Inhibition of EGF signaling protects the diabetic retina from insulin-induced vascular leakage.

Diabetes mellitus is a disease with considerable morbidity and mortality worldwide. Breakdown of the blood-retinal barrier and leakage from the retinal vasculature leads to diabetic macular edema, an important cause of vision loss in patients with diabetes. Although epidemiologic studies and randomized clinical trials suggest that glycemic control plays a major role in the development of vascular complications of diabetes, insulin therapies for control of glucose metabolism cannot prevent long-term retinal complications. The phenomenon of temporary paradoxical worsening of diabetic macular edema after insulin treatment has been observed in a number of studies. In prospective studies on non-insulin-dependent (type 2) diabetes mellitus patients, a change in treatment from oral drugs to insulin was often associated with a significant increased risk of retinopathy progression and visual impairment. Although insulin therapies are critical for regulation of the metabolic disease, their role in the retina is controversial. In this study with diabetic mice, insulin treatment resulted in increased vascular leakage apparently mediated by betacellulin and signaling via the epidermal growth factor (EGF) receptor. In addition, treatment with EGF receptor inhibitors reduced retinal vascular leakage in diabetic mice on insulin. These findings provide unique insight into the role of insulin signaling in mediating retinal effects in diabetes and open new avenues for therapeutics to treat the retinal complications of diabetes mellitus.

Self- and registry-reported cancer in a population-based longitudinal study.

PURPOSE: To evaluate the concordance of cancer diagnosis from self- and registry reports. METHODS: Self-reported diagnosis information from participants in a cohort study was compared with linkage data from the Wisconsin Cancer Reporting System. RESULTS: Overall, there was good agreement between self- and registry-reported cancers, with 90% of all matches being considered an exact match. Concordance varied by cancer site; agreement was excellent for breast (85.4%) and prostate (78.9%) cancers. CONCLUSIONS: While self-reported cancer diagnoses for some cancers such as breast and prostate cancer are important sources of information and may be reliable substitutes when registry data are incomplete or not available, a combination of self and registry reports with mortality information may yield the most accurate information about cancer for purposes of health care planning and conducting epidemiologic studies.

Retinal vessel caliber and microvascular and macrovascular disease in type 2 diabetes: XXI: the Wisconsin Epidemiologic Study of Diabetic Retinopathy.

OBJECTIVE: To describe the relationship of retinal arteriolar and venular calibers to the long-term incidence of microvascular and macrovascular complications in people with type 2 diabetes. DESIGN: Population-based prospective study. PARTICIPANTS: One thousand three hundred seventy persons diagnosed to have diabetes at > or =30 years of age in south central Wisconsin participated in the baseline examination from 1980 to 1982, 987 in the 4-year follow-up, and 533 in the 10-year follow-up. METHODS: Computer-assisted grading was used to determine the average caliber of retinal arterioles (central retinal arteriolar equivalent [CRAE]) and retinal venules (central retinal venular equivalent [CRVE]) at all examinations. MAIN OUTCOME MEASURES: Incidence and progression of diabetic retinopathy; incidence of proliferative diabetic retinopathy and macular edema; incidence of nephropathy, neuropathy, and lower extremity amputation; and ischemic heart disease, stroke, and overall mortality. RESULTS: While adjusting for other factors, smaller CRAE was associated with the 14-year cumulative incidence of lower extremity amputation (odds ratio [OR], first vs. second to fourth quartiles, 2.20; 95% confidence interval [CI], 1.14-4.24; P = 0.02), 22-year all-cause mortality (hazard ratio [HR], 1.18; 95% CI, 1.02-1.38; P = 0.03), and 22-year stroke mortality (HR, 1.47; 95% CI, 1.04-2.07; P = 0.03) but not with the other end points. Larger CRVE was associated with the 14-year incidence of diabetic nephropathy (OR, fourth vs. first to third quartiles, 2.08; 95% CI, 1.47-2.94; P<0.001) and 22-year stroke mortality (HR, 1.71; 95% CI, 1.20-2.44; P = 0.003) but with none of the other end points. CONCLUSIONS: Retinal vessel caliber is independently associated with risk of incident nephropathy, lower extremity amputation, and stroke mortality in persons with type 2 diabetes. Measurement of retinal vessel caliber from photographs may provide additional information for the prediction of these events.

