研究者詳細 - 坪田　一男

論文 - 坪田　一男

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Modified double-K method for intraocular lens power calculation after excimer laser corneal refractive surgery

Saiki Megumi, Negishi Kazuno, Kato Naoko, Ogino Rika, Arai Hiroyuki, Toda Ikuko, Dogru Murat, Tsubota Kazuo

Journal of Cataract and Refractive Surgery 39 （ 4 ） 556 - 562 2013年04月

ISSN 0886-3350

Purpose: To propose the new anterior-posterior method (A-P method) that does not require historical data to calculate intraocular lens (IOL) power after laser in situ keratomileusis (LASIK) and to compare the accuracy of the method with other IOL formulas after LASIK. Setting: Keio University Hospital, Tokyo, Japan. Design: Case series. Methods: Eyes having phacoemulsification and IOL implantation after myopic LASIK were analyzed retrospectively. The A-P method is a modification of the double-K method using the SRK/T formula in which the estimated pre-LASIK keratometry (K) power calculated from the post-LASIK posterior sagittal power in the 6.0 mm zone is used for the preoperative K value in the double-K method and the post-LASIK anterior sagittal power is used for the postoperative K value. The accuracy of the A-P method was compared with that of other formulas that do not require preoperative data and with formulas that require preoperative data. Results: The median values of the arithmetic and absolute prediction errors using the A-P method were 0.16 diopter (D) and 0.54 D, respectively. The prediction errors using the A-P method were within ±0.50 D in 46.4% of eyes and within ±1.00 D in 75.0%. The percentage of eyes within ±1.00 D of the prediction errors with the A-P method was highest with the no-history methods. Conclusion: The A-P method may be a good option for calculating IOL power in eyes having cataract surgery after LASIK when preoperative LASIK data are unavailable. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. © 2013 ASCRS and ESCRS.

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Glossiness and Perishable Food Quality

Murakoshi Takuma, Masuda Tomohiro, Utsumi Ken, Tsubota Kazuo, Wada Yuji

PLoS ONE 8 （ 3 ） 2013年03月

Background: Previous studies have reported the effects of statistics of luminance distribution on visual freshness perception using pictures which included the degradation process of food samples. However, these studies did not examine the effect of individual differences between the same kinds of food. Here we elucidate whether luminance distribution would continue to have a significant effect on visual freshness perception even if visual stimuli included individual differences in addition to the degradation process of foods. Methodology/principal findings: We took pictures of the degradation of three fishes over 3.29 hours in a controlled environment, then cropped square patches of their eyes from the original images as visual stimuli. Eleven participants performed paired comparison tests judging the visual freshness of the fish eyes at three points of degradation. Perceived freshness scores (PFS) were calculated using the Bradley-Terry Model for each image. The ANOVA revealed that the PFS for each fish decreased as the degradation time increased; however, the differences in the PFS between individual fish was larger for the shorter degradation time, and smaller for the longer degradation time. A multiple linear regression analysis was conducted in order to determine the relative importance of the statistics of luminance distribution of the stimulus images in predicting PFS. The results show that standard deviation and skewness in luminance distribution have a significant influence on PFS. Conclusions/significance: These results show that even if foodstuffs contain individual differences, visual freshness perception and changes in luminance distribution correlate with degradation time. © 2013 Murakoshi et al.

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Functional corneal endothelium derived from corneal stroma stem cells of neural crest origin by retinoic acid and Wnt/β-catenin signaling

Hatou Shin, Yoshida Satoru, Higa Kazunari, Miyashita Hideyuki, Inagaki Emi, Okano Hideyuki, Tsubota Kazuo, Shimmura Shigeto

