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Aims/hypothesis: The incidence of pre-eclampsia, a multisystem disorder of pregnancy, is fourfold higher in type 1 diabetic than non-diabetic women; it is also increased in women with features of the metabolic syndrome and insulin resistance. In a prospective study of pregnant women with type 1 diabetes, we measured plasma levels of adipokines known to be associated with insulin resistance: leptin, fatty acid binding protein 4 (FABP4), adiponectin (total and high molecular weight [HMW]; also known as high molecular mass), retinol binding protein 4 (RBP4) and resistin and evaluated associations with the subsequent development of pre-eclampsia. Methods: From an established prospective cohort of pregnant type 1 diabetic women, we studied 23 who developed pre-eclampsia and 24 who remained normotensive; for reference values we included 19 healthy non-diabetic normotensive pregnant women. Plasma adipokines were measured (by ELISA) in stored samples from three study visits (Visit 1– Visit 3) at different gestational ages (mean ± SD): Visit 1, 12.4 ± 1.8 weeks; Visit 2, 21.7 ± 1.4 weeks; and Visit 3, 31.4 ± 1.5 weeks. All the women were free of microalbuminuria and hypertension at enrolment. All study visits preceded the clinical onset of pre-eclampsia. Results: In all groups, leptin, the ratio of leptin to total or HMW adiponectin, FABP4 concentration, ratio of FABP4 to total or HMW adiponectin and resistin level increased, while total and HMW adiponectin decreased, with gestational age. At Visit 1: (1) in diabetic women with vs without subsequent pre-eclampsia, leptin, ratio of leptin to total or HMW adiponectin, and ratio of FABP4 to total or HMW adiponectin, were increased (p 1c, insulin kg−1 day−1 and gestational age), the best predictive models for pre-eclampsia were as follows: Visit 1, doubling of leptin, OR 9.0 (p

Aims/hypothesis The aim of this study was to investigate the association between routine vaccinations and the risk of childhood type 1 diabetes mellitus by systematically reviewing the published literature and performing meta-analyses where possible. Methods A comprehensive literature search was performed of MEDLINE and EMBASE to identify all studies that compared vaccination rates in children who subsequently developed type 1 diabetes mellitus and in control children. ORs and 95% CIs were obtained from published reports or derived from individual patient data and then combined using a random effects meta-analysis. Results In total, 23 studies investigating 16 vaccinations met the inclusion criteria. Eleven of these contributed to meta-analyses which included data from between 359 and 11,828 childhood diabetes cases. Overall, there was no evidence to suggest an association between any of the childhood vaccinations investigated and type 1 diabetes mellitus. The pooled ORs ranged from 0.58 (95% CI 0.24, 1.40) for the measles, mumps and rubella (MMR) vaccination in five studies up to 1.04 (95% CI 0.94, 1.14) for the haemophilus influenza B (HiB) vaccination in 11 studies. Significant heterogeneity was present in most of the pooled analyses, but was markedly reduced when analyses were restricted to study reports with high methodology quality scores. Neither this restriction by quality nor the original authors’ adjustments for potential confounding made a substantial difference to the pooled ORs. Conclusions/interpretation This study provides no evidence of an association between routine vaccinations and childhood type 1 diabetes. Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3800-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Systematic review of mortality in childhood-/adolescent-diagnosed Type 1 diabetes and examination of factors explaining the mortality variation between studies.Relevant studies were identified from systematic searches of MEDLINE and EMBASE. Observed and expected numbers of deaths were extracted, and standardised mortality ratios (SMRs) and 95 % confidence intervals (CIs) were calculated. Negative binomial regression was used to investigate association between mortality and study/country characteristics.Thirteen relevant publications with mortality data were identified describing 23 independent studies. SMRs varied markedly ranging from 0 to 854 (χ (2) = 70.68, df = 21, P0.0001). Significant associations were observed between SMR and mid-year of follow-up [incidence rate ratio (IRR) 0.95, 95 % CI 0.91-0.99 equivalent to a 5 % decrease per year], between SMR and infant mortality rate (IRR 1.07, 95 % CI 1.02-1.12, a 7 % increase for each death per 1,000 live births) and, after omitting an outlier, between SMR and health expenditure as a percentage of gross domestic product (GDP) (IRR 0.79, 95 % CI 0.68-0.93, a 21 % decrease for each one percent increase in GDP). No relationship was detected between SMR and a country's childhood diabetes incidence rate or GDP.Excess mortality in childhood-/adolescent-diagnosed Type 1 diabetes is apparent across countries worldwide. Excesses were less marked in more recent studies and in countries with lower infant mortality and higher health expenditure.

