Purpose. To measure levels of various inflammatory cytokines in the aqueous humor of patients with primary open-angle glaucoma (POAG), exfoliation glaucoma (EXG), and senile cataract. Methods. Aqueous humor samples were obtained from 64 eyes of 64 Japanese subjects (POAG, 20 eyes; EXG, 23 eyes; and cataract, 21 control eyes). The levels of eight cytokines including interleukin (IL)1-β, IL-6, IL-8, transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, serum amyloid A (SAA), migration inhibitory factor (MIF), and vascular endothelial growth factor (VEGF)-A were estimated using the multiplex bead immunoassay technique. Results. Compared with the cataract group, the levels of TGF-β1, IL-8, and SAA were significantly higher in aqueous humor samples from the POAG (5.0-fold, 2.3-fold, and 11.9-fold, respectively) and EXG (12.5-fold, 4.0-fold, and 18.3-fold, respectively) groups. Except for a significant decrease in the IL-6 level in the POAG (0.23-fold) group, no other cytokine levels differed in the POAG and EXG groups compared with the cataract group. The levels of TGF-β1, IL-8, and SAA were positively correlated with each other (ρ = 0.723–0.786; P < 0.0001), the intraocular pressure (IOP) (ρ = 0.392–0.662; P < 0.0001–0.0019), and the number of glaucoma medications (ρ = 0.478–0.659; P < 0.0001–0.0001). Conclusions. Cytokine networks including TGF-β1, IL-8, and SAA in aqueous humor may have critical roles in IOP elevations in patients with open-angle glaucoma.

Purpose.: To test the safety and efficacy of topical 1.5% dexamethasone aqueous eye drops with cyclodextrin microparticles for diabetic macular edema (DME). Methods.: Nineteen eyes of 19 consecutive patients with DME were administered dexamethasone-cyclodextrin eye drops three or six times a day for 4 weeks and then observed for 4 weeks without treatment. Visual acuity, intraocular pressure, and spectral domain optical coherent tomography–measured central macular thickness recordings at weeks 0 (baseline), 4, and 8. These parameters were compared using Bonferroni-corrected paired t-tests. Results.: At weeks 0, 4, and 8, logMAR visual acuity (mean ± SD) was 0.52 ± 0.41, 0.37 ± 0.40 (P = 0.0025 vs. baseline), and 0.45 ± 0.41, respectively; central macular thickness (μm) was 512 ± 164, 399 ± 154 (P = 0.0016 vs. baseline), and 488 ± 172 (P = 0.0116 versus week 4), respectively; and intraocular pressure (mm Hg) was 15.2 ± 3.1, 17.4 ± 4.2 (P = 0.0015 vs. baseline) and 15.8 ± 4.0, respectively. At week 4, in 12 (63%) of 19 eyes, central macular thickness had decreased more than 10%, and the mean change was −20% (−65% to +10%). In 14 of 19 eyes (74%) visual acuity (logMAR) had improved more than 0.1 at week 4. No subjects showed severe adverse effects related to the eye drops. Conclusions.: Based on this short pilot study, topical dexamethasone-cyclodextrin eye drops are well tolerated, decrease central macular thickness, and improve visual acuity in DME. The results encourage comparative studies between dexamethasone cyclodextrin microparticle eye drops and other treatments for DME. (http://www.umin.ac.jp/ctr number, UMIN000001790.)

Local and systemic oxidative stress in intraocular pressure (IOP) elevation and optic nerve damage may be involved in the pathogenesis of glaucoma. We reported previously that a lower level of systemic antioxidative capacity is associated with IOP elevation in open-angle glaucoma (OAG). We assessed the correlation between the visual field sensitivity value, i.e., mean deviation (MD) and systemic levels of prooxidants and antioxidants by analyzing the blood biochemistry in 202 patients with glaucoma. Serum levels of lipid peroxides, ferric-reducing activity and thiol antioxidant activity were measured using the diacron reactive oxygen metabolite (dROM), biological antioxidant potential (BAP) and sulfhydryl (SH) tests, respectively, using a free-radical analyzer. Univariate and multivariate analyses suggested a positive correlation between MD and BAP (R = 0.005 and P = 0.0442 by a multiple regression model adjusted for seven demographic parameters), but no significant associations between the MD and the dROM (R = 0.002 and P = 0.8556) and SH tests (R = −0.001 and P = 0.8280). Use of more antiglaucoma medication and primary OAG rather than normal tension glaucoma also were associated significantly with worse visual field damage. This large and comprehensive assessment of the association between systemic redox status and visual field damage in OAG suggests that lower systemic antioxidant capacity measured by ferric-reducing activity is associated with more severe visual field damage in OAG that partly explained its roles in IOP elevation.

