Details of a Researcher - Tsubota, Kazuo

Papers - Tsubota, Kazuo

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Mitochondrial superoxide anion overproduction in Tet-mev-1 transgenic mice accelerates age-dependent corneal cell dysfunctions

Onouchi Hiromi, Ishii Takamasa, Miyazawa Masaki, Uchino Yuichi, Yasuda Kayo, Hartman Phil S., Kawai Kenji, Tsubota Kazuo, Ishii Naoaki

Investigative Ophthalmology and Visual Science 53 ( 9 ) 5780 - 5787 2012.08

ISSN 0146-0404

Purpose. The Tet-mev-1 mouse expressing a mitochondrial complex-II mutated SDHC^V69E gene controlled by a tetracycline (Tet)-On/Off system can overproduce O₂·^- and is a versatile whole-animal model for studying mitochondrial oxidative stress. Here we report a series of age-dependent variations in corneal epithelium, endothelium, and parenchymal cells of the Tet-mev-1 mice relative to wild-type C57BL/6j mice. Methods. Measurements of (1) mitochondrial electron transport enzyme activities; (2) O₂·^- production; (3) carbonylated protein, and 8-hydroxydeoxyguanosine (8-OHdG) levels as markers of oxidative stress; (4) pathologic analyses under optical and electron microscopy; (5) hematoxylin-eosin or toluidine-blue staining; and (6) immunohistochemistry with an anti-β-catenin antibody were performed in the eye, especially the cornea. Results. Complex II-III activity was decreased by electron leakage between complex II and CoQ. This resulted in increased age-dependent intracellular oxidative stress in the eye of Tet-mev-1 mice. Corneal epithelialization was delayed in Tet-mev-1 mice after 20% ethanol treatment, as the number of cells and mitotic cells decreased in the corneal epithelium of Tet-mev-1 mice compared with that of wild type. The age-dependent decrease in cell number accelerated in the corneal endothelium cells. Moreover, it was suggested that the corneal thickness was decreased by thinning of parenchymal cells with age in Tet-mev-1 mice. Conclusions. These results suggest that mitochondrial oxidative stress with electron transport chain dysfunction can influence pathogenesis and progression of age-related corneal diseases, as well as generalized corneal aging acceleration. © 2012 The Association for Research in Vision and Ophthalmology, Inc.

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Congenital corneal staphyloma as a complication of Kabuki syndrome

Tanaka Ryuma, Takenouchi Toshiki, Uchida Keiko, Sato Takeshi, Fukushima Hiroyuki, Yoshihashi Hiroshi, Takahashi Takao, Tsubota Kazuo, Kosaki Kenjiro

American Journal of Medical Genetics, Part A 158 A ( 8 ) 2000 - 2002 2012.08

ISSN 1552-4825

Kabuki syndrome has long been clinically defined based mainly on its characteristic eye features. The recent discovery of MLL2 as a causative gene of Kabuki syndrome has enabled the extreme end of the phenotype to be explored. We herein report on two patients with striking visible congenital staphyloma at birth. A diagnosis of Kabuki syndrome was subsequently made in both patients based on a constellation of characteristic eye features, cardiac abnormalities and severe developmental delay, and finally by the confirmation of MLL2 mutations. In conclusion, congenital corneal staphyloma is a complication of Kabuki syndrome with MLL2 mutations. © 2012 Wiley Periodicals, Inc..

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Intraocular pressure elevation after Descemet's stripping endothelial keratoplasty

Ozeki Naoki, Yuki Kenya, Shiba Daisuke, Shimmura Shigeto, Murat Dogru, Tsubota Kazuo

