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[Purpose] To investigate the effectiveness of screening and subsequent intervention for age-related macular degeneration (AMD) in Japan. [Study design] Best-case-scenario analysis using a Markov model. [Methods] The clinical effectiveness and cost-effectiveness of screening for AMD were assessed by calculating the reduction proportion of blindness and the incremental cost-effectiveness ratio (ICER). The Markov model simulation began at screening at the age of 40 years and ended at screening at the age of 90 years. The first-eye and second-eye combined model assumed annual state-transition probabilities in the development and treatment of AMD. Data on prevalence, morbidity, transition probability, utility value, and treatment costs were obtained from previously published reports. Sensitivity analysis was performed to assess the influence of the parameters. [Results] In the base-case analysis, screening for AMD every 5 years, beginning at age 40 years and ending at age 74 years (reflecting the screening ages of the current Japanese legal “Specific Health Checkups”) showed a decrease of 40.7% in the total number of blind patients. The screening program reduced the number of blind people more than did the additional AREDS/AREDS2 formula supplement intake. However, the ICER of screening versus no screening was ¥9, 846, 411/QALY, which was beyond what people were willing to pay (WTP) in Japan. Sensitivity analysis revealed that neither OCT nor AI improved the ICER, but the scenario in which the prevalence of smoking decreased by 30% improved the ICER (¥4, 655, 601/QALY) to the level under the WTP. [Conclusions] Ophthalmologic screening for AMD is highly effective in reducing blindness but is not cost-effective, as demonstrated by a Markov model based on real-world evidence from Japan.

INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin (Depatux‐M), as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in 53 Japanese patients with World Health Organization (WHO) grade III/IV glioma. In second‐line arms, patients with EGFR‐amplified recurrent WHO grade III/IV glioma received Depatux‐M plus chemotherapy (temozolomide) or Depatux‐M alone regardless of EGFR status. In first‐line arms, patients with newly diagnosed WHO grade III/IV glioma received Depatux‐M plus chemoradiotherapy. The study was halted following lack of survival benefit with first‐line Depatux‐M in the global trial INTELLANCE‐1. The primary endpoint was 6‐month progression‐free survival (PFS) in patients with EGFR‐amplified tumors receiving second‐line Depatux‐M plus chemotherapy. Common nonocular treatment‐emergent adverse events (TEAEs) with both second‐line and first‐line Depatux‐M included lymphopenia (42%, 33%, respectively), thrombocytopenia (39%, 47%), alanine aminotransferase increase (29%, 47%), and aspartate aminotransferase increase (24%, 60%); incidence of grade ≥3 TEAEs was 66% and 53%, respectively. Ocular side effects (OSEs) occurred in 93% of patients receiving second‐line Depatux‐M plus chemotherapy and all patients receiving second‐line Depatux‐M alone or first‐line Depatux‐M plus chemoradiotherapy. Most OSEs were manageable with dose modifications and concomitant medications. The 6‐month PFS estimate was 25.6% (95% confidence interval [CI] 11.4‒42.6), and median PFS was 2.1 months (95% CI 1.9‒3.9) with second‐line Depatux‐M plus chemotherapy in the EGFR‐amplified subgroup. This study showed acceptable safety profile of Depatux‐M alone or plus chemotherapy/chemoradiotherapy in Japanese patients with WHO grade III/IV glioma. The study was registered at ClinicalTrials.gov (NCT02590263)., INTELLANCE‐J was a phase 1/2 study of a potent antibody‐drug conjugate targeting epidermal growth factor receptor (EGFR), depatuxizumab mafodotin, as a second‐ or first‐line therapy, alone or combined with chemotherapy or chemoradiotherapy in Japanese patients with World Health Organization grade III/IV glioma. The results of this trial demonstrate an acceptable safety profile of depatuxizumab mafodotin, with ocular side effects being the most common adverse events that were mostly reversible. Second‐line depatuxizumab mafodotin in combination with temozolomide resulted in a 6‐month progression‐free survival estimate of 25.6% (95% confidence interval 11.4‒42.6) in patients with EGFR‐amplified tumors and showed encouraging antitumor activity in this subgroup of patients (NCT02590263).

Background Improving the specific health checkups participation rate is an essential task nationwide; however, studies on measures to accomplish this are limited. This study aimed to examine the influence of ophthalmic checkups on the specific health checkups' participation rate. Methods We conducted a postal questionnaire survey on 1,741 countrywide municipalities in Japan from January to February 2019. The questionnaire specifically addressed health checkup participation rates of 2017, health checkups formats (group, individual, or both), simultaneous cancer screenings, simultaneous ophthalmic checkups, and the state of implementation of ophthalmic checkups. We used multiple linear regression analyses to calculate the partial regression coefficients (βs) and their 95% confidential intervals (CIs) to identify the influence of simultaneous ophthalmic checkups on specific health checkup participation rates. Results There was a significant association between specific health checkup participation rates and simultaneous ophthalmic checkups (β: +2.5%; 95% CI, 1.3-3.8) after adjusting for covariates. The fundus photos of all applicants, fundus photos with restrictions, and ophthalmology consultation for all applicants were associated with a significant increase in the specific health checkup participation rate (β: +2.8%, 95% CI, 1.2-4.4; β: +2.0%, 95% CI, 0.2-3.9; β: +7.4%, 95% CI, 1.2-13.6 respectively). Conclusions Our results suggest that additional simultaneous ophthalmic checkups as specific health checkups could increase the specific health checkup participation rate.

The pathophysiology of nasolacrimal duct obstruction (NLDO) may involve quantitative as well as qualitative changes in tears. We measured tear protein concentrations in patients with primary acquired NLDO and compared them with the tear proteins in healthy individuals and patients with dry eye disease. Case–control study. Twenty-four patients diagnosed with primary acquired NLDO who underwent endoscopic lacrimal passage intubation were included in the study. Tear fluid was collected with Schirmer’s test strips three times: before intubation, after intubation while the nasolacrimal tube was in place, and after extubation. At the same time, 24 age-matched normal controls and 24 patients with dry eye were selected from subjects whose tears were collected during the same study period. We measured the following components of tear fluid: total protein, lactoferrin, albumin, and interleukin 6 (IL-6) levels. Total proteins and albumin levels in tears of the NLDO group were significantly lower than those of the control group (P

OBJECTIVES To examine the severe ocular complications associated with contact lens wearing in Japan. METHOD A questionnaire was sent to 964 ophthalmologist training facilities inquiring for cases of contact lens-associated complications from April 2016 to March 2018. The inclusion criteria were as follows: (1) corrected distance visual acuity ≤0.1 decimal after treatment for 3 months, (2) corneal perforation observed during follow-up, and (3) requiring surgery. A secondary analysis was conducted, inquiring for further information on the type of contact lens, clinical manifestations, and course of treatment. RESULTS Forty-two patients with infectious keratitis met the inclusion criteria. Eight patients were users of rigid gas-permeable contact lens, and 34 were users of soft contact lens. Microbiological tests were positive in 73.0%. The organisms isolated in microbiological culture were bacteria in 11 patients (Pseudomonas aeruginosa in 9 patients), fungi in 2 patients, and Acanthamoeba in 14 patients. Ten patients were treated with local antibiotics, 11 with a combination of systemic antibiotics, and 21 with a combination of surgical approaches, including 13 with corneal transplantation. CONCLUSIONS The major cause of serious contact lens-associated ocular complications was microbial keratitis, and P. aeruginosa and Acanthamoeba were the major pathogens in Japan.

Purpose To determine normal corneal eccentricity in a rural Japanese population and to examine factors associated with eccentricity value. Methods This used data from the Locomotive Syndrome and Health Outcome in Aizu Cohort Study (LOHAS) project between 2009 and 2012. Residents of Minamiaizu and Tadami in Fukushima, Japan, who were aged 40 years or over, were invited for a comprehensive eye examination. For 1371 patients with no history of internal eye surgery, corneal eccentricity was measured using a Pentacam. Results Of 1371 people recruited to the study, 1215 (1215 eyes) met the inclusion criteria. The overall mean eccentricity was 0.46 (SD = 0.18; range, -0.85 to 0.88). Corneal eccentricity was significantly associated with age, spherical equivalent, pupil diameter, anterior chamber angle, anterior chamber volume, and central corneal thickness, but not with gender or body mass index. Conclusions In this study, the normal cornea in this Japanese population was prolate. Corneal eccentricity was likely to decrease with increasing age. Also, spherical equivalent and other anterior segment parameters had an influence on corneal eccentricity. Corneal eccentricity measurements might be helpful in the diagnosis of corneal diseases and in calculations for intraocular lens implantation and corneal refractive surgery.

