研究者詳細 - 坪田　一男

論文 - 坪田　一男

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Multivariable logistic regression model

Shiba Daisuke, Hatou Shin, Ono Takeshi, Hosoda Shingo, Tanabe Sachiko, Ozeki Naoki, Yuki Kenya, Shimoyama Masaru, Fukagawa Kazumi, Shimmura Shigeto, Tsubota Kazuo

PLoS ONE 9 （ 8 ） e104126 2014年

PURPOSE: To design a mathematical model that can predict the relationship between the ganglion cell complex (GCC) thickness and visual field sensitivity (VFS) in glaucoma patients.DESIGN: Retrospective cross-sectional case series.METHOD: Within 3 months from VFS measurements by the Humphrey field analyzer 10-2 program, 83 eyes underwent macular GCC thickness measurements by spectral-domain optical coherence tomography (SD-OCT). Data were used to construct a multiple logistic model that depicted the relationship between the explanatory variables (GCC thickness, age, sex, and spherical equivalent of refractive errors) determined by a regression analysis and the mean VFS corresponding to the SD-OCT scanned area. Analyses were performed in half or 8 segmented local areas as well as in whole scanned areas. A simple logistic model that included GCC thickness as the single explanatory variable was also constructed. The ability of the logistic models to depict the real GCC thickness/VFS in SAP distribution was analyzed by the χ2 test of goodness-of-fit. The significance of the model effect was analyzed by analysis of variance (ANOVA).RESULTS: Scatter plots between the GCC thickness and the mean VFS showed sigmoid curves. The χ2 test of goodness-of-fit revealed that the multiple logistic models showed a good fit for the real GCC thickness/VFS distribution in all areas except the nasal-inferior-outer area. ANOVA revealed that all of the multiple logistic models significantly predicted the VFS based on the explanatory variables. Although simple logistic models also exhibited significant VFS predictability based on the GCC thickness, the model effect was less than that observed for the multiple logistic models.CONCLUSIONS: The currently proposed logistic models are useful methods for depicting relationships between the explanatory variables, including the GCC thickness, and the mean VFS in glaucoma patients.

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International chronic ocular graft-vs-host-disease (GVHD) consensus group

Ogawa Yoko, Kim Stella K., Dana Reza, Clayton Janine, Jain Sandeep, Rosenblatt Mark I., Perez Victor L., Shikari Hasanain, Riemens Anjo, Tsubota Kazuo

Scientific Reports 3 2013年12月

The International Chronic Ocular GVHD Consensus Group held 4 working meetings to define new diagnostic metrics for chronic ocular graft-versus-host disease (GVHD). After considering the factors currently used to diagnose chronic ocular GVHD, the Consensus Group identified 4 subjective and objective variables to measure in patients following allogeneic hematopoietic stem cell transplantation (HSCT): OSDI, Schirmer's score without anesthesia, corneal staining, and conjunctival injection. Each variable was scored 0-2 or 0-3, with a maximum composite score of 11. Consideration was also given to the presence or the absence of systemic GVHD. On the basis of their composite score and the presence or absence of systemic GVHD, patients were assigned to one of three diagnostic categories: NO, PROBABLE, or DEFINITE ocular GVHD. New diagnostic criteria for chronic ocular GVHD are presented by the Consensus Group. Validation studies are needed to identify the best combination of the proposed metrics to maximize diagnostic sensitivity and specificity.

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Validation of Na,k-ATPase pump function of corneal endothelial cells for corneal regenerative medicine

Hatou Shin, Higa Kazunari, Inagaki Emi, Yoshida Satoru, Kimura Erika, Hayashi Ryuhei, Tsujikawa Motokazu, Tsubota Kazuo, Nishida Kohji, Shimmura Shigeto

