High frequency of diabetes-specific autoantibodies in parents of children with type 1 diabetes. DENIS study group.

Strategies to identify subjects at risk for type 1 diabetes are largely based on the detection of autoantibodies directed to various beta cell autoantigens. Most previous studies only comprise siblings and children of patients with type 1 diabetes; only scare data are available on the antibody profile in older relatives. In this study, we examined the prevalence of cytoplasmic islet cell antibodies (ICA), antibodies to glutamic acid decarboxylase (GADA), antibodies to the protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta (IA-2betaA) in 531 unaffected parents of patients with type 1 diabetes, and compared the results with antibody frequencies in 2425 siblings. The frequency of ICA, GADA and IA-2A was substantially higher among siblings as compared to parents of patients with type 1 diabetes (8.0% vs. 4.5%, 8.0% vs. 4.3%, and 4.5% vs. 1.9%, respectively; p<0.01). However, subdividing the probands according to age revealed a high prevalence of ICA (5.5 %), GADA (5.9 %), and IA-2A (3.1%) among parents aged 31 -40 years which was similar to that observed in siblings above 20 years of age (6.4%, 6.4%, and 3.1%). In both cohorts, GADA and IA-2A were significantly associated with the presence of ICA. The combined screening for GADA and IA-2A identified 100% of parents and 91.9% of siblings at high risk for type 1 diabetes (>10 JDF-U). Furthermore, the analysis of antibody combinations revealed that among antibody positive individuals the percentage of subjects with two or three antibodies was even higher in parents (69.0%) than in siblings (58.2%). The present study shows a high frequency of single and multiple autoantibodies in unaffected parents of patients with type 1 diabetes. Our data indicate that GAD and IA-2 not only represent the major target of autoantibodies in young siblings but also in adult relatives. These findings may be important for the design of future intervention studies.     

Thyroid autoimmunity in children and adolescents with type 1 diabetes mellitus. Effect of age, gender and HLA type

Type 1 diabetes is often associated with additional autoimmune phenomena. However, data reported on the frequency of thyroid autoimmunity differ vastly. Therefore, the prevalence of thyroid autoantibodies was evaluated at a large pediatric diabetes center in Southern Germany. 2,305 determinations (TPO and TG, ELISA) were performed in 495 patients with type 1 diabetes (234 boys, 261 girls; age at last measurement: 15.4 +/- 0.3 years, duration of diabetes 7. 5 +/- 0.2 years). The prevalence of elevated thyroid antibodies increased dramatically with age: from 3.7% in patients less than 5 years of age up to 25.3% in the age group 15-20 years (p < 0.0001). For children older than 10 years, girls were significantly more affected than boys (p < 0.0001). Thyroid autoimmunity tended to be more prevalent in the subgroup of patients with the HLA type DR3/DR4 compared to patients with other HLA types (p = 0.08). In children older than 10 years, basal TSH concentrations were significantly elevated in antibody-positive patients (p < 0.05). In conclusion, thyroid autoimmunity is prevalent in children and adolescents with type 1 diabetes. Adolescent girls and young women are especially affected. Yearly routine determinations of thyroid antibodies are therefore recommended.     

Mortality (1950-1999) and cancer incidence (1969-1999) in the cohort of Eldorado uranium workers

This study assessed the relationship between radon decay product (RDP) exposure and mortality and cancer incidence in a cohort of 17,660 Eldorado uranium workers first employed in 1932-1980 and followed up through 1999. The analysis was based on substantially revised identifying information and dosimetry for workers from the Beaverlodge and Port Radium uranium mines and for the first time includes workers from a radium and uranium refinery and processing facility in Port Hope, Canada. Overall, male workers had lower mortality rates of all causes and all cancers and lower incidence rates of all cancers compared with the general Canadian male population, a likely healthy worker effect. Individual cancer rates were also reduced except for lung cancer mortality (SMR = 1.31, P < 0.001) and incidence (SIR = 1.23, P < 0.001). The excess relative risk per 100 WLM (ERR/100 WLM) of lung cancer mortality (N = 618, ERR/100 WLM = 0.55, 95% CI: 0.37, 0.78, P < 0.01) and incidence (N = 626, ERR/100 WLM = 0.55, 95% CI: 0.37, 0.81, P < 0.001) increased linearly with increasing RDP exposure. Adjustment for effect modification by time since exposure, exposure rate and age at risk resulted in comparable estimates of risk of lung cancer for all three uranium worksites. RDP exposures and γ-ray doses were not associated with any other cancer site or other cause of death. The risk estimates are in agreement with the results of the pooled analysis of 11 miner cohorts and more recent studies of uranium workers. The current analysis provides more precise risk estimates and compares the findings from the mortality study with the incidence study. Future follow-up of the cohort and joint analysis with other uranium miners' studies should shed more light on the effects of low RDP exposures as experienced by current workers as well as help to understand and address the health risks associated with residential radon.     