Background The objectives of this study were to determine: 1) the prevalence of frailty using Fried’s phenotype method and the Short Performance Physical Battery (SPPB), 2) agreement between frailty assessment methods, 3) the feasibility of assessing frailty using Fried’s phenotype method and the SPPB. Methods This cross-sectional study was conducted at a geriatric out-patient clinic in Hamilton, Canada. A research assistant conducted all frailty assessments. Patients were classified as non-frail, pre-frail or frail according to Fried’s phenotype method and the SPPB. Agreement among methods is reported using the Cohen kappa statistic (standard error). Feasibility data included the percent of eligible participants agreeing to attempt the frailty assessments (criterion for feasibility: ≥90% of patients agreeing to the frailty assessment), equipment required, and safety considerations. A p-value of

Several studies have provided compelling evidence implicating the Notch signalling pathway in diabetic nephropathy. Co-regulation of Notch signalling pathway genes with GREM1 has recently been demonstrated and several genes involved in the Notch pathway are differentially expressed in kidney biopsies from individuals with diabetic nephropathy. We assessed single-nucleotide polymorphisms (SNPs; n = 42) in four of these key genes (JAG1, HES1, NOTCH3 and ADAM10) for association with diabetic nephropathy using a case–control design. Tag SNPs and potentially functional SNPs were genotyped using Sequenom or Taqman technologies in a total of 1371 individuals with type 1 diabetes (668 patients with nephropathy and 703 controls without nephropathy). Patients and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK ( http://pngu.mgh.harvard.edu/∼purcell/plink/ ) and haplotype frequencies in patients and controls were compared. Adjustment for multiple testing was performed by permutation testing. In analyses stratified by centre, we identified six SNPs, rs8708 and rs11699674 (JAG1), rs10423702 and rs1548555 (NOTCH3), rs2054096 and rs8027998 (ADAM10) as being associated with diabetic nephropathy before, but not after, adjustment for multiple testing. Haplotype and subgroup analysis according to duration of diabetes also failed to find an association with diabetic nephropathy. Our results suggest that common variants in JAG1, HES1, NOTCH3 and ADAM10 are not strongly associated with diabetic nephropathy in type 1 diabetes among white individuals. Our findings, however, cannot entirely exclude these genes from involvement in the pathogenesis of diabetic nephropathy.

SMAD proteins are involved in multiple signalling pathways and are key modulators of gene expression. We hypothesised that genetic variation in selected SMAD genes contributes to susceptibility to diabetic nephropathy.We selected 13 haplotype tag (ht) single nucleotide polymorphisms (SNPs) from 67 variants identified by resequencing the SMAD2 and SMAD3 genes. For SMAD1, SMAD4 and SMAD5 genes, genotype data were downloaded for 217 SNPs from Phase II of the International HapMap project. Of these, 85 SNPs met our inclusion criteria, resulting in the selection of 13 tag SNPs for further investigation. A case-control approach was employed, using 267 nephropathic patients and 442 controls with type 1 diabetes from Ireland. Two further populations (totalling 1,407 patients, 2,238 controls) were genotyped to validate initial findings. Genotyping was conducted using iPLEX, TaqMan and gel electrophoresis.The distribution of genotypes was in Hardy-Weinberg equilibrium. Analysis by the chi(2) test of genotype and allele frequencies in patients versus controls in the Irish population (n = 709) revealed evidence for the association of one allele at 5% level of significance (rs10515478, p(uncorrected) = 0.006; p(corrected) = 0.04). This finding represents a relatively small difference in allele frequency of 6.4% in the patient group compared with 10.7% in the control group; this difference was not supported in subsequent investigations using DNA from European individuals with similar phenotypic characteristics.We selected an appropriate subset of variants for the investigation of common genetic risk factors and assessed SMAD1 to SMAD5 genes for association with diabetic nephropathy. We conclude that common polymorphisms in these genes do not strongly influence genetic susceptibility to diabetic nephropathy in white individuals with type 1 diabetes mellitus.

