Details of a Researcher - Tsubota, Kazuo

Papers - Tsubota, Kazuo

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Hydrogen and N-acetyl-L-cysteine rescue oxidative stress-induced angiogenesis in a mouse corneal alkali-burn model

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

Investigative Ophthalmology and Visual Science 52 ( 1 ) 427 - 433 2011.01

ISSN 0146-0404

PURPOSE. To investigate the role of reactive oxygen species (ROS) as the prime initiators of the angiogenic response after alkali injury of the cornea and observe the effects of antioxidants in preventing angiogenesis. METHODS. The corneal epithelia of SOD-1-deficient mice or wild-type (WT) mice were removed after application of 0.15 N NaOH to establish the animal model of alkali burn. ROS production was semiquantitatively measured by dihydroethidium (DHE) fluorescence. Angiogenesis was visualized by CD31 immunohistochemistry. The effects of the specific NF-κB inhibitor DHMEQ, the antioxidant N-acetyl-L-cysteine (NAC), and hydrogen (H₂) solution were observed. RESULTS. ROS production in the cornea was enhanced immediately after alkali injury, as shown by increased DHE fluorescence (P< 0.01). NF-κB activation and the upregulation of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) were significantly enhanced (P< 0.01), leading to a significantly larger area of angiogenesis. Angiogenesis in SOD-1^-/- mice corneas were significantly higher in WT mice (P<0.01), confirming the role of ROS. Pretreatment with the specific NF-κB inhibitor DHMEQ or the antioxidant NAC significantly reduced corneal angiogenesis by downregulating the NF-κB pathway (P<0.01) in both WT and SOD-1^-/- mice. Furthermore, we showed that irrigation of the cornea with hydrogen (H₂) solution significantly reduced angiogenesis after alkali-burn injury (P<0.01). CONCLUSIONS. Immediate antioxidant therapy with H₂-enriched irrigation solution is a new potent treatment of angiogenesis in cornea to prevent blindness caused by alkali burn. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

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Functional visual acuity measurement in cataract and intraocular lens implantation

Yamaguchi Takefumi, Negishi Kazuno, Tsubota Kazuo

Current Opinion in Ophthalmology 22 ( 1 ) 31 - 36 2011.01

ISSN 1040-8738

Purpose of review: Recently, functional visual acuity (FVA) measurement has been reported to be an important method of determining 'masked impairment of visual function' and assessing visual acuity in detail. This review discusses a new continuous FVA measurement system for the assessment of visual performance and introduces the application of FVA measurement in cataract and intraocular lens implantation. Recent findings: The FVA was first developed to detect impaired visual function for daily activities in dry eye syndrome. The usefulness of this new methodology has been described in patients with tear instability, undergoing laser-assisted in-situ keratomileusis surgery, with Stevens-Johnson syndrome, Sjögren syndrome and mild cataract opacities. The microstructure of the lenticular opacities is highly variable (nucleus sclerosis and/or posterior capsular cataract and/or cortical opacity) causing a combination of different effects on the incident light rays that can be refracted, reflected, absorbed or scattered. In some cases, patients have a good visual acuity but may complain of disturbances in vision quality. We reported the improvement of FVA after cataract surgery in patients with mild cataracts and visual symptomatology despite a good preoperative and postoperative conventional visual acuity. To detect visual impairment due to cataract, measurement of FVA was useful in the evaluation of vision quality and changes in kinetic vision after phacoemulsification surgery. Summary: FVA measurement is an effective and noninvasive test that reflects the complaints of blurring/glare and postoperative satisfaction in patients with mild cataract. © 2010 Wolters Kluwer Health.