Japanese Journal of Ophthalmology 56 ( 4 ) 307 - 311 2012.07

ISSN 0021-5155

Purpose: To investigate the incidence of intraocular pressure (IOP) elevation after Descemet's stripping endothelial keratoplasty (DSEK) and associated clinical findings. Methods: Forty-eight eyes of 46 patients who underwent DSEK were studied in this single-center retrospective study. IOP elevation was defined as the presence of an increase in IOP above 21 mmHg lasting at least two - months, the need to introduce topical/oral antiglaucoma medications for at least two months, and the need for surgical therapy for uncontrolled IOP. Patients with pre-existing glaucoma or patients who were using antiglaucoma drugs before DSEK were excluded according to the protocol of the study. The incidence of post-DSEK IOP elevation was investigated. Results: The incidence of IOP elevation after DSEK was 16.7%. Glaucoma therapy following DSEK was needed in eight eyes of eight patients. IOP elevations were diagnosed from two to ten months after DSEK. There was no statistical difference in the survival probabilities of patients with different preoperative diagnoses. Pre-op IOP was observed to be a risk factor of IOP elevation in this series. Conclusions: IOP elevation appears to be a common postoperative complication of DSEK. Patients without preexisting glaucoma but with higher pre-op IOP need to be followed up carefully after DSEK. © Japanese Ophthalmological Society 2012.

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Topic of the month

Ayaki Masahiko, Tsubota Kazuo

Japanese Journal of Clinical Ophthalmology 66 ( 7 ) 953 - 956 2012.07

ISSN 0370-5579

Low diastolic blood pressure is associated with the progression of normal-tension glaucoma

Okumura Yoshihiko, Yuki Kenya, Tsubota Kazuo

Ophthalmologica 228 ( 1 ) 36 - 41 2012.06

ISSN 0030-3755

Aims: The objective of this study was to investigate the association between blood pressure (BP) and visual field defect progression in normal-tension glaucoma (NTG). Methods: The subjects were 35 consecutive patients with NTG who were admitted to Keio University Hospital for 24-hour intraocular pressure evaluation; all subjects underwent 6 or more visual field tests in either eye and were followed up for more than 5 years. Systolic and diastolic BPs were measured at 9.00 h. Subjects with negative regression lines and p values of less than 0.05 were classified as progressive; all others were defined as stable. Systolic BP, diastolic BP, and ocular perfusion pressure were compared between the 2 groups. Results: Twelve subjects showed progression in glaucomatous visual field defects (age 55.1 ± 15.1 years). Twenty-three subjects showed no progression (age 57.2 ± 10.9 years). Diastolic BP (stable group: 77.0 ± 12.1 mm Hg; progressive group: 67.7 ± 9.7 mm Hg; p = 0.03) was significantly lower in the progressive group than in the stable group. Multivariable analysis revealed that low diastolic BP is a significant risk factor for progression (OR 0.90; 95% CI 0.82-0.99). Conclusions: Low diastolic BP was associated with glaucomatous visual field progression in subjects with NTG. Copyright © 2012 S. Karger AG, Basel.

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Characterization of cultivated murine lacrimal gland epithelial cells

Kobayashi Shinya, Kawakita Tetsuya, Kawashima Motoko, Okada Naoko, Mishima Kenji, Saito Ichiro, Ito Masataka, Shimmura Shigeto, Tsubota Kazuo

Molecular Vision 18 1271 - 1277 2012.05

ISSN 1090-0535

Purpose: To date, mouse lacrimal gland epithelial cells have been cultured successfully but only in cases involving newborn mouse lacrimal glands. In this work, we attempted to cultivate and characterize adult mouse lacrimal gland epithelial cells. Methods: Lacrimal glands were removed from newborn mice (C57B/6) and isolated lacrimal gland epithelial cells were seeded onto tissue culture treated or low adherent culture dishes in Cnt-07 culture medium with or without cholera toxin. Cultivated cells were characterized by immunostaining with pan-cytokeratin, α-smooth muscle actin, and lactoferrin antibodies. Lacrimal gland cells from 7-week-old green fluorescent protein (GFP) and non-GFP (C57B/6) mice were mixed and seeded onto uncoated dishes to assess sphere-forming efficiency. Cells were also seeded onto 3T3 cell feeder layers to assess colony forming efficiency. Results: Lacrimal gland epithelial cells were selectively cultured with cholera toxin, and cell type was verified by pancytokeratin and α-smooth muscle actin immunostaining. Sphere formation from single cells of adult mice was observed using specific medium and low adherent culture dishes. These cells could also undergo colony formation on 3T3 feeder cells. Conclusions: Adult mouse lacrimal gland epithelial cells were successfully cultivated in cholera toxin-containing medium, and were observed to form spheres from single cells. © 2012 Molecular Vision.