To investigate the prevalence and factors associated with uncorrected presbyopia among rural community dwellers in Japan.A population-based cross-sectional study was conducted in 2011 among community dwellers aged 40-74 years who received specific health checkups in Minamiaizu and Tadami, Fukushima Prefecture, Japan.Uncorrected presbyopia was considered as when the distance-corrected visual acuity in the better eye was ≥0.5 and the near-presenting visual acuity in the better eye was0.4, regardless of distance refractive status. Multiple logistic regression analysis was employed to calculate the odds ratios (ORs) for uncorrected presbyopia and to adjust for possible confounders.A total of 2054 individuals participated in the specific health checkups. In the 1156 individuals (response rate: 56.28%) analyzed in the study, the mean (SD) age was 63.0 (8.7) years, the percentage of women was higher (57.87%), and the prevalence of uncorrected presbyopia was 26.38% (95% CI 23.86%-29.03%). Multivariate analysis revealed that the factors associated with uncorrected presbyopia were older age (adjusted OR: 1.054 [95% CI: 1.034-1.075]), female sex (adjusted OR: 1.388 [95% CI: 1.006-1.915]), and distance-presenting vision impairment (adjusted OR: 2.651 [95% CI: 1.697-4.143]).Approximately one-quarter of the participants in this study from a rural population of Japan did not have adequate near vision. It is recommended that a public health intervention should be enacted to correct presbyopia, especially in the older age group, women, and those with uncorrected refractive errors.

To evaluate the cost-effectiveness (CE) and budget impact (BI) of introducing a patient visit support system (ACT Pack) along with standard of care (SoC), in glaucoma treatment in Japan.A Markov model was designed to estimate the CE and BI of introducing the support system from Japanese payer and governmental perspective, respectively. Inputted data for CE and BI analysis were referred from published literature and based on medical specialists' inputs. Base case scenario for CE considered the support system cost of 30,000 yen per patient per year and a time horizon of 45 years. BI analysis compared the financial impact due to introduction of support system with SoC compared to SoC alone scenario on Japanese healthcare system with a time horizon of 20 years.The base case of CE analysis showed the incremental cost per quality-adjusted life years (QALYs) gained with the support system was 3,241,729 yen/QALY (29,470 USD/QALY). The sensitivity analysis showed that the probability of this support system being cost-effective at a threshold of 5 million yen/QALY (45,455 USD/QALY) was 53.26%. Blindness reduction after introduction of this support system was 8.68%. The BI analysis showed that the introduction of support system will lead to a cumulative cost savings of 1,132 billion yen (10 billion US dollars) for Japanese healthcare system over 20 years of time horizon.Due to paucity of similar comparative studies, some assumptions were made based on medical specialists' inputs. Death status was not considered in the analysis.Introduction of this support system with SoC is cost-effective and will lead to blindness reduction in Japanese patients with glaucoma. Over a 20 year period, it will lead to an overall cost savings of 1,132 billion yen (10 billion US dollars) for the Japanese healthcare system.

Purpose To report a difficult-to-identify case of keratitis due to Fusarium solani, diagnosed with the help of exhaustive gene analysis. Case A 47-year-old woman attended our hospital with a refractory corneal ulcer associated with contact lens wear in her left eye that had appeared two weeks earlier. On her initial visit, slit lamp examination revealed a small double-ringed irregular hyphate ulcer in the center of the cornea, which had no epithelial defect, suggesting fungal infection. Microscopic visualization and culture of corneal scrapings were performed repeatedly, but the results were negative. Despite intensive antifungal treatment, infiltration of the cornea worsened and therapeutic keratoplasty was performed. Specimens from a corneal button were microbiologically and histologically negative for microorganisms. During irrigation of the anterior chamber with amphotericin B, aspirated corneal infiltrations were submitted for culture and metagenomic analysis. Genes belonging to F. solani were identified by metagenomic analysis, and an isolate presumed to be a Fusarium species was cultured. Genotypic identification of the isolates confirmed F. solani. Conclusion The detection of microorganisms, especially fungi, can be extremely difficult. In difficult-to-culture cases, metagenomic analysis seems to be a promising technique for the identification of microbial pathogens.

Background To determine whether quality of life (QOL) and health utility are affected to the same extent among dry eye (DE) patients with short tear film break-up time dry eye (TBUT-DE) with minimal clinical signs were as severe as aqueous-deficient dry eye (ADDE). Methods A multicenter cross-sectional study was conducted among DE patients who visited one of 10 eye clinics in Japan. Among the 463 registered patients, this study involved 449 patients with DE who were aged 20 years or older. Ophthalmic examination findings were assessed, including tear film break-up time (TBUT), Schirmer I value, and keratoconjunctival staining score. QOL was evaluated with the Dry Eye-Related Quality-of-Life Score (DEQS; 0 [best], 100 [worst]) and health utility (1 [total health], 0 [worst]) with the Health Utilities Index Mark 3 (HUI-3); scores were stratified by DE subgroup. Results Median (interquartile range) of DEQS and HUI-3 scores across all participants were 21.7 (10.0–40.0) and 0.82 (0.69–0.91), respectively. Median (interquartile range) DEQS and HUI-3 scores in the ADDE group were 23.3 (10.0–40.0) and 0.79 (0.69–0.88), respectively; those in the short TBUT-DE group were 23.3 (13.3–38.3) and 0.82 (0.74–0.92), respectively. There were no significant between-group differences in questionnaire scores. Among the ophthalmic examination findings, a weak significant correlation between TBUT, corneal staining score and keratoconjunctival staining score to DEQS; TBUT and Schirmer test values to HUI-3, were seen. Conclusions The burden of short TBUT-DE on QOL as assessed by the DEQS and HUI-3 was as severe as that in ADDE. Our findings suggest that clinicians should be aware of the impact of short TBUT-DE on patients QOL and utility values. Trial registration University Hospital Medical Information Network (registration no. UMIN 000015890). Registered 10th December 2014, retrospectively registered.

To evaluate the association between vision-related quality of life (QoL), physical inactivity, and locomotor dysfunction in subjects with visual impairment.This cross-sectional study included 215 visually impaired subjects recruited from six ophthalmology departments in Japan. The physical inactivity and locomotor dysfunction associated with their visual impairment was investigated. The physical activity level was assessed using the short form of the International Physical Activity Questionnaire and classified as high, moderate, or low. Locomotor function was evaluated with the Geriatric Locomotive Function Scale. Vision-related QoL was evaluated using the 25-item National Eye Institute Visual Function Questionnaire. Background data, including for age, sex, best-corrected visual acuity for each eye, causative eye diseases, systemic comorbidities, and body mass index, were also collected.The average patient age was 69.6 (range, 20–93 years; standard deviation, 14.5 years) and 118 patients (54.9%) were men. Multivariate analysis showed that vision-related QoL and best-corrected visual acuity in the worse eye were significantly associated with physical inactivity and that vision-related QoL, female sex, age, and presence of systemic comorbidity were significantly associated with locomotor dysfunction. Vision-related quality of life is associated with physical inactivity and locomotor dysfunction.

To establish a method for the measurement of 5-fluorouracil (5-FU), and tegafur (FT) in tear samples from patients treated with oral fluoropyrimidine anticancer agent S-1. Cross-sectional study. High performance liquid chromatographic (HPLC) method reported for plasma samples was modified for tear samples. Simulated-tear solutions containing lactoferrin, lysozyme and standard solution containing 5-FU or FT were prepared for preliminary measurements. Tear samples from seven patients treated with S-1 were included. The tears were collected following S-1 administration using Schirmer’s strips. 5-FU and FT concentrations of pure standard solution without extraction process were detected as original concentration. However, on extraction, FT samples in simulated-tear solution showed a peak for 5-FU but not for FT. FT was converted to 5-FU in the extraction process. Decomposition from FT to 5-FU was suppressed when 50 mg/mL bovine serum albumin was added during extraction. The mean concentrations of 5-FU and FT in tears during S-1 treatment were 0.17 ± 0.11 and 1.94 ± 0.71 μg/mL, respectively. A simple HPLC method to determine 5-FU and FT in tear samples was established.

