Evaluating the efficacy of epinastine ophthalmic solution using a conjunctivitis allergen challenge model in patients with birch pollen allergic conjunctivitis.

BACKGROUND: The efficacy of epinastine 0.05% ophthalmic solution for pollen allergic conjunctivitis has already been shown in a conjunctival allergen challenge (CAC) test using cedar pollen as a challenge. The present study investigated the efficacy of this solution against birch pollen conjunctivitis in a CAC test. METHODS: Ten adult subjects (eight males and two females) with asymptomatic birch pollen conjunctivitis were enrolled in this study. The average age of the subjects was 41.1 years. This study was conducted during a period without birch pollen dispersion. In each subject, the epinastine 0.05% ophthalmic solution was instilled in one eye, and an artificial tear fluid was instilled in the fellow eye in a double-blind manner. Five minutes or 4 h after the drug instillation, both eyes were challenged with an optimal concentration of birch pollen, and ocular itching and conjunctival hyperemia were then graded. Tears were collected before the drug instillation and 20 min after the pollen challenge, and the histamine level was measured. RESULTS: The ocular itching scores and palpebral conjunctival hyperemia scores of the epinastine-treated eyes were significantly lower than those of the contralateral control eyes when the eyes were pretreated with the drug 4 h before the CAC. There was a significant correlation between the tear histamine level and mean ocular itching score of three time points (3, 5 and 10 min) following the CAC in the control eyes but not the epinastine-treated eyes. CONCLUSIONS: Epinastine is effective in suppressing ocular itching and conjunctival hyperemia in birch pollen conjunctivitis.

Invariant natural killer T cells play dual roles in the development of experimental autoimmune uveoretinitis.

Experimental autoimmune uveoretinitis (EAU) represents an experimental model for human endogenous uveitis, which is caused by Th1/Th17 cell-mediated inflammation. Natural killer T (NKT) cells recognize lipid antigens and produce large amounts of cytokines upon activation. To examine the role of NKT cells in the development of uveitis, EAU was elicited by immunization with a peptide from the human interphotoreceptor retinoid-binding protein (hIRBP1-20) in complete Freund's adjuvant and histopathology scores were evaluated in C57BL/6 (WT) and NKT cell-deficient mice. NKT cell-deficient mice developed more severe EAU pathology than WT mice. When WT mice were treated with ligands of the invariant subset of NKT cells (α-GalCer or RCAI-56), EAU was ameliorated in mice treated with RCAI-56 but not α-GalCer. IRBP-specific Th1/Th17 cytokines were reduced in RCAI-56-treated compared with vehicle-treated mice. Although the numbers of IRBP-specific T cells detected by hIRBP3-13/I-Ab tetramers in the spleen and the draining lymph node were the same for vehicle and RCAI-56 treatment groups, RORγt expression by tetramer-positive cells in RCAI-56-treated mice was lower than in control mice. Moreover, the eyes of RCAI-56-treated mice contained fewer IRBP-specific T cells compared with control mice. These results suggest that invariant NKT (iNKT) cells suppress the induction of Th17 cells and infiltration of IRBP-specific T cells into the eyes, thereby reducing ocular inflammation. However, in sharp contrast to the ameliorating effects of iNKT cell activation during the initiation phase of EAU, iNKT cell activation during the effector phase exacerbated disease pathology. Thus, we conclude that iNKT cells exhibit dual roles in the development of EAU.

Amelioration of experimental autoimmune uveoretinitis by inhibition of glyceraldehyde-derived advanced glycation end-product formation.