The relationship of diabetic retinopathy to preclinical diabetic glomerulopathy lesions in type 1 diabetic patients: the Renin-Angiotensin System Study.

Few epidemiological data exist regarding the correlation of anatomic measures of diabetic retinopathy and nephropathy, especially early in the disease processes. The aim of this study was to examine the association of severity of diabetic retinopathy with histological measures of diabetic nephropathy in normoalbuminuric patients with type 1 diabetes. The study included participants (n = 285) in the Renin-Angiotensin System Study (RASS; a multicenter diabetic nephropathy primary prevention trial) who were aged >/=16 years and had 2-20 years of type 1 diabetes with normal baseline renal function measures. Albumin excretion rate (AER), blood pressure, serum creatinine, and glomerular filtration rate (GFR) were measured using standardized protocols. Diabetic retinopathy was determined by masked grading of 30 degrees color stereoscopic fundus photographs of seven standard fields using the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale. Baseline renal structural parameters, e.g., fraction of the glomerulus occupied by the mesangium or mesangial fractional volume [Vv(Mes/glom)] and glomerular basement membrane width, were assessed by masked electron microscopic morphometric analyses of research percutaneous renal biopsies. No retinopathy was present in 36%, mild nonproliferative diabetic retinopathy in 53%, moderate to severe nonproliferative diabetic retinopathy in 9%, and proliferative diabetic retinopathy in 2% of the cohort. Retinopathy was not related to AER, blood pressure, serum creatinine, or GFR. All renal anatomical end points were associated with increasing severity of diabetic retinopathy, while controlling for other risk factors. These data demonstrate a significant association between diabetic retinopathy and preclinical morphologic changes of diabetic nephropathy in type 1 diabetic patients.

Retinal vascular caliber in persons with type 2 diabetes: the Wisconsin Epidemiological Study of Diabetic Retinopathy: XX.

PURPOSE: To describe retinal vascular caliber and correlates in people with type 2 diabetes. DESIGN: Population-based study. PARTICIPANTS: Thirteen hundred seventy persons diagnosed to have diabetes at or after 30 years of age in an 11-county area in south central Wisconsin from 1980 to 1982. METHODS: Retinal photographs of 7 standard fields were taken; light box grading was done to determine retinopathy severity. Computer-assisted grading was done from a digitized image of field 1 to determine the central retinal arteriolar equivalent (CRAE; arteriolar caliber) and central retinal venular equivalent (CRVE; venular caliber). MAIN OUTCOME MEASURES: Retinal arteriolar and venular calibers. RESULTS: In multivariable analyses in persons with panretinal photocoagulation excluded, while controlling for refractive error, CRAE was associated independently with age (per 10 years, beta = -2.0 microm), mean arterial blood pressure (BP) (per 10 mmHg, beta = -2.2 microm), smoking status (current vs. never smoked, beta = 5.6 microm), and intraocular pressure (IOP) (per 1 mmHg, beta = 0.2 microm). The CRVE was associated independently with age (per 10 years, beta = -2.5 microm), mean arterial BP (per 10 mmHg, beta = -2.1 microm), smoking status (current vs. never smoked, beta = 11.6 microm), pack-years smoked (per 10 pack-years, beta = 1.0 microm), body mass index (per kg/m2, beta = 0.3 mm), pulse rate (per 10 beats/minute, beta = 1.5 microm), retinopathy severity (per 1 level, beta = 1.05 microm), and IOP (per 10 mmHg, beta = -0.5 microm). Smaller CRAEs and CRVEs were found in eyes with panretinal photocoagulation treatment than in eyes without such treatment. CONCLUSIONS: In persons with type 2 diabetes, variations in retinal vascular caliber are related to various systemic and ocular factors. Understanding these relationships may provide further insights into early retinal vascular changes in diabetes.