Tear fluids are a mixture of secretions derived from lacrimal glands, accessory lacrimal glands, conjunctiva, and meibomian glands. Compositional changes to tears occur in the normal state and during ocular surface disease, such as dry eye conditions. We have investigated compositional changes to tears after topical application of ophthalmic solutions, with regard to tear-specific proteins (secretory immunoglobulin A, lactoferrin, lipocalin-1, and lysozyme) and ocular surface mucin in normal and dry eye conditions using high-performance liquid chromatography. After application of saline solution (0.9% sodium chloride) in normal subjects, transient but significant decreases in all tear components were observed. The recovery of protein concentrations took up to 30 minutes and lasted longer when the saline solution was applied more frequently. When applying ophthalmic solutions, a balance between washout and dilutional effects should be considered in addition to the therapeutic effect. Investigation of the effect of diquafosol solution (3%) in normal subjects revealed a significant increase in sialic acid concentration, a marker of ocular mucin, at 5 minutes after application, whereas a significant decrease was observed with saline. This result indicates the accelerated secretion of mucin from ocular tissues induced by diquafosol. A clinical study to determine the efficacy of diquafosol in patients with dry eye revealed improvements in tear breakup time, keratoconjunctival staining scores, and Schirmer test score, accompanied by an increase in sialic acid concentration in tears. Investigating normal and dry eye conditions through tear analysis may clarify the pathophysiology of dry eye conditions and support the efficacy of treatments.

Purpose To describe the relationship between retinal vascular calibre and cardiovascular risk factors in a Japanese population. Methods The Locomotive Syndrome and Health Outcome in Aizu Cohort Study is a population-based, cross-sectional survey that included 2346 persons (56.1% of the eligible population) aged 40 to 74 years old. Retinal vascular calibre was measured from digital retinal photographs using a validated standardized protocol. Data on major cardiovascular risk factors were collected from all participants. Results Of the 1787 participants with available retinal vascular calibre data, the mean retinal arteriolar calibre (CRAE) was 141.6 ± 18.6 μm, the mean venular calibre (CRVE) was 209.3 ± 26.1 μm, and the mean arteriole-to-venule ratio was 0.68 ± 0.08. A smaller CRAE was associated with male sex, increasing quartiles of systolic blood pressure and diastolic blood pressure, history of hypertension, current alcohol intake and higher quartiles of serum creatinine. A larger CRAE was associated with increasing quartiles of total cholesterol. A larger CRVE was associated with current cigarette smoking. Multivariate analyses showed that a smaller CRAE was associated with male sex, elevated mean arterial blood pressure and a history of hypertension; and a larger CRVE was associated with cigarette smoking. Conclusions The results of this study suggest that a narrowed diameter of the retinal arteriole in Japanese people is related to hypertension and sex (male) and that an enlarged retina venular diameter is related to a history of smoking. The pattern of these associations is similar to that in white populations and other Asian populations.

Purpose To report a case of ocular findings associated with chronic eosinophilic pneumonia (CEP). Case A 63-year-old man was referred to the National Institution of Hospital Organization Tokyo Medical Center with bilateral eyelid swelling due to giant papillomatous changes, each measuring approximately 10 mm in diameter with severe hyperemia on the tarsal conjunctiva. He was followed for CEP for 8 years and systemically treated with 6 mg oral prednisolone for an average of 5 years. Because the lesions did not respond to topical 0.1% tacrolimus and 0.025% levocabastine treatment and because an increase in intraocular pressure was found to occur as a side effect of 0.01% betamethasone instillation for several months, we performed surgical resection of the bilateral conjunctival lesions. Histopathological findings revealed extreme eosinophil, plasma cell, and lymphocytic infiltration and interstitial fibrosis. These conjunctival specimen findings were similar to those seen in the alveolar lesions in CEP. Topical antiinflammatory therapy using 0.1% tacrolimus eye drops was administered after surgery, which relieved the patient's lid swelling and itching. However, the lesions concurrently changed to be consistent with exacerbation and remission of systemic CEP. Conclusions Based on the clinical course and histopathology, the conjunctival proliferative masses in our case were assumed to be associated with CEP.

Background Falls and fall-related fractures are a major public health problem among the older adults. Although objective measures of poor vision have been reported to be associated with falls, the association of self-reported visual function and vision-specific quality of life (QOL) with falls has been inconsistent across several studies. We investigated the association of self-reported visual function and vision specific QOL with falls in community-dwelling older adults. Methods We conducted a cross-sectional analysis using the baseline data from participants of the Locomotive Syndrome and Health Outcome in Aizu Cohort Study (LOHAS), which is an ongoing population-based cohort study to evaluate the association of physical dysfunction with the clinical outcomes in community-dwelling people. In the present study, the participants aged over 65 years in 2010 were eligible. The exposure variable was the composite score of the VFQ-J11, which was newly developed using item response theory to evaluate vision specific QOL, and the self-reported outcomes were any fall and frequent falls (≥2) over a 1-month period. We estimated odds ratios using separate logistic regression models adjusted for relevant confounding factors. Results Among 1624 participants, the median (interquartile range) composite score of VFQ-J11 was 86.8 (76.0–95.9). Any fall and frequent falls were reported by 13.9% and 5.4% of participants, respectively. The composite score of the VFQ-J11 was significantly associated with both frequent falls (adjusted ORs per 10 points, 0.80; 95% CI, 0.68–0.93) and any fall (adjusted ORs per 10 points, 0.84; 95% CI, 0.76–0.94). Conclusions We found that the composite score of the VFQ-J11 was associated with falls in community-dwelling older adults. Detecting individuals with visual impairments associated with falls using the VFQ-J11 and improvement in the score by interventions could prevent falls. We may consider adding self-reported visual function and vision-specific QOL to conventional risk factors for fall among older adults.

Unstable tear film characterized by shorting of tear break-up time (BUT) is associated with discomfort and dryness in contact lens wearers. The glycocalyx is thought to be crucial in maintaining the wettability and lubrication of the ocular surface. We evaluated the ocular surface glycocalyx in soft contact lens (SCL) wearers using a fluorescein-labeled wheat germ agglutinin (F-WGA) as a marker to demonstrate the ocular surface glycoconjugates in vivo.Twenty experienced SCL wearers and 20 healthy volunteers with no history of CL wearing (controls) were enrolled in the study. After applying a 5% F-WGA solution to the eyes of study individuals, fluorescent intensities in their respective central corneas were measured by fluorophotometry. The relationship between F-WGA intensity in the corneal surface and clinical parameters associated with contact lens wear were analyzed.F-WGA fluorescence intensity in the SCL group was 418.5 ± 103.3, which was significantly lower than that of the controls (825.0 ± 179.8; p 0.0001, Mann-Whitney test). F-WGA fluorescence intensity was not correlated with Schirmer's test values or age, whereas a statistically significant correlation between F-WGA fluorescence intensity and tear film BUT was observed (r = 0.77, p 0.0001). The decrease in F-WGA fluorescence intensity could be reversed by discontinuation of SCL use.Reduction and/or compositional alteration of ocular surface glycocalyx may be one of the causative factors of SCL-induced eye dryness.

