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Objective: Sex, age, and education are associated with the level of cognitive performance. We investigated whether these factors modulate the change in cognitive performance in midlife by leveraging the longitudinal data from the Cardiovascular Risk in Young Finns Study (YFS). Methods: Participants of the YFS cohort performed a computer-based Cambridge Neuropsychological Test Automated Battery (CANTAB) in 2011 and 2018 (n = 1671, age 41–56 years in 2018). Overall cognitive performance and domains representing learning and memory, working memory, reaction time, and information processing were extracted by common principal component analysis from the longitudinal cognitive data. Linear models adjusted for baseline cognitive performance were used to study the association of sex, age, and education with changes in overall cognitive performance and in the cognitive domains. Results: Cognitive performance decreased in all domains (overall cognition -0.56 SD, p < 0.001; working memory -0.81 SD, p < 0.001; learning and memory -0.70 SD, p < 0.001; reaction time -0.06 SD, p = 0.019; information processing -0.03 SD, p = 0.016). The decrease in working memory and information processing was greater in females compared to males. Cognitive performance decreased more in older participants in all domains. Education alleviated the decrease in cognitive performance in all domains except reaction time. The beneficial effect of education was greater for males. Conclusions: This study describes the natural course of aging-related changes in cognitive performance in midlife, the critical time window for early prevention of clinical cognitive decline. These findings provide a reference for studies focusing on determinants of pathological cognitive decline deviating from normal changes in cognitive performance. [ABSTRACT FROM AUTHOR]

Epicardial adipose tissue (EAT) is the cardiac visceral fat depot proposed to play a role in the etiology of various cardiovascular disease outcomes. Little is known about EAT determinants in a general population. We examined cardiometabolic, dietary, lifestyle and socioeconomic determinants of echocardiograpghically measured EAT in early adulthood. Data on cardiometabolic, dietary, lifestyle and socioeconomic factors were collected from participants of the Cardiovascular Risk in Young Finns Study (YFS; N = 1667; age 34–49 years). EAT thickness was measured from parasternal long axis echocardiograms. Multivariable regression analysis was used to study potential EAT determinants. Possible effect modification of sex was addressed. Mean EAT thickness was 4.07 mm (95% CI 4.00–4.17). Multivariable analysis [β indicating percentage of change in EAT(mm) per one unit increase in determinant variable] indicated female sex (β = 11.0, P < 0.0001), type 2 diabetes (β = 14.0, P = 0.02), waist circumference (cm) (β = 0.38, P < 0.0001), systolic blood pressure (mmHg) (β = 0.18, P = 0.02) and red meat intake (g/day) (β = 0.02, P = 0.05) as EAT determinants. Sex-specific analysis revealed age (year) (β = 0.59, P = 0.01), alcohol intake (drinks/day) (β = 4.69, P = 0.006), heavy drinking (yes/no) (β = 30.4, P < 0.0001) as EAT determinants in women and fruit intake (g/day) (β = −1.0, P = 0.04) in men. In the YFS cohort, waist circumference, systolic blood pressure and red meat intake were directly associated with EAT among all participants. In women, age, alcohol intake, heavy drinking and type 2 diabetes associated directly with EAT, while an inverse association was observed between fruit intake and EAT in men. [ABSTRACT FROM AUTHOR]

Genetic architecture of plasma lipidome provides insights into regulation of lipid metabolism and related diseases. We applied an unsupervised machine learning method, PGMRA, to discover phenotype-genotype many-to-many relations between genotype and plasma lipidome (phenotype) in order to identify the genetic architecture of plasma lipidome profiled from 1,426 Finnish individuals aged 30–45 years. PGMRA involves biclustering genotype and lipidome data independently followed by their inter-domain integration based on hypergeometric tests of the number of shared individuals. Pathway enrichment analysis was performed on the SNP sets to identify their associated biological processes. We identified 93 statistically significant (hypergeometric p-value < 0.01) lipidome-genotype relations. Genotype biclusters in these 93 relations contained 5977 SNPs across 3164 genes. Twenty nine of the 93 relations contained genotype biclusters with more than 50% unique SNPs and participants, thus representing most distinct subgroups. We identified 30 significantly enriched biological processes among the SNPs involved in 21 of these 29 most distinct genotype-lipidome subgroups through which the identified genetic variants can influence and regulate plasma lipid related metabolism and profiles. This study identified 29 distinct genotype-lipidome subgroups in the studied Finnish population that may have distinct disease trajectories and therefore could be useful in precision medicine research. [ABSTRACT FROM AUTHOR]

Children have special rights for protection compared to adults in our society. However, more than 1/4 of children globally have no documentation of their date of birth. Hence, there is a pressing need to develop biological methods for chronological age prediction, robust to differences in genetics, psychosocial events and physical living conditions. At present, DNA methylation is the most promising biological biomarker applied for age assessment. The human genome contains around 28 million DNA methylation sites, many of which change with age. Several epigenetic clocks accurately predict chronological age using methylation levels at age associated GpG-sites. However, variation in DNA methylation increases with age, and there is no epigenetic clock specifically designed for adolescents and young adults. Here we present a novel age Predictor for Adolescents and Young Adults (PAYA), using 267 CpG methylation sites to assess the chronological age of adolescents and young adults. We compared different preprocessing approaches and investigated the effect on prediction performance of the epigenetic clock. We evaluated performance using an independent validation data set consisting of 18-year-old individuals, where we obtained a median absolute deviation of just below 0.7 years. This tool may be helpful in age assessment of adolescents and young adults. However, there is a need to investigate the robustness of the age predictor across geographical and disease populations as well as environmental effects. [ABSTRACT FROM AUTHOR]

