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Environmental risk factors that have an impact on the ocular surface were reviewed and associations with age and sex, race/ethnicity, geographical area, seasonality, prevalence and possible interactions between risk factors are reviewed. Environmental factors can be (a) climate-related: temperature, humidity, wind speed, altitude, dew point, ultraviolet light, and allergen or (b) outdoor and indoor pollution: gases, particulate matter, and other sources of airborne pollutants. Temperature affects ocular surface homeostasis directly and indirectly, precipitating ocular surface diseases and/or symptoms, including trachoma. Humidity is negatively associated with dry eye disease. There is little data on wind speed and dewpoint. High altitude and ultraviolet light exposure are associated with pterygium, ocular surface degenerations and neoplastic disease. Pollution is associated with dry eye disease and conjunctivitis. Primary Sjögren syndrome is associated with exposure to chemical solvents. Living within a potential zone of active volcanic eruption is associated with eye irritation. Indoor pollution, "sick" building or house can also be associated with eye irritation. Most ocular surface conditions are multifactorial, and several environmental factors may contribute to specific diseases. A systematic review was conducted to answer the following research question: "What are the associations between outdoor environment pollution and signs or symptoms of dry eye disease in humans?" Dry eye disease is associated with air pollution (from NO 2 ) and soil pollution (from chromium), but not from air pollution from CO or PM 10 . Future research should adequately account for confounders, follow up over time, and report results separately for ocular surface findings, including signs and symptoms., Competing Interests: Declaration of competing interest Monica Alves: FAPESP (G), FAEPEX (G), Alcon (L,C), Allergan (L,C), Latinofarma (L,C), Uniaoquimica (L); Penny Asbell: Regeron (F), Sylentis (F), Recordati (F), Senju (C), Olia (C); Murat Dogru: Kobayeshi Pharmaceuticals (F), Otsuka (F), Icorn GMBH (F), Twenty/Twenty Therapeutics (C); Giuseppe Giannaccare: Théa (C), Bausch + Lomb (R); Arturo Grau: None; Darren Gregory: None; Dong Hyun Kim: Santen (C), Taejoon Pharm (C), Chong Kun Dang Pharm (C), Hanlim Pharm (C), Hanmi Pharm (C); Maria Cecilia Marini: None; William Ngo: Alcon (C); Anna Nowinska: None; Ian J. Saldanha: None; Edoardo Villani: Allergan (F), Alfa Intes (F), Offhealth (F), Allergan (C), Bruschettini (C), FB Vision (C), Santen (C), Servimed (C), Shire (C), Théa (C), Visufarma (C); Tais Hitomi Wakamatsu: None; Mitasha Yu: World Health Organization (C); Fiona Stapleton: Alcon (C,F), Allergan (F), Azura Ophthalmics (F), Coopervision (C), Exonate (F), Menicon (F), nthalmic (F), Novartis (C,F), CSL Seqirus (C), Sun Pharmaceuticals (C)., (Copyright © 2023. Published by Elsevier Inc.)

The popularity and variety of temporary and permanent periocular aesthetic treatments has increased over the past decade. Patients frequently present to eye clinics with ocular complications and side effects following these treatments, their severity ranging from ocular irritation from dry eyes to visual loss from vascular occlusion. A careful, thorough history is essential, as many patients may not associate aesthetic procedures with ocular complications, and some may be embarrassed to disclose this information. All ophthalmologists should understand the potential ocular sequelae of these treatments and be able to initiate treatment in sight-threatening cases. We summarize the current literature on ophthalmic complications of the most common periocular aesthetic treatments., Competing Interests: Declarations of competing interest Mohammad Javed Ali receives royalties from Springer for the 2nd edition of the textbook “Principles and Practice of Lacrimal Surgery’ and treatise ‘Atlas of Lacrimal Drainage Disorders’., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Ocular surface neuropeptides are vital molecules primarily involved in maintaining ocular surface integrity and homeostasis. They also serve as communication channels between the nervous system and the immune system, maintaining the homeostasis of the ocular surface. Tear film and ocular surface neuropeptides have a role in disease often due to abnormalities in their synthesis (either high or low production), signaling through defective receptors, or both. This creates imbalances in otherwise normal physiological processes. They have been observed to be altered in many ocular surface and systemic diseases including dry eye disease, ocular allergy, keratoconus, LASIK-induced dry eye, pterygium, neurotrophic keratitis, corneal graft rejection, microbial keratitis, headaches and diabetes. This review examines the characteristics of neuropeptides, their synthesis and their signaling through G-protein coupled receptors. The review also explores the types of neuropeptides within the tears and ocular surface, and how they change in ocular and systemic diseases., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The purpose of this study was to investigate the changes in E-FABP in the salivary and lacrimal glands of the Sjögren syndrome (SS) model non-obese diabetic mice (NOD). Cotton thread and ocular vital staining tests were performed on 10-week NOD male mice ( n = 24) and age- and sex-matched wild-type (WT) mice ( n = 25). Tear and saliva samples were collected at sacrifice for E-FABP ELISA assays. Salivary and lacrimal gland specimens underwent immunohistochemistry stainings for E-FABP. Real-time RT-PCR was also performed for the quantification of mRNA expression levels in the salivary and lacrimal glands. Corneal vital staining scores in the NOD mice were significantly higher compared with those for the wild-type mice ( p = 0.0001). The mean tear E-FABP level showed a significantly lower concentration in the NOD mice ( p = 0.001). The mean saliva E-FABP level also showed a significantly lower concentration in the NOD mice ( p = 0.04). Immunohistochemistry revealed intense E-FABP staining in the LG acinar epithelium and less intense staining in the acinar epitheliae of the SGs in the NOD mice compared to the WT mice. Real-time RT-PCR for the mRNA expression of E-FABP showed a significantly decreased expression in the SG and a significant increase in the LG of the NOD mice compared to the WT mice. In conclusion, the E-FABP showed marked alterations in the tear film, saliva, lacrimal, and salivary glands of the NOD mouse, which may help explain the ocular surface changes in relation to the dry eye disease in this SS model mouse and keratoconjunctivitis sicca in SS patients.

Purpose: We investigated the early effects of alcohol intake on tear functions and ocular surface health in this prospective controlled study., Methods: Forty-four eyes of 22 subjects (17 males, 5 females; mean age: 35.3 years) who drank 200 mL of 25% Japanese vodka and 44 eyes of age- and sex-matched 22 control subjects who drank water were investigated. Subjects were requested to refrain from alcohol consumption from the previous day and food ingestion 6 hr before the study. Each subject consumed exactly the same order prepared dinner and same quantity of alcohol over the same time frame. Subjects underwent breath alcohol level, tear evaporation and blink rate, tear lipid layer interferometry, tear film break-up time (BUT), fluorescein and Rose Bengal stainings, Schirmer test, and visual analog scale (VAS) evaluation of dry eye symptoms before, as well as 2 and 12 hr after alcohol intake., Results: The mean breath alcohol level was significantly higher in the alcohol group compared to the water group at 2 and 12 hr (P<0.001). The mean tear evaporation increased significantly from 2.5×10-7 to 8.8×10-7 gr/cm2/sec 12 hr after alcohol intake (P<0.001). The mean BUT shortened significantly from 15.0±5.0 to 5.0±2.5 sec 12 hr after alcohol intake. Lipid layer interferometry showed signs of tear film thinning 12 hr after alcohol intake in all subjects of the alcohol intake group, which was not observed in the water group. The mean blink rates increased significantly from 10.6±1.5 blinks/min to 13.5±0.9 blinks/min and 15.1±1.2 blinks/min at 2 and 12 hr, respectively, in the alcohol group (P<0.001). The Schirmer test values decreased significantly 12 hr after alcohol intake (P<0.001). The mean VAS score for dryness increased from baseline significantly in the alcohol group at 12 hr (P<0.001). No significant time-wise changes in tear functions were observed in the water group., Conclusion: The tear film and ocular surface epithelia showed early and distinctive quantitative and qualitative changes associated with visual disturbances after alcohol intake., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Contact Lens Association of Ophthalmologists.)