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In vivo evaluation of ocular demodicosis using laser scanning confocal microscopy

Kojima Takashi, Ishida Reiko, Sato Enrique Adan, Kawakita Tetsuya, Ibrahim Osama M A, Matsumoto Yukihiro, Kaido Minako, Dogru Murat, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 52 ( 1 ) 565 - 569 2011.01

ISSN 0146-0404

PURPOSE. To investigate the applicability of in vivo laser scanning confocal microscopy in the diagnosis and follow-up of ocular demodicosis infestation in a prospective controlled study. METHODS. Fifteen right eyes of 15 patients with blepharitis associated with cylindrical dandruff (10 males, 5 females; mean age: 62.9 ± 9 years) and eight right eyes of eight age- and sex-matched control subjects underwent HRTII/RCM, evaluation of ocular symptom scores, tear function tests including vital stainings, Schirmer test, and tear clearance test, and evaluation of mite numbers in the eyelids. RESULTS. In vivo confocal microscopy effectively disclosed the mites in the terminal bulbs of the eyelashes, which were not observed after treatment. Eyelids with demodicosis infestation showed marked inflammatory infiltrates around the meibomian glands and conjunctiva, which cleared with tea tree oil treatment. CONCLUSIONS. Laser scanning confocal microscopy seems to be an efficient noninvasive tool in the diagnosis and follow-up of ocular demodicosis infestation. © 2011 The Association for Research in Vision and Ophthalmology, Inc.

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Interferometry in the evaluation of precorneal tear film thickness in dry eye

Hosaka Eri, Kawamorita Takushi, Ogasawara Yuko, Nakayama Nanami, Uozato Hiroshi, Shimizu Kimiya, Dogru Murat, Tsubota Kazuo, Goto Eiki

American Journal of Ophthalmology 151 ( 1 ) 2011.01

ISSN 0002-9394

Purpose To compare tear film thickness between normal subjects and aqueous tear deficiency dry eye patients by tear interferometry. Design Prospective case-control study. Methods Central precorneal tear film thickness was measured noninvasively using an interference thin-film thickness measurement device (Quore MSPA1100; Mamiya-OP). Tear film thickness of 14 eyes from 14 normal subjects and of 28 eyes from 28 aqueous tear deficiency dry eye patients were compared along with noninvasively measured tear meniscus height, DR-1 (Kowa) dry eye severity grading, fluorescein and rose bengal staining scores, tear film break-up time, and Schirmer test results. Among dry eye patients, 13 eyes underwent punctal occlusion, and tear film thickness was compared before and after the surgery. Results Tear film was significantly thinner in dry eye patients (2.0 ± 1.5 μm) than normal subjects (6.0 ± 2.4 μm; P < .0001). Tear film thickness showed good correlation with other dry eye examinations. After punctal occlusion, tear film thickness increased significantly from 1.7 ± 1.5 μm to 4.9 ± 2.8 μm (P = .001) with the improvement of tear meniscus height, fluorescein and rose bengal staining scores, tear film break-up time, and Schirmer test values. Conclusions Interferometric tear film thickness measurement revealed impaired precorneal tear film formation in aqueous tear deficiency dry eyes and was useful for showing the reconstruction of tear film after punctal occlusion surgery. Interferometry of precorneal tear film may be helpful for the evaluation of aqueous tear deficiency in conjunction with other dry eye examinations.

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Porous silk fibroin film as a transparent carrier for cultivated corneal epithelial sheets

Higa Kazunari, Takeshima Naomi, Moro Fumika, Kawakita Tetsuya, Kawashima Motoko, Demura Makoto, Shimazaki Jun, Asakura Tetsuo, Tsubota Kazuo, Shimmura Shigeto

