Background and Purpose
Vascular tone is regulated by the relative contractile state of vascular smooth muscle cells (VSMCs). Several integrins directly modulate VSMC contraction by regulating calcium ...influx through L‐type voltage‐gated Ca2+ channels (VGCCs). Genetic variants in ITGA9, which encodes the α9 subunit of integrin α9β1, and SVEP1, a ligand for integrin α9β1, associate with elevated blood pressure; however, neither SVEP1 nor integrin α9β1 has reported roles in vasoregulation. We determined whether SVEP1 and integrin α9β1 can regulate VSMC contraction.
Experimental Approach
SVEP1 and integrin binding were confirmed by immunoprecipitation and cell binding assays. Human induced pluripotent stem cell‐derived VSMCs were used in in vitro Ca2+i studies, and aortas from a Svep1+/− knockout mouse model were used in wire myography to measure vessel contraction.
Key Results
We confirmed the ligation of SVEP1 to integrin α9β1 and additionally found SVEP1 to directly bind to integrin α4β1. Inhibition of SVEP1, integrin α4β1 or α9β1 significantly enhanced Ca2+i levels in isolated VSMCs to Gαq/11‐vasoconstrictors. This response was confirmed in whole vessels where a greater contraction to U46619 was seen in vessels from Svep1+/− mice compared to littermate controls or when integrin α4β1 or α9β1 was inhibited. Inhibition studies suggested that this effect was mediated via VGCCs, PKC and Rho A/Rho kinase dependent mechanisms.
Conclusions and Implications
Our studies reveal a novel role for SVEP1 and the integrins α4β1 and α9β1 in reducing VSMC contractility. This could provide an explanation for the genetic associations with blood pressure risk at the SVEP1 and ITGA9 loci.
Genetic variants in SVEP1 associate with elevated blood pressure. SVEP1 is expressed in VSMCs. SVEP1 plays a novel role in reducing vascular smooth muscle contractility.
Given the rapid increase in the prevalence of childhood obesity, identifying the sociodemographic influences on obesity status is important for planning and implementing effective prevention ...initiatives. However, this type of data is limited for Greek children. Therefore the aim of the present study was to identify possible sociodemographic factors associated with childhood obesity at the national level.
Cross-sectional, population-based survey, carried out from October to May 2009. Setting Under the context of the GRECO (Greek Childhood Obesity) study, a nationwide sample of 2315 primary-school children.
Children aged 10-12 years and their parents were voluntarily enrolled. Direct anthropometric measurements of the children were obtained and information on sociodemographic characteristics of the parents, as well as their self-reported values of body weight and height, were collected.
Overweight and obesity prevalence was 29·5 % and 13·1 %, respectively, among boys; 29·5 % and 9·0 %, respectively, among girls. Multiple logistic regression analysis revealed that the most important sociodemographic predictors of childhood obesity were mother's age, parental BMI classification and father's type of occupation. More specifically, increased mother's age and normal BMI status of the parents seemed to have a protective effect on the likelihood of having an overweight/obese child. Additionally, the odds of a female child of being overweight/obese were reduced when the father's type of occupation tended to be less manual.
Anti-obesity health policy interventions have to address to the parents and promote their active involvement, to effectively confront the alarming magnitude of the paediatric obesity problem in Greece.
The Parent Report of Children's Abilities-Revised (PARCA-R) can be used to identify preterm born children at risk for developmental delay at age 24 months. However, standardised scores for assessing ...all children in the general population and quantifying development relative to the norm are unavailable, thus limiting the use of the questionnaire. We aimed to develop scores that are standardised by age and sex for the PARCA-R to assess children's cognitive and language development at age 24-27 months.
Anonymised data from PARCA-R questionnaires that were completed by parents of 2-year-old children in three previous studies were obtained to form a standardisation sample that was representative of the UK general population. Anonymised data were obtained from three further studies to assess the external validity and clinical validity of the standardised scores. We used the lambda-mu-sigma (lambda for skewness, mu for median, sigma for the coefficient of variation) method to develop scores that are standardised by age and sex for three scales (non-verbal cognitive development, language development, and total parent report composite PRC) for children in four 1-month age bands, spanning age 23·5-27·5 months.
We included 6402 children (mean age 25 months and 1 day range 23 months and 16 days to 27 months and 15 days) in the standardisation sample and 709 (mean age 24 months and 19 days 23 months and 16 days to 27 months and 15 days) to test the external validity and 1456 (mean age 24 months and 8·5 days 23 months and 16 days to 27 months and 15 days) to test the clinical validity of the standardised scores. For all PARCA-R scales, mean standardised scores approximated 100 (SD 15) in both sexes and all age groups. These scores were independent of socioeconomic status. Standardised scores were close to 100 (15) in the external validation sample, showing the validity of the scores. Standardised scores for the total PRC scale for children born very preterm (<32 weeks' gestation) were 0·47 SD lower on average than the normative mean, and for children with neonatal sepsis were 0·73 SD lower on average than the normative mean. These scores were equivalent to a standardised score of 93 (95% CI 91-94) for children born very preterm and 89 (88-91) for children with neonatal sepsis, thus showing clinical validity.
