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The binocular Esterman visual field test (EVFT) of 120 points was the first method to quantify the defects in the binocular visual field. It is used in many parts of the world as a standard test to determine whether an individual has the visual capabilities to drive safely. In Japan, it is required for the grading and issuance of visual disability certificates. The purpose of this study was to determine the reliability of the EVFT results. We studied 104 patients who had undergone the binocular EVFT at Mie University Hospital. Their mean age was 68.0 ± 11.4 years, and the best-corrected visual acuity of the better eye was 0.18 ± 0.38 logMAR units. The EVFT was performed twice on the same day, and the results of the first and second tests were compared. The mean Esterman scores for the first and second test were 89.3 ± 30.5 and 89.1 ± 30.2, respectively, and the test times were 338.9 ± 86.8 and 336.7 ± 76.4 s, respectively. The differences were not significant ( p = 0.69 and p = 0.33). In the Bland-Altman analyses (second-first test) of the Esterman scores, the mean difference was 0.38 without significant fixed errors ( p = 0.20) or proportional errors ( p = 0.27). The limits of agreement within the 1.96 standard deviation were -8.96 to +9.45 points. The agreement rate for the most peripheral 24 test points was significantly lower than the agreement rate for the other 96 test points ( p < 0.01). The agreement rate of the upper visual field was significantly lower than that of the lower field ( p < 0.01). The overall reliability rate of the EVFT is acceptable, but the peripheral and upper test points have relatively low reliability rates. These findings are important for interpretations of the EVFT results.

Epiretinal membrane (ERM) foveoschisis is a recently proposed clinical entity. The purpose of this study was to compare the clinical characteristics and surgical outcomes of eyes with ERM foveoschisis to those of typical ERM. The medical records of all patients with ERM-related disorders examined between 2011 and 2020 were reviewed. ERM foveoschisis was defined by the clinical criteria proposed by an international panel of experts on ERMs. The background factors, clinical characteristics, and surgical outcomes of ERM foveoschisis were compared to those of typical ERM. Forty eyes with ERM foveoschisis were compared to 333 eyes with typical ERM. The percentage of women was significantly higher in the ERM foveoschisis group (92.5%) than in the typical ERM group (48.9%, p < 0.001). The central macular thickness (CMT) was significantly thinner in the ERM foveoschisis group (340 ± 110 μm) than in the typical ERM groups (476 ± 111 μm, p < 0.01). The degree of improvement in the best-corrected visual acuity (BCVA) three months after the surgery did not differ between the two groups ( p = 0.59). These results suggest that the ERM foveoschisis is more likely to occur in women and that the prognosis after surgery is comparable to typical ERM.

Rationale: It is difficult to follow changes in the intraocular pressure (IOP) in glaucomatous eyes comprehensively because of the limited number of outpatient examinations. We report our findings in a case of normal tension glaucoma (NTG) in which frequent self-measurements of the IOP were used to evaluate the IOP-lowering effect of different medications., Patient Concerns: A 50-year-old man with NTG had a nasal step visual field defect in his right eye and was being treated with 0.005% latanoprost (LAT) ophthalmic solution (XALATAN®)., Diagnosis: The patient was diagnosed with NTG., Interventions: The patient had a mean IOP in the right eye of 10.9 ± 1.5 mm Hg (68 measurements in 1 month, Period A) during treatment with 0.005% LAT ophthalmic solution. During the second month (Period B), the mean IOP in the same eye was 9.8 ± 1.7 mm Hg (59 measurements) with treatment with a LAT and carteolol fixed combination (LCFC). And during the third month (Period C), the mean IOP was 7.4 ± 1.1 mm Hg (57 measurements) on the same right eye after the addition of brimonidine and brinzolamide fixed combination ophthalmic solution to the LCFC ophthalmic solution., Outcomes: Comparisons of the IOPs between Periods A and B and between B and C showed that the reductions in the IOP were significant., Conclusion: We conclude that frequent self-measurements of the IOP can determine that small changes of the IOPs are significant., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To determine the characteristics and cause of the increase in the amplitude of flicker electroretinography (ERG) after cataract surgery., Design: Prospective, observational clinical study., Participants: Thirty patients who underwent cataract surgery., Methods: Flicker ERGs were recorded with the RETeval system without mydriasis. The central macular thickness (CMT) was measured by OCT and the aqueous flare value (AFV) by laser flare-cell photometry. These examinations were performed before surgery and 1 day, 1 week, 1 month, 2 months, and 3 months after surgery. Linear regression analysis through the origin was used to compare the correlations between the relative changes in flicker ERG amplitudes and the changes in the CMT and AFV at different times after the surgery., Main Outcome Measures: The amplitude of flicker ERGs, CMT, and AFV., Results: The mean amplitude of flicker ERGs increased significantly by 31% at 1 week after surgery ( P  < 0.001); a significant increase in the amplitudes was not present at 3 months after the surgery. The mean AFV was significantly increased at 1 day after surgery ( P < 0.001), and the CMT was significantly increased at 1 to 3 months after surgery ( P < 0.001). The changes in flicker ERG amplitudes at 1 week after surgery were significantly associated with the changes in the CMT at 1 to 3 months after surgery ( P < 0.05), and they were weakly associated with the changes in AFV at 1 day after surgery ( P  = 0.05)., Conclusions: These results suggest that the increase in the amplitude of flicker ERGs after cataract surgery is a transient phenomenon that has a peak at 1 week after surgery. The increase of flicker ERG amplitude was associated with measures that are frequently used to evaluate postoperative inflammation., Financial Disclosures: Proprietary or commercial disclosure may be found after the references., (© 2022 Published by Elsevier Inc. on behalf of American Academy of Ophthalmology.)