Hyaluronic acid (HA) ophthalmic solution is widely used in dry eye treatment worldwide. However, there are no reports comparing the dry eye treatment effects of high molecular weight HA with low molecular weight HA. Sixty eight-week-old C57BL/6 mice were assigned to the following 6 groups and exposed to environmental dry eye stress (EDES) that mimics office work environment: 1) 0.1% low molecular weight HA (LMWHA) eye drops, 2) 0.3% LMWHA eye drops, 3) 3% diquafosol sodium (DQ) eye drops, 4) 0.15% high molecular weight HA (HMWHA) eye drops, 5) no treatment with exposure to EDES (EDES+/Treatment-), and 6) no treatment without exposure to EDES (EDES-/Treatment-). After EDES, the HMWHA group had significantly longer break-up time (BUT) than the 0.1%, 0.3% LMWHA groups and the DQ group. After EDES, the HMWHA group had significantly lower lissamine green staining scores than the LMWHA and DQ groups. Subepithelial presumed dendritic cell density in the HMWHA group was significantly lower than the EDES+/Treatment- group. After EDES exposure, Conjunctival Muc5AC mRNA expression in the HMWHA group was significantly higher than the 0.1 and 0.3% LMWHA groups. Ophthalmic HMWHA solution may have a better dry eye treatment effect than LMWHA or DQ solution, owing to its anti-inflammatory effect., Competing Interests: Dr. Wolfgang Mueller-Lierheim is the CEO of i.com medical GmbH, Munich, Germany, which is the sponsor of the current study. Dr. Gysbert-Botho van Setten was the scientific consultant of i.com medical GmbH. Other authors have no financial interest in this research.

Purpose: The present study aimed to compare the prevalence of dry eye disease (DED) among visual display terminal users using the revised and previous DED criteria., Methods: This cross-sectional study included 561 participants (187 women)., Results: The distribution of diagnostic status according to the previous DED criteria was as follows: definite DED (n = 65, 11.6%), probable DED (n = 303, 54.0%), and non-DED (n = 193, 34.4%). According to the revised criteria, 329 participants (58.6%) were classified as DED and 232 participants (41.4%) were classified as non-DED., Conclusions: The prevalence of DED among visual display terminal users has increased to 58.6% from 11.6%, according to the revised DED diagnostic criteria of the Asia Dry Eye Society.

The 2017 consensus report of the Asia Dry Eye Society (ADES) on the definition and diagnosis of dry eyes described dry eye disease as "Dry eye is a multifactorial disease characterized by unstable tear film causing a variety of symptoms and/or visual impairment, potentially accompanied by ocular surface damage." The report emphasized the instability of tear film and the importance of visual dysfunction in association with dry eyes, highlighting the importance of the evaluation of tear film stability. This report also discussed the concept of tear film-oriented therapy, which stemmed from the definition, and which is centered on provision of insufficient components in each tear film layer and ocular surface epithelium. The current ADES report proposes a simple classification of dry eyes based on the concept of tear film-oriented diagnosis and suggests that there are three types of dry eye: aqueous-deficient, decreased wettability, and increased evaporation. It is suggested that these three types respectively coincide with the problems of each layer: aqueous, membrane-associated mucins, and lipid/secretory mucin. Although each component cannot be quantitatively evaluated with the current technology, a practical diagnosis based on the patterns of fluorescein breakup is recommended. The Asia Dry Eye Society classification report suggests that for a practical use of the definition, diagnostic criteria and classification system should be integrated and be simple to use. The classification system proposed by ADES is a straightforward tool and simple to use, only through use of fluorescein, which is available even to non-dry eye specialists, and which is believed to contribute to an effective diagnosis and treatment of dry eyes.

Purpose: To investigate the effects of aging on the conjunctival P2Y2 receptors, tear functions, and corneal epithelial status from 10 to 50 weeks in the Sod1 in comparison with the wild-type mice., Methods: Eight eyes of 4 Sod1 male mice and 8 eyes of 4 C57BL6 strain wild-type male mice were examined at 10 and 50 weeks in this study. Tear film breakup time (BUT) and corneal epithelial damage by fluorescein staining were evaluated. Phenol red-impregnated cotton threads were performed without topical anesthesia to measure aqueous tear quantity. Anterior segment photography was also performed at 10 and 50 weeks. Conjunctival specimens underwent immunohistochemistry stainings with anti P2Y2 antibodies. P2Y2 receptor mRNA expression in the bulbar conjunctiva was investigated by using quantitative real-time polymerase chain reaction., Results: The mean tear quantity and BUT scores significantly declined, and the mean fluorescein staining scores significantly increased in both strains of mice from 10 to 50 weeks. % mRNA expression for P2Y2 receptors significantly increased in both mice strains from 10 to 50 weeks., Conclusion: The tear stability, quantity, and ocular surface health decline with aging as evidenced by the decrease in tear BUT, tear quantity, and the increase in ocular surface staining. Conjunctival P2Y2 receptor mRNA was upregulated from 10 to 50 weeks, which we believe is a compensation for the decline of tear functions with aging.

Rebamipide ophthalmic solution is a mucin secretagogue which is an important therapeutic agent in the treatment of dry eye. It has been noted that dry eye in office workers is associated with a decrease in secretory mucin. This study aimed to evaluate the effects of 2% rebamipide ophthalmic solution in mice subjected to environmental dry eye stress (EDES), which mimics the conditions of office workers. Thirty eyes from thirty BALB/c mice (eight-week-old males) were divided into three treatment groups: artificial tear (vehicle), 2% rebamipide ophthalmic solution, and 0.1% hyaluronic acid (HA) ophthalmic solution. After four days of pretreatment, mice were exposed to EDES for three days. The corneal subbasal nerve and inflammatory cells were then examined using in vivo confocal microscopy. Following EDES exposure, the lissamine green staining score was significantly lower and corneal sensitivity was more preserved in the 2% rebamipide group than in the HA group. In addition, the subbasal nerve fiber density was significantly higher and the DC density was significantly lower in the 2% rebamipide group than in the HA group. Overall, the topical rebamipide ophthalmic solution showed more favorable therapeutic effects when compared to the HA ophthalmic solution in a mouse model of EDES, likely owing to its anti-inflammatory and neuroprotective effects.