To evaluate the effect of meibomian gland dysfunction (MGD) and friction-related disease (FRD) on the severity of dry eye disease (DED).Cross-sectional observational study.This study enrolled 449 patients with DED (63 men and 386 women; mean age, 62.6±15.7 years [range, 21-90 years]) for analysis.Subjective symptoms, the ocular surface, tear function, and the presence of MGD and FRD (superior limbic keratoconjunctivitis, conjunctivochalasis, and lid wiper epitheliopathy) were investigated.Schirmer value, tear film breakup time (TBUT), and keratoconjunctival score.We classified the participants into aqueous-deficient dry eye (ADDE; n = 231 [51.4%]) and short TBUT dry eye subtype (TBUT-DE; n = 109 [24.3%]) subgroups. The TBUT was shorter in patients with MGD than in those without MGD, whereas other ocular signs showed no difference (TBUT: MGD present, 1.97±1.02 seconds; MGD absent, 2.94±1.63 seconds [P0.001]; ADDE/MGD present, 1.94±1.08 seconds; ADDE/MGD absent, 2.77±1.61 seconds [P0.001]; short TBUT-DE/MGD present, 2.07±0.97 seconds; short TBUT-DE/MGD absent, 2.94±1.23 seconds [P = 0.01]). The ADDE patients with FRD showed a worse TBUT than ADDE patients without FRD (TBUT: ADDE/FRD present, 2.08±1.39 seconds; ADDE/FRD absent, 2.92±1.54 seconds; P 0.001).This study showed associations between MGD, FRD, or both and ocular signs in DED. In the presence of MGD, FRD, or both, TBUT was significantly shortened regardless of the dry eye status or subtype.

To evaluate the cost-effectiveness for a screening interval longer than 1 year detecting diabetic retinopathy (DR) through the estimation of incremental costs per quality-adjusted life year (QALY) based on the best available clinical data in Japan.A Markov model with a probabilistic cohort analysis was framed to calculate incremental costs per QALY gained by implementing a screening program detecting DR in Japan. A 1-year cycle length and population size of 50,000 with a 50-year time horizon (age 40-90 years) was used. Best available clinical data from publications and national surveillance data was used, and a model was designed including current diagnosis and management of DR with corresponding visual outcomes. One-way and probabilistic sensitivity analyses were performed considering uncertainties in the parameters.In the base-case analysis, the strategy with a screening program resulted in an incremental cost of 5,147 Japanese yen (¥; US$64.6) and incremental effectiveness of 0.0054 QALYs per person screened. The incremental cost-effectiveness ratio was ¥944,981 (US$11,857) per QALY. The simulation suggested that screening would result in a significant reduction in blindness in people aged 40 years or over (-16%). Sensitivity analyses suggested that in order to achieve both reductions in blindness and cost-effectiveness in Japan, the screening program should screen those aged 53-84 years, at intervals of 3 years or less.An eye screening program in Japan would be cost-effective in detecting DR and preventing blindness from DR, even allowing for the uncertainties in estimates of costs, utility, and current management of DR.

To report a case of atypical corneal lesions presumably induced by trastuzumab emtansine, an antibody-drug conjugate that is designed to selectively deliver cytotoxic agents to human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells.A 64-year-old Japanese woman developed bilateral corneal epithelial abnormalities that originated from the limbus. The corneal lesions covered the superior area in the right eye and both superior and inferior areas including the visual axis in the left eye. The patient had advanced ductal carcinoma of the left breast and had been receiving anticancer treatment with trastuzumab emtansine for 15 months. After switching the chemotherapy from trastuzumab emtansine monotherapy to the combination of docetaxel, trastuzumab, and pertuzumab, the abnormal corneal lesions showed gradual improvement.As corneal epithelial cells express human epidermal growth factor receptor 2 under normal conditions, such cells may also be targeted by trastuzumab emtansine and lead to corneal epithelial lesions.

To evaluate the efficacy of topical application of 3% diquafosol tetrasodium solution for the treatment of soft contact lens (SCL) wearers with dryness. In addition to clinical tests and subjective symptoms, we assessed the fluorescence intensity of wheat germ agglutinin conjugate of fluorescein (F-WGA) used as a marker of membrane-associated mucins and sialic acid concentration in tear fluids as a marker of secreted mucins.Twelve SCL wearers with dryness symptoms were treated with diquafosol for 4 weeks. Clinical tests included the tear film break-up time (BUT), corneal and conjunctival fluorescein staining scores, and Schirmer values. Subjective symptoms were evaluated by the Dry Eye-Related Quality-of-Life Score (DEQS). Fluorescence intensities in the central cornea were measured by fluorophotometry at 5 minutes after a 5% F-WGA solution was applied to the eye. The tears collected by the Schirmer test strips were analyzed by high-performance liquid chromatography (HPLC), and the concentrations of sialic acid; total protein; and the four major tear proteins secretory IgA, lactoferrin, lipocalin-1, and lysozyme proteins were measured.Comparing the results before and after diquafosol treatment, BUT (p0.01), kerato-conjunctival staining score (p0.05), corneal staining score (p0.05), and DEQS score (p0.01) showed statistically significant improvements. The F-WGA fluorescence intensities (p0.0001) significantly increased after treatment, whereas the concentrations of sialic acid and tear proteins remained unchanged.Topical application of diquafosol solution to the SCL wearers with dryness improved biomarker of membrane-associated mucins, BUT, staining of cornea and conjunctiva, and subjective symptoms.

This study examines the impact of cataracts on health-related quality of life (HR-QOL) and health events in the older population. The study population consisted of 439 unoperated cataract patients aged 60 years or older who visited any of the facilities affiliated with the Cataract Survey Group of the National Hospital Organization of Japan, which has been conducting a prospective multicenter cohort study on cataract patients. HR-QOL of the patients was assessed using the Japanese version of Visual Function Questionnaire-25 (VFQ-25) and the 8-Item Short-Form Health Survey (SF-8). The health condition and health events of the patients were also investigated. The average age of the 439 patients enrolled (126 men and 313 women) was 73.0 ± 7.1 years. There were 323 patients with comorbidities (73.6%), 81 of whom (23.7%) felt it was hard to visit the hospital owing to their visual impairment. In the previous year, 74 patients (16.9%) had experienced a fall and 14 (3.2%) had been in a traffic accident. Of those, 43.2% and 8.3% respectively answered that the falls and the accident could have been triggered by their visual impairment. When the patients were classified according to visual acuity, most of the VFQ-25 subscale scores declined significantly with decreasing visual acuity, whereas the SF-8 scores showed no significant change. The participants of this study were patients with unoperated cataract, and thus the decline of HR-QOL was modest. The survey of health events, however, revealed that the visual constraint has a certain impact on the daily lives of the older population.

Aim: This study was performed to independently assess the turnover rates of aqueous and lipid layers of the tear film. Methods: Two fluorescent dyes, fluorescein sodium and 5-dodecanoylaminofluorescein (DAF), which is a free-fatty-acid conjugate of fluorescein, were applied to the right eye of 12 healthy volunteers. Fluorescent intensity of the precorneal tear film was measured at the central cornea every minute for 10 min for fluorescein sodium, and every 5 min for 50 min for DAF. The turnover rate was calculated by plotting fluorescent intensity against time in a semilog plot and expressed as %/min. Results: Turnover rates of fluorescein sodium and DAF were 10.3 (SD 3.7)%/min and 0.93 (0.36)%/min, respectively. The turnover rate of DAF was significantly lower than that of fluorescein sodium (p

PURPOSE Recent studies have shown that low tear phospholipid levels are associated with tear film instability in hydrophilic contact lens wearers. The concentration of secretory phospholipase A2 (sPLA2), the enzyme that hydrolyzes phospholipids, in tears is known to exceed the levels found in serum by four orders of magnitude. This study was performed to determine the levels of sPLA2 from the deposition on two different frequent-replacement contact lens materials. METHODS Polymacon and etafilcon A contact lenses worn for 2 weeks by 16 experienced contact lens wearers were used for the analysis. Total lipids were determined by the sulfo-phospho-vanillin reaction. Phospholipids in lipid extracts were estimated by phosphorus determination with ammonium molybdate through enzymatic digestion. Total protein was measured by bicinchoninic acid analysis. Double-antibody sandwich enzyme-linked immunosorbent assay was used to determine sPLA2 concentrations. RESULTS Total lipid deposition was found to be greater in the polymacon group (66.3+/-16.3 microg/lens) than in the etafilcon A group, although phospholipids were not detected in either group. The etafilcon A group had greater deposition of protein (3.7+/-0.7 mg/lens) than the polymacon group had. The etafilcon A group deposited statistically significantly more group IIa sPLA2 (1.1+/-0.3 microg/lens) than the polymacon group (0.07+/-0.04 microg/lens) did (P

