研究者詳細 - 坪田　一男

論文 - 坪田　一男

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Tear lipid layer deficiency associated with incomplete blinking

Kawashima Motoko, Tsubota Kazuo

BMC Ophthalmology 13 （ 1 ） 2013年

Abstract. Background: Meibomian gland obstruction induces hyposecretion of tear film lipids, which results in lipid layer deficiency and evaporative dry eye. Unfortunately, the importance of blinking in meibomian gland dysfunction has been largely overlooked, and it is not known whether incomplete blinking causes tear lipid deficiency, even in the unobstructed meibomian glands. Case presentation. A 38-year-old woman suffering from foreign body sensations in her eyes was examined. The cornea was clear and tear secretion was normal. Lid margin abnormalities were not observed and the meibum was clear. However, the lipid layer was very thin, and the patient was given a diagnosis of incomplete blinking. The patient was made aware of her condition and asked to blink consciously and completely. After that, an immediate increase in lipid flow was observed. Conclusion: Tear lipid layer deficiency can occur with incomplete blinking, even though meibomian gland structures are intact. This case highlights the importance of complete blinking. © 2013 Kawashima and Tsubota; licensee BioMed Central Ltd.

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Disruption of cell-cell junctions and induction of pathological cytokines in the retinal pigment epithelium of light-exposed mice

Narimatsu Toshio, Ozawa Yoko, Miyake Seiji, Kubota Shunsuke, Hirasawa Manabu, Nagai Norihiro, Shimmura Shigeto, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 54 （ 7 ） 4555 - 4562 2013年

ISSN 0146-0404

PURPOSE. To elucidate the influences of light exposure on the retinal pigment epithelium (RPE) in vivo that may be involved in the pathogenesis of AMD. METHODS. Six- to 7-week-old BALB/c mice were exposed to light at 2000 lux for 3 hours. Flatmount RPE samples were immunostained with anti-ZO-1 antibody for evaluating tight junction, anti-N-cadherin, and anti-b-catenin antibodies for adherens junction, and stained with phalloidin for actin cytoskeleton. The reactive oxygen species (ROS) level was measured using DCFH-DA; Rho-associated coiled-coil forming kinase (ROCK) activity was by ELISA. Cytokine expression was analyzed by real-time RT-PCR and/or ELISA in the RPE-choroid, and macrophage recruitment was by real-time RT-PCR and immunohistochemistry. Either an antioxidant, N-Acetyl-L-cysteine (NAC), or a ROCK inhibitor, Y-27632, were administered to analyze the roles of ROS and ROCK activation, respectively. RESULTS. Light exposure disrupted staining patterns of tight junctions, adherens junctions, and actin cytoskeleton in the RPE, where ROS was elevated. However, NAC treatment avoided the RPE changes, reducing ROS. ROCK activity increased after light exposure was suppressed by NAC, and the structural disruptions were suppressed by Y-27632. The levels of MCP-1, CCL11, and IL-6 increased after light exposure were suppressed by NAC. Light-induced MCP-1 and IL- 6 were suppressed by Y-27632. Macrophage recruitment after light exposure was also suppressed either by NAC or Y-27632. CONCLUSIONS. Light exposure induced ROS and Rho/ROCK activation, which caused disruption of cell-cell junctions (tight junctions and adherens junctions) and actin cytoskeleton, the RPE's barrier structure, and induced AMD-associated pathological changes in the RPE-choroid. Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc.

