Showing papers by "Ronald Klein published in 1991"

Cause-specific mortality in a population-based study of diabetes.

Abstract: BACKGROUND. Mortality from vascular diseases has been reported to be high in diabetic persons. METHODS. To evaluate mortality from these and other specific causes, we examined cause-specific age-sex standardized mortality ratios in a geographically defined population of younger onset (diagnosed before age 30 and taking insulin, n = 1200) and older onset (diagnosed after age 30, n = 1772) diabetic persons followed for 8.5 years. Cause of death was determined from death certificates. RESULTS. In younger onset persons, age-sex standardized mortality ratios were significantly high (P less than .05) for all causes of death (7.5) as well as for diabetes (191), all heart disease (9.1), ischemic heart disease (10.1), other heart disease (6.3), nephritis and nephrosis (41.2), accidents (2.9), and all other causes (3.2). In older onset persons, age-sex standardized mortality ratios were significantly high for all causes of death (2.0) as well as for diabetes (16.8), all heart disease (2.3), ischemic heart disease (...

Cost-effectiveness of strategies for detecting diabetic retinopathy.

Abstract: A computer model has been developed to determine cost-effectiveness of screening and treatment for diabetic retinopathy from a societal viewpoint. This model was used to evaluate biannual and annual screening programs using ophthalmoscopy, fundus photography with a "nonmydriatic camera," and photography with a "mydriatic camera." Computations were performed for three subpopulations formed by patients with younger onset diabetes (age at diagnosis less than 30 years) of 5 years or more duration, with older onset diabetes (age at diagnosis greater than or equal to 30 years) who are taking insulin, and with older onset diabetes not taking insulin. Population characteristics are from a well-described southern Wisconsin population where data are available, but the computer model may be specialized to other population. Generally costs of screening programs appear to be recovered by avoided costs of blindness in the population subgroups taking insulin; however, the cost of screening programs generally are not recovered by avoiding costs of blindness in the older onset population subgroup not taking insulin. It was estimated that supplying annual examination with mydriatic fundus photography as a screening program to a cohort of 1,000 diabetics from the younger onset population who have been diagnosed at least 5 years and who are currently not receiving care might save 319 sight years over the lifetime of the cohort. This program will save 62 sight years in an older onset cohort who are taking insulin, and 21 sight years in the older onset population not taking insulin (all benefits are presented as present values computed with an annual discount rate of 5%). Other programs achieve slightly lower savings in each subpopulation.

The validity of self-reported and surrogate-reported cataract and age-related macular degeneration in the Beaver Dam Eye Study.

Abstract: The validity of reported ocular disease was investigated in a population-based epidemiologic study of persons aged 43-86 years residing in Beaver Dam, Wisconsin. In a telephone survey conducted from September 1987 through May 1988, histories of cataract and age-related macular degeneration were obtained from the subject for 2,155 cases and from a surrogate for 1,433 cases. Within 2 years, these persons underwent a complete ocular examination. At that time, an "in-person" self-reported history of eye disease was obtained and disease presence was determined based on ocular photographs. The reporting methods, telephone versus in-person and surrogate versus subject, were compared and the validity of each assessed. Reporting methods were in agreement in better than 90% of all cases. Reporting of cataract showed a sensitivity of 20.4 for surrogate by telephone, 30.2 for self-report by telephone, and 37.8 for self-report at the examination. Sensitivity of reported age-related macular degeneration was poorer, with the highest rate of 17.9 for the "in-person" self-report. Specificity was better than 90.0 for all reporting methods for both cataract and age-related macular degeneration. These data suggest that estimates of prevalence of ocular disease should not be based solely on reported histories, and that clinical determinations are necessary.

The epidemiology of diabetes complications study. IV. Correlates of diabetic background and proliferative retinopathy.