Tissue Engineering - Part C: Methods 19 （ 12 ） 901 - 910 2013年12月

ISSN 1937-3384

Tissue-engineering approaches to cultivate corneal endothelial cells (CECs) or induce CECs from stem cells are under investigation for the treatment of endothelial dysfunction. Before clinical application, a validation method to determine the quality of these cells is required. In this study, we quantified the endothelial pump function required for maintaining the corneal thickness using rabbit CECs (RCECs) and a human CEC line (B4G12). The potential difference of RCECs cultured on a permeable polyester membrane (Snapwell), B4G12 cells on Snapwell, or B4G12 cells on a collagen membrane (CM6) was measured by an Ussing chamber system, and the effect of different concentrations of ouabain (Na,K-ATPase specific inhibitor) was obtained. A mathematical equation derived from the concentration curve revealed that 2 mM ouabain decreases pump function of RCECs to 1.0 mV, and 0.6 mM ouabain decreases pump function of B4G12 on CM6 to 1.0 mV. Ouabain injection into the anterior chamber of rabbit eyes at a concentration of <2 mM maintained the corneal thickness, while those over 3 mM significantly increased the corneal thickness. B4G12 cell sheets transplanted into rabbit eyes treated with 0.6 mM ouabain maintained the corneal thickness, while 3.5 mM ouabain significantly increased the corneal thickness. Taken together, pump function >1.0 mV is required to maintain the corneal thickness. These results can be used for standardization of CEC pump function and validation of tissue-engineered CEC sheets for clinical use. © Copyright 2013, Mary Ann Liebert, Inc. 2013.

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Changing trends in the treatment of dry-eye disease

Dogru Murat, Nakamura Masatsugu, Shimazaki Jun, Tsubota Kazuo

Expert Opinion on Investigational Drugs 22 （ 12 ） 1581 - 1601 2013年12月

ISSN 1354-3784

Introduction: Dry eye is a visually disabling disease encountered in many countries with a wide variation of treatment practices all over the world. On that front, the 2007 Report of the International Dry Eye WorkShop (DEWS) reviewed the current knowledge on all aspects of dry-eye disease (DED), in an evidence-based manner, and outlined the trends and recommendations in the treatment of DED on the basis of disease severity. Areas covered: This review mainly focuses on treatments for DED based on severity as recommended in the DEWS report, particularly artificial eye drops, hyaluronate sodium eye drops, autologous serum, anti-inflammatory eye drops including cyclosporine and steroids, and mucin secretagogues. New dry-eye treatment modalities in current trials outlined on the clinicaltrial.gov site are also outlined. Expert opinion: Further investigations into the mechanism of action of the new mucin and tear secretagogues which have been suggested to have anti-inflammatory properties will enrich our understanding in relation to relevant ocular surface responses after treatment with these new agents. © 2013 Informa UK, Ltd. © 2013 Informa UK, Ltd.

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Efficacy of a novel moist cool air device in office workers with dry eye disease

Hirayama Masatoshi, Murat Dogru, Liu Ying, Kojima Takashi, Kawakita Tetsuya, Tsubota Kazuo

Acta Ophthalmologica 91 （ 8 ） 756 - 762 2013年12月

ISSN 1755-375X

Purpose: To evaluate the efficacy and safety of new moist cool air device (MCAD) for ocular symptoms, tear film stability and ocular surface status in office workers with dry eye disease (DED). Methods: In this prospective single-centre clinical trial, 40 eyes of 20 patients with DED were recruited and randomly divided into two groups (group with MCAD exposure and group without MCAD). All subjects are visual display terminals (VDTs) workers spending at least 4 h/day in front of VDTs. Patients using MCAD underwent moist air applications for 4 h/day for a total of five working weekdays during VDT works at their offices. The other group of patients performed their VDT work without moist cool air device exposure. The change in symptoms of ocular surface (OS) dryness, fatigue and discomfort was evaluated using visual analogue scale (VAS) scores. Changes in visual function, tear functions and ocular surface status were evaluated using best-corrected visual acuity (BCVA), the functional visual acuity (FVA) test, blink rate, BUT measurements, strip meniscometry (SM), tear evaporation rate, fluorescein staining and rose bengal staining scores. Tear film lipid layer interferometry was also performed to assess the status of the lipid layer over the tear film. In addition, adverse events were recorded. Results: In group with MCAD, symptoms of OS dryness during VDTs work, and FVA and BUT were significantly improved. SM and tear evaporation rate were significantly improved. There were no statistically significant differences on lipid layer stability and corneal staining scores in both groups. Blink rate was significantly increased in group without MCAD. No adverse events were reported during this trial. Conclusion: Moist cool air device use provided symptomatic relief of ocular dryness and improvement on tear stability in office workers with DED. This new device seems to be a safe and promising alternative in the treatment of DED. © 2012 The Authors. Acta Ophthalmologica © 2012 Acta Ophthalmologica Scandinavica Foundation.