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Effects of dietary supplementation with fish oil on dry eye syndrome subjects

Kawakita Tetsuya, Kawabata Fuminori, Tsuji Tomoko, Kawashima Motoko, Shimmura Shigeto, Tsubota Kazuo

Biomedical Research (Japan) 34 （ 5 ） 215 - 220 2013年

ISSN 0388-6107

The purpose of this study was to evaluate the efficacy of fish oil supplementation added to usual dry eye treatment in dry eye subjects in a randomized controlled trial. Twenty-seven typical dry eye subjects were selected from 43 candidates by the diagnostic criterion for dry eye in this study. They were assigned to the randomized fish oil group (n = 15) or the placebo group (n = 12). Fish oil group ingested fish oil capsules containing eicosapentaenoic acid (EPA, 1245 mg/day) and docosahexaenoic acid (DHA, 540 mg/day) for 12 weeks. Placebo group ingested placebo capsules without EPA or DHA. A visual analog scale test estimating subjective symptoms, the Schirmer I test, tear film break-up time (BUT) measurement, fluorescein staining, and rose bengal staining were performed every 4 weeks during the 12-week supplementation period and 4-week washout period. The subjective symptom of "eye pain", BUT, and changes in rose bengal staining score of the fish oil group were significantly improved after 8-12 weeks of supplementation and/or 4 weeks of washout, compared to those of the placebo group. These results suggest that fish oil supplementation added to usual care may be effective in the treatment of dry eye.

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The effect of 3D visual simulator on children's visual acuity - A pilot study comparing two different modalities

Ide Takeshi, Ishikawa Mariko, Tsubota Kazuo, Miyao Masaru

Open Ophthalmology Journal 7 69 - 78 2013年

Purpose: To evaluate the efficacy of two non-surgical interventions of vision improvement in children. Methods: A prospective, randomized, pilot study to compare fogging method and the use of head mounted 3D display. Subjects were children, between 5 to 15 years old, with normal best corrected visual acuity (BCVA) and up to -3D myopia. Subjects played a video game as near point work, and received one of the two methods of treatments. Measurements of uncorrected far visual acuity (UCVA), refraction with autorefractometer, and subjective accommodative amplitude were taken 3 times, at the baseline, after the near work, and after the treatment. Results: Both methods applied after near work, improved UCVA. Head mounted 3D display group showed significant improvement in UCVA and resulted in better UCVA than baseline. Fogging group showed improvement in subjective accommodative amplitude. While 3D display group did not show change in the refraction, fogging group's myopic refraction showed significant increase indicating the eyes showed myopic change of eyes after near work and treatment. Discussion: Despite our lack of clear knowledge in the mechanisms, both methods improved UCVA after the treatments. The improvement in UCVA was not correlated to measured refraction values. Conclusion: UCVA after near work can be improved by repeating near and distant accommodation by fogging and 3D image viewing, although at the different degrees. Further investigation on mechanisms of improvements and their clinical significance are warranted. © Ide et al.

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Oral voriconazole induced visual disturbances that led to the diagnosis of optic radiation lesions in a patient with aplastic anemia

Horino Takeshi, Uchida Atsuro, Mochimaru Hiroshi, Koto Takashi, Nagai Norihiro, Shinoda Hajime, Shinoda Kei, Ohde Hisao, Ozawa Yoko, Tsubota Kazuo

Folia Japonica de Ophthalmologica Clinica 5 （ 12 ） 1129 - 1133 2012年12月

ISSN 1882-5176

The Semaphorin 3A Inhibitor SM-345431 Accelerates Peripheral Nerve Regeneration and Sensitivity in a Murine Corneal Transplantation Model

Omoto Masahiro, Yoshida Satoru, Miyashita Hideyuki, Kawakita Tetsuya, Yoshida Kenji, Kishino Akiyoshi, Kimura Toru, Shibata Shinsuke, Tsubota Kazuo, Okano Hideyuki, Shimmura Shigeto