Journal of Biomaterials Science, Polymer Edition 22 ( 17 ) 2261 - 2276 2011

ISSN 0920-5063

Biological carriers, such as the amniotic membrane and serum-derived fibrin, are currently used to deliver cultivated corneal epithelial sheets to the ocular surface. Such carriers require being transparent and allowing the diffusion of metabolites in order to maintain a healthy ocular surface. However, safety issues concerning biological agents encouraged the development of safer, biocompatible materials as cell carriers. We examined the application of porous silk fibroin films with high molecular permeability prepared by mixing silk fibroin and poly(ethylene glycol) (PEG), and then removal of PEG from the silk-PEG films. Molecular permeability of porous silk fibroin film is higher than untreated silk fibroin film. Epithelial cells were isolated from rabbit limbal epithelium, and seeded onto silk fibroin coated wells and co-cultured with mitomycin C-treated 3T3 fibroblasts. Stratified epithelial sheets successfully engineered on porous silk fibroin film expressed the cornea-specific cytokeratins K3 and K12, as well as the corneal epithelial marker pax6. Basement membrane components such as type-IV collagen and integrin β1 were expressed in the stratified epithelial sheets. Further more, colony-forming efficiency of dissociated cells was similar to primary corneal epithelial cells showing that progenitor cells were preserved. The biocompatibility of fibroin films was confirmed in rabbit corneas for up to 6 months. Porous silk fibroin film is a highly transparent, biocompatible material that may be useful as a carrier of cultivated epithelial sheets in the regeneration of corneal epithelium. © Koninklijke Brill NV, Leiden, 2011.

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Neural degeneration in the retina of the streptozotocin-induced type 1 diabetes model

Ozawa Yoko, Kurihara Toshihide, Sasaki Mariko, Ban Norimitsu, Yuki Kenya, Kubota Shunsuke, Tsubota Kazuo

Experimental Diabetes Research 2011 2011

ISSN 1687-5214

Diabetic retinopathy, a vision-threatening disease, has been regarded as a vascular disorder. However, impaired oscillatory potentials (OPs) in the electroretinogram (ERG) and visual dysfunction are recorded before severe vascular lesions appear. Here, we review the molecular mechanisms underlying the retinal neural degeneration observed in the streptozotocin-(STZ-) induced type 1 diabetes model. The renin-angiotensin system (RAS) and reactive oxygen species (ROS) both cause OP impairment and reduced levels of synaptophysin, a synaptic vesicle protein for neurotransmitter release, most likely through excessive protein degradation by the ubiquitin-proteasome system. ROS also decrease brain-derived neurotrophic factor (BDNF) and inner retinal neuronal cells. The influence of both RAS and ROS on synaptophysin suggests that RAS-ROS crosstalk occurs in the diabetic retina. Therefore, suppressors of RAS or ROS, such as angiotensin II type 1 receptor blockers or the antioxidant lutein, respectively, are potential candidates for neuroprotective and preventive therapies to improve the visual prognosis. © 2011 Yoko Ozawa et al.

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Transcriptional factors associated with epithelial-mesenchymal transition in choroidal neovascularization

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

Molecular Vision 17 1222 - 1230 2011

Purpose: To investigate the transcriptional factors associated with epithelial-mesenchymal transition (EMT) in choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) Methods: Paraffin sections of CNV obtained from patients with AMD (n=12) were stained for transcriptional factors related to EMT, i.e., Snail, Slug, SIP1, and Twist. As a control, postmortem sections of ocular normal tissue were used. Furthermore, using a human retinal pigment epithelial (RPE) cell line (ARPE-19), reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence microscopy were performed to explore the cellular localization and expression levels of EMT-associated transcriptional factors upon cytokine stimulation. Results: Of 12 specimens, 11 CNV tissues (91.6%) showed staining for Snail localized in cellular nuclei, particularly in those of RPE cells. Snail was strongly co-localized with α-smooth muscle antigen (SMA) in RPE cells. In contrast, postmortem human retina showed no Snail staining in RPE cells. Other transcriptional factors, Slug, Twist and SIP1 were not detected in CNV or normal human retina. In ARPE-19 cells, RT-PCR and immunofluorescence microscopy showed that Snail mRNA was upregulated by transforming growth factor (TGF)-β and VEGF stimulation. Furthermore, TGF-β induced relocalization of Snail to the nucleus in RPE cells. Conclusions: The current data indicate that Snail is a major transcriptional factor for EMT changes of RPE cells in human CNV. © 2011 Molecular Vision.