While sunlight may influence cognitive function through several pathways, associations of residential sunlight exposure with cognitive function are not well known. We evaluated associations of long-term residential sunlight exposure with cognitive function among a representative cohort of 1838 Finnish adults residing in Finland who underwent comprehensive cognitive assessment in midlife. We linked daily recordings of global solar radiation to study participants using residential information and calculated the average daily residential exposure to sunlight for four exposure time intervals: 2 months, 1 year, 2 years and 5 years prior to the date of the cognition assessment. Associations of the residential sunlight exposure with cognitive function were assessed using linear regression analyses adjusting for season, sex, age, and individual- and neighborhood-level socioeconomic characteristics. Greater average residential sunlight exposure over 2 and 5 years prior to the cognitive function assessment was associated with better global cognitive function (b = 0.13, 95% CI = 0.01, 0.25; b = 0.17, 95% CI = 0.05, 0.29, per 1 MJ/m2 difference in sunlight exposure), while no associations with global cognitive function were observed at shorter exposure time intervals. In domain-specific analyses, greater residential exposure to sunlight over 1, 2 and 5 years prior to the cognitive function assessment was associated with better performance on new learning and visual memory (b = 0.10, 95% CI = 0.00, 0.20; b = 0.16, 95% CI = 0.04, 0.28; b = 0.19, 95% CI = 0.08, 0.31) and sustained attention (b = 0.15, 95% CI = 0.05, 0.25; b = 0.18, 95% CI = 0.06, 0.30; b = 0.17, 95% CI = 0.05, 0.29), but worse performance on reaction time (b = − 0.12, 95% CI = − 0.22, − 0.02; b = -0.15, 95% CI = − 0.28, − 0.02; b = − 0.18, 95% CI = − 0.30, − 0.05). Residential sunlight exposure was not associated with executive function. These findings suggest long-term residential sunlight exposure may be an environmental factor influencing cognitive function among a cognitively healthy cohort residing in Northern Europe. Further studies in populations residing in different geographical locations are needed. [ABSTRACT FROM AUTHOR]

Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD. Physterols are cholesterol homologs derived from plants, which are found in humans through consumption of plant products. Here the authors have performed a genome-wide meta-analysis of 32 serum phytosterol traits, with evidence suggesting causality between sitosterol and coronary artery disease. [ABSTRACT FROM AUTHOR]

Preterm birth (PTB) is associated with increased risk of type 2 diabetes and neurocognitive impairment later in life. We analyzed for the first time the associations of PTB with blood miRNA levels in adulthood. We also investigated the relationship of PTB associated miRNAs and adulthood phenotypes previously linked with premature birth. Blood MicroRNA profiling, genome-wide gene expression analysis, computer-based cognitive testing battery (CANTAB) and serum NMR metabolomics were performed for Young Finns Study subjects (aged 34–49 years, full-term n = 682, preterm n = 84). Preterm birth (vs. full-term) was associated with adulthood levels of hsa-miR-29b-3p in a fully adjusted regression model (p = 1.90 × 10–4, FDR = 0.046). The levels of hsa-miR-29b-3p were down-regulated in subjects with PTB with appropriate birthweight for gestational age (p = 0.002, fold change [FC] = − 1.20) and specifically in PTB subjects with small birthweight for gestational age (p = 0.095, FC = − 1.39) in comparison to individuals born full term. Hsa-miR-29b-3p levels correlated with the expressions of its target-mRNAs BCL11A and CS and the gene set analysis results indicated a target-mRNA driven association between hsa-miR-29b-3p levels and Alzheimer's disease, Parkinson's disease, Insulin signaling and Regulation of Actin Cytoskeleton pathway expression. The level of hsa-miR-29b-3p was directly associated with visual processing and sustained attention in CANTAB test and inversely associated with serum levels of VLDL subclass component and triglyceride levels. In conlcusion, adult blood levels of hsa-miR-29b-3p were lower in subjects born preterm. Hsa-miR-29b-3p associated with cognitive function and may be linked with adulthood morbidities in subjects born preterm, possibly through regulation of gene sets related to neurodegenerative diseases and insulin signaling as well as VLDL and triglyceride metabolism. [ABSTRACT FROM AUTHOR]