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Pupillographic evaluation of relative afferent pupillary defect in glaucoma patients

Ozeki Naoki, Yuki Kenya, Shiba Daisuke, Tsubota Kazuo

British Journal of Ophthalmology 97 （ 12 ） 1538 - 1542 2013年12月

ISSN 0007-1161

Aim: To evaluate the association between the magnitude of relative afferent pupillary defect (RAPD) and the laterality of visual fields in glaucoma patients using pupillography. Methods: Evaluations were made with an RAPDx (Konan Medical USA, Irvine, California, USA), which is designed to analyse pupil responses to multiple colour stimuli (white, red, green, blue, and yellow) at multiple controlled stimulus intensities. Humphrey automated perimetry (SITA standard 30-2) was performed to determine mean deviations (MDs), which were used to evaluate associations between MD differences (better eye MD - worse eye MD) and RAPDx amplitude and latency measurements in pupil response to multiple colour stimuli. Results: 58 glaucoma patients (35 men, 23 women; mean age: 62.6±12.8 years; range 28-88 years) were enrolled. The MD values were -2.00±3.1 (range -9.64 to 2.33) dB in the better eyes and -8.17±7.1 (range -26.33 to 1.07) dB in the worse eyes. The differences in MD values (better eye MD - worse eye MD) were 6.17±6.1 (range 0.05-26.41) dB. The results of linear regression analysis between the log-scaled RAPD amplitudes and differences in MD values were as follows: white: R2=0.45 (p<0.001), red: R2=0.18 (p=0.002), green: R2=0.30 (p<0.001), blue: R2=0.29 (p<0.001), and yellow: R2=0.32 (p<0.001). The log-scaled RAPD latencies and the differences in MD values were: white: R2=0.17 (p=0.001), red: R2=0.03 (p=0.22), green: R2 =0.01 (p=0.52), blue: R2=0.1 (p=0.02), and yellow: R2=0.05 (p=0.11). Conclusions: The log-scaled RAPD amplitudes correlated moderately with the differences in MD values, but the log-scaled RAPD latencies showed a weaker correlation. Stimulation with white light produced the strongest correlation with differences in MD values.

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Future direction of the anti-aging medicine

Kawashima Motoko, Tsubota Kazuo

Japanese Journal of Clinical Urology 67 （ 13 ） 1019 - 1022 2013年12月

ISSN 0385-2393

A longitudinal study of Stargardt disease

Fujinami Kaoru, Lois Noemi, Mukherjee Rajarshi, McBain Vikki A., Tsunoda Kazushige, Tsubota Kazuo, Stone Edwin M., Fitzke Fred W., Bunce Catey, Moore Anthony T., Webster Andrew R., Michaelides Michel

Investigative ophthalmology & visual science 54 （ 13 ） 8181 - 8190 2013年12月

We characterized subtypes of fundus autofluorescence (AF) and the progression of retinal atrophy, and correlated these findings with genotype in Stargardt disease. Full clinical examination and AF imaging was undertaken in 68 patients with Stargardt disease. The baseline data were compared to those at follow-up. Patients were classified into three AF subtypes: type 1 had a localized low signal at the fovea surrounded by a homogeneous background, type 2 had a localized low signal at the macula surrounded by a heterogeneous background with numerous foci of abnormal signal, and type 3 had multiple low signal areas at the posterior pole with a heterogeneous background. At baseline, there were 19 patients with type 1, 41 with type 2, and 8 with type 3 disease. The areas of reduced AF signal were measured and rate of atrophy enlargement (RAE) was calculated as the difference of the atrophy size over time (mm²) divided by the follow-up interval (years). Molecular screening of ABCA4 was undertaken. The mean follow-up interval was 9.1 years. A total of 42% cases with type 1 disease progressed to type 2, and 12% with type 2 progressed to type 3. The RAE (mm²/y) based upon baseline AF subtypes was significantly different; 0.06 in type 1, 0.67 in type 2, and 4.37 in type 3. ABCA4 variants were identified in 57 patients. There was a significant association between AF subtype and genotype. The AF pattern at baseline influences the enlargement of atrophy over time and has genetic correlates. These data are likely to assist in the provision of counseling on prognosis in Stargardt disease and be valuable for future clinical trials.

The association between visual field defect severity and fear of falling in primary open-angle glaucoma

Yuki Kenya, Tanabe Sachiko, Kouyama Keisuke, Fukagawa Kazumi, Uchino Miki, Shimoyama Masaru, Ozeki Naoki, Shiba Daisuke, Ozawa Yoko, Abe Takayuki, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 54 （ 12 ） 7739 - 7745 2013年11月