Four cases of corneal perforation in patients with chronic graft-versus-host disease

Inagaki Emi, Ogawa Yoko, Matsumoto Yukihiro, Kawakita Tetsuya, Shimmura Shigeto, Tsubota Kazuo

Molecular Vision 17 598 - 606 2011

ISSN 1090-0535

Purpose: To report the clinical features and investigate the underlying pathological processes of spontaneous corneal perforation in patients with ocular chronic graft-versus-host disease (cGVHD). Methods: A full ophthalmological evaluation of corneal perforation in four patients with cGVHD was performed. Three of them underwent deep anterior lamellar keratoplasty and samples from two of three patients were used for histopathological analyses. Results: Three patients were successfully treated by corneal transplantation. One patient was treated with a therapeutic soft contact lens, and the wound healed within 2 days. The common clinical features of these patients were (1) the presence of definite dry eye related to cGVHD in 3 of 4 patients and probable dry eye in one patient, (2) a central or paracentral site of corneal ulceration and perforation, with no sign of infection, and (3) prior use of a topical or systemic corticosteroid, and/or topical non-steroidal anti-inflammatory drugs. Immunohistochemical findings revealed an increased number of cluster of differentiation 68⁺ (CD68⁺) macrophages and matrix metalloproteinase 9 (MMP-9) expression in the tissue surrounding the perforation. Conclusions: Our report extends current information on the clinical features and pathological processes of corneal perforation in cGVHD by showing increased MMP-9 expression and the accumulation of CD68⁺ positive macrophages in the affected areas. © 2011 Molecular Vision.

Comparison of telomere length and association with progenitor cell markers in lacrimal gland between sjögren syndrome and non-sjögren syndrome dry eye patients

Kawashima Motoko, Kawakita Tetsuya, Maida Yoshiko, Kamoi Mizuka, Ogawa Yoko, Shimmura Shigeto, Masutomi Kenkichi, Tsubota Kazuo

Molecular Vision 17 1397 - 1404 2011

ISSN 1090-0535

Purpose: Indicators of aging such as disruption of telomeric function due to shortening may be more frequent in dysfunctional lacrimal gland. The aims of this study were to 1) determine the viability of quantitative fluorescence in situ hybridization of telomeres (telo-FISH) for the assessment of telomere length in lacrimal gland in Sjögren and non- Sjögren syndrome patients; and 2) investigate the relationship between progenitor cell markers and telomere length in both groups. Methods: Quantitative fluorescence in situ hybridization with a peptide nucleic acid probe complementary to the telomere repeat sequence was performed on frozen sections from human lacrimal gland tissues. The mean fluorescence intensity of telomere spots was automatically quantified by image analysis as relative telomere length in lacrimal gland epithelial cells. Immunostaining for p63, nucleostemin, ATP-binding cassette, sub-family G, member 2 (ABCG2), and nestin was also performed. Results: Telomere intensity in the Sjögren syndrome group (6,785.0±455) was significantly lower than that in the non- Sjögren syndrome group (7,494.7±477; p=0.02). Among the samples from the non-Sjögren syndrome group, immunostaining revealed that p63 was expressed in 1-3 acinar cells in each acinar unit and continuously in the basal layer of duct cells. In contrast, in the Sjögren syndrome group, p63 and nucleostemin showed a lower level of expression. ABCG2 was expressed in acinar cells in both sjogren and non-Sjogren syndrome. Conclusions: The results of this study indicate that 1) telo-FISH is a viable method of assessing telomere length in lacrimal gland, and 2) telomere length in Sjögren syndrome is shorter and associated with lower levels of expression of p63 and nucleostemin than in non-Sjögren syndrome. © 2011 Molecular Vision.

[Demodex-related marginal blepharitis in Japan].

