The Rising Incidence of Type 1 Diabetes Is Accounted for by Cases With Lower-Risk Human Leukocyte Antigen Genotypes

OBJECTIVE—The rising incidence of type 1 diabetes has been attributed to environment, implying a lesser role for genetic susceptibility. However, the rise could be accounted for by either more cases with classic high-risk genes or by cases with other risk genes. Separately, for any degree of genetic susceptibility, age at presentation may decrease in a permissive environment. To examine these possibilities, human leukocyte antigen (HLA) class II DRB1 genes known to confer risk for type 1 diabetes were analyzed in relation to year of birth and age at diagnosis over the last five decades

Impact of metabolic syndrome and its components on cardiovascular disease event rates in 4900 patients with type 2 diabetes assigned to placebo in the field randomised trial

<p>Abstract</p> <p>Background</p> <p>Patients with the metabolic syndrome are more likely to develop type 2 diabetes and may have an increased risk of cardiovascular disease (CVD) events.We aimed to establish whether CVD event rates were influenced by the metabolic syndrome as defined by the World Health Organisation (WHO), the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and the International Diabetes Federation (IDF) and to determine which component(s) of the metabolic syndrome (MS) conferred the highest cardiovascular risk in in 4900 patients with type 2 diabetes allocated to placebo in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial.</p> <p>Research design and methods</p> <p>We determined the influence of MS variables, as defined by NCEP ATPIII, IDF and WHO, on CVD risk over 5 years, after adjustment for CVD, sex, HbA_1c, creatinine, and age, and interactions between the MS variables in a Cox proportional-hazards model.</p> <p>Results</p> <p>About 80% had hypertension, and about half had other features of the metabolic syndrome (IDF, ATPIII). There was no difference in the prevalence of metabolic syndrome variables between those with and without CVD at study entry. The WHO definition identified those at higher CVD risk across both sexes, all ages, and in those without prior CVD, while the ATPIII definition predicted risk only in those aged over 65 years and in men but not in women. Patients meeting the IDF definition did not have higher risk than those without IDF MS.</p> <p>CVD risk was strongly influenced by prior CVD, sex, age (particularly in women), baseline HbA1_c, renal dysfunction, hypertension, and dyslipidemia (low HDL-c, triglycerides > 1.7 mmol/L). The combination of low HDL-c and marked hypertriglyceridemia (> 2.3 mmol/L) increased CVD risk by 41%. Baseline systolic blood pressure increased risk by 16% per 10 mmHg in those with no prior CVD, but had no effect in those with CVD. In those without prior CVD, increasing numbers of metabolic syndrome variables (excluding waist) escalated risk.</p> <p>Conclusion</p> <p>Absence of the metabolic syndrome (by the WHO definition) identifies diabetes patients without prior CVD, who have a lower risk of future CVD events. Hypertension and dyslipidemia increase risk.</p

Measurement of islet cell antibodies in the Type 1 Diabetes Genetics Consortium: efforts to harmonize procedures among the laboratories

Background and Purpose Three network laboratories measured antibodies to islet autoantigens. Antibodies to glutamic acid decarboxylase (GAD65 [GADA]) and the intracellular portion of protein tyrosine phosphatase (IA-2ic [IA-2A]) were measured by similar, but not identical, methods in samples from participants in the Type 1 Diabetes Genetics Consortium (T1DGC)

The impact of socio-economic disadvantage on rates of hospital separations for diabetes-related foot disease in Victoria, Australia

