Carotid stiffness in young adults: a life-course analysis of its early determinants The Amsterdam Growth and Health Longitudinal Study

Cardiovascular risk factors affecting arterial stiffness in adulthood may develop at different critical periods earlier in life. We examined whether the trajectories, from adolescence to young adulthood, of blood pressure, body fatness and fat distribution, blood lipids, cardiorespiratory fitness, and heart rate determined levels of arterial stiffness in young adults. We investigated 373 apparently healthy adults in whom cardiovascular risk factors were repeatedly examined between the ages of 13 and 36 years and carotid stiffness estimates were obtained at the age of 36 years. Differences in the mean levels and the trajectories of risk factors throughout the 24-year longitudinal period between subjects with different levels of carotid stiffness at age 36 years were analyzed with generalized estimating equations. Compared with individuals with less stiff carotid arteries, those with stiffer carotid arteries at the age of 36 years were characterized from ages 13 to 36 years by greater levels of and steeper increases in blood pressure and central fatness, independently of each other and other risk factors. These increases were already present in adolescence, preceded the development of poorer levels of blood lipids, cardiorespiratory fitness, and heart rate, which were evident during adulthood only, and explained to a great extent the deleterious association between these risk factors and carotid stiffness at the age of 36 years. Multiple and intertwined mechanisms involved in the pathogenesis of arterial stiffness have their origins in early life. Blood pressure and central fatness have a pivotal role herein and should be specifically targeted to prevent arterial stiffening and its cardiovascular sequelae

Expression of BNIP3 in invasive breast cancer: correlations with the hypoxic response and clinicopathological features

<p>Abstract</p> <p>Background</p> <p>Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is a pro-apoptotic member of the Bcl-2 family induced under hypoxia. Low or absent expression has recently been described in human tumors, including gastrointestinal tumors, resulting in poor prognosis. Little is known about BNIP3 expression in invasive breast cancer. The aim of the present study was to investigate the expression of BNIP3 in invasive breast cancer at the mRNA and protein level in correlation with the hypoxic response and clinicopathological features.</p> <p>Methods</p> <p>In 40 cases of invasive breast cancer, BNIP3 mRNA <it>in situ </it>hybridization was performed on frozen sections with a digoxigenin labeled anti-BNIP3 probe. Paraffin embedded sections of the same specimens were used to determine protein expression of BNIP3, Hypoxia Inducible Factor 1 alpha (HIF-1α) and its downstream targets Glucose Transporter 1 (Glut-1) and Carbonic Anhydrase (CAIX) by immunohistochemistry.</p> <p>Results</p> <p>BNIP3 mRNA was expressed in 16/40 (40%) of the cases and correlated with BNIP3 protein expression (p = 0.0218). Neither BNIP3 protein nor mRNA expression correlated with expression of HIF-1α expression or its downstream targets. Tumors which showed loss of expression of BNIP3 had significantly more often lymph node metastases (82% vs 39%, p = 0.010) and showed a higher mitotic activity index (p = 0.027). BNIP3 protein expression was often nuclear in normal breast, but cytoplasmic in tumor cells.</p> <p>Conclusion</p> <p>BNIP3 expression is lost in a significant portion of invasive breast cancers, which is correlated with poor prognostic features such as positive lymph node status and high proliferation, but not with the hypoxic response.</p

Major decline of hepatitis C virus incidence rate over two decades in a cohort of drug users

