Posterior ond Anterior Permeability Defects? Morphologic Observations on Streptozotocin-treated Rats

Structural abnormalities of the blood-ocular barrier were examined in streptozotocin (STZ)-treated hyperglycemic rats, after 9 days, 6 months, and 10 months' duration of "diabetes," and in normoglycemic control animals using the horseradish peroxidase tracer technique combined with light and electron microscopy. The most frequent abnormalities consisted of small areas of diffuse dense staining by the tracer of (1) the retinal pigment epithelium and (2) the nonpigmented ciliary epithelium. Pigment epithelium abnormalities occurred occasionally in both groups of animals with approximately equal frequency and extent. Ciliary body abnormalities occurred also in both groups, but were frequent; statistically, the probability of these changes was not significantly different between the two groups. At the ora serrata, tracer escape was present through the retinal pigment epithelium into subretinal space and retina. Retinal vascular leakage occurred rarely and may be related to tracer toxicity rather than hyperglycemia. Thus, using the HRP method, we cannot confirm the claim that sustained STZinduced hyperglycemia causes breakdown of the blood-retinal barrier in the rat. Invest Ophthalmol Vis Sci 24:1259-1268, 1983 Streptozotocin (STZ)-induced hyperglycemia in rats has been used as an experimental model to study alterations of the blood-retinal barrier (BRB). " 6 Vitreous fluorophotometry has been employed to measure such alterations. 3 and interpreted as evidence for a breakdown of the barrier. Recovery of barrier function was ascribed to insulin administration 2 and to pancreatic islet transplantation. 3 Some morphologic studies have suspected the retinal pigment epithelium as a site of barrier breakdown. 5 * 6 Fluorescein produced large areas of relatively uniform pigment epithelial staining 5 while horseradish peroxidase (HRP) showed no difference between hyperglycemic and control rats in one study 5 but in another, showed several types of leaky RPE lesions almost exclusively in hyperglycemic animals. Materials and Methods Animals A total of 35 male hooded rats were studied at one of three intervals following the induction of hyperglycemia by STZ injection: (A) 9 days (acute stage), (B) 6 months (intermediate stage), and (C) 10 months (chronic stage). Eighteen rats received the STZ injection and became hyperglycemic while 17 of the rats served as controls. Fourteen of the 17 control rats never received STZ, three received one dose of STZ, but remained normoglycemic. STZ was administered as a freshly prepared 10% solution in citrate buffer at pH 4.5 in a dose of 65 mg/kg BW by injection into the femoral vein after a 24-hr fast. All 18 treated rats remained consistently hyperglycemic and glucosuric. Their blood glucose was measured periodically by the Eyetone-dextrostix system with the result occasionally monitored by the hexokinase enzymatic endpoint method. Urine sugar an

Aspirin Effects on Mortality and Morbidity in Patients With Diabetes Mellitus: Early Treatment Diabetic Retinopathy Study Report 14

Objectives.—This report presents information on the effects of aspirin on mortality, the occurrence of cardiovascular events, and the incidence of kidney disease in the patients enrolled in the Early Treatment Diabetic Retinopathy Study (ETDRS).Study Design.—This multicenter, randomized clinical trial of aspirin vs placebo was sponsored by the National Eye Institute.Patients.—Patients (N=3711) were enrolled in 22 clinical centers between April 1980 and July 1985. Men and women between the ages of 18 and 70 years with a clinical diagnosis of diabetes mellitus were eligible. Approximately 30% of all patients were considered to have type I diabetes mellitus, 31% type II, and in 39% type I or II could not be determined definitely.Intervention.—Patients were randomly assigned to aspirin or placebo (two 325-mg tablets once per day).Main Outcome Measures.—Mortality from all causes was specified as the primary outcome measure for assessing the systemic effects of aspirin. Other outcome variables included cause-specific mortality and cardiovascular events.Results.—The estimate of relative risk for total mortality for aspirin-treated patients compared with placebo-treated patients for the entire study period was 0.91 (99% confidence interval, 0.75 to 1.11). Larger differences were noted for the occurrence of fatal and nonfatal myocardial infarction; the estimate of relative risk was 0.83 for the entire follow-up period (99% confidence interval, 0.66 to 1.04).Conclusions.—The effects of aspirin on any of the cardiovascular events considered in the ETDRS were not substantially different from the effects observed in other studies that included mainly nondiabetic persons. Furthermore, there was no evidence of harmful effects of aspirin. Aspirin has been recommended previously for persons at risk for cardiovascular disease. The ETDRS results support application of this recommendation to those persons with diabetes at increased risk of cardiovascular disease.(JAMA. 1992;268:1292-1300