Stem Cells and Development 22 （ 5 ） 828 - 839 2013年03月

ISSN 1547-3287

Corneal endothelial dysfunction remains a major indication for corneal transplantation. Both corneal endothelial cells and stromal cells originate from the neural crest, but have distinct phenotypes and function in the adult cornea. We previously reported that stem cells isolated from the adult corneal stroma [cornea-derived precursors (COPs)] show characteristics of multipotent neural crest-derived stem cells. In this study, we report the induction of functional tissue-engineered corneal endothelium (TECE) from mouse and human COPs. TECE was engineered from Wnt1-Cre/Floxed EGFP mouse COPs in a medium containing retinoic acid and glycogen synthase kinase (GSK) 3β inhibitor (activator of Wnt/β-catenin signaling). The expression levels of major markers characterizing corneal endothelial function (Atp1a1, Slc4a4, Car2, Col4a2, Col8a2, and Cdh2) were significantly upregulated. Both retinoic acid and GSK 3β inhibitor upregulated the expression of Pitx2, a homeobox gene involved in the development of the anterior segment of the eye. GSK 3β inhibitor increased Atp1a1 expression and Na,K-ATPase pump activity of TECE, which was significantly higher than COPs or control 3T3 cells, and 2.6-fold higher than cultured mouse corneal endothelial cells. Mouse TECE transplanted into rabbit corneas maintained transparency and corneal thickness, whereas control corneas without TECE showed marked edema and increased corneal thickness. Furthermore, we successfully induced TECE from human COPs, and human TECE transplanted into rabbit corneas also maintained corneal transparency and thickness. This protocol enables efficient production of corneal endothelium from corneal stromal stem cells by direct induction, which may lead to a novel stem cell therapy for corneal endothelial dysfunction. © 2013, Mary Ann Liebert, Inc.

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A new central - Peripheral corneal curvature method for intraocular lens power calculation after excimer laser refractive surgery

Saiki Megumi, Negishi Kazuno, Kato Naoko, Arai Hiroyuki, Toda Ikuko, Torii Hidemasa, Dogru Murat, Tsubota Kazuo

Acta Ophthalmologica 91 （ 2 ） 2013年03月

ISSN 1755-375X

Purpose: To propose the central-peripheral (C-P) method, which requires no data history to calculate intraocular lens (IOL) powers for eyes that underwent laser in situ keratomileusis (LASIK), and compare the accuracy of the C-P method with other IOL formulas for eyes after LASIK. Methods: Sixteen patients with cataract (25 eyes) who underwent myopic LASIK were analysed retrospectively. The C-P method is a modified double-K method using the SRK/T formula, in which the estimated pre-LASIK keratometric power calculated from the post-LASIK peripheral anterior sagittal power (also called the axial power) is used for the Kpre in the double-K method using the SRK/T formula, and the post-LASIK anterior sagittal power is used for the Kpost. We compared the accuracy of the C-P method with other popular IOL calculation formulas for use in eyes after LASIK. Results: The median values of the arithmetic and absolute prediction errors with the C-P method were 0.11 diopter (D) (range, -1.67 to 1.97 D) and 0.55 D (range, 0.02-1.97 D), respectively. The prediction error using the C-P method was within ±0.5 D in 48% of eyes, within -1.0 to +0.5 D in 60% of eyes, and within ±1.0 D in 68% of eyes. The C-P method resulted in a significantly higher percentage of eyes within ±0.5 D than the BESSt formula, Shammas-PL formula, true net power method, double-K method using 43.5 D for Kpre, and Feiz-Mannis method. Conclusion: The C-P method may be a good option for calculating IOL powers in eyes undergoing cataract surgery after LASIK when the preoperative LASIK data are unavailable. © 2013 The Authors Acta Ophthalmologica © 2013 Acta Ophthalmologica Scandinavica Foundation.

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Serum vascular adhesion protein-1 correlates with vascular endothelial growth factor in patients with type II diabetes

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

Journal of Diabetes and its Complications 27 （ 2 ） 162 - 166 2013年03月

ISSN 1056-8727

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. © 2013 Elsevier Inc. All rights reserved.