Punctal plugs for treatment of post-LASIK dry eye

Yung Yang Hao, Toda Ikuko, Sakai Chikako, Yoshida Atsushi, Tsubota Kazuo

Japanese Journal of Ophthalmology 56 ( 3 ) 208 - 213 2012.05

ISSN 0021-5155

Purpose: To evaluate the efficacy of punctal plugs for patients with post-LASIK dry eye. Materials and methods: A prospective study was conducted on 25 eyes of 18 patients who underwent LASIK. All eyes fulfilled the Japanese dry-eye criteria and had not responded to conventional treatment with artificial tears by 1 month postsurgery. They were randomly divided into a plug and a non-plug group. Punctal plugs were inserted into the superior and inferior puncta in the plug group after the 1-month examination. Uncorrected and best corrected visual acuity (UCVA, BCVA), refraction, functional visual acuity (FVA) after 10 s eye opening (FVA 10), surface regularity index (SRI) after 10 s eye opening (SRI 10), corneal sensitivity, Schirmer test, fluorescein staining (FS), tear break-up time (TBUT), and symptoms were compared between the groups 1 and 3 months postsurgery. Changes in these data from 1 to 3 months were also compared between the groups. Results: The values in SRI 10, FS, and TBUT were significantly better in the plug group at 3 months. Changes in the values of UCVA, FVA 10, FS, TBUT, and symptoms between 1 and 3 months improved significantly in the plug group compared with the non-plug group. Conclusion: Our results suggest that punctal occlusion for both puncta is effective for patients with post-LASIK dry eye that cannot be controlled by artificial tears alone. Punctal plugs can improve not only the symptoms and tear function, but also the quality of vision, for example FVA. © Japanese Ophthalmological Society 2012.

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Age-related dysfunction of the lacrimal gland and oxidative stress

Kojima Takashi, Wakamatsu Tais H., Dogru Murat, Ogawa Yoko, Igarashi Ayako, Ibrahim Osama M A, Inaba Takaaki, Shimizu Takahiko, Noda Setsuko, Obata Hiroto, Nakamura Shigeru, Wakamatsu Alda, Shirasawa Takuji, Shimazaki Jun, Negishi Kazuno, Tsubota Kazuo

American Journal of Pathology 180 ( 5 ) 1879 - 1896 2012.05

ISSN 0002-9440

An imbalance between free radical generation and radical scavenging antioxidant systems results in oxidative stress, which has been associated with cell injury observed in many age-related diseases. The superoxide dismutase (SOD) family is a major antioxidant system, and deficiency of Cu,Zn-superoxide dismutase-1 (Sod1) in mice leads to many different phenotypes that resemble accelerated aging. In this study we examined the morphologic features and the secretory functions of the lacrimal glands in Sod1 ^-/- mice. Lacrimal glands showed atrophy of acinar units; fibrosis; infiltration with CD4 ⁺ T cells, monocytes, and neutrophils; increased staining with both 4-hydroxy-2-nonenal and 8-hydroxy-2′-deoxyguanosine; increases in apoptotic cells; and the presence of the epithelial-mesenchymal transition in senescent Sod1 ^-/- mice. Electron microscopy findings revealed evidence of epithelial-mesenchymal transition, presence of swollen and degenerated mitochondria, and the presence of apoptotic cell death in the lacrimal glands of senescent Sod1 ^-/- mice. These alterations were also associated with the accumulation of secretory vesicles in acinar epithelial cells, decreased production of both stimulated and nonstimulated tears, and a decline in total protein secretion from the lacrimal glands. Our results suggest that Sod1 ^-/- mice may be a good model system in which to study the mechanism of reactive oxygen species-mediated lacrimal gland alterations. © 2012 American Society for Investigative Pathology.

