晋  日本眼薬理学会プログラム・抄録集  32回-  29  -29  2012/09  [Not refereed][Not invited]
  
• 【臨床において必要なサプリメントの知識】 医家向けのサプリメント アスタキサンチン

  北市 伸義, 石田 晋  あたらしい眼科  29-  (8)  1069  -1073  2012/08  [Not refereed][Not invited]
  
• 第116回 日本眼科学会総会

  坪田 一男, 富田 剛司, 三木 淳司, 前田 直之, 石田 晋, 水木 信久, 栗本 康夫, 天野 史郎, 川北 哲也  日本眼科學会雜誌  116-  (7)  664  -668  2012/07/10  [Not refereed][Not invited]
  
• 【最新臨床糖尿病学 下-糖尿病学の最新動向-】 糖尿病合併症・糖尿病関連疾患 各種糖尿病合併症の概念・成因・診断・治療 糖尿病性細小血管症 糖尿病網膜症 糖尿病網膜症の成因

  石田 晋  日本臨床  70-  (増刊5 最新臨床糖尿病学(下))  343  -348  2012/07  [Not refereed][Not invited]
  
• 【眼科で使えるサプリメント】 レスベラトロール

  石田 晋  眼科  54-  (7)  861  -871  2012/07  [Not refereed][Not invited]
  
• 小児Coats病に対するbevacizumab硝子体内注射併用網膜光凝固

  橋本 勇希, 野田 航介, 齋藤 航, 藤谷 顕雄, 齋藤 理幸, 加瀬 諭, 吉澤 史子, 石田 晋  眼科臨床紀要  5-  (7)  651  -655  2012/07  [Not refereed][Not invited]
   

  背景:小児Coats病に対してbevacizumab硝子体内注射(以下;IVB)併用網膜光凝固を施行した一例の臨床経過報告。症例:12歳、男児。初診時矯正視力は右0.04で、眼底には右耳側周辺部に網膜毛細血管拡張と瘤状の異常網膜血管があった。異常血管周囲には強度の網膜浮腫があり、後極部および中心窩に硬性白斑が集積していた。フルオレセイン蛍光眼底造影(FA)では異常血管に一致した強い蛍光漏出を示した。Coats病stage 2Bと診断し、全身麻酔下でIVB(1.25mg)および網膜光凝固を施行した。治療4日後には黄斑浮腫と硬性白斑は軽減し、視力は0.3に改善した。その後、異常網膜血管に対する網膜光凝固を追加したところ、硬性白斑と網膜浮腫は著明に減少し、視力は1.0に改善した。結論:IVBを併用した網膜光凝固は、小児のCoats病において有効な治療法であることが示唆された。(著者抄録)
• 抗VEGF薬の基礎

  石田 晋  あたらしい眼科 = Journal of the eye  29-  (6)  797  -799  2012/06/30  [Not refereed][Not invited]
  
• 抗VEGF治療セミナー 基礎編 抗VEGF薬の基礎

  石田 晋  あたらしい眼科  29-  (6)  797  -799  2012/06  [Not refereed][Not invited]
   

  近年の細胞生物学的研究の進歩は、糖尿病網膜症や加齢黄斑変性などにみられる眼内血管新生の責任分子が血管内皮増殖因子(VEGF)であることを明らかにした。このため、VEGFを分子標的とした治療戦略の確立に向けて複数の新薬が開発された。本稿では、これらVEGF阻害薬の薬剤特性について概説する。(著者抄録)
• プロスタグランジン製剤・β遮断薬からトラボプロスト・チモロールマレイン酸塩配合液への切替え効果

  佐藤 出, 北市 伸義, 広瀬 茂樹, 高野 睦子, 赤沼 正堂, 唐 尚子, 田邊 章浩, 木下 平次郎, 堀江 幸弘, 木嶋 理紀, 大口 剛司, 仲 昌彦, 新田 卓也, 新明 康弘, 陳 進輝, 石田 晋  臨床眼科  66-  (5)  675  -678  2012/05  [Not refereed][Not invited]
   

  目的:広義の開放隅角緑内障治療におけるプロスタグランジン製剤とβ遮断薬点眼液からトラボプロスト・チモロールマレイン酸塩配合点眼液(デュオトラバ)への前向き切替え試験結果の報告。対象と方法:40例78眼を対象とした。変更前,2,4,6ヵ月後の眼圧とアンケート調査を行った。結果:眼圧は変更前が15.2±3.7mmHgに対し,変更後2ヵ月で14.3±3.4mmHg,4ヵ月で15.0±3.4mmHg,6ヵ月で14.1±3.4mmHgで,変更後2ヵ月,6ヵ月で有意に下降した。アンケート結果は23例から回答が得られ,点眼が楽になった患者は18例,点眼し忘れが減った患者は12例であった。結論:デュオトラバはアドヒアランスの改善が見込め,切替えによってさらに眼圧下降する可能性がある。(著者抄録)
• シクロホスファミドパルス療法が奏効した再発性乳頭血管炎の1例

  田中 敦, 齋藤 航, 吉沢 史子, 大友 耕太郎, 栗田 崇史, 石田 晋  臨床眼科  66-  (5)  707  -712  2012/05  [Not refereed][Not invited]
   

  目的:ステロイド依存性の乳頭血管炎にシクロホスファミドパルス療法が奏効した症例の報告。症例:35歳女性が1ヵ月前からの右眼視力低下で受診した。2歳時に再発不良性貧血と診断され,シクロスポリンの投与を受けていた。所見:視力は右0.6,左1.2で,右眼に乳頭の発赤腫脹があり,乳頭血管炎と診断した。2週後に自然寛解した。3ヵ月後に左眼視力が0.07に低下し,乳頭が蒼白浮腫状で,中心暗点と上水平半盲があった。視神経網膜炎と網膜血管炎と診断した。その3ヵ月後に右眼に乳頭血管炎が再発し,視力は右0.4,左0.05となった。ステロイドパルス療法で右眼視力は改善したが,ステロイドの減量に伴い右眼の病変が2度再発した。シクロホスファミドを2週または4週ごとに計14回静注し,初診から35ヵ月後の現在,視力は右1.0,左0.3に改善し,乳頭浮腫などは消失した。結論:ステロイド依存性のある再発性乳頭血管炎にシクロホスファミドが奏効することがある。(著者抄録)
• 小児Coats病に対するbevacizumab硝子体内注射併用網膜光凝固

  橋本 勇希, 野田 航介, 齋藤 航, 高橋 亜衣, 石田 晋  眼科臨床紀要  5-  (5)  471  -471  2012/05  [Not refereed][Not invited]
  
• 【サプリメント・フードファクターupdate】 加齢性眼疾患とサプリメント・フードファクター

  石田 晋  アンチ・エイジング医学  8-  (2)  194  -200  2012/04  [Not refereed][Not invited]
  
• 【食品と疾病 アスタキサンチン】 アスタキサンチンと眼疾患

  北市 伸義, 石田 晋  Functional Food  5-  (4)  307  -312  2012/04  [Not refereed][Not invited]
   

  ヒトは外界からの情報の80%以上を視覚に頼るとされるが、近年の情報化社会は眼への負担をこれまで以上に過酷なものにしている。まず動物モデルにアスタキサンチンを摂取させて検討したところ、眼内炎症である急性ぶどう膜炎を有意に抑制した。また、高齢化に伴って近年増加している加齢黄斑変性の動物モデルである、脈絡膜新生血管モデルにも有効性が示された。さらに健常者を対象にした臨床試験では、眼精疲労軽減、調節力回復、眼底血流速度の増加が示された。アスタキサンチンは、眼精疲労、炎症性疾患、紫外線障害、加齢黄斑変性など多くの疾患に有用である可能性がある。アスタキサンチンは古来人類が摂取してきた食品に広く含まれており、安全性も高い。眼科領域におけるその抗酸化作用、抗炎症作用の基礎的・臨床的エビデンスを蓄積すべきであると考える。(著者抄録)
• 今さら聞けないVEGFの基礎知識から抗VEGF療法の臨床における実際の考え方

  石田 晋  眼科臨床紀要  5-  (3)  279  -279  2012/03  [Not refereed][Not invited]
  
• (プロ)レニン受容体の増殖糖尿病網膜症組織検体における血管新生活動性への関与

  神田 敦宏, 野田 航介, 齋藤 航, 石田 晋  日本眼科学会雑誌  116-  (臨増)  238  -238  2012/03  [Not refereed][Not invited]
  
• 毒性終末糖化産物阻害薬による自己免疫性ぶどう膜網膜炎の軽症化

  董 震宇, 北市 伸義, 岩田 大樹, 竹内 正義, 安藤 亮, 福原 淳一, 木下 哲志, アントン・レニコフ, 神田 敦宏, 野田 航介, 石田 晋  日本眼科学会雑誌  116-  (臨増)  249  -249  2012/03  [Not refereed][Not invited]
  
• Vogt-小柳-原田病における隅角色素脱失(大野徴候)の検討

  水内 一臣, 南場 研一, 北市 伸義, 堀江 幸弘, 岩田 大樹, 石田 晋, 大野 重昭  日本眼科学会雑誌  116-  (臨増)  249  -249  2012/03  [Not refereed][Not invited]
  
• 光線力学的療法に伴う血管内皮増殖因子の発現亢進の生物学的意義

  鈴木 美砂, 久保田 俊介, 平沢 学, 三宅 誠司, 野田 航介, 門之園 一明, 坪田 一男, 石田 晋, 小沢 洋子  日本眼科学会雑誌  116-  (臨増)  255  -255  2012/03  [Not refereed][Not invited]
  
• マウス脈絡膜新生血管モデルにおけるカリジノゲナーゼの血管新生抑制効果

  福原 淳一, 野田 航介, 吉澤 史子, 木下 哲志, 董 震宇, 安藤 亮, アントン・レニコフ, 神田 敦宏, 石田 晋  日本眼科学会雑誌  116-  (臨増)  256  -256  2012/03  [Not refereed][Not invited]
  
• SOD-1ノックアウトマウスに伴うドライアイにおける2%レバミピド点眼薬の有効性

  大口 剛司, 小島 隆司, 永田 妙子, 難波 志帆, 野田 航介, 川北 哲也, 村戸 ドール, 島崎 潤, 坪田 一男, 石田 晋  日本眼科学会雑誌  116-  (臨増)  260  -260  2012/03  [Not refereed][Not invited]
  
• 増殖糖尿病網膜症におけるVEGF阻害剤の硝子体内VAP-1濃度への影響

  安藤 亮, 野田 航介, 村田 美幸, 難波 志帆, 木下 哲志, 福原 淳一, 董 震宇, アントン・レニコフ, 齋藤 航, 神田 敦宏, 石田 晋  日本眼科学会雑誌  116-  (臨増)  265  -265  2012/03  [Not refereed][Not invited]
  
• 急性ぶどう膜炎モデル(EIU)でのリソゾームホスホリパーゼA2(LPLA2)の役割

  平岡 美紀, 阿部 晃, 大黒 幾代, 北市 伸義, アントン・レニコフ, 石田 晋, 大黒 浩  日本眼科学会雑誌  116-  (臨増)  273  -273  2012/03  [Not refereed][Not invited]
  
• IKKβ阻害薬IMD0354によるラットEIUの軽症化

  アントン・レニコフ, 北市 伸義, 野田 航介, 南場 研一, 大野 重昭, 石田 晋  日本眼科学会雑誌  116-  (臨増)  274  -274  2012/03  [Not refereed][Not invited]
  
• ヒト結膜MALTリンパ腫におけるVEGFの発現

  木下 哲志, 加瀬 諭, 安藤 亮, 董 震宇, 福原 淳一, アントン・レニコフ, 神田 敦宏, 野田 航介, 石田 晋  日本眼科学会雑誌  116-  (臨増)  278  -278  2012/03  [Not refereed][Not invited]
  
• マウス正常涙腺における組織レニンアンジオテンシン系(RAS)の発現と局在

  谷口 紗織, 小川 葉子, 稲葉 隆明, 小沢 洋子, 石田 晋, 榛村 重人, 坪田 一男  日本眼科学会雑誌  116-  (臨増)  322  -322  2012/03  [Not refereed][Not invited]
  
• 漿液性網膜色素上皮剥離がある滲出型加齢黄斑変性の臨床経過

  吉澤 史子, 齋藤 航, 藤谷 顕雄, 齋藤 理幸, 加瀬 諭, 野田 航介, 石田 晋  日本眼科学会雑誌  116-  (臨増)  334  -334  2012/03  [Not refereed][Not invited]
  
• 自己免疫性網膜症疑い患者におけるWestern blot法を用いた抗網膜抗体陽性率

  齋藤 理幸, 齋藤 航, 加瀬 諭, 野田 航介, 吉沢 史子, 藤谷 顕雄, 大黒 浩, 石田 晋  日本眼科学会雑誌  116-  (臨増)  337  -337  2012/03  [Not refereed][Not invited]
  
• Unilateral acute idiopathic maculopathyにおける脈絡膜循環動態の経時的変化

  橋本 勇希, 齋藤 航, 齋藤 理幸, 野田 航介, 荻野 哲男, 石田 晋  日本眼科学会雑誌  116-  (臨増)  345  -345  2012/03  [Not refereed][Not invited]
  
• β遮断薬・炭酸脱水酵素阻害剤からコソプトへの切り替え効果

  佐藤 出, 大口 剛司, 仲 昌彦, 新田 卓也, 新明 康弘, 陳 進輝, 石田 晋  日本眼科学会雑誌  116-  (臨増)  353  -353  2012/03  [Not refereed][Not invited]
  
• 北海道大学病院眼科における眼瞼痙攣に対するボツリヌス療法の検討

  新田 卓也, 新明 康弘, 陳 進輝, 石田 晋  日本眼科学会雑誌  116-  (臨増)  359  -359  2012/03  [Not refereed][Not invited]
  
• アスタキサンチン

  北市 伸義, 石田 晋, 杉田 直  あたらしい眼科 = Journal of the eye  29-  (2)  211  -212  2012/02/29  [Not refereed][Not invited]
  
• 【疾患メカニズムの新しい理解と治療の展開】 加齢黄斑変性に対する抗VEGF療法

  石田 晋  臨床眼科  66-  (2)  132  -137  2012/02  [Not refereed][Not invited]
  