AGEs are permanently modified macromolecule derivatives that form through nonenzymatic glycation of amino groups of proteins. Glycer-AGEs are highly toxic and play an important role in the pathogenesis of chronic inflammatory diseases. However, the contribution of glycer-AGEs to the pathogenesis of uveitis is unclear. In this study, we measured serum levels of glycer-AGEs in 100 patients with endogenous uveitis (22 with HLA-B27-associated uveitis, 20 with VKH disease, 14 with Behçet's disease, and 44 with sarcoidosis) and 33 healthy volunteers. We then examined the effect of the AGE inhibitor in a mouse model of human endogenous uveitis (EAU) by continuous oral administration of pyridoxamine at 200 or 400 mg/kg/day. Regardless of the etiology, serum glycer-AGE levels were significantly higher in patients with uveitis than in healthy subjects. Treatment with 400 mg/kg pyridoxamine significantly reduced the clinical and histological severity of EAU and was accompanied by a significant decrease in serum and retinal glycer-AGE levels and suppression of translocation of NF-κB p65 into the nucleus of retinal cells. Serum glycer-AGE levels may therefore serve as a biomarker of human uveitis, as well as systemic inflammation, and may contribute to the progression of uveitis, including diabetic iritis, via the activation of NF-κB.

Improvement of visual acuity after transcorneal electrical stimulation in case of Best vitelliform macular dystrophy.

PURPOSE: To report an improvement of the visual acuity after transcorneal electrical stimulation (TES) in a case of Best vitelliform macular dystrophy (BVMD). PATIENT AND METHODS: A 26-year-old woman diagnosed with BVMD presented with reduced vision. Her best corrected visual acuity (BCVA) was reduced to 20/200 in the right eye, and TES was performed once a month for two sessions. The current of the biphasic pulses (anodic first; duration, 10 msec; frequency, 20 Hz) was delivered using a DTL-electrode, and the duration of the TES was 30 min. RESULTS: The BCVA in the right eye slowly improved after the TES, and 6 months later the BCVA was 20/25. The results of Humphrey visual field tests (VF) and multifocal ERGs (mfERGs) were only slightly changed. Two years later, the BCVA decreased, and it was improved again after another session of TES with the same parameters of the electrical pulses. CONCLUSION: The improvement of the visual acuity in our case of BVMD indicates that TES should be tried in other cases of retinal dystrophy. Further clinical and laboratory studies on TES are needed.

Biological role of lutein in the light-induced retinal degeneration.

Lutein, a xanthophyll of a carotenoid, is anticipated as a therapeutic product to prevent human eye diseases. However, its biological mechanism is still unclear. Here, we show the molecular mechanism of lutein's effect to reduce photodamage of the retina. We analyzed the light-exposed retinas of Balb/c mice given lutein-supplemented or normal diet. Visual function was measured by electroretinogram, and histological changes were observed. Immunohistochemical and immunoblot analyses were performed to analyze molecular mechanism. The reactive oxygen species induced in the retina was evaluated by fluorescent probes. In the mice after light exposure, reduction of a-wave and b-wave amplitudes in electroretinogram, indicating visual impairment, and thinning of the photoreceptor cell layer owing to apoptosis were both attenuated by lutein diet. Interestingly, γ-H2AX, a marker for double-strand breaks (DSBs) in DNA, was up-regulated in the photoreceptor cells after light exposure, but this increase was attenuated by lutein diet, suggesting that DSBs caused by photodamage contributed to the photoreceptor cell death and that this change was suppressed by lutein. Moreover, the expression of eyes absent (EYA), which promotes DNA repair and cell survival, was significantly up-regulated with lutein diet in the light-exposed retina. Therefore, lutein induced EYA for DNA repair, which could suppress DNA damage and photoreceptor cell apoptosis. Lutein reduced light-induced oxidative stress in the retina, which might contribute to promote DNA repair. The lutein-supplemented diet attenuated light-induced visual impairment by protecting the photoreceptor cells' DNA.

Mechanism of visual sensations experienced during pars plana vitrectomy under retrobulbar anesthesia.