We analysed whole blood genome-wide expression data to identify gene co-expression modules shared by early traits of osteoporosis and atherosclerosis. Gene expression was profiled for the Young Finns Study participants. Bone mineral density and content were measured as early traits of osteoporosis. Carotid and bulbus intima media thickness were measured as early traits of atherosclerosis. Joint association of the modules, identified with weighted co-expression analysis, with early traits of the diseases was tested with multivariate analysis. Among the six modules significantly correlated with early traits of both the diseases, two had significant (adjusted p-values (p.adj) < 0.05) and another two had suggestively significant (p.adj < 0.25) joint association with the two diseases after adjusting for age, sex, body mass index, smoking habit, alcohol consumption, and physical activity. The three most significant member genes from the significant modules were NOSIP, GXYLT2, and TRIM63 (p.adj ≤ 0.18). Genes in the modules were enriched with biological processes that have separately been found to be involved in either bone metabolism or atherosclerosis. The gene modules and their most significant member genes identified in this study support the osteoporosis-atherosclerosis comorbidity hypothesis and can provide new joint biomarkers for both diseases and their dual prevention. [ABSTRACT FROM AUTHOR]

Individuals experiencing socioeconomic disadvantage in childhood have a higher rate of inflammation-related diseases decades later. Little is known about the mechanisms linking early life experiences to the functioning of the immune system in adulthood. To address this, we explore the relationship across social-to-biological layers of early life social exposures on levels of adulthood inflammation and the mediating role of gene regulatory mechanisms, epigenetic and transcriptomic profiling from blood, in 2,329 individuals from two European cohort studies. Consistently across both studies, we find transcriptional activity explains a substantive proportion (78% and 26%) of the estimated effect of early life disadvantaged social exposures on levels of adulthood inflammation. Furthermore, we show that mechanisms other than cis DNA methylation may regulate those transcriptional fingerprints. These results further our understanding of social-to-biological transitions by pinpointing the role of gene regulation that cannot fully be explained by differential cis DNA methylation. [ABSTRACT FROM AUTHOR]

Background: Cardiac involvement accounts for the majority of morbidity and mortality in sarcoidosis. Pathological myocardial fluorodeoxyglucose (FDG)-uptake in positron emission tomography (PET) has been associated with cardiovascular events and quantitative metabolic parameters have been shown to add prognostic value. Our aim was to study whether the pattern of pathological cardiac FDG-uptake and quantitative parameters are able to predict cardiovascular events in patients with suspected cardiac sarcoidosis (CS). Methods: 137 FDG-PET examinations performed in Tampere University Hospital were retrospectively analyzed visually and quantitatively. Location of pathological uptake was noted and pathological metabolic volume, average standardized uptake value (SUV), and total cardiac metabolic activity (tCMA) were calculated. Patients were followed for ventricular tachycardia, decrease in left ventricular ejection fraction, and death. Results: Eleven patients had one or more cardiovascular events during the follow-up. Five patients out of 12 with uptake in both ventricles had an event during follow-up. Eight patients had high tCMA (> 900 MBq) and three of them had a cardiovascular event. Right ventricular uptake and tCMA were significantly associated with cardiovascular events during follow-up (P-value.001 and.018, respectively). Conclusions: High tCMA and right ventricular uptake were significant risk markers for cardiac events among patient with suspected CS. [ABSTRACT FROM AUTHOR]

High blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension. [ABSTRACT FROM AUTHOR]

Introduction: In up to 65% of cardiac sarcoidosis patients, the disease is confined to the heart. Diagnosing isolated cardiac sarcoidosis is challenging due to the low sensitivity of endomyocardial biopsy. If cardiac sarcoidosis is part of biopsy-confirmed systemic sarcoidosis, the diagnosis can be based on cardiac imaging studies. We compared the imaging features of patients with isolated cardiac FDG uptake on positron emission tomography with those who had findings indicative of systemic sarcoidosis.Materials and Methods: 137 consecutive cardiac FDG-PET/CT studies performed on subjects suspected of having cardiac sarcoidosis were retrospectively analyzed.Results: 33 patients had pathological left ventricular FDG uptake, and 12 of these also had pathological right ventricular uptake. 16/33 patients with pathological cardiac uptake had pathological extracardiac uptake. 10/12 patients with both LV- and RV-uptake patterns had extracardiac uptake compared to 6/21 of those with pathological LV uptake without RV uptake. SUVmax values in the myocardium were higher among patients with abnormal extracardiac uptake. The presence of extracardiac uptake was the only imaging-related factor that could predict a biopsy indicative of sarcoidosis.Conclusion: Right ventricular involvement seems to be more common in patients who also have findings suggestive of suspected systemic sarcoidosis, compared with patients with PET findings indicative of isolated cardiac disease. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case−control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods: NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24–45 years). Associations between baseline metabolites and risk of developing diabetes during 8–15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results: Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59–1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31–1.33) and triacylglycerol within VLDL particles (OR 1.33–1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years). Conclusions/interpretation: Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk. [ABSTRACT FROM AUTHOR]