PLoS ONE 7 （ 11 ） 2012年11月

Background: Peripheral nerve damage of the cornea is a complication following surgery or infection which may lead to decreased visual function. We examined the efficacy of the semaphorin 3A inhibitor, SM-345431, in promoting regeneration of peripheral nerves in a mouse corneal transplantation model. Methodology/Principal Findings: P0-Cre/Floxed-EGFP mice which express EGFP in peripheral nerves cells were used as recipients of corneal transplantation with syngeneic wild-type mouse cornea donors. SM-345431 was administered subconjunctivally every 2 days while control mice received vehicle only. Mice were followed for 3 weeks and the length of regenerating nerves was measured by EGFP fluorescence and immunohistochemistry against βIII tubulin. Cornea sensitivity was also measured by the Cochet-Bonnet esthesiometer. CD31 staining was used to determine corneal neovascularization as a possible side effect of SM-345431. Regeneration of βIII tubulin positive peripheral nerves was significantly higher in SM-345431 treated mice compared to control. Furthermore, corneal sensitivity significantly improved in the SM-345431 group by 3 weeks after transplantation. Neovascularization was limited to the peripheral cornea with no difference between SM-345431 group and control. Conclusions/Significance: Subconjunctival injections of SM-345431 promoted a robust network of regenerating nerves as well as functional recovery of corneal sensation in a mouse keratoplasty model, suggesting a novel therapeutic strategy for treating neurotrophic corneal disease. © 2012 Omoto et al.

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Surgical management of lacrimal punctal cauterization in chronic GVHD-related dry eye with recurrent punctal plug extrusion

Yaguchi S., Ogawa Y., Kamoi M., Uchino M., Tatematsu Y., Ban Y., Ohba E., Okamoto S., Goto E., Tsubota K.

Bone Marrow Transplantation 47 （ 11 ） 1465 - 1469 2012年11月

ISSN 0268-3369

We investigated the efficacy of lacrimal punctal occlusion surgery with a cautery device in patients with chronic GVHD (cGVHD)-related dry eye, with recanalization of puncta and recurrent punctal plug extrusion. A total of 23 puncta from 14 eyes of 10 patients with chronic GVHD (cGVHD)-related dry eye underwent punctual thermal cauterization with a high-temperature disposable cautery device. All patients were refractory to conventional treatment, including artificial tear eye drops, autologous serum eye drops and vitamin A eye drops, and had a history of recanalization and recurrent punctal plug extrusion. The effect of lacrimal punctal cauterization by thermal cautery device was evaluated by changes in subjective symptom scores, corrected distance visual acuity, Schirmer's test values, fluorescein staining scores, rose bengal staining scores, and tear-film break-up time before and 3 months after the surgery. Subjective symptom scores, Schirmer's test values, fluorescein and rose bengal scores, and tear-film break-up time improved significantly 3 months after the surgery. Recanalization of puncta was not observed in all the cases (0 of 14 eyes, 0%). Lacrimal punctal cauterization was effective with no recanalization and significant improvements in subjective symptoms and the ocular surface environment in cGVHD-related dry eye patients who had been refractory to conventional treatments. © 2012 Macmillan Publishers Limited All rights reserved.

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The antiaging approach for the treatment of dry eye

Tsubota Kazuo, Kawashima Motoko, Inaba Takaaki, Dogru Murat, Matsumoto Yukihiro, Ishida Reiko, Kaido Minako, Kojima Takashi, Uchino Miki, Uchino Yuichi, Ogawa Yoko, Nakamura Shigeru, Higuchi Akihiro, Shinmura Ken, Watanabe Mitsuhiro, Kawakita Tetsuya

Cornea 31 （ 11 SUPPL.1 ） 2012年11月

ISSN 0277-3740

ABSTRACT:: Dry eye is one of the most common eye disorders affecting millions of people. It causes ocular irritation or discomfort, and decreases functional vision, causing a dramatic deterioration in the quality of life. Although new treatments such as the P2Y2 agonist or cyclosporine eye drops have been developed and a certain level of patient satisfaction can now be obtained, no fundamental treatment has been developed. Currently, there is no therapy available to recover lacrimal function to its normal status. Recent progress in the understanding of aging has laid the foundations for a new way of thinking about intervention of the aging process. Because dry eye is accelerated by aging, a useful approach for the prevention or treatment of dry eye may be to interfere with the aging process. In the scientific community, there is a global consensus that calorie restriction can extend the life span of various kinds of animals, establishing an intervention to aging. Another important hypothesis believed to be involved in aging is the free radical theory. According to these theories, the aging process may be managed by controlling levels of calories or reactive oxygen species. In this review, these 2 important aging theories, calorie restriction and free radical aging, are examined, and we discuss how to apply these theories to the prevention and treatment of dry eye. Copyright © 2012 by Lippincott Williams & Wilkins.