PURPOSE: To investigate the visual sensations experienced by patients during vitrectomy under retrobulbar anesthesia. METHODS: 30 men and 45 women with a mean age of 65.3 +/- 10.6 years underwent vitrectomy under retrobulbar anesthesia for macular disease. 28 eyes had an idiopathic epiretinal membrane, 13 had an idiopathic macular hole, 32 had macular edema (17 diabetic retinopathy and 15 retinal vein occlusion), and 2 had submacular hemorrhage. 49 patients with nonmacular disease underwent similar vitrectomy procedures and were used for comparison. An interview was conducted with the patient about his/her visual sensations during and within 3 h of the vitrectomy. RESULTS: 70 (93.3%) of the patients reported seeing lights, 53 (70.7%) reported seeing colors, and 48 (64.0%) reported seeing movements or moving objects. Of the patients who reported seeing movements or moving objects, 44 (58.7%) reported seeing surgical instruments, and 5 (6.7%) saw the surgeon's fingers or hands. Patients with macular diseases tended to report more visual sensations than patients with nonmacular diseases. The patients' description and drawings appeared to arise mainly from the shadows cast by the intravitreal objects, and some patients perceived highly accurate details including the movements and color of the objects. CONCLUSIONS: Visual sensations are experienced by approximately 90% of the patients, and there may be a common mechanism by which patients perceive the intravitreal objects that are not focused on by the retina through the eye's optical system.

Inhibition of choroidal neovascularization with an anti-inflammatory carotenoid astaxanthin.

PURPOSE: Astaxanthin (AST) is a carotenoid found in marine animals and vegetables. The purpose of the present study was to investigate the effect of AST on the development of experimental choroidal neovascularization (CNV) with underlying cellular and molecular mechanisms. METHODS: Laser photocoagulation was used to induce CNV in C57BL/6J mice. Mice were pretreated with intraperitoneal injections of AST daily for 3 days before photocoagulation, and treatments were continued daily until the end of the study. CNV response was analyzed by volumetric measurements 1 week after laser injury. Retinal pigment epithelium-choroid levels of IkappaB-alpha, intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-6, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1, and VEGFR-2 were examined by Western blotting or ELISA. AST was applied to capillary endothelial (b-End3) cells, macrophages, and RPE cells to analyze the activation of NF-kappaB and the expression of inflammatory molecules. RESULTS: The index of CNV volume was significantly suppressed by treatment with AST compared with that in vehicle-treated animals. AST treatment led to significant inhibition of macrophage infiltration into CNV and of the in vivo and in vitro expression of inflammation-related molecules, including VEGF, IL-6, ICAM-1, MCP-1, VEGFR-1, and VEGFR-2. Importantly, AST suppressed the activation of the NF-kappaB pathway, including IkappaB-alpha degradation and p65 nuclear translocation. CONCLUSIONS: AST treatment, together with inflammatory processes including NF-kappaB activation, subsequent upregulation of inflammatory molecules, and macrophage infiltration, led to significant suppression of CNV development. The present study suggests the possibility of AST supplementation as a therapeutic strategy to suppress CNV associated with AMD.

Macular pigment lutein is antiinflammatory in preventing choroidal neovascularization.

BACKGROUND: Choroidal neovascularization (CNV) is a critical pathogenesis in age-related macular degeneration, the most common cause of blindness in the developed countries. The aim of the current study was to investigate the effect of lutein supplementation on the development of the murine model of laser-induced CNV together with underlying molecular mechanisms. METHODS AND RESULTS: Mice were orally pretreated with lutein daily from 3 days before laser photocoagulation until the end of the study. The index of CNV volume was significantly suppressed by the treatment with lutein, compared with vehicle-treated animals. Lutein treatment led to significant inhibition of macrophage infiltration into CNV and of the in vivo and in vitro expression of inflammation-related molecules including vascular endothelial growth factor, monocyte chemotactic protein -1, and intercellular adhesion molecule-1. Importantly, lutein suppressed IkappaB-alpha degradation and nuclear translocation of nuclear factor (NF)-kappaB p65 both in vivo and in vitro. Additionally, the development of CNV was significantly suppressed by inhibiting NF-kappaB p65 nuclear translocation, to the levels seen in the lutein treatment. CONCLUSIONS: Lutein treatment led to significant suppression of CNV development together with inflammatory processes including NF-kappaB activation and subsequent upregulation of inflammatory molecules, providing molecular evidence of potential validity of lutein supplementation as a therapeutic strategy to suppress CNV.