• 新しい治療と検査シリーズ アスタキサンチン

  北市 伸義, 石田 晋  あたらしい眼科  29-  (2)  211  -212  2012/02  [Not refereed][Not invited]
  
• 抗VEGF療法の基礎と臨床

  石田 晋  眼科臨床紀要  5-  (2)  180  -180  2012/02  [Not refereed][Not invited]
  
• A Case of Unilateral Candida Endophthalmitis in a Healthy Female

  UNO Tomoe, NAMBA Kenichi, KASE Satoru, SAITO Wataru, KITAICHI Nobuyoshi, OHNO Shigeaki, ISHIDA Susumu  あたらしい眼科  29-  (1)  135  -138  2012/01/30  [Not refereed][Not invited]
   

  目的:健康成人に発症した片眼性真菌性眼内炎の1例について報告する。症例:69歳、女性。眼および全身に既往歴はない。初診時の視力は右眼0.9で、右眼に線維素析出を伴う前房炎症および一部塊状の硝子体混濁がみられた。ステロイド薬の局所治療を行ったが、強膜充血、前房蓄膿の形成、硝子体混濁の増強および斑状網膜滲出斑が出現した。ステロイド薬全身投与後にさらに増悪したため、硝子体切除術を施行した。硝子体液の培養および血清中β-D-グルカンは陰性であったが、硝子体液中のβ-D-グルカン濃度は711.6pg/mlと高値を示し、硝子体細胞診のperiodic acid Schiff(PAS)染色で多数のカンジダ菌糸が確認された。結論:非典型的な内因性真菌性眼内炎の診断には、血中だけではなく、硝子体液中のβ-D-グルカン測定や切除検体の組織学的検査が有用である。(著者抄録)
• 創刊号座談会 Retina Medicine誌創刊意義と最新のトピックスを語る

  石田 晋, 近藤 峰生, 中澤 徹  Retina medicine : journal of retina medeicine : 網膜・硝子体領域を中心とした医学情報誌  1-  (1)  3  -9  2012
• 涙嚢様腺管組織を呈した涙腺嚢胞の1例

  山本 和幸, 加瀬 諭, 野田 実香, 岩口 佳史, 後藤田 裕子, 石田 晋  臨床眼科  66-  (1)  57  -60  2012/01  [Not refereed][Not invited]
   

  目的:涙腺嚢胞の1症例の報告。症例:80歳男性が右の上眼瞼腫脹で受診した。40年前に涙嚢炎で右の涙嚢摘出を受けていた。所見:右の上眼瞼の耳側に直径10mmの表面が平滑な軟性腫瘤が触知された。周囲組織との癒着はなかった。磁気共鳴画像検査(MRI)のT2強調画像で,内部が均一な高信号を示す嚢胞様病変があった。血液検査でCRPとIgGの上昇があった。摘出した腫瘤は,病理組織学的に大小の嚢胞腔腫瘤からなり,嚢胞内腔は多列線毛円柱上皮を示し,断頭分泌を伴っていた。嚢胞の上皮下にリンパ球とIgG陽性の形質細胞浸潤があった。結論:本症例は涙嚢様組織を呈する涙腺嚢胞と考えられる。血液のCRPとIgG値の上昇,嚢胞の上皮下に浸潤した形質細胞がIgG陽性であったことから,その発生に慢性炎症が関与した可能性がある。(著者抄録)
• Epidemiological Investigation of Retinal Angioma of von Hippel-Lindau Disease in Japan

  MATSUSHITA Eriko, FUKUSHIMA Atsuki, ISHIDA Susumu, SHIRAKI Kunihiko, YONEYA Shin, SHUIN Taro  あたらしい眼科  28-  (12)  1773  -1775  2011/12/30  [Not refereed][Not invited]
   

  過去における欧米の文献では、von Hippel-Lindau(VHL)病に一定の割合で網膜血管腫が発症することが知られている。しかし、わが国では正確な疫学調査がされておらず、VHL病患者の網膜血管腫の頻度や病態は明らかではない。平成21年から23年にかけて、筆者らはVHL病に合併する網膜血管腫について、国内脳神経外科、眼科、泌尿器科、膵臓病内科の各専門医を対象に疫学調査を行った。その結果、VHL病患者の網膜血管腫の発症数は140名で、VHL病全患者の34%に合併していた。男女比は1:1で、発症年齢は5〜68歳で、平均値28.5歳であった。患者分布は北海道、太平洋沿岸から瀬戸内海地域に帯状に多い傾向にあった。治療に関しては網膜光凝固術を施行されている症例が最も多く、ついで冷凍凝固術が施行されていた。抗vascular endothelial growth factor(VEGF)抗体硝子体注射など新たな治療に取り組む施設もあった。(著者抄録)
• Two Cases of Conjunctival Malignant Melanoma Treated with Topical Interferon α-2b Drop as an Adjuvant Therapy

  KASE Satoru, ISHIJIMA Kan, NODA Mika, ISHIDA Susumu  日本眼科学会雑誌  115-  (11)  1043  -1047  2011/11/10  [Not refereed][Not invited]
   

  背景:インターフェロンα-2b(IFNαL2b)は免疫賦活作用により,腫瘍抑制効果を有する.結膜悪性黒色腫は本邦ではまれな悪性腫瘍であるが,局所再発や所属リンパ節転移を来しやすい.今回我々は,IFNα-2b点眼液を結膜悪性黒色腫の術後後療法として使用した2例を報告する.症例:症例1は77歳,女性.主訴は右眼の結膜腫瘤.初診時,右球結膜耳側に黒色の隆起した腫瘤がみられ,角結膜に原発後天性メラノーシス(PAM)を伴っていた.症例2は84歳,女性.主訴は右眼の色素沈着の拡大.涙丘に黒色腫瘤がみられ,周囲の鼻側球結膜から下眼瞼結膜,角膜にPAMがみられた.両者とも腫瘤摘出術を施行し,病理組織学的に悪性黒色腫と確定診断された.術後IFNα-2b点眼液4回/日を毎日,半年間行った.術後24ヵ月経過するも腫瘍の局所再発はなく,PAMは軽快した.眼内浸潤や多臓器転移はみられなかった.経過中,新たな眼症状の発現や角結膜上皮障害などの副作用はみられなかった.結論:結膜悪性黒色腫切除後の後療法として,IFNα-2b点眼は有用な治療法であると考えられた.(著者抄録)
• 抗VEGF療法アップデート

  石田 晋  眼科  53-  (12)  1725  -1737  2011/11  [Not refereed][Not invited]
   

  抗VEGF(血管内皮増殖因子)療法を理解するための基礎知識として、VEGFの生物活性、VEGF阻害薬ペガプタニブ、ラニビスマブ、ベバシズマブ、アフリベルセプトの特徴を概説した。また、加齢黄斑変性、糖尿病網膜症に対する各種VEGF阻害薬の臨床試験成績を紹介した。加齢黄斑変性、糖尿病網膜症に対する抗VEGF療法の至適プロトコールの検討が今後の重要な課題である。
• 多発消失性白点症候群における網膜厚層別解析

  橋本 勇希, 齋藤 航, 石田 晋  日本視能矯正学会プログラム抄録集  52回-  50  -50  2011/11  [Not refereed][Not invited]
  
• 加齢黄斑変性に対するreduced-fluence PDTトリプル治療後の脈絡膜循環変化

  吉沢 史子, 齊藤 航, 齊藤 理幸, 江藤 悠美子, 森 祥平, 野田 航介, 石田 晋  眼科臨床紀要  4-  (10)  996  -996  2011/10  [Not refereed][Not invited]
  
• 狭心症を合併した乳頭血管炎患者における冠動脈の病理学的検討

  加瀬 諭, 齋藤 航, 吉沢 史子, 矢野 俊之, 石田 晋  眼科臨床紀要  4-  (10)  1002  -1002  2011/10  [Not refereed][Not invited]
  
• 同一眼に時期を変えて多発消失性白点症候群と急性帯状潜在性網膜外層症が生じた1例

  橋本 勇希, 齋藤 航, 吉沢 史子, 齋藤 理幸, 石田 晋  眼科臨床紀要  4-  (10)  1009  -1010  2011/10  [Not refereed][Not invited]
  
• 【食品と疾病-イソフラボン/ケルセチン】 イソフラボン イソフラボンと眼疾患

  木下 哲志, 野田 航介, 石田 晋  Functional Food  5-  (2)  119  -122  2011/10  [Not refereed][Not invited]
   

  イソフラボンは大豆などマメ科植物に由来するフラボノイドの一つであるが、その生理活性はエストロゲン作用・抗酸化作用・血管新生抑制作用など多様であり、その分子メカニズムも徐々に解明されつつある。本稿では、イソフラボンの眼科領域における臨床応用の可能性について考察する。(著者抄録)
• これからの眼科における新しい治療薬 レニン-アンジオテンシン系をターゲットとした糖尿病網膜症の新しい治療戦略

  石田 晋  眼薬理  25-  (1)  62  -66  2011/08  [Not refereed][Not invited]
   

  近年、海外の大規模臨床試験の結果より、糖尿病網膜症に対してレニン-アンジオテンシン系(RAS)をターゲットとした治療戦略が有望視されている。筆者らは、糖尿病網膜症動物モデルにおいてRAS活性化の下流で血管内皮増殖因子など主要な病態分子が誘導されることを明らかにし、RAS抑制薬による新しい治療戦略の生物学的根拠を示した。(著者抄録)
• 【糖尿病網膜症診療の最前線】 糖尿病網膜症における薬物療法

  石田 晋  Diabetes Frontier  22-  (4)  377  -384  2011/08  [Not refereed][Not invited]
  
• 網膜芽細胞腫の診断と臨床経過の検討

  野崎 真世, 加瀬 諭, 吉田 和彦, 石嶋 漢, 野田 実香, 鈴木 茂伸, 東 範行, 石田 晋  臨床眼科  65-  (7)  1123  -1127  2011/07  [Not refereed][Not invited]
   

  目的:網膜芽細胞腫の診断と臨床経過の報告。症例:過去8年間の網膜芽細胞腫の自験例7症例を検索した。結果:男児2例,女児5例で,5例が片眼性,2例が両眼性であった。年齢は6例が4歳以下で,1例が7歳であった。主訴は白色瞳孔と斜視が5例,視力低下が1例,結膜充血と眼瞼腫脹が1例にあった。国際分類での病期はB〜Eの範囲にあり,3例がE期であった。初回治療として眼球摘出術を5眼,眼窩内容除去術を1眼に行った。眼球を温存した3眼中,2眼では後に眼球摘出を必要とし,1眼では再発がなかった。眼球摘出術または眼窩内容除去術を行った6眼では転移はなかった。眼球外に浸潤した2例は不帰の転帰をとった。この2例は,初診時に網膜芽細胞腫の典型的所見がなかった。結論:網膜芽細胞腫の初診時の臨床像は,必ずしも予後を示さない。(著者抄録)
• Coats病に対するベバシズマブ硝子体内注射を併用した網膜光凝固

  藤谷 顕雄, 齋藤 航, 石田 晋  臨床眼科  65-  (6)  869  -873  2011/06  [Not refereed][Not invited]
   

  目的:Coats病に対して網膜光凝固とベバシズマブ硝子体注射を併用した3症例の報告。症例:症例は19歳女性,20歳男性,37歳男性で,いずれも片眼性でstage 2AのCoats病である。罹患眼の矯正視力はそれぞれ1.5,0.15,1.5であった。視力不良例には黄斑浮腫があった。全例にベバシズマブ硝子体注射後,網膜異常血管に低出力の光凝固を行った。黄斑浮腫と硬性白斑は消失し,全例で1.0以上の矯正視力が得られた。治療後6〜28ヵ月後の現在まで再発はない。結論:ベバシズマブ硝子体注射と網膜光凝固の併用療法は,早期のCoats病に対し有効であった。(著者抄録)
• 急性涙腺炎を初発症状とした眼部帯状疱疹の1例

  横山 千秋, 森 祥平, 鎌田 麻子, 加瀬 諭, 石田 晋  臨床眼科  65-  (6)  945  -948  2011/06  [Not refereed][Not invited]
   

  目的:急性涙腺炎を初発症状とした眼部帯状疱疹の1例の報告。症例:82歳女性が2日前からの右眼周囲の痛みで受診した。圧痛を伴う右眼瞼の発赤と腫脹があり,皮疹はなかった。磁気共鳴画像検査(MRI)の所見から急性涙腺炎を疑い,抗生物質を点滴した。4日後に涙腺腫脹が増悪し,その2日後に右角膜上皮に点状混濁と前房炎症が生じ,抗ウイルス薬治療を開始した。さらに2日後に右前額部に痂皮を伴う皮疹とびらんが生じ,帯状疱疹と診断した。初診から15日後に涙腺炎,前房の炎症,皮疹は寛解した。結論:典型的な皮疹や眼病変がなく,抗生物質に反応しない急性涙腺炎では,稀ではあるが眼部帯状疱疹による可能性がある。(著者抄録)
• ステロイドパルス療法が奏功した多発消失性白点症候群の1例

  橋本 勇希, 齋藤 航, 吉沢 史子, 齋藤 理幸, 石田 晋  眼科臨床紀要  4-  (6)  577  -578  2011/06  [Not refereed][Not invited]
  
• 糖尿病網膜症治療の進歩 糖尿病網膜症におけるレニン-アンジオテンシン系の役割

  石田 晋  糖尿病合併症  25-  (1)  63  -67  2011/06  [Not refereed][Not invited]
  
• Effect of Intravitreal Injection of Bevacizumab for Exudative Retinal Detachment Secondary to Metastatic Choroidal Tumor : Case Report

  INAGAKI Emi, SHINODA Hajime, UCHIDA Atsuro, KAWAMURA Ryosuke, SUZUKI Kotaro, NODA Kosuke, ISHIDA Susumu, TSUBOTA Kazuo, OZAWA Yoko  Journal of the eye  28-  (4)  587  -592  2011/04/30  [Not refereed][Not invited]
   

