研究者詳細 - 坪田　一男

論文 - 坪田　一男

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Fasting mitigates immediate hypersensitivity

Nakamura Shigeru, Hisamura Ryuji, Shimoda Sachiko, Shibuya Izumi, Tsubota Kazuo

Nutrition and Metabolism 11 （ 1 ） 2014年08月

Background: Fasting is a rigorous type of dietary restriction that is associate with a number of health benefits. During fasting, ketone bodies significantly increase in blood and become major body fuels, thereby sparing glucose. In the present study, we investigated effects of fasting on hypersensitivity. In addition, we also investigated the possible role of D-beta-hydroxybutyrate provoked by fasting in the attenuation of immediate hypersensitivity by fasting. Methods. Effects of fasting on systemic anaphylaxis were examined using rat model of toluene 2, 4-diisocyanate induced nasal allergy. In addition to food restriction, a ketogenic high-fat and low-carbohydrate diet that accelerates fatty acid oxidation and systemic instillation of D-beta-hydroxybutyrate were employed to elevate internal D-beta-hydroxybutyrate concentration. We assessed relationship between degranulation of rat peritoneal mast cells and internal D-beta-hydroxybutyrate concentration in each treatment. Changes in [Ca²⁺]i responses to compound 48/80 were analyzed in fura 2-loaded rat peritoneal mast cells derived from the ketogenic diet and fasting. Results: Immediate hypersensitivity reaction was significantly suppressed by fasting. A significant reduction in mast cells degranulation, induced by mast cell activator compound 48/80, was observed in rat peritoneal mast cells delivered from the 24 hours fasting treatment. In addition, mast cells delivered from a ketogenic diet and D-beta-hydroxybutyrate infusion treatment also had reduced mast cell degranulation and systemic D-beta-hydroxybutyrate concentrations were elevated to similar extent as the fasting state. The peak increase in [Ca²⁺]i was significantly lower in the ketogenic diet and fasting group than that in the control diet group. Conclusions: The results of the present study demonstrates that fasting suppress hypersensitivity reaction, and indicate that increased level of D-beta-hydroxybutyrate by fasting plays an important role, via the stabilization of mast cells, in suppression of hypersensitivity reaction.

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Rejuvenation effects of cataract surgery with ultraviolet blocking intra-ocular lens on circadian Rhythm and gait speed

Ayaki Masahiko, Negishi Kazuno, Tsubota Kazuo

Rejuvenation Research 17 （ 4 ） 359 - 365 2014年08月

ISSN 1549-1684

Background: Previously, we reported improvements in sleep quality and gait speed after implantation of a yellow-colored, blue light-blocking intra-ocular lens (IOL). This study evaluated systemic health parameters for 7 months after cataract surgery with implantation of a clear, ultraviolet (UV)-blocking IOL. Methods: A total of consecutive 71 patients (average age 74.1 years) underwent cataract surgery with the implantation of a clear, UV-blocking IOL. Participants were evaluated using the Pittsburgh Sleep Quality Index (PSQI) and the National Eye Institute Visual Function Questionnaire (VFQ-25) before and at 2 and 7 months after surgery. Four-meter gait speed was also determined. The metabolic parameters of serum glycated hemoglobin (HbA1c), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were tested. Results: The pre-operative and post-operative (2 and 7 months after surgery) results were 66.4±16.5, 79.5±12.6, and 81.0±13.0 for VFQ-25 score, 5.7±3.5, 5.1±3.1, and 4.8±2.9 for PSQI, and 0.90±0.22, 0.91±0.22, and 0.92±0.22 meters/sec for gait speed. Significant improvements following surgery were noted in the VFQ-25 score for all cases and in the PSQI for poor sleepers (preoperative PSQI >5.5) (P<0.05, paired t-test). The gait speed and metabolic parameters showed no significant changes. Conclusions: Cataract surgery with implantation of an UV-blocking clear IOL has the potential for improving circadian rhythm and systemic health parameters. © 2014 Mary Ann Liebert, Inc.