Kawakita Tetsuya, Kawashima Motoko, Ibrahim Osama, Murato Dogru, Tsubota Kazuo

Nippon Ganka Gakkai zasshi 114 ( 12 ) 1025 - 1029 2010.12

ISSN 0029-0203

Some marginal blepharitis is related to demodex, but this has not yet been reported in Japan. In this study, patients with severe marginal blepharitis with cylindrical dandruff were studied to examine the number of demodex in their cilia. Ten eyes of 10 patients (7 men and 3 women, mean age: 62.9 +/- 9.0 years) with unilateral marginal blepharitis which had cylindrical dandruff in their cilia were studied. Three cilia which had the most cylindrical dandruff were removed from the eyelids for microscopic examination. After cleaning the eyelid margins for 1 week, the examination was repeated. Scoring of itching and foreign body sensation of the patients was performed both before and after the treatment. Demodex folliculorum was detected in the cilia of 8 out of 10 eyes (80%), and 22 cilia out of 30 with cylindrical dandruff. The average number of demodex/cilia was 1.6 +/- 0.9. In all cases, the number of demodex/cillium decreased significantly with the improvement in symptoms and blepharitis. An Increase in the number of demodex might be the pathogen causing blepharitis with cylindrical dandruff, and cleaning of the eyelid margin is effective as a therapeutic method.

"Proud of our new era in internationalism" 15th annual meeting of the Kyoto cornea club, December 4-5, 2009

Tsubota Kazuo, Inoue Yoshitsugu, Oshika Tetsuro

Cornea 29 ( SUPPL. 1 ) 2010.11

ISSN 0277-3740

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Increased serum total antioxidant status and decreased urinary 8-hydroxy-2′-deoxyguanosine levels in patients with normal-tension glaucoma

Yuki Kenya, Murat Dogru, Kimura Itaru, Tsubota Kazuo

Acta Ophthalmologica 88 ( 7 ) 2010.11

ISSN 1755-375X

Purpose:- To investigate the amount of systemic oxidative stress-related DNA damage and serum total antioxidant status of patients with normal-tension glaucoma compared with healthy controls. Methods:- Forty-three patients with normal-tension glaucoma selected from 60 consecutive newly diagnosed patients with primary open-angle glaucoma were enrolled. Each patient's intraocular pressure (IOP) was measured seven times over a 24-hour period. Those whose highest IOP was over 21mmHg were excluded. Forty control subjects were recruited. The serum total antioxidant status was assessed colorimetrically by its ability to reduce the generation of the radical cation ABTS (2,2-azinobis-3-ethylbenzthiazoline sulphonate). The urinary 8-hydroxy-2′-deoxyguanosine was measured as a marker of oxidative DNA damage and normalized to creatinine. The results were compared between healthy subjects and patients with normal-tension glaucoma. Results:- The control and normal-tension glaucoma groups did now show significant differences for age, gender, serum fructosamine, cholesterol and triglyceride levels; systolic and diastolic blood pressure, body mass index; and prevalence of hypertension. The serum total antioxidant status was significantly higher (p=0.01) and the urinary 8-hydroxy-2′-deoxyguanosine/creatinine level significantly lower (p=0.03) in the patients with normal-tension glaucoma compared with the controls. Even after we adjusted the data for independent variables, the incidence of normal-tension glaucoma was significantly correlated with high serum total antioxidant levels (p=0.03; odds ratio, 1.007; 95% confidence interval, 1.001-1.013) and low urinary 8-hydroxy-2′-deoxyguanosine/creatinine (p=0.02; odds ratio 0.76; 95% confidence interval, 0.61-0.96). Conclusions:- Increased serum total antioxidant and decreased 8-hydroxy-2′- deoxyguanosine may reflect compensatory alterations in response to increased systemic oxidative stress in patients with normal-tension glaucoma. © 2010 Acta Ophthalmol.

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Immune processes and pathogenic fibrosis in ocular chronic graft-versus-host disease and clinical manifestations after allogeneic hematopoietic stem cell transplantation

Ogawa Yoko, Shimmura Shigeto, Dogru Murat, Tsubota Kazuo

Cornea 29 ( SUPPL. 1 ) 2010.11

ISSN 0277-3740

Activation of the immune system and progressive fibrosis are prominent features of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation. The main histologic findings in affected exocrine glands are marked fibrosis of the interstitium and prominent increase in the number of fibroblasts, accompanied by mild lymphocytic infiltration. Clinically, the severity of dry eye is correlated with the degree of fibrotic changes, rather than with the amount of lymphocytic infiltration, indicating that excessive extracellular matrix accumulation primarily contributes to the exocrine dysfunction. We have found that accumulated fibroblasts in the lacrimal gland of patients with cGVHD have a chimeric status. Thus, fibroblasts originating from circulating donor-derived precursors and recipient-derived fibroblasts by local epithelial mesenchymal transition may participate in the excessive fibrosis in patients with cGVHD by interacting with T cells. In this article, the immune response and pathogenic fibrosis in ocular cGVHD will be discussed. In addition, clinical findings of ocular complications after hematopoietic stem cell transplantation and currently available treatment will also be discussed. © 2010 by Lippincott Williams & Wilkins.