Eicosapentaenoic acid is anti-inflammatory in preventing choroidal neovascularization in mice.

PURPOSE: To investigate the role of eicosapentaenoic acid (EPA), the major omega-3 polyunsaturated fatty acid (PUFA), in the development of choroidal neovascularization (CNV), together with underlying molecular mechanisms. METHODS: Six-week-old C57BL/6 mice were fed with laboratory chow with 5% EPA or the omega-6 PUFA linoleic acid (LA) for 4 weeks. Laser photocoagulation was performed to induce CNV, and the volume of CNV tissue was evaluated by volumetric measurements. The expression and production of intercellular adhesion molecule (ICAM)-1, monocyte chemotactic protein (MCP)-1, vascular endothelial growth factor (VEGF) and interleukin (IL)-6 in the retinal pigment epithelium (RPE)-choroid in vivo, and stimulated b-End3 endothelial cells and RAW264.7 macrophages in vitro were evaluated by RT-PCR and ELISA. Fatty acid composition in the serum and the RPE-choroid was analyzed by gas chromatography and high-performance liquid chromatography, respectively. Serum levels of C-reactive protein (CRP), IL-6, VEGF, MCP-1, and soluble ICAM-1 were examined by ELISA. RESULTS: The CNV volume in EPA-fed animals was significantly suppressed compared with that in control mice, whereas the LA-rich diet did not affect CNV. The mRNA expression and protein levels of ICAM-1, MCP-1, VEGF, and IL-6 after CNV induction were significantly reduced in EPA-supplemented mice. In vitro, EPA application led to significant inhibition of mRNA and protein levels of ICAM-1 and MCP-1 in endothelial cells and VEGF and IL-6 in macrophages. EPA-fed mice exhibited significantly higher levels of EPA and lower levels of the omega-6 PUFA arachidonic acid in the serum and the RPE-choroid than control animals. EPA supplementation also led to significant reduction of serum levels of IL-6 and CRP after CNV induction. CONCLUSIONS: The present study demonstrates for the first time that an EPA-rich diet results in significant suppression of CNV and CNV-related inflammatory molecules in vivo and in vitro. These results suggest that frequent consumption of omega-3 PUFAs may prevent CNV and lower the risk of blindness due to age-related macular degeneration.

Patients' descriptions of visual sensations during pars plana vitrectomy under retrobulbar anesthesia.

PURPOSE: To investigate the visual sensations experienced by patients during vitrectomy under retrobulbar anesthesia. DESIGN: Cross-sectional study. METHODS: Fifty-six men and 45 women with a mean age of 62.2 +/- 11.9 years (range, 30 to 89 years) were studied. Twenty-two eyes had an idiopathic epiretinal membrane, 10 had an idiopathic macular hole, 29 had macular edema (16 resulting from diabetic retinopathy and 13 resulting from retinal vein occlusion), 14 had proliferative diabetic retinopathy, 13 had rhegmatogenous retinal detachment, four had proliferative vitreoretinopathy, and nine had other retinal diseases. The patients were questioned about their visual sensations during and within three hours after vitrectomy, which was performed under retrobulbar anesthesia using 2% lidocaine hydrochloride. Visual sensations perceived by the patients during surgery were reviewed. RESULTS: Ninety-one of the 101 patients experienced some type of visual sensation during the vitrectomy. Ninety-one (90.1%) patients reported seeing lights, 73 (72.3%) patients reported seeing one or more colors, and 57 (56.4%) patients reported seeing movements or moving objects. Of these latter 57 patients, 54 saw instruments and nine (8.9%) saw the surgeon's fingers or hands. In the 94 cases that had triamcinolone-assisted vitrectomy, 35 (37.2%) reported seeing many diffuse whirling black spots. Six patients (5.9%) found the visual experiences frightening. CONCLUSIONS: Visual sensations are experienced by approximately 90% of the patients despite full pain control, and surgeons should warn patients of these possibilities because they can be frightening. This should minimize patients' anxiety and stress during the surgery.