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Aquaporin 1-positive stromal niche-like cells directly interact with N-cadherin-positive clusters in the basal limbal epithelium

Higa Kazunari, Kato Naoko, Yoshida Satoru, Ogawa Yoko, Shimazaki Jun, Tsubota Kazuo, Shimmura Shigeto

Stem Cell Research 10 （ 2 ） 147 - 155 2013年03月

ISSN 1873-5061

Stem cells have a specialized microenvironment for maintaining self-renewal and multipotent capacities. It is believed that a cornea epithelial stem cell niche exists in the limbus. To characterize the niche of limbal epithelial stem cells, we observed the limbal basal epithelial layer by histological analysis.Cell clusters or cell suspensions from limbal tissue were prepared with collagenase or dispase II and fixed for cytospin sections. Adhesion assays were done to quantitate calcium-dependent cell adhesion. Limbal tissue and cytospin sections were analyzed by immunohistochemistry, transmission electron microscopy and confocal microscopy.AQP1 positive (AQP1⁺) cells were observed as non-epithelial cells in the subepithelial stroma. AQP1 expression did not co-localize with CD31, podoplanin, MART-1 positive cells, but were observed in vimentin positive stromal cells. When we made a thorough search of limbal basal cells by confocal microscopy, AQP1⁺ were observed in the proximity of N-cad, K15 and p63 positive limbal basal epithelial cells. Furthermore, electron microscope revealed stromal cells penetrating the epithelial basal membrane and forming calcium-dependent cellular adhesions with N-cad⁺ limbal basal epithelial cells.Although we could not clearly detect the expression of N-cad in the AQP1⁺ cells, AQP1⁺ cells immediately beneath the epithelial basement membrane may be stromal niche-like cells that directly interact with N-cad⁺ limbal basal epithelial progenitor cells. © 2012 Elsevier B.V.

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Validation of different sets of criteria for the diagnosis of Sjögren's syndrome in Japanese patients

Tsuboi Hiroto, Hagiwara Shinya, Asashima Hiromitsu, Umehara Hisanori, Kawakami Atsushi, Nakamura Hideki, Sano Hajime, Tsubota Kazuo, Ogawa Yoko, Takamura Etsuko, Saito Ichiro, Inoue Hiroko, Nakamura Seiji, Moriyama Masafumi, Takeuchi Tsutomu, Tanaka Yoshiya, Hirata Shintaro, Mimori Tsuneyo, Matsumoto Isao, Sumida Takayuki

Modern Rheumatology 23 （ 2 ） 219 - 225 2013年03月

ISSN 1439-7595

Objective: To validate the revised Japanese Ministry of Health criteria for the diagnosis of Sjögren's syndrome (SS) (JPN) (1999), The American-European Consensus Group classification criteria for SS (AECG) (2002), and American College of Rheumatology classification criteria for SS (ACR) (2012). Methods: The study subjects were 694 patients with SS or suspected SS who were followed-up in June 2012 at ten hospitals that form part of the Research Team for Autoimmune Diseases, The Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare (MHLW). All patients had been checked for all four criteria of the JPN (pathology, oral, ocular, anti-SS-A/SS-B antibodies). We studied the clinical diagnosis made by the physician in charge and the satisfaction of the above criteria. Results: Of the 694 patients, 499 patients did not have other connective tissue diseases (CTDs). SS was diagnosed in 476 patients (primary SS in 302, secondary SS in 174), whereas non-SS was diagnosed in 218 patients (without other CTDs in 197, with other CTDs in 21) by the physician in charge. The sensitivities of JPN, AECG, and ACR in the diagnosis of all forms of SS (both primary and secondary SS) were 79.6, 78.6, and 77.5 %, respectively, with respective specificities of 90.4, 90.4, and 83.5 %. The sensitivities of the same systems in the diagnosis of primary SS were 82.1, 83.1, and 79.1 %, respectively, with specificities of 90.9, 90.9, and 84.8 %, respectively. The sensitivities of the same systems in the diagnosis of secondary SS were 75.3, 70.7, and 74.7 %, respectively, with specificities of 85.7, 85.7, and 71.4 %, respectively. Conclusion: The sensitivity of JPN to all forms of SS and secondary SS, the sensitivity of AECG to primary SS, and the specificities of JPN and AECG for all forms of SS, primary SS, and secondary SS were highest in the diagnosis of SS in Japanese patients. These results indicate that the JPN criteria for the diagnosis of SS in Japanese patients are superior to ACR and AECG. © Japan College of Rheumatology 2012.