Maternal and paternal age at delivery, birth order, and risk of childhood onset type 1 diabetes: population based cohort study

ObjectiveTo estimate the associations of maternal and paternal age at delivery and of birth order with the risk of childhood onset type 1 diabetes.DesignCohort study by record linkage of the medical birth registry and the national childhood diabetes registry in Norway.SettingNorway.SubjectsAll live births in Norway between 1974 and 1998 (1.4 million people) were followed for a maximum of 15 years, contributing 8.2 million person years of observation during 1989-98. 1824 cases of type 1 diabetes diagnosed between 1989 and 1998 were identified.ResultsThere was no association between maternal age at delivery and type 1 diabetes among firstborn children, but among fourthborn children there was a 43.2% increase in incidence of diabetes for each five year increase in maternal age (95% confidence interval 6.4% to 92.6%). Each increase in birth order was associated with a 17.9% reduction in incidence (3.2% to 30.4%) when maternal age was 20-24 years, but the association was weaker when maternal age was 30 years or more. Paternal age was not associated with type 1 diabetes after maternal age was adjusted for.ConclusionsIntrauterine factors and early life environment may influence the risk of type 1 diabetes. The relation of maternal age and birth order to risk of type 1 diabetes is complex.

What is already known on this topic

Maternal age at birth is positively associated with risk of childhood onset type 1 diabetesStudies of the effect of birth order on risk of type 1 diabetes have given inconsistent results

What does this study add?

In a national cohort, risk of diabetes in firstborn children was not associated with maternal ageIncreasing maternal age was a risk factor in children born second or laterThe strength of the association increased with increasing birth order     

The physicochemical and biochemical characteristics of the cell walls in M+ and M- variants of Streptococcus group A type 29

The amino acid composition of cell walls and surface proteins, isolated from virulent (M+) and avirulent (M-) streptococcal strains (group A, type 29) has been determined by the method of E. H. Beachey et al. The kinetics of the lysis and proteolysis of streptococcal cell walls with muramidase and protease obtained from Actinomyces levoris and streptolysin has been studied. The constants describing the progress rates of these processes has been determined; their values in case of both lysis and proteolysis are higher in virulent strains than in avirulent ones.     

CYP2R1-, CYP27B1- and CYP24-mRNA expression in German type 1 diabetes patients

1,25(OH)(2)D(3) and 25(OH)D(3) have been associated with type 1 diabetes. Diverse enzymes are involved in the synthesis of these metabolites: the 25-Vitamin-D-hydroxylase (CYP2R1), the 25-hydroxyvitamin-D(3)-1-alpha-hydroxylase (CYP27B1) and the 25(OH)D(3)-24-hydroxylase (CYP24) among others. Serum levels of 25(OH)D(3) and 1,25(OH)(2)D(3) were investigated in type 1 diabetes patients (n=173) and the mRNA expression of the CYP2R1, CYP27B1 and CYP24 genes in type 1 diabetes patients (n=33) and healthy controls (n=23). These parameters were correlated with the -1260 (C/A) polymorphism in the CYP27B1 gene. Lower expression of CYP27B1 mRNA in comparison with healthy controls (1.7165 versus 1.7815, P=0.0268) was found. Additionally, patients carrying the genotype CC possessed a reduced amount of CYP27B1 mRNA compared to healthy controls (1.6855 versus 1.8107, respectively, P=0.0220). The heterozygosity rate of the -1260 C/A polymorphism was more frequent in patients with normal levels of 1,25(OH)(2)D(3) (> or =19.9 pmol/ml) than in whose with a level of less than 19.9 pmol/ml (46.7% versus 22.2%, P=0.0134). No correlation with serum levels of 25(OH)D(3) was found. Thus, CYP27B1 gene could play a functional role in the pathogenesis of type 1 diabetes through modulation of its mRNA expression and influence serum levels of 1,25(OH)(2)D(3) via the -1260 C/A polymorphism.     

Increasing incidence and age at diagnosis among children with type 1 diabetes mellitus over a 20-year period in Auckland (New Zealand)

Background

We aimed to evaluate the incidence of type 1 diabetes mellitus in children <15 years of age (yr) in the Auckland region (New Zealand) over 20 years (1990–2009).

Methods

We performed a retrospective review of all patients <15 yr diagnosed with type 1 diabetes, from an unselected complete regional cohort.

