Burden of Cardiovascular Risk Factors Over Time and Arterial Stiffness in Youth With Type 1 Diabetes Mellitus: The SEARCH for Diabetes in Youth Study

Background: The incidence of type 1 diabetes mellitus (T1DM) in children is increasing, resulting in higher burden of cardiovascular diseases due to diabetes mellitus–related vascular dysfunction. Methods and Results: We examined cardiovascular risk factors (CVRFs) and arterial parameters in 1809 youth with T1DM. Demographics, anthropometrics, blood pressure, and laboratory data were collected at T1DM onset and 5 years later. Pulse wave velocity and augmentation index were collected with tonometry. ANOVA or chi�square tests were used to test for differences in measures of arterial parameters by CVRF. Area under the curve of CVRFs was entered in general linear models to explore determinants of accelerate vascular aging. Participants at the time of arterial measurement were 17.6±4.5 years old, 50% female, 76% non�Hispanic white, and duration of T1DM was 7.8±1.9 years. Glycemic control was poor (glycated hemoglobin, 9.1±1.8%). All arterial parameters were higher in participants with glycated hemoglobin ≥9% and pulse wave velocity was higher with lower insulin sensitivity or longer duration of diabetes mellitus. Differences in arterial parameters were found by sex, age, and presence of obesity, hypertension, or dyslipidemia. In multivariable models, higher glycated hemoglobin, lower insulin sensitivity, body mass index, blood pressure, and lipid areas under the curve were associated with accelerated vascular aging. Conclusions: In young people with T1DM, persistent poor glycemic control and higher levels of traditional CVRFs are independently associated with arterial aging. Improving glycemic control and interventions to lower CVRFs may prevent future cardiovascular events in young individuals with T1DM

Inflammation and acute traffic-related air pollution exposures among a cohort of youth with type 1 diabetes

Background: Evidence remains equivocal regarding the association of inflammation, a precursor to cardiovascular disease, and acute exposures to ambient air pollution from traffic-related particulate matter. Though youth with type 1 diabetes are at higher risk for cardiovascular disease, the relationship of inflammation and ambient air pollution exposures in this population has received little attention. Objectives: Using five geographically diverse US sites from the racially- and ethnically-diverse SEARCH for Diabetes in Youth Cohort, we examined the relationship of acute exposures to PM2.5 mass, Atmospheric Dispersion Modeling System (ADMS)-Roads traffic-related PM concentrations near roadways, and elemental carbon (EC) with biomarkers of inflammation including interleukin-6 (IL-6), c-reactive protein (hs-CRP) and fibrinogen. Methods: Baseline questionnaires and blood were obtained at a study visit. Using a spatio-temporal modeling approach, pollutant exposures for 7 days prior to blood draw were assigned to residential addresses. Linear mixed models for each outcome and exposure were adjusted for demographic and lifestyle factors identified a priori. Results: Among the 2566 participants with complete data, fully-adjusted models showed positive associations of EC average week exposures with IL-6 and hs-CRP, and PM2.5 mass exposures on lag day 3 with IL-6 levels. Comparing the 25th and 75th percentiles of average week EC exposures resulted in 8.3% higher IL-6 (95%CI: 2.7%,14.3%) and 9.8% higher hs-CRP (95%CI: 2.4%,17.7%). We observed some evidence of effect modification for the relationships of PM2.5 mass exposures with hs-CRP by gender and with IL-6 by race/ethnicity. Conclusions: Indicators of inflammation were associated with estimated traffic-related air pollutant exposures in this study population of youth with type 1 diabetes. Thus youth with type 1 diabetes may be at increased risk of air pollution-related inflammation. These findings and the racial/ethnic and gender differences observed deserve further exploration

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

The Framingham Heart Study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reports