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Improvements in sleep quality and gait speed after cataract surgery

Ayaki Masahiko, Muramatsu Masahiro, Negishi Kazuno, Tsubota Kazuo

Rejuvenation Research 16 （ 1 ） 35 - 42 2013年02月

ISSN 1549-1684

Background: Gait speed and sleep quality are health indices related to longevity and mortality. In the present study, we measured sleep quality, quality of life, gait speed, and visual acuity before and after cataract surgery to evaluate the efficacy of the procedure on systemic health. Methods: The study was conducted on 155 patients (93 women; average age 74.8 years) undergoing cataract surgery with the implantation of a yellow soft acrylic lens. Patients were evaluated using the Pittsburgh Sleep Quality Index (PSQI) and the National Eye Institute Visual Function Questionnaire 25 (VFQ-25; vision-related quality of life) before and then 2 and 7 months after surgery. Four-meter gait speed was also determined. Results: Of the 155 patients, 68 (43.9%) were classified as poor sleepers (PSQI>5.5) prior to surgery. Significant improvements were noted in sleep 2 months after surgery (p<0.05, paired t-test), but thereafter the improvements were not significant. Prior to surgery, 117 patients (77.0%) were classified as slow walkers (speed<1.0 meter/s). Gait speed increased significantly in these patients 2 months after surgery (p<0.001, paired t-test). Multiple regression analysis revealed significant correlations between the preoperative VFQ-25 score and both PSQI (p<0.05) and gait speed (p<0.001). Postoperative increases in the VFQ-25 score were positively correlated with decreases in the PSQI (p<0.05). Improvements in visual acuity were correlated with improvements in the VFQ-25 score, but not with either PSQI or gait speed. Conclusion: Cataract surgery effectively improves sleep quality and slow gait speed. © 2013, Mary Ann Liebert, Inc.

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A case of impaired vision due to glistening and whitening of hydrophobic acrylic intraocular lens

Hidaka Yuki, Negishi Kazuno, Matsushima Hiroyuki, Torii Hidemasa, Saiki Megumi, Watanabe Kazuhiro, Inafuku Saori, Tsubota Kazuo

Japanese Journal of Clinical Ophthalmology 67 （ 2 ） 199 - 202 2013年02月

ISSN 0370-5579

To report a case who received exchange of intraocular lens (IOP) for impaired vision due to glistening and whitening. Case: A 78-year-old woman presented with impaired vision in her right eye. She had received cataract surgery with implantation of IOL 6 years before. She had had reportedly visual acuity of 0.8 immediately after surgery. Findings: Corrected visual acuity was 0.4 in the right eye. Slitlamp examination showed glistening and whitening of IOP. Funduscopy showed slight chorioretinal atrophy which was the same as immediately after surgery. She received exchange of IOL resulting in corrected visual acuity of 0.8. Conclusion: This case illustrates that glistening and whitening of IOL may result in impaired visual function. Exchange of IOL may be useful in such a situation.

Effect of pupil size on uncorrected visual acuity in pseudophakic eyes with astigmatism

Watanabe Kazuhiro, Negishi Kazuno, Dogru Murat, Yamaguchi Takefumi, Torii Hidemasa, Tsubota Kazuo

Journal of Refractive Surgery 29 （ 1 ） 25 - 29 2013年01月

ISSN 1081-597X

PURPOSE: To study the effect of pupil size on the relationship between refractive astigmatism and uncorrected distance visual acuity (UDVA) and pseudoaccommodation in pseudophakic eyes. METHODS: Thirty-six eyes from 36 patients who underwent phacoemulsifi cation and intraocular lens (IOL) implantation were included. All eyes were divided into two groups based on the presence of postoperative with-therule astigmatism or against-the-rule astigmatism. Uncorrected and corrected distance visual acuity (CDVA), refractive astigmatism, subjective accommodation amplitude, and pupil sizes under photopic and mesopic conditions were measured 1 month postoperatively. The effects of pupil size on the relationship between refractive astigmatism and UDVA were investigated. RESULTS: Against-the-rule astigmatism had a moderate but signifi cant negative linear correlation with UDVA irrespective of the pupil size (R²=0.60, P<.01). A moderate but signifi cant negative linear correlation was found when the pupil diameter exceeded 2.9 mm in eyes with with-the-rule astigmatism (R²=0.46, P=.04). Refractive astigmatism was not signifi cantly correlated with pseudoaccommodation regardless of the pupil diameter in either group. CONCLUSIONS: The results of the current study suggest that pupil size may have an impact on postoperative UDVA in eyes having against the-rule astigmatism and in eyes with a large pupil diameter and with-the-rule astigmatism. Copyright © SLACK Incorporated.