Purpose: To evaluate the relationship between the severity of ocular and systemic pain., Methods: A cross-sectional study was conducted in patients with ocular pain symptoms who were observed in Keio University Hospital between April 2017 and September 2018. Evaluations consisted of the Dry Eye-Related Quality of Life Score (DEQS), Short-Form McGill Pain Questionnaire (SF-MPQ), visual analog scale (VAS), and ophthalmologic examination, including tear breakup time measurement and Schirmer I test. The revised Asia Dry Eye Society Dry Eye Disease (DED) diagnostic criteria were used., Results: The present study involved 41 participants (31 women; mean age, 57.6 ± 17.5 years). Thirteen participants had aqueous-deficient DED, 18 participants had short tear break-up time DED, and 10 participants had no DED. Multivariate regression analysis revealed that the DEQS was significantly associated with both the SF-MPQ total (Coefficient score β = 0.92, p < 0.01) and the VAS (β = 0.25, p = 0.01). In addition, correlation analysis revealed that the DEQS had a significant positive linear correlation with both the SF-MPQ total (Spearman correlation score rs = 0.70, p < 0.01) and the VAS (rs = 0.66, p < 0.01)., Conclusions: The findings of the present study suggested that the ocular pain score was significantly associated with systemic pain score. Participants with higher systemic pain scores have an increased risk of having ocular pain., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To clarify the pharmacological effects of 2% rebamipide eye drops on mucosal membrane functions of the ocular surface epithelium, we investigated keratoconjunctival alterations at the cellular level in this study. Methods: Fifteen patients with definite dry eye disease were recruited from outpatient clinics of the Department of Ophthalmology, Ichikawa General Hospital. The patients received treatment with 2% rebamipide eye drops q.i.d for 12 weeks. Symptom score assessment, tear film breakup time, fluorescein and lissamine green ocular surface vital staining, grading of lid wiper epitheliopathy, Cochet-Bonnet corneal sensitivity, assessment of squamous metaplasia grades, and goblet cell density calculations from conjunctival impression cytology samples, as well as evaluation of nucleocytoplasmic ratios and corneal epithelial cells from in vivo confocal microscopy images before and 3 months after treatment were performed. Results: The mean symptom scores, tear film breakup time values, ocular surface fluorescein and lissamine green vital staining scores, and lid wiper scores showed a significant improvement after treatment ( P  < 0.01). The mean squamous metaplasia grade also showed a significant improvement (1.2 ± 0.1 → 0.3 ± 0.1) 3 months after treatment ( P  = 0.004). There were similar significant improvements in the mean corneal epithelial cell density (660.1 ± 62.6 → 1015.5 ± 43.5 cells/mm 2 ) ( P  = 0.002) and nucleocytoplasmic ratios (0.1 ± 0.0 → 0.2 ± 0.0) ( P  = 0.0042) after treatment. Conclusions: Topical use of 2% rebamipide for 3 months was associated with improvements in ocular surface differentiation due to changes of mucosal functions at the cellular level. These alterations may explain objective and subjective improvements in dry eye disease.

Purpose: Strip meniscometry quantitatively measures the volume of tears in the tear meniscus and has been reported to diagnose dry eyes in clinical settings conveniently, easily, and rapidly. In this study, we used a modified strip meniscometry to assess the applicability of measuring the tear volume in mice in experimental settings., Methods: Dry eye was induced in 11 9-week-old C57BL/6J wild-type male mice (11 right eyes) by exposing them to an air fan inside a small compartment for 5 hours for 2 consecutive days. Tear function tests, including the SMTube for mice (SMTM) for tear volume evaluation, break-up time, fluorescein staining score, and lissamine green staining score, were performed. The correlation between SMTM and other tear function parameters was assessed., Results: The mean SMTM value was 3.89 ± 0.603 mm before and 3.09 ± 0.625 mm after dry environment exposure (P = 0.0078*). The Spearman's correlation by rank test showed a strong positive correlation between SMTM and tear film break-up time and a strong linear negative correlation with fluorescein and lissamine green values., Conclusions: The SMTM was capable of rapidly measuring the minimum tear volume in mice and correlated well with tear function parameters and appears to be a promising new modality in the evaluation of dry eyes in mice.

Purpose: To evaluate the morphologic changes in the corneal subbasal nerve (CSN) plexus in wild-type (WT) mice after exposure to scopolamine-induced dry eye stress (DES) by using in vivo confocal microscopy., Methods: Twenty right eyes of twenty (n = 20) 8-week-old WT BALB/c male mice were investigated. The mice were divided into two experimental groups; 10 eyes of 10 mice exposed to DES for 28 days and 10 eyes of 10 mice were used as a control group. All mice underwent examinations for aqueous tear secretion quantity, tear film breakup time (TBUT), corneal vital staining. and corneal sensitivity thrice (pre-experiment, 2nd week, and 4th week). CSN density, tortuosity, reflectivity, and dendritic cell (DC) densities were examined., Results: The mean aqueous tear secretion (P < 0.0001) and TBUTs (P < 0.0001) were significantly decreased after DES. The mean corneal vital staining scores were significantly higher (fluorescein, P < 0.0001; lissamine, P < 0.0001), the mean TBUTs were significantly shorter (P < 0.0001), and the corneal sensitivities (P < 0.0001) were significantly lower in the dry eye-induced mice than the control mice. The mean CSN fiber density (P < 0.0001) and the reflectivity (P < 0.001) were significantly lower; the mean tortuosity and the mean DC density were significantly higher (P < 0.0001) in the dry eye mice., Conclusions: Our data demonstrated that prolonged exposure to DES resulted in alterations of CSN density; DC intensity, reflectivity, and tortuosity as well as in tear volume; TBUT; fluorescein and lissamine green staining scores; and the corneal sensitivity in WT mice.

Purpose: To evaluate the effect of moist chamber spectacle wear on the ocular surface and tear functions in a controlled wind exposure environment., Methods: Twenty-eight eyes of 14 probable dry eye subjects (4 men, 10 women; mean age: 34.5 years) underwent constant wind exposure for 10 min without spectacle, with conventional spectacle wear, and with moist chamber spectacle wear. Dryness Visual Analog Scale (VAS) scores, tear evaporation, blink rate, tear film breakup testing, and fluorescein staining were performed before and after wind exposure., Results: The mean dryness VAS score after wind exposure was significantly higher when no spectacles were worn or when conventional spectacles with no moist chambers were worn compared with after exposure scores when moist chamber spectacles were worn (P=0.02). The mean of tear evaporation rate from the ocular surface and blink rate increased significantly with wind exposure when no spectacles were worn or when conventional spectacles with no moist chambers were worn (P=0.04). There were no significant changes before and after wind exposure when the moist chamber spectacles were worn (P=0.1)., Conclusion: Moist chamber spectacles appear to have favorable effects on dry eye symptomatology, tear stability, and blink rates in adverse environment conditions such as wind exposure.

Reactive oxygen species (ROS) are produced as a by-product during the mitochondrial respiration of the oxygen and potentially able to damage the tissues. Oxidative stress occurs as a result of the disruption of the balance between the anti-oxidant system and the pro-oxidant system found in cells. It has been accepted that overexpression of ROS can be induced in the ocular surface as a result of many acute and chronic diseases and even in normal aging. Recent studies demonstrated that oxidative stress damages the ocular surface and plays an important role in the mechanism of dry eye disease. There is a need to investigate the therapeutic modalities employing topical/systemic use of antioxidants in dry eye disease. This review will summarize the recent studies showing the important relationship between oxidative stress and dry eye disease.

Purpose: To investigate the applicability of CASIA SS-1000 anterior-segment optical coherence tomography (AS-OCT) imaging parameters in testing the efficacy of the new strip meniscometry (SM) namely "Strip Meniscometry Tube" (SMTube) in the diagnosis of dry eyes., Methods: Forty-three eyes of 22 patients (4 men and 18 women) with definite dry eye disease (DED) and 49 eyes of 28 normal controls (6 men and 22 women) were studied. All subjects underwent symptom questionnaires, SMTube, the Schirmer-1 test, tear film break-up time measurement, vital staining examinations, as well as tear meniscus height (TMH) and TM area (TMA) measurements using an AS-OCT system. We evaluated the cutoff values for the diagnosis of DED, looked into the correlations between TMH, TMA, and SMTube scores and checked the sensitivity and specificity of these parameters in the diagnosis of DED., Results: The mean values of TMH, TMA, and SMTube scores in the patient group were 0.138±0.102 mm, 0.013±0.015 mm and 1.4±2.3 mm, whereas those for the control group were 0.27±0.10 mm, 0.033±0.025 mm and 5.8±2.8 mm, respectively. The differences between both groups were significant (P<0.001). The cutoff values of TMH, TMA, and SMTube for DED were 0.197 mm, 0.020 mm and 3.8 mm, respectively. SMTube had significant correlations with TMH (r=0.82, P<0.001) and TMA (r=0.86, P<0.001)., Conclusions: The SMTube was useful in DED diagnosis, the validity of which could be effectively evaluated by the CASIA SS-1000 AS-OCT TM parameters.

