論文 - 坪田　一男

Retinal aging and sirtuins

Ozawa Yoko, Kubota Shunsuke, Narimatsu Toshio, Yuki Kenya, Koto Takashi, Sasaki Mariko, Tsubota Kazuo

Ophthalmic Research 44 （ 3 ） 199 - 203 2010年09月

ISSN  0030-3747

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<p>The process of aging involves the accumulating changes in the microenvironment that lead to cell senescence or apoptosis, and subsequent tissue or organ dysfunction. Multiple extrinsic and intrinsic events that cause DNA instability are associated with aging. Cells containing unstable DNA are biologically vulnerable, and if the DNA damage is too great for the cell to repair, it becomes senescent or dies by apoptosis. Thus, the cell's capacity to repair its DNA determines the progress of aging, at least in part. Here, we focus on the sirtuins, the mammalian homologs of the yeast life-span-extending molecule, Sir2. Among the sirtuin family proteins in mammals, the one most similar to yeast Sir2 is SIRT1, which is involved in multiple pathways, including the repair of DNA double-strand breaks. Although the role of SIRT1 in mammalian longevity is not clear, it is expressed throughout the retina, where it may suppress aging. In fact, a mutant mouse model of retinal degeneration shows an abnormal subcellular localization of SIRT1 protein and accelerated retinal cell apoptosis. Further analyses are required to elucidate the mechanism of DNA damage and repair, including the contributions of the sirtuins, in the aged or diseased retinas, which will help us understand the mechanisms of retinal aging. © 2010 S. Karger AG, Basel.</p>

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The era of antiaging ophthalmology comes of age

Tsubota Kazuo, Kawashima Motoko, Inaba Takaaki, Dogru Murat, Ogawa Yoko, Nakamura Shigeru, Shinmura Ken, Higuchi Akihiro, Kawakita Tetsuya

Ophthalmic Research 44 （ 3 ） 146 - 154 2010年09月

ISSN  0030-3747

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<p>Recent advances in the understanding of aging have paved a new way of thinking about intervening with the aging process. There is a global agreement in the scientific community that calorie restriction (CR) can actually extend the life span of various kinds of animals so that this has become a real intervention in aging. In addition to the CR theory, the free radical theory is another important hypothesis, which is believed to be involved in aging. According to this theory, we can manage the aging process by controlling calories or reactive oxygen species. In this paper, these two important aging theories, CR and free radical aging, are reviewed, and it is discussed how to apply these theories to the prevention and treatment of eye diseases. Finally, we share the preliminary results of our animal study on dry eye, and I report my personal experience as a dry eye patient, which has been alleviated by the antiaging approach. © 2010 S. Karger AG, Basel.</p>

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Ophthalmic Research

Tsubota Kazuo

Ophthalmic Research 44 （ 3 ） 145 2010年09月

ISSN  0030-3747

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Evaluation of therapeutic effects of astaxanthin on impairments in salivary secretion

Yamada Takashi, Ryo Koufuchi, Tai Yoshinori, Tamaki Yoh, Inoue Hiroko, Mishima Kenji, Tsubota Kazuo, Saito Ichiro

Journal of Clinical Biochemistry and Nutrition 47 （ 2 ） 130 - 137 2010年09月

ISSN  0912-0009

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<p>The involvement of reactive oxygen species (ROS) in the pathophysiology of Sjögren's syndrome (SS), an autoimmune disorder, and irradiation-induced impairments in salivary secretion has been reported. Meanwhile, the strong antioxidant astaxanthin (Ast) has been suggested to have therapeutic effects on various diseases. In the present study, we examined the ROS scavenging capacity of Ast using a human salivary gland epithelial cell line (HSY) and investigated the effects of Ast on salivary secretion in a mouse model of irradiation-induced salivary gland dysfunction. Furthermore, we performed a clinical study of Ast in six SS patients and six normal individuals, quantifying the volume of saliva secretion and the level of oxidative stress markers in the saliva. Ast partially suppressed hydrogen peroxide-induced ROS in HSY cells. The mouse model demonstrated that the preadministration of Ast resulted in the suppression of irradiation-induced hyposalivation. Furthermore, the administration of Ast appeared to increase salivary output in both the SS and normal groups. The level of oxidative stress marker, hexanoyl-lysine, in the saliva was reduced after Ast intake. These results suggest that Ast might act as an ROS scavenger, providing benefits to SS patients with impaired salivary secretion.</p>

