研究者詳細 - 坪田　一男

論文 - 坪田　一男

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Long-term maintenance of limbal epithelial progenitor cells using rho kinase inhibitor and keratinocyte growth factor

Miyashita Hideyuki, Yokoo Seiichi, Yoshida Satoru, Kawakita Tetsuya, Yamagami Satoru, Tsubota Kazuo, Shimmura Shigeto

Stem Cells Translational Medicine 2 （ 10 ） 758 - 765 2013年10月

ISSN 2157-6564

Corneal epithelial stem cells are located in the limbus, the junction between the cornea and the conjunctiva. A limbal epithelium model in vitro would be useful for the study of epithelial stem cells, as well as improving the quality of cultivated epithelial sheets for the treatment of limbal stem cell deficiency. In this study, we succeeded in constructing a limbal epithelium-like structure that could be maintained for at least 5 months in vitro. We modified conventional medium by replacing epidermal growth factor with keratinocyte growth factor (KGF) and adding Y-27632, a rho kinase inhibitor. Using this medium, epithelial cells freshly isolated from human limbus were cocultured with human mesenchymal stem cell-derived feeder cells. Cells formed a stratified layer without air exposure, and both basal and suprabasal layers maintained their unique morphologies for up to 5 months. Basal layers expressed the progenitor marker p63 uniformly and K15 heterogeneously. Expressions of PAX6, K3, and K12 indicated that cell sheets underwent normal differentiation in the corneal epithelium lineage. Although medium was changed daily after day 7, cell debris was observed every day, suggesting that cell sheets underwent turnover. Furthermore, secondary colonies were observed from cells dissociated from 1-month and 3-month cultured sheets. In conclusion, human limbal epithelial cell sheet cultures with KGF and Y-27632 maintained stratification, high expression of both stem/progenitor markers and differentiation markers, and colony-forming cells long-term. This protocol may be useful as an in vitro limbal epithelial model for basic studies. © AlphaMed Press 2013.

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Ophthalmic viscoelastic device injection for the treatment of flat anterior chamber after trabeculectomy

Hosoda Shingo, Yuki Kenya, Ono Takeshi, Tsubota Kazuo

Clinical Ophthalmology 7 1781 - 1785 2013年09月

ISSN 1177-5467

Purpose: Flat anterior chamber (FAC) in association with overfiltration is a complication after trabeculectomy. The aim of the current study was to investigate the efficacy of injection of an ophthalmic viscoelastic device (OVD) to treat FAC after trabeculectomy in a retrospective consecutive case series study. Materials and methods: Twenty-five consecutive patients who underwent injection of OVD for the treatment of FAC after trabeculectomy were analyzed. The primary outcome variable was the qualified success of trabeculectomy, which was defined at three different levels by the achievement of one of three IOP-related criteria with or without glaucoma medication. Kaplan-Meier plots were generated to estimate survival functions for trabeculectomy with OVD injection. Results: Twenty-one patients (21/25 = 84.0%) recovered from FAC by one OVD injection. The postoperative intraocular pressure (IOP) measured at 12 months, 24 months, 36 months, 48 months, and 60 months was 14.7 ± 3.6 mmHg, 15.6 ± 7.0 mmHg, 14.2 ± 2.8 mmHg, 14.2 ± 3.8 mmHg, and 14.6 ± 2.7 mmHg, respectively. All postoperative IOP measurements were significantly lower than the preoperative IOP (P < 0.001). The probabilities of qualified success for 5 years after trabeculectomy with OVD injection were as follows: 24.4% (IOP ≦ 21 mmHg and ≧20% reduction of preoperative IOP), 16.5% (IOP ≦ 16 mmHg and ≧20% reduction) and 6.3% (IOP ≦ 12 mmHg and ≧30% reduction). One patient, who had undergone deep lamellar keratoplasty, experienced a complication associated with the injection of the viscoelastic material, Descemet's membrane detachment. Conclusion: Injection of OVD may be effective for the treatment of FAC; however, the longterm success rate was relatively low. © 2013 Hosoda et al.