Abstract: The roles of potential risk factors for background and proliferative retinopathy were evaluated in cross-sectional analyses from the Epidemiology of Diabetes Complications Study, Pittsburgh, Pennsylvania. This report presents results from the 657 insulin-dependent diabetic participants seen at the baseline examination (1986-1988). The presence of and severity of retinopathy were judged from stereoscopic photographs of three views of the ocular fundus using the modified Airlie House classification system. Fifty-three percent of the participants had background retinopathy, and 31% had proliferative retinopathy. Logistic regression analyses showed that among participants aged less than 18 years, those with background retinopathy were older and had higher levels of glycosylated hemoglobin compared with those without retinopathy. In the 18-29-year age group, participants with background retinopathy had a longer duration of diabetes, higher low density lipoprotein (LDL) cholesterol levels, and lower high density lipoprotein cholesterol levels and were more likely to have microalbuminuria compared with those without retinopathy. Participants aged 18-29 years with proliferative retinopathy had a longer duration of diabetes, higher diastolic blood pressure, and higher fibrinogen and LDL cholesterol levels than those with background retinopathy. In the age group greater than or equal to 30 years, diabetes duration, diastolic blood pressure, and fibrinogen, LDL cholesterol, and triglyceride levels were increased in participants with proliferative retinopathy versus those with background retinopathy. In a multivariate model of proliferative retinopathy, controlling for concurrent renal disease weakened the influence of blood pressure, fibrinogen, triglycerides, and LDL cholesterol and improved the overall fit of the model. These results suggest that diabetic nephropathy may contribute to the development of proliferative (but not background) retinopathy by increasing blood pressure and fibrinogen, by altering the lipoprotein profile, and possibly through other mechanisms.

Age-related eye disease, visual impairment, and driving in the elderly.

Abstract: As people age, a number of visual functions such as acuity, visual field, and night vision deteriorate. This decline in vision is associated in part with an increase in vehicular accidents per mile driven by the elderly. Four age-related ocular conditions--cataract, macular degeneration, open-angle glaucoma, and diabetic retinopathy--are primarily responsible for the decline in visual acuity and visual field in the elderly. Few epidemiologic data are available about these diseases, and at present they cannot be prevented. There is need for more information about visual decline and how it affects driving performance and for development of pragmatic approaches for detecting and assessing the elderly driver with functional visual deficits.

Association of elevated IGF-I levels with increased retinopathy in late-onset diabetes.

Abstract: Insulinlike growth factor I (IGF-I) has been suggested to play a role in the pathogenesis of proliferative diabetic retinopathy (PDR). We determined IGF-I levels in subjects in a large population-based study of 928 people with diabetes diagnosed at 30 yr of age or older. PDR was found in 15.7% of the insulin-using group (n = 517) and in 2.8% of those not using insulin (n = 397). The mean serum level of IGF-I was 208 micrograms/L in individuals using insulin and 222 micrograms/L in those not using insulin, both significantly lower than in a nondiabetic comparison group (278 micrograms/L, P less than 0.0001). Logistic regression analysis was used to examine the relationship between IGF-I and PDR while controlling for other factors associated with the presence of PDR. After controlling for duration of diabetes, glycosylated hemoglobin, systolic blood pressure, presence of proteinuria, and age at diagnosis, higher levels of IGF-I were significantly associated with an increased frequency of PDR (P = 0.025) in the group using insulin. In individuals not using insulin, higher levels of IGF-I were associated with an increased frequency of PDR or moderate non-PDR (P = 0.08). These data suggest that higher IGF-I levels may be a risk factor for the development of severe retinopathy in people with diabetes diagnosed at 30 yr of age or older.

Association of Cigarette Smoking With Diabetic Retinopathy

Abstract: Objective To determine whether cigarette smoking is associated with the incidence and progression of diabetic retinopathy. Research Design and Methods Younger-onset diabetic subjects who had been diagnosed at >30 yr of age and taking insulin ( n = 1210) and a random sample of older-onset diabetic subjects diagnosed at ≥30 yr of age ( n = 1780) were selected. Baseline examinations were conducted on 996 youngerand 1370 older-onset subjects. Incidence of retinopathy was based on 138 younger-onset and 154 older-onset insulin-taking subjects and 321 older-onset non-insulintaking subjects who were free of retinopathy at baseline. Progression of retinopathy was based on 530 youngeronset and 418 older-onset insulin-taking subjects and 486 older-onset non-insulin-taking subjects with less than proliferative diabetic retinopathy at baseline. Results Baseline smoking history was categorized by status (nonsmoker, ex-smoker, current smoker) and pack-years smoked while diabetic. Retinopathy was documented by stereoscopic fundus photography. In univariate analyses, the only significant association was between pack-years and progression to proliferative diabetic retinopathy in older-onset insulin-taking subjects ( P < 0.01). After controlling for known risk factors for the incidence and progression of retinopathy, pack-years smoked was borderline significant ( P = 0.052) in predicting incidence of retinopathy in youngeronset subjects. Smoking was not associated with incidence in older-onset subjects or with progression or progression to proliferative diabetic retinopathy in any of the groups. Conclusions Smoking is not likely to be an important risk factor for diabetic retinopathy.

Visual Impairment and Retinopathy in People With Normal Glucose Tolerance, Impaired Glucose Tolerance, and Newly Diagnosed NIDDM

Abstract: Objective Prevalence rates of visual impairment and retinopathy were compared in 1992 people with normal glucose tolerance, impaired glucose tolerance (IGT), or newly diagnosed non-insulin-dependent diabetes mellitus (NIDDM). Research Design and Methods Glucose tolerance status was based on an oral glucose tolerance test after exclusion of those with a history of diabetes and/or diabetes medication use in an upper middle-class community of older white adults in southern California between 1984 and 1987. Results Although many sex-specific comparisons were made between glucose tolerance groups, only a few emerged as statistically significant. Among those, women with IGT had significantly higher age-adjusted rates of visual impairment (10.8%) than women with normal glucose tolerance (4.4%). Among men, those with IGT had significantly higher age-adjusted rates of visual impairment (7.9%) than men with newly diagnosed NIDDM (4.0%). Conclusions Low frequencies of retinopathy were found in all three glucose tolerance groups.

The trk family of oncogenes and neurotrophin receptors.

Abstract: To date more than twenty five different oncogenes have been identified in human neoplasias. One of these oncogenes is trk, a transforming gene originally isolated from a colon carcinoma biopsy by using gene transfer assays. This oncogene encodes a chimeric molecule that contains the 221 amino terminal residues of a non-muscle tropomyosin followed by the transmembrane and cytoplasmic domains of the trk proto-oncogene product, a tyrosine protein kinase receptor. trk oncogenes have also been identified in a significant fraction of thyroid papillary carcinomas. Some of these trk oncogenes contain sequences derived from genes other than tropomyosin. One such gene is tpr, a gene first identified as a component of the human met oncogene. The trk proto-oncogene, non-muscle tropomyosin and tpr map in the long arm of chromosome 1. Therefore, trk oncogenes are likely to result from internal rearrangements or from unequal cross-overs between two chromosome 1s. Recent studies have demonstrated that the product of the trk proto-oncogene, gp140trk, is the functional receptor for nerve growth factor (NGF). NGF elicits the rapid phosphorylation of gp140trk on tyrosine residues. Moreover, addition of NGF to NIH3T3 cells expressing gp140trk induces the transient expression of c-Fos, DNA synthesis and morphologic transformation. Finally, transfection of the trk proto-oncogene into NGF non-responsive PC12 mutant cells restores NGF responsiveness. Two additional genes designated trkB and trkC have recently been isolated in our laboratory. These genes are highly related to the trk proto-oncogene and encode tyrosine protein kinases which serve as functional receptors for the NGF-related neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophic-3 (NT-3), respectively. Whether mutations in these novel members of the trk family of receptor genes are also implicated in human cancer remains to be determined.

