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W J Riley

Publications and source records attributed to W J Riley.

At least 37 records · Page 2Linked to original sources
PubMed1992

Standardization of IVGTT to predict IDDM.

OBJECTIVE: To review current practice in centers that use the IVGTT for prediction of IDDM. To establish consensus protocol for performance of the test. RESEARCH DESIGN AND METHODS: Postal questionnaires were delivered to 12 centers. RESULTS: Eleven centers used a glucose dose of 0.5 g/kg and 1 used 0.3 g/kg; the dosage in adults was limited to a maximum of 25-50 g in some centers but others applied no upper limit. The glucose concentration of the infusate varied between 20 and 66%. Eight centers injected glucose manually, two used a syringe pump, and two used gravity infusion. The period of infusion ranged from 30 +/- 10 s to 4 +/- 2 min, and time zero was taken as the start (1 center), middle (1 center), or end (10 centers) of the infusion. The potential range in timing of the +1-min sample varied between 1 and 7 min from the start of the infusion. Quality-assurance standards for the insulin assays used were not always appropriate for the fasting and low stimulated range of insulin levels. CONCLUSIONS: The first-phase insulin response to the IVGTT is widely measured as an index of risk of progression to IDDM. We established that methodology varies widely. Because of this, a new standard protocol for use in prediction of IDDM was agreed by an ICARUS working group and is described herein.

Adult↗
PubMed1992

Elimination of matrix effects in electrothermal atomic absorption spectrophotometric determinations of bismuth in serum and urine.

A sensitive and precise electrothermal atomic absorption spectrophotometric method for determining bismuth concentration is described. Protein precipitation and the use of a palladium modifier reduce the problems of foaming and permit the use of a higher ashing temperature. The detection limit of the assay is 0.9 nmol/L. Total CVs (intra- and interassay) for serum ranged from 3.5% to 15.1% and for urine from 4.8% to 14.5% at concentrations of 60.0 and 6.0 nmol/L, respectively. Analytical recoveries of bismuth added to serum and urine were 102% and 103% over the same range. The method is robust and reproducible and can be accurately calibrated with aqueous standards.

Adult↗
PubMed1991

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

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.

Diabetes Mellitus, Type 1↗
PubMed1991

Effect of HLA phenotype and gender on expression of various forms of class I HLA in plasma.

To understand the complexity of plasma HLA antigens, the distribution of different molecular weight forms of class I HLA in plasma was investigated in 44 HLA-phenotyped and unrelated individuals. Plasma class I HLA were immunoprecipitated by using the W6/32 anti-HLA monoclonal antibody, separated by SDS-polyacrylamide gel electrophoresis and characterized by immunoblotting with the HC-10 monoclonal antibody. Four different forms of HLA heavy chains (HLA-HC) with relative molecular masses of 44, 39, 36, and 34 kd were detected. Plasma samples from all individuals contained 44 and 36 kd HLA-HC, but varied as to the presence of 39 and 34 kd HLA-HC. Eighteen percent of the individuals did not have any detectable class I HLA with 39-kd heavy chains in their plasma and 61% did not have plasma class I HLA with 34-kd heavy chains. Thus, four different distribution patterns were identified for plasma class I HLA among all individuals included in our study. The distribution patterns in four different individuals were evaluated quarterly and remained unchanged during 1 year follow-up. A significant association of absence of 39-kd plasma class I HLA-HC with female gender (p less than 0.05) and HLA-B7 phenotype (p less than 0.00015) was also found. Further pedigree analyses of four families of HLA-B7-positive and 39-kd HLA-HC-negative probands indicated that genetic factor(s) other than those associated with HLA-B7 allele and female gender is involved in regulating the expression of the plasma class I HLA with 39-kd heavy chains.

Adolescent↗
PubMed1991

Defective inducer T-cell function before the onset of insulin-dependent diabetes mellitus.