  滲出性網膜剥離に対してベバシズマブ硝子体内投与が奏効した転移性脈絡膜腫瘍の1症例を経験したので報告する。症例は53歳、男性で、左眼の視力低下を主訴に受診した。肺腺癌(臨床病期T2N0M1、stage IV)と診断されていた。初診時矯正視力は右眼1.2、左眼0.4、左眼眼底に2乳頭径大の脈絡膜腫瘍を認め、黄斑部に滲出性網膜剥離を伴っていた。肺癌原発の転移性脈絡膜腫瘍と診断し、ベバシズマブ1.25mg硝子体内投与を計2回施行した。初回の投与で漿液性網膜剥離は減少し、死亡するまで矯正視力0.8を維持した。ベバシズマブ硝子体内投与は転移性脈絡膜腫瘍の寛解を必ずしも期待できる治療ではないものの、末期癌患者の残されたquality of lifeの改善に寄与する可能性がある。(著者抄録)
• Effects of Carteolol Hydrochloride on Experimental Choroidal Neovascularization

  ISHIDA Susumu, MOCHIMARU Hiroshi, NAGAI Norihiro, NODA Kousuke, OZAWA Yoko  Journal of Japanese Ophthalmological Society  115-  (4)  355  -361  2011/04/10  [Not refereed][Not invited]
   

  目的:カルテオロール塩酸塩の脈絡膜血管新生(choroidal neovascularization:CNV)への影響を検討したので報告する.方法:レーザー誘導CNVをC57BL/6マウスに作製し,蛍光標識レクチン染色により定量した.網膜色素上皮-脈絡膜組織におけるintercellular adhesion molecule(ICAM)-1とmonocyte chemotactic protein(MCP)-1,ならびにRAW 264.7マクロファージ培養系におけるtumor necrosis factor(TNF)-αを酵素結合免疫吸着法により測定した.結果:カルテオロール塩酸塩の投与により,CNV形成,網膜色素上皮-脈絡膜組織におけるICAM-1とMCP-1の発現,さらに培養マクロファージにおけるTNF-α発現が抑制された.結論:カルテオロール塩酸塩は抗炎症作用を介して実験的CNVを抑制した.(著者抄録)
• くすり 白金-金コロイド標識抗体を用いたアデノウイルス迅速診断検査キットの評価

  北市 伸義, 明尾 潔, 熊埜御堂 隆, 三島 宣彦, 三宅 瑞絵, 大塚 宏之, 高橋 弘毅, 溝口 晋弘, 東 真千子, 日隈 陸太郎, 安里 良盛, 青木 功喜, 石田 晋, 大野 重昭  医学のあゆみ  237-  (2)  210  -214  2011/04  [Not refereed][Not invited]
   

  ヒトアデノウイルス(HAdV)迅速診断検査キットの新しい検出方法である、白金-金コロイドを用いたキットでの臨床的評価を行った。全国10施設にてHAdV疑い患者の結膜擦過物171検体を対象とし、白金-金コロイドキットの感度および特異度を滴下後3分、10分および15分で検討した。対照として金コロイドキット(対照キット)を用い、同じ反応時間での感度および特異度を比較検討した。また、全検体についてPCR法でHAdVの同定を行った。その結果、94検体からPCR法でHAdV-DNAが検出された(55%)。15分後の判定では白金-金コロイドキット、対照キットともに86検体が陽性を示し、感度は91.5%、特異度は100%であった。白金-金コロイドキットでは3分後で84検体、10分後で86検体全例が陽性を示したのに対し、対照キットでは、3分後では83検体、10分後では85検体、15分後では86検体全例が陽性を示した。白金-金コロイドキットではバンドが黒色のため、金コロイドの赤色より目視が容易で判定しやすく判定時間が短縮したことから、眼科診療におけるHAdV結膜炎診断に有用であることが示唆された。(著者抄録)
• 眼内血管新生の病態と治療 眼内血管新生の基礎 今さら聞けないVEGFの豆知識・研究史

  石田 晋  日本眼科学会雑誌  115-  (臨増)  68  -68  2011/04  [Not refereed][Not invited]
  
• 比較ゲノム解析による新型アデノウイルス54型の進化過程の検討

  青木 功喜, 北市 伸義, 石田 晋, 石古 博昭, 金子 久俊, 渡邉 日出海, 小柳 香奈子, ゴンザレス・ガブリエル, 大野 重昭  日本眼科学会雑誌  115-  (臨増)  202  -202  2011/04  [Not refereed][Not invited]
  
• ヒト翼状片におけるTissue Factorの発現

  安藤 亮, 加瀬 諭, 大橋 勉, 董 震宇, 福原 淳一, アントン・レニコフ, 神田 敦宏, 村田 美幸, 野田 航介, 石田 晋  日本眼科学会雑誌  115-  (臨増)  203  -203  2011/04  [Not refereed][Not invited]
  
• AlphaB-crystallinによる実験的脈絡膜新生血管の制御

  加瀬 諭, 園田 祥三, 北村 瑞, Stephen Ryan, David Hinton, 石田 晋  日本眼科学会雑誌  115-  (臨増)  219  -219  2011/04  [Not refereed][Not invited]
  
• アスタキサンチン点眼による紫外線急性角膜炎の軽症化

  アントン・レニコフ, 北市 伸義, 深瀬 理沙, 村田 美幸, 野田 航介, 大野 重昭, 石田 晋  日本眼科学会雑誌  115-  (臨増)  227  -227  2011/04  [Not refereed][Not invited]
  
• 増殖糖尿病網膜症の線維血管膜におけるalphaB-crystallinの発現

  董 震宇, 加瀬 諭, 安藤 亮, 福原 淳一, アントン・レニコフ, 神田 敦宏, 村田 美幸, 野田 航介, 斎藤 航, 石田 晋  日本眼科学会雑誌  115-  (臨増)  231  -231  2011/04  [Not refereed][Not invited]
  
• 増殖糖尿病網膜症患者の硝子体液におけるVAP-1濃度

  福原 淳一, 野田 航介, 村田 美幸, 齋藤 航, 董 震宇, 安藤 亮, アントン・レニコフ, 神田 敦宏, 石田 晋  日本眼科学会雑誌  115-  (臨増)  231  -231  2011/04  [Not refereed][Not invited]
  
• SOD1ノックアウトマウスにおける網膜神経節細胞数の減少

  結城 賢弥, 小沢 洋子, 吉田 哲, 栗原 俊英, 平沢 学, 野田 航介, 石田 晋, 坪田 一男  日本眼科学会雑誌  115-  (臨増)  252  -252  2011/04  [Not refereed][Not invited]
  
• 360度トラベクロトミー変法(S-LOT変法)の白内障同時手術の成績

  新明 康弘, 新田 卓也, 仲 昌彦, 野澤 亜紀子, 陳 進輝, 石田 晋  日本眼科学会雑誌  115-  (臨増)  267  -267  2011/04  [Not refereed][Not invited]
  
• 糖尿病網膜症におけるAMPキナーゼの役割について

  久保田 俊介, 小澤 洋子, 栗原 俊英, 佐々木 真理子, 結城 賢弥, 三宅 誠司, 野田 航介, 石田 晋, 坪田 一男  日本眼科学会雑誌  115-  (臨増)  292  -292  2011/04  [Not refereed][Not invited]
  
• PDTトリプル療法とreduced-fluence PDTトリプル療法の脈絡膜循環への影響

  吉澤 史子, 齋藤 航, 齋藤 理幸, 藤谷 顕雄, 野田 航介, 石田 晋  日本眼科学会雑誌  115-  (臨増)  297  -297  2011/04  [Not refereed][Not invited]
  
• 原発開放隅角緑内障(POAG)として紹介された続発緑内障の臨床像

  新田 卓也, 新明 康弘, 仲 昌彦, 野澤 亜紀子, 南場 研一, 陳 進輝, 石田 晋  日本眼科学会雑誌  115-  (臨増)  316  -316  2011/04  [Not refereed][Not invited]
  
• 【加齢黄斑変性の診断治療の最近の進歩】 老年病・生活習慣病としての加齢黄斑変性

  石田 晋  Geriatric Medicine  49-  (4)  369  -372  2011/04  [Not refereed][Not invited]
   

  黄斑とは、外部からの光線が角膜・水晶体により屈折し集中する網膜の中心部であり、視力は同部位の機能に依存する。加齢黄斑変性(AMD:age-related macular degeneration)は、わが国で高齢化社会・食生活の欧米化に伴い失明原因として増加中の眼底疾患であり、高齢者のほぼ1%が罹患している。近年の分子遺伝学的研究や臨床疫学的研究により、AMDは単なる老年病ではなく、生活習慣病として予防医学的に介入可能な疾患概念へと変遷しつつある。(著者抄録)
• 【加齢黄斑変性の診断治療の最近の進歩】 加齢黄斑変性と酸化ストレス制御

  小沢 洋子, 石田 晋  Geriatric Medicine  49-  (4)  435  -438  2011/04  [Not refereed][Not invited]
   

  加齢黄斑変性は、欧米では失明原因の首座を占めており本邦でも高齢化社会に伴い増加しつつある重要な眼底疾患である。加齢黄斑変性では、酸化ストレスから炎症病態が惹起され、終末病態の血管新生に至る。近年、加齢黄斑変性における血管新生病態に対する新しい治療として、光線力学的療法や血管内皮増殖因子に対する分子標的療法が確立したが、より良好な視力を確保するためには、早期の介入による発症予防にも関心が集まっている。特に黄斑色素ルテインは、高い抗酸化作用をもち、生理的に黄斑に存在する物質であることからサプリメントとしての有用性が期待されている。(著者抄録)
• 眼科における抗加齢医学の実際 抗加齢眼科学とレニン-アンジオテンシン系

  石田 晋  日本抗加齢医学会総会プログラム・抄録集  11回-  94  -94  2011/04  [Not refereed][Not invited]
  
• 酸化ストレスと感覚器疾患、そして新しいアプローチ 水素分子とN-アセチルシステインによる角膜血管新生の抑制

  久保田 みゆき, 榛村 重人, 久保田 俊介, 宮下 英之, 加藤 直子, 野田 航介, 小沢 洋子, 臼井 智彦, 石田 晋, 梅澤 一夫, 栗原 俊英, 坪田 一男  日本抗加齢医学会総会プログラム・抄録集  11回-  157  -157  2011/04  [Not refereed][Not invited]
  
• 糖尿病網膜症におけるAMPキナーゼの役割

  久保田 俊介, 小沢 洋子, 栗原 俊英, 佐々木 真理子, 結城 賢弥, 三宅 誠司, 野田 航介, 石田 晋, 坪田 一男  日本抗加齢医学会総会プログラム・抄録集  11回-  264  -264  2011/04  [Not refereed][Not invited]
  
• 加齢黄斑変性の抗加齢眼科学 サプリメントの分子基盤

  石田 晋  日本抗加齢医学会総会プログラム・抄録集  11回-  377  -377  2011/04  [Not refereed][Not invited]
  
• 周辺部硝子体切除の程度により経過が異なったと考えられた両眼悪性緑内障の1例

  木下 哲志, 陳 進輝, 廣瀬 茂樹, 新明 康弘, 新田 卓也, 吉田 和彦, 石田 晋  眼科臨床紀要  4-  (2)  143  -147  2011/02  [Not refereed][Not invited]
   

  背景:周辺部の圧迫なしで前部硝子体切除を行った片眼と、最周辺部まで圧迫して前部硝子体皮質も含めた硝子体郭清を行った僚眼で、経過が異なった両眼の悪性緑内障を経験した。症例:症例は76歳の女性。左眼に閉塞隅角緑内障発作を起こし来院。当初は両眼性の原発閉塞隅角緑内障と診断し、両眼に水晶体乳化吸引術+眼内レンズ挿入術を施行したところ、術後一時眼圧は下降したが、その後、両眼の浅前房と眼圧の再上昇がみられ、両眼の悪性緑内障と診断した。そこで、硫酸アトロピン点眼およびNd:YAGレーザー後嚢切開術を施行したが効果が不十分であったため、経毛様体扁平部から前部硝子体切除を行ったところ術後眼圧は下降した。左眼に比べ、圧迫して十分に周辺部硝子体切除を行った右眼のほうがより早期に眼圧が下降した。結論:悪性緑内障に対する硝子体切除では、症例によっては毛様体付近の前部硝子体皮質を可及的に切除することが望ましいと考えられた。(著者抄録)
• 北海道におけるアカントアメーバ角膜炎18症例の検討

  山本 哲平, 大口 剛司, 西堀 宗樹, 西坂 紀実利, 有賀 理美, 田川 義継, 石田 晋  眼科臨床紀要  4-  (1)  20  -23  2011/01  [Not refereed][Not invited]
   

  目的:アカントアメーバ角膜炎の18症例を経験したので報告する。対象および方法:2007年8月〜2009年7月の2年間に北海道大学病院眼科で治療したアカントアメーバ角膜炎18例20眼を対象とした。結果:20眼すべてがソフトコンタクトレンズ(以下;SCL)装用眼であった。2週間頻回交換SCLが16例、2ヵ月装用のSCLが1例、毎日交換使い捨てSCLが1例であった。初診時視力は0.5以上が11眼、0.4以下が9眼であった。治療は角膜病巣掻爬、抗真菌薬点眼、抗真菌薬内服を行い、全例が治療により鎮静化した。最終視力は0.5以上が19眼、0.4以下が1眼であった。結論:2007年から北海道でもアカントアメーバ角膜炎が増加傾向にあると考えられた。温暖化などの環境の変化やコンタクトレンズ消毒法などが主な原因と推測されたが、より正確な原因の究明が必要である。(著者抄録)
• Pyogenic Granuloma Developing Rapidly after Excision of Corneal/Conjunctival Intraepithelial Neoplasia

  ISHIJIMA Kan, KASE Satoru, NODA Mika, ISHIDA Susumu  Journal of Japanese Ophthalmological Society  114-  (12)  1036  -1039  2010/12/10  [Not refereed][Not invited]
   