Purpose: The purpose of the study is to investigate the effect of 3% diquafosol sodium eye drops on meibomian gland and ocular surface alterations in the superoxide dismutase-1 (Sod1 -/- ) mice in comparison to the wild-type mouse., Methods: Three percent diquafosol sodium eye drop was instilled to 20 eyes of 10 50-week-old male Sod1 -/- mice and 22 eyes of 11 C57BL/6 strain 50-week-old wild-type (WT) male mice six times a day for 2 weeks. Aqueous tear secretion quantity was measured with phenol red-impregnated cotton threads without anesthesia. Tear film stability and corneal epithelial damage were assessed by fluorescein and lissamine green staining. We also performed oil red O (ORO) lipid staining to evaluate the lipid changes in the meibomian glands. Meibomian gland specimens underwent hematoxylin and eosin staining to examine histopathological changes and meibomian gland acinar unit density after sacrifice. Immunohistochemistry staining was performed using cytokeratin 4, cytokeratin 13, and transglutaminase-1 antibodies. Quantitative real-time polymerase chain reaction for cytokeratin 4, cytokeratin 13, and transglutaminase-1 mRNA expression was also performed., Results: The aqueous tear quantity, the mean tear film breakup time, and the number of lipid droplets significantly improved in the Sod1 -/- mice with treatment. The mean meibomian acinar unit density did not change in the Sod1 -/- mice and WT mice after treatment. Application of 3% diquafosol sodium eye drop significantly decreased the corneal fluorescein and lissamine green staining scores in the Sod1 -/- mice after 2 weeks. We showed a notable increase in cytokeratin 4, cytokeratin 13 immunohistochemistry staining, and cytokeratin 4, cytokeratin 13 mRNA expressions with a marked decrease in immunohistochemistry staining and significant decline in mRNA expression of transglutaminase-1 after 3% diquafosol sodium treatment., Conclusion: Topical application of 3% diquafosol sodium eye drop improved the number of lipid droplets, tear stability, and tear production which in turn appeared to have a favorable effect on the ocular surface epithelium. Three percent diquafosol sodium eye drop may be a potential treatment for age-related meibomian gland and dry eye disease based on the observations of the current study.

Purpose: To investigate the morphologic changes in the corneal subbasal nerve (CSN) plexus in wild-type mice after exposure to environmental dry eye stress (EDES) using in vivo confocal microscopy (IVCM)., Methods: We examined 22 eyes of 8-week-old wild-type male mice (Balb/c, n = 11). The mice were exposed to an air fan inside a small compartment 5 hours/day for 3 days (EDES). Aqueous tear secretion and corneal epithelial damage were assessed. The CSNs were investigated by laser-scanning IVCM. Density; tortuosity; and reflectivity of CSNs; and dendritic cell (DC) densities were evaluated using semi-automated NeuronJ software., Results: EDES significantly decreased the aqueous tear secretion quantity (P = 0.0019) and significantly increased the corneal fluorescein (P = 0.005) and lissamine green staining scores (P = 0003). The CSN density showed a significant decrease after EDES exposure (before, 2813 ± 762 pixels/frame; after, 1906 ± 896 pixels/frame, P = 0.0071). The tortuosity and the reflectivity grades did not show statistically significant differences after EDES exposure (tortuosity, P = 0.307; reflectivity, P = 0.758). However, the mean DC density showed a significant increase after EDES exposure (before, 12.62 ± 5.94 cells/mm2; after, 15.93 ± 5.30 cells/mm2, P = 0.026)., Conclusions: Even short-term exposure to EDES induced alterations in the CSN plexus morphology including decreased subbasal corneal nerve density and increased amount of DCs in mice. The EDES mouse model is a promising model to study the ocular surface and corneal nerve changes associated with dry eye disease.

Purpose: The superoxide dismutase-1 knockout (Sod1-/-) mouse is an age-related dry eye mouse model. We evaluated the role of 2% rebamipide ophthalmic solution on the conjunctiva and ocular surface alterations in Sod1-/- mice., Methods: Rebamipide eye drops (2%) were instilled in six 50-week-old male Sod1-/- mice and six C57BL/6 strain wild-type (WT) male mice four times a day for 2 weeks. Aqueous tear secretion quantity and tear film breakup time measurements as well as vital stainings were performed. Immunohistochemistry staining of the conjunctiva was performed using SAM pointed domain-containing ETS transcription factor (SPDEF), transglutaminase-1, and involucrin antibodies. Quantitative RT-PCR was carried out to study mRNA expression of the same markers., Results: The mean tear quantities showed no significant changes in both mice strains after treatment (P = 0.24). The mean tear film breakup time (P = 0.003) and vital staining scores significantly improved in the Sod1-/- mice after treatment. Treatment with 2% rebamipide eye drops significantly decreased the corneal fluorescein (P = 0.0093) and Rose Bengal (P = 0.002) staining scores in the Sod1-/- mice. We showed a notable increase in SPDEF and a marked decrease in transglutaminase-1 and involucrin immunohistochemistry stainings, together with a significant increase in SPDEF (P = 0.0003) and a significant decline in transglutaminase-1 (P = 0.0072) and involucrin (P = 0.009) mRNA expression after treatment in the Sod1-/- mice., Conclusions: Topical use of 2% rebamipide drops was observed to improve conjunctival epithelial differentiation and suppress keratinization in the Sod1-/- mice.

The role of the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II Diagnostic Methodology Subcommittee was 1) to identify tests used to diagnose and monitor dry eye disease (DED), 2) to identify those most appropriate to fulfil the definition of DED and its sub-classifications, 3) to propose the most appropriate order and technique to conduct these tests in a clinical setting, and 4) to provide a differential diagnosis for DED and distinguish conditions where DED is a comorbidity. Prior to diagnosis, it is important to exclude conditions that can mimic DED with the aid of triaging questions. Symptom screening with the DEQ-5 or OSDI confirms that a patient might have DED and triggers the conduct of diagnostic tests of (ideally non-invasive) breakup time, osmolarity and ocular surface staining with fluorescein and lissamine green (observing the cornea, conjunctiva and eyelid margin). Meibomian gland dysfunction, lipid thickness/dynamics and tear volume assessment and their severity allow sub-classification of DED (as predominantly evaporative or aqueous deficient) which informs the management of DED. Videos of these diagnostic and sub-classification techniques are available on the TFOS website. It is envisaged that the identification of the key tests to diagnose and monitor DED and its sub-classifications will inform future epidemiological studies and management clinical trials, improving comparability, and enabling identification of the sub-classification of DED in which different management strategies are most efficacious., (Copyright © 2017 Elsevier Inc. All rights reserved.)