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

Journal of Cataract and Refractive Surgery 39 （ 9 ） 1451 2013年09月

ISSN 0886-3350

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Clinical and molecular analysis of stargardt disease with preserved foveal structure and function

Fujinami Kaoru, Sergouniotis Panagiotis I., Davidson Alice E., Wright Genevieve, Chana Ravinder K., Tsunoda Kazushige, Tsubota Kazuo, Egan Catherine A., Robson Anthony G., Moore Anthony T., Holder Graham E., Michaelides Michel, Webster Andrew R.

American Journal of Ophthalmology 156 （ 3 ） 2013年09月

ISSN 0002-9394

Purpose: To describe a cohort of patients with Stargardt disease who show a foveal-sparing phenotype. Design: Retrospective case series. Methods: The foveal-sparing phenotype was defined as foveal preservation on autofluorescence imaging, despite a retinopathy otherwise consistent with Stargardt disease. Forty such individuals were ascertained and a full ophthalmic examination was undertaken. Following mutation screening of ABCA4, the molecular findings were compared with those of patients with Stargardt disease but no foveal sparing. Results: The median age of onset and age at examination of 40 patients with the foveal-sparing phenotype were 43.5 and 46.5 years. The median logMAR visual acuity was 0.18. Twenty-two patients (22/40, 55%) had patchy parafoveal atrophy and flecks; 8 (20%) had numerous flecks at the posterior pole without atrophy; 7 (17.5%) had mottled retinal pigment epithelial changes; 2 (5%) had multiple atrophic lesions, extending beyond the arcades; and 1 (2.5%) had a bull's-eye appearance. The median central foveal thickness assessed with spectral-domain optical coherence tomographic images was 183.0 μm (n = 33), with outer retinal tubulation observed in 15 (45%). Twenty-two of 33 subjects (67%) had electrophysiological evidence of macular dysfunction without generalized retinal dysfunction. Disease-causing variants were found in 31 patients (31/40, 78%). There was a higher prevalence of the variant p.Arg2030Gln in the cohort with foveal sparing compared to the group with foveal atrophy (6.45% vs 1.07%). Conclusions: The distinct clinical and molecular characteristics of patients with the foveal-sparing phenotype are described. The presence of 2 distinct phenotypes of Stargardt disease (foveal sparing and foveal atrophy) suggests that there may be more than 1 disease mechanism in ABCA4 retinopathy. © 2013 by Elsevier Inc. All rights reserved.

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Increased urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG)/creatinine level is associated with the progression of normal-tension glaucoma

Yuki Kenya, Tsubota Kazuo

Current Eye Research 38 （ 9 ） 983 - 988 2013年09月

ISSN 0271-3683

Purpose: The objective of this study was to investigate the association between systemic oxidative stress and visual field defect progression in normal-tension glaucoma (NTG). Patients and methods: The subjects were 40 consecutive patients with NTG who were admitted to Keio University Hospital for 24-h intraocular pressure (IOP) evaluation; all subjects underwent six or more visual field tests in either eye and were followed up for >5 years. Spot samples of morning urine were collected during admission from all participants to determine the levels of urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) by ELISA kit. A linear regression line was calculated with the least squares method. Those subjects whose regression lines were negative and the p value <0.05 were classified as progressive, while all others were defined as non-progressive. Urinary 8-OHdG/creatinine level was compared between the two groups. Adjusted odds ratio and 95% confidence intervals for the progression were estimated with logistic regression models. Results: Seventeen subjects showed visual field defect progression (age: 59.9±9.5 years, untreated IOP in the right eye: 15.8±2.1mmHg), and 23 subjects showed no progression (age: 57.4±10.4 years, untreated IOP in the right eye: 16.0±2.6mmHg). Urinary 8-OHdG/creatinine level was significantly higher in the progressive group than in the non-progressive group (progressive group: 9.0±2.4ng/mg creatinine, non-progressive group: 7.3±1.8ng/mg creatinine, p=0.02). Multivariable analysis revealed that higher urinary 8-OHdG/creatinine level was a significant risk factor for the progression (odds ratio 1.54, 95% confidence interval 1.03-2.29). Conclusions: Increased urinary 8-OHdG/creatinine was associated with glaucomatous visual field progression in subjects with NTG. © Informa Healthcare USA, Inc.