  背景:化膿性肉芽腫(毛細血管拡張性肉芽腫)は外傷や手術後に結膜に発生することが知られている.これは表面平滑な易出血性の良性腫瘤であり,物理的,化学的な刺激に対する創傷治癒機転の異常がその発生病理に関与している.今回,角結膜上皮内新生物(corneal/conjunctival intraepithelial neoplasia:CIN)の切除術後に急速に増大した化膿性肉芽腫の診断に,擦過細胞診が有用であった1例を経験したので報告する.症例:70歳男性で左下眼瞼の違和感を自覚し受診.左眼の下方球結膜から角膜へ連続する扁平の腫瘤がみられた.病変部を一塊にして切除し,切除部の強膜に冷凍凝固術を施行した.病理組織学的にCINであった.切除1ヵ月後,急速に増大した弾性軟の有茎性赤色腫瘤がみられた.擦過細胞診では,異型角化上皮細胞は採取されず,紡錘形核を有する血管内皮細胞と好中球の集塊がみられた.続発腫瘤は病理組織学的に化膿性肉芽腫と確認された.結語:CIN摘出術後に急速に増大した化膿性肉芽腫の1例を報告した.臨床検査所見の詳細な観察により,摘出術を待たずに続発腫瘤の診断が可能であった.(著者抄録)
• 炎症性眼疾患の診療 糖尿病虹彩炎

  北市 伸義, 石田 晋, 大野 重昭  臨床眼科  64-  (13)  2010  -2013  2010/12  [Not refereed][Not invited]
  
• 【加齢黄斑変性up to date】 加齢とAMD

  石田 晋, 神田 敦宏  Pharma Medica  28-  (12)  9  -12  2010/12  [Not refereed][Not invited]
  
• 【血管研究と血管治療 血管形成メカニズムの新たな概念から炎症・がん治療、虚血性疾患の血管再生療法まで】 抗血管新生療法 眼科領域における抗VEGF療法はここまで進歩した

  石田 晋  実験医学  28-  (17)  2910  -2915  2010/11  [Not refereed][Not invited]
   

  わが国の失明原因の上位を占める糖尿病網膜症と加齢黄斑変性は、病理的血管新生を合併する網膜疾患である。眼内血管新生の責任分子である血管内皮増殖因子VEGFを分子標的としてpegaptanibとranibizumabが加齢黄斑変性治療に実用化され、さらにVEGF Trap-Eyeの第III相臨床試験が進行中である。それぞれのVEGF阻害薬の創薬デザイン等の多様性が、有効性や安全性の差を生んでいると考えられる。眼内血管新生に対する抗VEGF療法のプロトコールはいまだ最適化されておらず、これらVEGF阻害薬の薬剤特性の相違点をしっかり理解したうえで、よりよい適応症例や至適な使用法、また限界などを検討していくことが今後の課題である。(著者抄録)
• 【アンチエイジングとリハビリテーション】 視覚のアンチエイジングとリハビリテーション

  北市 伸義, 石田 晋  MEDICAL REHABILITATION  (124)  51  -57  2010/11  [Not refereed][Not invited]
   

  加齢による眼の調節力低下は老視(老眼)として自覚される。白内障、緑内障、加齢黄斑変性は加齢性眼疾患の代表的なものである。糖尿病網膜症、網膜色素変性症、網脈絡膜萎縮も加齢関連疾患であり、これらはいずれも現在の日本の失明原因の上位を占める。眼は酸化ストレスと光老化によりエイジングが進むため、まず禁煙し、サプリメントをとる場合は、ルテインやアスタキサンチンがよい。普段の食生活では動物性油脂を減らし、青背魚を心がける。調理油はサラダ油やキャノーラ油、エゴマ油、ナタネ油を選び、緑黄色野菜や抗酸化ビタミンを十分摂取する。ブルーベリー、ハスカップなどのベリー類も摂取するとよい。(著者抄録)
• ステロイド治療に抵抗し、シクロフォスファミド大量静注療法が有効であったMPO-ANCA関連視神経症の一例

  田川 義晃, 新明 康弘, 新田 卓也, 七戸 夏子, 陳 進輝, 石田 晋  神経眼科  27-  (増補1)  53  -53  2010/11  [Not refereed][Not invited]
  
• 片眼性に甲状腺眼症と重症筋無力症を合併した1例

  新田 卓也, 新明 康弘, 田川 義晃, 七戸 夏子, 陳 進輝, 石田 晋  神経眼科  27-  (増補1)  69  -69  2010/11  [Not refereed][Not invited]
  
• 炎症性眼疾患の診療 多巣性脈絡膜炎

  董 震宇, 齋藤 航, 北市 伸義, 石田 晋, 大野 重昭  臨床眼科  64-  (12)  1830  -1834  2010/11  [Not refereed][Not invited]
  
• 【糖尿病性細小血管症(第2版) 発症・進展制御の最前線】 糖尿病網膜症 病態生理・機能異常 レニン-アンジオテンシン系

  石田 晋  日本臨床  68-  (増刊9 糖尿病性細小血管症)  255  -261  2010/11  [Not refereed][Not invited]
  
• 【糖尿病性細小血管症(第2版) 発症・進展制御の最前線】 糖尿病網膜症 治療 新しい治療薬 VEGF阻害薬

  石田 晋  日本臨床  68-  (増刊9 糖尿病性細小血管症)  304  -309  2010/11  [Not refereed][Not invited]
  
• これからの眼科における新しい治療薬 レニン-アンジオテンシン系をターゲットとした糖尿病網膜症の新しい治療戦略

  石田 晋  日本眼薬理学会プログラム・抄録集  30回-  27  -27  2010/10  [Not refereed][Not invited]
  
• 糖尿病網膜症治療の進歩 糖尿病網膜症におけるレニン-アンジオテンシン系の役割

  石田 晋  糖尿病合併症  24-  (Suppl.1)  53  -53  2010/10  [Not refereed][Not invited]
  
• 炎症性眼疾患の診療 仮面症候群

  岩田 大樹, 北市 伸義, 石田 晋, 大野 重昭  臨床眼科  64-  (10)  1650  -1655  2010/10  [Not refereed][Not invited]
  
• 特発性網膜上膜におけるCyclooxygenase(COX)-2の発現

  加瀬 諭, 齋藤 航, 石田 晋  眼科臨床紀要  3-  (10)  996  -996  2010/10  [Not refereed][Not invited]
  
• 加齢黄斑変性に対するreduced fluence PDT併用トリプル治療の短期成績

  江藤 悠美子, 齋藤 航, 吉沢 史子, 森 祥平, 齋藤 理幸, 田辺 章浩, 石田 晋  眼科臨床紀要  3-  (10)  1001  -1001  2010/10  [Not refereed][Not invited]
  
• Acute macular neuroretinopathyにおける脈絡膜循環障害

  齋藤 理幸, 齋藤 航, 森 祥平, 石田 晋  眼科臨床紀要  3-  (10)  1032  -1032  2010/10  [Not refereed][Not invited]
  
• 加齢黄斑変性に対するPDTトリプル治療後早期の網脈絡膜循環変化

  吉沢 史子, 齋藤 航, 齋藤 理幸, 森 祥平, 石田 晋  眼科臨床紀要  3-  (10)  1038  -1039  2010/10  [Not refereed][Not invited]
  
• エンドトキシン誘導ぶどう膜炎モデルにおけるPSGL-1の経時的機能変化

  野田 航介, Lama Almulki, 石田 晋, Hafezi-Moghadam Ali  日本眼科学会雑誌  114-  (10)  894  -894  2010/10  [Not refereed][Not invited]
  
• Molecular Pathogenesis of Diabetic Retinopathy and Maculopathy : Vascular Complications

  ISHIDA Susumu  Journal of the eye  27-  (9)  1185  -1193  2010/09/30  [Not refereed][Not invited]
  
• 炎症性眼疾患の診療 甲状腺眼症

  新明 康弘, 北市 伸義, 石田 晋, 大野 重昭  臨床眼科  64-  (9)  1456  -1462  2010/09  [Not refereed][Not invited]
  
• 【糖尿病と糖尿病網膜症】 糖尿病網膜症・黄斑症の分子病態 血管症の特性から

  石田 晋  あたらしい眼科  27-  (9)  1185  -1193  2010/09  [Not refereed][Not invited]
  
• 炎症性眼疾患の診療 眼窩蜂巣炎

  仲 昌彦, 野田 実香, 北市 伸義, 石田 晋, 大野 重昭  臨床眼科  64-  (8)  1244  -1247  2010/08  [Not refereed][Not invited]
  
• ASSOCIATION OF TLR4 POLYMORPHISMS WITH BEHCET'S DISEASE IN JAPANESE AND KOREAN POPULATIONS

  Yukihiro Horie, Akira Meguro, Nobuyoshi Kitaichi, Masao Ota, Kenichi Namba, Yeong Wook Song, Kyung Sook Park, Eun Bong Lee, Hidetoshi Inoko, Nobuhisa Mizuki, Susumu Ishida, Shigeaki Ohno  CLINICAL AND EXPERIMENTAL RHEUMATOLOGY  28-  (4)  S161  -S161  2010/07  [Not refereed][Not invited]
  
• 炎症性眼疾患の診療 アレルギー性結膜疾患

  合田 千穂, 北市 伸義, 石田 晋, 大野 重昭  臨床眼科  64-  (7)  1058  -1063  2010/07  [Not refereed][Not invited]
  
• 診断が困難な症例 網膜血管炎を合併したacute zonal occult outer retinopathyの1症例

  齋藤 航, 南場 研一, 石田 晋  眼科臨床紀要  3-  (7)  693  -693  2010/07  [Not refereed][Not invited]
  
• 炎症性眼疾患の診療 強膜炎

  北市 伸義, 石田 晋, 大野 重昭  臨床眼科  64-  (6)  836  -840  2010/06  [Not refereed][Not invited]
  
• 【アレルギー疾患の治癒を考える】 アレルギー性結膜疾患は治癒するか

  北市 伸義, 石田 晋, 大野 重昭  Topics in Atopy  9-  (2)  32  -36  2010/06  [Not refereed][Not invited]
  
• Postoperative visual field defects after 25-gauge transconjunctival vitrectomy for macular hole surgery

  HOSODA Shingo, KAWAMURA Ryosuke, SUZUKI Kotaro, SHINODA Hajime, IMAMURA Yutaka, OZAWA Yoko, ISHIDA Susumu, INOUE Makoto  Folia japonica de ophthalmologica clinica  3-  (5)  439  -441  2010/05/15  [Not refereed][Not invited]
   

  目的:25ゲージ(25G)経結膜硝子体手術は眼内灌流量が少なく、術中の眼内空気灌流による視野障害を減少させる可能性がある。そこで特発性黄斑円孔に対する硝子体手術後の視野欠損発生率を25G硝子体手術(25G群)と20G硝子体手術(20G群)とで比較検討した。対象および方法:1998年7月〜2007年3月までに、特発性黄斑円孔に対し、硝子体手術を施行した連続症例62例67眼を対象とした。その内20G群は22例25眼、25G群は40例42眼であった。術式は全例でインドシアニングリーンを用いずに内境界膜を剥離し、空気または10〜20%SF6ガスによるタンポナーデを行った。視野はGoldmann視野計を用い、術前と術後3ヵ月目以降に施行した。なお緑内障合併症例は対象から除外した。結果:円孔は全例で閉鎖した。術前に視野障害はなかったが、術後には20G群では25眼中4眼(16%)に、25G群では42眼中0眼(0%)に視野欠損がみられ、両群間で有意差を認めた(P=0.017、Fisher直接法)。結論:25G硝子体手術により特発性黄斑円孔術後の視野欠損を予防できる可能性が考えられた。(著者抄録)
• Rhegmatogenous retinal detachment in eyes undergoing laser in situ keratomileusis at Keio University Hospital

  YAGUCHI Saori, UCHIDA Atsuro, KAWAMURA Ryosuke, SUZUKI Kotaro, SHINODA Hajime, NODA Kousuke, IMAMURA Yutaka, OZAWA Yoko, NEGISHI Kazuno, ISHIDA Susumu  Folia japonica de ophthalmologica clinica  3-  (5)  472  -476  2010/05/15  [Not refereed][Not invited]
   

  目的:Laser in situ keratomileusis(LASIK)術後に生じた裂孔原性網膜剥離の特徴と治療成績についての報告。対象および方法:1999年12月〜2008年7月までに慶應義塾大学病院眼科を受診したLASIK術後の裂孔原性網膜剥離症例8例8眼の治療経過を検討した。結果:全例が男性であった。LASIK術前後の等価球面度数は、術前平均-7.91D、術後平均-0.34Dであった。網膜剥離に対して部分強膜バックリング術3例、硝子体手術3例、強膜バックリング術と硝子体手術の併施2例を行い、全例で水晶体を温存した。術後最終(平均7.1ヵ月)での等価球面度数は、部分強膜バックリング術施行例では平均-0.17D、硝子体手術施行例では平均-1.63D、強膜バックリング術と硝子体手術の併施例では平均-5.94Dの近視化を認めた。結論:強膜バックリング術よりも硝子体手術に近視化が多く認められる傾向があった。LASIK後の網膜剥離に対して水晶体温存硝子体手術を施行する場合には、術後近視化についての十分な説明を術前に行うことが重要である。(著者抄録)
• 急性網膜色素上皮炎様所見を合併した急性後部多発性斑状色素上皮症の1例

  木嶋 理紀, 齋藤 航, 藤谷 顕雄, 石田 晋  臨床眼科  64-  (5)  707  -711  2010/05  [Not refereed][Not invited]
   

  目的:急性網膜色素上皮炎に似た所見を呈した急性後部多発性斑状色素上皮症(APMPPE)の症例の報告。症例:16歳男性が1週間前からの左眼視力低下で受診した。所見:矯正視力は右1.5,左0.6で,両眼に淡い滲出斑が網膜下に散在していた。蛍光眼底造影所見からAPMPPEと診断した。多数の暗灰色点が左眼黄斑部の深層にあり,黄白色輪に囲まれていた。左眼黄斑部は地図状の低蛍光を呈し,光干渉断層計で視細胞内外節の欠損と脈絡膜の高輝度の陰影があった。この所見は急性網膜色素上皮炎に相当すると解釈した。無治療で2ヵ月後に滲出斑は消失し,蛍光眼底造影と光干渉断層計所見は改善し,左眼視力は1.2になった。結論:APMPPEに急性網膜色素上皮炎に似た病変が併発する可能性がある。(著者抄録)
• 未熟児網膜症に対する抗VEGF治療を検証する 未熟児網膜症に対する抗VEGF療法 基礎研究からの検証

  石田 晋  眼科臨床紀要  3-  (4)  402  -402  2010/04  [Not refereed][Not invited]
  
• 脈絡膜新生血管を合併した急性網膜色素上皮炎の1例

  田島 佳奈, 齋藤 航, 石田 晋  臨床眼科  64-  (4)  553  -558  2010/04  [Not refereed][Not invited]
   

  目的:眼底に白点と脈絡膜新生血管が併発した再発性急性網膜色素上皮炎の症例の報告。症例:18歳女性が2週間前からの右眼視力低下と光視症で受診した。所見:矯正視力は右0.6,左1.2で,両眼の黄斑部に多数の暗灰色病巣と,これを黄白色の輪が囲んでいた。2週間後に視力は回復した。4年後に右眼視力が0.4に低下した。黄斑病変は初診時と同様であったが,中間周辺部に白斑が多発していた。急性網膜色素上皮炎と診断した。2ヵ月後に白斑は消失し視力は0.6に回復した。4ヵ月後に右眼視力が0.09になり,黄斑の下耳側に脈絡膜新生血管を伴う漿液性網膜剥離があった。ベバシズマブの硝子体注入を3回行い,再発から10ヵ月後に視力は0.4に改善した。結論:急性網膜色素上皮炎の予後は概して良好であるが,脈絡膜新生血管の併発に注意する必要がある。(著者抄録)
• 加齢黄斑変性の病態解明 受容体随伴プロレニン系と脈絡膜血管新生

  石田 晋  日本眼科学会雑誌  114-  (臨増)  72  -72  2010/03  [Not refereed][Not invited]
  
• 網膜硝子体疾患の新しい診断と治療 抗VEGF薬の薬剤特性から考えた使い分け

  石田 晋  日本眼科学会雑誌  114-  (臨増)  159  -159  2010/03  [Not refereed][Not invited]
  
• 閉塞性網膜血管炎を合併する乳頭血管炎

  吉澤 史子, 齋藤 航, 石田 晋  日本眼科学会雑誌  114-  (臨増)  230  -230  2010/03  [Not refereed][Not invited]
  
• ω-3不飽和脂肪酸によるマウス網膜炎症モデルにおける炎症抑制効果

  鈴木 美砂, 野田 航介, 久保田 俊介, 平沢 学, 小沢 洋子, 坪田 一男, 水木 信久, 石田 晋  日本眼科学会雑誌  114-  (臨増)  234  -234  2010/03  [Not refereed][Not invited]
  
• 実験的自己免疫性ぶどう膜網膜炎に対する抗VEGF抗体硝子体内投与の有効性

  北市 伸義, 大神 一浩, 石田 晋, 大野 重昭  日本眼科学会雑誌  114-  (臨増)  235  -235  2010/03  [Not refereed][Not invited]
  
• 流行性角結膜炎を起こす新しいヒトアデノウイルス53、54型の起源と進化過程の解明

  青木 功喜, 金 学海, 北市 伸義, 大野 重昭, 金子 久俊, 石田 晋  日本眼科学会雑誌  114-  (臨増)  244  -244  2010/03  [Not refereed][Not invited]
  
• 熱ショックタンパク質70発現量増加によるマウス紫外線角膜炎の回復(Amelioration of UV-photokeratitis in mice by heat shock protein 70 upregulation)

  アントン・レニコフ, 北市 伸義, 加瀬 諭, 石田 晋, 大野 重昭  日本眼科学会雑誌  114-  (臨増)  246  -246  2010/03  [Not refereed][Not invited]
  
• 中心窩下に小白点が多発する症候群8例の臨床像

  齋藤 理幸, 齋藤 航, 吉澤 史子, 野田 航介, 石田 晋  日本眼科学会雑誌  114-  (臨増)  252  -252  2010/03  [Not refereed][Not invited]
  
• ストレプトゾトシン誘発糖尿病ラット網膜におけるVAP-1阻害剤の白血球遊走抑制

  野田 航介, 中尾 新太郎, 吉川 奈美, 石田 晋, 真島 行彦, Hafezi-Moghadam Ali  日本眼科学会雑誌  114-  (臨増)  254  -254  2010/03  [Not refereed][Not invited]
  
• レスベラトロールの網膜光障害に対する保護効果

  久保田 俊介, 栗原 俊英, 小沢 洋子, 石田 晋, 坪田 一男  日本眼科学会雑誌  114-  (臨増)  255  -255  2010/03  [Not refereed][Not invited]
  
• くも膜下腔に浸潤したびまん性浸潤型網膜芽細胞腫の一例

  吉田 和彦, 加瀬 諭, 野崎 真世, 石田 晋  日本眼科学会雑誌  114-  (臨増)  258  -258  2010/03  [Not refereed][Not invited]
  
• 開放隅角緑内障に対する360度トラベクロトミー変法(S-LOT変法)の手術成績

  新明 康弘, 陳 進輝, 新田 卓也, 吉田 和彦, 七戸 夏子, 奥谷 梨絵子, 青柳 麻衣子, 石田 晋  日本眼科学会雑誌  114-  (臨増)  271  -271  2010/03  [Not refereed][Not invited]
  
• 正常若年サルに一過性に出現した振子眼振類似の眼球運動と小脳片葉領域ニューロン活動

  七戸 夏子, 赤尾 鉄平, クルキン・セルゲイ, 新田 卓也, 新明 康弘, 陳 進輝, 加瀬 学, 福島 菊郎, 石田 晋  日本眼科学会雑誌  114-  (臨増)  289  -289  2010/03  [Not refereed][Not invited]
  
• アレルギー性結膜炎患者の治療前後における涙液中IgEの経時的検討

  赤沼 正堂, 石嶋 漢, 北市 伸義, 南場 研一, 大野 重昭, 石田 晋  日本眼科学会雑誌  114-  (臨増)  297  -297  2010/03  [Not refereed][Not invited]
  
• ヒト脈絡膜新生血管組織における上皮間葉移行(EMT)関連転写因子の局在

  平沢 学, 野田 航介, 小沢 洋子, 小川 葉子, 鈴木 美砂, 坪田 一男, 石田 晋  日本眼科学会雑誌  114-  (臨増)  310  -310  2010/03  [Not refereed][Not invited]
  
• 脈絡膜血管異常を伴ったacute zonal occult outer retinopathy様網膜障害の1例

  齋藤 航, 吉澤 史子, 齋藤 理幸, 森 祥平, 野田 航介, 石田 晋  日本眼科学会雑誌  114-  (臨増)  320  -320  2010/03  [Not refereed][Not invited]
  
• 眼瞼脂腺癌におけるalpha-crystallinの発現

  加瀬 諭, 吉田 和彦, 野田 実香, Rao Narsing, 石田 晋  日本眼科学会雑誌  114-  (臨増)  336  -336  2010/03  [Not refereed][Not invited]
  
• 【糖尿病と網膜症】 糖尿病網膜症の分子病態 サイトカインを中心に

  石田 晋  月刊糖尿病  2-  (3)  33  -42  2010/02  [Not refereed][Not invited]
  
• わかりやすい臨床講座 加齢黄斑変性とVEGF阻害剤

  野田 航介, 石田 晋  日本の眼科  81-  (2)  156  -159  2010/02  [Not refereed][Not invited]
   

  近年、滲出型加齢黄斑変性に対する治療はVEGF阻害剤によって大きく変化した。しかし、同剤は臨床応用されてからまだ数年しか経過しておらず、その最適な治療プロトコールはいまだ模索段階にある。本稿では、日本国内で眼科領域における使用が認可されているVEGF阻害剤、pegaptanibとranibizumabについてその創薬デザインや特徴、多施設臨床試験のサマリー、副反応などを概説する。(著者抄録)
• Optimal Nutrition for Eye Health

  TSUBOTA Kazuo, ISHIDA Susumu  あたらしい眼科 = Journal of the eye  27-  (1)  1  -2  2010/01/30  [Not refereed][Not invited]
  
• Salmon, Salmon Roe, Shrimp and Crab : Astaxanthin

  KITAICHI Nobuyoshi, OHNO Shigeaki, ISHIDA Susumu  Journal of the eye  27-  (1)  43  -46  2010/01/30  [Not refereed][Not invited]
  
• 【糖尿病診療の新時代 2010年代の展望】 わかってきた合併症の病態とこれからの治療 網膜症治療のこれまでとこれから

  石田 晋  内科  105-  (1)  70  -74  2010/01  [Not refereed][Not invited]
   

  糖尿病網膜症の眼科的治療として、レーザー網膜光凝固術や硝子体手術が以前より適用されてきた。これらの治療法は有効であるが、網膜症の進行を持って行うため、視機能予後は限定的である。最近、網膜症の分子細胞メカニズムとして血管内皮増殖因子(VEGF)や炎症細胞の関与が明らかにされ、抗VEGF療法や抗炎症ステロイド薬が網膜症診療において、未認可ながらも汎用されるようになった。さらに早期から積極的に行える安全かつ有効な治療戦略として、レニン-アンジオテンシン系(RAS)への介入が有望視されている。網膜症において、RAS活性化によりVEGFなどさまざまな炎症関連分子が誘導されることが、明らかにされている。(著者抄録)
• 【眼に良い食べ物】 「海の幸」編 サケ、イクラ、エビ、カニ(アスタキサンチン)

  北市 伸義, 大野 重昭, 石田 晋  あたらしい眼科  27-  (1)  43  -46  2010/01  [Not refereed][Not invited]
  
• 眼科医の手引 抗VEGF薬の動向

  石田 晋  日本の眼科  81-  (1)  29  -30  2010/01  [Not refereed][Not invited]
  
• 【糖尿病とRASの関連を探る】 糖尿病網膜症とRASの関連を探る 臨床試験結果をふまえて

  石田 晋  Angiotensin Research  7-  (1)  41  -47  2010/01  [Not refereed][Not invited]
   

  最近、糖尿病網膜症の分子細胞メカニズムとして血管内皮増殖因子(VEGF)や炎症細胞の関与が明らかにされ、従来のレーザー網膜光凝固術や硝子体手術に加えて、抗VEGF療法や抗炎症ステロイド薬が網膜症診療において未認可ながらも汎用されるようになった。さらに早期から積極的におこなえる安全かつ有効な治療戦略として、生活習慣病における臓器障害の鍵因子レニン・アンジオテンシン系(RAS)への介入が考えられる。実際、網膜症動物モデルにおいてRAS活性化の下流でVEGFなどさまざまな炎症関連分子が誘導されることが明らかにされ、さらに大規模臨床試験の結果から、RAS抑制薬の網膜症への適応拡大は有望視されている。(著者抄録)
• 【気になる目の病気のすべて】 失明につながる目の病気とその治療 加齢黄斑変性

  齋藤 航, 石田 晋  からだの科学  (263)  69  -73  2009/11  [Not refereed][Not invited]
  
• 【気になる目の病気のすべて】 フードファクターと目 アスタキサンチン

  北市 伸義, 石田 晋, 大野 重昭  からだの科学  (263)  131,np6  -134,np6  2009/11  [Not refereed][Not invited]
  
• 裂孔原性網膜剥離に対する20G硝子体手術と23、25G小切開硝子体手術の術後成績

  伴 紀充, 川村 亮介, 内田 敦郎, 鈴木 浩太郎, 篠田 肇, 野田 航介, 小沢 洋子, 石田 晋  眼科臨床紀要  2-  (11)  1057  -1057  2009/11  [Not refereed][Not invited]
  
• 硝子体手術後に生じた黄斑円孔にトリアムシノロンを投与した網膜中心静脈閉塞症の一例

  山中 美穂, 野田 航介, 内田 敦郎, 川村 亮介, 篠田 肇, 小沢 洋子, 坪田 一男, 石田 晋  眼科臨床紀要  2-  (11)  1076  -1076  2009/11  [Not refereed][Not invited]
  
• トリアムシノロンテノン嚢下注入を行なったmacular microholeの一例

  森山 あづさ, 野田 航介, 内田 敦郎, 川村 亮介, 篠田 肇, 小沢 洋子, 坪田 一男, 石田 晋  眼科臨床紀要  2-  (11)  1076  -1077  2009/11  [Not refereed][Not invited]
  
• 免疫抑制剤(シクロスポリン・タクロリムス)の眼科治療 今と昔 免疫抑制剤(カルシニューリン阻害薬)の歴史・作用機序・副作用

  南場 研一, 石田 晋, 大野 重昭  日本の眼科  80-  (9)  1143  -1147  2009/09  [Not refereed][Not invited]
   

  カルシニューリン阻害薬として使用されているものにはシクロスポリン、タクロリムスがあり、臓器移植後の拒絶反応の抑制、ベーチェット病を含む膠原病、アトピー性皮膚炎に対し内服薬として使用され、最近では外用薬(軟膏)、点眼薬として局所でも使われるようになってきた。T細胞が活性化する際に細胞内で活躍するカルシニューリンを阻害することでT細胞の活性化を抑制する薬剤である。それぞれに特有の副作用がある薬剤であり、薬剤血中濃度のモニタリングや定期的な血液検査を行いながら使用する必要がある。(著者抄録)
• レスベラトロールの可能性

  久保田 俊介, 石田 晋  Functional Food  3-  (2)  155  -160  2009/09  [Not refereed][Not invited]
   

  レスベラトロールはポリフェノールの一種で、ぶどうの皮や赤ワイン、ピーナッツの皮などに多く含まれる物質である。ポリフェノールには抗酸化作用があることがよく知られている。レスベラトロールには抗酸化作用以外にも血管拡張作用、抗血管新生作用、神経保護作用、抗癌作用、抗加齢作用など、多くの生理活性があることが報告されている。しかし、これまでに眼科学の領域で生体内における効果の報告は少ない。そこで我々は、レスベラトロールをぶどう膜炎モデル動物に投与することで、その抗炎症効果を示し報告した。レスベラトロールは天然のポリフェノールであり安全性は高いと考えられ、将来的には抗炎症治療の一翼を担える物質と考えられる。(著者抄録)
• 糖尿病血管合併症と炎症 糖尿病網膜症の炎症病態におけるレニン-アンジオテンシン系の役割