The incidence of gross proteinuria in people with insulin-dependent diabetes mellitus.

Abstract: Epidemiologic data on the incidence of gross proteinuria in people with diabetes are important in medical counseling, in projecting estimates of needs and costs of health care, and for developing approaches to prevent renal complications. We performed a population-based incidence study in southern Wisconsin of insulin-taking diabetic persons diagnosed before 30 years of age. The presence of gross proteinuria ≥0.30 g/L) was determined by means of a reagent strip. The incidence of proteinuria in a 4-year interval was 14.4% (95% confidence interval, 11.7% to 17.0%). The relative risk of developing proteinuria after 4 years for those with glycosylated hemoglobin levels in the highest quartile compared with those in the lowest quartile was 3.0 (95% confidence interval, 1.6 to 5.3). The incidence of proteinuria was also associated with higher diastolic blood pressure, being male, taking more insulin, and having more severe retinopathy at the baseline examination. The relationship between glycosylated hemoglobin level and the incidence of proteinuria was significant even after controlling for these other risk variables. These data suggest that hyperglycemia, as measured by glycosylated hemoglobin level, is a significant risk factor for the development of gross proteinuria. ( Arch Intern Med. 1991;151:1344-1348)

A Novel Synaptic Vesicle-Associated Phosphoprotein: SVAPP-120

Abstract: Generation of antibodies and direct protein sequencing were used to identify and characterize proteins associated with highly purified synaptic vesicles from rat brain A protein doublet of low abundance of 119 and 124 kDa apparent molecular mass [synaptic vesicle-associated phosphoprotein with a molecular mass of 120 kDa (SVAPP-120)] was identified using polyclonal antibodies SVAPP-120 was found to copurify with synaptic vesicles and to be enriched in the purified synaptic vesicle fraction to the same extent as synapsin I Like synapsin I, SVAPP-120 is not an integral membrane protein because it was released from synaptic vesicles by high salt concentrations This protein was demonstrated to be brain specific, and its distribution in various brain regions paralleled the distribution of synapsin I and synaptophysin During the postnatal development of the rat cortex and cerebellum, its expression correlated with synaptogenesis SVAPP-120 was demonstrated to be a phosphoprotein both in vivo and in vitro It was shown to be phosphorylated on serine and to a lesser extent on threonine residues These results provide evidence that SVAPP-120 represents a novel synaptic vesicle-associated phosphoprotein In addition, aldolase, a glycolytic enzyme, and alpha c-adaptin, a clathrin assembly-promoting protein, were identified on purified synaptic vesicles by direct protein sequencing

The 5' insulin gene polymorphism and the genetics of vascular complications in type 1 (insulin-dependent) diabetes mellitus.

Abstract: Recent data suggest genetic contributions to the microvascular complications of Type 1 (insulin-dependent) diabetes mellitus. Most research has focused on the HLA region, and the potential role of other genetic loci has not been adequately explored. We examined the possible relationship between DNA polymorphisms in the region 5' to the insulin gene on chromosome 11 and diabetic nephropathy. This was done by comparison of those diabetic patients homozygous for class 1 alleles at the 5' insulin gene polymorphism locus to 1/3 heterozygotes in a well-characterized series of 324 insulin-requiring diabetic patients from the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Proteinuria (defined as greater than or equal to 0.3 g protein/l urine), was used as suggestive evidence for diabetic nephropathy. Hypertension, a frequent associated finding in diabetic patients with nephropathy, was defined as a blood pressure greater than 140/90 or a history of previous treatment of hypertension. The two genotypically defined groups did not differ from each other in regard to sex ratio, age at diagnosis, age at examination, duration of diabetes, body mass, HbAlc or C-peptide. The 1+1 group had a higher prevalence of proteinuria, 29% as compared to 16.2% in other genotypes (p less than 0.05). There was no significant difference in the frequency of hypertension between the two genotypic groups. This finding suggests that the 5' insulin gene polymorphism may be associated with risk for nephropathy, but the pathophysiologic mechanism remains unclear.