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Comparison of long-term outcome of penetrating and deep anterior lamellar keratoplasty

Adachi Sayaka, Ichihashi Yoshiyuki, Kawakita Tetsuya, Matsumoto Yukihiro, Uchino Miki, Shimmura Shigeto, Tsubota Kazuo

Japanese Journal of Clinical Ophthalmology 67 （ 1 ） 85 - 89 2013年01月

ISSN 0370-5579

Purpose: To report and compare the long-term outcome of penetrating and deep anterior lamellar keratoplasty. Cases and Method: This retrospective study was made on 36 cases who received keratoplasty by a single surgeon during past 10 years. The series comprised 27 males and 9 females. There were 25 eyes of keratoconus, 7 eyes of corneal leukoma, and 3 eyes of corneal degeneration. Deep anterior lamellar keratoplasty was performed on 21 cases and penetrating keratoplasty on 21 eyes. Cases were followed up for 2 to 10 years, average 5 years. Results: Final visual acuity averaged 0.72 after lamellar and 0.85 after penetrating keratoplasty. There was no significant difference. Spherical equivalent of refraction showed a tendency to myopia with no difference between the two groups. Corneal endothelial cell density decreased by 11.0±6.6% immediately after lamellar and 59.5±29.0% after penetrating keratoplasty (p< 0.01). Conclusion: There was no difference in visual function and safety between deep anterior lamellar keratoplasty and penetrating keratoplasty for 2 years or longer.

Effect of experimentally induced astigmatism on functional, conventional, and low-contrast visual acuity

Watanabe Kazuhiro, Negishi Kazuno, Kawai Miho, Torii Hidemasa, Kaido Minako, Tsubota Kazuo

Journal of Refractive Surgery 29 （ 1 ） 19 - 24 2013年01月

ISSN 1081-597X

PURPOSE: To report the changes in functional visual acuity (FVA) in eyes with experimentally induced astigmatism. METHODS: This study included 26 right eyes from 26 healthy participants (mean age: 27.0±4.4 years). After confi rming best correction under cycloplegia, the cylinder power ×90° and ×180° (against-the-rule [ATR] and with-the-rule [WTR] astigmatism, respectively) were added with 0.50-diopter (D) steps, from 0.50 to 2.50 D. Conventional visual acuity (VA), FVA as measured by the FVA Measurement System (NIDEK Co Ltd), and 10% low-contrast visual acuity (LCVA) were measured with 3-mm artifi cial pupil under each condition. RESULTS: The mean corrected logMAR VA, FVA, LCVA were -0.18±0.00 (20/13), -0.10±0.08 (20/16), and 0.06±0.06 (20/23), respectively. The VA, FVA, and LCVA had a signifi cant linear negative correlation with the addition of cylinder irrespective of the axes. A significant decrease in FVA was noted on addition of ≥0.50 D WTR astigmatism and ≥1.00 D ATR astigmatism. With the addition of 1.00 D of cylindrical lens, 96% of eyes with WTR and ATR astigmatism could maintain 20/20 in VA testing, whereas only 50% and 62% of eyes with WTR and ATR astigmatism, respectively, could maintain 20/20 in FVA testing. CONCLUSIONS: Astigmatism may be associated with deterioration of visual function even when conventional VA of 20/20 is attained. Functional VA testing seems to be useful in evaluating the masked astigmatic visual impairment that cannot be detected by conventional VA testing. Copyright © SLACK Incorporated.