  石田 晋  糖尿病合併症  23-  (Suppl.1)  50  -50  2009/09  [Not refereed][Not invited]
  
• テーラーメイド薬物療法の実際と可能性

  内田 英二, 柏木 賢治, 竹内 大, 石田 晋, 東出 朋巳, 越前 宏俊, 植田 俊彦  眼薬理 = Japanese journal of ocular pharmacology  23-  (1)  18  -40  2009/08/31  [Not refereed][Not invited]
  
• レスベラトロール

  久保田 俊介, 石田 晋  あたらしい眼科 = Journal of the eye  26-  (8)  1081  -1084  2009/08/30  [Not refereed][Not invited]
  
• サプリメントサイエンスセミナー レスベラトロール

  久保田 俊介, 石田 晋  あたらしい眼科  26-  (8)  1081  -1084  2009/08  [Not refereed][Not invited]
  
• テーラーメイド薬物療法の実際と可能性 糖尿病網膜症における薬物療法の現状と今後の展望

  石田 晋  眼薬理  23-  (1)  26  -32  2009/08  [Not refereed][Not invited]
  
• Bevacizumab(商標名アバスチン)の硝子体注射が血管新生緑内障に有効であった一例

  伊藤 由美子, 川村 亮介, 鈴木 浩太郎, 篠田 肇, 今村 裕, 小沢 洋子, 石田 晋  眼科臨床紀要  2-  (7)  646  -646  2009/07  [Not refereed][Not invited]
  
• ルテインによるマウス網膜炎症モデルにおける網膜神経保護効果の解析

  佐々木 真理子, 小沢 洋子, 石田 晋, 坪田 一男  日本老年医学会雑誌  46-  (Suppl.)  113  -113  2009/05  [Not refereed][Not invited]
  
• 抗加齢物質レスベラトロールによる糖尿病網膜症の病態改善

  久保田 俊介, 石田 晋, 坪田 一男  日本老年医学会雑誌  46-  (Suppl.)  113  -113  2009/05  [Not refereed][Not invited]
  
• Effect of intravitreal bevacizumab for a neovascular glaucoma

  ITO Yumiko, KAWAMURA Ryosuke, SUZUKI Kotaro, SHINODA Hajime, NODA Kosuke, OZAWA Yoko, ISHIDA Susumu  Folia japonica de ophthalmologica clinica  2-  (4)  303  -305  2009/04/15  [Not refereed][Not invited]
   

  背景:抗VEGF薬であるbevacizumab(アバスチン)が糖尿病網膜症に続発した血管新生緑内障に対して、有効であった1症例を経験したので報告する。症例:71歳男性。糖尿病網膜症で経過観察中に右眼の視力低下を自覚した。再診時の視力は0.5で、眼圧は44mmHg、虹彩と隅角に新生血管を認めた。眼底は点状出血と硬性白斑を認めるのみで造影上、新生血管は認めなかった。右眼に対し、bevacizumab 1.25mgを硝子体内に投与した。投与後3日目には眼圧は正常化し隅角、虹彩の新生血管も著明な退縮を認めた。投与後3日目より汎網膜光凝固術を通常の間隔で合計1,247発施行した。投与後6ヵ月の時点で右眼視力0.8と改善し新生血管の再発は認めず、眼圧も10mmHg台後半と落ち着いた。結論:bevacizumab硝子体投与は早期の血管新生緑内障に対し光凝固術が奏功するまでの有効な治療手段と考えられた。(著者抄録)
• 糖尿病網膜症とReceptor-associated protenin system(RAPS)

  里深 信吾, 市原 淳弘, 伊藤 裕, 石田 晋  日本内分泌学会雑誌  85-  (1)  336  -336  2009/04  [Not refereed][Not invited]
  
• 加齢黄斑変性の分子病態

  石田 晋  日本抗加齢医学会総会プログラム・抄録集  9回-  159  -159  2009/04  [Not refereed][Not invited]
  
• 抗加齢物質レスベラトロールによる糖尿病網膜症の病態改善

  久保田 俊介, 石田 晋, 坪田 一男  日本抗加齢医学会総会プログラム・抄録集  9回-  204  -204  2009/04  [Not refereed][Not invited]
  
• 抗血管新生治療の新戦略 血管細胞生物学からのアプローチ 脈絡膜血管新生における炎症機序と病態抑制

  石田 晋  日本眼科学会雑誌  113-  (臨増)  73  -73  2009/03  [Not refereed][Not invited]
  
• テーラーメイド薬物療法の実際と可能性 糖尿病網膜症における薬物療法の現状と今後の展望

  石田 晋  日本眼科学会雑誌  113-  (臨増)  97  -97  2009/03  [Not refereed][Not invited]
  
• ヒアルロン酸およびヒアルロン酸受容体CD44の脈絡膜新生血管における関与

  持丸 博史, 高橋 枝里, 厚東 隆志, 野田 航介, 小沢 洋子, 谷原 秀信, 佐谷 秀行, 石田 晋, 坪田 一男  日本眼科学会雑誌  113-  (臨増)  200  -200  2009/03  [Not refereed][Not invited]
  
• ルテインによるマウス網膜炎症モデルにおける網膜神経保護効果の解析

  小沢 洋子, 佐々木 真理子, 栗原 俊英, 野田 航介, 石田 晋, 坪田 一男  日本眼科学会雑誌  113-  (臨増)  211  -211  2009/03  [Not refereed][Not invited]
  
• 抗酸化物質レスベラトロールの糖尿病網膜症への影響

  久保田 俊介, 栗原 俊英, 野田 航介, 小沢 洋子, 石田 晋, 坪田 一男  日本眼科学会雑誌  113-  (臨増)  257  -257  2009/03  [Not refereed][Not invited]
  
• SOD1による角膜血管新生の制御

  久保田 みゆき, 栗原 俊英, 久保田 俊介, 石田 晋, 坪田 一男, 榛村 重人  日本眼科学会雑誌  113-  (臨増)  263  -263  2009/03  [Not refereed][Not invited]
  
• 【糖尿病網膜症の成因と治療 最近の知見】 糖尿病網膜症の血管・神経病態におけるレニン-アンジオテンシン系の役割

  石田 晋  内分泌・糖尿病科  28-  (3)  211  -218  2009/03  [Not refereed][Not invited]
  
• Nuclear factor-kappa B inhibitor, dehydroxy methyl epoxyquinomicin ameliorates experimental autoimmune uveoretinitis (EAU) in mice

  Iwata, D, Kitaichi, N, Ebihara, A, Iwabuchi, K, Yoshida, K, Namba, K, Ozaki, M, Ohno, S, Umezawa, K, Yamashita, K, Todo, S, Ishida, S, Onoé, K  IOVS  in press-  2009  [Not refereed][Not invited]
  
• Molecular Mechanisms of Age-Related Macular Degeneration

  NAGAI Norihiro, ISHIDA Susumu  Journal of the eye  25-  (9)  1197  -1203  2008/09/30
• 樹状細胞ワクチンによるアルカリ外傷角膜血管新生抑制のメカニズム

  臼井 智彦, 持丸 博史, 臼井 嘉彦, 山上 聡, 天野 史郎, 坪田 一男, 河上 裕, 石田 晋  日本眼科学会雑誌  112-  (臨増)  288  -288  2008/03  [Not refereed][Not invited]
  
• 加齢黄斑変性症の環境要因に関する時間断面疫学研究

  道川 武紘, 西脇 祐司, 菊池 有利子, 石上 愛, 細田 加那江, 岩澤 聡子, 中野 真規子, 石田 晋, 武林 亨  日本衞生學雜誌  63-  (2)  2008/03/01  [Not refereed][Not invited]
  
• Metabolic Syndrome and Eye Diseases : Involvement of the Renin-Angiotensin System

  SATOFUKA Shingo, ISHIDA Susumu  Journal of the eye  25-  (1)  15  -21  2008/01/30
• 黄斑浮腫に続発した黄斑円孔に対して硝子体手術を施行した2例

  富田洋平, 野田航介, 内田敦郎, 川村亮介, 鈴木浩太郎, 篠田肇, 小沢洋子, 坪田一男, 石田晋  眼科手術  22-  2008
• Residual crystals of triamcinolone acetonide in macular hole may prevent complete closure

  Takashi Koto, Makoto Inoue, Kei Shinoda, Susumu Ishida, Kazuo Tsubota  ACTA OPHTHALMOLOGICA SCANDINAVICA  85-  (8)  913  -914  2007/12  [Not refereed][Not invited]
  
• Medical treatment for ocular neovascularization

  石田 晋  眼科  49-  (11)  1707  -1714  2007/10  [Not refereed][Not invited]
  
• 患者QOLにおけるアンチエイジング--より良い視機能を確保する新しい戦略とは? (特集 アンチエイジングに迫る)

  石田 晋, 根岸 一乃, 坪田 一男  Life style medicine  1-  (2)  108  -116  2007/04
• 角膜血管新生におけるアンジオテンシンII

  臼井 智彦, 杉崎 顕史, 横尾 誠一, 山上 聡, 天野 史郎, 永井 紀博, 石田 晋  日本眼科学会雑誌  111-  (臨増)  217  -217  2007/03  [Not refereed][Not invited]
  
• 目でみるバイオサイエンス 糖尿病網膜症の発症機構

  石田 晋  内科  99-  (3)  551  -555  2007/03  [Not refereed][Not invited]
  
• 網膜症 (眼科専門医に必要な「全身疾患と眼」のすべて) -- (糖尿病)

  石田 晋  臨床眼科  61-  (11)  128  -135  2007  [Not refereed][Not invited]
  
• 血清抗酸化物質レベルと眼底の高血圧・動脈硬化性変化に関する時間断面研究

  坪井 樹, 西脇 祐司, 石田 晋, 細田 加那江, 菊池 有利子, 岩澤 聡子, 島田 直樹, 岡本 ミチ子, 上村 隆元, 武林 亨  日本公衆衛生学会総会抄録集  65回-  596  -596  2006/10  [Not refereed][Not invited]
  
• Molecular Targeting Therapy (Angiotensin II Type 1 Receptor and VEGF)

  ISHIDA Susumu, NAGAI Norihiro  眼薬理 = Japanese journal of ocular pharmacology  20-  (1)  66  -70  2006/09/08
• 糖尿病網膜症--手術に踏み切るタイミング (手術のタイミングとポイント) -- (網膜・硝子体)

  石田 晋  臨床眼科  60-  (11)  126  -130  2006  [Not refereed][Not invited]
  
• Vitrectomy for Cystoid Macular Edema Following Latanoprost Use

  FUSEYA Miki, IMAMURA Yutaka, OHTAKE Yuichirou, TANINO Tomihiko, NAGAI Norihiro, NODA Kousuke, ISHIDA Susumu, INOUE Makoto  眼科手術 = Journal of ophthalmic surgery  18-  (2)  249  -254  2005/04/30  [Not refereed][Not invited]
  
• A Case of Proliferative Vitreoretinopathy With a Large Retinal Fold Beneath an Intravitreally Dislocated IOL Within Lens Capsule

  SHIGEYASU Chika, IMAMURA Yutaka, NAGAI Norihiro, NODA Kousuke, ISHIDA Susumu, INOUE Makoto  眼科手術 = Journal of ophthalmic surgery  18-  (2)  275  -278  2005/04/30  [Not refereed][Not invited]
  
• 加齢黄斑変性治療の新しい可能性--光線力学療法と抗血管新生療法 (特集 先生!ご存知ですか? 知って得する各科の"ノウハウ"--日常診療で役立つ,各専門領域のコツや定石を集めました!) -- (眼科)

  石田 晋  治療  87-  (0)  1372  -1374  2005/03  [Not refereed][Not invited]
  
• Triamcinolone-assisted Pars Plana Vitrectomy for Retinal Detachment of Cicatricial Retinopathy of Prematurity

  NAGAI Norihiro, IMAMURA Yutaka, NODA Kousuke, ISHIDA Susumu, INOUE Makoto, OGUCHI Yoshihisa  眼科手術 = Journal of ophthalmic surgery  18-  (1)  97  -100  2005/01/30  [Not refereed][Not invited]
  
• 話題の新薬, 抗VEGFアプタマー

  石田 晋  あたらしい眼科 = Journal of the eye  21-  (11)  1501  -1503  2004/11/30  [Not refereed][Not invited]
  
• New Angiostatic Drugs Combined with Photodynamic Therapy

  ISHIDA Susumu  あたらしい眼科 = Journal of the eye  21-  (10)  1341  -1343  2004/10/30  [Not refereed][Not invited]
  
• Diagnostic Value of Interleukin-10 and Interleukin-6 in the Vitreous of Intraocular Malignant Lymphoma Patients

  HIRAKATA Akito, INAMI Tatsuya, SAITO Maki, OKADA Annabelle A, HIDA Tetsuo, ISHIDA Susumu, SHINODA Kei, HOMORI Masashi, KAWANO Koichi, SUZUKI Saburosuke  日本眼科學会雜誌 = Journal of Japanese Ophthalmological Society  108-  (6)  359  -367  2004/06/10  [Not refereed][Not invited]
  
• Significance of Leukocytes in the Regulation of Retinal Edema, Ischemia, and Angiogenesis

  ISHIDA Susumu, YAMASHIRO Kenji, USUI Tomohiko, AMANO Shiro, OGURA Yuichiro, HIDA Tetsuo, OGUCHI Yoshihisa  日本眼科學会雜誌 = Journal of Japanese Ophthalmological Society  108-  (4)  193  -201  2004/04/10  [Not refereed][Not invited]
  
• Outcome of Silicone Oil Removal from Eyes with Complicated Retinal Detachment

  NOGUCHI Mizuka, ESHITA Tadahiko, HANAZONO Gen, KITAMURA Shizuaki, INOUE Makoto, SHINODA Kei, ISHIDA Susumu, OGUCHI Yoshihisa, KATSURA Hiroshi  Journal of the eye  21-  (1)  129  -132  2004/01/30  [Not refereed][Not invited]
  
• FasL, leukocytes and vascular modeling [2] (multiple letters)

  Thomas A. Ferguson, Patrick M. Stuart, Susumu Ishida, Kenji Yamashiro, Tomohiko Usui, Anthony P. Adamis  Nature Medicine  10-  (1)  12  -13  2004/01  [Not refereed][Not invited]
  