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Dietary restriction

Baur Joseph A., Chen Danica, Chini Eduardo N., Chua Katrin, Cohen Haim Y., De Cabo Rafael, Deng Chuxia, Dimmeler Stefanie, Gius David, Guarente Leonard P., Helfand Stephen L., Imai Shin Ichiro, Itoh Hiroshi, Kadowaki Takashi, Koya Daisuke, Leeuwenburgh Christiaan, Mcburney Michael, Nabeshima Y. O Ichi, Neri Christian, Oberdoerffer Philipp, Pestell Richard G., Rogina Blanka, Sadoshima Junichi, Sartorelli Vittorio, Serrano Manuel, Sinclair David A., Steegborn Clemens, Tatar Marc, Tissenbaum Heidi A., Tong Qiang, Tsubota Kazuo, Vaquero Alejandro, Verdin Eric

Science 329 （ 5995 ） 1012 - 1013 2010年08月

ISSN  0036-8075

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In vivo evaluation of superior limbic keratoconjunctivitis using laser scanning confocal microscopy and conjunctival impression cytology

Kojima Takashi, Matsumot Yukihiro, Ibrahim Osama M A, Sato Enrique Adan, Dogru Murat, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 51 （ 8 ） 3986 - 3992 2010年08月

ISSN  0146-0404

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<p>PURPOSE. To investigate the cytologic findings of superior bulbar conjunctiva in superior limbic keratoconjunctivitis (SLK) using laser scanning confocal microscopy and impression cytology in a prospective controlled study. METHODS. Twenty-one eyes of 11 SLK patients (9 women, 2 men; mean age, 49.3 ± 17.9 years) and 18 eyes of 9 control subjects (6 women, 3 men; mean age, 46.4 ± 8.7 years) underwent tear function tests including vital stainings, Schirmer test, tear clearance test, digital confocal laser scanning microscopy, and conjunctival impression cytology. After confocal microscopy and impression cytology images were obtained, the mean individual epithelial cell area (MIECA), nucleocytoplasmic (N/C) ratio, and inflammatory cell density were analyzed. The correlation between confocal microscopy and impression cytology parameters was investigated. RESULTS. The MIECA of SLK patients and control subjects in confocal microscopy was 786.54 ± 463.88 μm² and 311.50 ± 78.30 μm², respectively. The mean N/C ratio was 0.356 ± 0.090 and 0.490 ± 0.038, respectively. The MIECA and N/C ratio in impression cytology showed significant correlation with the corresponding confocal microscopy parameters (MIECA, P ± 0.0028; N/C, P= 0.0051). The inflammatory cell density in confocal microscopy significantly correlated with superior bulbar conjunctival Rose-Bengal scores (P= 0.0264). CONCLUSIONS. Laser scanning confocal microscopy seems to be an efficient noninvasive tool in the evaluation of phenotypic alterations of the conjunctival epithelium in SLK and may serve as an alternative for impression cytology. N/C ratio and inflammatory cell density appear to be two new promising parameters of in vivo confocal microscopy in the assessment of ocular surface disease in SLK. © Association for Research in Vision and Ophthalmology.</p>

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A new method to prevent loss of mitomycin C soaked sponges under the conjunctiva during trabeculectomy

Yuki Kenya, Shiba Daisuke, Ota Yu, Ozeki Naoki, Murat Dogru, Tsubota Kazuo

British Journal of Ophthalmology 94 （ 8 ） 1111 - 1112 2010年08月

ISSN  0007-1161

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Role of insulin in regulation of Na⁺-/K⁺-dependent ATPase activity and pump function in corneal endothelial cells