Introduction: Fluorodeoxyglucose positron emission tomography (FDG-PET) is a non-invasive imaging modality that has been shown to be a feasible method to demonstrate myocardial inflammation. The aim of this study was to identify the patients suspected of having cardiac sarcoidosis (CS), who are most likely to benefit from PET imaging.Materials and Methods: 137 patients suspected of having CS underwent a dedicated cardiac FDG-PET examination at Tampere University Hospital between August 2012 and September 2015. These examinations were retrospectively analyzed.Results: 33 and 12 of the 137 patients had abnormal left and right ventricular (LV and RV) FDG-uptake, respectively. Abnormal LV-uptake and RV-uptake were significantly associated with female sex and a history of advanced AV-block (P < 0.05). Abnormal RV-uptake was also associated with ventricular tachycardia and atrial fibrillation (P < 0.05). 56% of the 27 female patients with a history of AV-block had a pathological PET finding compared to only 6% of the 49 male patients without a history of AV-block. There were 17 female patients with history of both AV-block and ventricular tachycardia, 71% of them had abnormal PET finding.Conclusions: Abnormal FDG-PET findings were associated with female sex, AV-block, and arrhythmias in this clinical cohort. [ABSTRACT FROM AUTHOR]

Genetic lactase nonpersistence may influence calcium intake and thereby bone health. We investigated in the Cardiovascular Risk in Young Finn Study whether young adults aged 31-46 years with the C/C(-13910) genotype are more susceptible to reduced bone phenotypes, low-energy fractures, and low calcium intake than subjects with other lactase genotypes. We also analyzed the gene-environment interactions on bone with calcium intake and physical activity. Peripheral quantitative computed tomography bone traits were measured from the distal and shaft sites of the radius and tibia. The total number of those subjects whose nondominant forearm was measured and the lactase genotype was defined was 1551. Information on diet, lifestyle factors, and fractures was collected with questionnaires. The mean intake of calcium was the lowest in men with the C/C(-13910) genotype (P = 0.001). Men with the T/T(-13910) genotype had ~3% higher trabecular density at the distal radius and distal tibia compared to other lactase genotypes (P = 0.03 and 0.02, respectively). In women, we found no evidence of the gene effect at the radius and tibia. No major interactions of the C/T(-13910) polymorphism with calcium intake or physical activity on bone phenotypes were found in either sex. In conclusion, the C/T(-13910) polymorphism was associated with trabecular density at the distal radius and tibia in men. These differences may be due to the differences in calcium intake between the lactase genotypes. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin (PCSK) enzymes cleave and convert their immature substrates into biologically active forms. Polymorphisms in the PCSK genes have been reported to associate with human diseases and phenotypes, including hypercholesterolemia and blood pressure (BP), and targeting PCSKs is considered a promising future form of drug therapy. PCSK processing is readily induced upon upregulation of the enzyme, but the genetic factors contributing to PCSK expression have not been thoroughly characterized. To gain a comprehensive understanding of the genetic regulation of PCSK expression, we performed, for the first time, a genome-wide expression quantitative trait loci (eQTL) analysis using mRNA expression in >1400 human peripheral blood samples from the Cardiovascular Risk in Young Finns Study and ca. ten million single-nucleotide polymorphisms (SNPs). The expression data showed clear expression for FURIN, PCSK5, PCSK7 and MBTPS1 (membrane-bound transcription factor peptidase, site 1) mRNAs in virtually all tested samples. A discovery analysis demonstrated a genome-wide significant ( p < 5 × 10) association with the selected PCSK probes for 1024 variants, which were located at ten independent loci. Of these loci, 5/10 could be confirmed to regulate PCSK expression in two additional and independent sample sets. Finally, a phenotypic analysis demonstrated that a novel cis-eQTL SNP rs4702 for FURIN is strongly associated with both diastolic ( p = 0.012) and systolic ( p = 0.035) BP levels, as well as peripheral vascular resistance ( p = 0.003). These findings indicate that the expression of the PCSK enzymes is regulated by genetic factors, which have biological roles in health and disease. [ABSTRACT FROM AUTHOR]

The serotonin system has been shown to be involved in the regulation of hostility, anger, and aggressive behavior. Previous molecular genetic studies suggest that the serotonin receptor 1B (HTR1B) rs6296 genotype might have a particular role in these types of behaviors. We examined whether HTR1B is related to hostility, anger, and aggressive behavior phenotypes over a lifespan and whether it modifies the connection between childhood aggressive behavior and adulthood hostility and anger. The participants were 967 women and men from a large population based sample (The Young Finns Study) with a 27-year follow-up. Childhood aggressive behavior was reported by the mother twice when the participants were 3 to 12 years of age. Adulthood hostility and anger were self-reported by the participants between ages 24 and 36. Childhood aggressive behavior predicted adulthood hostility over 27 years. HTR1B SNP rs6296 was associated with childhood aggressive behavior but not with adulthood anger or hostility. The HTR1B SNP rs6296 modified the association between childhood aggressive behavior and adulthood hostility. Aggressive behavior and hostility might form a life course pattern, and the HTR1B might contribute to a development of this pattern. [ABSTRACT FROM AUTHOR]

In this article the affiliation details for Helena Gylling were incorrectly given as Department of Internal Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland but this should have been Heart and Lung Center, Cardiology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. The original article can be found online at https://doi.org/10.1038/s41467-021-27706-6. [Extracted from the article]