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A field test of web-Based screening for dry eye disease to enhance awareness of eye problems among general internet users

Kawashima Motoko, Uchino Miki, Kawazoe Takashi, Kamiyashiki Masaaki, Sano Kokoro, Tsubota Kazuo

Journal of Medical Internet Research 15 （ 9 ） 2013年09月

Background: A Web-based self-check system including a brief questionnaire would seem to be a suitable tool for rapid disease screening. Objective: The purpose of this preliminary study was to test a Web-based self-screening questionnaire for drawing attention to dry eye disease among general Internet users and identifying those with a higher risk of developing the condition. Methods: A survey website was launched and used to recruit participants from general Internet users. In the first phase, volunteers were asked to complete a Web-based self-screening questionnaire containing 12 questions on dry eye symptoms. The second phase focused on the respondents who reported five or more dry eye symptoms and expressed their intention to seek medical attention. These participants performed the Schirmer test, for evaluating tear production, and completed a paper-based lifestyle questionnaire to provide relevant background data. Results: Of the 1689 visitors to the website, 980 (58.0%) volunteers completed the Web-based self-screening questionnaire. Among these, 355 (36.2%) respondents reported five or more dry eye symptoms. Then, 99 (27.9%) of the symptomatic participants performed the Schirmer test and completed the paper-based lifestyle questionnaire. Out of these, 32 (32.2%) had abnormal tear production (≤5 mm). Conclusions: The proposed Web-based self-screening questionnaire seems to be a promising tool for raising awareness of dry eye disease among general Internet users and identifying those with a higher risk of developing the condition, although further research is needed to validate its effectiveness.

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Detection of early visual impairment in patients with epiretinal membrane

Nishi Yasuyo, Shinoda Hajime, Uchida Atsuro, Koto Takashi, Mochimaru Hiroshi, Nagai Norihiro, Tsubota Kazuo, Ozawa Yoko

Acta Ophthalmologica 91 （ 5 ） 2013年08月

ISSN 1755-375X

Purpose: Patients with epiretinal membrane sometimes complain of impaired central visual function, despite good best corrected visual acuity (BCVA), as measured by visual acuity (VA) charts. Here, we evaluate early epiretinal membrane-induced changes in central VA. Methods: Subjects were 72 eyes of 36 patients with epiretinal membrane in only one eye and a BCVA in each eye better than 1.0, as measured by conventional Landolt C chart, at the Retina Division Clinic of the Department of Ophthalmology, Keio University Hospital, between December 2010 and November 2011. The conventional Landolt VA, functional VA (FVA) and contrast VA measurements were taken after a general eye examination. For the FVA, Landolt optotypes were sequentially displayed every 2 seconds, which size was changed according to the correctness of the answer. To exclude the influence of other diseases, a standard Schirmer test was performed to diagnose dry eye, and corneal and lens densities were evaluated. Results: Average BCVA measured by Landolt C chart was not changed between affected and unaffected fellow eyes. However, the affected eyes showed a poorer FVA score (0.21 ± 0.12, affected; 0.09 ± 0.12, fellow) and visual maintenance ratio (VMR) (0.90 ± 0.04, affected; 0.94 ± 0.04, fellow), measured by the FVA system, and contrast VA score (0.35 ± 0.11, affected; 0.25 ± 0.14, fellow) than fellow eyes. The FVA and contrast VA values were correlated with the presence of epiretinal membrane, but not with the presence of dry eye, cataract and corneal densities. Conclusion: FVA and contrast VA results reflected early changes in central visual function caused by epiretinal membrane, which were not detected by conventional Landolt BCVA. © 2013 The Authors. Acta Ophthalmologica © 2013 Acta Ophthalmologica Scandinavica Foundation. Published by Blackwell Publishing Ltd.

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Ocular surface complications after trabeculectomy

Ono Takeshi, Yuki Kenya, Ozeki Naoki, Shiba Daisuke, Tsubota Kazuo

Ophthalmologica 230 （ 2 ） 93 - 99 2013年08月

ISSN 0030-3755

Purpose: To investigate the incidence, risk factors, time course and prognosis of ocular surface complications after trabeculectomy. Procedures: This is a retrospective, case-control study. Data on 399 consecutive patients who underwent trabeculectomy between 1999 and 2009 were evaluated. Cases of postoperative corneal epithelial defects, filamentary keratitis and dellen were evaluated. The risk factors for these ocular surface complications were analyzed with a logistic regression model. Results: Corneal epithelial defects were found in 44 of the 399 patients (11%), filamentary keratitis in 12 patients (3%) and dellen in 7 patients (2%). Dellen required surgical intervention at a statistically significantly higher rate than corneal epithelial defects or filamentary keratitis (p = 0.0001, Fisher's exact test). The significant risk factors for these ocular surface complications were found to be a history of preoperative superficial punctate keratopathy (odds ratio, OR: 2.10, 95% confidence interval, CI: 1.25-3.51, p = 0.005) and a history of diabetes mellitus (OR: 1.69, 95% CI: 1.02-2.81, p = 0.04). Conclusions: Ocular surface complications following trabeculectomy are not rare. The biggest risk factors for these complications were found to be a history of preoperative superficial punctate keratopathy and a history of diabetes mellitus. Surgery is likely to be required for the treatment of dellen. Copyright © 2013 S. Karger AG, Basel.

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Long-term results of amniotic membrane transplantation for partial limbal deficiency

Konomi Kenji, Satake Yoshiyuki, Shimmura Shigeto, Tsubota Kazuo, Shimazaki Jun

Cornea 32 （ 8 ） 1110 - 1115 2013年08月

ISSN 0277-3740

PURPOSE: To evaluate the long-term efficacy of amniotic membrane transplantation as a treatment option in cases with partial limbal deficiency. METHODS: Sixteen eyes of 14 patients with partial limbal deficiency underwent amniotic membrane patch (AMP) or amniotic membrane graft with patch (AMGP) following keratectomy for conjunctivalization of the cornea. The average follow-up period was 52 months. We evaluated the mean corneal epithelialization time, visual acuity improvement, complications, and recurrence rate after the surgery. RESULTS: Eleven eyes underwent AMP, and the remaining 5 eyes received AMGP. All eyes eventually attained corneal reepithelialization. The mean time to reepithelialization was not significantly different between the AMP group (9 days) and the AMGP group (27 days). At the final follow-up visit, improved Landolt visual acuity was observed in 6 of the 11 eyes in the AMP group and in 2 of the 5 eyes in the AMGP group. No intraoperative complications were observed. However, 6 eyes in the AMP group and 3 eyes in the AMGP group had a recurrence or developed a persistent epithelial defect after mean durations of 21.2 and 17.7 months, respectively. CONCLUSION: Both AMP and AMGP appear to be effective in attaining corneal reepithelialization, but neither could provide stable, clear corneal epithelialization in the long term. Copyright © 2013 by Lippincott Williams & Wilkins.