Purpose: This study was performed to separately assess the aqueous flow applied with hyaluronic acid, and the behaviour of hyaluronic acid itself on the ocular surface. Methods: Two different fluorescent dyes, fluorescein sodium dissolved in 0.1% hyaluronic acid (HA) solution and 0.1% fluorescein conjugated with hyaluronic acid (F-HA) dissolved in saline, were used. A volume of 20 μl of tested solution was applied to the eye of 10 healthy volunteers. Fluorescein sodium dissolved in saline served as a control. The fluorescent intensity of the precorneal tear film was measured at the central cornea every minute for 10 min. The turnover rate was calculated using the equation that plots fluorescent intensity against time in a semilog plot and expressed as %/min. Results: Turnover rates of topically applied 0.1% F-HA, 0.1% HA and saline were 8.1 (SD 3.6)%/min, 21.6 (2.8)%/min, and 31.0 (3.7)%/min, respectively. The turnover rate of F-HA was significantly lower than those of HA and saline (p = 0.00012 and p = 0.00000022, respectively; Mann–Whitney test). The turnover rate of HA was significantly lower than that of saline (p = 0.00001; Mann–Whitney test). Conclusion: Our results indicate that the bulk aqueous flow applied with HA and the turnover of HA itself are different. HA molecules may adhere to the ocular surface by surface-chemical and/or biochemical properties. The long retention time of HA on the ocular surface may explain the mechanism in which hyaluronic acid has been shown to enhance tear film stability for a few hours.

To evaluate and grade the extent and severity of chronic ocular manifestations in Stevens-Johnson syndrome (SJS).Prospective multicenter case series.We enrolled 73 patients (138 eyes) with SJS seen between April 2003 and March 2005 at 3 tertiary referral centers.Patients with a confirmed history of SJS and chronic ocular complications that persisted for at least 1 year from the onset of SJS were included. Their detailed medical history and ophthalmic examination results were recorded on an itemized data collection form. Complications were categorized as corneal, conjunctival, and eyelid complications, and 13 components were evaluated and graded on a scale from 0 to 3 according to their severity.These were broadly classified as corneal (superficial punctate keratopathy, epithelial defect, loss of the palisades of Vogt, conjunctivalization, neovascularization, opacification, keratinization), conjunctival (hyperemia, symblepharon formation), and eyelid (trichiasis, mucocutaneous junction involvement, meibomian gland involvement, punctal damage) complications.The most severely affected complication components were loss of the palisades of Vogt (114 eyes; 82.6%) and meibomian gland involvement (102 eyes; 73.9%). Visual acuity in 74 of the 138 eyes (53.6%) was worse than 20/200. The severity of corneal, conjunctival, and eyelid complications was significantly correlated with visual loss. All 13 complications were correlated significantly with logarithm of the minimum angle of resolution (logMAR) visual acuity; the correlation coefficient (R) ranged from 0.359 to 0.810 (P0.0001); for corneal epithelial defects, R was 0.169 (P = 0.0473). Eyes with a higher total score for the 3 complication categories had poorer vision (R = 0.806; P0.0001). Multivariate regression analysis showed that corneal neovascularization, opacification, keratinization, and cataracts significantly affected logMAR visual acuity (P0.0001, P0.0001, P = 0.0142, P = 0.0375, respectively).The authors describe a new method for grading the extent and severity of ocular involvement in patients with SJS and demonstrate that the severity of ocular involvement is correlated significantly with the final visual outcome. This new grading system provides a more objective method for evaluating SJS patients and may be adapted for use in other cicatricial ocular surface diseases.

Purpose To describe a method of quantifying the tear meniscus height (TMH) and using these values to diagnose patients with dry eye. Methods Thirty-eight eyes of 19 healthy subjects and 14 patients diagnosed with dry eye were studied. Each eye received 2 microL of 1% fluorescein-sodium solution in the conjunctival sac, and digital photographs were taken of the external surface of the eye with a fundus camera. The tear meniscus was extracted from the digitalized image and used to measure the TMH with NIH image software. The correlation between the mean TMH and Schirmer test values or cotton-thread test values was evaluated. Results The means of the upper and lower TMH in healthy subjects were 0.22 +/- 0.06 and 0.24 +/- 0.08 mm, respectively. The comparable values in patients with dry eye were 0.17 +/- 0.04 and 0.17 +/- 0.07 mm (upper TMS, P = 0.01; lower TMH, P = 0.04; unpaired t test). A significant correlation was found between the TMH and Schirmer test values (r = 0.72, P = 0.01) but not with cotton-thread test values. Conclusions Fluorescein photographs of the eye can be used to quantify the upper and lower TMH separately and simultaneously without specialized equipment. This technique can be used for the diagnosis of dry eye.

To evaluate the clinical efficacy of 3 % diquafosol sodium ophthalmic solution for dry eye, and to analyze the concentration of tear proteins and mucin-like substances after the treatment. Fifty eyes of 25 patients with dry eye syndrome were prospectively enrolled. The patients were treated with diquafosol solution at a dose of 1 drop in each eye 6 times daily for 4 weeks. The parameters of clinical efficacy were tear osmolarity, tear breakup time (BUT), fluorescein staining scores for the cornea and conjunctiva, Schirmer test values, and subjective symptoms evaluated using the ocular surface disease index (OSDI). Tears collected with Schirmer test strips were analyzed by high-performance liquid chromatography, and the concentrations of the total protein and the 4 major tear proteins, namely, secretory IgA, lactoferrin, lipocalin-1, lysozyme, and N-acetyl-neuraminic acid (Neu5Ac), were measured. Neu5Ac is a major sialic acid, a marker of secretory mucins. The BUT, keratoconjunctival staining scores, and Schirmer test values were improved with statistical significance after the treatment with diquafosol solution, while changes in the other parameters, including tear osmolarity, corneal staining scores, and OSDI scores were not significant. The Neu5Ac concentration was significantly increased, which was not accompanied by changes in tear proteins. Topical application of diquafosol significantly improved the clinical parameters of the BUT, keratoconjunctival staining scores, and Schirmer test values and was accompanied by increased sialic acid content in the tears of patients with dry eye.

This study examines the relationship between quality of life (QOL) and the legal Japanese grade of visual impairment as defined by the Physically Disabled Persons Welfare Act. Participants of this cross-sectional study were 98 Japanese patients legally classified as visually impaired, from six ophthalmology departments. Vision-related QOL was evaluated using the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25). The short Japanese version of this questionnaire (VFQ-J11) score was calculated from the VFQ-25 results for each participant. Health utility was measured using the EuroQoL Index (EQ-5D). Data were collected for age, gender, vision-disability level, the corrected visual acuity of each eye, and disease type. The mean age was 66.8 years (SD = 17.8). Visual impairment grade was significantly associated with VFQ-J11 score and the composite score developed from the VFQ-25 (p

Low tear phospholipids levels are associated with tear film instability in soft contact lens wearers. We assayed levels of phospholipids and their degrading enzyme secretory phospholipase A2 (sPLA2) both in tears and deposited on contact lenses composed of 2 hydrophilic materials after 1 day of routine use.Polymacon (Medalist; FDA group 1, low water/nonionic) and Etafilcon A (One Day Acuvue; group 4, high water/ionic) contact lenses were worn for 12 hours by 16 experienced contact lens wearers. Phospholipids in tear fluids and deposited on contact lenses were estimated by phosphorus determination with ammonium molybdate through enzymatic digestion. Double-antibody sandwich ELISA was used to determine group IIa sPLA2 concentrations, and sPLA2 activity was assayed using 1,2-diheptanoyl thio-phosphatidylcholine as substrate.Phospholipids concentrations in tears with Polymacon and Etafilcon A were 186 +/- 39 and 162 +/- 33 microg/mL, respectively. The latter concentration was significantly lower than that observed in the same subjects when not wearing contact lenses (P = 0.0023). In tears, both group IIa sPLA2 concentrations and enzymatic activity remained unchanged, regardless of lens wearing. However, Etafilcon A (0.57 +/- 0.09 microg/lens) showed more group IIa sPLA2 deposition than Polymacon (0.01 +/- 0.01 microg/lens; P0.001). Furthermore, group IIa sPLA2 deposited on Etafilcon A but not on Polymacon lenses retained its enzymatic activity.Significant differences of group IIa sPLA2 deposition were found in the 2 lenses tested. Such deposition might induce phospholipid hydrolysis in tears and thereby promote tear film instability in hydrophilic contact lens wearers.