The involvement of local and systemic oxidative stress in intraocular pressure (IOP) elevation and optic nerve damage has been hypothesized in the pathogenesis of glaucoma. To test this, we measured the systemic levels of prooxidants and antioxidants by analyzing the blood biochemistry in patients with glaucoma. Peripheral blood samples were collected from Japanese patients with primary open-angle glaucoma (PG) (n = 206), exfoliation syndrome (EX) (n = 199), and controls (n = 126). Plasma levels of lipid peroxides, ferric-reducing activity, and thiol antioxidant activity were measured by diacron reactive oxygen metabolites (dROM), biological antioxidant potential (BAP), and sulfhydryl (SH) tests, respectively, using a free radical analyzer. In the PG, EX, and control groups, the mean ± standard deviation values were 355±63, 357±69, and 348±56 (U. Carr), respectively, for dROM; 1,951±282, 1,969±252, and 2,033±252 (µmol/L), respectively, for BAP (µmol/L); and 614±98, 584±91, and 617±99 (µmol/L), respectively, for SH. The differences in the BAP values were significant between the PG and control groups (p = 0.0062), for SH between the EX and control groups (p = 0.0017), and for SH between the PG and EX groups (p = 0.0026). After adjustment for differences in age and sex among groups using multiple regression analysis, lower BAP values were correlated significantly with PG (p = 0.0155) and EX (p = 0.0049). Higher dROM values with and without glaucoma were correlated with female gender, and lower SH values with older age. There were no significant differences between the higher (≥21 mmHg) and lower (<21 mmHg) baseline IOPs in the PG group or between the presence or absence of glaucoma in the EX group. Lower systemic antioxidant capacity that measured by ferric-reducing activity is involved in the pathogenesis of PG and EX.

The involvement of local and systemic oxidative stress in intraocular pressure (IOP) elevation and optic nerve damage has been hypothesized in the pathogenesis of glaucoma. We reported previously that the level of systemic antioxidative capacity is lower in patients with open-angle glaucoma than controls without glaucoma. Here, we assessed the correlation between IOP and systemic levels of prooxidants and antioxidants by analyzing the blood biochemistry in patients with glaucoma. Peripheral blood samples were collected from Japanese patients with primary open-angle glaucoma (n = 206), exfoliation syndrome (n = 199), and controls (n = 126). Serum levels of lipid peroxides, ferric-reducing activity, and thiol antioxidant activity were measured by diacron reactive oxygen metabolite (dROM), biological antioxidant potential (BAP), and sulfhydryl (SH) tests, respectively, using a free radical analyzer. To test the possible effect of oxidative stress on IOP levels, the patients were classified into one of four groups (Q1, Q2, Q3, and Q4, with Q1 having the lowest IOP) based on the quartile value of IOP. For this classification, the known highest IOP value in both the right and left eyes was regarded as each subject’s IOP. For comparisons among the IOP groups, the differences were calculated using one-way analysis of variance followed by post-hoc unpaired t-tests. To adjust for differences in demographic characteristic distributions, the dROM, BAP, and SH test values were compared among the IOP groups using multiple logistic regression analysis; the odds ratio (OR) of each variable was calculated with the Q1 group as the reference. The dROM and the SH levels did not differ significantly (p = 0.6704 and p = 0.6376, respectively) among the four IOP groups. The BAP levels differed significantly (p = 0.0115) among the four IOP groups; the value was significantly lower in the Q4 group (1,932 μmol/L) compared with the Q1 (2,023 μmol/L, p = 0.0042) and Q2 (2,003 μmol/L, p = 0.0302) groups and significantly lower in the Q3 group (1,948 μmol/L) than the Q1 (p = 0.0174) group. After adjustment for differences in various demographic characteristics, lower BAP values were significantly associated with the classification into higher IOP groups (Q3 group, p = 0.0261 and OR = 0.06/range; Q4 group, p = 0.0018 and OR = 0.04/range). The dROM and SH values did not reach significance in any comparisons. Lower systemic antioxidant capacity measured by ferric-reducing activity is involved in the pathogenesis of open-angle glaucoma via its roles in IOP elevation.

To evaluate the association of lysyl oxidase like 1 (LOXL1) gene variants in Japanese patients with open-angle glaucoma. We evaluated the association of three LOXL1 variants (rs1048661, rs3825942, and rs2165241) in 142 Japanese patients with exfoliation syndrome (EX; n=59) and exfoliation glaucoma (EG; n=83) as well as in 251 control patients aged 70 years or older with primary open-angle glaucoma (PG; n=40), normal tension glaucoma (NG; n=54), and cataract (CT; n=157). In comparison with the CT group, the single nucleotide polymorphisms (SNPs) showed significant association with EX, EG, and EX+EG. The odds ratio (OR)=19.71–28.23 and p=1.69x10−23-3.00x10−45 for allele T of rs1048661; OR=28.21–39.78 and p=1.77x10−8-2.42x10−22 for allele G of rs3825942; and OR=16.59–23.40 and p=4.79x10−5-1.08x10−9 for allele C of rs2165241. In comparison with the controls (CT+PG+NG), the haplotype rs1048661/rs3825942 (T/G) was significantly associated with EX+EG (p=8.27x10−44), and haplotype G/A had a significant protective effect (p=2.25x10−14). None of the three SNPs showed significant differences between the EX and EG groups or between the PG and NG groups. These SNPs are associated with exfoliation syndrome/glaucoma in the Japanese population. The risk alleles in rs1048661 and rs2165241 are different from other populations. Additional genetic or environmental risk factors other than these LOXL1 SNPs could be associated with the development of exfoliation syndrome as well as exfoliation glaucoma among exfoliation syndrome patients.