The relation of ambulatory blood pressure and pulse rate to retinopathy in type 1 diabetes mellitus: the renin-angiotensin system study.

PURPOSE: To examine the association of ambulatory blood pressure (ABP) and ambulatory pulse rate (APR) with diabetic retinopathy (DR) in persons with type 1 diabetes in the Renin-Angiotensin System Study (RASS), a multicenter primary diabetic nephropathy (DN) prevention trial. DESIGN: Cross-sectional study. PARTICIPANTS: One hundred ninety-four normotensive RASS participants in 3 centers who are 16 years of age or older with type 1 diabetes mellitus (DM) of 2 to 20 years' duration. METHODS: Ambulatory blood pressure and APR were monitored using standardized protocols. Patients were defined as nondippers if the night-to-day ratios for both systolic and diastolic blood pressures were >0.9. Diabetic retinopathy was determined by masked grading of 30 degrees color stereoscopic fundus photographs of 7 standard fields using the Early Treatment Diabetic Retinopathy Study severity scale. MAIN OUTCOME MEASURE: Severity of DR. RESULTS: No DR was present in 32%, mild nonproliferative DR (NPDR) was present in 55%, and moderate to severe NPDR or proliferative DR was present in 13% of the cohort. Neither 24-hour systolic ABP or diastolic ABP, daytime systolic or diastolic ABP, nor nighttime diastolic ABP were related to severity of DR. Statistically significant associations were found between nighttime systolic ABP and mean ABP and DR. Among those with no DR, 19% were nondippers; for those with mild NPDR, 28% were nondippers; and for those with severe NPDR or proliferative DR, 36% were nondippers (P = 0.08). The ratio of nighttime to daytime APR, but not the 24-hour APR or daytime or nighttime APR, was related positively to the severity of DR. In multivariable analyses, only the nighttime systolic ABP was related to severity of DR (P<0.05). CONCLUSIONS: These data suggest that ABP, especially during the night, may provide a better measure than clinical BP regarding the relationship of BP to the severity of retinopathy in normotensive persons with type 1 DM without clinical DN.

Ankle-brachial index and the prevalence of age-related maculopathy.

PURPOSE: To examine the association of ankle-brachial blood pressure index (ABI) with prevalence of age-related maculopathy (ARM). DESIGN: A cross-sectional cohort study. METHODS: ABI was measured in 2447 subjects aged 53 to 97 years. ARM was determined from 30-degree color stereoscopic fundus photographs. RESULTS: Low ABI (< or =0.9) was present in 5.4% of subjects. Early ARM was present in 22.1% of subjects with and 18.8% without low ABI. Late ARM was present in 5.3% of subjects with and 1.7% without low ABI. This result was not statistically significant. CONCLUSIONS: Low ABI does not appear to be a risk factor for ARM.

Ten-year incidence of self-reported erectile dysfunction in people with long-term type 1 diabetes.

OBJECTIVE: The purpose of this report is to examine the overall 10-year incidence of erectile dysfunction and its relationships to other characteristics in men with younger onset diabetes. METHODS: In a population-based cohort study in southern Wisconsin, a 10-year cumulative incidence of reported erectile dysfunction was obtained in men who were 21 years of age or older, were less than 30 years of age at diagnosis of diabetes, had 10 or more years of diabetes, and were taking insulin (n=264). RESULTS: Twenty-five percent developed erectile dysfunction. The incidence of erectile dysfunction increased with age (from 10.2% in those 21-29 years of age to 48.6% in those 40 years of age or older, P<.0001) and with increasing duration of diabetes (from 16.0% in those with 11-14 years of diabetes at baseline to 38.2% in those with 25 or more years of diabetes, P=.01). In multivariate analyses, incidence of erectile dysfunction was associated with age [odds ratio (OR) 1.10, 95% confidence interval (CI), 1.06, 1.14], untreated hypertension (OR 5.01, 95% CI, 2.05, 12.27), and a history of smoking (OR 2.41, 95% CI, 1.09, 5.30) at baseline. CONCLUSIONS: These data suggest that cessation of cigarette smoking and tighter control of blood pressure might prevent or delay the onset of erectile dysfunction in persons with type 1 diabetes.