To investigate the possible role of CD4+ T lymphocyte immunoregulatory abnormalities in the pathogenesis of human insulin-dependent diabetes mellitus (IDD), we studied the in vitro function of CD4+ helper/inducer and suppressor/inducer T-cell subpopulations in 25 high risk non-diabetic individuals who tested positive for islet-cell antibodies (ICA). Helper-inducer T-cell function, as measured in the pokeweed mitogen T-B co-culture system, was decreased in the ICA+ subjects in comparison to controls. This abnormality in helper/inducer T-cell function was present for both IgG (P = 0.0001) and IgM (P = 0.004) secretion by B cells. Diminished helper/inducer function correlated with ICA titer (Pearson correlation coefficient -0.44) with subjects having an ICA titer greater than or equal to 40 JDF units demonstrating the most significant disturbances in function (P = 0.01). The helper/inducer T-cell subset percentage was also decreased in ICA+ subjects when compared to matched controls (30 +/- 3% vs 39 +/- 2%; P = 0.02). The abnormality in helper/inducer function was intrinsic to the CD4+ CD45RA+ subset and was not simply due to diminished numbers of helper/inducer T-cells added in the co-culture experiments, since the defect persisted when CD4+ CD45RA+ helper/inducer T-cells were purified and added to B cells as the only source of T-cell help. Our results indicate that ICA+ subjects have functional defects in the helper/inducer subpopulation of CD4+ T-cells. This abnormality may contribute to the pathogenesis of IDD and may provide a novel marker for identifying persons at risk for developing IDD.

Adolescent↗
PubMed1991

Increased T lymphocytes bearing the gamma-delta T cell receptor in subjects at high risk for insulin dependent diabetes.

The effector mechanisms responsible for autoimmune beta cell destruction in insulin dependent (type 1) diabetes (IDD) remain elusive. In order to investigate whether T lymphocytes bearing the gamma-delta T cell receptor (gamma delta+ T cells) could be involved in this process, we measured percentages of peripheral blood gamma delta+ T cells in IDD patients, relatives of IDD probands and controls. High levels of gamma delta+ T cells strongly differentiated 23 relatives at high risk for IDD on the basis of positive islet cell autoantibodies (ICA positive relatives) from 59 controls (P = 0.0013), whereas 26 ICA negative relatives, 14 recent-onset and nine long term IDD patients could not be distinguished from controls on the basis of percentages of gamma delta+ T cells. These data suggest that increased levels of circulating gamma delta+ T cells correlate with the ongoing autoimmune process in pancreatic islets of subjects at high risk for IDD and may thus represent an additional marker for the development of the disease.

Adolescent↗
PubMed1991

CD5+ B lymphocytes in high-risk islet cell antibody-positive and newly diagnosed IDDM subjects.

Human CD5+ B lymphocytes produce autoantibodies that bind to self- and exogenous antigens. Extremely high percentages of CD5+ B lymphocytes are present in the fetal and newborn periods, whereas they constitute only a minority of B lymphocytes in healthy adults. Increased percentages of circulating CD5+ lymphocytes have previously been demonstrated in several autoimmune diseases, including rheumatoid arthritis, progressive systemic sclerosis, Graves' disease, and Sjögren's syndrome. We measured the percentages of B lymphocytes that expressed the CD5 determinant in 93 control subjects (age range 1 day to 59 yr, mean +/- 22.6 +/- 17.7 yr), 17 subjects with newly diagnosed insulin-dependent diabetes mellitus (IDDM; range 5-29 yr, mean +/- SD 13 +/- 5.9 yr), 31 high-risk islet cell antibody (ICA)-positive nondiabetic subjects (range 4-45 yr, mean +/- SD 19.8 +/- 14.1 yr), and 13 subjects with IDDM of greater than 5 yr duration (range 10-43 yr, mean +/- SD 24.2 +/- 9.9 yr). We report that CD5+ B-lymphocyte percentages are strikingly age dependent in healthy control subjects, declining progressively from the newborn period to the middle-age years (r = -0.75, P = 0.0001). In ICA+ nondiabetic and recent-onset IDDM subjects less than 29 yr of age, the percentage of circulating CD5+ B lymphocytes fell within the 95% confidence intervals established for control subjects. However, the age-dependent rate of decline in the percentage of CD5+ B lymphocytes within the control range was slower in ICA+ and newly diagnosed IDDM subjects than in control subjects.

Adolescent↗
PubMed1991

The interface between epidemiology and molecular biology in the search for the causes of insulin-dependent diabetes mellitus.