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

Journal of Cataract and Refractive Surgery 39 （ 8 ） 1280 - 1281 2013年08月

ISSN 0886-3350

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Molecular characteristics of four Japanese cases with KCNV2 retinopathy

Fujinami Kaoru, Tsunoda Kazushige, Nakamura Natsuko, Kato Yu, Noda Toru, Shinoda Kei, Tomita Kaoru, Hatase Tetsuhisa, Usui Tomoaki, Akahori Masakazu, Itabashi Takeshi, Iwata Takeshi, Ozawa Yoko, Tsubota Kazuo, Miyake Yozo

Molecular Vision 19 1580 - 1590 2013年07月

ISSN 1090-0535

Purpose: To describe the molecular characteristics of four Japanese patients with cone dystrophy with supernormal rod responses (CDSRR). Methods: Four individuals with a clinical and electrophysiological diagnosis of CDSRR were ascertained. The pathognomonic findings of the full-field electroretinograms (ERGs) included a decrease in the rod responses, a square-shaped a-wave, an excessive increase in the b-wave in the bright flash responses, and decreased cone-derived responses. Mutational screening of the coding regions and flanking intronic sequences of the potassium channel, subfamily V, member 2 (KCNV2) gene was performed with bidirectional sequencing. The segregation of each allele was confirmed by screening other family members. Subsequent in silico analyses of the mutational consequences for protein function were performed. Results: There were two siblings from one family and one case in each of the two families. One family had a consanguineous marriage. Mutational screening revealed compound heterozygosity for the two alleles, p.C177R and p.G461R, in three patients, and homozygosity for complex alleles, p.R27H and p.R206P, in one patient from the consanguineous family. There were three putative novel variants, p.R27H, p.C177R, and p.R206P. The four variants in the families with KCNV2 were highly conserved in other species. In silico analyses predicted that all of the missense variants would alter protein function. Conclusions: Biallelic disease-causing variants were identified in four Japanese patients with CDSRR suggesting that the pathognomonic electrophysiological features are helpful in making a molecular diagnosis of KCNV2. Three novel variants were identified, and we conclude that there may be a distinct spectrum of KCNV2 alleles in the Japanese population. © 2013 Molecular Vision.

Effects of diquafosol tetrasodium administration on visual function in short break-up time dry eye

Kaido Minako, Uchino Miki, Kojima Takashi, Dogru Murat, Tsubota Kazuo

Journal of Ocular Pharmacology and Therapeutics 29 （ 6 ） 595 - 603 2013年07月

ISSN 1080-7683

Purpose: To investigate the effect of diquafosol tetrasodium on tear and visual function in short break-up time (sBUT) dry eye (DE). Methods: This interventional nonrandomized comparative study involved 11 eyes in 11 patients with sBUT DE (symptom-positive sBUT group) and 13 eyes in 13 volunteers with BUT values≤5 s without DE symptoms (symptom-negative sBUT group). Tear function was assessed by measuring BUT and Schirmer values. Serial measurements were made of visual acuities (using a functional visual acuity measurement system) and higher-order aberrations (using a wavefront sensor). The parameters were compared before and 1 month after diquafosol tetrasodium instillation. Any changes in symptomatology after administration were also recorded. Results: After diquafosol tetrasodium administration, BUT values tended to increase in the symptom-positive sBUT group (P=0.07) and significantly increased in the symptom-negative sBUT group (P<0.05). LogMAR functional, minimal, and maximal visual acuities and higher-order aberrations significantly decreased after diquafosol tetrasodium administration in the symptom-positive sBUT group (P<0.05), while there were no significant changes in these values in the symptom-negative sBUT group (P>0.05). Diquafosol tetrasodium administration provided relief of DE symptoms in 75% of patients in the symptom-positive sBUT group. Conclusions: Diquafosol tetrasodium appeared to improve tear film stability and visual function in sBUT DE. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

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Improvement of visual acuity after transcorneal electrical stimulation in case of Best vitelliform macular dystrophy

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

Graefe's Archive for Clinical and Experimental Ophthalmology 251 （ 7 ） 1867 - 1870 2013年07月

ISSN 0721-832X

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.