<p>Abstract</p> <p>Background</p> <p>Information describing variation in health outcomes for individuals with diabetes related foot disease, across socioeconomic strata is lacking. The aim of this study was to investigate variation in rates of hospital separations for diabetes related foot disease and the relationship with levels of social advantage and disadvantage.</p> <p>Methods</p> <p>Using the Index of Relative Socioeconomic Disadvantage (IRSD) each local government area (LGA) across Victoria was ranked from most to least disadvantaged. Those LGAs ranked at the lowest end of the scale and therefore at greater disadvantage (Group D) were compared with those at the highest end of the scale (Group A), in terms of total and per capita hospital separations for peripheral neuropathy, peripheral vascular disease, foot ulceration, cellulitis and osteomyelitis and amputation. Hospital separations data were compiled from the Victorian Admitted Episodes Database.</p> <p>Results</p> <p>Total and per capita separations were 2,268 (75.3/1,000 with diabetes) and 2,734 (62.3/1,000 with diabetes) for Group D and Group A respectively. Most notable variation was for foot ulceration (Group D, 18.1/1,000 <it>versus </it>Group A, 12.7/1,000, rate ratio 1.4, 95% CI 1.3, 1.6) and below knee amputation (Group D 7.4/1,000 <it>versus </it>Group A 4.1/1,000, rate ratio 1.8, 95% CI 1.5, 2.2). Males recorded a greater overall number of hospital separations across both socioeconomic strata with 66.2% of all separations for Group D and 81.0% of all separations for Group A recorded by males. However, when comparing mean age, males from Group D tended to be younger compared with males from Group A (mean age; 53.0 years <it>versus </it>68.7 years).</p> <p>Conclusion</p> <p>Variation appears to exist for hospital separations for diabetes related foot disease across socioeconomic strata. Specific strategies should be incorporated into health policy and planning to combat disparities between health outcomes and social status.</p

Substrate Micropatterning as a New in Vitro Cell Culture System to Study Myelination

Artículo de publicación ISIMyelination is a highly regulated developmental process whereby oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system ensheathe axons with a multilayered concentric membrane. Axonal myelination increases the velocity of nerve impulse propagation. In this work, we present a novel in vitro system for coculturing primary dorsal root ganglia neurons along with myelinating cells on a highly restrictive and micropatterned substrate. In this new coculture system, neurons survive for several weeks, extending long axons on defined Matrigel tracks. On these axons, myelinating cells can achieve robust myelination, as demonstrated by the distribution of compact myelin and nodal markers. Under these conditions, neurites and associated myelinating cells are easily accessible for studies on the mechanisms of myelin formation and on the effects of axonal damage on the myelin sheath.Regenerative Medicine and Nanomedicine Initiative of the Canadian Institutes of Health Research (CIHR) RMF-7028 FONDECYT 1080252 CIHR Ministry of Industry of Canada Rio Tinto Alcan Molson Foundatio

A questionnaire for determining prevalence of diabetes related foot disease (Q-DFD): construction and validation

<p>Abstract</p> <p>Background</p> <p>Community based prevalence for diabetes related foot disease (DRFD) has been poorly quantified in Australian populations. The aim of this study was to develop and validate a survey tool to facilitate collection of community based prevalence data for individuals with DRFD via telephone interview.</p> <p>Methods</p> <p>Agreed components of DRFD were identified through an electronic literature search. Expert feedback and feedback from a population based construction sample were sought on the initial draft. Survey reliability was tested using a cohort recruited through a general practice, a hospital outpatient clinic and an outpatient podiatry clinic. Level of agreement between survey findings and either medical record or clinical assessment was evaluated.</p> <p>Results</p> <p>The Questionnaire for Diabetes Related Foot Disease (Q-DFD) comprised 12 questions aimed at determining presence of peripheral sensory neuropathy (PN) and peripheral vascular disease (PVD), based on self report of symptoms and/or clinical history, and self report of foot ulceration, amputation and foot deformity. Survey results for 38 from 46 participants demonstrated agreement with either clinical assessment or medical record (kappa 0.65, sensitivity 89.0%, and specificity 77.8%). Correlation for individual survey components was moderate to excellent. Inter and intrarater reliability and test re-test reliability was moderate to high for all survey domains.</p> <p>Conclusion</p> <p>The development of the Q-DFD provides an opportunity for ongoing collection of prevalence estimates for DRFD across Australia.</p

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts