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The major histocompatibility complex (MHC) is known to harbour genetic risk factors for type 1 diabetes (T1D) additional to the class II determinants HLA-DRB1, -DQA1 and -DQB1, but strong linkage disequilibrium (LD) has made efforts to establish their location difficult. This study utilizes a dataset generated by the T1D genetics consortium (T1DGC), with genotypes for 2965 markers across the MHC in 2321 T1D families of multiple (mostly Caucasian) ethnicities. Using a comprehensive approach consisting of complementary conditional methods and LD analyses, we identified three regions with T1D association, independent both of the known class II determinants and of each other. A subset of polymorphisms that could explain most of the association in each region included single nucleotide polymorphisms (SNPs) in the vicinity of HLA-G, particular HLA-B and HLA-DPB1 alleles, and SNPs close to the COL11A2 and RING1 genes. Apart from HLA-B and HLA-DPB1, all of these represent novel associations, and subpopulation analyses did not indicate large population-specific differences among Caucasians for our findings. On account of the unusual genetic complexity of the MHC, further fine mapping is demanded, with the possible exception of HLA-B. However, our results mean that these efforts can be focused on narrow, defined regions of the MHC.

To investigate whether silencing of a T-DNA-carried nptII gene in five single-copy transgenic Arabidopsis lines might be due to position effects, genomic DNA flanking the insertions was analysed for gene density, GC content, presence of short repeats and transposable elements, i.e. factors suggested to promote silencing. No single, common factor could explain the observed silencing. However, in two lines, a transcript covering the nos promoter driving the nptII gene was detected. In sibling sublines with approximately 100% silencing, the nos promoter was heavily methylated. In silico analysis suggested the presence of cryptic core promoters upstream of the nos promoter, in one case in the plant DNA and in the other in a short inverted TDNA region. These fragments were able to drive reporter gene expression in transgenic Arabidopsis plants. Our results indicate that methylation and silencing of transgenic promoters may be mediated by aberrant RNA transcribed from cryptic promoters at the transgene insertion site.

The Diabetes Virus Detection study (DiViD) is the first to examine fresh pancreatic tissue at the diagnosis of type 1 diabetes for the presence of viruses. Minimal pancreatic tail resection was performed 3–9 weeks after onset of type 1 diabetes in six adult patients (age 24–35 years). The presence of enteroviral capsid protein 1 (VP1) and the expression of class I HLA were investigated by immunohistochemistry. Enterovirus RNA was analyzed from isolated pancreatic islets and from fresh-frozen whole pancreatic tissue using PCR and sequencing. Nondiabetic organ donors served as controls. VP1 was detected in the islets of all type 1 diabetic patients (two of nine controls). Hyperexpression of class I HLA molecules was found in the islets of all patients (one of nine controls). Enterovirus-specific RNA sequences were detected in four of six patients (zero of six controls). The results were confirmed in various laboratories. Only 1.7% of the islets contained VP1+ cells, and the amount of enterovirus RNA was low. The results provide evidence for the presence of enterovirus in pancreatic islets of type 1 diabetic patients, which is consistent with the possibility that a low-grade enteroviral infection in the pancreatic islets contributes to disease progression in humans.