Retinal vascular changes and 20-year incidence of lower extremity amputations in a cohort with diabetes.

OBJECTIVE: To examine the association of retinal vascular changes with the incidence of lower extremity amputations (LEAs) in a cohort with diabetes mellitus. METHODS: Baseline examinations were performed in a cohort of 996 persons with diabetes diagnosed before the age of 30 years and using insulin. History of LEA was obtained at baseline and at 4, 10, 14, and 20 years. The cumulative 20-year incidence of first LEA was calculated by the product-limit method in 906 persons with follow-up information. Retinal arterioles and venules were measured on digitized fundus photographs obtained at baseline by a standard protocol. Generalized arteriolar narrowing was defined as the lowest 25% of the arteriole-venule ratio. Measurements were obtained in at least one eye for 820 persons. Focal arteriolar narrowing and arteriovenous nicking were also determined from fundus photographs by a standard protocol. RESULTS: The 20-year cumulative incidence of LEAs was 9.9%. The unadjusted risk of undergoing a LEA was higher in persons with generalized arteriolar narrowing than in those without it (15.7% vs 5.7%; odds ratio [OR], 3.08; 95% confidence interval [CI], 1.60-4.68), and in persons with focal narrowing (33.1% vs 6.8%; OR, 5.59; 95% CI, 3.27-9.54). The results for arteriovenous nicking were not significant. With control for age, sex, levels of glycosylated hemoglobin, diastolic blood pressure, and history of ulcers of the feet, the relationships were attenuated but still statistically significant for both generalized narrowing (OR, 1.89; 95% CI, 1.06-3.35) and focal narrowing (OR, 3.56; 95% CI, 1.87-6.78). CONCLUSION: In persons with diabetes, generalized as well as focal retinal arteriolar narrowing may reflect damage to the microvasculature, which manifests itself elsewhere in the body as a need for LEAs.

Cardiovascular disease, mortality, and retinal microvascular characteristics in type 1 diabetes: Wisconsin epidemiologic study of diabetic retinopathy.

BACKGROUND: Diabetic retinopathy and proteinuria, manifestations of microvascular abnormalities, occur early in the course of diabetes mellitus; in contrast, macrovascular cardiovascular complications usually occur later. Retinal vessel characteristics may be informative about risk of cardiovascular disease in persons with diabetes. We evaluated this in a longitudinal cohort study of persons with type 1 diabetes. METHODS: The population consisted of persons with type 1 diabetes who were receiving care in 11 counties in Wisconsin. Subjects (n = 996) were examined at baseline (1980-1982), and 4, 10, 14, and 20 years later. Evaluations included medical history and measurements of height, weight, blood pressure, and glycosylated hemoglobin. Fundus photographs were graded for diabetic retinopathy at baseline, and the same photographs were graded later for the diameters of retinal blood vessels. At each examination, a history of cardiovascular disease events since the last examination (and prior to baseline) was obtained. Mortality was monitored yearly. RESULTS: The 20-year age-adjusted cumulative incidences were 18.1% for angina, 14.8% for myocardial infarction, and 5.9% for stroke. Severity of diabetic retinopathy was associated with angina and stroke. Arteriovenous ratio was associated with myocardial infarction. Of 273 deaths, 176 involved heart disease. The severity of retinopathy and arteriovenous ratio was associated with heart disease mortality. Nephropathy was more informative about the cardiovascular end points than were the blood vessel characteristics. CONCLUSIONS: Incidences of cardiovascular disease, including mortality, were common in people with type 1 diabetes during a 20-year interval. Retinal vascular characteristics were associated with these end points, but this association was confounded by nephropathy.