Purpose. To evaluate transcorneal penetration of topically applied 0.5% levofloxacin into the aqueous humor in human eyes. Methods. Twenty cataract patients (14 females, 6 males) received 3 drops of 0.5% levofloxacin at 15 min intervals from 90 minutes before the surgery. At the beginning of the cataract surgery, 50 µL of aqueous humor was aspirated from the anterior chamber and stored at -80°C until analysis. The drug concentration of the samples was analyzed using high-performance liquid chromatography. Results. A mean aqueous humor level of levofloxacin was 1.00 ± 0.48 µg/mL (mean ± standard deviation, n = 20), ranging from 0.30 µg/mL to 2.32 µg/mL. Conclusions. The mean concentration of levofloxacin in the aqueous humor was higher than the MIC 90 values against some common pathogens of postoperative endophthalmitis, although a great degree of interpatient variability was present.

This study was undertaken to determine the effect of topical application of diquafosol tetrasodium on proteins and mucin-like substances from tears of clinically healthy subjects.Tears were collected from both the eyes of 10 healthy volunteers. Diquafosol tetrasodium solution (3%) was applied once to the right eye and 0.9% sodium chloride solution (saline) once to the left eye. Tear samples were collected by Schirmer test strips before application and 5, 15, 30 and 60 min after application. Sialic acid, a marker of mucin-like substances, and major tear proteins including secretory IgA, lactoferrin, lipocalin-1, and lysozyme were measured by high performance liquid chromatography.Levels of total protein, sIgA and lysozyme were transiently decreased in both groups but returned to baseline levels within 15 min after application. The concentration of lactoferrin and lipocalin-1 did not change significantly in both groups. Sialic acid in tears was significantly decreased 5 min after saline application, but significantly increased 5 min after diquafosol application. No significant difference in sialic acid was seen after 15 min in both groups.Topical application of saline and diquafosol resulted in transient decrease of tear proteins possibly due to wash out or dilution effects. In contrast, diquafosol application significantly increased sialic acid, although the effect was transient. This suggests diquafosol stimulates the secretion of mucins from ocular tissues of healthy human subjects.

To investigate vision-related quality of life (VRQoL) and associated factors in patients with cataracts and the outcomes of cataract surgery using the newly developed VRQoL instrument: the visual function questionnaire, 11-item Japanese version (the VFQ-J11). A total of 457 patients scheduled for cataract surgery at 12 clinical sites from November 2008 through February 2010 were included in the study. The patients completed the VFQ-J11 before and 3 months after surgery. The VFQ-J11 was used to investigate factors associated with VRQoL of the cataract patients, the outcome of cataract surgery, and the predictors of improved VRQoL due to cataract surgery. In a multiple regression model, the VFQ-J11 score was significantly associated with corrected distance visual acuity in the better-seeing eye (better eye VA), and improvement in the VFQ-J11 score after cataract surgery was associated not only with improvement in the better eye VA, but also with improvement in the worse eye VA. Compared to one-eye cataract surgery, both-eyes surgery had a greater impact on VFQ-J11 score improvement. The VFQ-J11 is a good measure of VRQoL in cataract patients. The present study indicates that by including the domains measured in the VFQ, the VFQ-J11 can provide valid data on VRQoL and be less of a burden for patients.

We present two cases of severe dry eye in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (SCT) who were successfully treated by the systemic administration of FK506 and corticosteroids.A 29-year-old man with chronic myelogenous leukemia underwent SCT. Oral and lung CGVHD developed on approximately day 130, and dry eye associated with CGVHD was diagnosed on day 168. The patient began receiving cyclosporin A (150 mg/d) for the treatment of oral and lung CGVHD. Treatment with prednisolone (1 mg/kg/d) began on approximately day 300. Oral and lung GVHD improved slightly, but worsened again although systemic administration of cyclosporin A and prednisolone were continued. Cyclosporin A was discontinued, and systemic administration of FK506 was started on day 376. Forty-four days later, marked improvement in the ocular surface and other organs was observed. However, the dry eye worsened while tapering FK506, with no flare of other affected organs. A 43-year-old woman with myelodysplastic syndrome underwent SCT. She received FK506 for prophylaxis of CGVHD. She had mild dry eye before SCT. Oral and intestinal CGVHD developed, and the dry eye worsened significantly on approximately day 150 while tapering FK506. Treatment with prednisolone (1 mg/kg/d) began, and the dose of FK506 was increased. By day 240, the symptoms of dry eye and the findings of the ocular surface markedly improved, and CGVHD in other organs was completely resolved. However, the improvement in the dry eye was lost when FK506 was tapered for the second time.Systemic administration of FK506 with corticosteroids is an effective treatment of severe dry eye in patients with CGVHD, but long-term administration may be required to achieve a lasting response. These cases also suggest that further investigation into the use of topical FK506 and prednisolone as a maintenance therapy should be pursued.

Mutations in kerato-epithelin are responsible for a group of hereditary cornea-specific deposition diseases, 5q31-linked corneal dystrophies. These conditions are characterized by progressive accumulation of protein deposits of different ultrastructure. Herein, we studied the corneas with mutations at kerato-epithelin residue Arg-124 resulting in amyloid (R124C), non-amyloid (R124L), and a mixed pattern of deposition (R124H). We found that aggregated kerato-epithelin comprised all types of pathological deposits. Each mutation was associated with characteristic changes of protein turnover in corneal tissue. Amyloidogenesis in R124C corneas was accompanied by the accumulation of N-terminal kerato-epithelin fragments, whereby species of 44 kDa were the major constituents of amyloid fibrils. R124H corneas with prevailing non-amyloid inclusions showed accumulation of a new 66-kDa species altogether with the full-size 68-kDa form. Finally, in R124L cornea with non amyloid deposits, we found only the accumulation of the 68-kDa form. Two-dimensional gels revealed mutation-specific changes in the processing of the full-size protein in all affected corneas. It appears that substitutions at the same residue (Arg-124) result in cornea-specific deposition of kerato-epithelin via distinct aggregation pathways each involving altered turnover of the protein in corneal tissue.

To investigate clinical factors related to the aqueous humor levels of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in patients with proliferative diabetic retinopathy (PDR).Undiluted aqueous humor was obtained during ocular surgery from 46 eyes of 46 patients and the levels of growth factors were measured using enzyme-linked immunosorbent assays. VEGF and HGF levels were compared with the number of photocoagulation. VEGF and HGF levels in patient groups stratified according to the existence of vitreous hemorrhage, retinal detachment, and fibrovascular membrane were analyzed. And clinical parameters associated with the growth factors were determined by multiple regression analysis.The levels of VEGF decreased significantly as the extent of photocoagulation increased and showed significant positive correlation with the existence of vitreous hemorrhage. There was no significant correlation between VEGF levels and the existence of fibrovascular membrane and traction retinal detachment. The levels of HGF also decreased significantly as the extent of photocoagulation increased, but increased significantly when fibrovascular membrane existed. There were no significant correlations between HGF levels and the existence of vitreous hemorrhage and traction retinal detachment. Concerning systemic conditions, each growth factor has no significant correlation with duration and type of diabetes mellitus, the treatment regimen, the control of hemoglobin A1C, and the existence of hypertension or renal dysfunction.The therapeutic effect of panretinal photocoagulation on PDR might be partly exerted by reduction of the levels of VEGF and HGF in ocular fluid. Since the clinical parameters associated with VEGF were different from those associated with HGF, these growth factors might influence the progression of retinopathy in different ways.