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Improvement of accommodation with anti-oxidant supplementation in visual display terminal users

Uchino Y., Uchino M., Dogru M., Fukagawa K., Tsubota K.

Journal of Nutrition, Health and Aging 16 ( 5 ) 478 - 481 2012.05

ISSN 1279-7707

Objective: To determine the antioxidant supplementation effect on accommodation among VDT users. Design: a double blind randomized placebo controlled study. registered under clinical Trials.gov identifier no. ncT00877201. Participants and Controls: Fourty right eyes of 40 healthy VDT users (30 females, 10 males, mean age: 43.8±2.8 years, range: 40-49 years). 20 subjects (15 females, 5 males; mean age: 44.0±2.7 years, range: 40-49 years). Methods: subjects were required to take an antioxidant supplement, 20 age and sex matched subjects (15 females, 5 males; mean age: 43.6±3.1 years, range: 40-49 years) were required to take placebo medication for 4 weeks. Results: The mean of the change in accommodation power was significantly higher in the group receiving antioxidant supplements (0.20±0.50 Diopter (D)) compared to the placebo group (-0.12±0.48 (D)) (p<0.05). Conclusions: antioxidant supplementation was observed to improve accommodation in Japanese Visual Display Terminal (VDT) Users.

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OCT assessment of tear meniscus after punctal occlusion in dry eye disease

Ibrahim Osama M A, Dogru Murat, Kojima Takashi, Matsumoto Yukihiro, Wakamatsu Tais Hitomi, Tsubota Kazuo, Fujishima Hiroshi

Optometry and Vision Science 89 ( 5 ) 2012.05

ISSN 1040-5488

PURPOSE.: To evaluate the tear meniscus changes after punctal occlusion in dry eye patients using Visante optical coherence tomography (OCT) in a prospective controlled study. METHODS.: Thirty eyes of 15 symptomatic dry eye patients not responding to non-preserved artificial tears received additional upper and lower punctal occlusion with silicone plugs, and 30 eyes of 15 age-and sex-matched dry eye control patients received only non-preserved artificial tears treatment for 1 month. All subjects underwent tear meniscus height (TMH) measurements with Visante OCT. All study participants also underwent slitmicroscopy graticule scale TMH measurement, strip meniscometry testing, tear film break-up time measurement, ocular surface vital staining with fluorescein and Rose Bengal dyes, and the Schirmer-1 test. Both groups, dry eye and control group patients, were examined before and after 1-month treatment. Wilcoxon-matched pair test was performed. The study was conducted in compliance with the Tenets of the Declaration of Helsinki. RESULTS.: TMH measurements by OCT and slitlamp graticule scale significantly improved after punctal occlusion (p < 0.001) and remain unchanged in the dry eye control patients. Similarly, strip meniscometry scores, mean tear stability values, Rose Bengal, and fluorescein staining scores showed significant improvement after punctal occlusion (p < 0.05). Schirmer-1 test values tended to be higher after 1 month of treatment in both groups without any statistical significance (p > 0.05). CONCLUSIONS.: OCT TMH measurement appears to be effective in monitoring tear meniscus changes after punctal occlusion. OCT can be a valuable non-invasive and quick clinical tool for evaluation of treatment responses in dry eye patients. Copyright © 2012 American Academy of Optometry.