The association between diabetes and subclinical atherosclerosis is well established. The effect of non-diabetic glucose intolerance on early atherosclerosis is not as straightforward, and the data regarding sex-related differences in this matter are limited. Therefore, our aim was to investigate these associations in men and women separately. We studied 1,304 Finnish men and women over 45 years of age who participated in the Finnish Health 2000 Survey. Ultrasonically determined carotid artery intima-media thickness and elasticity were used as markers of early atherosclerosis. Glucose tolerance was categorized according to the American Diabetes Association criteria for diabetes mellitus. Age-adjusted means for carotid artery intima-media thickness and elasticity indices were significantly ( P < 0.05) associated with glucose tolerance status in both sexes. There was a trend of increasing early atherosclerosis with the worsening of glucose tolerance in men and women. These associations were weakened in both sexes after further adjustments for other cardiovascular risk factors. In women, but not in men, significant ( P < 0.05) associations between glucose tolerance status and carotid artery elasticity were seen even after these further adjustments. Diabetes and non-diabetic glucose intolerance are associated with increased early carotid atherosclerosis compared with normal glucose tolerance in both sexes. Our results suggest that women with glucose intolerance may be in greater risk than men. [ABSTRACT FROM AUTHOR]

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10?10) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders. [ABSTRACT FROM AUTHOR]

Recent healthcare policies have influenced the manner in which patient data is handled in research projects, and the regulations concerning protected health information have become significantly tighter. Thus, new procedures are needed to facilitate research while protecting the confidentiality of patient data and ensuring the integrity of clinical work in the expanding environment of electronic files and databases. We have addressed this problem in a university hospital setting by developing the Tampere Research Archival System (TARAS), an extensive data warehouse for research purposes. This dynamic system includes numerous integrated and pseudonymized imaging studies and clinical data. In a pilot study on asthma patients, we tested and improved the functionality of the data archival system. TARAS is feasible to use in retrieving, analyzing, and processing both image and non-image data. In this paper, we present a detailed workflow of the implementation process of the data warehouse, paying special attention to administrative, ethical, practical, and data security concerns. The establishment of TARAS will enhance and accelerate research practice at Tampere University Hospital, while also improving the safety of patient information as well as the prospects for national and international research collaboration. We hope that much can be learned from our experience of planning, designing, and implementing a research data warehouse combining imaging studies and medical records in a university hospital. [ABSTRACT FROM AUTHOR]

Summary: Peripheral bone strength and fracture risk were studied in young adult Finns. Peripheral bone measures were associated with risk factors of osteoporosis in young adults and discriminated between those with and without low-energy fractures. In men, trabecular bone loss at peripheral bone sites starts before the age of 40 years. Purpose: This is a cross-sectional study of the determinants of bone strength and fracture risk in young Finns using peripheral quantitative computed tomography (pQCT) and quantitative ultrasound (QUS). Methods: pQCT scans were performed in 1,884 subjects at distal and shaft sites of non-dominant radius and left tibia, and QUS measures ( n = 1,415) at the left calcaneus. Lifestyle factors and medical conditions affecting bone health were assessed with questionnaires. Results: In men, the youngest age cohort had the lowest trabecular volumetric bone mineral density (vBMD) at radius and tibia (difference between the youngest and the oldest, 4.4% and 5.6%, respectively, P < 0.001) and lowest speed of ultrasound at the calcaneus (difference 0.5%, P = 0.016). In women, bone traits did not differ by age groups. When sexes were pooled, underweight (relative risk (RR) = 2.95, P < 0.001), excess alcohol intake (1.52, P = 0.036), smoking (1.29, P = 0.025), Crohn's disease or inflammatory bowel syndrome (2.43, P = 0.016), epilepsy (2.54, P = 0.011), use of corticosteroids (2.01, P < 0.001) and inactivity (1.34, P = 0.045) increased the risk of low trabecular vBMD. RRs for low-energy fractures were excess alcohol intake (2.58, P = <0.001), anorexia (3.74, P = 0.041) and hypogonadism (2.08, P = 0.015). Same risk factors predicted BMD and fractures in both sexes. Trabecular bone mineral content, vBMD and bone strength index showed greatest differences (4-9%; P < 0.05) between those with and without low-energy fractures. Conclusions: Peripheral QCT traits are associated with common risk factors of osteoporosis in young Finns and discriminate between those with and without low-energy fractures. In men, trabecular bone loss at peripheral bone sites starts before the age of 40 years. [ABSTRACT FROM AUTHOR]

Officially 10–26 cases of vibration-induced white fingers (VWF) have been reported annually in Finland. It has been suggested that the numbers are underestimated. The purpose of the present study was to estimate the cumulative exposure to hand–arm vibration (HAV) and the prevalence of clinically diagnosed cases of VWF and carpal tunnel syndrome (CTS) in a population of Finnish metal workers and to determine the symptoms and clinical tests that would best predict the diagnosis. A questionnaire on vibration exposure at the workplace and symptoms of the upper extremities was sent to a sample ( n = 530) of members of the local Metalworkers Union. Those who reported finger blanching, numbness or tingling of the fingers or symptoms of CTS were invited to take part in clinical examinations. Their cumulative lifelong exposure to HAV was evaluated. Those whose symptoms referred to VWF or CTS were given a cold provocation test with the measurement of finger systolic blood pressure and electroneuromyography of the upper arms. Altogether 285 metal workers (54%) responded to the questionnaire, and 24 new cases of VWF (8.4%) and 12 cases of CTS (4.2%) were diagnosed. In the group of VWF patients, seven workers had both VWF and CTS. All of the workers diagnosed as having VWF also had numbness or tingling in their fingers. Consequently, questions concerning numbness and tingling, a two-point discrimination test, Phalen’s test, and Tinell’s test had a high predicting value for VWF. The exposure time of the VWF cases did not differ significantly from that of the study group as whole, but the cumulative exposure index was significantly higher. The results suggest that VWF is underdiagnosed in Finland. In screening for the health effects of HAV, sensorineural symptoms of hands should be carefully inquired about and examined in patients complaining of white fingers. More education on the recognition and evaluation of HAV exposure and its health effects is needed. [ABSTRACT FROM AUTHOR]