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A new mouse model of dry eye disease

Uchino Yuichi, Kawakita Tetsuya, Ishii Takamasa, Ishii Naoaki, Tsubota Kazuo

Cornea 31 （ 11 SUPPL.1 ） 2012年11月

ISSN 0277-3740

PURPOSE:: Oxidative damage and inflammation are proposed to be involved in the age-related functional decline of lacrimal glands. The molecular mechanism(s) of how oxidative stress affects the secretory function of lacrimal glands was investigated because this is currently unclear. METHODS:: We used a novel mev-1 conditional transgenic mouse model (Tet-mev-1) with a modified tetracycline system. The mev-1 gene encodes the cytochrome b560 large subunit of succinate-ubiquinone oxidoreductase in complex II of mitochondria. RESULTS:: Expression of the mev-1 gene induced excessive oxidative stress associated with ocular surface epithelial damage and a decrease in aqueous secretory function. Tear volume in Tet-mev-1 mice was lower than in wild-type mice, and histopathological analyses showed the hallmarks of lacrimal gland inflammation by intense mononuclear leukocytic infiltration and fibrosis in the lacrimal gland of Tet-mev-1 mice. CONCLUSIONS:: This new model provides evidence that mitochondria-induced oxidative damage in the lacrimal gland induces lacrimal dysfunction, resulting in dry eye disease. Our findings strongly suggest that oxidative stress can be a causative factor in the development of dry eye disease. Copyright © 2012 by Lippincott Williams & Wilkins.

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Oxidative Stress Induced Inflammation Initiates Functional Decline of Tear Production

Uchino Yuichi, Kawakita Tetsuya, Miyazawa Masaki, Ishii Takamasa, Onouchi Hiromi, Yasuda Kayo, Ogawa Yoko, Shimmura Shigeto, Ishii Naoaki, Tsubota Kazuo

PLoS ONE 7 （ 10 ） 2012年10月

Oxidative damage and inflammation are proposed to be involved in an age-related functional decline of exocrine glands. However, the molecular mechanism of how oxidative stress affects the secretory function of exocrine glands is unclear. We developed a novel mev-1 conditional transgenic mouse model (Tet-mev-1) using a modified tetracycline system (Tet-On/Off system). This mouse model demonstrated decreased tear production with morphological changes including leukocytic infiltration and fibrosis. We found that the mev-1 gene encodes Cyt-1, which is the cytochrome b₅₆₀ large subunit of succinate-ubiquinone oxidoreductase in complex II of mitochondria (homologous to succinate dehydrogenase C subunit (SDHC) in humans). The mev-1 gene induced excessive oxidative stress associated with ocular surface epithelial damage and a decrease in protein and aqueous secretory function. This new model provides evidence that mitochondrial oxidative damage in the lacrimal gland induces lacrimal dysfunction resulting in dry eye disease. Tear volume in Tet-mev-1 mice was lower than in wild type mice and histopathological analyses showed the hallmarks of lacrimal gland inflammation by intense mononuclear leukocytic infiltration and fibrosis in the lacrimal gland of Tet-mev-1 mice. These findings strongly suggest that oxidative stress can be a causative factor for the development of dry eye disease. © 2012 Uchino et al.