Purpose: To assess the blood flow and vascular visibility of irises in relation to pigmentation and pupil size, using an anterior segment optical coherence tomography angiography (OCTA)., Materials and Methods: This is a cross-sectional study. OCTA images were acquired in the nasal and temporal quadrants from a cohort of 30 healthy subjects in photopic (miosis) and scotopic (mydriasis) conditions. Patients were divided according to iris color (less pigmented: group L vs more pigmented: group D). Vascular parameters (vessel density (VD), vessel length density (VLD), fractal dimension (FD)) were applied and compared among groups L and D, location and different pupil status. A novel vascular index called Luminance Index (LI) was developed and applied in order to quantify vascular flow and evaluate its variation in photopic and scotopic conditions. Multivariable analyses were performed to evaluate possible predictors of VD and LI., Results: No differences were found for all vascular measurements (VD, VDL, FD, LI) between nasal and temporal quadrants. All vascular measurements were higher in group L than in group D ( p  < 0.05), except for LI and FD in photopic condition. In group L, all vascular parameters increased ( p  < 0.001) after dark adaptation. In group D, only LI increased after dark adaptation ( p  < 0.001). Pigmentation and iris thickness were significantly associated with VD in scotopic and photopic conditions, and with LI only in scotopic condition., Conclusions: Pigmentation still remains a major issue for vascular visibility. Quantitative and qualitative vascular changes follow pupil size variation. LI could be a new surrogate to quantify blood flow.