To investigate corneal deposits associated with kerato-epithelin (KE) in three corneal dystrophies harboring mutations at Arg-124 in the BIGH3 gene.Six patients with Avellino corneal dystrophy (ACD) associated with R124H, one patient with superficial granular corneal dystrophy (SGCD) associated with R124L, and seven patients with lattice corneal dystrophy type 1 (CDL1) associated with R124C were examined. Corneal buttons obtained during keratoplasties were stained with Masson's trichrome and with Congo red, and immunostained with antibodies specific for N-terminal and C-terminal portions of KE (KE-15 and KE-2, respectively).In all corneas with ACD, subepithelial to midstromal deposits of granular material stained with KE-2 and KE-15. However, deep stromal deposits containing amyloid reacted with KE-2, but not KE-15. Granular deposits in the subepithelial layer observed in SGCD stained intensely with KE-2 and KE-15. In all corneas with CDL1, subepithelial and midstromal amyloid deposits stained with KE-2; these deposits did not stain with KE-15. Deposits between the epithelial layer and Bowman's layer stained with Masson's trichrome but not with Congo red in five of the seven corneas; these deposits were stained with both KE-2 and KE-15.Deposits in corneal buttons involved by ACD, SGCD, and CDL1 included forms of the BIGH3 gene product, KE. An N-terminal sequence of KE may be related to formation of amyloid associated with R124 mutations.

AIMS—To determine the relation between the stages of diabetic retinopathy (DR) and the levels of hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) in aqueous fluid and serum. METHODS—Levels of HGF and VEGF in serum and aqueous humour obtained during ocular surgery were measured by enzyme linked immunosorbent assay in 58 diabetic patients with 32 non-diabetic patients (NDM) as controls. The patients with diabetes were classified into three groups according to the stage of DR: no DR (NDR; 15 cases), non-proliferative DR (NPDR; six cases), and proliferative DR (PDR; 37 cases). RESULTS—No significant differences were found between any of the groups in serum concentrations of HGF or VEGF. The aqueous HGF levels increased with the stage of DR: NDM, median 397 pg/ml, range 133-930 pg/ml; NDR, 371 pg/ml, 142-1536 pg/ml; NPDR, 455 pg/ml, 162-1007 pg/ml; and PDR, 638 pg/ml, 187-2222 pg/ml. The aqueous VEGF levels in PDR (median 212 pg/ml, range 14-1216 pg/ml) were significantly higher than in NDM (105 pg/ml, 9-203 pg/ml), but aqueous HGF concentrations were unrelated to those of VEGF. CONCLUSION—The results of the present study suggest that both HGF and VEGF present in the ocular tissues may play important roles in the progression of DR.

AIM—To confirm the mutation of the keratoepithelin gene in patients with a severe form of superficial juvenile granular corneal dystrophy (GCD). METHODS—Five Japanese probands in whom GCD was diagnosed after histopathological examination and who developed severe manifestations of GCD in their first decade of life were investigated. Other affected family members of two probands were also examined. All probands were the offspring of consanguineous parents. DNA was extracted from their peripheral blood leucocytes and mutational analysis of the gene was performed by the polymerase chain reaction and direct sequencing. RESULTS—Four of the five probands underwent their first keratectomy or keratoplasty in their teens and subsequently underwent a second or third keratoplasty. Each proband had a homozygous G → A transition at codon 124, replacing Arg → His, of the keratoepithelin gene. Their moderately affected family members were heterozygous for the mutation. CONCLUSIONS—This finding suggests that the severity of the corneal phenotype depends on the dose effect of the mutant gene. Keywords: Avellino corneal dystrophy; keratoepithelin; R124H mutation; homozygote

PURPOSE. To measure the pH in the precorneal tear film of humans in vivo using a pH-sensitive fluorescent dye, bis-carboxyethyl-carboxyfluorescein (BCECF). METHODS. The measurement was initiated by instilling 1 µl of 2 mM BCECF solution into the subject's eye. The pH was calculated by measuring the ratio of fluorescent intensities at two excitation wavelengths (490/430 ratio), which was dependent on pH, but independent of the dye concentration and other variables. The tears of the same subject were then collected and loaded on to a micro pH-meter to ensure the accuracy of the measurement. RESULTS. The mean pH values of 40 eyes from 20 healthy volunteers was 7.50 (SD ± 0.23), which corresponded well with those measured by the micro pH-meter. CONCLUSIONS. The method described was useful in measuring the pH of the precorneal tear film of humans with minimal invasion.

To determine and compare the effects of single and frequent topical applications of saline solution on tear protein concentration in clinically normal subjects.Tears were collected from both eyes of 11 normal volunteers using Schirmer's strips. Saline solution (0.9% sodium chloride) was applied once in the right eye and five times with an interval of 1 min each in the left eye. Tears were collected before and 5, 15, 30 and 60 min after application of the solution. Total tear protein concentration in the samples was measured by the Bradford method and major tear protein concentration (secretory immunoglobulin A, lactoferrin, lipocalin-1, lysozyme and sialic acid) was measured using a high-performance liquid chromatography assay.A significant decrease was observed in the concentration of total tear protein, major tear proteins and sialic acid after topical application of saline solution. This decrease was attributed to the washout and dilution effect. A low protein concentration persisted longer with more frequent application of the solution. The concentration of secretory immunoglobulin A and sialic acid concentration recovered slowly compared with that of other proteins.Even a single application of saline solution resulted in significant changes in major tear protein and sialic acid concentration in the tears of normal subjects. Differences in the recovery of tear protein concentration may be related to the process of protein production and secretion. A balance between normal tear function and the therapeutic effects of ophthalmic solutions should be considered when deciding the frequency of application, particularly in patients with dry eye.

OBJECTIVE: To evaluate with the best available clinical data in Japan the cost-effectiveness of cataract surgery through the estimation of the incremental costs per quality-adjusted life years (QALYs) gained. METHODS: A Markov model with a probabilistic cohort analysis was constructed to calculate the incremental costs per QALY gained by cataract surgery in Japan. A 1-year cycle length and a 20-year horizon were applied. Best available evidence in Japan supplied the model with data on the course of cataract surgery. Uncertainty was explored using univariate and probabilistic sensitivity analysis. RESULTS: In base case analysis, cataract surgery was associated with incremental costs of Japanese yen (¥) 551,513 (US$ 6,920) and incremental effectiveness of 3.38 QALYs per one cataract patient. The incremental cost effectiveness ratio (ICER) was ¥ 163,331 (US$ 2,049) per QALY. In Monte Carlo simulation, the average patient with cataract surgery accrued 4.65 [95 % confidence interval (CI): 2.75-5.69] more QALYs than patients without surgery, giving an ICER of ¥ 118,460 (95 % CI: 73,516-207,926) (US$ 1,486) per QALY. CONCLUSIONS: Cataract surgery in Japan is highly cost-effective even when allowing for the uncertainty of the known variability that exists in estimates of the costs, utilities, and postoperative complication rate.

Purpose To classify secondary corneal amyloidosis (SCA) by its clinical appearance, to analyze the demographics of the patients, and to determine the involvement of lactoferrin. Design Retrospective, observational, noncomparative, multicenter study. Participants Twenty-nine eyes of 29 patients diagnosed with SCA by corneal specialists at 9 ophthalmologic institutions in Japan were studied. Methods The clinical appearance of SCA was determined by slit-lamp biomicroscopy and was classified into 3 types. The demographics of the patients, for example, age, gender, and the duration of the basic disease (trichiasis, keratoconus, and unknown), were determined for each clinical type. Surgically excised tissues were stained with Congo red and antilactoferrin antibody. The postoperative prognosis also was determined. Main Outcome Measures Clinical appearance of the 3 types of SCA, along with the gender, age, and duration of the basic diseases were determined. Results Classification of SCA into 3 types based on clinical appearance found 21 cases with gelatinous drop-like dystrophy (GDLD)-like appearance (GDLD type), 3 cases with lattice corneal dystrophy (LCD)-like appearance (LCD type), and 5 cases with the combined type. Patients with the GDLD type were younger (average age: 40.9 years for the GDLD type, 74.3 years for the LCD type, and 46.8 years for the combined type), predominantly women (85.7% for the GDLD type, 33.3% for the LCD type, and 60% for the combined type), and had the basic disease over a longer time (average duration: 22.1 years for the GDLD type, 14.0 for the LCD type, and 11.4 for the combined type). The distribution of the basic diseases (trichiasis vs. keratoconus vs. unknown) was not significantly different for each type. Surgical treatments, for example, phototherapeutic keratectomy, lamellar keratoplasty, and simple keratectomy, resulted in a good resolution in all surgically treated cases. One subject dropped out of the study. Spontaneous resolution was seen in one subject after epilation of the cilia. Amorphous materials in the excised tissues showed positive staining results by Congo red and by antilactoferrin antibody. Conclusions Secondary corneal amyloidosis can be classified into 3 clinical types based on its clinical appearance. Larger numbers of females and lactoferrin expression were seen in all 3 types. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

We report here a case of fungal keratitis caused by Aspergillus viridinutans, a member of the genus which was found to have clinical and antifungal susceptibility characteristics distinct from the species it most closely resembles, Aspergillus fumigatus. A 26-year-old woman presented with contact lens-associated keratitis, the etiologic agent of which was initially slow growing and found to be resistant to amphotericin B and voriconazole. Therapeutic keratoplasty was performed and an isolate from a corneal scraping was identified as A. viridinutans through partial DNA sequencing of the β-tubulin gene, along with its slow growth 42°C. In contrast with A. fumigatus, A. viridinutans proved to be resistant to a wider variety of antifungal agents. To the best of our knowledge, this is the first case of keratitis caused by A. viridinutans. Clinical isolates of the genus Aspergillus include rarely encountered species such as A. viridinutans. These species may show clinical manifestations distinct from those of A. fumigatus, including clinical resistance to amphotericin B and voriconazole and relatively low susceptibility to other antifungal agents.

