A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes.

PURPOSE: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy. METHODS: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. RESULTS: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10-9 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10-8 and 1.23 × 10-8 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429). CONCLUSION: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.

Acute aminoglycoside retinal toxicity in vivo and in vitro.

PURPOSE: Intentional and inadvertent intraocular administration of aminoglycosides is associated with cases of retinal toxicity. Clinical manifestations resemble a vaso-occlusive event and include edema, intraretinal hemorrhage, and nonperfusion detected by fluorescein angiogram. This study was conducted to measure the retinal function in avascular and isolated perfused retinas to separate vascular and neurologic effects of gentamicin. Enhanced understanding of the mechanism of gentamicin toxicity may lead to development of aminoglycosides that can be used to treat ophthalmic infections without retinal damage. METHODS: Whole animals and isolated rabbit and rat retina preparations were used to study the dose dependence and reversibility of toxicity on the ERG, with a 1- and a 10-mg/mL solution of gentamicin. The amplitude and implicit times of the a-, b-, and c-waves were measured before, during, and after exposure to the drug. RESULTS: In whole-animal ERG studies, intraocular administration of gentamicin eliminated the b-wave but left the a-wave intact. The c-wave was reduced in amplitude. Histopathologic evaluation demonstrated diffuse disruption of the nerve fiber layer and the inner plexiform layers. Isolated retinal studies showed that the b-wave was reduced in amplitude in the presence of low-dose gentamicin (1 mg/mL) and completely eliminated by high-dose gentamicin (10 mg/mL). This effect was reversible for short-term exposure to gentamicin. CONCLUSIONS: The results indicate that the initial loss of function due to exposure to aminoglycoside antibiotics is independent of the vascular supply. Elimination of the b-wave was dose dependent and reversible, indicating that a component of gentamicin toxicity is mediated through pathways other than vascular supply. Short-term effects are reversible, suggesting a receptor-mediated process.

Oscillatory potential analysis and ERGs of normal and diabetic rats.

PURPOSE: To identify and characterize the early alterations of the ERG oscillatory potentials (OPs) under conditions of poor glycemic control associated with diabetes in an animal model. To characterize and correlate the a- and b-wave properties of the ERGs of diabetic animals in parallel with the changes in oscillatory potentials. METHODS: Blood sugars, weights, and ERGs were measured for a group of rats each week for 3 weeks to obtain baseline information. A single injection of streptozotocin was given to the experimental animals. Weights, blood sugar, glycosylated hemoglobin, and detailed ERGs were recorded weekly for up to 12 weeks in control and experimental animals. RESULTS: OP kinetics were found to be inherently related to amplitude. Amplitude-matched OPs were delayed in diabetic animals when compared with baseline data from the same animal. The kinetics of OPs in control animals stayed the same or were slightly accelerated relative to their baseline values. For a given recording condition, OP kinetics were very stable over time and this stability was not disturbed in diabetic animals. Diabetic animals showed a small but significant delay in the a-wave, but no change in b-wave timing. The sensitivity of the b-wave was reduced twofold, but that of the a-wave was not changed. CONCLUSIONS: OPs have been used to evaluate retinal function in both diabetic models and patients. The comparison of amplitude-matched OPs is a robust determinant of changes in kinetics. Researchers and clinicians who use OPs may wish to consider the relationship between OP amplitude and kinetics to avoid confounding assessments of abnormalities. The amplitude versus kinetics relationship does not change form in diabetic animals; it is merely shifted (delayed) on the time axis.

Human oscillatory potentials: intensity-dependence of timing and amplitude.

Oscillatory potentials (OPs) have been described as reduced in amplitude or delayed in diabetic retinopathy, glaucoma, and vascular occlusions. Although OPs are thought to have useful diagnostic applications, some of their basic physiologic properties remain to be fully described. In the present study, we examined the relationship between the timing and amplitude of OPs and stimulus intensity. Five normal volunteers had one eye anesthetized and dilated. Dark-adapted full-field ERGs were recorded to white stimuli of 0.0125-40 cd s/m(2). The timing of the OPs was measured as the sum of the time to the peak (TTP) of four peaks beginning at 15 ms after the stimulus. The amplitude was taken as the sum of the amplitudes of those same peaks. As an alternative value, OP strength was represented by the area under the OP curve or power around 150 Hz (+/-30 Hz) in the frequency domain. The OP timing, as measured by TTP, was found to be inversely related to stimulus intensity. OP-amplitudes grew with intensity, but then declined for stimulus intensities above about 4 cd s/m(2). At bright light intensities, the TTP continued to shorten, yet amplitudes, power, and area all declined. Individual OPs behaved similarly and reflected the overall response pattern of the group as a whole. Brighter stimuli produced larger, faster OPs for stimulus strengths up to the intensity standard used to produce OPs (3.5 cd s/m(2)). We have extended the range of stimuli to some 10-fold higher than the ISCEV standard for producing OPs and found that the timing continued to accelerate but that OP-amplitudes, OP-area, and OP-power all decline at higher stimulus intensities. These alternative measures of OP energy are easily measured and may be useful for further studies.

Vitreal penetration of oral moxifloxacin in humans.

PURPOSE: To investigate the vitreal penetration of moxifloxacin after oral administration. DESIGN: Prospective, nonrandomized clinical series. METHODS: Twenty-four patients (mean age = 62.8 years) undergoing elective pars plana vitrectomy were assigned to a dosing group: control (n = 3), which received no medication; single-dose (n = 11), which received one 400 mg oral dose of moxifloxacin 3 hours before surgery; and five-dose (n = 10), which received one 400 mg dose on each of the 4 days preceding surgery and a fifth dose 3 hours before surgery. Vitreous samples were obtained and analyzed. RESULTS: Control, below quantifiable levels; single-dose, 0.572 +/- 0.239 microg/mL; and five-dose, 1.200 +/- 0.645 microg/mL. CONCLUSIONS: Five doses of oral moxifloxacin lead to higher intravitreal drug concentrations than single-dose administration. Both regimens, however, achieve levels that exceed the MIC90 of many bacteria implicated in postoperative endophthalmitis.