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Biological role of lutein in the light-induced retinal degeneration

Sasaki Mariko, Yuki Kenya, Kurihara Toshihide, Miyake Seiji, Noda Kosuke, Kobayashi Saori, Ishida Susumu, Tsubota Kazuo, Ozawa Yoko

Journal of Nutritional Biochemistry 23 ( 5 ) 423 - 429 2012.05

ISSN 0955-2863

Lutein, a xanthophyll of a carotenoid, is anticipated as a therapeutic product to prevent human eye diseases. However, its biological mechanism is still unclear. Here, we show the molecular mechanism of lutein's effect to reduce photodamage of the retina. We analyzed the light-exposed retinas of Balb/c mice given lutein-supplemented or normal diet. Visual function was measured by electroretinogram, and histological changes were observed. Immunohistochemical and immunoblot analyses were performed to analyze molecular mechanism. The reactive oxygen species induced in the retina was evaluated by fluorescent probes. In the mice after light exposure, reduction of a-wave and b-wave amplitudes in electroretinogram, indicating visual impairment, and thinning of the photoreceptor cell layer owing to apoptosis were both attenuated by lutein diet. Interestingly, γ-H2AX, a marker for double-strand breaks (DSBs) in DNA, was up-regulated in the photoreceptor cells after light exposure, but this increase was attenuated by lutein diet, suggesting that DSBs caused by photodamage contributed to the photoreceptor cell death and that this change was suppressed by lutein. Moreover, the expression of eyes absent (EYA), which promotes DNA repair and cell survival, was significantly up-regulated with lutein diet in the light-exposed retina. Therefore, lutein induced EYA for DNA repair, which could suppress DNA damage and photoreceptor cell apoptosis. Lutein reduced light-induced oxidative stress in the retina, which might contribute to promote DNA repair. The lutein-supplemented diet attenuated light-induced visual impairment by protecting the photoreceptor cells' DNA. © 2012 Elsevier Inc.

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Corneal and retinal effects of ultraviolet-B exposure in a soft contact lens mouse model

Ibrahim Osama M A, Kojima Takashi, Wakamatsu Tais Hitomi, Dogru Murat, Matsumoto Yukihiro, Ogawa Yoko, Ogawa Junko, Negishi Kazuno, Shimazaki Jun, Sakamoto Yasuo, Sasaki Hiroshi, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 53 ( 4 ) 2403 - 2413 2012.04

ISSN 0146-0404

PURPOSE. To investigate the lipid and DNA oxidative stress as well as corneal and retinal effects after ultraviolet B (UV-B) exposure in mice, with or without silicon hydrogel soft contact lenses (SCL). METHODS. Twenty-eight C57BL6-strain male mice were divided into four groups: group I, control group with no SCL (SCL [-]) and no UV-B exposure (UV-B [-]); group II, senofilcon A SCL (senofilcon [+]) with UV-B exposure (UV-B [+]); group III, lotrafilcon A SCL (lotrafilcon [+]) with UV-B exposure (UV-B [+]); and group IV, no SCL (SCL [-]), but with UV-B exposure (UV-B [+]). All mice except group I received UV-B exposure for 5 days for a total dose of 2.73 J/cm ². All mice underwent tear hexanoyl-lysine (HEL) and tear cytokine ELISA measurements, and fluorescein and rose bengal corneal staining before and after UV-B exposure. Corneal specimens underwent immunohistochemistry staining with CD45, HEL, 4-hydroxynonenal (4-HNE), and 8-hydroxy-20-deoxyguanosine (8-OHdG) antibodies and evaluation with electron microscopy. RESULTS. All mice without SCL but exposed to UV-B developed corneal edema, ulcers, or epithelial damage compared with mice with senofilcon A SCL and exposure to UV-B. Tear HEL and cytokine levels significantly increased in mice without SCL after UV-B exposure. Immunohistochemistry showed a significantly higher number of cells positively stained for CD45, 8-OHdG, HEL, and 4-HNE in the corneas of mice without SCLs compared with those with senofilcon A after UV-B exposure. CONCLUSION. Silicon hydrogel SCL showed corneal and retinal protective effects, owing to UV blocking properties, against oxidative stress-related membrane lipid and cellular DNA damage. © 2012 The Association for Research in Vision and Ophthalmology, Inc.