• 私の経験 原発性抗リン脂質抗体症候群に伴う網膜血管病変を呈した3例

  海野 貴光, 篠田 啓, 石田 晋  眼科  45-  (10)  1463  -1468  2003/10  [Not refereed][Not invited]
  
• The Correlation between Retinal Circulation and Function in Branch Retinal Artery Occlusion

  ISHIKAWA Karin, KIMURA Itaru, SHINODA Kei, OHDE Hisao, KITAMURA Shizuaki, INOUE Makoto, ISHIDA Susumu, MASHIMA Yukihiko, OGUCHI Yoshihisa  日本眼科學会雜誌  106-  (4)  215  -220  2002/04/10  [Not refereed][Not invited]
  
• Two Cases of Retinal Detachment following Laser In Situ Keratomileusis Repaired by Scleral Buckling Surgery

  ONGUCHI Tatsuya, ESHITA Tadahiko, MITA Shinji, ISHIDA Susumu, SHINODA Kei, KITAMURA Shizuaki, KAWASHIMA Shinichi, INOUE Makoto, OGUCHI Yoshihisa, TODA Ikuko, KATO Naoko  日本眼科學会雜誌  106-  (2)  103  -108  2002/02/10  [Not refereed][Not invited]
  
• A Case of Macular Burn Due to Accidental Use of an Industrial YAG Laser,Evaluated by Scanning Laser Ophthalmoscopic Microperimetry

  ISHIKAWA Karin, KAWSHIMA Shinichi, INOUE Makoto, SHINODA Kei, ISHIDA Susumu, KITAMURA Shizuaki, ESHITA Tadahiko, MASHIMA Yukihiko  日本眼科紀要 = Folia ophthalmologica Japonica  53-  (1)  52  -55  2002/01/28  [Not refereed][Not invited]
  
• Evaluation of the Inner Retina by Electroretinography in 11 Cases of Juvenile Retinoschisis

  SHINODA Kei, OHDE Hisao, INOUE Rikako, ISHIDA Susumu, KIMURA Itaru, KITAMURA Shizuaki, ESHITA Tadahiko, INOUE Makoto, KITA Kazunori, MASHIMA Yukihiko, OGUCHI Yoshihisa  日本眼科紀要 = Folia ophthalmologica Japonica  52-  (9)  777  -781  2001/09/28  [Not refereed][Not invited]
  
• Multifocal Electroretinography After Scleral Buckling for Rhegmatogenous Retinal Detachment

  MATSUZAKI Tadayuki, SHINODA Kei, INOUE Makoto, ISHIDA Susumu, KAWASHIMA Shinichi, TSUNODA Kazushige, BETSUIN Yasuki, INOUE Rikako, OHDE Hisao, KATSURA Hiroshi  眼科手術 = Journal of ophthalmic surgery  14-  (3)  391  -394  2001/07/30  [Not refereed][Not invited]
  
• Intra- and Post-operative Complications Caused by Surgical Adjunctive Agents

  ISHIDA Susumu  あたらしい眼科 = Journal of the eye  17-  (10)  1331  -1336  2000/10/30  [Not refereed][Not invited]
  
• A Case of Proliferative Diadetic Retinopathy with Development of Ischemic Optic Neuropathy after Pars Plana Vitrectomy

  SHINODA Kei, OHDE Hisao, ISHIDA Susumu, KAWASHIMA Shinichi, KITAMURA Shizuaki, MITA Shinji, INOUE Makoto, KATSURA Hiroshi  日本眼科紀要 = Folia ophthalmologica Japonica  51-  (10)  925  -929  2000/10/28  [Not refereed][Not invited]
  
• Three Cases of Ocular Ischemic Syndrome with Different Clinical Courses

  NAKAJIMA Hideto, KAWASHIMA Shinichi, ISHIDA Susumu, SHINODA Kei, MASHIMA Yukihiko  日本眼科紀要 = Folia ophthalmologica Japonica  51-  (7)  674  -679  2000/07/28  [Not refereed][Not invited]
  
• Two cases of Macular Hole Retinal Detachment with complete Posterior Vitreous Detachment

  OGATA Masaro, ISHIDA susumu, SHINODA Kei, KATSURA Hiroshi  日本眼科紀要 = Folia ophthalmologica Japonica  51-  (6)  600  -603  2000/06/28  [Not refereed][Not invited]
  
• Clinical Features and Surgical Results for Pseudophakic Retinal Detachment

  MATSUZAKI Tadayuki, ISHIDA Susumu, SHINODA Kei, KAWASHIMA Shinichi, KOMATSU Yuuko, TERAO Yuuko, KATSURA Hiroshi  眼科手術 = Journal of ophthalmic surgery  13-  (2)  251  -253  2000/04/30  [Not refereed][Not invited]
  
• Clinical Role of Vascular Endothelial Growth Factor (VEGF) and Hepatocyte Growth Factor (HGF) in Type-2 Diabetic Patients

  Michiyo Takayama, Ken Shinmura, Hiroshi Hasegawa, Masato Tani, Toshiko Wakabayashi, Kei Shinoda, Susumu Ishida, Masakazu Yamada  Journal of the Japan Diabetes Society  43-  (5)  347  -354  2000  [Not refereed][Not invited]
   

  We performed two studies to investigate the clinical roles of VEGF and HGF in diabetes mellitus. (1) Serum concentrations of VEGF and HGF were measured in type-2 diabetic patients (DM, n = 74) and control subjects (C, n = 44) by enzyme-linked immunosorbent assay, and their relationship to fasting plasma glucose (FPG), hemoglobin Aic, total cholesterol, high-density lipoprotein cholesterol (HDL-C), liver function, systolic blood pressure, smoking, and diabetic angiopathy were analyzed. (2) VEGF and HGF concentrations were measured in both the serum and anterior aqueous humor of type-2 diabetic patients (n = 33) and non-diabetic patients (n = 12) who underwent eye surgery, and their correlations with diabetic retinopathy were determined. (1) There were no differences in serum VEGF between C and DM, but, serum VEGF was significantly higher in DM with diabetic angiopathy. Serum HGF was higher in DM and smokers, and inversely correlated with HDL-C and FPG. (2) Neither serum VEGF nor HGF were associated with retinopathy, but anterior aqueous humor VEGF was extremely higher and HGF tended to be higher in DM with preproliferative diabetic retinopathy. VEGF and HGF were not correlated in serum, but a positive correlation was observed in anterior aqueous humor. These results suggest that VEGF and HGF affect diabetic retinopathy, however, no relationship to diabetic macroangiopathy could be detected. © 2000, THE JAPAN DIABETES SOCIETY. All rights reserved.
• Therapeutic Pars Plana Vitrectomy for Chronic Uveitis

  OZAWA Yoko, SUZUKI Saburosuke, ISHIDA Susumu, SHINODA Kei, KATSURA Hiroshi  日本眼科紀要 = Folia ophthalmologica Japonica  50-  (12)  933  -937  1999/12/28  [Not refereed][Not invited]
  
• A New Method for Quantification of Metamorphopsia in Patients with Epiretinal Membrane

  SHINODA Kei, ISHIDA Susumu, KAWASHIMA Shinichi, MATSUZAKI Tadayuki, YAMADA Kyoko, KATSURA Hiroshi  日本眼科學会雜誌  103-  (11)  806  -810  1999/11/10  [Not refereed][Not invited]
  
• A Case of Diabetic Tractional Retinal Detachment with Good Visual Outcome despite Macular Hole Formation

  HASHIMOTO Chigusa, SHINODA Kei, ISHIDA Susumu, KAWASHIMA Shinichi, KATSURA Hiroshi  日本眼科紀要 = Folia ophthalmologica Japonica  50-  (7)  567  -570  1999/07/28  [Not refereed][Not invited]
  
• Postoperative Ocular Infections Caused by Methicillin-Resistant Staphylococcus aureus (MRSA) in Cases with Atopic Dermatitis

  HARUHATA Yuji, YAMADA Masakazu, OHTAKE Yuichiro, SHINODA Kei, ISHIDA Susumu, MASHIMA Yukihiko  日本眼科紀要 = Folia ophthalmologica Japonica  50-  (6)  471  -475  1999/06/28  [Not refereed][Not invited]
  
• A Case of Benign Concentric Annular Macular Dystrophy

  SHINODA Kei, OHDE Hisao, BETSUIN Yasuki, ISHIDA Susumu, KAWASHIMA Shinichi, MATSUZAKI Tadayuki, MASHIMA Yukihiko, OGUCHI Yoshihisa, KATSURA Hiroshi  日本眼科紀要 = Folia ophthalmologica Japonica  50-  (5)  370  -376  1999/05/28  [Not refereed][Not invited]
  
• A Case of Macular Hole Retinal Detachment in Behcet Disease

  TAMURA Tomonori, INOUE Makoto, ISHIDA Susumu, SHINODA Kei, OZAWA Yoko, ANDO Yasutaka, SUZUKI Saburosuke, KATSURA Hiroshi  日本眼科紀要 = Folia ophthalmologica Japonica  50-  (4)  312  -315  1999/04/28  [Not refereed][Not invited]
  
• Electrophysiological Evaluation of Visual Field Defect after Vitrectomy

  OZAWA Yoko, KATSURA Hiroshi, BETSUIN Yasuki, ISHIDA Susumu, SHINODA Kei, INOUE Makoto, OHDE Hisao, OGUCHI Yoshihisa  日本眼科紀要 = Folia ophthalmologica Japonica  50-  (3)  199  -202  1999/03/28  [Not refereed][Not invited]
  
• A Case of Suprachoroidal Expulsive Hemorrhage during Vitreous Surgery for Dislocated Intraocular Lens

  ISHIDA Susumu, SHINODA Kei, KATSURA Hiroshi  日本眼科紀要 = Folia ophthalmologica Japonica  50-  (1)  66  -69  1999/01/28  [Not refereed][Not invited]
  
• A Case of Occlusive Retinal Vasculitis with Sever Proliferation

  ISIDA Susumu, SUZUKI Saburousuke, SHINODA Kei, OZAWA Youko, INOUE Makoto, KATURA Hiroshi  日本眼科紀要 = Folia ophthalmologica Japonica  49-  (8)  701  -705  1998/08/28  [Not refereed][Not invited]
  
• Vitrectomy for Diabetic Macular Edema

  SHINODA Kei, KUMATA Nelson Eiji, INOUE Makoto, KATSURA Hiroshi, ISHIDA Susumu, OZAWA Yoko, OGAWA Liliana Sayuri  あたらしい眼科 = Journal of the eye  15-  (7)  1026  -1031  1998/07/30  [Not refereed][Not invited]
  
• A Case of Traumatic Retinal Detachment Produced by True Retinal Dialysis

  OZAWA Yoko, ISHIDA Susumu, SHINODA Kei, KATSURA Hiroshi, INOUE Makoto, OGAWA Liliana Sayuri  あたらしい眼科 = Journal of the eye  15-  (5)  725  -728  1998/05/30  [Not refereed][Not invited]
  
• Aqueous Levels of Eosinophil Cationic Protein and Major Basic Protein in Patients with Retinal Detachment Associated with Atopic Dermatitis

  MATSUDA Hideho, KATSURA Hiroshi, ISHIDA Susumu, INOUE Makoto  日本眼科學会雜誌  102-  (3)  189  -192  1998/03/10  [Not refereed][Not invited]
  
• Macular Hole Following Scleral Buckling Surgery

  ISHIDA Susumu, INOUE Makoto, KATSURA Hiroshi, KUMATA Eiji Nelson, OGAWA Sayuri Liliana, SHINODA Kei, OZAWA Yoko  眼科手術 = Journal of ophthalmic surgery  10-  (4)  577  -580  1997/10/30  [Not refereed][Not invited]
  
• 網膜中心静脈閉塞症に対する網膜光凝固と血管新生緑内障

  篠田 肇, 石田 晋, 小沢 洋子, 篠田 啓, 桂 弘  緑内障 = Journal of Japan Glaucoma Society  7-  (1)  1997/07/30  [Not refereed][Not invited]
  

Industrial Property Rights

• 特開2018-140037:角膜上皮疾患の予防または治療用の環状デバイス  2018/09/13

  石田 晋, 野田 航介, 神田 敦宏, 大口 剛司, 中村 暁, 福島 努, 小畑 晴香, 庄司 潔  国立大学法人北海道大学, 株式会社シード, 千寿製薬株式会社  201803001562001508
• 特開2018-140969:後眼部疾患治療用環状デバイス  2018/09/13

  石田 晋, 野田 航介, 神田 敦宏, 大口 剛司, 小畑 晴香, 松永 透, 佐藤 隆郎  国立大学法人北海道大学, 株式会社シード, 千寿製薬株式会社  201803008414932459
• 特開2018-141911:環状デバイス装着用補助具  2018/09/13

  石田 晋, 野田 航介, 神田 敦宏, 大口 剛司, 中村 暁, 福島 努, 庄司 潔  国立大学法人北海道大学, 株式会社シード, 千寿製薬株式会社  201803019654184800
• 特許第6215555号:眼底画像処理装置および眼底画像処理プログラム  2017/09/29

  石田 晋, 野田 航介, 齋藤 理幸, 小林 正彦, 星川 靖裕  株式会社ニデック, 国立大学法人北海道大学  201703017946087058
• 特開2017-141185:プロレニン受容体リガンド及びアンタゴニスト  2017/08/17

  周東 智, 石田 晋, 神田 敦宏, 桑原 智希  国立大学法人北海道大学  201703002616438876
• WO2017-115872:プロレニン遺伝子またはプロレニン受容体遺伝子の発現を抑制する一本鎖核酸分子およびその用途  2017/07/06

  石田 晋, 神田 敦宏, 黒田 雅彦, 豊福 秀一  国立大学法人北海道大学, 学校法人東京医科大学, 株式会社ボナック  201803016021305706
• WO2014-168154:眼疾患を評価するためのマイクロアレイ及び眼疾患の評価方法  2014/10/16

  生田 健次郎, 石田 晋, 神田 敦宏  三菱レイヨン株式会社  201703013141254033
• 特開2014-193225:眼底画像処理装置および眼底画像処理プログラム  2014/10/09