HLA-DRB1 shared epitope (SE) alleles are the strongest genetic determinants for autoantibody positive rheumatoid arthritis (RA). One of the key regulators in expression of HLA class II receptors is MHC class II transactivator (CIITA). A variant of the CIITA gene has been found to associate with inflammatory diseases. We wanted to explore whether the risk variant rs3087456 in the CIITA gene interacts with the HLA-DRB1 SE alleles regarding the risk of developing RA. We tested this hypothesis in a case-control study with 11767 individuals from four European Caucasian populations (6649 RA cases and 5118 controls). We found no significant additive interaction for risk alleles among Swedish Caucasians with RA (n = 3869, attributable proportion due to interaction (AP) = 0.2, 95%CI: −0.2–0.5) or when stratifying for anti-citrullinated protein antibodies (ACPA) presence (ACPA positive disease: n = 2945, AP = 0.3, 95%CI: −0.05–0.6, ACPA negative: n = 2268, AP = −0.2, 95%CI: −1.0–0.6). We further found no significant interaction between the main subgroups of SE alleles (DRB1*01, DRB1*04 or DRB1*10) and CIITA. Similar analysis of three independent RA cohorts from British, Dutch and Norwegian populations also indicated an absence of significant interaction between genetic variants in CIITA and SE alleles with regard to RA risk. Our data suggest that risk from the CIITA locus is independent of the major risk for RA from HLA-DRB1 SE alleles, given that no significant interaction between rs3087456 and SE alleles was observed. Since a biological link between products of these genes is evident, the genetic contribution from CIITA and class II antigens in the autoimmune process may involve additional unidentified factors.

Background Studies have shown that residents in nursing homes often are exposed to inappropriate medication. Particular concern has been raised about the consumption of psychoactive drugs, which are commonly prescribed for nursing home residents suffering from dementia. This review is an update of a Norwegian systematic review commissioned by the Norwegian Directorate of Health. The purpose of the review was to identify and summarise the effect of interventions aimed at reducing potentially inappropriate use or prescribing of drugs in nursing homes. Methods We searched for systematic reviews and randomised controlled trials in the Cochrane Library, MEDLINE, EMBASE, ISI Web of Knowledge, DARE and HTA, with the last update in April 2010. Two of the authors independently screened titles and abstracts for inclusion or exclusion. Data on interventions, participants, comparison intervention, and outcomes were extracted from the included studies. Risk of bias and quality of evidence were assessed using the Cochrane Risk of Bias Table and GRADE, respectively. Outcomes assessed were use of or prescribing of drugs (primary) and the health-related outcomes falls, physical limitation, hospitalisation and mortality (secondary). Results Due to heterogeneity in interventions and outcomes, we employed a narrative approach. Twenty randomised controlled trials were included from 1631 evaluated references. Ten studies tested different kinds of educational interventions while seven studies tested medication reviews by pharmacists. Only one study was found for each of the interventions geriatric care teams, early psychiatric intervening or activities for the residents combined with education of health care personnel. Several reviews were identified, but these either concerned elderly in general or did not satisfy all the requirements for systematic reviews. Conclusions Interventions using educational outreach, on-site education given alone or as part of an intervention package and pharmacist medication review may under certain circumstances reduce inappropriate drug use, but the evidence is of low quality. Due to poor quality of the evidence, no conclusions may be drawn about the effect of the other three interventions on drug use, or of either intervention on health-related outcomes.

Objectives: Since the early 1990s there has been an increasing awareness of social and ethnic inequity in health and for the last few years there has also been an increasing focus on disparities in the quality of health services to ethnic minority groups. The aim of this review was to collect and summarise in a systematic and transparent manner the effect of interventions to improve health care services for ethnic minorities.Methods: We searched several medical databases for systematic reviews and randomised controlled trials. Two researchers independently screened for and selected studies, assessed risk of bias, extracted data and graded the quality of the evidence for each outcome in the included studies. The analysis was done qualitatively by describing studies and presenting them in tables.Results: We included 19 primary studies. The interventions were targeted at reducing clinical, structural and organisational barriers against good quality health care services. Eight studies examined the effect of educational interventions in improving outcomes within cross-cultural communication, smoking cessation, asthma care, cancer screening and mental health care. In six comparisons the effect of reminders for improving health care services and patient outcomes within cancer screening and diabetes care was examined. Two studies compared professional remote interpretation services to traditional interpretation services, two studies compared ethnic matching of client and therapist and two studies examined the effect of providing additional support in the form of more personnel in the treatment of diabetes and kidney transplant patients. Most patients were African-Americans and Latin-Americans and all ages were represented.Conclusions: Educational interventions and electronic reminders to physicians may in some contexts improve health care and health outcomes for minority patients. The quality of the evidence varied from low to very low. The quality of available evidence for the other interventions was too low to draw reliable conclusions. We found no studies that only included young patients, but we suggest that interventions targeted at health personnel or health organisations may be applicable regardless of the age of the patient population. This review reveals that the evidence for interventions to improve health care for minorities is sparse and generally of low quality.