Purpose: To report abnormal full-field electroretinograms (ERGs) in a patient with cystoid macular edema (CME) induced by systemic paclitaxel., Methods: This is an observational case report. Full-field ERGs were recorded to evaluate the retinal function using the RETeval system and conventional ERGs using contact lens electrodes with built-in white light-emitting diodes. Optical coherence tomography (OCT) was also used to assess the retinal morphology., Results: A 70-year-old man, who was diagnosed with gastric cancer, had undergone gastrectomy. Subsequently, systemic paclitaxel was administered once a week as an adjuvant therapy. After the tenth course of paclitaxel, he experienced blurred vision in both eyes and visited our department of ophthalmology. OCT revealed the presence of CME in both eyes, and the RETeval flicker ERGs showed a marked reduction in the amplitudes and a prolongation of the implicit times in both eyes. Conventional ERGs showed that the amplitudes of the oscillatory potentials (OPs) were also severely attenuated. The abnormal OCT findings and reduced visual acuity recovered to normal at 1 and 2 months, respectively, after the discontinuation of paclitaxel. However, the flicker ERGs did not recover to normal values until 4 months after the discontinuation of paclitaxel., Conclusion: These results suggest that the ERGs can be used to monitor the changes in the overall retinal function in patients receiving paclitaxel., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: A new handheld electroretinographic (ERG) recording system can record ERGs without mydriasis. However, this RETeval system cannot record ERGs from both eyes simultaneously. Thus, the purpose of this study was to determine whether the sequence of the ERG recordings will alter the results., Methods: We studied 30 eyes of 30 healthy subjects. The flicker ERGs were recorded with the RETeval system without mydriasis and were elicited by 8, 16 and 32 photopic Td-s. The flicker ERGs were recorded at two sessions. Session 1, the ERGs were recorded from the right eye and then the left eye, and Session 2, ERGs were recorded from the left eye then the right eye. We compared the implicit times, amplitudes and pupil diameters of the right eye between these two sessions., Results: The implicit time of the flicker ERGs was significantly shorter (p < 0.001), and the pupil diameters were significantly smaller (p = 0.013) at Session 2 than Session 1 but only for the lower stimulus intensity of eight Td-s. There was a significant correlation of the differences in the implicit times and the differences in the pupil diameter between the two sessions (r = 0.406, p = 0.026)., Conclusions: The results indicate that the implicit times of the fundamental components of RETeval flicker ERGs can be affected by the sequence of recordings for lower stimulus intensities. This was most likely due to the differences of the pupil diameter during the recordings. We recommend that stronger stimuli be used to record the RETeval flicker ERGs to minimize the effects of the sequence of recordings., (© 2020 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: To report our findings in a case of lens fragment-induced uveitis associated with supernormal flicker electroretinograms (ERGs) twenty months after the cataract surgery., Methods: This is an observational case report. Full-field flicker ERGs were recorded with the RETeval system. Optical coherence tomography (OCT) and slit-lamp biomicroscopy were used to assess the uveitis during the follow-up period., Results: A 70-year-old man, who had undergone cataract surgery 20 months earlier, visited our hospital with a complaint of decreased vision in his right eye. Slit-lamp biomicroscopy revealed corneal edema and a lens fragment was detected in the inferior part of the anterior chamber. OCT showed cystoid macular edema, and flicker ERGs showed a marked increase in the amplitude and a delay in the implicit time in the right eye. These abnormalities of the flicker ERGs improved gradually after the removal of lens fragment and application of topical anti-inflammatory medications., Conclusion: Our case of lens-induced uveitis had supernormal flicker ERG amplitudes. Clinicians should be aware that eyes with uveitis can have larger-than-normal ERG amplitudes.

Purpose: To determine whether there is a significant correlation between the amplitude of the photopic negative response (PhNR) and the peripapillary retinal nerve fiber layer thickness (pRNFLT) in eyes of young, healthy subjects., Methods: We analyzed 136 eyes of 136 young, healthy subjects (89 males and 47 females; age, 20-29 years). The PhNRs were recorded with the RET eval system without mydriasis using red flashes on a blue background. PhNR amplitude was measured at two points: at 72 ms (P 72 ) and at the negative trough following the b-wave (P min ). Univariate and multivariable linear regression analyses were performed to identify the independent variables that were significantly correlated with P 72 and P min . The variables included age, sex, axial length, pRNFLT, intraocular pressure (IOP), a-wave amplitude, b-wave amplitude, and pupillary area during the electroretinogram recordings., Results: The amplitudes of P 72 and P min were significantly larger in female subjects ( P = 0.021 and P = 0.001, respectively). Univariate analyses showed that PhNR amplitudes were significantly correlated with pRNFLT (P 72 : r = 0.246, P = 0.004; P min : r = 0.219, P = 0.011). Female sex was significantly and negatively correlated with P 72 ( r = -0.206; P = 0.016) and P min ( r = -0.271; P = 0.001). Multivariable regression analyses showed that greater pRNFLT was an independent factor significantly associated with a larger P 72 ( r = 0.283; P = 0.004) and P min ( r = 0.299; P = 0.002). Female sex was an independent factor that was significantly associated with a larger P min ( r = -0.208; P = 0.022)., Conclusions: These findings indicate that PhNR amplitude is significantly associated with pRNFLT and female sex in young, healthy subjects., Translational Relevance: The amplitude of the PhNR recorded with RET eval is smaller in subjects with thinner pRNFLT not only in glaucoma patients but also in young healthy subjects., Competing Interests: Disclosure: K. Kato, None; A. Sugawara, None; R. Nagashima, None; K. Ikesugi, None; M. Sugimoto, None; M. Kondo, Novartis (F), (Copyright 2020 The Authors.)