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The impact of tear functions on visual outcome following keratoplasty in eyes with keratoconus

Hara Shuya, Kojima Takashi, Dogru Murat, Uchino Yuichi, Goto Eiki, Matsumoto Yukihiro, Kawakita Tetsuya, Tsubota Kazuo, Shimazaki Jun

Graefe's Archive for Clinical and Experimental Ophthalmology 251 （ 7 ） 1763 - 1770 2013年07月

ISSN 0721-832X

Background: To investigate the impact of preoperative and postoperative tear functions on visual outcome and the recovery of visual function following keratoplasty in eyes with keratoconus. Methods: Twenty-five eyes of 25 consecutive patients (5 females, 20 males, mean age: 34.3 ± 15.8 years (range: 19-70 years) with keratoconus who underwent either penetrating keratoplasty (PKP) or deep anterior lamellar keratoplasty (DALK) were included in this prospective study. One patient who had a rejection episode during the follow-up period was excluded. All subjects underwent best corrected visual acuity (BCVA), corneal topography (refractive cylinder, surface regularity index: SRI and surface asymmetry index: SAI), Schirmer I test, tear film break-up time (BUT), corneal sensitivity, and fluorescein staining score measurements before as well as 1, 3, 6 and 12 months after keratoplasty. The relation between the tear functions and the duration until the achievement of maximum BCVA was also evaluated. Linear regression analysis was performed to study the statistical significance of the correlations and the time wise change of each examined parameter. Results: SRI, SAI, and BCVA significantly improved after keratoplasty. The postoperative corneal sensitivity was still significantly low even at 12 months postoperatively. Postoperative BCVA at 3, 6 months and maximum BCVA showed a significant linear negative correlation with the preoperative BUT (3 months; r = -0.461, p = 0.036, 6 months; r = -0.494, p = 0.023, maximum BCVA; r = -0.473, p = 0.030). The duration until the achievement of maximum BCVA showed a significant negative correlation with the preoperative Schirmer test (r = -0.429, p = 0.036). BCVA at 1 and 3 months postoperatively showed significant linear negative correlations with BUT value at the respective periods (1 month; r = -0.665, p = 0.0036, 3 months; r = -0.580, p = 0.0059). Conclusion: Preoperative tear functions appeared to have an influence on postoperative BCVA and the duration of visual recovery in keratoconus patients undergoing keratoplasty. Postoperative tear film stability appears to play an important role for obtaining a better BCVA in the early postoperative period after keratoplasty. © 2013 Springer-Verlag Berlin Heidelberg.

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Patient satisfaction following treatment with sodium hyaluronate or diquafosol ophthalmic solution for dry eye with short tear film break-up time

Uchino Miki, Uchino Yuichi, Fukagawa Kazumi, Tsubota Kazuo

Japanese Journal of Clinical Ophthalmology 67 （ 8 ） 1403 - 1411 2013年07月

ISSN 0370-5579

Purpose: To report the outcome of treatment with sodium hyaluronate or diquafosol ophthalmic solution for dry eye. Cases and Method: This study was made on 95 cases who were diagnosed with dry eye at the Ryogoku Eye Clinic, Tokyo. The series comprised 28 males and 67 females. The age ranged from 20 to 89 years. Forty-seven cases were treated with 3% diquafosol and 48 were treated with sodium hyaluronate ophthalmic solution. Patient satisfaction was evaluated after 10 weeks of treatment with 100 points as the full score. Dry eye was divided into 2 groups according to the tear break-up time (BUT). Results: Fourteen of dry eye patients with short BUT gave an average of 77.1 points after treatment with diquafosol. Eleven similar patients gave an average of 62.1 points after treatment with sodium hyaluronate. Conclusion: Higher satisfaction was obtained after treatment with diquafosol than sodium hyaluronate by dry eye patients with short BUT.