For the last 20 years, a great amount of evidence has accumulated through epidemiological studies that most of the dry eye disease encountered in daily life, especially in video display terminal (VDT) workers, involves short tear film breakup time (TFBUT) type dry eye, a category characterized by severe symptoms but minimal clinical signs other than short TFBUT. An unstable tear film also affects the visual function, possibly due to the increase of higher order aberrations. Based on the change in the understanding of the types, symptoms, and signs of dry eye disease, the Asia Dry Eye Society agreed to the following definition of dry eye: "Dry eye is a multifactorial disease characterized by unstable tear film causing a variety of symptoms and/or visual impairment, potentially accompanied by ocular surface damage." The definition stresses instability of the tear film as well as the importance of visual impairment, highlighting an essential role for TFBUT assessment. This paper discusses the concept of Tear Film Oriented Therapy (TFOT), which evolved from the definition of dry eye, emphasizing the importance of a stable tear film., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Dry eye disease has become an important health problem. A lack of concordance between self-reported symptoms and the outcome of dry eye examinations has raised questions about dry eye disease., Objective: To explore the association between subjective happiness and objective and subjective symptoms of dry eye disease., Design: The study adopted a cross-sectional design., Setting: All the employees of a company in Osaka, Japan., Participants: 672 Japanese office workers using Visual Display Terminals (age range: 26-64 years)., Methods: The dry eye measurement tools included the Schirmer test, conjunctivocorneal staining, the tear film break-up time, as well as the administration of a dry eye symptoms questionnaire. Happiness was measured by the Subjective Happiness Scale., Main Outcome Measures: Dry eye examination parameters, dry eye symptoms questionnaires, and the Subjective Happiness Scale score., Results: Of the 672 workers, 561 (83.5%) completed the questionnaires and examinations. The mean Subjective Happiness Scale score was 4.91 (SD = 1.01). This score was inversely correlated with the dry eye symptom score (r = -0.188, p < 0.001), but was not associated with objective findings which include conjunctivocorneal staining, low Schirmer test score, or low tear film break-up time. The level of subjective happiness was the lowest in the group without objective results, but reported subjective symptoms of dry eyes (p < 0.05)., Conclusions and Relevance: There is evidence of the relationship between subjective happiness and self-reported symptoms of dry eyes. Findings of this study revealed a new perspective on dry eye disease, including the potential for innovative treatments of a specific population with dry eye disease.

Purpose: To evaluate the relationship between subjective symptoms and clinical signs in dry eye disease (DED) in office workers using visual display terminals (VDTs)., Design: Cross-sectional study., Methods: This study involved 672 Japanese young and middle-aged office workers who use VDTs. The subjects completed questionnaires designed to detect subjective symptoms and risk factors for DED. Dry eye tests, including tear film break-up time (TBUT), corneal-conjunctival staining with fluorescein and lissamine green, and the Schirmer test, were performed. Based on the Japanese diagnostic criteria for DED, the subjects were classified into 3 groups: definite DED, probable DED, and non-DED. Between each group, subjective symptoms and clinical signs were compared., Results: Of the 672 subjects, 561 (374 male, 187 female) completed the questionnaire (response rate: 83.5%). Definite DED was diagnosed in 65 subjects (11.6%), probable DED in 303 subjects (54.0%), and non-DED in 193 subjects (34.4%). The mean subjective symptom score was significantly less in subjects with probable DED (2.05 ± 0.42) and non-DED (1.63 ± 0.38) than in those with definite DED (2.19 ± 0.40) (P < .05 and P < .01, respectively). In the subjects with probable DED, a subgroup with positive subjective symptoms and abnormal TBUT (≤5 seconds) was categorized as short TBUT-type DED, and it was found that they had a higher subjective symptom score (2.09 ± 0.40), equivalent to that of those with definite DED (P = .269)., Conclusions: Despite no or minor epithelial damage, the severity of subjective symptoms was greater in short TBUT-type DED, most likely attributable to tear film instability. Thus, it might prove important to evaluate TBUT to successfully treat those patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Importance: There are limited reports on the relationship between mucin 5AC (MUC5AC) concentrations in tears, working hours, and the frequency of ocular symptoms in visual display terminal (VDT) users. This investigation evaluated these relationships among patients with dry eye disease (DED) and individuals serving as controls., Objective: To determine the relationship between MUC5AC concentration in the tears of VDT users based on the diagnosis of DED and frequency of ocular symptoms., Design, Setting, and Participants: An institutional, cross-sectional study was conducted. Participants included 96 young and middle-aged Japanese office workers. Both eyes of 96 volunteers (60 men and 36 women) were studied. Participants working in a company that used VDTs completed questionnaires about their working hours and the frequency of ocular symptoms. Dry eye disease was diagnosed as definite or probable, or it was not present. Tear fluid was collected from the inferior fornix after instillation of 50 μL of sterilized saline. The MUC5AC concentration was normalized to tear protein content and expressed as MUC5AC (nanograms) per tear protein (milligrams). The differences in MUC5AC concentration between DED groups, between VDT working hours (short, intermediate, and long), and between symptomatic and asymptomatic groups were evaluated with 95% CIs based on nonparametric Hodges-Lehmann determination., Main Outcomes and Measures: Ocular surface evaluation, prevalence of DED, and MUC5AC concentration., Results: The prevalence of definite and probable DED was 9% (n = 9) and 57% (n = 55), respectively. The mean MUC5AC concentration was lower in the tears of VDT users with definite DED than in those with no DED (P = .02; Hodges-Lehmann estimator, -2.17; 95% CI, -4.67 to -0.30). The mean MUC5AC concentration in tears was lower in the group that worked longer hours than in the group that worked shorter hours (P = .049; estimated difference, -1.65; 95% CI, -3.12 to 0.00). Furthermore, MUC5AC concentration was lower in participants with symptomatic eye strain than in asymptomatic individuals (P = .001; estimated difference, -1.71; 95% CI, -2.86 to -0.63)., Conclusions and Relevance: The data obtained in the present study suggest that office workers with prolonged VDT use, as well as those with an increased frequency of eye strain, have a low MUC5AC concentration in their tears. Furthermore, MUC5AC concentration in the tears of patients with DED may be lower than that in individuals without DED.

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., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

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.

In vivo confocal microscopy (IVCM) is an emerging technology that provides minimally invasive, high resolution, steady-state assessment of the ocular surface at the cellular level. Several challenges still remain but, at present, IVCM may be considered a promising technique for clinical diagnosis and management. This mini-review summarizes some key findings in IVCM of the ocular surface, focusing on recent and promising attempts to move "from bench to bedside". IVCM allows prompt diagnosis, disease course follow-up, and management of potentially blinding atypical forms of infectious processes, such as acanthamoeba and fungal keratitis. This technology has improved our knowledge of corneal alterations and some of the processes that affect the visual outcome after lamellar keratoplasty and excimer keratorefractive surgery. In dry eye disease, IVCM has provided new information on the whole-ocular surface morphofunctional unit. It has also improved understanding of pathophysiologic mechanisms and helped in the assessment of prognosis and treatment. IVCM is particularly useful in the study of corneal nerves, enabling description of the morphology, density, and disease- or surgically induced alterations of nerves, particularly the subbasal nerve plexus. In glaucoma, IVCM constitutes an important aid to evaluate filtering blebs, to better understand the conjunctival wound healing process, and to assess corneal changes induced by topical antiglaucoma medications and their preservatives. IVCM has significantly enhanced our understanding of the ocular response to contact lens wear. It has provided new perspectives at a cellular level on a wide range of contact lens complications, revealing findings that were not previously possible to image in the living human eye. The final section of this mini-review provides a focus on advances in confocal microscopy imaging. These include 2D wide-field mapping, 3D reconstruction of the cornea and automated image analysis.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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