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Efficacy and safety of diquafosol ophthalmic solution in patients with dry eye syndrome

Matsumoto Yukihiro, Ohashi Yuichi, Watanabe Hitoshi, Tsubota Kazuo

Ophthalmology 119 （ 10 ） 1954 - 1960 2012年10月

ISSN 0161-6420

Objective: To investigate the dose-dependent efficacy and safety of diquafosol ophthalmic solution for the treatment of dry eye syndrome. Design: Randomized, double-masked, multicenter, parallel-group, placebo-controlled trial. Participants: A total of 286 Japanese patients with dry eye who were prescribed topical diquafosol (1%, n = 96; 3%, n = 96) or placebo ophthalmic solution (n = 94). Methods: After a washout period of 2 weeks, qualified subjects were randomized to receive a single drop of 1% or 3% diquafosol or placebo ophthalmic solutions 6 times per day for 6 weeks. Main Outcome Measures: The primary outcome measure was fluorescein corneal staining score assessment. The secondary outcome measures were Rose Bengal corneal and conjunctival staining scores, tear break-up time (BUT), and subjective symptom assessment. Safety measures were clinical blood and urine examination and recording of adverse events. Results: Fluorescein corneal staining scores significantly improved with both 1% and 3% topical diquafosol compared with placebo at 4 weeks, respectively (P = 0.037, P = 0.002). There was a dose-dependent effect among the groups. Rose Bengal corneal and conjunctival staining scores also improved significantly with both 1% and 3% diquafosol compared with placebo (P = 0.007 and P = 0.004, respectively). Subjective dry eye symptom scores significantly improved with both diquafosol ophthalmic solutions (P ≤ 0.033), although there were no significant differences in BUT compared with placebo. No significant differences between the treatment groups were observed in relation to the occurrence of adverse events. Conclusions: Both 1% and 3% diquafosol ophthalmic solutions are considered effective and safe for the treatment of dry eye syndrome. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. © 2012 American Academy of Ophthalmology.

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In vivo confocal microscopy evaluation of meibomian gland dysfunction in atopic-keratoconjunctivitis patients

Ibrahim Osama M A, Matsumoto Yukihiro, Dogru Murat, Adan Enrique Sato, Wakamatsu Tais Hitomi, Shimazaki Jun, Fujishima Hiroshi, Tsubota Kazuo

Ophthalmology 119 （ 10 ） 1961 - 1968 2012年10月

ISSN 0161-6420

Purpose: To clarify meibomian gland (MG) alterations in atopic keratoconjunctivitis (AKC) patients and compare the findings with obstructive MG dysfunction (MGD) patients and control subjects using in vivo confocal microscopy (CM). Design: Prospective, controlled, single-center study. Participants: Twelve AKC patients (10 males, 2 females; mean age, 31.0±16.5 years), 12 obstructive MGD patients (7 males, 5 females; mean age, 37.6±5.6 years), and 26 control subjects (13 males, 13 females; mean age, 32.9±5.7 years) were recruited. No significant age or gender differences were observed between the 3 groups. Methods: All subjects underwent assessment of tear evaporation rate from the ocular surface (TEROS), slit-lamp examinations, tear break-up time (BUT) measurements, vital staining, Schirmer test I, meibography, MG expressibility, and CM examination of the MG (HRTII-RCM). Statistical analysis was performed using the Mann-Whitney test. Main Outcome Measures: The MG acinar unit density, inflammatory cell density, MG acinar unit longest diameter, MG acinar unit shortest diameter, and MG acinar unit area as observed by in vivo CM, MG drop-out, MG expressibility grading, tear stability, tear evaporation, and vital staining scores. Results: The TEROS values, mean BUT, vital staining scores, MG expressibility, and MG dropout grades were significantly worse in AKC patients compared with those in obstructive MGD patients and controls (P<0.05). The mean values of the CM parameters in AKC patients were significantly worse than those observed in the obstructive MGD patients and controls (P<0.001). Conclusions: Changes in MG in AKC patients seem to be more severe than in patients with obstructive MGD and controls. In vivo CM is a noninvasive, efficient tool in the assessment of MG status and ocular surface disease in AKC. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2012 American Academy of Ophthalmology.