Injecting drug users (DU) are at high risk for hepatitis C virus (HCV) and HIV infections. To examine the prevalence and incidence of these infections over a 20-year period (1985–005), the authors evaluated 1276 DU from the Amsterdam Cohort Studies who had been tested prospectively for HIV infection and retrospectively for HCV infection. To compare HCV and HIV incidences, a smooth trend was assumed for both curves over calendar time. Risk factors for HCV seroconversion were determined using Poisson regression. Among ever-injecting DU, the prevalence of HCV antibodies was 84.5% at study entry, and 30.9% were co-infected with HIV. Their yearly HCV incidence dropped from 27.5/100 person years (PY) in the 1980s to 2/100 PY in recent years. In multivariate analyses, ever-injecting DU who currently injected and borrowed needles were at increased risk of HCV seroconversion (incidence rate ratio 29.9, 95% CI 12.6, 70.9) compared to ever-injecting DU who did not currently inject. The risk of HCV seroconversion decreased over calendar time. The HCV incidence in ever-injecting DU was on average 4.4 times the HIV incidence, a pattern seen over the entire study period. The simultaneous decline of both HCV and HIV incidence probably results from reduced risk behavior at the population level

Identification of Novel Genetic Markers Associated with Clinical Phenotypes of Systemic Sclerosis through a Genome-Wide Association Strategy

Contains fulltext : 97006.pdf (publisher's version ) (Open Access)The aim of this study was to determine, through a genome-wide association study (GWAS), the genetic components contributing to different clinical sub-phenotypes of systemic sclerosis (SSc). We considered limited (lcSSc) and diffuse (dcSSc) cutaneous involvement, and the relationships with presence of the SSc-specific auto-antibodies, anti-centromere (ACA), and anti-topoisomerase I (ATA). Four GWAS cohorts, comprising 2,296 SSc patients and 5,171 healthy controls, were meta-analyzed looking for associations in the selected subgroups. Eighteen polymorphisms were further tested in nine independent cohorts comprising an additional 3,175 SSc patients and 4,971 controls. Conditional analysis for associated SNPs in the HLA region was performed to explore their independent association in antibody subgroups. Overall analysis showed that non-HLA polymorphism rs11642873 in IRF8 gene to be associated at GWAS level with lcSSc (P = 2.32x10(-12), OR = 0.75). Also, rs12540874 in GRB10 gene (P = 1.27 x 10(-6), OR = 1.15) and rs11047102 in SOX5 gene (P = 1.39x10(-7), OR = 1.36) showed a suggestive association with lcSSc and ACA subgroups respectively. In the HLA region, we observed highly associated allelic combinations in the HLA-DQB1 locus with ACA (P = 1.79x10(-61), OR = 2.48), in the HLA-DPA1/B1 loci with ATA (P = 4.57x10(-76), OR = 8.84), and in NOTCH4 with ACA P = 8.84x10(-21), OR = 0.55) and ATA (P = 1.14x10(-8), OR = 0.54). We have identified three new non-HLA genes (IRF8, GRB10, and SOX5) associated with SSc clinical and auto-antibody subgroups. Within the HLA region, HLA-DQB1, HLA-DPA1/B1, and NOTCH4 associations with SSc are likely confined to specific auto-antibodies. These data emphasize the differential genetic components of subphenotypes of SSc

Lessons from the Amsterdam Growth and Health Longitudinal Study

The Amsterdam Growth and Health Longitudinal Study is one of a handful of long-term cohort studies that began in childhood/adolescence. The unique characteristics of this cohort, with many repeated measures on a wide range of lifestyle and biological cardiovascular risk factors covering periods from adolescence through adulthood, when arterial aging phenotypes were thoroughly characterized, has provided valuable information for the better understanding of the etiology of arterial aging. This chapter describes the cohort profile and summarizes its key findings on the early and lifelong determinants of carotid stiffness (used as a marker of early vascular aging). Emphasis was put on findings derived from a life course approach to the analyses of the repeated risk factor exposure data since adolescence. We were able to identify pivotal risk factors and pinpoint the critical periods earlier in life when these were likely to start exerting its deleterious effects on vascular aging later in life. Adoption of healthy lifestyle early in life and sustained throughout the life course are of utmost importance to prevent early vascular aging