Purpose: To investigate tear function and prevalence of dry eye disease (DED) in visual display terminal (VDT) users., Design: Cross-sectional study., Methods: Six hundred and seventy-two young and middle-aged Japanese office workers who used VDT completed questionnaires and underwent dry eye testing. We estimated the prevalence of DED using logistic regression analysis to examine associations between DED and possible risk factors. The ocular surface feature, prevalence of DED, and risk factors were evaluated., Results: Of the 672 workers, 561 (83.5%, mean age: 43.3 ± 9.1 years) completed the questionnaire. The percentage of women with a composite outcome of definite DED or probable DED was 76.5%, which was higher than that among men (60.2%; odds ratio [OR] = 2.00; 95% confidence interval [CI], 1.29-3.10, P = .002). Workers over 30 years of age had a higher risk of DED (OR = 2.22; 95% CI, 1.06-4.66), as did workers using a VDT >8 hours per day (OR = 1.94; 95% CI, 1.22-3.09). Average Schirmer value was 18.7 ± 11.7 mm and tear break-up time (TBUT) was 4.0 ± 2.5 seconds (78.6% of study participants had TBUT ≤5 seconds)., Conclusions: DED is prevalent among young to middle-aged Japanese VDT users. Ophthalmic findings revealed short TBUT and corneal staining accompanied by normal Schirmer test values. Increased risk for DED was noted for women aged over 30 years and prolonged VDT use. Measures to modify the adverse impact of VDT use on the ocular surface may provide a positive impact on public health and quality of life for office workers using VDTs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Importance: A validated questionnaire that assesses symptoms and the effect of dry eye disease (DED) on the patient's daily life is needed to evaluate the condition., Objective: To develop and validate the Dry Eye-Related Quality-of-Life Score (DEQS) questionnaire in Japan., Design, Setting, and Participants: Development and evaluation of the DEQS questionnaire were conducted in 4 phases: (1) item generation, (2) pilot study to assess content and face validity, (3) preliminary psychometric validation study to examine factor structure and reduce the number of items, and (4) final psychometric validation with 224 participants (203 with DED and 21 serving as controls). Participants completed the DEQS questionnaire, the Short Form-8, and the National Eye Institute Visual Function Questionnaire-25. To evaluate reproducibility and responsiveness, individuals with DED completed the DEQS questionnaire twice., Main Outcomes and Measures: Internal consistency, reproducibility, discriminant validity, concurrent validity, and responsiveness., Results: Items were generated from a literature review, and 35 items were selected for the draft version. In the pilot study, 11 items were deleted; furthermore, 9 items were deleted based on the results of item analysis and factor analysis in the preliminary validation study. The final 15-item DEQS questionnaire consisted of an Overall Summary scale and 2 multi-item subscales: Impact on Daily Life and Bothersome Ocular Symptoms. The psychometric analysis revealed that the DEQS questionnaire has good internal consistency, test-retest reliability, discriminant validity, and responsiveness to change. The DEQS questionnaire correlated well with the mental component of the Short Form-8 and showed strong correlations with 4 subscales (Ocular Pain, Near Vision, Distance Vision, and Mental Health) of the National Eye Institute Visual Function Questionnaire-25., Conclusions and Relevance: The DEQS questionnaire is valid and reliable for evaluating the multifaceted effect of DED on the patient's daily life, including mental health, and it can be used easily in routine clinical practice.

Purpose: We examined symptoms, tear stability, visual function, and conjunctival cytology in eyes with an unstable tear film (UTF), expressed as a short tear film breakup time without epithelial damage or low tear secretion, and compared the results with those from eyes with aqueous deficiency (AD) associated with epithelial damage, and healthy eyes., Methods: We divided the patients with ocular discomfort into 2 groups according to the breakup time, Schirmer value, and epithelial staining score: UTF group (≤5 seconds, >5 mm, and <3 points; 21 eyes of 21 patients) and AD group (≤5 seconds, ≤5 mm, and ≥3 points; 21 eyes of 21 patients). We examined all patients and 17 healthy subjects for symptoms, tear functions, tear film stability by tear film lipid layer interferometry and tear film analysis system, and functional visual acuity. Conjunctival impression cytology was performed to investigate changes in goblet cell density, squamous metaplasia, and messenger RNA expression of MUC5AC and MUC16., Results: The symptom scores, tear film analysis system index, and functional visual acuity testing were significantly worse in the UTF and AD groups compared with those in the control group (P < 0.05). The messenger RNA expression levels of MUC5AC and MUC16 were significantly lower in UTF and AD eyes compared with those in the control eyes (P < 0.0001)., Conclusions: An UTF itself can cause dry eye symptoms and visual disturbance comparable with those of AD dry eyes.

Purpose: To investigate the effects of diquafosol sodium (DQS) eye drops, a purinergic P2Y2 receptor agonist, on tear film stability in patients with unstable tear film (UTF)., Methods: Two prospective studies were conducted. One was an exploratory nonrandomized trial on 39 eyes with dry eye symptoms and short tear film break-up time (BUT), but without epithelial damage. Changes in symptoms, BUT, Schirmer value, and ocular surface fluorescein staining (FS) scores were studied for 3 months. The other was a randomized clinical trial of DQS and artificial tears (AT) in 17 eyes with short BUT. Eyes with decreased Schirmer values (≤ 5 mm) were excluded. Changes in symptoms, BUT, FS scores, and tear film stability using continuous corneal topographic analysis were studied for 4 weeks., Results: In the exploratory study, while Schirmer values were not significantly increased, significant improvements in symptoms and BUT were noted at both 1 and 3 months. In the randomized clinical trial, significant improvements in symptoms were noted in the DQS group, but not in the AT group, at 2 weeks. BUT was significantly prolonged in the DQS group at 4 weeks but not in the AT group. No significant changes were noted in FS scores or tear film stability., Conclusions: DQS improved subjective symptoms and prolonged BUT in eyes with UTF not associated with low tear secretion and ocular surface epithelial damage. Because many patients who have UTF are refractory to conventional treatments, DQS may offer benefits in the treatment of dry eyes.

Purpose: To investigate the effect of diquafosol tetrasodium on tear and visual function in short break-up time (sBUT) dry eye (DE)., Methods: This interventional nonrandomized comparative study involved 11 eyes in 11 patients with sBUT DE (symptom-positive sBUT group) and 13 eyes in 13 volunteers with BUT values ≤5 s without DE symptoms (symptom-negative sBUT group). Tear function was assessed by measuring BUT and Schirmer values. Serial measurements were made of visual acuities (using a functional visual acuity measurement system) and higher-order aberrations (using a wavefront sensor). The parameters were compared before and 1 month after diquafosol tetrasodium instillation. Any changes in symptomatology after administration were also recorded., Results: After diquafosol tetrasodium administration, BUT values tended to increase in the symptom-positive sBUT group (P=0.07) and significantly increased in the symptom-negative sBUT group (P<0.05). LogMAR functional, minimal, and maximal visual acuities and higher-order aberrations significantly decreased after diquafosol tetrasodium administration in the symptom-positive sBUT group (P<0.05), while there were no significant changes in these values in the symptom-negative sBUT group (P>0.05). Diquafosol tetrasodium administration provided relief of DE symptoms in 75% of patients in the symptom-positive sBUT group., Conclusions: Diquafosol tetrasodium appeared to improve tear film stability and visual function in sBUT DE.