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A randomised, double-masked comparison study of diquafosol versus sodium hyaluronate ophthalmic solutions in dry eye patients

Takamura Etsuko, Tsubota Kazuo, Watanabe Hitoshi, Ohashi Yuichi

British Journal of Ophthalmology 96 （ 10 ） 1310 - 1315 2012年10月

ISSN 0007-1161

Aims: To compare the efficacy and safety of 3% diquafosol ophthalmic solution with those of 0.1% sodium hyaluronate ophthalmic solution in dry eye patients, using mean changes in fluorescein and rose bengal staining scores as endpoints. Trial design and methods: In this multicenter, randomised, double-masked, parallel study of 286 dry eye patients with fluorescein and rose bengal staining scores of ≥3 were randomised to the treatment groups in a 1:1 ratio. Efficacy and safety were evaluated after drop-wise instillation of the study drug, six times daily for 4 weeks. Results: After 4 weeks, the intergroup difference in the mean change from baseline in fluorescein staining score was -0.03; this verified the non-inferiority of diquafosol. The mean change from baseline in rose bengal staining score was significantly lower in the diquafosol group (p=0.010), thus verifying its superiority. The incidence of adverse events was 26.4% and 18.9% in the diquafosol and sodium hyaluronate groups, respectively, with no significant difference. Conclusions: Diquafosol (3%) and sodium hyaluronate (0.1%) exhibit similar efficacy in improving fluorescein staining scores of dry eye patients, whereas, diquafosol exhibits superior efficacy in improving rose bengal staining scores. Diquafosol has high clinical efficacy and is well tolerated with a good safety profile.

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Selenium Compound Protects Corneal Epithelium against Oxidative Stress

Higuchi Akihiro, Inoue Hiroyoshi, Kawakita Tetsuya, Ogishima Tadashi, Tsubota Kazuo

PLoS ONE 7 （ 9 ） 2012年09月

The ocular surface is strongly affected by oxidative stress, and anti-oxidative systems are maintained in corneal epithelial cells and tear fluid. Dry eye is recognized as an oxidative stress-induced disease. Selenium compound eye drops are expected to be a candidate for the treatment of dry eye. We estimated the efficacy of several selenium compounds in the treatment of dry eye using a dry eye rat model. All of the studied selenium compounds were uptaken into corneal epithelial cells in vitro. However, when the selenium compounds were administered as eye drops in the dry eye rat model, most of the selenium compounds did not show effectiveness except for Se-lactoferrin. Se-lactoferrin is a lactoferrin that we prepared that binds selenium instead of iron. Se-lactoferrin eye drops suppressed the up-regulated expression of heme oxygenase-1, cyclooxygenase-2, matrix metallopeptidase-9, and interleukin-6 and also suppressed 8-OHdG production in the cornea induced by surgical removal of the lacrimal glands. Compared with Se-lactoferrin, apolactoferrin eye drops weakly improved dry eye in high dose. The effect of Se-lactoferrin eye drops on dry eye is possibly due to the effect of selenium and also the effect of apolactoferrin. Se-lactoferrin is a candidate for the treatment of dry eye via regulation of oxidative stress in the corneal epithelium. © 2012 Higuchi et al.

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Accumulation of Secretory Vesicles in the Lacrimal Gland Epithelia Is Related to Non-Sjögren's Type Dry Eye in Visual Display Terminal Users

Kamoi Mizuka, Ogawa Yoko, Nakamura Shigeru, Dogru Murat, Nagai Toshihiro, Obata Hiroto, Ito Masataka, Kaido Minako, Kawakita Tetsuya, Okada Yasunori, Kawakami Yutaka, Shimmura Shigeto, Tsubota Kazuo