ISSN 0146-0404

Purpose. To determine if glaucomatous visual field defect severity is associated with fear of falling. Methods. This is a cross-sectional study. A total of 387 consecutive subjects with POAG were enrolled in this study along with 293-ocular disease-free control subjects, who were screened at the same institutions. We defined mild POAG as MD of -6 dB or better, moderate POAG as MD of -6 to -12 dB, and severe POAG as MD of -12 dB or worse in the better eye. All participants were requested to answer a questionnaire on fear of falling. Associations between POAG severity and the prevalence of fear of falling were evaluated with the Cochran-Armitage trend test. Multivariable factors including age-adjusted odds ratios (ORs) for the prevalence of fear of falling and 95% confidence intervals (CIs) were evaluated with logistic regression models. Results. The p revalence of fear of falling was 35/293 (11.9%) in the control group, 38/313 (12.1%) in the mild POAG group, 12/48 (25.0%) in the moderate POAG group, and 6/26 (23.1%) in the severe POAG group, and the trend was statistically significant (P =0.028 Cochran-Armitage trend test). The adjusted ORs for prevalence in the mild, moderate, and severe POAG groups compared with that in the control group were 1.44 (95% CI: 0.83-2.51), 2.33 (95% CI: 1.00-5.44), and 4.06 (95% CI: 1.39-11.90), respectively. Conclusions. Among patients with POAG, the severity of visual field defects is associated with fear of falling. (http://www.umin.ac.jp/ctr/index.htm number, UMIN000005574.). © 2013 The Association for Research in Vision and Ophthalmology, Inc.

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The effects of 2% rebamipide ophthalmic solution on the tear functions and ocular surface of the superoxide dismutase-1 (sod1) knockout mice

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

Investigative Ophthalmology and Visual Science 54 （ 12 ） 7793 - 7802 2013年11月

ISSN 0146-0404

Purpose. To investigate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status of the superoxide dismutase-1(Sod1^-/-) mice. Methods. Two percent Rebamipide ophthalmic solution was applied to 40-week-old male Sod1^-/- and wild-type (WT) mice four times a day for 2 weeks. We examined the cytokine concentrations in the tear fluid (by CytoBead assay), tear film break-up time, amount of tear production, and expressions of mucins 1, 4, and 5AC, by RT-PCR. We also performed vital staining of the ocular surface, PAS staining for muc5AC, and immunohistochemical stainings for 4-hydroxy-2-nonenal (4-HNE), 8-hydroxy-2′-deoxyguanosine (8-OHdG), in the conjunctiva to compare the Results before and after rebamipide instillations. Results. The tear functions and ocular surface epithelial damage scores were significantly worse in the Sod1^-/- than in the WT mice. Application of 2% rebamipide for 2 weeks significantly improved the tear film break-up time, the amount of tear production, and the corneal epithelial damage scores, which also significantly increased the conjunctival goblet cell density and muc5 mRNA expression, in the Sod1^-/- mice. The mean IL-6, IL-17, TNF-α, and IFN-γ levels in the tear fluid were reduced significantly along with a significant decrease in the density of cells positive for 4-HNE and 8-OHdG in the conjunctiva. Conclusions. Two percent Rebamipide ophthalmic solution significantly improved the tear stability and corneal epithelial damage, and enhanced the expression of muc5 mRNA on the ocular surface. We also observed anti-inflammatory effects in the tear film together with antioxidative effects in the conjunctiva, suggesting the efficacy of rebamipide in age-related dry eye disease attributable to SOD1 knockout. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

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The clinical effect of homozygous ABCA4 ALLELES in 18 patients

Fujinami Kaoru, Sergouniotis Panagiotis I., Davidson Alice E., Mackay Donna S., Tsunoda Kazushige, Tsubota Kazuo, Robson Anthony G., Holder Graham E., Moore Anthony T., Michaelides Michel, Webster Andrew R.

Ophthalmology 120 （ 11 ） 2324 - 2331 2013年11月

ISSN 0161-6420

Purpose: To describe the phenotypic presentation of a cohort of individuals with homozygous disease-associated ABCA4 variants. Design: Retrospective case series. Participants: Eighteen affected individuals from 13 families ascertained from a total cohort of 214 families with ABCA4-related retinal disease presenting to a single center. Methods: A detailed history was obtained, and color fundus photography, autofluorescence (AF) imaging, optical coherence tomography (OCT), and electrophysiologic assessment were performed. Phenotypes based on ophthalmoscopy, AF, and electrophysiology were assigned using previously reported characteristics. ABCA4 mutation detection was performed using the ABCR400 microarray (Asper Biotech, Tartu, Estonia) and high-throughput DNA sequencing, with direct sequencing used to assess segregation. Main Outcome Measures: Detailed clinical, electrophysiologic, and molecular genetic findings. Results: Eleven disease-associated homozygous ABCA4 alleles were identified, including 1 frame shift, 2 stops, 1 intronic variant causing splice-site alteration, 2 complex missense variants, and 5 missense variants: p.Glu905fsX916, p.Arg1300X, p.Gln2220X, c.4253+4 C>T, p.Leu541Pro and p.Ala1038Val (homozygosity for complex allele), p.Val931Met and p.Arg1705Gln (complex allele), p.Arg212Cys, p.Cys1488Arg, p.Arg1640Trp, p.Gly1961Glu, and p.Leu2027Phe. Eight of these 11 homozygous alleles have not been reported previously. Six of 7 patients with homozygous null alleles had early-onset (<10 years) disease, with all 7 having a severe phenotype. Two patients with homozygous missense variants (p.Leu541Pro and p.Ala1038Val [complex], and p.Arg1640Trp) presented with a severe phenotype. Three patients with homozygous p.Gly1961Glu had adult-onset disease and a mild phenotype. One patient with homozygous p.Leu2027Phe showed a spared fovea and preserved visual acuity. Conclusions: The phenotypes represented in patients identified as homozygous for presumed disease-associated ABCA4 variants gives insight into the effect of individual alleles. Null alleles have severe functional effects, and certain missense variants are similar to nulls, suggesting complete abrogation of protein function. The common alleles identified, p.Gly1961Glu and p. Leu2027Phe, both have a mild structural and functional effect on the adult retina; the latter is associated with relatively retained photoreceptor architecture and function at the fovea. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. © 2013 by the American Academy of Ophthalmology.

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Postoperative flat anterior chamber

Ono Takeshi, Yuki Kenya, Shiba Daisuke, Abe Takayuki, Kouyama Keisuke, Tsubota Kazuo

Japanese Journal of Ophthalmology 57 （ 6 ） 520 - 528 2013年11月

ISSN 0021-5155

Purpose: To investigate the long-term effects of postoperative flat anterior chamber (FAC) development on outcomes following trabeculectomy with mitomycin C. Methods: This was a retrospective cohort study. Data on 383 consecutive patients (383 eyes) who underwent trabeculectomy at our institution between 1999 and 2009 were followed up. Patients who developed FAC after trabeculectomy and patients with maintained anterior chamber were evaluated. The primary outcome variable was the success of the initial trabeculectomy, which was defined at 3 different levels by the achievement of the following intraocular pressure (IOP)-related criteria without secondary IOP-lowering surgery: (a) IOP ≤ 12 mmHg and ≤30 % reduction in IOP from the preoperative level; (b) IOP ≤ 16 mmHg and ≤20 % reduction in IOP; and (c) IOP ≤ 21 mmHg. The hazard ratios (HRs) for the failure of trabeculectomy caused by FAC within 5 years of surgery were examined in conjunction with the Cox proportional hazards regression model. Results: FAC was observed in 90 of the 383 eyes examined (23.4 %). Postoperative mild FAC was associated with the long-term success of trabeculectomy when evaluated according to our strictest success criterion, Criterion-A [HR = 0.72 (95 % CI 0.53-0.98); P = 0.04]. In contrast, severe FAC was inversely associated with the long-term success of the surgery when evaluated according to our most lenient criterion, Criterion-C [HR = 1.93 (95 % CI 1.16-3.22); P = 0.01]. Conclusion: Mild postoperative FAC after trabeculectomy is associated with a favorable long-term outcome, whereas severe postoperative FAC leads to an unfavorable prognosis. © 2013 Japanese Ophthalmological Society.

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Light-dark condition regulates sirtuin mRNA levels in the retina

Ban Norimitsu, Ozawa Yoko, Inaba Takaaki, Miyake Seiji, Watanabe Mitsuhiro, Shinmura Ken, Tsubota Kazuo

Experimental Gerontology 48 （ 11 ） 1212 - 1217 2013年11月

ISSN 0531-5565

Sirtuins (Sirt1-7) are nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylases/ADP-ribosyltransferases that modulate many metabolic responses affecting aging. Sirtuins expressed in tissues and organs involved in systemic metabolism have been extensively studied. However, the characteristics of sirtuins in the retina, where local energy expenditure changes dynamically in response to light stimuli, are largely unknown. Here we analyzed sirtuin mRNA levels by real-time PCR, and found that all seven sirtuins are highly expressed in the retina compared with other tissues, such as liver. We then analyzed the sirtuin mRNA profiles in the retina over time, under a 12-h light/12-h dark cycle (LD condition) and in constant darkness (DD condition). All seven sirtuins showed significant daily variation under the LD condition, with all except Sirt6 being increased in the dark phase. The expression patterns were different under the DD condition, suggesting that sirtuin mRNA levels except Sirt6 are affected by light-dark condition. These findings were not obtained in the brain and liver. In addition, the mRNA expression patterns of Nicotinamide phosphoribosyltransferase (Nampt), peroxisome proliferator-activated receptor gamma coactivator (PGC1α), and transcription factor A, mitochondrial (Tfam) in the retina, were similar to those of the sirtuins except Sirt6. Our observations provide new insights into the metabolic mechanisms of the retina and the sirtuins' regulatory systems. © 2013 The Authors.

