Chris Van Schravendijk

Tuning research competences for Bologna three cycles in medicine: report of a MEDINE2 European consensus survey

Medical curricula, like healthcare systems and medical practice, have a strong cultural component and vary considerably between countries. Increasing mobility of medical graduates, and increasing pressure to ensure they are all fit for practice, have highlighted an urgent need to establish common ground in learning outcomes at all stages of training. A research-based approach, developed by the Tuning project, was used previously by the MEDINE Thematic Network to gain consensus on core learning outcomes/competences for primary medical degrees (www.tuning-medicine.com), but no consensus was reached for learning outcomes relating to research. As part of MEDINE2, a focussed Tuning project was undertaken to explore opinions on more detailed core learning outcomes in research for all three Bologna cycles (Bachelor, Master, and Doctor). Responses from 417 stakeholders, representing 29 European and 13 non-European countries, revealed a relatively high degree of consensus. The findings strongly suggest that these stakeholders think that learning outcomes related both to ‘using research’ and ‘doing research’ should be core components of medical curricula in Europe. The challenge now, however, is to promote further local and international discussion on these issues, and to find ways of achieving these competences within the context of already crowded medical curricula.

IFIH1 gene polymorphisms in type 1 diabetes: Genetic association analysis and genotype–phenotype correlation in the Belgian population

The evaluation of susceptibility loci in a registry-based setting could be an important addition to the current predictive and screening models in T1D. Therefore, the aim of this study was to evaluate the importance of one of these loci, IFIH1. T1D patients (n=1981), control subjects (n=2092) and 430 families were genotyped for HLA-DQ and IFIH1 nsSNP rs1990760 (Ala946Thr). In the association analysis, the allelic frequencies, A (62.4% vs. 61.3%) and G (37.6% vs. 38.7%) were similar in cases and controls (chi(2) = 0.98, p = 0.32), the genotypic frequencies reveals a weak association with T1D (chi(2) = 6.79, p = 0.03), no significant transmission distortions in families (%T; A = 51.4%, G = 48.0 %, chi(2) = 1.76, p = 0.19) and no interaction with HLA-DQ-linked risk. Furthermore, no genotype-phenotype correlation was observed. In conclusion, IFIH1 has no important role in T1D risk assessment in a registry-based Belgian population.

HLA-A*24 Is an Independent Predictor of 5-Year Progression to Diabetes in Autoantibody-Positive First-Degree Relatives of Type 1 Diabetic Patients

We investigated whether HLA-A*24 typing complements screening for HLA-DQ and for antibodies (Abs) against insulin, GAD, IA-2 (IA-2A), and zinc transporter-8 (ZnT8A) for prediction of rapid progression to type 1 diabetes (T1D). Persistently Ab+ siblings/offspring (n = 288; aged 0–39 years) of T1D patients were genotyped for HLA-DQA1-DQB1 and HLA-A*24 and monitored for development of diabetes within 5 years of first Ab+. HLA-A*24 (P = 0.009), HLA-DQ2/DQ8 (P = 0.001), and positivity for IA-2A ± ZnT8A (P < 0.001) were associated with development of T1D in multivariate analysis. The 5-year risk increased with the number of the above three markers present (n = 0: 6%; n = 1: 18%; n = 2: 46%; n = 3: 100%). Positivity for one or more markers identified a subgroup of 171 (59%) containing 88% of rapid progressors. The combined presence of HLA-A*24 and IA-2A+ ± ZnT8A+ defined a subgroup of 18 (6%) with an 82% diabetes risk. Among IA-2A+ ± ZnT8A+ relatives, identification of HLA-A*24 carriers in addition to HLA-DQ2/DQ8 carriers increased screening sensitivity for relatives at high Ab- and HLA-inferred risk (64% progression; P = 0.002). In conclusion, HLA-A*24 independently predicts rapid progression to T1D in Ab+ relatives and complements IA-2A, ZnT8A, and HLA-DQ2/DQ8 for identifying participants in immunointervention trials.