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Evaluation of lipid oxidative stress status in Sjögren syndrome patients

Wakamatsu Tais H., Dogru Murat, Matsumoto Yukihiro, Kojima Takashi, Kaido Minako, Ibrahim Osama M A, Sato Enrique A., Igarashi Ayako, Ichihashi Yoshiyuki, Satake Yoshiyuki, Shimazaki Jun, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 54 （ 1 ） 201 - 210 2013年01月

ISSN 0146-0404

PURPOSE. We evaluated the levels of lipid oxidative stress markers and inflammatory cells from tears and conjunctiva of patients with Sjögren syndrome (SS) and normal subjects. METHODS. We examined 31 eyes of 16 patients (16 females) with SS and 15 eyes of 10 healthy controls (2 males and 8 females) in this prospective study. All subjects underwent a Schirmer test, measurement of tear film break-up time, vital stainings, confocal microscopy of the conjunctiva, tear collection for hexanoyl-lysine (HEL), ELISA, and conjunctival brush cytology. Brush cytology samples underwent immunohistochemistry (IHC) staining with HEL and 4-hydroxy-2- nonenal (4HNE). Hematoxylin-eosin and IHC staining with HEL and 4HNE also were performed on conjunctival samples of SS patients and controls. RESULTS. The tear stability and vital staining scores were significantly worse in eyes of SS patients compared to the controls. Conjunctival inflammatory cell density was significantly higher in SS subjects compared to controls. The numbers of conjunctival cells stained positively for HEL and 4HNE were significantly higher in SS patients compared to controls. Tear HEL concentrations correlated significantly with staining scores and inflammatory cell density in confocal microscopy. Conjunctival specimens also revealed higher numbers of cells stained positively for inflammatory markers, as well as HEL and 4HNE in the IHC stainings. CONCLUSIONS. Increase of the oxidative stress status in the conjunctiva of SS patients appears to have a role in the pathogenesis of dry eye disease. A close relationship may exist between reactive oxygen species (ROS) production, lipid peroxidation related membrane damage, and inflammatory processes in dry eye. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

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Morphological evaluation of meibomian glands using noncontact infrared meibography

Ban Yumiko, Shimazaki-Den Seika, Tsubota Kazuo, Shimazaki Jun

Ocular Surface 11 （ 1 ） 47 - 53 2013年01月

ISSN 1542-0124

Meibography is used to study morphological changes in the meibomian glands (MGs), and semiquantitative analysis has been used for MG assessment. We conducted a detailed morphometric assessment of MGs using noncontact infrared meibography (NIM) and investigated the relationship between MG morphology and the ocular surface and MG morphology associated with aging and sex in 37 subjects. The MGs in the upper and lower eyelids showed significant correlations in their morphology, with the former having longer ducts than the latter. The mean length of the MG ducts, percent area of MG acini, and number of gland dropouts were significantly correlated with age. The mean length of the MG ducts in the upper and lower eyelids showed negative correlations with the meibum (P=.043) and fluorescein staining score (P=.008), respectively. The percent area of MG acini in the upper eyelid showed a positive correlation with tear film breakup time (P=.012) and negative correlations with tear film lipid layer interferometry and meibum (P=.005 and .002, respectively). The mean length of the male's MG ducts in the lower eyelid was significantly longer than that of the females (P=.03). These results indicate that morphometric analysis using NIM may be useful for assessing ocular surface conditions. © 2013 Elsevier Inc.

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Renin-angiotensin system involvement in the oxidative stress-induced neurodegeneration of cultured retinal ganglion cells