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Dietary lactoferrin alleviates age-related lacrimal gland dysfunction in mice

Kawashima Motoko, Kawakita Tetsuya, Inaba Takaaki, Okada Naoko, Ito Masataka, Shimmura Shigeto, Watanabe Mitsuhiro, Shinmura Ken, Tsubota Kazuo

PLoS ONE 7 ( 3 ) 2012.03

Background: Decrease in lacrimal gland secretory function is related to age-induced dry eye disease. Lactoferrin, the main glycoprotein component of tears, has multiple functions, including anti-inflammatory effects and the promotion of cell growth. We investigated how oral administration of lactoferrin affects age-related lacrimal dysfunction. Methods and Findings: Twelve-month-old male C57BL/6Cr Slc mice were randomly divided into a control fed group and an oral lactoferrin treatment group. Tear function was measured at a 6-month time-point. After euthanasia, the lacrimal glands were subjected to histological examination with 8-hydroxy-2′-deoxyguanosine (8-OHdG) antibodies, and serum concentrations of 8-OHdG and hexanoyl-lysine adduct (HEL) were evaluated. Additionally, monocyte chemotactic protein-1(MCP-1) and tumor necrosis factor-α (TNF-α) gene expression levels were determined by real-time PCR. The volume of tear secretion was significantly larger in the treated group than in the control. Lactoferrin administration reduced inflammatory cell infiltration and the MCP-1 and TNF-α expression levels. Serum concentrations of 8-OHdG and HEL in the lactoferrin group were lower than those in the control group and were associated with attenuated 8-OHdG immunostaining of the lacrimal glands. Conclusion: Oral lactoferrin administration preserves lacrimal gland function in aged mice by attenuating oxidative damage and suppressing subsequent gland inflammation. © 2012 Kawashima et al.

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Blockade of vascular adhesion protein-1 attenuates choroidal neovascularization

Yoshikawa Nami, Noda Kousuke, Ozawa Yoko, Tsubota Kazuo, Mashima Yukihiko, Ishida Susumu

Molecular Vision 18 593 - 600 2012.03

Purpose: Vascular adhesion protein (VAP)-1 is an adhesion molecule elucidated as a mediator of the leukocyte recruitment cascade. The purpose of this study was to investigate the role of VAP-1 in ocular inflammatory neovascularization using a mouse laser-induced choroidal neovascularization (CNV) model. Methods: CNV was induced with 532 nm laser irradiation in C57BL/6 mice, and production of VAP-1 protein in the retinal pigment epithelium (RPE) choroid during CNV formation was examined. CNV animals were treated with the specific VAP-1 inhibitor U-V002 or vehicle solution, and the volume of CNV tissue was evaluated with volumetric measurements. Macrophage infiltration into the CNV lesions was evaluated using two different techniques, flatmount staining and real-time polymerase chain reaction (PCR) for F4/80. The protein levels of intercellular adhesion molecule (ICAM)-1, monocyte chemoattractant protein (MCP)-1, P-selectin, and vascular endothelial growth factor (VEGF) in the RPE-choroid were measured with enzyme-linked immunosorbent assay (ELISA). Results: VAP-1 inhibition significantly suppressed CNV formation in a dose-dependent manner and reduced macrophage infiltration into CNV lesions. Furthermore, VAP-1 blockade decreased the expression of ICAM-1 and MCP-1, both of which play a pivotal role in macrophage recruitment. Conclusions: Our data suggest VAP-1 has an important role during ocular inflammatory neovascularization through leukocyte recruitment. VAP-1 inhibition may be a novel and potent therapeutic strategy in treating CNV formation. © 2012 Molecular Vision.