Association of IL-2RA/CD25 with type 1 diabetes in the Belgian population

Our goals were to study the proposed association of IL-2RA /CD25 with type 1 diabetes in the Belgian population over a broad age range, and to explore possible correlations with disease phenotypes, immune markers, HLA-DQ, INS, and PTPN22. Patients (n = 1954), healthy controls (n = 2082), and families (n = 420) were genotyped for IL-2RA/CD25 rs41295061(C>A), HLA-DQ, INS-VNTR and PTPN22. IL-2RA/CD25 was associated with type 1 diabetes (χ(2) = 26.8, p < 0.001 for alleles and χ(2) = 29.6, p < 0.001 for genotypes). The C allele (odds ratios [OR] = 1.59) and C/C genotype (OR = 1.56) were identified as susceptibility variants, whereas the A allele (OR = 0.63), A/A genotype (OR = 0.14), and A/C genotype (OR = 0.69) as protective variants. IL-2RA/CD25 is associated with both early-onset and late-onset type 1 diabetes, but with a larger effect size in early-onset disease. There was a nonsignificant tendency toward transmission distortion (p = 0.063). Except a tendency toward younger age at onset in carriers of the C/C genotype, no correlations with disease phenotype, immune markers, HLA-DQ, INS and PTPN22 were observed. Also, the frequency of the susceptible genotype was higher in early-onset compared with late-onset TID patients (p = 0.015). In conclusion, IL-2RA/CD25 is associated with type 1 diabetes in the Belgian population, independently of disease phenotype and other biologic markers.

Clinical and biological characteristics of diabetic patients under age 40 in Cameroon: relation to autoantibody status and comparison with Belgian patients.

AIMS We investigated the prevalence of diabetes autoantibodies (Abs) in Cameroonian patients and controls, assessed their contribution in disease classification and compared results with data from Belgium. METHODS Abs against GAD (GADA), IA-2 (IA-2A) and zinc transporter 8 (ZnT8A) were assessed in 302 recently diagnosed Cameroonian patients with diabetes and 184 control subjects without diabetes aged below 40 years. RESULTS Only 27 (9%) Cameroonian patients were younger than 15 years. Overall, 29% of patients presented at least one diabetes-associated antibody vs 9% in healthy controls (24% vs 7% for GADA (p<0.001), 10% vs 3% for IA-2A (p<0.006), 4% vs 2% for ZnT8A). Ab(+) patients had lower C-peptide levels (p<0.001), were more often insulin-treated (p<0.002) and were as frequently diagnosed with type 1 diabetes as Ab(-) patients. Only 43% of Ab(+) patients aged 15-39 years were clinically classified as having type 1 diabetes in Cameroon vs 96% in Belgium (p<0.001). Not one Ab(+) Cameroonian patient carried HLA-DQ2/DQ8 genotype vs 23% of Belgian Ab(+) patients (p<0.001). Younger age at diagnosis and antibody positivity were independent predictors of insulin therapy. Ab(+) Cameroonian patients were older (p<0.001), had higher BMI (p<0.001) and lower Ab titers than Belgian Ab(+) patients. In ketonuric patients, prevalence of autoantibodies was similar as in non-ketonuric patients. CONCLUSIONS In Cameroonian patients with diabetes aged under 40 years, antibody-positivity is not clearly related to disease phenotype, but may help predict the need for insulin treatment.

Development of a multipurpose time-resolved fluorescence immunoassay for rat insulin

We present a time-resolved fluorescence immunoassay (TR-FIA) for the measurement of rat insulin in cell extracts and culture media. This assay is based on the binding of two monoclonal antibodies to different parts of the insulin molecule in a 96-well microtiter plate. For the detection, europium-labeled streptavidin that interacts with the second biotinylated antibody is used. Samples of 25 microl could be analyzed in less than 2 days with a measuring range between 5 and 1250 pg (0.2-50 microg/L or 34.4-8600 pM). The inter- and intraassay percentage coefficients of variation were less than 8.3 and 5.1, respectively. Recoveries of 0.48 to 40 microg/L rat insulin, added to culture medium, ranged between 94 and 107%. Results were significantly correlated with those of an in-house radioimmunoassay (RIA) for rodent insulin (P<0.0001, r(2)=0.99). The TR-FIA method had a similar detection limit (0.16 microg/L), but its working range was at least 5-fold larger. Additional advantages include the lower cost, the applicability to measurements in tissue and serum, and the quantification of insulin from other species.