Lessons from the Amsterdam Growth and Health Longitudinal Study

The Amsterdam Growth and Health Longitudinal Study is one of a handful of long-term cohort studies that began in childhood/adolescence. The unique characteristics of this cohort, with many repeated measures on a wide range of lifestyle and biological cardiovascular risk factors covering periods from adolescence through adulthood, when arterial aging phenotypes were thoroughly characterized, has provided valuable information for the better understanding of the etiology of arterial aging. This chapter describes the cohort profile and summarizes its key findings on the early and lifelong determinants of carotid stiffness (used as a marker of early vascular aging). Emphasis was put on findings derived from a life course approach to the analyses of the repeated risk factor exposure data since adolescence. We were able to identify pivotal risk factors and pinpoint the critical periods earlier in life when these were likely to start exerting its deleterious effects on vascular aging later in life. Adoption of healthy lifestyle early in life and sustained throughout the life course are of utmost importance to prevent early vascular aging

Lifetime Vigorous But Not Light-To-Moderate Habitual Physical Activity Impacts Favorably on Carotid Stiffness in Young Adults

Higher levels of habitual physical activity favorably impact on arterial stiffness. It is not clear, however, whether lifetime habitual physical activities of different intensities carry the same protective effect and to what extent any such effect is mediated by other biological cardiovascular risk factors. We, therefore, examined longitudinal data on habitual physical activity and cardiovascular risk factors (8 repeated measures between the ages of 13 and 36 years) in 373 subjects in whom stiffness estimates of the carotid artery were assessed at age 36 years using noninvasive ultrasonography. The time spent in habitual physical activities (in minutes per week) throughout the longitudinal period was compared between subjects across tertiles of the following stiffness estimates: β-stiffness index, distensibility and compliance coefficients, and the Young\u27s elastic modulus. After adjustments for sex, body height, and other lifestyle variables, subjects in the highest tertile of the β-stiffness index (ie, with stiffer arteries) had spent, on average, throughout the longitudinal period, less time in vigorous (−26.5 [95% CI: −45.9 to −7.1]) but less so in light-to-moderate habitual physical activities (−11.2 [95% CI: −53.5 to 31.1]) as compared with subjects in the lowest tertile. The difference in time spent in vigorous activities was greatly attenuated when further adjusted for blood lipids, cardiorespiratory fitness, fat distribution, resting heart rate, and mean arterial pressure (to −11.2 [95% CI: −29.4 to 7.0]). Similar results were found for the other stiffness estimates. Promoting vigorous intensity physical activities among the healthy young may, therefore, prevent arterial stiffness and related cardiovascular sequelae later in life, partly through its favorable impact on other biological cardiovascular risk factors

Self-reported time spent watching television is associated with arterial stiffness in young adults: The Amsterdam growth and health longitudinal study

Objectives: To investigate whether time spent watching television (a marker of sedentary behaviour) is associated with arterial stiffness, a major determinant of cardiovascular disease, and whether any such association could be explained by related deleterious levels of habitual physical activity (HPA) and/or other lifestyle and biological risk factors. Methods: Prospective measures (ages 32 and 36 years) of television time and risk factors were retrieved from 373 participants (196 women) in whom stiffness of the carotid, brachial and femoral arteries was assessed by means of ultrasonography at age 36 years. Data were analysed with generalised estimating equations. Results: Participants with stiffer carotid arteries spent more time (in min/day) watching television during the four preceding years than did those with less stiff arteries, as defined on the basis of the highest compared with the lowest gender-specific tertiles of the distensibility or compliance coefficients (reversed) or the Young's elastic modulus: +22.4 (95%CI 8.7 to 36.1), +18.4 (4.2 to 32.5) and +19.7 (6.0 to 33.4), respectively. These differences were independent of potential confounders, such as vigorous intensity HPA and other lifestyle risk factors, and could only in part (up to 31%) be explained by the adverse associations of television time with traditional biological risk factors. Qualitatively similar results were found for femoral, but not brachial, stiffness estimates. Conclusions: Given the independent associations of time spent watching television and vigorous intensity HPA with arterial stiffness, our study suggests that not only promotion of physical activity, but also discouragement of sedentary behaviours should be targeted in younger adults to prevent arterial stiffening