Deep stromal opacity after corneal cross-linking

Kato Naoko, Konomi Kenji, Saiki Megumi, Negishi Kazuno, Takeuchi Masaru, Shimazaki Jun, Tsubota Kazuo

Cornea 32 （ 7 ） 895 - 898 2013年07月

ISSN 0277-3740

Purpose: To describe 3 cases with deep corneal stromal opacity that occurred several months after corneal cross-linking. Methods: A 36-year-old man, a 19-year-old man, and a 14-yearold girl underwent corneal cross-linking for their progressive keratoconus. Corneal cross-linking was performed according to the Dresden protocol. The corneal epithelium was ablated using an excimer laser in 2 cases and manually in 1 case. After 30 minutes of riboflavin presoaking, hypotonic riboflavin solution was applied until the corneal stroma swelled, after which the eyes were exposed to ultraviolet irradiation. Slit-lamp microscopy findings, uncorrected visual acuity, best-corrected visual acuity, manifest refraction, intraocular pressure, and corneal endothelial cell counts were evaluated, and corneal topography with Scheimpflug imaging was performed. Results: In all cases, the epithelium healed without delay. All eyes showed mild stromal infiltration a few days after the procedure; however, the inflammation was resolved within 1 week. The corneal stroma revealed no opacity up to 1 month after the procedure. A deep stromal opacity that extended to the inferior paracentral area developed after a few months and remained for 6 months to 1 year. Because the opacity was not on the visual axis, the visual acuity was not involved. Conclusions: Deep stromal opacity developed several months after uneventful corneal cross-linking. Postoperative inflammation may play a crucial role in its pathogenesis. © 2013 by Lippincott Williams & Wilkins.

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Angiotensin II Type 1 Receptor Antagonist Attenuates Lacrimal Gland, Lung, and Liver Fibrosis in a Murine Model of Chronic Graft-Versus-Host Disease

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

PLoS ONE 8 （ 6 ） 2013年06月

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. © 2013 Yaguchi et al.

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A longitudinal study of Stargardt disease

Fujinami Kaoru, Lois Noemi, Davidson Alice E., Mackay Donna S., Hogg Chris R., Stone Edwin M., Tsunoda Kazushige, Tsubota Kazuo, Bunce Catey, Robson Anthony G., Moore Anthony T., Webster Andrew R., Holder Graham E., Michaelides Michel

American Journal of Ophthalmology 155 （ 6 ） 2013年06月

ISSN 0002-9394

Purpose: To investigate the clinical and electrophysiologic natural history of Stargardt disease and correlate with the genotype. Design: Cohort study of 59 patients. Methods: Clinical history, examination, and electrophysiologic assessment were undertaken in a longitudinal survey. Patients were classified into 3 groups based on electrophysiologic findings, as previously published: Group 1 had dysfunction confined to the macula; Group 2 had macular and generalized cone system dysfunction; and Group 3 had macular and both generalized cone and rod system dysfunction. At baseline, there were 27 patients in Group 1, 17 in Group 2, and 15 in Group 3. Amplitude reduction of >50% in the relevant electroretinogram (ERG) component or a peak time shift of >3 ms for the 30 Hz flicker ERG or bright flash a-wave was considered clinically significant ERG deterioration. Molecular screening of ABCA4 was undertaken. Results: The mean age at baseline was 31.7 years, with the mean follow-up interval being 10.5 years. A total of 22% of patients from Group 1 showed ERG group transition during follow-up, with 11% progressing to Group 2 and 11% to Group 3. Forty-seven percent of patients in Group 2 progressed to Group 3. There was clinically significant ERG deterioration in 54% of all subjects: 22% of Group 1, 65% of Group 2, and 100% of Group 3. At least 1 disease-causing ABCA4 variant was identified in 47 patients. Conclusions: All patients with initial rod ERG involvement demonstrated clinically significant electrophysiologic deterioration; only 20% of patients with normal full-field ERGs at baseline showed clinically significant progression. Such data assist counseling by providing more accurate prognostic information and are also highly relevant in the design, patient selection, and monitoring of potential therapeutic interventions. © 2013 by Elsevier Inc. All Rights Reserved.