Raised risks of several cancers have been found in patients with type II diabetes, but there are few data on cancer risk in type I diabetes. We conducted a cohort study of 28 900 UK patients with insulin-treated diabetes followed for 520 517 person-years, and compared their cancer incidence and mortality with national expectations. To analyse by diabetes type, we examined risks separately in 23 834 patients diagnosed with diabetes under the age of 30 years, who will almost all have had type I diabetes, and 5066 patients diagnosed at ages 30–49 years, who probably mainly had type II. Relative risks of cancer overall were close to unity, but ovarian cancer risk was highly significantly raised in patients with diabetes diagnosed under age 30 years (standardised incidence ratio (SIR)=2.14; 95% confidence interval (CI) 1.22–3.48; standardised mortality ratio (SMR)=2.90; 95% CI 1.45–5.19), with greatest risks for those with diabetes diagnosed at ages 10–19 years. Risks of cancer at other major sites were not substantially raised for type I patients. The excesses of obesity- and alcohol-related cancers in type II diabetes may be due to confounding rather than diabetes per se.

Background: There are little data available on the prevalence of chronic obstructive pulmonary disease (COPD) in the United Kingdom. The Northern Ireland Cost and Epidemiology of Chronic Obstructive Pulmonary Disease (NICECOPD) study is a two-stage survey to examine the prevalence of obstructive lung disease in a general population sample in the Greater Belfast area. Methods: In stage one 4000 subjects aged 40–69 years were selected at random from the general population. They were posted a short screening questionnaire concerning respiratory symptoms. Respondents were divided into ‚symptomatic’ and ‚asymptomatic’ groups according to their responses. In stage two, a sample of symptomatic and asymptomatic subjects completed a more intensive assessment that included a detailed questionnaire on medical history, spirometry, skin allergy testing and serial peak flow measurements. Spirometric criteria for airflow obstruction were FEV1/FVC ratio of

Atherosclerosis has an inflammatory basis, with cytokines, cellular adhesion molecules and pro-inflammatory cells having important roles in the initiation and progression of this process. Interleukin (IL) 6, IL-10 and transforming growth factor (TGF) beta1 have been proposed as important modulators of the atherosclerotic process, with IL-6 having a pro-inflammatory, atherogenic effect and IL-10 and TGF-beta1 having anti-inflammatory, protective roles. The possible role of functional polymorphisms in the promoter regions of the IL-6, IL-10 and TGF-beta1 genes in the susceptibility to ischaemic heart disease (IHD) was investigated in a well-defined Irish population using two recently described family-based tests of association. We genotyped 1,012 individuals from 386 families with at least one member prematurely affected with IHD. Using the combined transmission disequilibrium test (TDT)/sib-TDT and the pedigree disequilibrium test, no association between any of the IL-6 -174G/C, IL-10 -1082G/A and TGF-beta1 -509C/T polymorphisms and IHD was found. Our data demonstrate that, in an Irish population, these polymorphisms are not associated with IHD.

Variations in the interleukin 4 receptor A (IL4RA) gene have been reported to be associated with atopy, asthma, and allergy, which may occur less frequently in subjects with type 1 diabetes (T1D). Since atopy shows a humoral immune reactivity pattern, and T1D results from a cellular (T lymphocyte) response, we hypothesised that alleles predisposing to atopy could be protective for T1D and transmitted less often than the expected 50% from heterozygous parents to offspring with T1D. We genotyped seven exonic single nucleotide polymorphisms (SNPs) and the -3223 C>T SNP in the putative promoter region of IL4RA in up to 3475 T1D families, including 1244 Finnish T1D families. Only the -3223 C>T SNP showed evidence of negative association (P=0.014). There was some evidence for an interaction between -3233 C>T and the T1D locus IDDM2 in the insulin gene region (P=0.001 in the combined and P=0.02 in the Finnish data set). We, therefore, cannot rule out a genetic effect of IL4RA in T1D, but it is not a major one.

Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.

Aims/hypothesis. Maternal fuel metabolism is known to exert long range effects on the later development of children of diabetic mothers. Recently cardiovascular disease in adult life has been linked retrospectively with foetal malnutrition. The aim of this study was to identify whether markers for fuel-related cardiovascular programming exist for the offspring of diabetic pregnancy. Methods. Sixty-one children aged 5 to 11 years, of mothers with Type I (insulin-dependent) diabetes mellitus were compared with 57 randomly selected control children of non-diabetic mothers similar in age, sex and social class. Fasting blood was taken for plasma glucose, insulin, lipids, IGF-1, plasminogen activating inhibitor 1 (PAI-1) and the adhesion molecules ICAM-1, VCAM-1 and E-Selectin. Results. Fasting glucose and insulin were similar in the two groups. Differences existed between the offspring of diabetic and non-diabetic pregnancies (mean ± SD) for total cholesterol (4.45±0.56 vs 4.18±0.66, p=0.03 ), LDL cholesterol (2.73±0.49 vs 2.39±0.54, p=0.001), Cholesterol-to-HDL ratio (3.41±0.76 vs 3.09±0.73, p=0.03), IGF-1 (22.5±7.3 vs 19.3±8, p=0.04), PAI-1 (20.1±6.2 vs 14.9±7.3, p=0.000), VCAM-1 (1852±444 vs 1509±385, p=0.000) and E-Selectin (geometric mean; 83.1 vs 63.9, p=0.001). Conclusion/interpretation. These results indicate that important differences in cardiovascular risk factors exist between glucose-tolerant children of Type I diabetic and non-diabetic mothers, even in childhood. These data suggest that offspring of diabetic mothers might be at an increased risk for the development of vascular disease in later life.

No study has compared Campylobacter isolates from a human source in Northern Ireland over an extended period of time.To investigate the clonal stability of thermophilic campylobacters isolated from acute bacterial enteritis in Northern Ireland from 1992 to 1999.Human isolates (n=272), originating from faeces, were characterised at the sub-species level using enterobacterial repetitive intergenic consensus sequence (ERIC2)--random amplification of polymorphic DNA (RAPD) typing.Thirteen genotypes were identified where three types, namely ERIC A, ERIC C and ERIC I, accounted for 28.3%, 14.3% and 13.6%, respectively. There were no significant associations (p0.05) between sex, age groupings and year of isolation and ERIC2 genotype, with the exception of ERIC D, which showed a significant decline in isolation with time (p=0.019).ERIC genotypes were stable over this period, except genotype C which was lost during this time. Previous molecular typing methods showed campylobacters to be heterogeneous but this study suggests that the local human Campylobacter population consists of several common and stable genotypes. This study has established a database of local ERIC2 genotypes. This methodology may allow the establishment of an all-island database of clinical campylobacters that would be valuable in reducing human campylobacteriosis in Ireland.

Aims/hypothesis: We aimed to describe the frequency and degree of diabetic ketoacidosis in children across Europe at the time of diagnosis of Type I (insulin-dependent) diabetes mellitus and to determine if factors such as age and geographical region contribute to the risk of diabetic ketoacidosis.