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AMPK-NF-κB axis in the photoreceptor disorder during retinal inflammation

Kamoshita Mamoru, Ozawa Yoko, Kubota Shunsuke, Miyake Seiji, Tsuda Chiduru, Nagai Norihiro, Yuki Kenya, Shimmura Shigeto, Umezawa Kazuo, Tsubota Kazuo

PLoS ONE 9 （ 7 ） 2014年07月

Recent progress in molecular analysis has revealed the possible involvement of multiple inflammatory signaling pathways in pathogenesis of retinal degeneration. However, how aberrant signaling pathways cause tissue damage and dysfunction is still being elucidated. Here, we focus on 5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK), originally recognized as a key regulator of energy homeostasis. AMPK is also modulated in response to inflammatory signals, although its functions in inflamed tissue are obscure. We investigated the role of activated AMPK in the retinal neural damage and visual function impairment caused by inflammation. For this purpose, we used a mouse model of lipopolysaccharide-induced inflammation in the retina, and examined the effects of an AMPK activator, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). During inflammation, activated AMPK in the neural retina was decreased, but AICAR treatment prevented this change. Moreover, the electroretinogram (ERG) a-wave response, representing photoreceptor function, showed visual dysfunction in this model that was prevented by AICAR. Consistently, the model showed shortened photoreceptor outer segments (OSs) with reduced levels of rhodopsin, a visual pigment concentrated in the OSs, in a post-transcriptional manner, and these effects were also prevented by AICAR. In parallel, the level of activated NF-κB increased in the retina during inflammation, and this increase was suppressed by AICAR. Treatment with an NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) preserved the rhodopsin level during inflammation, suppressing NF-κB. These findings indicated that AMPK activation by AICAR and subsequent NF-κB inhibition had a protective effect on visual function, and that AMPK activation played a neuroprotective role during retinal inflammation. © 2014 Kamoshita et al.

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Oxidative stress induced age dependent meibomian gland dysfunction in Cu, Zn-superoxide dismutase-1 (Sod1) knockout mice

Ibrahim Osama M A, Dogru Murat, Matsumoto Yukihiro, Igarashi Ayako, Kojima Takashi, Wakamatsu Tais Hitomi, Inaba Takaaki, Shimizu Takahiko, Shimazaki Jun, Tsubota Kazuo

PLoS ONE 9 （ 7 ） 2014年07月

Purpose: The purpose of our study was to investigate alterations in the meibomian gland (MG) in Cu, Zn-Superoxide Dismutase-1 knockout (Sod1 ^-/-) mouse. Methods: Tear function tests [Break up time (BUT) and cotton thread] and ocular vital staining test were performed on Sod1 ^-/- male mice (n = 24) aged 10 and 50 weeks, and age and sex matched wild-type (+/+) mice (n = 25). Tear and serum samples were collected at sacrifice for inflammatory cytokine assays. MG specimens underwent Hematoxylin and Eosin staining, Mallory staining for fibrosis, Oil Red O lipid staining, TUNEL staining, immunohistochemistry stainings for 4HNE, 8-OHdG and CD45. Transmission electron microscopic examination (TEM) was also performed. Results: Corneal vital staining scores in the Sod1^-/- mice were significantly higher compared with the wild type mice throughout the follow-up. Tear and serum IL-6 and TNF-α levels also showed significant elevations in the 10 to 50 week Sod1^-/- mice. Oil Red O staining showed an accumulation of large lipid droplets in the Sod1^-/- mice at 50 weeks. Immunohistochemistry revealed both increased TUNEL and oxidative stress marker stainings of the MG acinar epithelium in the Sod1^-/- mice compared to the wild type mice. Immunohistochemistry staining for CD45 showed increasing inflammatory cell infiltrates from 10 to 50 weeks in the Sod1^-/- mice compared to the wild type mice. TEM revealed prominent mitochondrial changes in 50 week Sod1^-/- mice. Conclusions: Our results suggest that reactive oxygen species might play a vital role in the pathogensis of meibomian gland dysfunction. The Sod1^-/- mouse appears to be a promising model for the study of reactive oxygen species associated MG alterations. © 2014 Ibrahim et al.

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Short break-up time type dry eye has potential ocular surface abnormalities

Ichihashi Yoshiyuki, Ide Takeshi, Kaido Minako, Ishida Reiko, Hatou Shin, Tsubota Kazuo

Taiwan Journal of Ophthalmology 2014年07月

ISSN 2211-5056

Purpose: To describe a case series in which corneal fluorescein staining (CFS) development occurred in short break-up time (s-BUT) dry eyes after a short period during prolonged opening of the eye. Methods: The study was designed as a clinical case series. Ocular surface evaluations were performed on 13 individuals with s-BUT dry eye. Tear function examinations included Schirmer's test and BUT evaluation. Results: In all 13 cases, the BUT was short, but the tear quantity was not so bad. In all cases, CFS developed following a single eye opening, and the staining was observed at sites that showed as dark spots. In several cases, the CFS disappeared later. Conclusions: In this study, we demonstrated that CFS could develop following a single eye opening. Based on our findings, CFS is a dynamic phenomenon rather than a stable indicator of ocular surface abnormalities. Moreover, s-BUT dry eye has the potential to show ocular surface abnormalities.

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The effects of 3% diquafosol sodium application on the tear functions and ocular surface of the Cu,Zn-superoxide dismutase-1 (Sod1)-knockout mice

Kojima Takashi, Dogru Murat, Ibrahim Osama M., Nagata Taeko, Higa Kazunari, Shimizu Takahiko, Shirasawa Takuji, Satake Yoshiyuki, Shimazaki Seika, Shimazaki Jun, Tsubota Kazuo

Molecular Vision 20 929 - 938 2014年06月

To investigate the role of a water and mucin secretagogue (3% diquafosol sodium eye drops) on the tear function and conjunctival ocular surface changes in Sod1^-/- in comparison to the wild-type (WT) mice. Methods: Fourteen eyes of 7 Sod1^-/- male mice with C57BL/background and 14 eyes of 7 C57BL6 strain wild-type male mice were examined at 40 weeks in this study. All mice had application of 3% diquafosol ophthalmic solution six times a day for 2 weeks. Tear film stability and corneal epithelial damage was evaluated by fluorescein and Rose Bengal stainings. Anterior segment photography was performed before and after eye drop instillations. Aqueous tear quantity was measured with phenol red-impregnated cotton threads without anesthesia. Animals were sacrificed at 42 weeks after diquafosol treatment and the whole globe specimens were subjected to periodic acid Schiff staining. Goblet cell density was quantified by J Image software. Quantitative real-time PCR for conjunctival muc 5AC messenger RNA expression was also performed. Results: Sod1^-/- mice had significantly higher fluorescein staining scores compared to the WT mice before eye drop instillation. The mean tear film breakup time, Rose Bengal staining scores, and muc5 messenger RNA expression improved significantly with diquafosol treatment in both the WT and the knockout mice. The mean fluorescein staining score and aqueous tear quantity significantly improved in the Sod1^-/- mice with treatment. A notable and consistent increase in goblet cells and decrease in inflammatory cell infiltrates could be confirmed in all specimens after 2 weeks of diquafosol eye drop application. Conclusions: Three percent diquafosol ophthalmic solution appears to be effective in the treatment of ocular surface disease in this age-related dry eye disease mouse model. © 2014 Molecular Vision.

The use of induced pluripotent stem cells to reveal pathogenic gene mutations and explore treatments for retinitis pigmentosa

Yoshida Tetsu, Ozawa Yoko, Suzuki Keiichiro, Yuki Kenya, Ohyama Manabu, Akamatsu Wado, Matsuzaki Yumi, Shimmura Shigeto, Mitani Kohnosuke, Tsubota Kazuo, Okano Hideyuki

Molecular Brain 7 （ 1 ） 2014年06月

Background: Retinitis pigmentosa (RP) is an inherited human retinal disorder that causes progressive photoreceptor cell loss, leading to severe vision impairment or blindness. However, no effective therapy has been established to date. Although genetic mutations have been identified, the available clinical data are not always sufficient to elucidate the roles of these mutations in disease pathogenesis, a situation that is partially due to differences in genetic backgrounds. Results: We generated induced pluripotent stem cells (iPSCs) from an RP patient carrying a rhodopsin mutation (E181K). Using helper-dependent adenoviral vector (HDAdV) gene transfer, the mutation was corrected in the patient's iPSCs and also introduced into control iPSCs. The cells were then subjected to retinal differentiation; the resulting rod photoreceptor cells were labeled with an Nrl promoter-driven enhanced green fluorescent protein (EGFP)-carrying adenovirus and purified using flow cytometry after 5 weeks of culture. Using this approach, we found a reduced survival rate in the photoreceptor cells with the E181K mutation, which was correlated with the increased expression of endoplasmic reticulum (ER) stress and apoptotic markers. The screening of therapeutic reagents showed that rapamycin, PP242, AICAR, NQDI-1, and salubrinal promoted the survival of the patient's iPSC-derived photoreceptor cells, with a concomitant reduction in markers of ER stress and apoptosis. Additionally, autophagy markers were found to be correlated with ER stress, suggesting that autophagy was reduced by suppressing ER stress-induced apoptotic changes. Conclusion: The use of RP patient-derived iPSCs combined with genome editing provided a versatile cellular system with which to define the roles of genetic mutations in isogenic iPSCs with or without mutation and also provided a system that can be used to explore candidate therapeutic approaches. © 2014 Yoshida et al.; licensee BioMed Central Ltd.

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Mice lacking inositol 1,4,5-trisphosphate receptors exhibit dry eye

Inaba Takaaki, Hisatsune Chihiro, Sasaki Yasumasa, Ogawa Yoko, Ebisui Etsuko, Ogawa Naoko, Matsui Minoru, Takeuchi Tsutomu, Mikoshiba Katsuhiko, Tsubota Kazuo

PLoS ONE 9 （ 6 ） 2014年06月

Tear secretion is important as it supplies water to the ocular surface and keeps eyes moist. Both the parasympathetic and sympathetic pathways contribute to tear secretion. Although intracellular Ca²⁺ elevation in the acinar cells of lacrimal glands is a crucial event for tear secretion in both the pathways, the Ca²⁺ channel, which is responsible for the Ca ²⁺ elevation in the sympathetic pathway, has not been sufficiently analyzed. In this study, we examined tear secretion in mice lacking the inositol 1,4,5-trisphosphate receptor (IP₃R) types 2 and 3 (Itpr2 ^-/-;Itpr3^-/-double-knockout mice). We found that tear secretion in both the parasympathetic and sympathetic pathways was abolished in Itpr2^-/-;Itpr3^-/- mice. Intracellular Ca²⁺ elevation in lacrimal acinar cells after acetylcholine and epinephrine stimulation was abolished in Itpr2^-/-;Itpr3^-/- mice. Consequently, Itpr2^-/-;Itpr3^-/- mice exhibited keratoconjunctival alteration and corneal epithelial barrier disruption. Inflammatory cell infiltration into the lacrimal glands and elevation of serum autoantibodies, a representative marker for Sjögren's syndrome (SS) in humans, were also detected in older Itpr2^-/-;Itpr3^-/- mice. These results suggested that IP3Rs are essential for tear secretion in both parasympathetic and sympathetic pathways and that Itpr2 ^-/-;Itpr3^-/- mice could be a new dry eye mouse model with symptoms that mimic those of SS. © 2014 Inaba et al.

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Dry-eye screening by using a functional visual acuity measurement system

Kaido Minako, Uchino Miki, Yokoi Norihiko, Uchino Yuichi, Dogru Murat, Kawashima Motoko, Komuro Aoi, Sonomura Yukiko, Kato Hiroaki, Kinoshita Shigeru, Tsubota Kazuo

Investigative Ophthalmology and Visual Science 55 （ 5 ） 3275 - 3281 2014年05月

ISSN 0146-0404

Purpose. We determined whether functional visual acuity (VA) parameters and a dry eyes (DEs) symptoms questionnaire could predict DEs in a population of visual terminal display (VDT) users. Methods. This prospective study included 491 VDT users from the Osaka Study. Subjects with definite DE, diagnosed with the presence of DE symptoms, tear abnormality (Schirmer test ≤ 5 mm or tear breakup time [TBUT] ≤ 5 seconds), and conjunctivocorneal epithelial damage (total staining score of ≥3 points), or probable DE, diagnosed with the presence of two of them, were assigned to a DE group, and the remainder to a non-DE group. Functional VA was assessed, and DE questionnaires were administered. We assessed whether univariate and discriminant analyses could determine to which group a subject belonged. Sensitivity and specificity were assessed. Results. Of 491 subjects, 320 and 171 were assigned to the DE and non-DE groups, respectively. No significant differences were observed between DE and non-DE groups in Schirmer test value and epithelial damage, but TBUT value (3.1 ± 1.5 vs. 5.9 ± 3.0 seconds). The sensitivity and specificity of single test using functional VA parameters were 59% and 49% in functional VA, 60% and 50% in visual maintenance ratio, and 83% and 30% in frequency of blinking, respectively. According to a discriminant analysis using a combination of functional VA parameters and a DE questionnaire, six variables were selected for the discriminant equation, of which area under the curve (AUC) was 0.735. Sensitivity and specificity of diagnoses predicted by the discriminant equation were 85.9% and 45.6%, respectively. Conclusions. The discriminant equation obtained using functional VA measurement combined with a symptoms questionnaire may suggest the possibility for the first step screening of DE with unstable tear film. Since the questionnaire has an overall poor sensitivity and specificity, further amelioration may be necessary for the actual utilization of this screening tool. © 2014 The Association for Research in Vision and Ophthalmology, Inc.

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Short-term effects of instillation of a rebamipide suspension on visual function

Kaido Minako, Ishida Reiko, Dogru Murat, Tsubota Kazuo

Journal of Ocular Pharmacology and Therapeutics 30 （ 4 ） 313 - 318 2014年05月

ISSN 1080-7683

Purpose: To investigate the short-term adverse effects of using rebamipide for the treatment of dry eye by assessing visual function and optical quality. Methods: This interventional noncomparative study included 14 right eyes of 14 healthy volunteers. Serial measurements of visual acuity (VA) and higher-order aberrations were obtained prior to instillation of the rebamipide suspension (baseline) and immediately after and at 5, 10, 20, and 30 min after instillation. Functional VA measurement was performed over a 60-s period with the subject blinking naturally. Ocular aberrations were measured for 10 s while the subject was told not to blink, but no topical anesthesia was applied. Each patient also filled out a questionnaire exploring the rebamipide-Associated adverse effects. Results: There was no significant difference between functional VA measured at baseline and at each time point after the instillation of rebamipide. In contrast, the root mean square of third-order and total higher-order aberrations increased significantly immediately after drug instillation (P<0.05). The severity of higher-order aberrations at baseline was similar to that observed at 5, 10, 20, and 30 min after instillation (P>0.05). Conclusions: The transient reduction in optical quality immediately after administration of rebamipide is corrected by the patient's natural blink reflex. The adverse effects observed in this study do not outweigh the benefits of rebamipide treatment. © Copyright 2014, Mary Ann Liebert, Inc.

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Role of the Vision Van, a mobile ophthalmic outpatient clinic, in the Great East Japan Earthquake

Yuki Kenya, Nakazawa Toru, Kurosaka Daijiro, Yoshida Tsunehiko, Alfonso Eduardo C., Lee Richard K., Takano Shigeru, Tsubota Kazuo

Clinical Ophthalmology 8 691 - 696 2014年04月

ISSN 1177-5467

Purpose: The Great East Japan Earthquake of March 11, 2011 triggered powerful tsunami waves off the northeastern Pacific coast of Japan that destroyed almost all of the built-up areas along the coast. The study reported here examined the role played by the Vision Van, a mobile outpatient ophthalmological clinic, in providing eye care to disaster evacuees. Methods: This was a retrospective case-series study of 2,070 victims (male: 732, female: 1,338) who visited the Vision Van. The subjects' medical records were examined retrospectively and analyzed in terms of age, sex, and date of visit to the Vision Van. Information regarding each patient's chief complaint, diagnosis, medication(s) prescribed, and eyeglasses and contact lenses provided, was also examined.Results: The Vision Van was used to conduct medical examinations on 39 days between April 23 and June 29, 2011. The average number of subjects visiting the Vision Van each day was 53±31 (range: 7-135), with examinations carried out in Miyagi Prefecture and Iwate Prefecture. The most frequent complaint was a need for eye drops (871/2,070 [42.1%]). The second and third most frequent complaints, respectively, were the need for contact lenses (294/2,070 [14.2%]) and eyeglasses (280/2,070 [13.5%]). The most frequent ocular disease diagnosis was cataract (497/2,070 [24.0%]). Eye drops were prescribed to 74.1% of the subjects.Conclusion: Mobile clinics such as the Vision Van provide valuable care, in this case, particularly to individuals who lost or left behind eyeglasses or contact lenses while escaping a natural disaster, and to subjects with chronic eye disease. © 2014 Yuki et al. This work is published by Dove Medical Press Limited.

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Phase II enzyme induction by a carotenoid, lutein, in a PC12D neuronal cell line

Miyake Seiji, Kobayashi Saori, Tsubota Kazuo, Ozawa Yoko

Biochemical and Biophysical Research Communications 446 （ 2 ） 535 - 540 2014年04月

ISSN 0006-291X

The mechanism by which lutein, a carotenoid, acts as an antioxidant in retinal cells is still not fully understood. Here, lutein treatment of a neuronal cell line (PC12D) immediately resulted in reduced intracellular ROS levels, implying that it has a direct role in ROS scavenging. Significantly, lutein treatment also induced phase II antioxidative enzyme expression, probably via a nuclear factor-like 2 (Nrf2) independent pathway. This latter mechanism could explain why lutein acts diversely to protect against oxidative/cytotoxic stress, and why it is physiologically involved in the human neural tissue, such as the retina. © 2014 The Authors. Published by Elsevier Inc.

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Diclofenac protects cultured human corneal epithelial cells against hyperosmolarity and ameliorates corneal surface damage in a rat model of dry eye

Sawazaki Ryoichi, Ishihara Tomoaki, Usui Shinya, Hayashi Erika, Tahara Kayoko, Hoshino Tatsuya, Higuchi Akihiro, Nakamura Shigeru, Tsubota Kazuo, Mizushima Tohru

Investigative Ophthalmology and Visual Science 55 （ 4 ） 2547 - 2556 2014年03月

ISSN 0146-0404

Purpose. Dry eye syndrome (DES) is characterized by an increase in tear osmolarity and induction of the expression and nuclear localization of an osmoprotective transcription factor (nuclear factor of activated T-cells 5 [NFAT5]) that plays an important role in providing protection against hyperosmotic tears. In this study, we screened medicines already in clinical use with a view of finding compounds that protect cultured human corneal epithelial cells against hyperosmolarity-induced cell damage. Methods. Viable cell number was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and cellular NFAT5 level was measured by immunoblotting. The rat model for DES was developed by removal of the lacrimal glands, with an assessment of corneal surface damage based on levels of fluorescein staining and epithelial apoptosis. Results. Some nonsteroidal anti-inflammatory drugs (NSAIDs), including diclofenac sodium (diclofenac), were identified during the screening procedure. These NSAIDs were able to suppress hyperosmolarity-induced apoptosis and cell growth arrest. In contrast, other NSAIDs, including bromfenac sodium (bromfenac), did not exert such a protective action. Treatment of cells with diclofenac, but not bromfenac, stimulated both the nuclear localization and expression of NFAT5 under hyperosmotic conditions. In the rat model for DES, topical administration of diclofenac (but not bromfenac) to eyes reduced corneal surface damage without affecting the volume of tear fluid. Conclusions. Diclofenac appears to protect cells against hyperosmolarity-induced cell damage and NFAT5 would play an important role in this protective action. The findings reported here may also indicate that the topical administration of diclofenac to eyes may be therapeutically beneficial for DES patients. © 2014 The Association for Research in Vision and Ophthalmology, Inc.

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Vitrectomy for myopic foveoschisis with internal limiting membrane peeling and no gas tamponade

Uchida Atsuro, Shinoda Hajime, Koto Takashi, Mochimaru Hiroshi, Nagai Norihiro, Tsubota Kazuo, Ozawa Yoko

Retina 34 （ 3 ） 455 - 460 2014年03月

ISSN 0275-004X

PURPOSE:: To evaluate the outcome of vitrectomy with internal limiting membrane peeling and no gas tamponade in the treatment of eyes with myopic foveoschisis. METHODS:: Medical records of 10 eyes of 9 consecutive patients with myopic foveoschisis without macular hole treated by vitrectomy were reviewed. RESULTS:: The patientsÊ1/4 refractive error was-4.00 diopters to-34.00 diopters, and axial length was 28.38 mm to 35.90 mm. Six eyes had foveal retinal detachment with retinoschisis. All cases were treated by vitrectomy with internal limiting membrane removal without gas tamponade. The mean preoperative best-corrected visual acuity was 0.61 ± 0.42 in logarithm of the minimum angle of resolution units (Snellen equivalent of 20/82). Myopic foveoschisis was reduced in 8 eyes (80%) with a single surgery. Two eyes without improvement developed a postoperative macular hole and were treated by additional vitreoretinal surgery. All 10 eyes showed anatomical repair, and 5 eyes showed improvement in best-corrected visual acuity to 0.47 ± 0.48 (Snellen equivalent of 20/60), by 17 months after the initial surgery. CONCLUSION:: Vitrectomy with internal limiting membrane peeling and no gas tamponade can effectively treat some cases of myopic foveoschisis, suggesting that tractional forces at the vitreoretinal interface may contribute to the pathogenesis of myopic foveoschisis, thereby avoiding gas tamponade. © 2013 Ophthalmic Communications Society, Inc.

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Endoscopy-guided vitreoretinal surgery

Kawashima Shinichi, Kawashima Motoko, Tsubota Kazuo

Expert Review of Medical Devices 11 （ 2 ） 163 - 168 2014年03月

ISSN 1743-4440

Vitreoretinal surgery has recently undergone remarkable developments. The introduction of micro-incision vitrectomy surgery using 25-and 23-gauge techniques has led to minimally invasive, faster, safer, and more accurate surgeries. Similarly, intraocular illumination and observation systems have advanced from light pipes to chandelier illumination, slit illumination, wide-angle viewing systems, and intraocular endoscopes. Compared to observation via the cornea and optic media, vitreous surgery using an endoscope is extremely useful, as the endoscope is inserted directly into the eye, circumventing the difficulties of corneal clouding and small pupil diameters. Furthermore, there are no blind spots after surgery. We here discuss the advantages of intraocular endoscope use, the current state of endoscopy-guided vitreoretinal surgery, and its future prospects. © 2014 Informa UK Ltd.

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Combination therapy with diquafosol tetrasodium and sodium hyaluronate in patients with dry eye after laser in situ keratomileusis

Toda Ikuko, Ide Takeshi, Fukumoto Teruki, Ichihashi Yoshiyuki, Tsubota Kazuo

American Journal of Ophthalmology 157 （ 3 ） 2014年03月

ISSN 0002-9394

Purpose To evaluate the possible advantages of combination therapy with diquafosol tetrasodium and sodium hyaluronate for dry eye after laser in situ keratomileusis (LASIK). Design Prospective randomized comparative trial. Methods A total of 206 eyes of 105 patients who underwent LASIK were enrolled in this study. Patients were randomly assigned to 1 of 4 treatment groups according to the postoperative treatment: artificial tears, sodium hyaluronate, diquafosol tetrasodium, and a combination of hyaluronate and diquafosol. Questionnaire responses reflecting subjective dry eye symptoms, uncorrected and corrected visual acuity, functional visual acuity, manifest refraction, tear break-up time, fluorescein corneal staining, Schirmer test, and corneal sensitivity were examined before and 1 week and 1 month after LASIK. Results Distance uncorrected visual acuity was significantly better in the combination group than in the hyaluronate group 1 week and 1 month after LASIK. Near uncorrected visual acuity was significantly better in the combination group than in the artificial tear and diquafosol groups 1 week and 1 month after LASIK. Distance functional visual acuity improved significantly only in the combination group 1 month after LASIK. The Schirmer value in the combination group was significantly higher than that in the hyaluronate group at 1 month after LASIK. Subjective dry eye symptoms in the combination group improved significantly compared with those in the other groups 1 week after surgery. Conclusions Our results suggest that hyaluronate and diquafosol combination therapy is beneficial for early stabilization of visual performance and improvement of subjective dry eye symptoms in patients after LASIK.

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Decreased tear volume in patients with metabolic syndrome

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

British Journal of Ophthalmology 98 （ 3 ） 418 - 420 2014年03月

ISSN 0007-1161

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Association of serum lipids with macular thickness and volume in type 2 diabetes without diabetic macular edema

Sasaki Mariko, Kawashima Motoko, Kawasaki Ryo, Uchida Atsuro, Koto Takashi, Shinoda Hajime, Tsubota Kazuo, Wang Jie Jin, Ozawa Yoko

Investigative Ophthalmology and Visual Science 55 （ 3 ） 1749 - 1753 2014年02月

ISSN 0146-0404

Purpose. To assess the relationship between macular thickness and volume as characterized by optical coherence tomography (OCT) and known risk factors for diabetic retinopathy (DR) or macular edema (DME) in type 2 diabetic patients with no DME. Methods. Seventy-four patients with type 2 diabetes without DME and no or only minimal DR (n = 67 with no DR; n = 7 with minimal DR; mean age, 59.5 years) were recruited at a tertiary eye hospital. Central subfield macular thickness (CSMT; circle of 500-μm radius) and central subfield macular volume (CSMV) were measured using spectral-domain OCT. Associations between OCT parameters and known risk factors for DR were examined using multiple linear regression models. Results. The mean CSMT and CSMV values were 273.7 ± 17.8 μm and 0.215 ± 0.015 mm³, respectively. After adjusting for age, sex, duration of diabetes, hemoglobin A1c, and urine protein, low-density lipoprotein (LDL) cholesterol was positively associated with CSMT and CSMV; each 1 mmol/L increase in LDL was associated with a mean increase in CSMT of 6.52 μm (95% confidence interval [CI], 1.96-11.08; P = 0.006) and a mean increase in CSMV of 0.0047 mm3 (95% CI, 0.001-0.0085; P = 0.015). Conclusions. A higher LDL cholesterol level was associated with increased CSMT and CSMV in diabetic patients without DME. Prospective longitudinal studies are warranted to assess whether having both elevated levels of LDL and higher CSMT or CSMV is a risk indicator for subsequent development of DME. © 2014 The Association for Research in Vision and Ophthalmology, Inc.

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Dry eye disease and work productivity loss in visual display users

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

American Journal of Ophthalmology 157 （ 2 ） 294 - 300 2014年02月

ISSN 0002-9394

Purpose To estimate the impact of dry eye disease (DED) on work performance and productivity in office workers using visual display terminals (VDTs). Design Cross-sectional study. Methods Six hundred seventy-two Japanese young and middle-aged office workers using VDTs completed a questionnaire that was designed to measured at-work performance deficits and productivity losses using the Japanese version of the Work Limitations Questionnaire, completed by e-mail. Using the Japanese dry eye diagnostic criteria, respondents were classified into 3 groups: definite DED, probable DED, and non DED. Results Of the 672 office workers, 553 subjects (82.3%), including 366 men and 187 women, completed the questionnaire and underwent clinical evaluation. As for the total workplace productivity loss, the non DED group demonstrated a loss of 3.56%, those with probable DED demonstrated a loss of 4.06%, and those with definite DED demonstrated a loss of 4.82%, indicating significantly worse performance and productivity (P =.014, trend test). For the 4 subscales, DED was associated with significantly lower on-the-job time management (P =.009, trend test) and combined mental performance and interpersonal functioning (P =.011, trend test). After controlling for age, sex, VDT working hours, and diagnosis of DED, time management, physical demands, and mental and interpersonal functioning showed a significant relationship to DED (each P >.05). Annual DED productivity losses were estimated to be $6160 per employee when measured by total production and $1178 per employee calculated by wage. Conclusions This study indicated that there is a significant impact of DED on the total productivity of Japanese VDT users. © 2014 BY ELSEVIER INC. ALL RIGHTS RESERVED.

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Evaluation of a thermosensitive atelocollagen punctal plug treatment for dry eye disease

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

American Journal of Ophthalmology 157 （ 2 ） 2014年02月

ISSN 0002-9394

Purpose To evaluate the efficacy of a thermosensitive atelocollagen punctal plug in the treatment of dry eye disease. Design Prospective observational case series. Methods The thermosensitive atelocollagen punctal plug was warmed at 37 C, 39 C, 41 C, and 43 C to evaluate the appropriate temperature and time for solidification. Dry eye patients were divided into 2 groups according to the preparation method of the atelocollagen punctal plug. In the conventional implantation group, atelocollagen gel was kept at room temperature for 15 minutes before implantation (27 eyes of 14 patients). In the preheating group, atelocollagen was warmed at 41 C for 8 minutes before implantation (23 eyes of 13 dry eye patients). Strip meniscometry, vital stainings, tear film break-up time (BUT), and symptom scores were evaluated before and 1 month after plug implantation. Results In vitro experiments revealed that heating at 41 C for 8 minutes was sufficient to solidify the gel. The mean fluorescein score in the conventional implantation group significantly improved after treatment (before, 3.5 ± 2.3 points; after, 2.5 ± 0.9 points, P <.05). In the preheating group, the mean fluorescein score (before, 3.7 ± 1.7 points; after, 1.5 ± 1.2 points), strip meniscometry (before, 0.6 ± 0.7 mm; after, 1.1 ± 0.3 mm), BUT (before, 3.2 ± 0.7 seconds; after, 4.8 ± 1.0 seconds), and visual analog scale scores (before, 6.6 ± 1.5 points; after, 4.1 ± 0.9 points) significantly improved after treatment (P <.05). Conclusion The thermosensitive atelocollagen punctal plug was effective for dry eye treatment. The preheating method was found to be useful to strengthen the efficacy of the thermosensitive atelocollagen punctal plug. © 2014 BY ELSEVIER INC. ALL RIGHTS RESERVED.

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