Incidence of dry eye in an older population.

OBJECTIVES: To estimate the 5-year incidence of dry eye and to examine its association with risk factors. METHODS: The population of Beaver Dam, Wis, that was 43 to 84 years of age (n = 5924) was examined in the 1988-1990 (n = 4926), 1993-1995 (n = 3722), and 1998-2000 study phases (n = 2962). At the 1993-1995 examination, when dry eye data were first collected, and the 1998-2000 examination, 2783 subjects participated, and 44 were interviewed. Of these, 2802 provided dry eye history. The incidence cohort consisted of 2414 subjects not reporting dry eye in the 1993-1995 examination. Risk factor information was ascertained at the 1993-1995 examination and included demographics, medical history, cardiovascular disease risk factors, medications, and lifestyle factors. RESULTS: During the 5-year interval between examinations, a history of dry eye developed in 322 of 2414 subjects, for an incidence of 13.3% (95% confidence interval [CI], 12.0%-14.7%). Incidence was significantly associated with age (P<.001). After adjusting for age, incidence was greater in subjects with a history of allergy or diabetes, who used antihistamines or diuretics, and with poorer self-rated health (P<.05). Age-adjusted incidence was less in subjects using angiotensin-converting enzyme inhibitors or consuming alcohol (P<.05). It was not significantly associated with sex, blood pressure, hypertension, serum total or high-density lipoprotein cholesterol level, body mass index, history of arthritis, gout, osteoporosis, cardiovascular disease, thyroid disease, or smoking, and use of caffeine, vitamins, antianxiety medications, antidepressants, calcium channel blockers, or anticholesterolemics. CONCLUSIONS: Incidence of dry eye is substantial. However, there are few associated risk factors. Some drugs (eg, diuretics and antihistamines) are associated with a greater risk, whereas others (angiotensin-converting enzyme inhibitors) are associated with lower risk.

Retinal emboli and cardiovascular disease: the Beaver Dam Eye Study.

OBJECTIVE: To describe the 10-year incidence of retinal emboli, associated risk factors, and relationship of retinal emboli at baseline to stroke and ischemic heart disease mortality. METHODS: The Beaver Dam Eye Study is a large (N = 4926) population-based study of persons 43 to 86 years of age at the time of the baseline examination. Retinal emboli were detected at baseline (1988-1990) and at a 5-year (1993-1995) and 10-year (1998-2000) follow-up by grading of stereoscopic 30 degrees color fundus photographs using standardized protocols. Cause-specific mortality was determined from death certificates. RESULTS: The 10-year cumulative incidence of retinal emboli was 1.5%. After adjustment for age and sex, the incidence of retinal emboli was associated with increased pulse pressure (odds ratio [OR] [fourth vs first quartile range], 2.42; 95% confidence interval [CI], 0.98-5.97; P =.03, for test of trend), higher serum total cholesterol level (OR, 2.77; 95% CI, 1.06-7.23; P =.03), higher white blood cell count (OR, 2.28; 95% CI, 1.04-4.96; P =.05), smoking status (OR [current vs never-smoker], 4.60; 95% CI, 2.08-10.16; P<.001), and a history of coronary artery bypass surgery (OR, 7.17; 95% CI, 3.18-16.18; P<.001) at baseline. After controlling for age, sex, and systemic factors, a significantly higher hazard of dying with a mention of stroke on the death certificate was found in people with retinal emboli (hazard ratio, 2.40; 95% CI, 1.16-4.99) compared with those without. CONCLUSIONS: We found associations of smoking and cardiovascular disease with the incidence of retinal emboli. Persons with retinal emboli are also at increased risk of stroke-related death.

The prevalence of diabetic retinopathy among adult type 1 diabetic persons in the United States.