Background and objectives: Several studies have shown that treatment of coronary heart disease (CHD) does not meet the goals set in recommendations. The aim of this study was to investigate the adequacy of CHD drug treatment and secondary prevention measures, particularly with respect to age and gender biases, in a Finnish university hospital setting. Methods: The participant pool consisted of patients in FINCAVAS (Finnish Cardiovascular Study), which is a cohort study recruiting consecutive patients performing a clinical exercise test at Tampere University Hospital, Tampere, Finland. 802 patients (581 men, 221 women) with a prior diagnosis of CHD recruited between October 2001 and December 2004 were included in the analysis. Results: Only roughly 12% of both men and women had an optimal risk factor profile. High blood pressure and hypercholesterolaemia were more common in women than in men, whereas smoking was more frequent among men. Men used ACE inhibitors (32.9% vs 20.4%, respectively), β-adrenoceptor antagonists (80.8% vs 68.3%, respectively) and aspirin (acetylsalicylic acid) [69.7% vs 58.8%, respectively] more frequently than women, but the frequency of use of these medications was also not at the recommended levels in men. Risk factor control is poorer in older than younger age groups. Conclusions: CHD patients, particularly women, who performed an exercise stress test in a university hospital are suboptimally treated. [ABSTRACT FROM AUTHOR]

The purpose of the study was to compare the systemic safety and risk–benefit ratio of 0.1% timolol hydrogel and 0.5% aqueous timolol eye drops in the treatment of glaucoma. An 8-week randomised, double-blind, cross-over, multicentre study. A total of 25 patients with primary open-angle glaucoma, exfoliation glaucoma, or ocular hypertension was enrolled. After completing a wash-out period, patients were randomly chosen to receive either 0.1% timolol hydrogel once daily or 0.5% aqueous timolol eye drops twice daily. Intraocular pressure and heart rate during rest and exercise, head-up tilt test results, spirometry readings, and plasma concentrations of timolol were recorded. The risk–benefit ratio was determined by calculating the ratio between several heart rate endpoints and the change in intraocular pressure (IOP). The mean drug-induced change in the peak heart rate during exercise was −13.5 beats/min (SD 7.6) in the 0.5% aqueous timolol group and −5.1 beats/min (SD 6.7) in the 0.1% timolol hydrogel group ( P<0.001; 95% CI 4.06–12.18). There was no significant difference in the IOP-reducing efficacy between these compounds. The risk–benefit ratio was significantly improved when 0.1% timolol hydrogel was used, compared with 0.5% aqueous timolol in the exercise test. In the head-up tilt test the risk–benefit ratio was significantly improved at rest ( P<0.05), at 1 min ( P<0.05) and at 5 min ( P<0.001) after patients had received 0.1% timolol hydrogel. There were, however, no differences in spirometry readings. After patients had been treated with 0.1% timolol hydrogel, plasma concentrations of timolol were 1/6 (at peak) and 1/50 (at trough) of those of 0.5% aqueous timolol. Drug-induced changes in the peak heart rate, and head-up tilt test results as well as plasma concentrations of timolol, were significantly more pronounced after treatment with 0.5% aqueous timolol than with 0.1% timolol hydrogel. Because of the statistically similar IOP-reducing efficacy of these formulations the risk–benefit ratio was significantly improved when patients used 0.1% timolol hydrogel instead of 0.5% aqueous timolol. [ABSTRACT FROM AUTHOR]

We describe pronounced hypotension in a patient during orthostatic testing while receiving treatment with sildenafil and tamsulosin, but not with placebo. The patient was 71 years of age and had no history of orthostatic reactions. He had been diagnosed with benign prostatic hyperplasia (BPH) and glaucoma simplex (open-angle glaucoma). The only regular medication used was a combination of latanoprost and timolol one drop daily into each eye. The patient was among 16 men with BPH enrolled in a study of the haemodynamic effects of tamsulosin and sildenafil. The present patient was excluded from data analysis because of atypical reactions: he experienced a decrease in peripheral vascular resistance upon orthostasis during treatment with sildenafil and tamsulosin. This led to marked hypotension and cancellation of the tilt tests with both sildenafil alone (Riva-Rocci [RR] 75/50mm Hg) and a combination of sildenafil and tamsulosin (RR 60/45mm Hg); however, tamsulosin alone also lowered blood pressure to some extent (RR 100/80mm Hg). In conclusion, even though sildenafil and tamsulosin are considered haemodynamically safe, they may induce considerable vasodilation and, subsequently, harmful hypotension in susceptible patients. [ABSTRACT FROM AUTHOR]