Ozawa Yoko, Yuki Kenya, Yamagishi Reiko, Tsubota Kazuo, Aihara Makoto

Japanese Journal of Ophthalmology 57 （ 1 ） 126 - 132 2013年01月

ISSN 0021-5155

Purpose: To analyze the influence of oxidative stress on retinal ganglion cells (RGCs) by using a selective culture system of rat RGCs. Methods: Rat RGCs were purified by a two-step immunopanning procedure and cultured either with or without antioxidant (AO) compounds. Reactive oxygen species (ROS) in RGCs were analyzed using dihydroethidium. Expression of angiotensin II, cleaved caspase 3, and netrin-1 was analyzed by immunocytochemistry. Live RGCs were detected by use of calcein-acetoxymethyl ester. The roles of angiotensin II type 1 receptor (AT1R) signaling and netrin-1 were analyzed by use of an AT1R blocker (telmisartan) and an anti-netrin-1 neutralizing antibody, respectively. Results: ROS and angiotensin II were induced in RGCs cultured without AO compounds (AO-). In these cultures, the number of live RGCs decreased and expression of cleaved and activated caspase 3 increased, but these changes were attenuated by addition of the AT1R blocker. Reduction in netrin-1 expression under the AO- condition was also prevented by the AT1R blocker. The AT1R blocker's effects on RGC survival and reduction in cleaved caspase 3-positive cells were cancelled by the anti-netrin-1 neutralizing antibody. Conclusions: Oxidative stress induced cell death through AT1R signaling and netrin-1 reduction in cultured RGCs. © 2012 Japanese Ophthalmological Society.

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[Development of a monitor for quantifying personal eye exposure to visible and ultraviolet radiation and its application in epidemiology].

Eto Norihito, Tsubota Kazuo, Tanaka Taichiro, Nishiwaki Yuji

Nihon eiseigaku zasshi. Japanese journal of hygiene 68 （ 2 ） 118 - 125 2013年

ISSN 0021-5082

Eye diseases including cataract, keratitis and pterygium have been reported to be sun-exposure-related. The association between macular degeneration and blue light has also been discussed. Moreover, it is hypothesized that retinal exposure to blue light may influence the human circadian rhythm. However, no monitoring devices exist that can measure eye exposure to visible and ultraviolet (UV) radiation over time. To measure the exact dose at specific times, we have developed a novel sensing system (ray-sensing glass system: RaySeG). RaySeG can continuously measure and record the composition and intensity of light with a time-stamped system. Subjects wearing RaySeG were instructed to walk under various light conditions such as indoor and outdoor. RaySeG consists of two sensors embedded in the eyeglasses. These sensors are for UV (260-400 nm), visible lights (red, 615 nm; green, 540 nm; and blue, 465 nm: peak wavelength for each). The total weight of the system is about 100 g, and the size is comparable to that of a digital audio player. The system continuously recorded changes in visible and UV light exposure under various conditions. After accuracy validation, further experiments with a larger number of subjects are required. Our final goal is to apply the system to evaluating personal eye exposure to UV and visible light in epidemiological studies of eye diseases and circadian rhythm abnormality.

Expression and localization of aging markers in lacrimal gland of chronic graft-versus-host disease.

Kawai Masataka, Ogawa Yoko, Shimmura Shigeto, Ohta Shigeki, Suzuki Takanori, Kawamura Naoshi, Kuwana Masataka, Kawakami Yutaka, Tsubota Kazuo

Scientific Reports 3 2455 2013年

Aging is commonly defined as the accumulation of diverse deleterious changes in cells and tissues with advancing age. To investigate whether aging changes are involved in the lacrimal glands of chronic graft-versus-host disease (cGVHD) model mice, we obtained the specimens from cGVHD model mice, untreated aged and young mice, and examined by histopathology, and immunoblotting. Oxidative stress markers, 8-OHdG, 4-HNE, and hexonoyl lesion (HEL), and other aging markers, p16 and p38, were used to assess the samples. The infiltrating mononuclear cells and endothelia of capillaries in the cGVHD and aged mice expressed the oxidative stress markers and other aging markers, but not in the young mice. Histological changes and the expression of aging markers in the samples from cGVHD mice exhibited similar features to those in aging mice. These results suggest that changes that typically appear with advanced age occur earlier in the lives of mice with lacrimal gland cGVHD.