To study the epidemiology of childhood-onset (Type I) insulin-dependent diabetes mellitus in Europe, the EURODIAB collaborative group in 1988 established prospective, geographically-defined registers of all children diagnosed with Type I diabetes under 15 years of age. This report is based on 24,423 children, registered by 36 centres, with complete participation during the period 1989-1998 and representing most European countries with a population coverage of approximately 20 million children.Multiple sources of ascertainment were used to validate the level of ascertainment. Trends in Type I diabetes incidence during the period were analysed using Poisson regression with the results from the 36 centres pooled into nine regions.The standardised average annual incidence rate of Type I diabetes varied more than tenfold between centres. Overall, the annual increase in incidence was 3.2% (95%-CI: 2.7%, 3.7%), being highest for children in the 0-4-year age-group 4.8% (3.8%, 5.9%) and lowest for children in the 10-14-year age group 2.1 % (1.4%, 2.8%). However, the absolute increases in Type I diabetes were roughly similar in the three age-groups of 0-4, 5-9 and 10-14 years. Central Eastern Europe showed the highest increase whereas Sardinia and Northern Europe (except Finland) showed no evidence of an increase. For all age-groups relatively fewer cases had disease onset during the summer months, especially the 10-14-year age-group.The extremely large range of incidence rates within Europe has been confirmed. The incidence rate is generally increasing but is more pronounced in some regions than in others. Seasonality at disease onset is apparent even in the youngest age-group.

To assess the predictive value of central obesity for risk of ischaemic heart disease (IHD) in a long-term follow-up, measured by skinfold thickness in comparison to general measures of overweight and obesity such as Quetelet's index.A total of 2512 men aged 45-59 y from the general population first examined in 1979-1982. Men were re-examined at approximately 5 y intervals. All fatal and non-fatal cases of IHD during a 14 y follow-up were recorded.Skinfold thickness was measured at four sites. Height (m) and weight (kg) were also measured and Quetelet's index (weight/height(2)) was used as the reference body mass index (BMI).Data were available for 2512 men among whom 411 new cases of IHD (fatal and non-fatal) occurred during 14 y of follow-up. Increasing values of BMI showed a statistically significant trend with increasing risk of new IHD that contributed independently to risk of IHD when adjusted for age, smoking habit and social class. Skinfold thickness measures were entered singly and in combination into this model with and without the additional inclusion of BMI. All individual skinfolds were significantly associated with risk of new IHD when BMI was excluded from the regression model, as was the sum of four skinfolds and the sum of subscapular and abdominal skinfolds. Only the subscapular skinfold measure contributed independently to risk of subsequent IHD when BMI was included in the model although biceps, biceps plus triceps and total sum of skinfolds were close to achieving statistical significance. The relative odds of IHD in the upper quintile of subscapular skinfold compared to the lowest was 1.9 (95% CI 1.3-2.8) when adjusted for age, smoking habit and social class.In general skinfold measurements contribute only marginally to improved prediction of risk of IHD as measured by BMI, but central obesity, as measured by the subscapular skinfold, is predictive of IHD independently of BMI.

Purpose Endothelin-1, and constitutive endothelial nitric oxide synthase, have been implicated in the pathogenesis of diabetic retinopathy. We therefore screened polymorphisms within the genes encoding these two vasoactive agents in a sample of individuals with 15 years of diabetes and no retinopathy (ETDRS level 10 or better) and those with severe retinopathy (ETDRS level 50 or worse). Methods PCR primers for highly polymorphic sites within the EDN1 and NOS3 genes were used to genotype individuals with type 1 or type 2 diabetes with severe or no retinopathy. Allele frequencies were compared between groups using chi-squared analysis and adjusting for multiple comparisons. Results No significant differences were observed in allele frequencies for these two markers between the patients who had retinopathy and the patients who did not. Conclusion Polymorphic variability in the EDN1 and NOS3 genes does not appear to have a major impact on determining susceptibility or resistance to diabetic retinopathy.