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Keratoplasty postoperative treatment update

Shimmura-Tomita MacHiko, Shimmura Shigeto, Satake Yoshiyuki, Shimazaki-Den Seika, Omoto Masahiro, Tsubota Kazuo, Shimazaki Jun

Cornea 32 （ 11 SUPPL ） 2013年11月

ISSN 0277-3740

Immunosuppressive therapy is the main postoperative treatment for keratoplasty, but there are considerable differences in protocols for the use of steroids and other immunosuppressants. Therefore, we conducted 2 prospective randomized clinical trials and 1 prospective nonrandomized clinical trial on keratoplasty postoperative treatment. One study evaluated the efficacy and safety of long-term topical corticosteroids after a penetrating keratoplasty was performed. Patients who underwent keratoplasty and maintained graft clarity for >1 year were randomly assigned to either a steroid or a no-steroid group. At the 12-month follow-up, the no-steroid group developed significantly more endothelial rejection than did the steroid group. A second study elucidated the effectiveness and safety of systemic cyclosporine in high-risk corneal transplantation. The patients were assigned to a systemic cyclosporine or control group. At a mean follow-up of 42.7 months, no difference was observed in the endothelial rejection rates and graft clarity loss between the 2 groups. A third study elucidated the effectiveness and the safety of systemic tacrolimus in high-risk corneal transplantation. Of 11 consecutive eyes decompensated despite systemic cyclosporine treatment, there was no irreversible rejection in eyes treated with tacrolimus, which was significantly better than in previous penetrating keratoplasty with systemic cyclosporine treatment. Prognosis after keratoplasty in patients with keratoconus is relatively good, but special attention is required for patients with atopic dermatitis. Postkeratoplasty atopic sclerokeratitis (PKAS) is a severe form of sclerokeratitis after keratoplasty in atopic patients. Our retrospective study showed that 35 eyes of 29 patients from a total of 247 keratoconus eyes undergoing keratoplasty were associated with atopic dermatitis, of which 6 eyes of 5 patients developed PKAS. Eyes with PKAS had a significantly higher incidence of atopic blepharitis and preoperative corneal neovascularization, and therefore, we suggest systemic corticosteroids or cyclosporine to prevent PKAS in such high-risk cases. © 2013 by Lippincott Williams & Wilkins.

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Expression and distribution of claudin subtypes in human corneal endothelium

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

Investigative Ophthalmology and Visual Science 54 （ 12 ） 7258 - 7265 2013年10月

ISSN 0146-0404

Purpose. To investigate the expression pattern of claudins in human corneal endothelium, and to evaluate the functional role of the claudin-10b subtype. Methods. Corneal endothelium with Descemet's membrane and the corneal epithelium were stripped from donor human corneal stroma. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate the claudin subtypes expressed in corneal endothelium, stroma, and epithelium. Immunohistochemistry was performed to confirm the expression of claudin subtypes in corneal endothelium, and the expression pattern was compared to that of corneal epithelium. Finally, transendothelial resistance (TER), short-circuit current (SCC), and potential difference (PD) were measured in human corneal endothelial cell line B4G12 cells with or without claudin-10 small interfering RNA (siRNA) transfection by Ussing chamber system. Results. Transcripts for claudin-1, -2, -3, -4, -7, -10b, -11, -15, -22, -23, and -24 were identified in corneal endothelium sample by RT-PCR. Immunohistochemistry confirmed the expression of claudin-1, -2, -4, -7, -10, -11 -15, -22, and -23 in corneal endothelium. In corneal stroma, claudin-1, -2, -3, -4, -5, -6, -7, -8, -10b, -11, -12, -14, -15, -22, -23, and -24 were identified by RTPCR. In corneal epithelium, claudin-1, -3, -4, -7, -11, -14, and -23 were identified by immunohistochemistry and RT-PCR. Downregulation of claudin-10b by siRNA resulted in the decrease of SCC and PD, but not TER, in B4G12 cells. Conclusions. The expression pattern of claudin-10b⁺/claudin-14^- was specific in corneal endothelium among the three corneal layers. Claudin-10b may play an important role in the tight junction of corneal endothelium. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

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Secondary implantation of piggyback intraocular lens for residual refractive error after cataract surgery

Kobayashi Fumitaka, Torii Hidemasa, Negishi Kazuno, Watanabe Kazuhiro, Saiki Megumi, Tsubota Kazuo

Japanese Journal of Clinical Ophthalmology 67 （ 10 ） 1679 - 1684 2013年10月

ISSN 0370-5579

Purpose: To report a case who received implantation of piggyback intraocular lens (IOL) for residual refractive error after cataract surgery. Case: A 70-year-old man presented to our clinic complaining of decreased visual acuity in his both eyes. Both eyes had received radial keratotomy 23 years before and photorefractive keratectomy 12 years before. Findings: Visual acuity was 0.5 right and 0.4 left without correction, and 0.9 right and 1.0 left with correction. Under diagnosis of age-related cataract, both eyes received phacoemulsification-aspiration with IOL implantation. Visual acuity was 0.5 in either eye without correction and 1.2 right and 1.0 left with correction one year later. The left eye had refraction of +3.00D()cyl-2.00D 65°. By request of the patient, monofocal piggyback IOL was implanted into the left eye. Six months after surgery, left visual acuity was 0.63 without and 1.0 with correction. There has been no complication throughout. Conclusion: Implantation of piggyback IOL can be a therapeutic option for residual refractive error after cataract surgery.

Calorie restriction (CR) and CR mimetics for the prevention and treatment of age-related eye disorders

Kawashima Motoko, Ozawa Yoko, Shinmura Ken, Inaba Takaaki, Nakamura Shigeru, Kawakita Tetsuya, Watanabe Mitsuhiro, Tsubota Kazuo

Experimental Gerontology 48 （ 10 ） 1096 - 1100 2013年10月

ISSN 0531-5565

The morbidity of ocular diseases, including macular degeneration, diabetic retinopathy, and dry eye disease, has been gradually increasing worldwide. Because these diseases develop from age-associated ocular dysfunctions, interventions against the aging process itself may be a promising strategy for their management. Among the several approaches to interrupt aging processes, calorie restriction (CR) has been shown to recover and/or slow age-related functional declines in various organs, including the eye. Here, we review interventions against the aging process as potential therapeutic approaches to age-related ocular diseases. The effects of CR and CR mimetics in animal models of age-related eye diseases are explored. Furthermore, we discuss the possibilities of expanding this research to prospective studies to elucidate the molecular mechanisms by which CR and/or CR mimetics preserve ocular functions. © 2013 The Authors.

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Changes in higher-order aberrations after iris-fixated phakic intraocular lens implantation

Torii Hidemasa, Negishi Kazuno, Watanabe Kazuhiro, Saiki Megumi, Kato Naoko, Tsubota Kazuo

Journal of Refractive Surgery 29 （ 10 ） 693 - 700 2013年10月

ISSN 1081-597X

PURPOSE: To evaluate surgically induced changes in corneal, internal, and ocular higher-order aberrations (HOAs) after phakic intraocular lens (PIOL) implantation and compare them between two PIOLs with different pupillary diameters. METHODS: Twenty-three eyes with an Artisan PIOL (Ophtec BV, Groningen, The Netherlands) (Artisan group) and 30 eyes with an Artiflex PIOL (Ophtec BV) (Artiflex group) were retrospectively evaluated. The corneal, internal, and ocular HOAs and refractive data were recorded preoperatively and 6 months postoperatively. The root mean squares (RMSs) of the total HOAs from the third- to sixth-order Zernike coefficients were calculated. The RMSs of the third- and fourth-order coefficients represented coma-like aberrations (S3) and spherical-like aberrations (S4), respectively. The main outcome measures were the differences in the parameters among the groups with different pupillary diameters. RESULTS: The mean postoperative spherical equivalents decreased from -11.84 ± 4.90 to -0.16 ± 0.40 diopters and -9.78 ± 3.20 to -0.09 ± 0.26 diopters in the Artisan and Artiflex groups, respectively. With the 4- and 5-mm pupillary diameters, the postoperative internal and ocular spherical aberrations (Z₄⁰) were significantly lower in the Artiflex group than in the Artisan group (4 mm, P = .002, .024; 5 mm, P = .004, .022, respectively). With the 6-mm pupillary diameter, there were no significant postoperative differences in any parameter measured between groups; both groups had positive spherical aberration values. CONCLUSIONS: The postoperative ocular spherical aberrations were positive after Artisan and Artiflex implantation. The postoperative ocular spherical aberration was greater in the Artisan group, possibly due to differences in the SAs of both PIOLs. Copyright © SLACK Incorporated.