Purpose: To compare the effective fields of the Optos 200Tx® and Clarus 500™, two ultra-widefield ophthalmoscopes, based on their ability to image branches of retinal vessel in the four retinal quadrants., Methods: Ninety retinal images from 90 patients with various eye diseases were studied. All patients had undergone 200° retinal imaging to obtain a single image of Optos (O) and the montage of two images of the Clarus (C). The highest number of traceable vessel branches in the four retinal quadrants was determined by two masked raters. An image was classified as "O > C" when the number of identifiable branch was greater in the Optos than the Clarus, as "O = C" when the number was equal and as "O < C" when the number was fewer in the Optos than the Clarus., Results: The appearance probability of "O > C" was significantly higher at the upper temporal quadrant than "O < C" ( p < 0.01 for both raters). In contrast, the appearance probability of "O < C" was significantly higher at the lower nasal quadrant than "O > C" ( p < 0.01 for both raters). There were no significant differences in the appearance probability between "O > C" and "O < C" at the other two retinal quadrants ( p > 0.50 for both raters)., Conclusions: These results demonstrate that the effective field of views was different between the two devices at different retina quadrants. Further studies are needed to clarify possible factors such as artifacts by the eyelashes, differences in the depth of focus, motion of the device, and different locations of the images on the effective field of views., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Yoshitsugu Matsui et al.)

Purpose: To determine the clinical characteristics, prognosis, and effect of anti-vascular endothelial growth factor (VEGF) agents on eyes with a central retinal vein occlusion (CRVO) with and without supernormal flicker ERG amplitudes., Methods: Forty-eight eyes of 48 patients with a CRVO were studied. Flicker ERGs were recorded from fully dilated eyes with the RETeval system. The amplitudes and implicit times of the fundamental component were analyzed. "Supernormal flicker ERGs" were defined as those whose amplitudes were ≥117% of the unaffected fellow eyes., Results: Ten of the 48 eyes (20.8%) with a CRVO showed supernormal flicker ERGs before the treatment. The difference in the implicit times of these 10 CRVO eyes and those of normal fellow eyes was <4 millisecond. There was a significant correlation between the implicit time delay and the relative amplitude in the 48 CRVO eyes. All 10 CRVO eyes with supernormal flicker ERGs had the nonischemic type of CRVO and tended to have better visual acuities than did the 28 nonischemic CRVO eyes without supernormal flicker ERGs at 12 months after the treatment (P = 0.058). The CRVO eyes with supernormal flicker ERGs had a significant amplitude reduction after a single injection of an anti-VEGF agent., Conclusions: These results indicated that the supernormal flicker ERGs can be a sign of a mild degree of ischemia, and these eyes have a better prognosis. The results also suggest that the supernormal flicker ERG may be caused by changes in the electrical activities of retinal cells following a mild increase in the VEGF levels in eyes with CRVO.

Purpose: A small, full-field flicker electroretinogram (ERG) recording system was recently developed to record flicker ERGs without mydriasis (RETeval). The device delivers a stimulus with constant retinal illuminance by adjusting the retinal luminance to compensate for changes in the pupillary area. The purpose of this study was to determine what factors affect the fundamental components of the flicker ERGs recorded by RETeval in young healthy subjects., Methods: Flicker ERGs were recorded with the RETeval system from 150 eyes of 150 young healthy subjects (age, 20-29 years). Univariate and multivariate linear regression analyses were performed to identify the factors that affected the implicit times and amplitudes of the fundamental component of the flicker ERGs. The independent variables included age, sex, refractive error, axial length, and pupillary area., Results: Multivariate regression analyses indicated that a longer axial length (P = 0.03) and larger pupillary area (P = 0.008) were independent factors that were significantly associated with longer implicit times of the fundamental component of the flicker ERGs. Multivariate regression analyses also showed that the female sex (P = 0.03) was an independent factor, which was significantly associated with larger amplitude fundamental component of the flicker ERGs., Conclusions: These results indicate that the fundamental components of the RETeval flicker ERGs are significantly affected by the axial length, pupillary area, and sex of young healthy subjects. The results also suggest that it would be better to compensate for the Stiles-Crawford effect when flicker ERGs are recorded with natural pupils.

