Viral triggers for autoimmunity: Is the ‘glass of molecular mimicry’ half full or half empty?

In this review we want to consider some of the requirements for autoimmune disease to develop and how this may be reproduced in animal models. Besides a genetic predisposition, environmental triggering factors seem to play a central role in the etiology of many autoimmune diseases. In theory, a structural similarity or identity between the host and an invading pathogen might cause the immune system of the host to react not only to the pathogen but also to self-components. However, in order for such a process of molecular mimicry to induce autoimmunity the mechanisms of maintaining tolerance or ignorance to the self-components need to be circumvented. Subsequently, in order to advance autoimmunity to overt autoimmune disease the frequency and avidity of autoaggressive lymphocytes has to be of sufficient magnitude. Intuitively, one would assume that tolerance might be stronger to identical structures than to structures that just share a certain degree of similarity. Self-reactive lymphocytes with high-avidity are more likely to be deleted or functionally silenced by central and/or peripheral tolerance mechanisms. Thus, perfect mimicry between identical structures might fail in inducing autoimmunity because of efficient tolerance mechanisms. In contrast, imperfect mimicry between similar but not identical structures might on one hand circumvent tolerance but on the other hand result in the generation of lymphocytes with only low- to intermediate avidity. Here we examine animal models that use the concept of molecular mimicry as a potential mechanism for inducing or accelerating autoimmunity. We focus on the RIP-LCMV model for type 1 diabetes and the novel cytochrome P450 2D6 (CYP2D6) model for autoimmune hepatitis, which use either identical or similar triggering and target antigens.     

Characteristics of self‐regulation in adolescent girls with Type 1 diabetes with and without eating disorders: A cross‐sectional study

Objectives. Pathology of the regulative mechanisms of self seems to be connected with eating disorders (EDs). The present study aimed to explore the hypothesis that there are differences in self‐regulation in adolescent girls with Type 1 diabetes with and without EDs. Design. A cross‐sectional design was employed comparing patterns of self‐regulation in adolescent girls with Type 1 diabetes with and without EDs in two eating status groups. Methods. For the presence of EDs, 76 adolescent girls with Type 1 diabetes were assessed. Of these, 23 were diagnosed with an ED. In addition, dimensions of self‐regulation as conceptualized in terms of Kohuts' psychodynamic theory of self were assessed. Results. Adolescent girls with Type 1 diabetes and an ED were higher in three aspects of self‐regulation – negative body self, object depreciation, and narcissistic gain from illness – in comparison with their peers without EDs. Conclusions. This study is the first to show evidence of deficits in self‐regulation in adolescent girls with Type 1 diabetes and EDs. The importance of evaluating parameters of self‐regulation for treatment planning for these youths is outlined.     

A decade of work on organized labor and tobacco control: reflections on research and coalition building in the United States

Labor unions can and should make strong allies in tobacco control efforts. Through much of the 1980s and 1990s, however, the organized labor and tobacco control communities rarely formed coalitions to achieve mutual gains. Recently, labor unions and tobacco control organizations have begun to work together on smoking cessation programs, smoke-free worksite policies, and increased insurance coverage for cessation treatments. This paper explores the historic and present-day intersections among organized labor and tobacco control advocates. We summarize research in this area and report on our recent programmatic efforts to promote collaboration between the labor and tobacco control communities. We discuss lessons learned with the aims of promoting deeper understanding among tobacco control and labor advocates of how each views tobacco control issues, and most importantly, stimulating further collaboration toward mutual gains in protecting workers' health.     

EPIC-Heart: the cardiovascular component of a prospective study of nutritional, lifestyle and biological factors in 520,000 middle-aged participants from 10 European countries

EPIC-Heart is the cardiovascular component of the European Prospective Investigation into Cancer and Nutrition (EPIC), a multi-centre prospective cohort study investigating the relationship between nutrition and major chronic disease outcomes. Its objective is to advance understanding about the separate and combined influences of lifestyle (especially dietary), environmental, metabolic and genetic factors in the development of cardiovascular diseases by making best possible use of the unusually informative database and biological samples in EPIC. Between 1992 and 2000, 519,978 participants (366,521 women and 153,457 men, mostly aged 35–70 years) in 23 centres in 10 European countries commenced follow-up for cause- specific mortality, cancer incidence and major cardiovascular morbidity. Dietary information was collected with quantitative questionnaires or semi-quantitative food frequency questionnaires, including a 24-h dietary recall sub-study to help calibrate the dietary measurements. Information was collected on physical activity, tobacco smoking, alcohol consumption, occupational history, socio-economic status, and history of previous illnesses. Anthropometric measurements and blood pressure recordings were made in the majority of participants. Blood samples were taken from 385,747 individuals, from which plasma, serum, red cells, and buffy coat fractions were separated and aliquoted for long-term storage. By 2004, an estimated 10,000 incident fatal and non-fatal coronary and stroke events had been recorded. The first cycle of EPIC-Heart analyses will assess associations of coronary mortality with several prominent dietary hypotheses and with established cardiovascular risk factors. Subsequent analyses will extend this approach to non-fatal cardiovascular outcomes␣and to further dietary, biochemical and genetic factors.     