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Prevalence of dry eye disease and its risk factors in visual display terminal users

Uchino Miki, Yokoi Norihiko, Uchino Yuichi, Dogru Murat, Kawashima Motoko, Komuro Aoi, Sonomura Yukiko, Kato Hiroaki, Kinoshita Shigeru, Schaumberg Debra A., Tsubota Kazuo

American Journal of Ophthalmology 156 （ 4 ） 2013年10月

ISSN 0002-9394

Purpose To investigate tear function and prevalence of dry eye disease (DED) in visual display terminal (VDT) users. Design Cross-sectional study. Methods Six hundred and seventy-two young and middle-aged Japanese office workers who used VDT completed questionnaires and underwent dry eye testing. We estimated the prevalence of DED using logistic regression analysis to examine associations between DED and possible risk factors. The ocular surface feature, prevalence of DED, and risk factors were evaluated. Results Of the 672 workers, 561 (83.5%, mean age: 43.3 ± 9.1 years) completed the questionnaire. The percentage of women with a composite outcome of definite DED or probable DED was 76.5%, which was higher than that among men (60.2%; odds ratio [OR] = 2.00; 95% confidence interval [CI], 1.29-3.10, P =.002). Workers over 30 years of age had a higher risk of DED (OR = 2.22; 95% CI, 1.06-4.66), as did workers using a VDT >8 hours per day (OR = 1.94; 95% CI, 1.22-3.09). Average Schirmer value was 18.7 ± 11.7 mm and tear break-up time (TBUT) was 4.0 ± 2.5 seconds (78.6% of study participants had TBUT ≤5 seconds). Conclusions DED is prevalent among young to middle-aged Japanese VDT users. Ophthalmic findings revealed short TBUT and corneal staining accompanied by normal Schirmer test values. Increased risk for DED was noted for women aged over 30 years and prolonged VDT use. Measures to modify the adverse impact of VDT use on the ocular surface may provide a positive impact on public health and quality of life for office workers using VDTs.

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Neuroprotective role of superoxide dismutase 1 in retinal ganglioncells and inner nuclear layer cells against N-methyl-d-aspartate-induced cytotoxicity

Yuki Kenya, Yoshida Tetsu, Miyake Seiji, Tsubota Kazuo, Ozawa Yoko

Experimental Eye Research 115 230 - 238 2013年10月

ISSN 0014-4835

The N-methyl- d-aspartate (NMDA) receptor-induced apoptosis is implicated in the pathological mechanisms of neural tissues, increasing the release of reactive oxygen species (ROS), resulting in a type of apoptotic cell death called excitotoxicity. Although intrinsic mechanisms to remove ROS, such as antioxidant enzymes, are provided by the tissue, the association between NMDA-induced excitotoxicity and antioxidative enzymes is not well understood. In this study, we focused on superoxide dismutase 1 (SOD1), an antioxidant enzyme, and investigated the role of SOD1 in the NMDA-induced neuronal cell death in the retina. NMDA was intravitreally injected into wild-type (WT) and SOD1 total knock-out (SOD1-deficient) mice. The number of TUNEL-positive cells in the retinal ganglion cell layer (GCL) and inner nuclear layer (INL) counted in the retinal sections and flatmount retinas were significantly higher in the SOD1-deficient mice than the WT mice after NMDA injection. Visual function assessed by dark-adapted electroretinogram (ERG) showed that the amplitudes of a-wave, b-wave, and oscillatory potential 2 were significantly reduced in the NMDA-injected SOD1-deficient mice. The level of ROS in the GCL and INL, measured using dihydroethidium, and the number of positive cells for γ-H2AX, a marker for DNA double strand breaks, and 8-OHdG, a marker for DNA oxidation, in the GCL were significantly increased in the SOD1-deficient mice after NMDA injection. We also measured mRNA and protein levels of SOD1 and SOD2 in the retina of WT mice, to find that mRNA and protein levels of SOD1, but not SOD2, were significantly reduced after NMDA injection. SOD1 deficiency exacerbated NMDA-induced damage to the inner retinal neurons, and NMDA reduced SOD1 levels in the retina of WT mice. Therefore, SOD1 protected retinal neurons against NMDA-induced retinal neurotoxicity, and NMDA-induced SOD1 reduction may be involved in neuronal vulnerability to excitotoxicity. © 2013 Elsevier Ltd.

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