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The anti-oxidative role of ABCG2 in corneal epithelial cells

Kubota Miyuki, Shimmura Shigeto, Miyashita Hideyuki, Kawashima Motoko, Kawakita Tetsuya, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 51 ( 11 ) 5617 - 5622 2010.11

ISSN 0146-0404

PURPOSE. ABCG2 is a putative marker of progenitor cells, including the corneal epithelium. The authors investigated whether ABCG2 functions in the homeostasis of corneal epithelial cells using abcg2 knockout (KO) mice and corneal epithelial cell lines. METHODS. abcg2 KO mice and a spontaneously immortalized murine corneal epithelial cell line (TKE2) were used for experiments. Flow cytometry was used to determine the presence of side population (SP) cells based on the ability of ABCG2 to efflux Hoechst 33342 dye. Expression of ABCG2 was also examined by RT-PCR. Cytotoxicity assay (IC ₅₀) and propidium iodide staining were performed in semiconfluent cells treated with hypoxia (1% O ₂) or with the pro-oxidant mitoxantrone. RESULTS. abcg2 KO mice had a normal corneal epithelial phenotype; however, cultured abcg2 KO epithelial cells were prone to oxidative damage by mitoxantrone. TKE2 cells were resistant to mitoxantrone at low doses, but higher concentrations were toxic in a dose-dependent manner. Coculture with the ABCG2 inhibitors reserpine and Ko143 inhibited resistance to mitoxantrone, with a statistically higher cell death ratio. abcg2 KO cells were also significantly more sensitive to hypoxia than were wild-type control cells. CONCLUSIONS. ABCG2 may protect corneal epithelial progenitor SP cells against oxidative stress induced by toxins and hypoxia. © Association for Research in Vision and Ophthalmology.

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Simultaneous deep anterior lamellar keratoplasty and limbal allograft in bilateral limbal stem cell deficiency

Omoto Masahiro, Shimmura Shigeto, Hatou Shin, Ichihashi Yoshiyuki, Kawakita Tetsuya, Tsubota Kazuo

Japanese Journal of Ophthalmology 54 ( 6 ) 537 - 543 2010.11

ISSN 0021-5155

Purpose: To report the efficacy of simultaneous keratolimbal allograft (KLAL) surgery and deep anterior lamellar keratoplasty (DALK) for limbal stem cell deficiency (LSCD). Methods: We conducted a retrospective, interventional case series of six consecutive eyes of five patients with LSCD and stromal opacity due to gelatinous drop-like dystrophy (two eyes), Stevens-Johnson syndrome (SJS, two eyes), or aniridia (two eyes). Only patients with normal lid anatomy and Schirmer test values greater than 3 mm were enrolled. DALK was performed by viscodissection followed by a thin, 360° KLAL designed by using an artificial anterior chamber. KLAL sutures were removed after 2 weeks. Results: DALK and KLAL were successfully performed in all eyes, which were followed for an average of 17.2 ± 10.8 months. All eyes recovered a smooth corneal epithelium, although one SJS patient developed a persistent epithelial defect (PED) leading to opacification of the central cornea. Visual acuity improved by more than 2 lines in all eyes except that of the SJS patient with PED. No other complications were observed. Conclusion: Simultaneous DALK and thin-section KLAL is an effective treatment for ocular surface disease in patients with residual tear function and normal lid anatomy. © 2010 Japanese Ophthalmological Society (JOS).