PLoS ONE 7 （ 9 ） 2012年09月

Previous observations in a rat model of a non-Sjögren's syndrome (non-SS) type of dry eye seen in users of visual display terminals (VDT) indicated that secretory vesicle (SV) accumulation in the lacrimal gland epithelia contributes to the condition. Here, to examine this possibility in humans, we compared the lacrimal gland histology and percent SV area in the cytoplasm of acinar epithelial cells using light microscopy and transmission electron microscopy, in patients with VDT work-related non-SS dry-eye (VDT group), SS-induced dry-eye, and autopsied normal controls. In addition, the VAMP8 (vesicle-associated membrane protein 8, an exocrine-pathway molecule) and Rab3D (mature vesicle marker) were histochemically examined in lacrimal gland tissue sections. The lacrimal gland acini were larger in the VDT group than in the SS group, and the percent SV area was significantly higher in the VDT group than in the normal controls (P = 0.021) or SS group (P = 0.004). Immunostaining revealed abnormal distributions of VAMP8 in the VDT and SS groups. Rab3D was more strongly expressed in the cytoplasm of acinar epithelial cells in the VDT group than in that of normal controls. The duration of VDT use was significantly longer in the VDT group than in the other groups. These findings suggest that excessive SV accumulation in the acinar epithelia may contribute to the reduced tear secretion in VDT users. © 2012 Kamoi et al.

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Comparison of domestic and overseas donor corneas for keratoplasty

Nishi Yasuyo, Kawakita Tetsuya, Yasu Masako, Ichihashi Yoshiyuki, Matsumoto Yukihiro, Shimmura Shigeto, Tsubota Kazuo

Japanese Journal of Clinical Ophthalmology 66 （ 9 ） 1337 - 1342 2012年09月

ISSN 0370-5579

Purpose: To compare the safety of domestic and overseas donor corneas for keratoplasty. Objects and Method: This study was made on 490 eyes donated to us through eyebanks in the past 5 years through 2010. The series comprised 245 eyes from domestic donors and 245 eyes from USA. Results: Age of domestic donors averaged 68.8 years and that of overseas donors averaged 63.1 years. The difference was significant (p<0.01). Corneal endothelial density averaged 2713.3 and 2515.3/mm ² respectively. The difference was significant (p<0.01). Primary graft failure occurred in 4 domestic eyes and none in overseas eyes. There was no difference in the positive rate of culture from corneal limbus or preservation medium between domestic and overseas donor eyes. Conclusion: The mean corneal endothelial density was higher in domestic than in overseas cornea. Primary graft failure was more frequent in domestic than overseas eyes. More strict quality control is desired for donated corneas.

Visual function changes after punctal occlusion with the treatment of short but type of dry eye

Kaido Minako, Ishida Reiko, Dogru Murat, Tsubota Kazuo

Cornea 31 （ 9 ） 1009 - 1013 2012年09月

ISSN 0277-3740

Purpose: To evaluate visual function changes after punctal plug (PP) occlusion in patients with short breakup time of tear film (BUT) type of dry eyes. Methods: A prospective comparative study was performed in 43 eyes of 43 dry eye patients with short BUTbreakup time of tear film receiving PP occlusion. Patients were divided into 2 groups as those receiving only upper or only lower occlusion. Functional visual acuity measurements, tear function evaluations, and questionnaire on satisfaction with treatment in relation to presence of epiphora were performed before and 1 month after PP insertion. Results: Twenty eyes of 43 eyes (46.5%) with only lower occlusion and 17 eyes of 43 eyes (39.5%) with only upper occlusion showed satisfactory outcomes with treatment. One of 43 eyes (2.3 %) had epiphora. Vital staining scores and BUT values significantly improved in both groups after occlusion. The mean logarithm of the minimum angle of resolution functional visual acuity value significantly improved only in eyes receiving upper PP occlusion. Conclusion: Upper PP occlusion seems to be associated not only with improvement of tear stability, vital staining scores, and treatment-related satisfaction but also with better quality of visual function. Copyright © 2012 by Lippincott Williams & Wilkins.