The purpose of this study was to determine the corneal epithelial alterations induced by various types of contact lenses. By employing the specular microscope, the corneal epithelia of 60 patients who had worn contact lenses for more than 1 year were re-examined along with 15 myopic controls. The morphological changes in aphakic patients who changed from extended wear soft to extended wear rigid gas permeable lenses were also studied. The mean cell area of the corneal epithelium was 621.5 (SD 92.5) microns 2 for daily wear rigid gas permeable lenses (n = 15), 645.8 (98.1) microns 2 for daily wear soft lenses (n = 15), and 634.7 (88.6) microns 2 for extended wear rigid gas permeable lenses (n = 15), none of which differed significantly from the control value of 610.5 (98.1) microns 2. Only the extended wear soft lens group (n = 15) showed significantly enlarged epithelia (806.1 (50.1) microns 2, p < 0.01 versus the other groups). The epithelium partially returned to normal after changing from extended wear soft lenses to extended wear rigid gas permeable ones. The corneal epithelium showed increased cell area only with extended wear soft contact lenses which are known to pose a risk for corneal infection.

Purpose: Although the combination of a hard contact lens "piggybacked" on a soft lens base for the correction of severe astigmatism in keratoconus has existed for two decades, little is known about its effect on the corneal epithelium and endothelium. This study involves two parts: the measure of oxygen pressure in rabbits, and the longterm effects on patients with keratoconus wearing these hybrid lenses. Methods: A polarographic sensor was used to measure the oxygen pressure on rabbit corneas under two types of piggyback lenses: oxygen-permeable hard lenses on high water-content soft lenses, and polymethylmethacrylate (PMMA) lenses on low watercontent soft lenses. In the clinical evaluation, 11 patients with keratoconus (8 men, 3 women; 25.1 ± 4.9 years of age) who could not wear hard contact lenses due to constant pain or inadequate lens fitting were given oxygen-permeable piggyback contact lenses and were observed for at least 9 months. Results: In the animal study, the oxygen pressure under piggybacked oxygenpermeable hard contact lenses was 95 ± 14 mmHg after 5 minutes wear, but it was only 34 ± 14 mmHg when PMMA and low water-content lenses were used. Ten of 11 patients were successfully treated using this technique, whereas one patient had persistent contact lens loss, requiring penetrating keratoplasty. Specular microscopic observation of the corneal epithelium and endothelium did not show any changes during the follow-up period. Conclusions: These results suggest the efficacy and safety of the piggyback combination of oxygen-permeable hard and soft contact lenses for the correction of astigmatism in patients with keratoconus.

Aims: To evaluate corneal electrolysis as a treatment for recurrent diffuse corneal opacities at the host-graft interface of the stroma or at the subepithelial region in two types of granular corneal dystrophy (GCD). Methods: Recurrence developed at the host-graft interface of the stroma after lamellar keratoplasty in a patient with Avellino corneal dystrophy (ACD). At surgery, the deep aspect of the graft in this patient was partially separated from host tissue to expose the deposits, with one third of the host-graft junction left intact. The graft was everted, and electrolysis was applied directly to remove the deposits attached to both surfaces of the host and the graft. Then the graft was returned to its place and sutured. In two patients with homozygous ACD and one patient with the superficial variant of GCD, diffuse subepithelial opacities developed following penetrating keratoplasty. Electrolysis was applied directly to the corneal surface. Results: Deposits at the host-graft interface of the stroma and in the subepithelial region disappeared following treatment, and vision recovered in all patients. Conclusions: This method is a simple, easy, and inexpensive way to remove deposits that recur after lamellar or penetrating keratoplasty.

PURPOSE Anterior segment dysgenesis is one of the main causes of congenital corneal opacities. In this study, we investigated the clinical features and visual outcomes of patients with anterior segment dysgenesis in a large number of cases. METHODS The medical records of patients with congenital corneal opacities in relation to anterior segment dysgenesis seen in the National Center for Child Health and Development, Japan, between April 2002 and October 2009, were retrospectively studied. RESULTS Records of 220 eyes of 139 patients were reviewed. Mean follow-up period was 5 years. Clinical diagnoses were Peters anomaly (72.7%), anterior staphyloma (11.4%), Rieger anomaly (7.7%), sclerocornea (6.4%), and others (1.8%). Visual acuity was measured in 61 patients. The best-corrected visual acuity in the better eye of bilaterally involved patients was 20/60 to 20/1000 (low vision according to the International Classification of Diseases, Ninth Revision, Clinical Modification) in 43.2% and less than 20/1000 (legally blind) in 24.3%. Fundus examination was performed in 82 eyes, and disorders were seen in 12 (12 of 82; 14.6%). Systemic abnormalities were present in 35 patients (35 of 139; 25.2%); a family history was present in 5 patients (5 of 139; 3.6%). Of the 160 eyes of 109 patients with Peters anomaly, 51 patients (51 of 109; 46.8%) had bilateral Peters anomaly, 30 (30 of 109; 27.5%) had fellow eyes that were normal, and 28 (28 of 109, 25.7%) showed other abnormal ocular findings in the fellow eye. CONCLUSIONS Anterior segment dysgenesis shows diverse clinical features, various severities of corneal opacities, and visual outcomes. Further understanding of the disease as an abnormality during embryogenesis and neural crest cell differentiations may be required.

Achieving high antibiotic concentrations is important for preventing and treating postoperative infections. However, no study has simultaneously compared the achieved concentrations of moxifloxacin, gatifloxacin, and levofloxacin in the human cornea and aqueous humor. The authors therefore performed a randomized study to determine the concentrations of 0.5% moxifloxacin, 0.3% gatifloxacin, and 0.5% levofloxacin in the corneal tissue and aqueous humor after topical instillation in patients undergoing penetrating keratoplasty.Patients who required penetrating keratoplasty were eligible for this study. The topical preparations of 0.5% moxifloxacin, 0.3% gatifloxacin, and 0.5% levofloxacin used in the study were preservative free (Japanese formulations). Patients were randomly assigned to one of three sequential drug groups, in which each drug was administered three times before surgery. In each administration cycle, the patients received two drops of each drug at 2-minute intervals. Samples of corneal tissue and aqueous humor were collected during surgery. The concentrations of each drug in the samples were determined by high-performance liquid chromatography.A total of 63 patients across eight centers in Japan were enrolled in the study. Overall, 61 corneal and 58 aqueous humor samples were evaluated. The concentration (mean±standard deviation) of moxifloxacin in corneal tissues was 12.66±8.93 μg/g, which was significantly higher than that of gatifloxacin (4.71±3.39 μg/g; P0.0001) and levofloxacin (5.95±4.02 μg/g; P0.0001). The mean concentration of moxifloxacin in aqueous humor samples was 1.40±1.17 μg/mL, which was significantly higher than that of gatifloxacin (0.65±0.80 μg/mL; P=0.0001) and levofloxacin (0.89±0.86 μg/mL; P0.05). The sequence of drug administration did not significantly affect the results.These results show that 0.5% moxifloxacin achieved superior ocular concentration than both 0.3% gatifloxacin and 0.5% levofloxacin.