Purpose: To determine the annual incidence of visual impairment in a Japanese population during a 10-year period., Methods: We examined the physical disability certificates issued yearly between 2004 and 2013 in Mie prefecture, Japan. During this period 2468 visually impaired people were registered under the newly defined Act on Welfare of the Physically Disabled Persons' criteria. The age, sex distribution, and causes of visual impairment were determined from the certificates., Results: The major causes of visual impairment during the ten-year period were glaucoma (23.3%), diabetic retinopathy (17.3%), retinitis pigmentosa (12.2%), macular degeneration (9.0%), chorioretinal degeneration or high myopia (7.4%), optic atrophy (5.8%), stroke or brain tumor (5.4%) and cataracts (3.7%). The incidence of glaucoma was significantly higher throughout the period (2004-2013), and that of diabetic retinopathy was lower between 2007 and 2013. The incidence of retinitis pigmentosa did not change significantly during the 10-year period. The incidence of macular degeneration tended to increase between 2004 and 2007, but it decreased significantly between 2007 and 2013., Conclusions: The results indicate that in Japan, the rates of the major causes of visual impairment altered in the most recent 10-year period reflecting the recent changes in the social background and advances in ocular and systemic treatment.

Diabetic retinopathy (DR) is a leading cause of blindness among working-age adults. Therefore, it is important to detect DR accurately during mass screening. The purpose of this study was to determine whether a small, hand-held, mydriasis-free, full-field flicker electroretinographic (ERGs) device called RETeval can be used to screen for DR. To accomplish this, we recorded full-field flicker ERGs with this device from 48 normal eyes and 118 eyes with different severities of DR in patients with diabetes mellitus (DM). This system delivered a constant flash retinal luminance by adjusting the flash luminance that compensated for changes in the pupil size. Our results showed that there were significant correlations between the severity of DR and the implicit times (P < 0.001; r = 0.55) and the amplitudes (P = 0.001; r = -0.29). When the implicit time was used for the index, the area under the receiver operating characteristic curve was 0.84 for the detection of DR, and was 0.89 for the detection of DR requiring ophthalmic treatments. These results suggest that the implicit times of the flicker ERGs recorded by the small, mydryasis-free ERG system can be used as an adjunctive tool to screen for DR.

Purpose . To describe a method of quantifying the size of the retinal hemorrhages in branch retinal vein occlusion (BRVO) and to determine the interrater and intrarater reliabilities of these measurements. Methods . Thirty-five fundus photographs from 35 consecutive eyes with BRVO were studied. The fundus images were analyzed with Power-Point® software, and a grid of 14 squares was laid over the fundus image. Raters were asked to judge the percentage of each of the 14 squares that was covered by the hemorrhages, and the average of the 14 squares was taken to be the relative size of the retinal hemorrhage. Results . Interrater reliability between three raters was higher when a grid with 14 squares was used (intraclass correlation coefficient (ICC), 0.96) than that when a box with no grid was used (ICC, 0.78). Intrarater reliability, which was calculated by the retinal hemorrhage area measured on two different days, was also higher (ICC, 0.97) than that with no grid (ICC, 0.86). Interrater reliability for five fundus pictures with poor image quality was also good when a grid with 14 squares was used (ICC, 0.88). Conclusions . Although our method is subjective, excellent interrater and intrarater reliabilities indicate that this method can be adapted for clinical use.

Purpose: We studied whether pupil size affects the flicker electroretinograms (ERGs) recorded by RETeval, a new mydriasis-free full-field flicker ERG system., Methods: We studied 10 healthy subjects. The RETeval manufacturer claims that the system delivers a constant flash retinal illuminance by adjusting the flash luminance to compensate for changes in the pupil size. Two experiments were performed. First, the flicker ERG was recorded every 3 minutes after the instillation of mydriatics. Second, the flicker ERG was recorded while the subjects wore soft contact lenses with two different artificial pupil sizes., Results: The first experiment showed that as pupil size increased, the amplitudes of the fundamental component of the flicker ERG did not change significantly, but the implicit times of the fundamental component were significantly prolonged for larger pupil sizes. There was a significant positive correlation between the pupillary area and implicit time of the fundamental component (r = 0.93, P < 0.001). The second experiment showed that the implicit times of the fundamental component in the flicker ERG were significantly longer with larger artificial pupil., Conclusions: The results suggest that the effective retinal illuminance of the stimulus delivered by the RETeval system decreases for large pupil sizes. However, in most clinical testing situations, patients' undilated pupils will likely be sufficiently small to fall within the range for which the system delivers a stimulus of constant retinal illuminance.