The PARCA-R provides a norm-referenced, standardised assessment of cognitive and language development at 24-27 months of age. The questionnaire is available non-commercially in English with translations available in 14 other languages, thus providing clinicians and researchers with a cost-effective tool for assessing development and identifying children with delay.
Action Medical Research (Ref: GN2580).
Telomere length is associated with risk of several age-related diseases and cancers. We aimed to investigate the extent to which telomere length might be modifiable through lifestyle and behaviour, ...and whether such modification has any clinical consequences.
In this population-based study, we included participants from UK Biobank who had leukocyte telomere length (LTL) measurement, ethnicity, and white blood cell count data. We investigated associations of LTL with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating between them smoking, physical activity, diet, maintenance of a healthy bodyweight, and alcohol intake, using both available and imputed data. To help interpretation, associations were summarised as the number of equivalent years of age-related change in LTL by dividing the trait β coefficients with the age β coefficient. We used mendelian randomisation to test causality of selected associations. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease might be mediated through LTL.
422 797 participants were available for the analysis (227 620 53·8% were women and 400 036 94·6% were White). 71 traits showed significant (p<4·27 × 10–4) associations with LTL but most were modest, equivalent to less than 1 year of age-related change in LTL. In multivariable analyses of 17 traits with stronger associations (equivalent to ≥2 years of age-related change in LTL), oily fish intake, educational attainment, and general health status retained a significant association of this magnitude, with walking pace and current smoking being additionally significant at this level of association in the imputed models. Mendelian randomisation analysis suggested that educational attainment and smoking behaviour causally affect LTL. Both indices of healthy behaviour were positively and linearly associated with LTL, with those with the most healthy behaviours having longer LTL equivalent to about 3·5 years of age-related change in LTL than those with the least heathy behaviours (p<0·001). However, healthy behaviours explained less than 0·2% of the total variation in LTL and did not significantly modify the association of LTL with risk of any of the diseases studied. Neither the association of more healthy behaviours on greater life expectancy or lower risk of coronary artery disease were substantially mediated through LTL.
Although several potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy. Attempts to change telomere length through lifestyle or behavioural changes might not confer substantial clinical benefit.
UK Medical Research Council, UK Biotechnology and Biological Sciences Research Council, and British Heart Foundation.
To evaluate time trends in the availability of soft drinks, to identify food choices associated with their consumption and to assess the relationship between socio-economic status and daily soft ...drink availability in a wide range of European countries.
Data on food and beverage availability collected through the national household budget surveys and harmonized in the DAFNE (Data Food Networking) project were used. Averages and variability of soft drink availability were estimated and tests for time trends were performed. The daily availability of food groups which appear to be correlated with that of soft drinks was further estimated. Multivariate logistic and linear regression models were applied to evaluate the association between socio-economic status and the acquisition of soft drinks.
Twenty-four European countries.
Nationally representative samples of households.
The availability of soft drinks is steadily and significantly increasing. Households in West and North Europe reported higher daily availability of soft drinks in comparison to other European regions. Soft drinks were also found to be correlated with lower availability of plant foods and milk and higher availability of meat and sugar products. Lower socio-economic status was associated with more frequent and higher availability of soft drinks in the household.
Data collected in national samples of twenty-four European countries showed disparities in soft drink availability among socio-economic strata and European regions. The correlation of soft drinks with unfavourable dietary choices has public health implications, particularly among children and adolescents.
This study investigated temporal trends in the epidemiology of primary myopia and associations with key environmental risk factors in a UK population. Data were collected at recruitment ...(non-cycloplegic autorefraction, year of birth, sex, ethnicity, highest educational attainment, reason and age of first wearing glasses and history of eye disease) from 107,442 UK Biobank study participants aged 40 to 69 years, born between 1939 and 1970. Myopia was defined as mean spherical equivalent (MSE) ≤-1 dioptre (D). Temporal changes in myopia frequency by birth cohort (5-year bands using date of birth) and associations with environmental factors were analysed, distinguishing both type (childhood-onset, <18 years versus adult-onset) and severity (three categories: low -1.00 to -2.99D, moderate -3.00 to -5.99D or high ≥-6.00D). Overall myopia frequency increased from 20.0% in the oldest cohort (births 1939–1944) to 29.2% in the youngest (1965–1970), reflecting a relatively higher increase in frequency of adult-onset and low myopia. Childhood-onset myopia peaked in participants born in 1950–54, adult-onset myopia peaked in the cohort born a decade later. The distribution of MSE only shifted for childhood-onset myopia (median: -3.8 IQR -2.4, -5.4 to -4.4 IQR -3.0, -6.2). The magnitude of the association between higher educational attainment (proxy for educational intensity) and myopia overall increased over time (adjusted Odds Ratio (OR) 2.7 2.5, 2.9 in the oldest versus 4.2 3.3, 5.2 in the youngest cohort), being substantially greater for childhood-onset myopia (OR 3.3 2.8, 4.0 to 8.0 4.2, 13). Without delineating childhood-onset from adult-onset myopia, important temporal trends would have been obscured. The differential impact of educational experience/intensity on both childhood-onset and high myopia, amplified over time, suggests a cohort effect in gene-environment interaction with potential for increasing myopia frequency if increasing childhood educational intensity is unchecked. However, historical plateauing of myopia frequency does suggest some potential for effective intervention.
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