Neuroprotective role of VEGF induced in response to photodynamic therapy

Ozawa Yoko, Suzuki Misa, Niikura Serina, Kamoshita Mamoru, Nagai Norihiro, Tsubota Kazuo

Advances in Neuroimmune Biology 4 （ 3 ） 161 - 165 2013年

ISSN 1878-948X

Age-related macular degeneration (AMD) is a vision-threatening disease, and its prevalence is increasing worldwide. Two approaches are commonly used to suppress the pathological choroidal neovascularization (CNV) that characterizes 'wet' AMD. One is photodynamic therapy (PDT), which involves using a systemic photosensitizer in combination with low-power laser irradiation of CNV through the neural retina and retinal pigment epithelium (RPE); the other involves the intravitreous injection of drugs targeting vascular endothelial growth factor (VEGF). In some cases, both methods are used simultaneously. However, recent results from animal experiments indicate that transient increase in VEGF in the tissue following PDT is required for retinal cell survival in overcoming the cellular stress caused by PDT. To maximize the visual outcome and retinal protection, it will be necessary to optimize the combination therapy, which requires the elucidation of the molecular and cellular changes that occur in the retinal tissue during the course of treatment. © 2013 - IOS Press and the authors. All rights reserved.

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ABCA4 gene screening by next-generation sequencing in a British cohort

Fujinami Kaoru, Zernant Jana, Chana Ravinder K., Wright Genevieve A., Tsunoda Kazushige, Ozawa Yoko, Tsubota Kazuo, Webster Andrew R., Moore Anthony T., Allikmets Rando, Michaelides Michel

Investigative Ophthalmology and Visual Science 54 （ 10 ） 6662 - 6674 2013年

ISSN 0146-0404

Purpose. We applied a recently reported next-generation sequencing (NGS) strategy for screening the ABCA4 gene in a British cohort with ABCA4-associated disease and report novel mutations. Methods. We identified 79 patients with a clinical diagnosis of ABCA4-associated disease who had a single variant identified by the ABCA4 microarray. Comprehensive phenotypic data were obtained, and the NGS strategy was applied to identify the second allele by means of sequencing the entire coding region and adjacent intronic sequences of the ABCA4 gene. Identified variants were confirmed by Sanger sequencing and assessed for pathogenicity by in silico analysis. Results. Of the 42 variants detected by prescreening with the microarray, in silico analysis suggested that 34, found in 66 subjects, were disease-causing and 8, found in 13 subjects, were benign variants. We detected 42 variants by NGS, of which 39 were classified as disease-causing. Of these 39 variants, 31 were novel, including 16 missense, 7 splice-site-altering, 4 nonsense, 1 in-frame deletion, and 3 frameshift variants. Two or more disease-causing variants were confirmed in 37 (47%) of 79 patients, one disease-causing variant in 36 (46%) subjects, and no disease-causing variant in 6 (7%) individuals. Conclusions. Application of the NGS platform for ABCA4 screening enabled detection of the second disease-associated allele in approximately half of the patients in a British cohort where one mutation had been detected with the arrayed primer extension (APEX) array. The time- and cost-efficient NGS strategy is useful in screening large cohorts, which will be increasingly valuable with the advent of ABCA4-directed therapies. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

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Functional lacrimal gland regeneration by transplantation of a bioengineered organ germ

Hirayama Masatoshi, Ogawa Miho, Oshima Masamitsu, Sekine Yurie, Ishida Kentaro, Yamashita Kentaro, Ikeda Kazutaka, Shimmura Shigeto, Kawakita Tetsuya, Tsubota Kazuo, Tsuji Takashi

Nature Communications 4 2013年

The lacrimal gland has a multifaceted role in maintaining a homeostatic microenvironment for a healthy ocular surface via tear secretion. Dry-eye disease, which is caused by lacrimal gland dysfunction, is one of the most prevalent eye diseases that cause corneal epithelial damage and results in significant loss of vision and a reduction in the quality of life. Here we demonstrate orthotopic transplantation of bioengineered lacrimal gland germs into adult mice with an extra-orbital lacrimal gland defect, a mouse model that mimics the corneal epithelial damage caused by lacrimal gland dysfunction. The bioengineered lacrimal gland germs and harderian gland germs both develop in vivo and achieve sufficient physiological functionality, including tear production in response to nervous stimulation and ocular surface protection. This study demonstrates the potential for bioengineered organ replacement to functionally restore the lacrimal gland. © 2013 Macmillan Publishers Limited. All rights reserved.

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