During the period 1989–1994, 462 cases of insulin-dependent diabetes mellitus were registered among children from Northern Ireland aged under 15 years. The estimated completeness of the register was 98.8% (95% confidence interval (CI) 97.7%, 99.9%). A standardised rate of 19.6 (95% CI 17.8, 21.4) per 100 000 person years was obtained, placing Northern Ireland near the top of the range of published incidence in the United Kingdom, with a rate close to that reported for Scotland. In an analysis based on 217 postcode sectors, areas with a high population density and the most material deprivation were observed to have the lowest incidence rates. After inclusion of population density in a Poisson regression analysis, the component of deprivation which was found to be most significant was household crowding. Relative to children living in areas of low population density, there was a reduced risk for children in medium (relative incidence 0.85 (95% confidence limits CI 0.67,1.09)) and high (0.62 (95% CI 0.48,0.80)) population density areas. Similarly, relative to children living in areas with low levels of household crowding, there was a reduced risk for children in medium (relative incidence 0.73 (95% CI 0.58,0.93)) and high (0.67 (95%CI 0.53,0.83)) levels of household crowding. Tests for space-time clustering at diagnosis and at birth were negative. A possible explanation for the differences in incidence rate observed in this study is that exposure to infections very early in childhood is a protective factor. Later infections may act as either initiators or promoters of diabetes, but the absence of space-time clustering suggests that no single specific infectious agent is responsible.

A recent study employing Australian and UK type 1 diabetes families has demonstrated significant transmission bias to affected offspring of a polymorphism (1188A allele; termed allele 1) in the 3' untranslated region (3'UTR) of the interleukin 12B (IL12B) gene which encodes the IL-12p40 subunit of the pro-inflammatory cytokine IL-12. However, results from replication studies in other populations have been controversial. We performed both case-control (n=120 cases; n=330 controls) and family-based (n=307 families) association studies, using the transmission disequilibrium test, to investigate if allele 1 is associated with early-onset type 1 diabetes in Northern Ireland. No association was observed between allele 1 and type 1 diabetes in either case-control (80.8% vs 80.8%; P=0.98) or family-based (49.7% transmissions; P=0.94) studies. Our results do not support earlier reports of an association between allele 1 in the 3'UTR of the IL12B gene and type 1 diabetes.

Increased newborn adiposity is associated with later adverse metabolic outcomes. Previous genome-wide association studies (GWAS) demonstrated strong association of a locus on chromosome 3 (3q25.31) with newborn sum of skinfolds, a measure of overall adiposity. Whether this locus is associated with childhood adiposity is unknown. Genotype and sum of skinfolds data were available for 293 children at birth and age 2, and for 350 children at birth and age 6 from a European cohort (Belfast, UK) who participated in the Hyperglycemia and Adverse Pregnancy Outcome GWAS. We examined single nucleotide polymorphisms (SNPs) at the 3q25.31 locus associated with newborn adiposity. Linear regression analyses under an additive genetic model adjusting for maternal body mass index were performed. In both cohorts, a positive association was observed between all SNPs and sum of skinfolds at birth (P=2.3 × 10(-4), β=0.026 and P=4.8 × 10(-4), β=0.025). At the age of 2 years, a non-significant negative association was observed with sum of skinfolds (P=0.06; β =-0.015). At the age of 6 years, there was no evidence of association (P=0.86; β=0.002). The 3q25.31 locus strongly associated with newborn adiposity had no significant association with childhood adiposity suggesting that its impact may largely be limited to fetal fat accretion.

Association of microsatellite markers on chromosomes 6q27 region and 10p15 region with end-stage renal disease in a UK renal transplant population

It is inevitable that when discoveries are made in any medical fi eld there is pressure to move expeditiously to clinical applications of these discoveries. While there is every reason to disseminate widely the results of effi cacious therapeutic trials that improve meaningful clinical outcomes, and diagnostic strategies that are more sensitive, more specifi c, less burdensome to the patient and more parsimonious of resources, some restraint is advisable when the benefi ts are less compelling. For example, a technique that allows an earlier diagnosis of an incurable disease – such as Alzheimer’s disease (AD) – risks labeling an individual, aff ecting the person’s ability to acquire life, health or travel insurance, and may result in suspension of driving privileges. Finding the balance between embracing leading-edge technologies prematurely and failing to accept proven therapies or diagnostic strategies in a timely manner is the sweet spot to which we should all aspire. We must try to avoid repeating the unfortunate experiences occasioned by widespread prescription of medications before the true range of adverse eff ects has been elucidated (for example, rofecoxib), by surgical procedures of dubious value (for example, external carotid artery to internal