Results

There were 884 new cases of type 1 diabetes, and age at diagnosis rose from 7.6 yr in 1990/1 to 8.9 yr in 2008/9 (r² = 0.31, p = 0.009). There was a progressive increase in type 1 diabetes incidence among children <15 yr (p<0.0001), reaching 22.5 per 100,000 in 2009. However, the rise in incidence did not occur evenly among age groups, being 2.5-fold higher in older children (10–14 yr) than in the youngest group (0–4 yr). The incidence of new cases of type 1 diabetes was highest in New Zealand Europeans throughout the study period in all age groups (p<0.0001), but the rate of increase was similar in New Zealand Europeans and Non-Europeans. Type 1 diabetes incidence and average annual increase were similar in both sexes. There was no change in BMI SDS shortly after diagnosis, and no association between BMI SDS and age at diagnosis.

Conclusions

There has been a steady increase in type 1 diabetes incidence among children <15 yr in Auckland over 20 years. Contrary to other studies, age at diagnosis has increased and the greatest rise in incidence occurred in children 10–14 yr. There was little change in BMI SDS in this population, providing no support for the ‘accelerator hypothesis’.     

Population based study of rates of multiple pregnancies in Denmark, 1980-94.

OBJECTIVE: To study trends in multiple pregnancies not explained by changes in maternal age and parity patterns. DESIGN: Trends in population based figures for multiple pregnancies in Denmark studied from complete national records on parity history and vital status. POPULATION: 497,979 Danish women and 803,019 pregnancies, 1980-94. MAIN OUTCOME MEASURES: National rates of multiple pregnancies, infant mortality, and stillbirths controlled for maternal age and parity. Special emphasis on primiparous women > or = 30 years of age, who are most likely to undergo fertility treatment. RESULTS: The national incidence of multiple pregnancies increased 1.7-fold during 1980-94, the increase primarily in 1989-94 and almost exclusively in primiparous women aged > or = 30 years, for whom the adjusted population based twinning rate increased 2.7-fold and the triplet rate 9.1-fold. During 1989-94, the adjusted yearly increase in multiple pregnancies for these women was 19% (95% confidence interval 16% to 21%) and in dizygotic twin pregnancies 25% (21% to 28%). The proportion of multiple births among infant deaths in primiparous women > or = 30 years increased from 11.5% to 26.9% during the study period. The total infant mortality, however, did not increase for these women because of a simultaneous significant decrease in infant mortality among singletons. CONCLUSIONS: A relatively small group of women has drastically changed the overall national rates of multiple pregnancies. The introduction of new treatments to enhance fertility has probably caused these changes and has also affected the otherwise decreasing trend in infant mortality. Consequently, the resources, both economical and otherwise, associated with these treatments go well beyond those invested in specific fertility enhancing treatments.     

The KL-VS polymorphism of KLOTHO gene is protective against retinopathy incidence in patients with type 1 diabetes

Background and aims

KLOTHO is an anti-ageing circulating hormone involved in insulin signaling, inflammation and vascular homeostasis through its protective effects on the endothelium and antioxidant actions. The common functional “KL-VS” variant of the KLOTHO gene is reproducibly associated with longevity in humans. Large number of studies have evaluated close relationship between KLOTHO protein and diabetes but the association between KL-VS variant and retinopathy in type 1 diabetes mellitus (T1D) is unknown. Therefore, in the present study we examined the association between the KL-VS polymorphism and the risk of diabetic retinopathy (DR) in patients with T1D.

Gerbich blood group deficiency of the Ge:-1,-2,-3 and Ge:-1,-2,3 types. Immunochemical study and genomic analysis with cDNA probes

Human erythrocytes carry several transmembrane glycoproteins, among which the two minor species associated with the blood group Gerbich (Ge) antigens, GP C and GP D, play pivotal role since they interact with the membrane cytoskeleton and contribute to maintain the normal red cell shape. On the red cells from two categories of homozygous donors lacking the Ge determinants (Ge:-1,-2,-3 and Ge:-1,-2,3), GP C and GP D are missing but instead there is a new glycoprotein, easily detected by SDS/polyacrylamide gel electrophoresis, which exhibits some properties shared by GP C and GP D. This was shown by immunochemical analyses with a murine monoclonal antibody, extraction of the glycoproteins by organic solvents and binding studies with the 125I-labelled Lens culinaris lectin. The red cells from obligate heterozygotes for the Ge:-1,-2,-3 condition also carry this new glycoprotein component but in a much lesser amount than expected on the basis of one gene dose response. Using a cDNA probe containing the coding sequence of human GP C and the entire 3' untranslated region of its mRNA, we have demonstrated by Southern analyses that the Ge:-1,-2,-3 and the Ge:-1,-2,3 conditions are associated with a constant 3-kbp deletion within the GP C gene. Similar studies indicated that this gene is present as a unique copy per haploid genome of Ge-positive control donors (Ge:1,2,3). To account for these data and for the glycoprotein profile of Ge-negative erythrocytes, it is proposed that a unique Gerbich gene encodes for GP C and GP D, either by alternative RNA splicing or by different post-translational events, and that, following a 3-kbp deletion within this gene, a new glycoprotein having properties common to GP C and GP D can be produced.