OBJECTIVE: To estimate the US prevalence of diabetic retinopathy (DR) among persons with type 1 diabetes mellitus (DM). METHODS: Prevalence data from the New Jersey 725 and Wisconsin Epidemiologic Study of Diabetic Retinopathy were used to estimate the prevalence of DR by age, gender, and race among persons 18 years and older having type 1 DM diagnosed before age 30 years. Severity of DR was determined via masked grading of 7-field stereoscopic fundus photographs. Any DR was defined as retinopathy severity level of 14 or more; and vision-threatening retinopathy, as retinopathy severity level of 50 or more, the presence of clinically significant macular edema, or both. The estimates of the prevalence of DR among persons with type 1 DM were applied to the estimated number of persons with type 1 DM diagnosed before age 30 years in the 2000 US population to obtain prevalence estimates of DR due to type 1 DM in the general population. RESULTS: Among 209 million Americans 18 years and older, an estimated 889 000 have type 1 DM diagnosed before age 30 years. Among persons with type 1 DM, the crude prevalences of DR of any level (74.9% vs 82.3% in black and white persons, respectively) and of vision-threatening retinopathy (30.0% vs 32.2%, respectively) are high. The prevalence of DR due to type 1 DM diagnosed before age 30 years in the general population 18 years and older is estimated at 767 000 persons having DR of any level (0.37%), and 376 000 persons having vision-threatening retinopathy (0.18%). CONCLUSION: Retinopathy due to type 1 DM is an important public health problem in the United States, affecting 1 per 300 persons 18 years and older, and 1 per 600 persons with advanced, vision-threatening retinopathy.

The prevalence of diabetic retinopathy among adults in the United States.

OBJECTIVE: To determine the prevalence of diabetic retinopathy among adults 40 years and older in the United States. METHODS: Pooled analysis of data from 8 population-based eye surveys was used to estimate the prevalence, among persons with diabetes mellitus (DM), of retinopathy and of vision-threatening retinopathy-defined as proliferative or severe nonproliferative retinopathy and/or macular edema. Within strata of age, race/ethnicity, and gender, US prevalence rates were estimated by multiplying these values by the prevalence of DM reported in the 1999 National Health Interview Survey and the 2000 US Census population. RESULTS: Among an estimated 10.2 million US adults 40 years and older known to have DM, the estimated crude prevalence rates for retinopathy and vision-threatening retinopathy were 40.3% and 8.2%, respectively. The estimated US general population prevalence rates for retinopathy and vision-threatening retinopathy were 3.4% (4.1 million persons) and 0.75% (899 000 persons). Future projections suggest that diabetic retinopathy will increase as a public health problem, both with aging of the US population and increasing age-specific prevalence of DM over time. CONCLUSION: Approximately 4.1 million US adults 40 years and older have diabetic retinopathy; 1 of every 12 persons with DM in this age group has advanced, vision-threatening retinopathy.

Detection of age-related macular degeneration using a nonmydriatic digital camera and a standard film fundus camera.

OBJECTIVE: To compare gradings of lesions associated with age-related macular degeneration (AMD) from digital and stereoscopic film images. DESIGN: Instrument validation study. PARTICIPANTS: Sixty-two subjects (124 eyes) with varying degrees of AMD, including no AMD. METHODS: Images of the optic disc and macula were taken using a 45 degrees digital camera (6.3 megapixels) through dark-adapted pupils and pharmacologically dilated pupils. In addition, 30 degrees stereoscopic retinal film images were taken through pharmacologically dilated pupils of the same eyes. All images were graded for drusen size, type, and area; pigmentary abnormalities; geographic atrophy; and neovascular lesions using the modified Wisconsin Age-Related Maculopathy Grading System. Exact agreement and unweighted kappa scores were calculated for paired gradings resulting from digital and film images. MAIN OUTCOME MEASURE: Agreement between gradings obtained from stereoscopic slide transparencies and digital nonstereoscopic images. RESULTS: Exact agreement between gradings of digital and stereoscopic film images taken through pharmacologically dilated pupils was 91% (kappa = 0.85) for the categories of none, early AMD, and late AMD. Exact agreement for gradings of digital images taken through dark-adapted pupils compared with gradings of film images was 80% (kappa = 0.69). Exact agreement for gradings of digital images captured through dark-adapted and pharmacologically dilated pupils was 86% (kappa = 0.78). In addition, kappa scores for agreement between different approaches for individual lesions were moderate to almost perfect. CONCLUSIONS: Gradings resulting from high-resolution digital images, especially when the pupil is pharmacologically dilated, are comparable with those resulting from film-based images. We conclude that digital imaging of the retina is useful for epidemiological studies of AMD.