Background: The Framingham Heart Study (FHS), founded in 1948 to examine the epidemiology of cardiovascular disease, is among the most comprehensively characterized multi-generational studies in the world. Many collected phenotypes have substantial genetic contributors; yet most genetic determinants remain to be identified. Using single nucleotide polymorphisms (SNPs) from a 100K genome-wide scan, we examine the associations of common polymorphisms with phenotypic variation in this community-based cohort and provide a full-disclosure, web-based resource of results for future replication studies. Methods: Adult participants (n = 1345) of the largest 310 pedigrees in the FHS, many biologically related, were genotyped with the 100K Affymetrix GeneChip. These genotypes were used to assess their contribution to 987 phenotypes collected in FHS over 56 years of follow up, including: cardiovascular risk factors and biomarkers; subclinical and clinical cardiovascular disease; cancer and longevity traits; and traits in pulmonary, sleep, neurology, renal, and bone domains. We conducted genome-wide variance components linkage and population-based and family-based association tests. Results: The participants were white of European descent and from the FHS Original and Offspring Cohorts (examination 1 Offspring mean age 32 ± 9 years, 54% women). This overview summarizes the methods, selected findings and limitations of the results presented in the accompanying series of 17 manuscripts. The presented association results are based on 70,897 autosomal SNPs meeting the following criteria: minor allele frequency ≥ 10%, genotype call rate ≥ 80%, Hardy-Weinberg equilibrium p-value ≥ 0.001, and satisfying Mendelian consistency. Linkage analyses are based on 11,200 SNPs and short-tandem repeats. Results of phenotype-genotype linkages and associations for all autosomal SNPs are posted on the NCBI dbGaP website at http:// www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. Conclusion: We have created a full-disclosure resource of results, posted on the dbGaP website, from a genome-wide association study in the FHS. Because we used three analytical approaches to examine the association and linkage of 987 phenotypes with thousands of SNPs, our results must be considered hypothesis-generating and need to be replicated. Results from the FHS 100K project with NCBI web posting provides a resource for investigators to identify high priority findings for replication.Molecular and Cellular Biolog

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Over-expression of BAD increases tumor growth rate and tumor take.

<p>Nude mice received four subcutaneous injections of 2×10⁶ C4-2Luc or C4-2LucBAD cells. A) Representative whole body images of the animals obtained at 1 day and 2 weeks after implantations using the IVIS100 and Living Image® software (Xenogen). B) Dot plot showing fold increase and median luminescence in mice injected with C4-2Luc and C4-2LucBAD cells. C) Percent of palpable tumors (over 5 mm) developed at injection sites. D) Representative tissue sections of formalin-fixed tumors stained for proliferation marker Ki67.</p

BAD expression increases proliferation of prostate cancer cells.

<p>(A) HA-BAD expression in C4-2LucBAD clone. (B) C4-2LucBAD cells proliferate at a faster rate than C42 cells. C4-2LucBAD cells or C4-2Luc cells were plated in triplicate 6 cm dishes. At days 1 and 4 after plating, cells were trypsinized and counted. Results at 4 days were significantly different with a p value of <0.001. Comparable results were obtained in experiments in which proliferation was measured with the MTT assay. C) Transient expression of HA-BAD stimulates proliferation. LNCaP cells were transfected with 9∶1 mixture of GFP and either of HA-BAD or empty expression vector. Seven days after transfection, the number of GFP positive cells was counted. Graph shows the HA-BAD/empty vector ratio of GFP positive cells. Proliferation of GFP-positive cells was confirmed by time lapse video recording. D) Knocking down BAD expression with shRNA decreases proliferation. A lentiviral vector (pLentiLox 3.7) with a BAD shRNA insert was used to infect C42cells. C4-2Luc cells were plated in triplicate 6 cm dishes. At day 1 and 4 after plating, cells were trypsinized and counted. Experiments were repeated at least 3 times. E) Western blot analysis of BAD expression in cells infected with empty lentiviral vector, scrambled shRNA or BAD-specific shRNA. Expression of total ERK was used as loading control.</p

Estimating incidence of type 1 and type 2 diabetes using prevalence data: the SEARCH for Diabetes in Youth study

Hoyer A, Brinks R, Tonnies T, et al. Estimating incidence of type 1 and type 2 diabetes using prevalence data: the SEARCH for Diabetes in Youth study. BMC Medical Research Methodology. 2023;23(1): 39.BACKGROUND: Incidence is one of the most important epidemiologic indices in surveillance. However, determining incidence is complex and requires time-consuming cohort studies or registries with date of diagnosis. Estimating incidence from prevalence using mathematical relationships may facilitate surveillance efforts. The aim of this study was to examine whether a partial differential equation (PDE) can be used to estimate diabetes incidence from prevalence in youth.; METHODS: We used age-, sex-, and race/ethnicity-specific estimates of prevalence in 2001 and 2009 as reported in the SEARCH for Diabetes in Youth study. Using these data, a PDE was applied to estimate the average incidence rates of type 1 and type 2 diabetes for the period between 2001 and 2009. Estimates were compared to annual incidence rates observed in SEARCH. Precision of the estimates was evaluated using 95% bootstrap confidence intervals.; RESULTS: Despite the long period between prevalence measures, the estimated average incidence rates mirror the average of the observed annual incidence rates. Absolute values of the age-standardized sex- and type-specific mean relative errors are below 8%.; CONCLUSIONS: Incidence of diabetes can be accurately estimated from prevalence. Since only cross-sectional prevalence data is required, employing this methodology in future studies may result in considerable cost savings. © 2023. The Author(s)