Purpose: To investigate the retention rate and complications of 2 different types of silicon lacrimal punctal plugs with the focus on the relationship to punctum size., Design: A prospective, nonrandomized, interventional, comparative study., Method: Forty-four patients with dry eye syndrome received lacrimal punctal plug insertion with the Punctal Plug F (FCI Ophthalmics) and 30 patients received plug insertion with the Super Flex plug (Eagle Vision; Softplug-Oasis Medical Inc). In total, 110 plug insertion regions were performed using the Punctal Plug F (group A) and 110 insertion regions were carried out using Super Flex plug (group B). The gauging system of Eagle Vision was used before the lacrimal punctal plug insertion in all subjects. Plug conditions (retention rates, spontaneous plug loss, and removal) and complications related to lacrimal punctal sizes were compared between the 2 groups., Results: Retention rates were 70.4% in group A and 30.1% in group B at 6 months. Spontaneous plug loss occurrence was significant with the larger lacrimal punctum size in group A (P < .05), whereas no significant differences were observed between lacrimal punctum sizes and spontaneous loss in group B. Spontaneous plug loss occurrence was significant in elderly patients in group B (P < .05). Granuloma and injector troubles were observed in 1 and 2 cases in group A, respectively., Conclusions: The Punctal Plug F seems to be more applicable for insertion into the smaller punctal sizes. Punctum size and age seem to be important factors in determining the appropriate types of lacrimal punctal plugs., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Dry eye is one of the most common eye disorders affecting millions of people. It causes ocular irritation or discomfort, and decreases functional vision, causing a dramatic deterioration in the quality of life. Although new treatments such as the P2Y2 agonist or cyclosporine eye drops have been developed and a certain level of patient satisfaction can now be obtained, no fundamental treatment has been developed. Currently, there is no therapy available to recover lacrimal function to its normal status. Recent progress in the understanding of aging has laid the foundations for a new way of thinking about intervention of the aging process. Because dry eye is accelerated by aging, a useful approach for the prevention or treatment of dry eye may be to interfere with the aging process. In the scientific community, there is a global consensus that calorie restriction can extend the life span of various kinds of animals, establishing an intervention to aging. Another important hypothesis believed to be involved in aging is the free radical theory. According to these theories, the aging process may be managed by controlling levels of calories or reactive oxygen species. In this review, these 2 important aging theories, calorie restriction and free radical aging, are examined, and we discuss how to apply these theories to the prevention and treatment of dry eye.

Purpose: To evaluate visual function changes after punctal plug (PP) occlusion in patients with short breakup time of tear film (BUT) type of dry eyes., Methods: A prospective comparative study was performed in 43 eyes of 43 dry eye patients with short BUTbreakup time of tear film receiving PP occlusion. Patients were divided into 2 groups as those receiving only upper or only lower occlusion. Functional visual acuity measurements, tear function evaluations, and questionnaire on satisfaction with treatment in relation to presence of epiphora were performed before and 1 month after PP insertion., Results: Twenty eyes of 43 eyes (46.5%) with only lower occlusion and 17 eyes of 43 eyes (39.5%) with only upper occlusion showed satisfactory outcomes with treatment. One of 43 eyes (2.3 %) had epiphora. Vital staining scores and BUT values significantly improved in both groups after occlusion. The mean logarithm of the minimum angle of resolution functional visual acuity value significantly improved only in eyes receiving upper PP occlusion., Conclusion: Upper PP occlusion seems to be associated not only with improvement of tear stability, vital staining scores, and treatment-related satisfaction but also with better quality of visual function.

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.

Purpose: Our aim was to evaluate changes in dry eye diagnostic status following implementation of the new dry eye diagnostic criteria in Japan., Design: This was a multicenter cross-sectional study., Methods: We recruited 295 individuals (81 men, 214 women, average age 43.6 ± 14.3 years) seen for general ophthalmic checkup and dry eye examinations. Using results of the Schirmer I test, tear breakup time, and fluorescein and Rose Bengal staining, patients were diagnosed as having definite dry eye (DDE), probable dry eye (PDE), or as being normal according to both the old and new Japanese dry eye diagnostic criteria., Results: Mean ages of normal participants and patients with PDE and DDE were 37.0 ± 10.4, 41.7 ± 14.4, and 47.7 ± 15.3 years, respectively (p < 0.001). All 37 individuals diagnosed as normal following the old criteria were also diagnosed as normal with the new diagnostic criteria. Among the 60 patients diagnosed as PDE with the old criteria, 19 (31.7%) were diagnosed as normal and 41 (68.3%) as PDE with the new diagnostic criteria. Of the 198 patients diagnosed with DDE following the old criteria, 59 (29.7%) were diagnosed as PDE and 139 (70.2%) as DDE with the new diagnostic criteria. There was no significant difference in dry eye severity index scores between the old and new diagnostic criteria., Conclusion: A shift in the final dry eye diagnostic status from DDE to PDE and from PDE to normal was observed with the implementation of the new dry eye diagnostic criteria, suggesting that patients at the severe end of the dry eye disease spectrum are now diagnosed as DDE disease under the new criteria.

Purpose: To investigate the changes in functional visual acuity (VA) and higher order aberrations in dry eye patients., Methods: In this prospective comparative case series, 22 right eyes were classified into those with or without superficial punctate keratopathy (SPK) in the central cornea of 22 patients with Sjögren syndrome; 10 right eyes of 10 normal subjects served as the control. Serial measurements of VAs using a functional VA measurement system and higher order aberrations using a wavefront sensor were performed under blink-free conditions without topical anesthesia over a 10-second period. The parameters for each measurement were compared among the SPK-positive and -negative and normal groups. The correlation between those parameters was also analyzed., Results: Dry eye with SPK showed significant deterioration of visual function and optical quality compared with dry eye without SPK and in normal eyes, as detected by both the visual maintenance ratio (VMR; P < 0.05) and the variation of VA (P < 0.05) and by comalike and total higher order aberrations (P < 0.05). Moreover, the severity of epithelial damage at the central cornea correlated significantly with VMR (P < 0.01) and variation of VA (P < 0.01) as well as comalike (P < 0.05) and total higher order aberrations (P < 0.05). The dry eye group without SPK showed minor visual deterioration compared with normal eyes, as detected only by VMR (P < 0.05)., Conclusions: Optical disturbances at the central optical zone of the cornea in dry eye disease may affect visual performance. Functional VA measurement may be an applicable method of evaluating visual performance in dry eyes that is as efficient as wavefront aberration measurements.