Analysis of multiple SNPs in genetic association studies: comparison of three multi-locus methods to prioritize and select SNPs

Nonparametric approaches have been developed that are able to analyze large numbers of single nucleotide polymorphisms (SNPs) in modest sample sizes. These approaches have different selection features and may not provide similar results when applied to the same dataset. Therefore, we compared the results of three approaches (set association, random forests and multifactor dimensionality reduction [MDR]) to select from a total of 93 candidate SNPs a subset of SNPs that are important in determining high-density lipoprotein (HDL)-cholesterol levels. The study population consisted of a random sample from a Dutch monitoring project for cardiovascular disease risk factors and was dichotomized into cases (low HDL-cholesterol, n = 533) and non-cases (high HDL-cholesterol, n = 545) based on gender-specific median values for HDL cholesterol. Clearly, all three approaches prioritized three SNPs as important (CETP Taq1B, CETP-629 C/A and LPL Ser447X). Two SNPs with weaker main effects were additionally prioritized by random forests (APOC3 3175 G/C and CCR2 Val62Ile), whereas MTHFR 677 C/T was selected in combination with CETP Taq1B as best model by MDR. Obtained p-values for the selected models were significant for the set association approach (p =.0019), random forests (p<.01) and MDR (p<.02). In conclusion, the application of a combination of multi-locus methods is a useful approach in genetic association studies to select a well-defined set of important SNPs for further statistical and epidemiological interpretation, providing increased confidence and more information compared with the application of only one method.     

Vaccination practices in pediatric transplantation: A survey among member centers of the European reference network TransplantChild

Background

There is considerable variation in vaccination practices between pediatric transplant centers. This study aims to evaluate active immunization attitudes and practices among ERN-TransplantChild centers and identify potential areas of improvement that could be addressed by shared evidence-based protocols.

Methods

A cross-sectional questionnaire of attitudes and practices toward immunization of pediatric SOT and HSCT candidates and recipients was sent to a representative member of multidisciplinary teams from 27 European centers belonging to the ERN-TransplantChild.

Results

A total of 28/62 SOT programs and 6/12 HSCT programs across 21 European centers participated. A quarter of centers did not have an on-site protocol for the immunizations. At the time of transplantation, pediatric candidates were fully immunized (80%–100%) in 57% and 33% of the SOT and HSCT programs. Variations in the time between vaccine administration and admission to the waiting list were reported between the centers, with 2 weeks for inactivated vaccines and variable time (2–4 weeks) for live-attenuated vaccines (LAVs). Almost all sites recommended immunization in the post-transplant period, with a time window of 4–8 months for the inactivated vaccines and 16–24 months for MMR and Varicella vaccines. Only five sites administer LAVs after transplantation, with seroconversion evaluated in 80% of cases.

Conclusions

The immunization coverage of European pediatric transplant recipients is still inconsistent and far from adequate. This survey is a starting point for developing shared evidence-based immunization protocols for safe vaccination among pediatric transplant centers and generating new research studies.     

Factors affecting long-term outcome after allogeneic haematopoietic stem cell transplantation for acute myelogenous leukaemia: a retrospective study of 172 adult patients reported to the Austrian Stem Cell Transplantation Registry

Between 1982 and 2000, 172 patients with acute myelogenous leukaemia (AML) received haematopoietic stem cell transplants (SCT) from related (n = 132) or unrelated (n = 40) donors at four Austrian transplant centres and their results were reported to the Austrian Stem Cell Transplantation Registry. Conditioning for SCT consisted of cyclophosphamide and total body irradiation in 156 (91%) patients. Graft-versus-host disease (GVHD) prophylaxis was with standard cyclosporine and methotrexate in 95 (55%) patients. Median post-transplant follow-up was 5.6 years (range, 0.2--16.7). Multivariate analysis of transplant-related mortality (TRM) identified four variables associated with a lower risk: disease status of first complete remission (CR) at SCT, patient age of 45 years and younger, transplant performed during or after 1995, and lack of acute GVHD. Variables associated with significantly improved leukaemia-free survival were: bone marrow as the stem cell source, disease status of first CR at SCT, and occurrence of chronic GVHD. In multivariate analysis, transplantation performed during or after 1995, first CR at SCT, occurrence of limited chronic GVHD and lack of acute GVHD grades III to IV were associated with increased overall survival. Based on these analyses, options for the improvement of results obtained with allogeneic SCT in patients with AML could be defined.