The relation of retinal vessel caliber to the incidence and progression of diabetic retinopathy: XIX: the Wisconsin Epidemiologic Study of Diabetic Retinopathy.

OBJECTIVE: To describe the relation of retinal arteriolar and venular caliber to the incidence and progression of diabetic retinopathy in people with type 1 diabetes mellitus. DESIGN: Incidence findings in a population-based study of diabetic retinopathy in Wisconsin. Participants included 996 persons diagnosed as having diabetes mellitus before 30 years of age who took insulin and underwent the baseline examination, 891 in the 4-year follow-up, 765 in the 10-year follow-up, and 634 in the 14-year follow-up. Retinal photographs of 7 standard fields were taken at all examinations. Computer-assisted grading was performed from a digitized image of field 1 to determine the average diameter of retinal arterioles and venules and their ratio. Main outcome measures included incidence and progression of retinopathy, incidence of proliferative retinopathy, and macular edema. RESULTS: While adjusting for other factors, larger arteriolar (relative risk [RR] for the fourth vs first quartile range, 2.04; 95% confidence interval [CI], 1.20-3.47; test of trend, P =.008) and venular diameters (RR, 2.33; 95% CI, 1.37-3.95; test of trend, P =.005) were associated with greater 4-year progression of retinopathy. Larger venular diameters (RR, 4.28; 95% CI, 1.50-12.19; test of trend, P =.006) but not arteriolar diameters were associated with greater 4-year incidence of proliferative retinopathy. In multivariable analyses, arteriolar and venular calibers were not associated with the 4-year incidence of retinopathy. While adjusting for other factors, arteriolar and venular calibers were not associated with incidence of macular edema at 4 years. There were few associations of arteriolar or venular caliber with the 10- or 14-year incidence or the progression of retinopathy. CONCLUSIONS: Larger arteriolar and venular caliber, independent of retinopathy severity level, is related to the progression of retinopathy, and larger venular caliber is associated with the 4-year incidence of proliferative retinopathy. Caliber of retinal vessels is not associated with incident retinopathy. These data suggest a quantitative measure of retinal vascular caliber provides additional information regarding risk for progression of retinopathy.

Retinal emboli and cardiovascular disease: the Beaver Dam Eye Study.

PURPOSE: To describe the 10-year incidence of retinal emboli, the associated risk factors, and the relationship of retinal emboli to stroke and ischemic heart disease mortality. METHODS: The Beaver Dam Eye Study (n = 4,926) is a population-based study of persons 43 to 86 years of age. Retinal emboli were detected at baseline (1988-1990) and at a 5-year (1993-1995) and a 10-year (1998-2000) follow-up by grading of stereoscopic 30 degrees color fundus photographs using standardized protocols. Cause-specific mortality was determined from death certificates. RESULTS: The 10-year cumulative incidence of retinal emboli was 1.5%. While adjusting for age and sex, the incidence of retinal emboli was associated with increased pulse pressure (odds ratio [OR] 4th versus 1st quartile range, 2.42; 95% confidence interval (CI), 0.98-5.97; P test of trend = .03), higher serum total cholesterol (OR, 2.77; 95% CI, 1.06-7.23; P = .03), higher leukocyte count (OR, 2.28; 95% CI, 1.04-4.96; P = .05), smoking status (OR current versus never smoker, 4.60: 95% CI, 2.08-10.16; P < .001), and a history of coronary artery bypass surgery (OR, 7.17; 95% CI, 3.18-16.18; P < .001) at baseline. While controlling for age, sex, and systemic factors, a significantly higher hazard of dying with a mention of stroke on the death certificate was found in people with retinal emboli (hazard ratio, 2.40; 95% CI, 1.16-4.99) compared with those without. CONCLUSIONS: The data show an association of smoking and cardiovascular disease with the incidence of retinal emboli. Also, persons with retinal emboli are at increased risk of stroke-related death.