Objective: To test the hypotheses that (1) CYP2D6 genotype is associated with pharmacokinetics of ophthalmic timolol and (2) variation in genotypes of ADRB1 (β1-adrenoceptor) and GNAS1 (α-subunit of G-protein) modulate heart rate (HR), and systolic (SAP) and diastolic (DAP) arterial pressure responses to timolol. Methods: Nineteen glaucoma patients and eighteen healthy volunteers were treated with 0.5% aqueous and 0.1% hydrogel formulations of ophthalmic timolol using a randomised cross-over design. The participants conducted head-up tilt and maximum exercise test at four visits. Plasma concentration of timolol was measured twice for glaucoma patients and ten times for healthy volunteers on each visit. Also, the genotypes for CYP2D6, ADRB1 and GNAS1 were determined. Results: Among healthy volunteers using aqueous timolol, poor metabolisers (PMs, n=2) of CYP2D6 had higher maximum plasma concentrations (Cmax, values 2.63 and 2.94 ng/ml), longer elimination half-lives (T½, 5.49 and 6.75 h), and higher area-undercurve (AUC, 19.54 and 23.25 ng·h/ml) than intermediate [IMs, n=6, mean±SD 1.73±0.59 ng/ml (not significant), 3.30±0.48 h, 11.32±3.72 ng·h/ml], extensive (EMs, n=8, 1.60±0.72 ng/ml, 3.24±1.24 h, 8.52±6.12 ng·h/ml) and ultra-rapid (UMs, n=2, values 1.23 and 1.67 ng/ml, 2.22 and 2.52 h, 6.16 and 6.94 ng·h/ml) metabolisers. The IMs, EMs and UMs did not differ from each other for any of the kinetic variables. Also, the elevation of HR from rest to maximum level tended to differ between PMs and IMs, and between PMs and UMs. The pharmacokinetics and pharmacodynamics between the CYP2D6 groups did not differ with statistical significance when hydrogel timolol was used. Upon head-up tilt, the Ser49 homozygotes (n=26) had higher SAP (P=0.03) and DAP (P«0.01) than the Gly carriers (n=11). The change in DAP from rest to maximum during exercise was lower (P«0.01) in subjects with CC alleles of GNAS1 (n=13) than those with at least one T allele (n=24). Conclusion: The CYP2D6 poor metabolisers may be more prone to systemic adverse events with aqueous timolol than extensive metabolisers. Since CYP2D6 genotyping is not routine clinical practice, using 0.1% timolol hydrogel instead of 0.5% aqueous preparation will increase patient safety. [ABSTRACT FROM AUTHOR]

Objectives: The aims of the study were to assess the correlation between the plasma concentration of ophthalmic timolol and cardiovascular parameters, and the influence of timolol on advanced haemodynamic variables, such as stroke (SI), cardiac (CI) and systemic vascular resistance (SVRI) indices and arterial pulse wave velocity (PWV). Methods: Twenty-five glaucoma or ocular hypertensive patients were treated with 0.5% aqueous and 0.1% hydrogel formulations of timolol using a randomised, double-masked, crossover, multicentre design. All the patients were subjected to passive head-up tilt, electrocardiography, exercise test and measurement of plasma concentration of timolol. In the analysis, the data on the two treatments were combined, and the Spearman correlation coefficients between the plasma level of timolol and physiological effects were calculated. Results: During the head-up tilt test before rising the bed up, the resting heart rate (HR; R=-0.52, P=0.001) and PWV (R=-0.34, P=0.04) were inversely correlated with timolol level. In the upright position, ophthalmic timolol effectively suppressed the rise in HR (R=-0.36, P=0.03). The SI did not change with timolol concentration, while CI diminished as timolol concentration rose (R=-0.39, P=0.02). The SVRI correlated with timolol concentration (R=0.38, P=0.02). In the exercise test, correlation between HR and plasma level of timolol steadily grew stronger as the load increased, reaching R=-0.6< (P<0.0001) at the maximum load. Systolic and diastolic arterial pressures were not associated with the timolol concentration. Conclusion: The plasma concentration of ophthalmic timolol correlates with several haemodynamic effects. As HR decreases, SVRI increases and blood pressure is kept unchanged. [ABSTRACT FROM AUTHOR]

The majority of the findings concerning arterial physiology and pathophysiology originate from studies with experimental animals, while only limited information exists about the functional characteristics of human arteries. Therefore, the aim of the present work was to compare the control of vascular tone in vitro in mesenteric arterial rings of corresponding size (outer diameter 0.75–1 mm) from humans and Wistar-Kyoto rats. The relaxations to acetylcholine (ACh) were clearly less marked in the mesenteric arteries of humans when compared with rats. How-ever, when calcium ionophore A23187 was used as the vasodilator, the endothelium-mediated relaxations did not significantly differ between these species. The NO synthase inhibitor N G-nitro-l-arginine methyl ester (l-NAME) attenuated the relaxations to ACh and A23187 in both groups. The endothelium-independent relaxations to the β-adrenoceptor agonist isoprenaline and the nitric oxide (NO)-donor nitroprusside were somewhat lower in human arteries, while vasodilation induced by the K+ channel opener cromakalim was similar between humans and rats. Arterial contractile sensitivity to noradrenaline and serotonin was slightly lower in human vessels, whereas contractile sensitivity to KCl was similar between these species. The contractions induced by cumulative addition of Ca2+ with noradrenaline as the agonist were effectively inhibited in both groups by the calcium channel blocker nifedipine, the effect of which was clearly more pronounced in human arteries. In conclusion, the control of vascular tone of isolated arteries of corresponding size from humans and rats appeared to be rather similar. The most marked differences between these species were the impaired endothelium-mediated dilation to ACh and the more pronounced effect of nifedipine on the Ca2+-induced contractions in human arteries. [ABSTRACT FROM AUTHOR]