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Application of visante optical coherence tomography tear meniscus height measurement in the diagnosis of dry eye disease

Ibrahim Osama M A, Dogru Murat, Takano Yoji, Satake Yoshiyuki, Wakamatsu Tais Hitomi, Fukagawa Kazumi, Tsubota Kazuo, Fujishima Hiroshi

Ophthalmology 117 ( 10 ) 1923 - 1929 2010.10

ISSN 0161-6420

Purpose: To investigate the applicability of tear meniscus height (TMH) measurement using Visante optical coherence tomography (OCT) in the diagnosis of dry eye disease. Design: Prospective, controlled, single-center study. Participants: Twenty-four right eyes of 24 patients (6 males, 18 females; mean age, 63.14±13.4 years) with definite dry eye according to the Japanese dry eye diagnostic criteria and 27 right eyes of 27 control subjects (12 males, 15 females; mean age, 56.04±14.22 years) were recruited. Methods: All subjects underwent slit-lamp TMH measurement, OCT upper and lower TMH measurements, tear film breakup time (BUT) measurements, vital stainings, and Schirmer test. The results were compared between the 2 groups by Mann-Whitney test. Main Outcome Measures: The correlation between the clinical findings of slit-lamp TMH, strip meniscometry examination, tear functions, vital staining scores, and the OCT upper and lower TMH parameters were tested by Spearman's correlation test. Receiver operating characteristic (ROC) curve technique was used to evaluate the sensitivity, specificity and cutoff values of OCT TMH examination in the diagnosis of dry eye. Results: The OCT upper and lower TMH values, slit-lamp TMH, strip meniscometry, tear film BUT, and vital staining scores were significantly lower in the dry eye patients compared with controls (P<0.001). A significant correlation between the OCT upper and lower TMH measurements as well as slit-lamp TMH, strip meniscometry, tear functions, vital staining scores, and the Schirmer test was found. The ROC curve technique analysis of the OCT lower TMH showed that, when the cutoff value was set at <0.30 mm, the sensitivity and specificity of the testing were 67% and 81%, respectively. Conclusions: The Visante OCT is a quick, noninvasive method for assessing the TMH, with acceptable sensitivity, specificity, and repeatability, and may have potential applications for the diagnosis and evaluation of dry eye disease. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2010 American Academy of Ophthalmology.

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Comparison of anterior and posterior corneal surface irregularity in descemet stripping automated endothelial keratoplasty and penetrating keratoplasty

Yamaguchi Takefumi, Negishi Kazuno, Yamaguchi Kazuko, Dogru Murat, Uchino Yuichi, Shimmura Shigeto, Tsubota Kazuo

Cornea 29 ( 10 ) 1086 - 1090 2010.10

ISSN 0277-3740

Purpose: To evaluate the irregularity of the anterior and posterior cornea after Descemet stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty (PK). Methods: This clinical study comprised 39 eyes: 13 consecutive eyes after DSAEK, 13 consecutive eyes after PK, and 13 age-matched normal eyes. Corneal elevation data were acquired using a rotating Scheimpflug camera 1 and 3 months after DSAEK and PK. Anterior and posterior corneal elevation data were decomposed into a set of Zernike polynomials up to eighth order. Total higher-order root mean square (RMS) and RMS from third to eighth order were calculated. The astigmatism and irregularity of the anterior and posterior surfaces were compared between DSAEK and PK. Results: The regular astigmatism and tilt components of the anterior surface were significantly lower after DSAEK than after PK at 1 and 3 months (P < 0.001), whereas there was no difference in astigmatism of the posterior surface between the groups (P = 0.07, 0.22). The higher-order RMS and RMSs of third- to eighth-order components of the anterior surface were significantly larger after PK than those after DSAEK at 1 and 3 months (P < 0.01), whereas there were no significant differences between DSAEK and PK in higher-order aberration RMS and RMSs of third- to eighth-order components of the posterior surface. Conclusions: Postoperative corneal irregularity of the anterior surface was greater after PK than after DSAEK, whereas there was no significant difference in posterior surface irregularity. DSAEK is superior to PK in terms of the higher-order irregularity of the anterior surface. Copyright © 2010 by Lippincott Williams & Wilkins.