Hatou Shin, Yamada Masakazu, Akune Yoko, Mochizuki Hiroshi, Shiraishi Atsushi, Joko Takeshi, Nishida Teruo, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 51 （ 8 ） 3935 - 3942 2010年08月

ISSN  0146-0404

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<p>PURPOSE. The Na⁺-/K⁺-dependent ATPase (Na, K-ATPase) expressed in the basolateral membrane of corneal endothelial cells plays an important role in the pump function of the corneal endothelium. The role of insulin in the regulation of Na,K-ATPase activity and pump function in corneal endothelial cells was investigated. METHODS. Confluent monolayers of mouse corneal endothelial cells were exposed to insulin. ATPase activity was evaluated by spectrophotometric measurement of phosphate released from ATP with the use of ammonium molybdate; Na, K-ATPase activity was defined as the portion of total ATPase activity sensitive to ouabain. Pump function was measured with the use of a Ussing chamber; pump function attributable to Na, K-ATPase activity was defined as the portion of the total short-circuit current sensitive to ouabain. Western blot analysis and immunocytochemistry were performed to measure the expression of the Na,K-ATPase α₁-subunit. RESULTS. Insulin increased the Na, K-ATPase activity and pump function of cultured corneal endothelial cells. These effects were blocked by protein kinase C (PKC) inhibitors and protein phosphatases 1 and 2A inhibitor. Western blot analysis indicated that insulin decreased the ratio of the inactive Na, KATPase α₁-subunit. Immunocytochemistry indicated that insulin increased the cell surface expression of the Na, K-ATPase α₁-subunit. CONCLUSIONS. These results suggest that insulin increases the Na, K-ATPase activity and pump function of cultured corneal endothelial cells. The effect of insulin is mediated by PKC and presumably results in the activation of PP1, 2A, or both, which are essential for activating Na,K-ATPase by α₁-subunit dephosphorylation. © Association for Research in Vision and Ophthalmology.</p>

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Calorie restriction

Kawashima Motoko, Kawakita Tetsuya, Okada Naoko, Ogawa Yoko, Murat Dogru, Nakamura Shigeru, Nakashima Hideo, Shimmura Shigeto, Shinmura Ken, Tsubota Kazuo

Biochemical and Biophysical Research Communications 397 （ 4 ） 724 - 728 2010年07月

ISSN  0006-291X

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<p>A decrease in lacrimal gland secretory function is closely related to aging and leads to an increased prevalence of dry eye syndrome. Since calorie restriction (CR) is considered to prevent functional decline of various organs due to aging, we hypothesized that CR could prevent age-related lacrimal dysfunction. Six-month-old male Fischer 344 rats were randomly divided into ad libitum (AL) and CR (-35%) groups. After 6. months of CR, tear function was examined under conscious state. After euthanasia, lacrimal glands were subjected to histological examination, tear protein secretion stimulation test with Carbachol, and assessment of oxidative stress with 8-hydroxy-2 deoxyguanosine (8-OHdG) and 4-hydroxynonenal (HNE) antibodies. CR significantly improved tear volume and tended to increase tear protein secretion volume after stimulation with Carbachol compared to AL. The acinar unit density was significantly higher in the CR rats compared to AL rats. Lacrimal glands in the CR rats showed a lesser degree of interstitial fibrosis. CR reduced the concentration of 8-OHdG and the extent of staining with HNE in the lacrimal gland, compared to AL. Furthermore, our electron microscopic observations showed that mitochondrial structure of the lacrimal gland obtained from the middle-aged CR rats was preserved in comparison to the AL rats. Collectively, these results demonstrate for the first time that CR may attenuate oxidative stress related damage in the lacrimal gland with preservation of lacrimal gland functions. Although molecular mechanism(s) by which CR maintains lacrimal gland function remains to be resolved, CR might provide a novel therapeutic strategy for treating dry eye syndrome. © 2010 Elsevier Inc.</p>

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Secondary macular hole formation with presumed evulsion of foveal hard exudates in a patient with diabetic retinopathy

Tomita Yohei, Kousuke Noda, Hajime Shinoda, Yoko Ozawa, Kazuo Tsubota, Susumu Ishida

Japanese Journal of Ophthalmology 54 （ 4 ） 366 - 368 2010年07月

ISSN  0021-5155

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Baseline profiles of ocular surface and tear dynamics after allogeneic hematopoietic stem cell transplantation in patients with or without chronic GVHD-related dry eye

Wang Y., Ogawa Y., Dogru M., Tatematsu Y., Uchino M., Kamoi M., Okada N., Okamoto S., Tsubota K.

Bone Marrow Transplantation 45 （ 6 ） 1077 - 1083 2010年06月

ISSN  0268-3369

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<p>We evaluated ocular surface alterations in allogeneic hematopoietic stem cell transplantation (HSCT) recipients with or without chronic GVHD-related dry eye in a prospective study. Fifty eyes of 25 post-HSCT patients and 28 eyes of 14 age-matched healthy controls were included. Meibomian gland (MG) obstruction, tear evaporation rate, corneal sensitivity (CS), Schirmer test-I, tear break-up time (BUT) and ocular surface vital staining were examined. Conjunctival impression and brush cytology specimens were collected to evaluate the goblet cell density (GCD) and the inflammatory cell numbers. Obvious MG obstruction, decreased CS and enhanced tear evaporation rate were found in post-HSCT patients compared with normal controls. In addition, decreased conjunctival GCD, increased conjunctival squamous metaplasia and inflammatory cells were noted in cGVHD-related dry eyes compared with normal controls and post-HSCT without dry eye subjects. Furthermore, the conjunctival inflammatory cells were significantly higher in severe dry eyes compared with mild dry eyes (P=0.03). We found comprehensive ocular surface alteration in post-HSCT patients, regardless of whether they had cGVHD-related dry eye or not. The results suggest that the extent of inflammatory process seems to have a pivotal role in the outcome of the cGVHD-related dry eye. © 2010 Macmillan Publishers Limited All rights reserved.</p>

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S-1 Induces Meibomian Gland Dysfunction

Matsumoto Yukihiro, Dogru Murat, Sato Enrique Adan, Ibrahim Osama M A, Tatematsu Yukako, Ogawa Yoko, Tsubota Kazuo

Ophthalmology 117 （ 6 ）  2010年06月

ISSN  0161-6420

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Efficacy of small-incision intraocular lens exchange of opacified Hydroview implants

Yamaguchi Takefumi, Shimizu Tsutomu, Yamaguchi Kazuko, Dogru Murat, Negishi Kazuno, Tsubota Kazuo

British Journal of Ophthalmology 94 （ 6 ） 808 - 809 2010年06月

ISSN  0007-1161

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Implantation of multifocal intraocular lens in two cases after LASIK

Shirahata Reiko, Negishi Kazuno, Torii Hidemasa, Dogru Murat, Tsubota Kazuo

Japanese Journal of Clinical Ophthalmology 64 （ 6 ） 881 - 884 2010年06月

ISSN  0370-5579

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<p>Purpose : To report two cases who had received LASIK previously and who underwent cataract surgery with implantation of multifocal intraocular lens (IOL). Cases and Findings : Both were males aged 47 and 55 years respectively. LASIK had been performed 6 years and 2 years before respectively. Both cases were diagnosed with cataract in the right eye. Corrected visual acuity was 1.2 and 0.7 respectively. The affected eye was treated by cataract surgery and implantation of diffractive multifocal IOL. After surgery, near and far visual acuity with the naked eye was 1.2 and 1.0 in one case and 1.0 each in the other. Both patients expressed satisfaction with the outcome. Contrast sensitivity was at the lower limit of normal range in both cases. Conclusion : These two cases illustrate that refractive error and impaired visual function may result following implantation of multifocal IOL after LASIK. We advocate due explanation to obtain informed consent in such cases.</p>

Ocular complications in mulvihill-smith syndrome

Ibrahim O. M A, Takefumi Y., Dogru M., Negishi K., Kosaki K., Tsubota K.

Eye 24 （ 6 ） 1123 - 1124 2010年06月

ISSN  0950-222X

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Von Hippel-Lindau protein regulates transition from the fetal to the adult circulatory system in retina

Kurihara Toshihide, Kubota Yoshiaki, Ozawa Yoko, Takubo Keiyo, Noda Kousuke, Simon M. Celeste, Johnson Randall S., Suematsu Makoto, Tsubota Kazuo, Ishida Susumu, Goda Nobuhito, Suda Toshio, Okano Hideyuki

Development 137 （ 9 ） 1563 - 1571 2010年05月

ISSN  0950-1991

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<p>In early neonates, the fetal circulatory system undergoes dramatic transition to the adult circulatory system. Normally, embryonic connecting vessels, such as the ductus arteriosus and the foramen ovale, close and regress. In the neonatal retina, hyaloid vessels maintaining blood flow in the embryonic retina regress, and retinal vessels take over to form the adult-type circulatory system. This process is regulated by a programmed cell death switch mediated by macrophages via Wnt and angiopoietin 2 pathways. In this study, we seek other mechanisms that regulate this process, and focus on the dramatic change in oxygen environment at the point of birth. The von Hippel-Lindau tumor suppressor protein (pVHL) is a substrate recognition component of an E3-ubiquitin ligase that rapidly destabilizes hypoxia-inducible factor as (HIF-αs) under normoxic, but not hypoxic, conditions. To examine the role of oxygen-sensing mechanisms in retinal circulatory system transition, we generated retina-specific conditional-knockout mice for VHL (Vhl ^α-CreKO mice). These mice exhibit arrested transition from the fetal to the adult circulatory system, persistence of hyaloid vessels and poorly formed retinal vessels. These defects are suppressed by intraocular injection of FLT1-Fc protein [a vascular endothelial growth factor (VEGF) receptor-1 (FLT1)/Fc chimeric protein that can bind VEGF and inhibit its activity], or by inactivating the HIF-1a gene. Our results suggest that not only macrophages but also tissue oxygen-sensing mechanisms regulate the transition from the fetal to the adult circulatory system in the retina. © 2010. Published by The Company of Biologists Ltd.</p>

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Predictability of ocular spherical aberration after cataract surgery determined using preoperative corneal spherical aberration

Negishi Kazuno, Kodama Chiyo, Yamaguchi Takefumi, Torii Hidemasa, Saiki Megumi, Dogru Murat, Ohnuma Kazuhiko, Tsubota Kazuo

Journal of Cataract and Refractive Surgery 36 （ 5 ） 756 - 761 2010年05月

ISSN  0886-3350

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<p>Purpose: To evaluate the predictability of total postoperative spherical aberration after aspheric intraocular lens (IOL) implantation using preoperative corneal spherical aberration. Setting: Keio University Hospital, Tokyo, Japan. Methods: Corneal and ocular higher-order aberrations (HOAs) were analyzed preoperatively and postoperatively in eyes having cataract extraction with aspheric IOL implantation. The predicted postoperative total spherical aberration Z(4,0) was calculated by adding the preoperative corneal spherical aberration and the labeled spherical aberration of the IOL. The prediction error of the postoperative total spherical aberration was calculated by subtracting the predicted postoperative total spherical aberration from the postoperative total spherical aberration. Surgically induced corneal spherical aberration was calculated by subtracting the postoperative from the preoperative corneal spherical aberration. Results: There were no statistically significant differences between preoperative and postoperative corneal spherical aberration, 3rd-order aberration, or HOAs. The prediction error of the postoperative total spherical aberration was within ±0.05 μm in 9 (24.3%) of the 37 eyes evaluated and within ±0.10 μm in 18 eyes (48.6%). Statistically significantly correlations were found between the surgically induced corneal spherical aberration and prediction error of postoperative total spherical aberration, the preoperative corneal spherical aberration and surgically induced corneal spherical aberration, and the preoperative corneal spherical aberration and prediction error of postoperative total spherical aberration. Conclusions: Predictability of postoperative ocular spherical aberration after cataract surgery with aspheric IOL implantation was insufficient because of the surgically induced corneal spherical aberration. Considering surgically induced corneal spherical aberration could improve the predictability of postoperative ocular spherical aberration. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. © 2010 ASCRS and ESCRS.</p>

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Comparison of effects of periocular region dry and wet warming on visual acuity and near reflex

Takahashi Yoko, Igaki Michihito, Sakamoto Ichirou, Suzuki Atsushi, Takahashi Genichiro, Dogru Murat, Tsubota Kazuo

Nippon Ganka Gakkai zasshi 114 （ 5 ） 444 - 453 2010年05月

ISSN  0029-0203

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<p>PURPOSE: To investigate the influence of warming the periocular region for 10 minutes after visual display terminal (VDT) work on the near reflex, and the differences in influence between lid closure, dry and wet warming, and the amounts of water vapor. SUBJECTS AND METHODS: Subjects in the first trial were 10 healthy volunteers (10 eyes). Following VDT, subjects wore either a warming eye steamer (water vapor: 200 mg/10 min) or an eye mask with their eyelids closed for 10 minutes. Subjects in the second trial were 5 healthy volunteers (5 eyes). Following VDT, subjects applied either a dry-warming sheet (water vapor: 0 mg/10 min) or a wet-warming sheet (water vapor: 20, 35, 160 and 200 mg/10 min) to there eyelids and the periocular region for 10 minutes. In both experiments, subjective amplitude of accommodation, pupillary reaction, convergence reaction, near vision, and breakup time were measured before and immediately after VDT work and after 2 experimental settings. RESULTS: The warming eye steamer significantly improved amplitude of accommodation (p&lt;0.05), and near vision (p&lt;0.05). Warming the periocular region with water vapor improved subjective amplitude of accommodation, and near vision, the effect of which depended on the amount of water vapor (p&lt;0.05). CONCLUSIONS: Warming the periocular region with water vapor improved subjective amplitude of accommodation, near vision and the effect depended on the amount of water vapor.</p>

Passive cigarette smoke exposure and soft contact lens wear

Ward Samantha K., Dogru Murat, Wakamatsu Tais, Ibrahim Osama, Matsumoto Yukihiro, Kojima Takashi, Sato Enrique Adan, Ogawa Junko, Schnider Cristina, Negishi Kazuno, Tsubota Kazuo

Optometry and Vision Science 87 （ 5 ） 367 - 372 2010年05月

ISSN  1040-5488

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<p>PURPOSE.: To prospectively investigate the effects of passive cigarette smoke exposure on the ocular surface and tear film in soft contact lens (SCL) wearers. METHODS.: Twelve right eyes of 12 SCL wearers without any ocular or systemic diseases and 10 right eyes of 10 subjects who never wore CLs were examined before and 2 h after 5 min of passive cigarette smoke exposure in a controlled smoke chamber. Tear evaporation rate measurement, tear film break-up time (TBUT) examination, ocular surface fluorescein, rose bengal stainings, and Schirmer I test were performed at each visit. RESULTS.: The mean tear evaporation rates, TBUTs, and vital staining scores were significantly worse in CL wearers compared with healthy control subjects. TBUTs showed significant worsening after passive smoke exposure in both groups. The mean tear evaporation rate and vital staining scores showed a significant increase with brief passive smoke exposure in subjects not wearing CLs but not in CL wearers. CONCLUSION.: Even brief passive exposure to cigarette smoke is associated with adverse effects on the ocular surface as evidenced by an increase in tear instability and damage to the ocular surface epithelia in SCL wearers and non-CL wearers. Copyright © 2010 American Academy of Optometry.</p>

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Lacrimal Gland in Sjögren's Syndrome

Sato Enrique Adan, Matsumoto Yukihiro, Dogru Murat, Kaido Minako, Wakamatsu Tais, Ibrahim Osama M A, Obata Hiroto, Tsubota Kazuo

Ophthalmology 117 （ 5 ）  2010年05月

ISSN  0161-6420

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