Purpose: To evaluate the effect of contact lens (CL) wear and visual display terminal (VDT) work on the ocular surface and tear functions., Design: Prospective case-control study., Methods: Sixty-nine CL wearers (45 women and 24 men; mean age, 35.2 ± 7.3 years), and 102 age- and sex-matched non-CL wearers were enrolled in the study (66 women and 36 men; mean age, 36.7 ± 7.3 years). Ocular surface and tear function tests, including vital stainings (fluorescein and rose bengal), Schirmer test, tear meniscus height measurement, and tear film break-up time were performed. The subjective symptoms of dry eyes were evaluated using a dry eye symptom questionnaire. The participants were divided into 4 subgroups according to the total time of VDT work in 1 day (VDT work time in 1 day ≥ 4 hours or < 4 hours) and presence of CL wear. Main outcome measures included ocular surface vital staining scores, Schirmer test results, tear film break-up time, tear meniscus height measurement, and symptom questionnaire score., Results: CL users and long-term VDT workers showed significantly worse tear meniscus height values than non-CL users and short-term VDT workers (P < .001). The mean visual symptom scores in CL wearers and long-term VDT workers were significantly higher than the other groups (P < .001)., Conclusions: Office workers who wore CLs and spent more than 4 hours engaged in VDT work had a lower tear meniscus volume with significant dry eye and visual symptoms triggered by environmental factors., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To estimate the prevalence and risk factors of dry eye disease (DED) in a rural setting in Japan., Design: Cross-sectional study., Participants: We included 3294 subjects, aged ≥ 40 years who were in the residential registry for Koumi town., Intervention: Subjects in a rural mountain area, Koumi town, completed questionnaires designed to detect dry eye diagnosis and risk factors., Main Outcome Measures: Clinically diagnosed DED was defined as the presence of a previous clinical diagnosis of DED by ophthalmologists or severe symptoms of DED (both dryness and irritation constantly or often). Current symptoms of DED and possible risk factors such as age, gender, educational history, smoking history, alcohol drinking history, height and weight, visual display terminal (VDT) use, and contact lens (CL) wear, and past/current history of certain common systemic diseases were the main outcome measures. We used logistic regression analysis to examine associations between DED and other demographic factors., Results: Of the 3294 eligible residents, 2791 residents (85%) completed the questionnaire. The percentage of women with a composite outcome of clinically diagnosed DED or severe symptoms (21.6%; 95% confidence interval [CI], 19.5-23.9) was higher than that of men (12.5%; 95% CI, 10.7-14.5; P<0.001). A low body mass index (BMI; odds ratio [OR], 2.07; 95% CI, 0.98-4.39), CL use (OR, 3.84; 95% CI, 1.46-10.10), and hypertension (HT) (OR, 1.39; 95% CI, 0.94-2.06) were risk factors for DED in men. Use of a VDT (OR, 2.33; 95% CI, 1.12-4.85), CL use (OR, 3.61; 95% CI, 2.13-6.10), and myocardial infarction or angina were the risk factors (OR, 2.64; 95% CI, 1.51-4.62), whereas high BMI was a preventive factor (OR, 0.69; 95% CI, 0.48-1.01) for DED in women., Conclusions: Among a Japanese cohort, DED leading to a clinical diagnosis or severe symptoms is prevalent. Use of CLs was a common dry eye risk factor in both genders. The condition is more prevalent in men with low BMI, HT, and in women with myocardial infarction or angina and VDT use. Relevant measures directed against the modifiable risks may provide a positive impact on public health and quality of life of Japanese., Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2011 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the efficacy of surgical treatment for conjunctivochalasis using the Tear Film Stability Analysis System., Methods: Fifteen eyes of 15 patients (74.5 ± 4.8 years; 14 females and 1 male) who had surgical reconstruction of the tear meniscus for conjunctivochalasis underwent evaluation with a symptom questionnaire, Schirmer I test, fluorescein tear film break-up time (FBUT), and break-up time index (BUI) measurement by Tear Film Stability Analysis System examinations that were performed preoperatively and 3 months after the surgery. Changes of these tear parameters were statistically analyzed using the paired t test., Results: After the surgery, the mean FBUT and BUI values significantly improved from 5.7 ± 3.2 s and 42.8 ± 18.7, respectively, to 8.4 ± 2.5 s and 60.7 ± 16.5, respectively (FBUT, p = 0.0438; BUI, p = 0.0036). The mean Schirmer test value showed no significant changes before and after surgery (p = 0.9064). Fourteen eyes (93.3%) had improvement of ocular symptoms after surgery. One eye (6.7%) with no improvement of ocular symptoms, FBUT, and BUI after surgery appeared to have aqueous tear deficiency., Conclusions: Surgical treatment for conjunctivochalasis was associated with improvement of tear stability and clinical dry eye symptoms.

Purpose: To investigate the relation of functional visual acuity (FVA) measurements with dry eye test parameters and to compare the testing methods with and without blink suppression and anesthetic instillation., Design: A prospective comparative case series., Methods: Thirty right eyes of 30 dry eye patients and 25 right eyes of 25 normal subjects seen at Keio University School of Medicine, Department of Ophthalmology were studied. FVA testing was performed using a FVA measurement system with two different approaches, one in which measurements were made under natural blinking conditions without topical anesthesia (FVA-N) and the other in which the measurements were made under the blink suppression condition with topical anesthetic eye drops (FVA-BS). Tear function examinations, such as the Schirmer test, tear film break-up time, and fluorescein and Rose Bengal vital staining as ocular surface evaluation, were performed., Results: The mean logMAR FVA-N scores and logMAR Landolt visual acuity scores were significantly lower in the dry eye subjects than in the healthy controls (p < 0.05), while there were no statistical differences between the logMAR FVA-BS scores of the dry eye subjects and those of the healthy controls. There was a significant correlation between the logMAR Landolt visual acuities and the logMAR FVA-N and logMAR FVA-BS scores. The FVA-N scores correlated significantly with tear quantities, tear stability and, especially, the ocular surface vital staining scores., Conclusions: FVA measurements performed under natural blinking significantly reflected the tear functions and ocular surface status of the eye and would appear to be a reliable method of FVA testing. FVA measurement is also an accurate predictor of dry eye status.

Purpose: To evaluate the specificity and sensitivity of strip meniscometry (SM) testing in conjunction with tear function tests in the diagnosis of dry eye (DE) disease and to investigate the effect of SM on reflex tearing., Methods: One hundred seven left eyes of 107 patients with definite DE disease according to the Japanese DE diagnostic criteria and 68 left eyes of 68 age- and sex-matched control subjects were studied. Tear meniscus height (TMH) measurements, fluorescein tear film break-up time (FTBUT), fluorescein (F) and rose bengal (RB) staining, and Schirmer's test-1 (ST) were also performed. The assessment of reflex tearing before and after SM application was assessed with a graticule scale at the slit lamp and by optical coherence tomography. The sensitivity and specificity of SM alone and in combination with tear function tests were also sought., Results: The SM scores, TMH measurements, FTBUTs, and STs were significantly lower in dry eye patients than in the controls (P < 0.001). The RB and F staining scores were significantly higher in the dry eye group than in the control group (P < 0.001). The meniscometry strips did not induce significant changes in relation to reflex tearing. SM had an acceptable sensitivity and specificity., Conclusions: SM is a swift, noninvasive, promising method of assessing tear meniscus volume. The combined SM and FTBUT examination appears to be a sensitive approach to the assessment of dry eye disease.

Purpose: To report the rate of recanalization and the efficacy of punctal occlusion surgery with a high heat-energy-releasing cautery device in patients with severe dry eye disease and recurrent punctal plug extrusion., Design: Prospective, interventional case series., Methods: Seventy puncta from 44 eyes of 28 dry eye patients underwent punctal occlusion with thermal cautery. All patients had a history of recurrent punctal plug extrusion. A high heat-energy-releasing thermal cautery device (Optemp II V; Alcon Japan) was used for punctal occlusion surgery. Symptom scores, best-corrected visual acuity, fluorescein staining score, rose bengal staining score, tear film break-up time, and Schirmer test values were compared before and 3 months after the surgery. Rate of punctal recanalization also was examined., Results: Three months after surgical cauterization, symptom score decreased from 3.9 ± 0.23 to 0.56 ± 0.84 (P < .0001). Logarithm of the minimal angle of resolution best-corrected visual acuity improved from 0.11 ± 0.30 to 0.013 ± 0.22 (P = .003). Fluorescein staining score, rose bengal staining score, tear film break-up time, and the Schirmer test value also improved significantly after the surgery. Only 1 of 70 puncta recanalized after thermal cauterization (1.4%)., Conclusions: Punctal occlusion with the high heat-energy-releasing cautery device not only was associated with a low recanalization rate, but also with improvements in ocular surface wetness and better visual acuity., (Copyright © 2011 Elsevier Inc. All rights reserved.)