The association between primary open-angle glaucoma and fall

Tanabe Sachiko, Yuki Kenya, Ozeki Naoki, Shiba Daisuke, Tsubota Kazuo

Clinical Ophthalmology 6 ( 1 ) 327 - 331 2012.03

ISSN 1177-5467

Purpose: Falls are among the most serious public health concerns for the elderly. Information conveyed via the visual sense is relevant to postural balance and movement, and proper visual function is essential to avoid falls. Here we investigated the prevalence of injurious falls among patients with primary open-angle glaucoma (POAG) who were more than 45 years old, compared with comparably aged healthy subjects. Methods: This is a cross-sectional study. Consecutive patients who visited the Tanabe Eye Clinic, Yamanashi, Japan between January 1 and March 30, 2009 were screened for eligibility by ophthalmic examination. A total of 117 control subjects (77 men, 40 women; aged 60.2 ± 7.5 years) who were free of ocular disease and 101 POAG patients (58 men, 43 women; aged 62.3 ± 8.7 years) were consecutively enrolled. Participants answered a questionnaire on injurious fall experience during the previous 10 years. The prevalence of injurious fall in subjects with POAG versus healthy controls was examined with Fisher's exact test. Adjusted odds ratios and 95% confidence intervals were estimated with logistic regression models for the subjects with POAG (factors: age, gender, mean deviation in the better eye or worse eye). Results: The self-reported prevalence of injurious fall was 0.9% (1/117) in the control group and 6.9% (7/101) in the POAG group. The association between injurious fall and POAG was statistically significant (P = 0.026, Fisher's exact test). Within the POAG patients, the group reporting falls was significantly older and had a lower BMI, worse BCVA, and worse mean deviation in both the better and worse eye than the group reporting no falls. Worse mean deviation in the eye with the better visual field (odds ratios 0.75; 95% confidence intervals: 0.57 to 0.99; P = 0.036) was a significant risk factor for injurious falls in subjects with POAG. Conclusions: POAG was significantly associated with injurious falls. © 2012 Tanabe et al, publisher and licensee Dove Medical Press Ltd.

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The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner

Nakamura-Ishizu Ayako, Kurihara Toshihide, Okuno Yuji, Ozawa Yoko, Kishi Kazuo, Goda Nobuhito, Tsubota Kazuo, Okano Hideyuki, Suda Toshio, Kubota Yoshiaki

Developmental Biology 363 ( 1 ) 106 - 114 2012.03

ISSN 0012-1606

The vascular and nervous systems display a high degree of cross-talk and depend on each other functionally. In the vascularization of the central nervous system, astrocytes have been thought to sense tissue oxygen levels in hypoxia-inducible factors (HIFs)-dependent manner and control the vascular growth into the hypoxic area by secreting VEGF. However, recent genetic evidences demonstrate that not only astrocyte HIFs but also astrocyte VEGF expression is dispensable for developmental angiogenesis of the retina. This study demonstrates that hypoxia-inducible factor 1 alpha subunit (HIF-1α), a key transcription factor involved in cellular responses to hypoxia, is most abundantly expressed in the neuroretina, especially retinal progenitor cells (RPCs). A neuroretina-specific knockout of HIF-1α (αCre ⁺Hif1α ^flox/flox) showed impaired vascular development characterized by decreased tip cell filopodia and reduced vessel branching. The astrocyte network was hypoplastic in αCre ⁺Hif1α ^flox/flox mice. Mechanistically, platelet-derived growth factor A (PDGF-A), a mitogen for astrocytes, was downregulated in the neuroretina of αCre ⁺Hif1α ^flox/flox mice. Supplementing PDGF-A restored reduced astrocytic and vascular density in αCre ⁺Hif1α ^flox/flox mice. Our data demonstrates that the neuroretina but not astrocytes acts as a primary oxygen sensor which ultimately controls the retinal vascular development by regulating an angiogenic astrocyte template. © 2011 Elsevier Inc.

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Mucosal microvilli in dry eye patients with chronic GVHD

Tatematsu Y., Ogawa Y., Shimmura S., Dogru M., Yaguchi S., Nagai T., Yamazaki K., Kameyama K., Okamoto S., Kawakami Y., Tsubota K.