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Visante optical coherence tomography and tear function test evaluation of cholinergic treatment response in patients with Sjögren syndrome

Ibrahim Osama M A, Dogru Murat, Kawashima Shinichi, Wakamatsu Tais H., Tsubota Kazuo, Fujishima Hiroshi

Cornea 32 （ 5 ） 653 - 657 2013年05月

ISSN 0277-3740

Purpose: To evaluate tear meniscus changes in patients with Sjögren syndrome (SS) receiving oral pilocarpine with Visante optical coherence tomography (OCT). Methods: Eight patients with primary SS were recruited in this prospective interventional case series study. Patients received pilocarpine tablets twice a day for 3 months. Visual analog scale assessment for dry eye and dry mouth symptoms was carried out. Patients underwent OCT and slit-lamp microscopy graticule scale tear meniscus height (TMH) measurements, strip meniscometry testing, tear film breakup time measurement, fluorescein and Rose Bengal staining, and the Schirmer 1 test. The data were analyzed 1 week, 1 month, and 3 months after treatment. Mann-Whitney test was performed. Results: Visual analog scale assessment showed a significant time-wise improvement (P < 0.05). OCT and graticule scale TMH measurements significantly improved after 1 week (P < 0.05), 1 month, and 3 months of treatment (P < 0.001). Strip meniscometry, mean tear film stability, and fluorescein and Rose Bengal scores remained improved 3 months after treatment (P < 0.001), whereas Schirmer 1 test values tended to improve without statistical significance. Conclusions: Visante OCT was effective in monitoring tear meniscus changes during the course of treatment noninvasively and quickly. Oral pilocarpine seemed to be effective in improving TMH, and the signs and symptoms of dryness in patients with SS. © 2013 Lippincott Williams & Wilkins.

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Comparison of retention rates and complications of 2 different types of silicon lacrimal punctal plugs in the treatment of dry eye disease

Kaido Minako, Ishida Reiko, Dogru Murat, Tsubota Kazuo

American Journal of Ophthalmology 155 （ 4 ） 2013年04月

ISSN 0002-9394

Purpose: To investigate the retention rate and complications of 2 different types of silicon lacrimal punctal plugs with the focus on the relationship to punctum size. Design: A prospective, nonrandomized, interventional, comparative study. Method: Forty-four patients with dry eye syndrome received lacrimal punctal plug insertion with the Punctal Plug F (FCI Ophthalmics) and 30 patients received plug insertion with the Super Flex plug (Eagle Vision; Softplug-Oasis Medical Inc). In total, 110 plug insertion regions were performed using the Punctal Plug F (group A) and 110 insertion regions were carried out using Super Flex plug (group B). The gauging system of Eagle Vision was used before the lacrimal punctal plug insertion in all subjects. Plug conditions (retention rates, spontaneous plug loss, and removal) and complications related to lacrimal punctal sizes were compared between the 2 groups. Results: Retention rates were 70.4% in group A and 30.1% in group B at 6 months. Spontaneous plug loss occurrence was significant with the larger lacrimal punctum size in group A (P <.05), whereas no significant differences were observed between lacrimal punctum sizes and spontaneous loss in group B. Spontaneous plug loss occurrence was significant in elderly patients in group B (P <.05). Granuloma and injector troubles were observed in 1 and 2 cases in group A, respectively. Conclusions: The Punctal Plug F seems to be more applicable for insertion into the smaller punctal sizes. Punctum size and age seem to be important factors in determining the appropriate types of lacrimal punctal plugs. © 2013 BY ELSEVIER INC. ALL RIGHTS RESERVED.

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