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Topography-guided conductive keratoplasty

Kato Naoko, Toda Ikuko, Kawakita Tetsuya, Sakai Chikako, Tsubota Kazuo

American Journal of Ophthalmology 150 ( 4 ) 2010.10

ISSN 0002-9394

Purpose: To evaluate the use of topography-guided conductive keratoplasty in eyes with keratoconus. Design: Interventional case series. Methods: We examined 21 eyes in 21 patients with advanced keratoconus. Topography-guided conductive keratoplasty was performed with intraoperative monitoring of corneal astigmatism using a surgical keratometer. Uncorrected visual acuity (UCVA), best spectacle-corrected visual acuity (BSCVA), corneal topography, manifest refraction, intraocular pressure (IOP), corneal endothelial cell counts, complications, and eventual outcomes were evaluated. Results: UCVA (logarithm of the minimal angle of resolution [logMAR]), which was 1.65 ± 0.49 preoperatively, improved to 1.04 ± 0.64 at 1 week (P < .001) and 1.12 ± 0.61 at 1 month after surgery (P < .001). BSCVA, which was 1.02 ± 0.56 preoperatively, improved to 0.76 ± 0.65 at 1 week (P = .026) and 0.76 ± 0.60 at 1 month after surgery (P = .003). Manifest refraction, which was -15.13 ± 6.66 diopters (D) before surgery, declined to -9.97 ± 6.71 D at 1 month after surgery (P = .002). Although corneal topography reverted to the preoperative pattern and UCVA and BSCVA also regressed toward preoperative values, 12 of 21 eyes were better able to tolerate and conduct normal daily activities using contact lenses. Five subjects have undergone or are considering corneal transplantation after unsatisfactory postoperative results. No serious perioperative complication was observed. Conclusions: Topography-guided conductive keratoplasty may be effective in reshaping corneal configuration in eyes with keratoconus, without serious complications, and possibly contributed to avoiding or delaying corneal transplantation. © 2010 Elsevier Inc. All Rights Reserved.

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Resveratrol prevents light-induced retinal degeneration via suppressing activator protein-1 activation

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

American Journal of Pathology 177 ( 4 ) 1725 - 1731 2010.10

ISSN 0002-9440

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

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Elevated serum immunoglobulin G titers against chlamydia pneumoniae in primary open-angle glaucoma patients without systemic disease

Yuki Kenya, Kimura Itaru, Shiba Daisuke, Imamura Yutaka, Tsubota Kazuo

Journal of Glaucoma 19 ( 8 ) 535 - 539 2010.10

ISSN 1057-0829

Purpose: To determine if Chlamydia pneumoniae infection is associated with primary open-angle glaucoma (POAG). Patients and Methods: Consecutive patients with newly diagnosed primary POAG attending the Glaucoma clinic of Keio University Hospital between June 2007 and January 2008 were considered for inclusion in this prospective case-control study. Forty consecutive POAG patients and 41 normal healthy individuals as a control population met the inclusion criteria. The exclusion criteria for both groups were; taking steroids or immunosuppressive agents, smoking, and history of any acute or chronic systemic disease including stroke, heart attack, diabetes mellitus, hypertension, asthma, and autoimmune diseases. The serum was analyzed for C. pneumoniae and C. trachomatis immunoglobulin G antibody titers by enzyme-linked immunosorbent assay. Seroactivity to each antigen between case and control groups was evaluated by Mann-Whitney U test. Results: The age, male/female ratio, and intraocular pressure of the cases and control groups were not significantly different. Immunoglobulin G titers for C. pneuemoniae was significantly higher in patients with POAG than in controls (P=0.009). The titers to C. trachomatis were not significantly different between the 2 groups (P=0.99). Conclusion: The results suggest that higher C. pneumoniae titers are associated with POAG. If confirmed, this may indicate either a common factor that causes susceptibilities to both glaucoma and C. pneumoniae infection or that C. pneumoniae may be a causal factor for developing POAG. Copyright © 2010 by Lippincott Williams & Wilkins.

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