Purpose: The purpose of this study was to determine the causes of visual impairment in Mie prefecture during a five-year period., Subjects and Methods: The study was conducted between April 2004 and March 2009 in Mie Prefecture. 1,322 visually impaired people as defined by the Act on Welfare of Physically Disabled Persons were enrolled. We reviewed age, sex, causes of visual impairment, degree of disability and medical conditions according to their physical disability certificate., Results: The four major causes of visual impairment were glaucoma (20.3%), diabetic retinopathy (18.9%), retinitis pigmentosa (12.2%), and macular degeneration (9.1%), followed by chorioretinal degeneration, stroke or brain tumor, optic atrophy, and cataract. The average ages of the four major causes were glaucoma (77.1 years), diabetic retinopathy (65.1 years), retinitis pigmentosa (62.5 years) and macular degeneration (77.7 years)., Conclusions: The most common cause of visual impairment in Mie prefecture was glaucoma. The four major causes in Mie prefecture were the same as the results of the nation-wide investigation reported in 2006.

Purpose: We wanted to determine the intraocular pressure (IOP)-lowering effect of H-1152P by utilizing a rabbit ocular hypertension-glaucoma model and normal eyes. H-1152P is a potent, Rho-associated, coiled, coil-forming protein kinase (ROCK) inhibitor., Methods: IOPs were monitored by a pneumatonometer in New Zealand White rabbits that were given topically administered H-1152P or vehicle alone. Animals were divided into four groups followed by topical administration of 0.1, 1.0, 10, and 28 mM H-1152P. To study the IOP-lowering effects on an elevated IOP model, a rabbit ocular hypertension model was created by water loading. All studies were carried out by monitoring of IOPs on H-1152P-administered right eyes and phosphate-buffered saline (PBS)-administered left eyes., Results: In normotensive IOP rabbits, topical administration of H-1152P significantly decreased IOPs by 46.1 +/- 5.0% at 1% (28 mM) solution. This effect was dose dependent, as the maximum reduction of IOPs were observed between 60 and 90 min after topical administration (3.6 +/- 0.9 mmHg, 5.4 +/- 0.7 mmHg, 6.8 +/- 0.7 mmHg, and 7.2 +/- 1.9 mmHg at 0.1, 1.0, 10, and 28 mM H-1152P). In addition, in the rabbit ocular hypertension model, the topical administration of H-1152P (28 mM) significantly lowered IOPs starting at 30 minutes and lasting up to 300 minutes after water loading. The maximum IOP reduction, however, was observed at 90 minutes after water loading (10.6 +/- 2.3 mmHg). No serious side effects were observedin ocular tissues except for some conjunctival congestion that shortly disappeared within 3 hours., Conclusion: Topical administration of H-1152P potently decreased rabbit normotensive IOPs in a dose-dependent manner, and the duration of the IOP lowering was also elongated in a dose-dependent manner. In addition, H-1152P has a potent IOP-lowering effect on an ocular hypertension model. These result suggested that H-1152P could be a candidate for the next generation of glaucoma therapy.

Purpose: The aim of this study was to investigate the intraocular pressure (IOP)-lowering effect of a new anti-glaucoma drug, the Rho-associated protein kinase (ROCK) inhibitor, HA-1077, in a rabbit ocular hypertension model., Methods: Experiments were carried out in 18 male New Zealand white rabbits, with ocular hypertension induced by water loading. Animals were divided into three groups followed by topical administration of 1 mM, 2 mM, and 3 mM HA-1077 in the left eye. As a control, phosphate buffered saline was administered in the opposite eye., Results: After administration of HA-1077 eye drops, there was a significant time- and dose-dependent decrease of the IOP. While minor conjunctival injection was seen in a few cases, no abnormalities of the anterior chamber or fundus were observed., Conclusions: This is the first report of the effect of the ROCK inhibitor, HA-1077, on the IOP in an ocular hypertension model. Study results indicated that HA-1077 has a strong IOP-lowering effect.

Diabetic retinopathy is one of the major microvascular complications associated with diabetes mellitus, and the selective degeneration of retinal capillary pericytes is considered to be a hallmark of early retinopathy. Because glucose fluctuations commonly occur in diabetes, we hypothesized that these fluctuations will increase the endoplasmic reticulum (ER) stress and induce the unfolded protein response (UPR) in retinal pericytes. To study whether ER stress and the UPR can be induced in retinal pericytes, rat retinal capillary pericytes were cultured in different concentrations of glucose. Hypoglycemia but not hyperglycemia was found to activate UPR-specific enzymes in pericytes. Strong UPR activation leading to apoptosis was also observed when pericytes were cultured in glucose concentrations that were reduced from high to low or no glucose. These results indicate that induction of UPR is related not only to absolute concentrations but also to a shifting from higher to lower concentrations of glucose.