Bone Marrow Transplantation 47 ( 3 ) 416 - 425 2012.03

ISSN 0268-3369

The ocular surface is a frequent target tissue of mucosal chronic GVHD (cGVHD). We investigated the histopathological features of the conjunctival microvilli in patients with cGVHD. Conjunctival tissue specimens from patients with cGVHD or Sjögren's syndrome (SS) or from healthy individuals were examined by light microscopy and EM, impression cytology, and immunohistochemistry. The cGVHD conjunctivae showed significantly more metaplasia and fewer goblet cells than the SS and normal conjunctivae. Abundant CD8 ⁺ T cells infiltrated the basal epithelia in the cGVHD conjunctiva. The microvilli per standard epithelial unit and the secretory vesicles were counted by analyzing electron micrographs. The mean number of mucosal microvilli was significantly lower in the cGVHD than that in the SS or normal specimens, and the microvilli were significantly shorter, with a smaller height-width ratio. The mean number of secretory vesicles was also significantly lower, and the membrane-spanning mucin thinner, in the cGVHD compared with the SS and normal specimens. Thus, the conjunctival mucosal microvilli of cGVHD patients were significantly different in number and morphology from those of SS and normal subjects. These may be important factors affecting the stability of the tear-film layer and its contribution to cGVHD-related dry eye. © 2012 Macmillan Publishers Limited All rights reserved.

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The Vision van, a mobile eye clinic, Aids relief Efforts in Tsunami-Stricken areas

Oshima Catherine Ross, Yuki Kenya, Uchida Atsuro, Dogru Murat, Koto Takashi, Ozawa Yoko, Tsubota Kazuo

Keio Journal of Medicine 61 ( 1 ) 10 - 14 2012.03

ISSN 0022-9717

In the wake of the devastating earthquake and tsunami of March 11, our group at Keio University worked diligently to bring the Vision Van, a mobile eye clinic, from Miami, Florida, to disaster areas where medicines, eyeglasses, and indeed all other ophthalmological supplies and services, were nonexistent, thereby assisting many tsunami survivors suffering from eye problems. This act was encouraging not only to the patients and those working in the disaster-hit areas but also to ophthalmologists who wanted to use their medical specialty to assist those in need. © 2012 by The Keio Journal of Medicine.

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Use of micronutrient supplement for preventing advanced age-related macular degeneration in Japan

Sasaki Mariko, Shinoda Hajime, Koto Takashi, Uchida Atsuro, Tsubota Kazuo, Ozawa Yoko

Archives of Ophthalmology 130 ( 2 ) 254 - 255 2012.02

ISSN 0003-9950

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A novel clinical entity, IgG4-relateddisease (IgG4RD)

Umehara Hisanori, Okazaki Kazuichi, Masaki Yasufumi, Kawano Mitsuhiro, Yamamoto Motohisa, Saeki Takako, Matsui Shoko, Sumida Takayuki, Mimori Tsuneyo, Tanaka Yoshiya, Tsubota Kazuo, Yoshino Tadashi, Kawa Shigeyuki, Suzuki Ritsuro, Takegami Tsutomu, Tomosugi Naohisa, Kurose Nozomu, Ishigaki Yasuhito, Azumi Atsushi, Kojima Masaru, Nakamura Shigeo, Inoue Dai, Fujikawa Keita, Hamano Hideaki, Kubo Keiji, Yamamoto Hiroshi, Hirokawa Mitsuyosi, Itoh Kunihiko, Kamisawa Terumi, Kawabata Daisuke, Matsumoto Morio, Minamoto Seijiro, Murayama Kayoko, Nishiyama Susumu, Ogawa Yoko, Origuchi Tomoki, Oyama Norihide, Sato Yasuharu, Seto Masao, Sugai Susumu, Tsukamoto Norifumi, Takahira Masayuki, Takahashi Hiroki, Tsuboi Hiroto, Waseda Yuko, Kitagawa Kazuko, Nojima Takayuki, Yokoyama Hitoshi, Tonami Hisao, Fukushima Toshihiro, Tanaka Masao, Fujita Yoshimasa, Sawaki Toshioki, Kawanami Takafumi, Miki Miyuki, Iwao Haruka, Nakajima Akio, Nakamura Takuji

Modern Rheumatology 22 ( 1 ) 1 - 14 2012.02

ISSN 1439-7595

IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz's disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity. © Japan College of Rheumatology 2011.

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