Epidemiological techniques have been utilized to accumulate new knowledge about insulin-dependent diabetes mellitus (IDDM), leading to important insights into the disease process and the alteration of these mechanisms when viewed from a geographic or population base. More recently, highly powerful and sophisticated techniques of molecular biology have been added to the research arsenal, extending the knowledge on the genetic basis for IDDM and the probable environmental factors involved. The development and growth of the new discipline of epidemiological genetics promises exciting new developments for the future of our field as well as that of other major medical problems having a genetic base, but significantly influenced by environmental factors. This review stresses the importance of carefully validated diabetes registries in the study of the epidemiology of IDDM. The Children's Hospital of Pittsburgh and the University of Pittsburgh Medical Center have spear-headed the development of such registries, worldwide. The first international meeting on IDDM epidemiology in 1983 gave as a result, i.e., the finding that there were truly remarkable differences in the risk of developing IDDM depending upon the geographic location of the individual. Later collaborative work via the Diabetes Epidemiology Research International (DERI) group has confirmed the previous finding and added the description of secular trends and epidemics of IDDM. It is remarkable that the incidence rate of IDDM in children below 15 years vary from 1/100,000/yr in the Orient to 35/100,000/yr in Finland. The epidemiological approach in the study of IDDM has also stimulated research into the various facets of the etiology of the disease, genetic factors, autoimmune mechanisms and environmental factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoantibodies↗
PubMed1990

A prospective study of the development of diabetes in relatives of patients with insulin-dependent diabetes.

BACKGROUND: The presence of cytoplasmic islet-cell autoantibodies has been recognized as a risk factor for the development of diabetes mellitus in relatives of patients with insulin-dependent diabetes mellitus (IDDM), but the magnitude of the risk is unknown, as is the influence of other factors, such as age, sex, and race. METHODS: From 1979 through 1989, we studied 4015 initially nondiabetic relatives of 1590 probands with IDDM to determine the risk of IDDM according to the presence and titer of autoantibodies, as well as other factors. RESULTS: Of the 4015 nondiabetic relatives, 125 (3.1 percent) had islet-cell antibodies in their initial serum samples, and 40 contracted IDDM. Islet-cell antibodies were most frequent (4.3 percent) in relatives who were under 20 years of age (P = 0.001) and in those (4.8 percent) from families with more than one affected member (a multiplex pedigree) (P = 0.003). Independent risk factors for the development of diabetes in the relatives included age of less than 10 years at the time of the initial study (P = 0.001), membership in a multiplex pedigree (P = 0.02), and a positive test for islet-cell antibodies in the initial serum sample (P = 0.0001). Twenty-seven of the relatives in whom diabetes developed (67.5 percent) had positive tests for islet-cell antibodies before the diagnosis of IDDM, giving a relative risk of IDDM of 68 (95 percent confidence interval, 34 to 134) for antibody-positive relatives. Islet-cell-antibody titers of 20 Juvenile Diabetes Foundation units or higher were associated with an increasing risk of diabetes. CONCLUSIONS: Nondiabetic relatives of probands with IDDM who are in the first two decades of life, are members of multiplex pedigrees, and have increased titers of islet-cell antibodies are the most likely to contract IDDM themselves.

Adolescent↗
PubMed1990

64,000 Mr autoantibodies as predictors of insulin-dependent diabetes.

The occurrence of autoantibodies to an islet-cell protein of 64,000 Mr (64KA) was examined in relation to development of insulin-dependent diabetes. 64KA were absent in 26 normal controls and present in only 1 of 41 first-degree relatives who lacked islet-cell cytoplasmic autoantibodies (ICA) or insulin autoantibodies (IAA). Among first-degree relatives at high risk for IDD, 64KA were identified in 23 of 28 persons positive for ICA and 4 of 5 with IAA but no ICA. Among 31 patients with newly diagnosed IDD, 64KA were found in 26. 64KA were identified in 23 of 28 persons studied up to 75 months before clinical onset of IDD. Of these 23 64KA-positive prediabetic subjects, 5 were ICA-negative and 10 lacked IAA. 64KA were most predictive in those who became diabetic before age 34 (22/24). In several individuals, 64KA were detected before the other autoantibodies appeared. These findings suggest that 64KA may be an early and useful predictive marker for IDD.

Adolescent↗
PubMed1990

Relationship of autoimmunity to thyroid dysfunction in children and adults with Down syndrome.

The extent to which autoimmunity contributes to thyroid dysfunction in Down Syndrome (DS) individuals has not been clarified. We studied 61 persons (34 males and 27 females) with DS (age 5 months to 48 years) for the presence of thyroid autoantibodies (thyroid microsomal antibodies and thyroglobulin antibodies), pancreatic islet cell autoantibodies, gastric parietal cell autoantibodies, and adrenocortical autoantibodies. Thyroid function was determined by measurement of TSH. HLA-A, B and -DR typing was performed on 52 subjects. Forty of 61 subjects (66%) had thyroid dysfunction: elevated TSH values (greater than 5 mcIU/ml) were found in 35 of 61 individuals; 3 subjects had previously documented Hashimoto thyroiditis and were on therapy for hyperthyroidism; and 2 persons had Graves disease. No age or sex variation was detected. Seventeen (28%) subjects had thyroid autoantibodies. Fifteen of the 17 had thyroid dysfunction. Twelve of 25 subjects (48%) over 10 years with thyroid dysfunction had thyroid autoantibodies compared to only 3 of 15 (20%) under the age of 10 years. However, children less than of 10 years tended to have higher TSH values. Only 1 individual who had thyroid antibodies had gastric parietal cell autoantibodies present. Islet cell and adrenocortical autoantibodies were not found in any individuals. Neither thyroid dysfunction nor thyroid autoantibodies correlated with any HLA allele. These findings suggest that thyroid dysfunction in individuals with DS of all ages is a common heterogeneous disorder which cannot be solely explained on the basis of autoimmunity. We recommend that thyroid function be followed closely whether or not thyroid autoantibodies are present.

Adolescent↗
PubMed1990

Psychological impact of islet cell-antibody screening. Preliminary results.

The identification of at-risk individuals before the onset of insulin-dependent diabetes mellitus with islet cell-antibody (ICA) screening programs could have significant psychological sequelae. We initiated a descriptive study of ICA+ subjects and their family members in which reactions to study participation, anxiety, and coping responses are monitored. Described here are preliminary results from 18 ICA+ youngsters, 6 ICA+ adults, and their family members. ICA+ identification resulted in clinically significant anxiety that dissipated to normal levels over time for all participants. Both ICA+ subjects and family members coped with the news in similar ways, relying primarily on problem-focused and social-support coping strategies. Few blamed themselves for their own or their loved one's ICA+ status. There was some evidence that the ICA+ participants may minimize the potential impact of their at-risk status. Compared with family members, ICA+ subjects used more avoidance coping strategies, and few believed they would ever develop diabetes. In contrast, many family members believed their loved one would ultimately develop diabetes. Although the initial findings support the resiliency of this population, the long-term effects of ICA screening remain to be seen.

Adaptation, Psychological↗
PubMed1990

Development of IDDM after donating kidney to diabetic sibling.

The goal of this study was to describe a patient who developed insulin-dependent diabetes mellitus (IDDM) after donating a kidney to his sibling and to suggest a possible solution to prevent such an occurrence. A 42-yr-old man was found to have islet cell autoantibodies (ICAs) as part of a screening program of first-degree relatives with IDDM. Two years previously, he had donated his kidney to his HLA-identical sibling with long-standing IDDM. Both oral and intravenous glucose tolerance tests demonstrated a gradual loss of insulin secretion and increasing glucose intolerance until the patient developed IDDM 6 yr after the nephrectomy. Whether the presence of ICA is an absolute contraindication to being a kidney donor could be debated. Nonetheless, ICA should be used as a screening test to identify individuals at risk for subsequent IDDM. For those found to be positive, counseling should be provided.

Adult↗
PubMed1990

Islet cell and other organ-specific autoantibodies in Chinese children with insulin-dependent diabetes mellitus.

Islet cell autoantibodies (ICA) and other organ-specific autoantibodies were detected in 27 Chinese children with insulin-dependent diabetes mellitus (IDDM). The frequency of ICA within the first year of diagnosis was 67%, and it declined as the duration of the disease increased. The frequencies of thyroid microsomal autoantibodies and gastric parietal cell autoantibodies were 26% and 11%, respectively. None of the patients had adrenal autoantibodies. These results are comparable to those reported in Caucasian patients. Similar frequencies of islet cell autoantibodies and other organ-specific autoantibodies in children with IDDM between Chinese and Caucasians suggest that the autoimmune process may play an important role in the pathogenesis of Chinese children with IDDM.

Adolescent↗