Aim The aim of this study was to test the microsatellites in the Type 1 Diabetes Genetics Consortium major histocompatibility complex (MHC) data set for association with type 1 diabetes (T1D) independent of the HLA-DRB1, -DQA1 and -DQB1 genes. Methods The data set was edited to contain only one affected child per family, and broad ethnic subgroups were defined. Genotypes for HLA-DRB1, -DQA1 and -DQB1 were replaced by a haplotype code spanning all three loci, with phase inferred based on common haplotypes. The final data set contained 8190 samples in 2301 families, 59 microsatellites and the DRB1-DQA1-DQB1 haplotype code. Statistical analyses consisted of conditional logistic regression and haplotype estimations and linkage disequilibrium calculations. Results The data set was screened using a main effects test approach adjusted for DRB1-DQA1-DQB1, and significant results tested for validity. After these procedures, four markers remained significant at the Bonferroni-corrected threshold: D6S2773 (p = 0.00014), DG6S185 (p = 0.00015), DG6S398 (p = 0.00043) and D6S2998 (p = 0.00015). These results were supported by allelic tests conditioned on DRB1-DQA1-DQB1 haplotypes, except for DG6S185, which may contain artefacts. Conclusions We have identified three microsatellites that mark additional risk factors for T1D at highly significant levels in the MHC. Further analyses are needed to establish the relationship with other possible genetic determinants in this region.

The main genetic predisposition to type 1 diabetes (T1D) is known to be conferred by the HLA-DRB1, -DQA1 and -DQB1 genes in the major histocompatibility complex (MHC). Other genetic factors within this complex are known to contribute, but their identity has often been controversial. This picture is shared with several other autoimmune diseases (AIDs). Moreover, as common genetic factors are known to exist between AIDs, associations reported with other AIDs may also be involved in T1D. In this study, we have used these observations in a candidate gene approach to look for additional MHC risk factors in T1D. Using complementary conditional methods (involving conditional logistic regression and family-based haplotype tests) and analyses of linkage disequilibrium (LD) patterns, we confirmed association for alleles of the HLA-A and HLA-B genes and found preliminary evidence for a novel association of a single-nucleotide polymorphism (rs2259571) in the AIF1 gene, independent of the DRB1-DQA1-DQB1 genes and of each other. However, no evidence of independent associations for a number of previously suggested candidate polymorphisms was detected. Our results illustrate the importance of a comprehensive adjustment for LD effects when performing association studies in this complex.

Transgene silencing in plants is most often dependent on homologous sequences, e.g. tandemly repeated T-DNAs. We have identified an Arabidopsis line (ex2–4 line 4) displaying silencing of the T-DNA-born nptII gene. This line contains a truncated copy of the T-DNA encompassing the nptII gene with its nos promoter adjacent to an intact T-DNA copy. The orientation of the intact and the truncated copies preclude the generation of a double-stranded nptII transcript. Therefore, we have investigated the genomic landscape surrounding T-DNA insertion in the silenced ex2–4 line 4 and five single-copy ex2–4 lines without silencing in search of features that might explain the silencing phenomenon. GC content, putative matrix-attachment regions and transcriptional interference from neighbouring genes could all be ruled out as major causes of silencing. Bisulphite sequencing revealed de novo methylation of the nos promoter both in non-silenced and silenced plants of this line, thus silencing was not correlated to DNA methylation level. Also, the methylation pattern deviated from that characteristic for RNA-mediated DNA methylation and silencing. Our data therefore suggest that ex2–4 line 4 represents a case where silencing is due to DNA-DNA pairing, i.e. pairing between the intact T-DNA and the adjacent truncated, inverted T-DNA copy.