HLA-DR and the 5' insulin gene polymorphism in insulin-dependent diabetes.

Abstract: While the human leukocyte antigen (HLA) region provides the major susceptibility for insulin-dependent (type I) diabetes mellitus (IDDM), other (non-HLA) genes must also play a role. Population studies have shown an increased frequency of small insertions (class I alleles) 5′ to the insulin gene in individuals with IDDM, suggesting that this region may account for part, if not all, of the non-HLA genetic predisposition. However, no data are available as to whether the relation of the insulin gene polymorphism is to a DR-defined subset of IDDM or with all of IDDM. To test the hypothesis that specific combinations of HLA and insulin gene polymorphism alleles may interact in providing susceptibility for IDDM, HLA-DR and 5′ insulin gene insertion size have been determined in 300 individuals with IDDM. The frequency of class 1 insulin gene alleles in the entire sample is 0.79 and the frequency of class 3 alleles (large inserts) is 0.20. The frequencies of class 1 alleles were equal across all DR classes: 0.79 in the DR3 X IDDM subjects, 0.80 in the DR4 X , 0.79 in the DR3 4 , and 0.78 in those with DRX X . Additionally, the frequencies of class 1 1 homozygotes and 1 3 heterozygotes were similar between HLA-DR types. These results suggest that the HLA region and the region 5′ to the insulin gene provide independent and nonsynergistic genetic risks for IDDM.

A pilot study of glaucoma visual field screening in diabetes.

Abstract: Because people with diabetes may be at increased risk of glaucoma, we performed a pilot study using automated visual field testing for screening them. One hundred and seventy-six diabetic persons who had participated in the Wisconsin Epidemiologic Study of Diabetic Retinopathy were tested with the Armaly-Drance screening pattern on the Humphrey Visual Field Analyzer. Individuals with moderate diabetic retinopathy or worse tended to have lower sensitivity of the central visual field and missed more points than those with no or only mild retinopathy. People with a history of glaucoma had slightly less sensitivity and missed more points than controls. These preliminary findings suggest that although people with diabetes and glaucoma may more frequently have visual field defects than people with diabetes but no glaucoma, a larger study is needed. This pilot study shows that such a study would be feasible and should be designed to indicate the sensitivity, specificity, and cost-benefit ratio of a screening program so as to assess the utility of the screening visual field test for finding glaucoma amongst people with diabetes.

Factors Determining Recall of Examination Results in Diabetic Population

Abstract: Objective To determine factors influencing recall of examination results after 4 yr. Research Design and Methods At two examinations that were 4 yr apart, a diabetic population was asked, “Have you been told that your diabetes has affected the back of your eyes, that is the retina?” Participants were informed by letter whether they had retinopathy. Subjects in this study included younger-onset ( n = 311) and older-onset ( n = 279) diabetic subjects who had retinopathy at baseline and did not know it. Results Forty-two percent of younger-onset and 29% of older-onset subjects recalled at follow-up that they had been told their diabetes had affected their eyes. People in both groups were more likely to recall they had retinopathy if they had more severe retinopathy, had more symptoms of neuropathy and peripheral vascular disease, had seen an ophthalmologist within 2 yr, or monitored their blood glucose more often. In addition, younger-onset diabetic subjects with poorer visual acuity or who were on a combination insulin regimen and older-onset people taking insulin, having more education, or who were younger were more likely to recall they had retinopathy. Factors not associated with recall in either group included sex, duration of diabetes, proteinuria, glycosylated hemoglobin, and family income. Conclusions These results underscore the need to develop better methods to deliver health-care information to people who have diabetes.