Cataract is a multifactorial disease, and a large variety of stressors induce cataracts. Many cataractogenic stressors and endoplasmic reticulum (ER) stressors induce the unfolded protein response (UPR) in various cell types. The UPR is known to produce reactive oxygen species (ROS) prior to the inducement of apoptosis. We investigated whether ER stressors induce the UPR in lens epithelial cells (LECs) or whole rat lenses. Our results showed that higher levels of ER stressors activated Bip/GRP78, ATF4, and caspase-12. In addition, ROS were produced, free glutathione was decreased, and apoptosis was induced. LECs in the mitotic zone were the most susceptible to the UPR while the central LECs were the most resistant. The UPR induced the production of ROS in the ER and probably in the mitochondria. The detectable ROS production in cultured lenses is limited to the epithelial cells. These findings indicate that ER stressors induce the UPR in LECs with and without the induction of apoptosis, and we conclude that the UPR is probably one of the initiating factors of many types of cataracts.

Purpose: Diabetic complications are associated with hypoglycemia and hyperglycemia. The purpose of this study was to investigate the effect of both glucose deprivation and hyperglycemia on the induction of endoplasmic reticulum (ER) stress and the subsequent activation of the unfolded protein response (UPR) that results in apoptosis in in vitro cultured lens epithelial cells (LECs) and in vivo cataract formation in galactose-fed rats., Methods: Lenses from rats fed a standard diet containing 50% galactose with or without an aldose reductase inhibitor (ARI) were investigated. Transformed human LECs were cultured in standard 10% FCS-DMEM containing various concentrations of sugar. UPR-specific proteins from both the rat lenses and lens cultures were quantified by protein blot analysis. Cell death was evaluated with TUNEL staining and ethidium homodimer-1 (EthD) dyes. Reactive oxygen species (ROS) were quantified with H2-DCF, and free glutathione (GSH) levels were measured with a commercial GSH quantification kit., Results: Increased apoptosis of the LECs was observed in the lenses of rats fed the galactose diet for 5 to 9 days, and nuclear cataracts subsequently developed in these lenses after 13 to 15 days. Protein blot analysis of the LECs from these galactose-fed rats showed higher levels of the UPR-specific proteins Bip/GRP78, ATF4, and CHOP. These LECs also demonstrated activation of the UPR-specific procaspase-12 and the increased presence of ROS, whereas GSH was reduced. Because these results indicate that the UPR is activated in LECs along with the production of ROS and apoptosis during cataract formation in the galactose-fed rats, subsequent studies were conducted to determine the role of nonenzymatic glycation, osmotic stress, and oxidative stress on these biochemical processes. In vitro cultures of human LECs showed that the UPR was induced by osmotic and oxidative stress, but not by glycation. In addition, the UPR and apoptosis in LECs was induced by glucose deprivation. The ARI blocked the induction of the UPR, cell death, and cataract formation., Conclusions: The UPR that is induced by abnormally high or low concentrations of sugar is linked to the production of ROS, increased apoptosis in LECs, and cataract formation. The inhibition of the UPR induction by ARI suggests that osmotic stress may be the primary inducer of the UPR. Modulation of the UPR pathways may offer novel methods for the development of therapeutic tools to delay cataracts.

Many cataracts are caused by unfolded protein aggregates in highly oxidized lenses, but the underlying mechanisms of their formation are poorly understood. A literature search has shown that many cataractogenic stressors are also endoplasmic reticulum (ER) stressors, which induce the unfolded protein response (UPR) in a wide range of cell types. Since the lumen of the ER is highly oxidized, ER stressors might generate unfolded protein aggregates, which activate the UPR leading to the production of reactive oxygen species (ROS) in lens epithelial cells (LECs). ROS decrease the amount of free glutathione from whole lenses and elicit a more oxidized environment, where unfolded protein aggregates are formed and grown to large protein aggregate particles to scatter light. Recently, we have shown that ER stressors, homocysteine, tunicamycin, Ca(2+) ionophore (A23187), and glucose deprivation induce the UPR in LECs. Here we hypothesize the cataractogenic stressors induce ER stress, initiate the UPR and ROS production in LECs with or without apoptosis and eventually resulted in cataracts.