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Transplantation of side population cells restores the function of damaged exocrine glands through clusterin

Mishima Kenji, Inoue Hiroko, Nishiyama Tatsuaki, Mabuchi Yo, Amano Yusuke, Ide Fumio, Matsui Makoto, Yamada Hiroyuki, Yamamoto Gou, Tanaka Junichi, Yasuhara Rika, Sakurai Takashi, Lee Masaichi Chang Il, Chiba Kan, Sumimoto Hidetoshi, Kawakami Yutaka, Matsuzaki Yumi, Tsubota Kazuo, Saito Ichiro

Stem Cells 30 （ 9 ） 1925 - 1937 2012年09月

ISSN 1066-5099

Stem cell-based therapy has been proposed as a promising strategy for regenerating tissues lost through incurable diseases. Side population (SP) cells have been identified as putative stem cells in various organs. To examine therapeutic potential of SP cells in hypofunction of exocrine glands, SP cells isolated from mouse exocrine glands, namely, lacrimal and salivary glands, were transplanted into mice with irradiation-induced hypofunction of the respective glands. The secretions from both glands in the recipient mice were restored within 2 months of transplantation, although the transplanted cells were only sparsely distributed and produced no outgrowths. Consistent with this, most SP cells were shown to be CD31-positive endothelial-like cells. In addition, we clarified that endothelial cell-derived clusterin, a secretory protein, was an essential factor for SP cell-mediated recovery of the hypofunctioning glands because SP cells isolated from salivary glands of clusterin-deficient mice had no therapeutic potential, whereas lentiviral transduction of clusterin restored the hypofunction. In vitro and in vivo studies showed that clusterin had an ability to directly inhibit oxidative stress and oxidative stress-induced cell damage. Thus, endothelial cell-derived clusterin possibly inhibit oxidative stress-induced hypofunction of these glands. © AlphaMed Press.

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The relation between visual performance and clinical ocular manifestations in Stevens-Johnson syndrome

Kaido Minako, Yamada Masakazu, Sotozono Chie, Kinoshita Shigeru, Shimazaki Jun, Tagawa Yoshitsugu, Hara Yuko, Chikama Taiichiro, Tsubota Kazuo

American Journal of Ophthalmology 154 （ 3 ） 2012年09月

ISSN 0002-9394

Purpose: To investigate the relation between visual function, clinical findings, and visual symptoms in Stevens-Johnson syndrome (SJS) and to compare the results with Sjögren syndrome (SS) patients and normal subjects. Design: Cross-sectional comparative study. Methods: One hundred fifteen eyes of 59 consecutive patients with SJS and toxic epidermal necrolysis (TEN), 208 eyes of 104 healthy normal subjects, and 132 eyes of 66 SS patients were investigated in this multicenter study. All study subjects underwent tear function and ocular surface examinations, Landolt and functional visual acuity examinations, and the Japanese version of the NEI VFQ-25 (National Eye Institute Visual Function Questionnaire). Results: The mean ocular surface grading scores were significantly higher and the mean score of all 12 NEI VFQ subscales was significantly lower in the SJS patients compared to the SS patients and the normal subjects (P <.05). The conventional and functional logarithm of minimal angle of resolution (logMAR) visual acuities in SJS patients with minimal corneal complications were significantly higher and the mean total composite NEI VFQ scores were lower compared to SS patients. The conventional and functional logMAR visual acuities and the mean ocular surface grading scores in SJS with aqueous deficiency were significantly higher and the mean total composite NEI VFQ scores were lower compared to SS patients. Strong correlations between best-corrected logMAR functional visual acuities and either ocular surface grading scores or the composite NEI VFQ-25 scores were observed. Conclusions: The functional visual acuity examination reflects the severity of clinical ocular surface findings and vision-related quality of life more than the standard conventional visual acuity in SJS. © 2012 Elsevier Inc. All rights reserved.

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Presence and physiologic function of the renin-angiotensin system in mouse lacrimal gland

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

Investigative Ophthalmology and Visual Science 53 （ 9 ） 5416 - 5425 2012年08月

ISSN 0146-0404

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. © 2012 The Association for Research in Vision and Ophthalmology, Inc.

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