  石田 晋, 野田 航介, 齋藤 理幸, 小林 正彦, 星川 靖裕  国立大学法人北海道大学  201403071143091600
• 特許第5033643号:脈絡膜血管新生を伴う疾患の治療剤  2012/07/06

  石田 晋  学校法人慶應義塾, 中外製薬株式会社  201303005115016172
• WO2007-086490:脈絡膜血管新生を伴う疾患の治療剤  2007/08/02

  石田 晋  学校法人慶應義塾, 中外製薬株式会社  200903090372662292

Research Grants & Projects

• Glycer-AGEによる網膜神経病態の機序解明と糖尿病網膜症に対する創薬

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2020/04 -2024/03 

  Author : 石田 晋, 村田 美幸, 神田 敦宏

   

  糖尿病網膜症は重篤な視機能障害をきたす疾患であり、その病態理解は眼科学における重要課題である。これまでの糖尿病網膜症治療はその血管病態を制御することを目的とされてきたが、近年、糖尿病網膜症における「神経病態」が注目されている。しかし、糖尿病網膜症における神経保護的治療法は現在のところ確立されていない。 グリセルアルデヒド由来の終末糖化産物(Glycer-AGE)は、その細胞障害性の強さからToxic AGE(TAGE)とも呼ばれ、糖尿病網膜症を含む様々な疾患での病態形成への関与が報告されている。申請者グループの検討により、このTAGEが糖尿病モデルマウスの視細胞変性に寄与していることが明らかになった。本研究では、TAGEによる網膜神経病態の機序を解明し、さらにTAGEを標的とした創薬開発を行い、糖尿病網膜症の新規治療法開発を目指す。 本研究におけるこれまでの検討により、ヒト培養網膜色素上皮細胞にグリセルアルデヒドを添加してTAGE化反応を誘導し、抗TAGEモノクローナル抗体で免疫沈降をおこなって質量分析に供し、グリセルアルデヒドを添加しないコントロール群と比較することで、網膜色素上皮細胞内でTAGE化される複数のタンパク質を同定している。また、ヒト培養網膜色素上皮細胞にグリセルアルデヒドと牛血清アルブミン(BSA)を反応させて作製したTAGE化BSAを添加し、TAGE負荷が網膜色素上皮細胞機能に及ぼす影響について現在解析を進めている。
• VIPR2による中心性漿液性脈絡網膜症における分子病態の解明

  日本学術振興会：科学研究費助成事業

  Date (from‐to) : 2021/07 -2023/03 

  Author : 石田 晋, 齋藤 理幸, 田川 義晃

   

  Vasoactive intestinal peptide (VIP)およびvasoactive intestinal peptide receptor (VIPR)2の中枢および血管に対する作用は、中心性漿液性脈絡網膜症(CSC)患者の病態と考えられている精神的ストレスと脈絡膜血管局所的収縮の両者と反対の特徴を持つ。これまで、VIPR2-KOマウスを用いたCSCの研究は無く、CSCの神経生理学的・細胞生物学的な病態は証明することができなかった。 本研究では、VIPR2-KOマウスにストレス負荷を与えた実験系において、中枢神経系および脈絡膜局所の両面における神経生理学的・細胞生物学的探索、および脈絡膜の形態・血流変化を観察することによって、VIPR2-KOマウスがCSCのモデル動物となりうるかを検証し、その病態を分子メカニズムから解明する。 現在、CSCモデル動物を構築するために、VIPR2-KOマウスの樹立について準備を進めているところである。同時に、恐怖刺激などの刺激を行うために必要な機材、器具等の準備、予備検討などを進めている段階である。また、ヒトのCSC患者についても安静時機能的 MRIおよびミネソタ多面人格目録などの質問票による性格検査などを行うためデータをとる必要がある。コロナウイルスの影響などによりやや遅れが生じているものの、網膜および黄斑などの専門外来において患者の適格性を検討し、今後の状況などを見極めつつ選定を進めていこうと考えている。
• Generation of a marmoset model of normal tension glaucoma and investigation into neuroprotection and neuroregeneration for glaucoma therapy

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2015/04 -2018/03 

  Author : HARADA Takayuki, SASAKI Erika, ISHIDA Susumu, MITAMURA Yoshinori, ICHIJO Hidenori, TOKUNO Hironobu, NAMEKATA Kazuhiko

   

  The most common cause of blindness in Japan is glaucoma. Normal tension glaucoma (NTG) is a subtype of glaucoma that presents with statistically normal intraocular pressure (IOP), suggesting that non-IOP-dependent factors may contribute to the disease progression. Interestingly, 70% of glaucoma patients in Japan have NTG. In this project, we demonstrated that some existing drugs, nutrients that suppress oxidative stress and caloric restriction are effective for suppression of retinal degeneration in mouse models of glaucoma. In addition, we found that some aged marmosets, non-human primates, develop spontaneous NTG and we are preparing for generation of genetically modified NTG marmosets.
• Cohort study on the sensory system in the community-dwelling older persons

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2012/04 -2015/03 

  Author : NISHIWAKI Yuji, TAKEBAYASHI Toru, ISHIDA Susumu, ETO Norihito, OKAMURA Tomonori, TANAKA Taichiro, MICHIKAWA Takehiro, KANZAKI Sho

   

  Our finding from the population-based cohort study suggested that 1) self-reported hearing loss was associated with a decline in IADL, but not with social participation, 2) tinnitus was independently associated with the risk of depressive symptoms developing in men, but not in women, 3) sunlight exposure might be a risk factor of hearing impairment, and 4) baseline glycemic levels (glycosylated hemoglobin (HbA1c)) was associated with future hearing impairment in a general older population. The measurement of light exposure to the eye (LEE) of urban office workers during work hours using an eyeglass-type measuring device suggested that the extent of the LEE levels varied by the type of job and by the individual behavior within the same job type.
• Comprhensive examination for serum autoantigens in endogenous uveitis patients

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2011 -2013 

  Author : OHNO Shigeaki, ISHIDA Susumu, NAMBA Kenichi, KITAICHI Nobuyoshi, MEGURO Akira, MIZUKI Nobuhisa, SAWASAKI Tatsuya

   

  In this study, serum autoantigens were examined comprhensively in the patients with endogenous uveitis by using our novel detection system.Serum samples were divided into 3 pooled groups. Among Vogt-Koyanagi-Harada disease patients, 10 kinds of proteins were elevated more than one-and-a-half levels compared with healthy volunteers in sera. Behcet's disease patients also showed that 6 kinds of serum proteins were increased levels by half compared with those of healthy subjects. We further demonstarted that 3 of these elevated proteins were common to Vogt-Koyanagi-Harada disease and Behcet disease.
• Preventing visual impairments of the community-dwelling older adults

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2009 -2011 

  Author : TAKEBAYASHI Toru, NISHIWAKI Yuji, ISHIDA Susumu, ASAKURA Keiko

   

  We examined the association of vision impairments(as measured by objective methods) with the composite outcome of dependence in ADL and death, and whether this association differed by gender. In both genders, vision impairment was related to an elevated risk of the outocme(multi-adjusted RR for men & women=1. 60, 95% CI=1. 05-2. 44), with no significant differences between the genders.
• Investigation of disease susceptibility genes associated with intractable intraocular inflammation with racial differences and development of new antioxidant therapy

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2007 -2009 

  Author : OHNO Shigeaki, ISHIDA Susumu, YOSHIDA Kazuhiko, NAMBA Kenichi, KITAICHI Nobuyoshi, TAGAWA Yoshitsugu, ONOE Kazunori, MIZUKI Nobuhisa, INOKO Hidetoshi

   

  In GWAS studies in Behcet disease, 2 new genes and HLA-B*510101 were found. In Vogt-Koyanagi-Harada disease, HLA-DRB1*0405 and several genetic associations were also found. Virological studies revealed 2 new human adenoviruses (HAdV 53 and 54). One of the carotenoids, astaxanthin showed significant increase of choroidal blood flow. DHMEQ, a new NF-κB blocker also showed significant suppression of experimental uveoretinitis.
• Epidemiological study on age-related macular degeneration

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2007 -2008 

  Author : TAKEBAYASHI Toru, NISHIWAKI Yuji, ISHIDA Susumu, ASAKURA Keiko

   

  65歳以上の地域在住高齢者を対象とした本研究での有病率は、早期加齢黄斑変性症4.5%、晩期加齢黄斑変性症1.1%であった。血清抗酸化物質は、カロテン類、キサントフィル類、プロビタミンA類、カロテノイド類のいずれも統計学的に晩期加齢黄斑変性症と有意な関連を認め、個々の抗酸化物質単独の影響よりも複合的な影響が示唆された。一方、早期加齢黄斑変性症との明らかな関連を示す要因はなかった。
• The relation ofATM in the pathology of retinal and chuoidal neovascularization

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2006 -2007 

  Author : INOUE Makoto, ISHIDA Susumu

   

  The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide. The ATM protein also assists cells in recognizing damaged or broken strands of DNA. Moreover, the appearance of disease of a malignant tumor such as the lymphoid tumors is admitted in high frequency in the patients of ataxia telangiectasia, and gene mutation and loss of Atm are found in the tumor cells. The function of DNA restoration is injured in the tumor cell that has the Atm gene mutation, and it is suggested that the function loss of the ATM relate to carcinogenesis. Recently, it is shown that the self-renewal capacity of hematopoietic stem cells depends on ATM-mediated inhibition of oxidative stress in ATM KO mice. (Ito K, et al. Nature 2004, 997-1002). Then, we hypothesize that the background for the diabetic retinopathy such as the oxidative stresses can be improved by properly controlling the ATM. By perfusion-labeling method with fluorescein-isothiocyanate (FITC)-coupled concanavalin A lectin (Con A), we show that the number of adherent leukocytes was significantly higher in Atm+/- mice and Atm-/- mice than in C57BL/6 normal mice. Moreover, the number of adherent leukocytes doesn't change with making the STZ diabetic model. The oxidative stress is known to be accelerated in the STZ diabetic model mice, and so these results imply that the accelerated stress is influenced by ATM.
• Molecular mechanisms underlying the retinal vascular lesions in diabetic retinopathy

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2005 -2006 

  Author : IKEDA Eiji, SHINODA Hajime, ISHIDA Susumu, OKADA Yasunori

   

  Blood-retinal barrier (BRB) is known to be disrupted in diabetic retinopathy, which subsequently accelerates the progression of disease processes. However, it has not been clarified how the BRB breakdown occurs during the course of diabetic retinopathy, although the tissue hypoxia is thought to be involved as a trigger. In the present study, the mechanisms of BRB disruption in diabetic retinopathy were analyzed with reference to the retinal tissue hypoxia as well as the expression of claudin-5, a component of tight junctions, in vascular endothelial cells. In vitro, the movement of claudin-5 from the cytoplasm to the plasma membrane of cultured confluent brain-derived endothelial (bEND.3) cells was closely correlated with the increase in the transendothelial electrical resistance (TEER) which is an idex of barrier function of the cell monolayer. Inhibition of the expression of claudin-5 by RNAi resulted in a reduction of TEER indicating a critical role of claudin-5 in the barrier property. Hypoxia (1% O_2) altered the location of claudin-5 in the plasma membrane and the level of claudin-5 protein in bEND.3 cells, and these changes were accompanied by a decrease in the TEER. In vivo, the claudin-5 molecules are expressed under normoxia in the plasma membrane of retinal microvascular endothelial cells, but were significantly reduced under hypoxic conditions. Tracer experiments revealed that the barrier function of hypoxic retinal vasculature with depressed claudin-5 expression was selectively disrupted against small molecules, which is very similar to the phenotype of claudin-5-deficient mice. These in vitro and in vivo data indicate that claudin-5 is a target molecule of hypoxia leading to the BRB disruption. Furthermore, the hypoxia-induced changes in claudin-5 expression were shown to be suppressed in the presence of an inhibitor of ubiquitin-proteasome pathway, MG-132, suggesting that the ubiquitin-proteasome pathway is involved in the hypoxia-induced breakdown of BRB.
• Molecular mechanisms underlying the vascular lesions in proliferative diabetic retinopathy

  Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research

  Date (from‐to) : 2003 -2004 

  Author : IKEDA Eiji, ISHIDA Susumu, OKADA Yasunori

   

  In diabetic retinopathy, the visual acuity of patients is impaired by the formation of fibrovascular tissue as well as retinal edema. Through analysis of clinical samples, we had obtained the data to suggest that the fibrovascular tissue formation is attributed to the induction of vascular endothelial growth factor (VEGF), especially its isoform VEGF_<165>, and membrane-type 1 matrix metalloproteinase(MT1-MMP) in retinal glial cells. In this study, the mechanisms underlying the induction of these molecules were investigated, with reference to tissue hypoxia. Retinal glial cells were isolated from the rabbit retina, and cultured under either normoxic(20% O_2) or hypoxic(1% O_2) condition. RT-PCR and real-time PCR analyses showed that hypoxia induces the expression of MT1-MMP and VEGF in retinal glial cells. As concerns VEGF, the isoform VEGF_<165> was selectively up-regulated in hypoxic retinal glial cells. One of the high-affinity receptors for VEGF, VEGFR-2, was also found to be expressed in retinal glial cells under hypoxia, while negligible in those under normoxia. Furthermore, the hypoxia-induced MT1-MMP expression was inhibited in the presence of the VEGFR-2 inhibitor SU1498 or the anti-VEGF antibody, indicating that the expression of MT1-MMP in hypoxic retinal glial cells is mediated by VEGF-VEGFR-2 system in an autocrine fashion. On the other hand, the mechanisms of retinal edema formation due to the breakdown of blood-retinal barrier were analyzed in reference to the expression of tight junction molecules, claudins. First, retinal vascular endothelial cells were shown to express claudin-5 at their cell borders. Using cultured bEND.3 endothelial cells, it was demonstrated that the localization of claudin-5 at the cell borders of endothelial cells disappears under hypoxic condition with close correlation to the breakdown of barrier function. MAP kinase cascades were involved in the hypoxia-induced changes in claudin-5 expression. The data obtained in this study suggest the role of tissue hypoxia in the formation of fibrovascular tissue and retinal edema through alteration of VEGF_<165>, MT1-MMP and claudin-5 expression.

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