Postural blood pressure changes and associated factors in long-term Type 1 diabetes: Wisconsin Epidemiologic Study of Diabetic Retinopathy.

PURPOSE: To describe the frequency of orthostatic hypotension and hypertension and associations with risk factors in a cohort of persons with long-term Type 1 diabetes (n=440) participating in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. METHODS: Evaluations included detailed medical history, electrocardiography (ECG), and laboratory tests. Blood pressure (BP) was measured in supine and standing positions. Standing decrease in systolic (SBP) or diastolic (DBP) BP of at least 20 or 10 mmHg, respectively, was defined as orthostatic hypotension; increase of SBP from <140 to >or=140 mmHg or DBP from <90 to >or=90 mmHg was defined as orthostatic hypertension. RESULTS: Prevalence of orthostatic hypotension and orthostatic hypertension was 16.1% and 15.2%, respectively. Some ECG measurements of cardiac autonomic dysfunction were significantly associated with orthostatic hypotension. Association between SBP and orthostatic hypotension and orthostatic hypertension were significant [odds ratio, 1.02 (95% confidence interval, or CI, 1.01-1.05) and 1.02 (95% CI, 1.01-1.04), per 1 mmHg, respectively] after adjusting for confounders. Interaction between SBP and age was observed. SBP was significantly associated with orthostatic hypotension and orthostatic hypertension in people

Long-term incidence of dry eye in an older population.

PURPOSE: To estimate the ten-year incidence of dry eye in an older population and examine its association with various risk factors. METHODS: The 43 to 86 year old population of Beaver Dam, WI, was examined in 1988 to 1990 (n = 4926) and 1993 to 1995 (n = 3722). Dry eye data were first collected in 1993 to 1995. Subsequent examinations or interviews occurred in 1998 to 2000 (n = 2827) and 2003 to 2005 (n = 2124). The incidence cohort comprised 2414 subjects not reporting dry eye in 1993 to 1995. Risk factor information, ascertained in 1993 to 1995, included demographics, medical history, cardiovascular disease risk factors, medications, and life-style factors. Ten-year cumulative incidence was estimated by the product-limit method. RESULTS: Over the 10-year period, 482 subjects developed a history of dry eye for an incidence of 21.6% (95% confidence interval, 19.9 to 23.3%). Incidence increased significantly (p < 0.001) with age. Incidence was greater in women (25.0%) than men (17.2%, p < 0.001). After adjusting for age, incidence was greater (p < 0.05) in subjects with arthritis, allergy or thyroid disease not treated with hormone, using antihistamines, antianxiety medications, antidepressants, oral steroids or vitamins, and poorer self-rated health. Incidence was less (p < 0.05) in subjects consuming alcohol. It was not significantly associated with blood pressure, hypertension, serum total or high density lipoprotein cholesterol, body mass, diabetes, gout, osteoporosis, cardiovascular disease, smoking, caffeine use, or taking calcium channel blockers or anticholesterol medications. In a multivariable model with time-varying covariates, increased incidence was associated with age, female gender, poorer self-rated health, antidepressant or oral steroid use, and thyroid disease untreated with hormone. It was lower for those using angiotensin-converting enzyme inhibitors or with a sedentary lifestyle. CONCLUSIONS: Dry eye incidence is substantial. However, there are few associated risk factors. Some drugs (antihistamines, antianxiety drugs, antidepressants, oral steroids) are associated with greater risk, while angiotensin-converting enzyme inhibitors may be associated with lower risk.