Responses to cumulative addition of Ca (0.2-2.5 mM) after precontraction with potassium chloride (KCl) and noradrenaline in Ca-free medium were studied in isolated mesenteric arterial rings from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). The Ca contractions in 125 mM KCl-stimulated endothelium-denuded rings in the presence of atenolol (10 μM) and phentolamine (10 μM) were less marked in SHR than WKY, although the contractions to high concentrations of KCl in normal organ bath Ca (1.6 mM) were similar in these strains. The difference in Ca contractions between SHR and WKY during KCl stimulation was also present after 10-min pretreatment with 1 mM ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA) in Ca-free medium. However, when noradrenaline (1 μM) was used as the agonist the Ca contractions of endothelium-denuded rings in the two strains were comparable, while exposure to EGTA reduced these responses more effectively in SHR than WKY. Nifedipine (0.5 nM and 10 nM in KCl- and noradrenaline-stimulated rings, respectively) more efficiently inhibited the Ca contractions in hypertensive than in normotensive rats. The presence of intact vascular endothelium attenuated the contractions to Ca addition comparably (during KCl stimulation) or even more (during noradrenaline) in SHR when compared with WKY NG-nitro-L-arginine methyl ester (L-NAME, 0.1 mM) counteracted this attenuation correspondingly in WKY and SHR, and L-arginine (1 mM) restored it in both strains, whereas indomethacin (10 mM) was without effect on the response. However, mesenteric arterial relaxations induced by the endothelium-dependent agonists acetylcholine and ADP in noradrenaline-precontracted (1 μM) rings were clearly impaired in SHR, and also L-NAME (0.1 mM) reduced the responses to acetylcholine more efficiently in SHR. In contrast, the relaxations to acetylcholine and ADP in KCl-precontracted (60 mM) rings in the absence and presence of L-NAME were comparable between the two strains. In conclusion, attenuated contractile response to cumulative Ca addition during stimulation with KCl clearly differentiated arterial smooth muscle of hypertensive and normotensive rats, suggesting altered function of cell membrane in SHR. The more pronounced effect of nifedipine on the response indicates abnormal function of voltage-dependent Ca channels, and higher diminishing effect of EGTA on the contraction during noradrenaline suggests exaggerated action of the chelator on membrane-bound Ca in SHR. Interestingly, the depressant effect of intact endothelium on the Ca contraction response, mediated largely via nitric oxide, was not attenuated in SHR. Furthermore, impaired endothelium-dependent agonist-induced relaxations can be attributed to reduced release of endothelium-derived hyperpolarizing factor in this type of genetic hypertension. [ABSTRACT FROM AUTHOR]

The atherogenic process begins already in childhood and progresses to symptomatic condition with age. We investigated the association of cholesterol efflux capacity (CEC) and vascular markers of subclinical atherosclerosis in healthy, young adults. CEC was determined in 2282 participants of the Young Finns study using cAMP treated 3H-cholesterol-labeled J774 cells. The CEC was correlated to baseline and 6-year follow-up data of cardiovascular risk factors and ultrasound measurements of arterial structure and function. CEC was higher in women, correlated with total cholesterol, HDL-C, and apolipoprotein A-I, but not with LDL-C or apolipoprotein B. Compared to the lowest CEC quartile, the highest CEC quartile was significantly associated with high CRP levels and inversely associated with adiponectin. At baseline, high CEC was associated with decreased flow-mediated dilation (FMD) and carotid artery distensibility, as well as an increased Young's modulus of elasticity, indicating adverse changes in arterial structure, and function. The association reversed with follow-up FMD data, indicating the interaction of preclinical parameters over time. A higher CEC was directly associated with a lower risk of subclinical atherosclerosis at follow-up. In young and healthy subjects, CEC was associated with important lipid risk parameters at baseline, as in older patients and CAD patients, but inversely with early risk markers for subclinical atherosclerosis. [ABSTRACT FROM AUTHOR]

The increase in cardiovascular risk associated with metabolic syndrome (MS) seems higher in women than in men. We examined hemodynamics during head-up tilt in 252 men and 250 women without atherosclerosis, diabetes, or antihypertensive medication, mean age 48 years, using whole-body impedance cardiography and radial pulse wave analysis. MS was defined according to Alberti et al. 2009. Men and women with MS presented with corresponding elevations of systolic and diastolic blood pressure (10-14%, p ≤ 0.001) versus controls. Supine pulse wave velocity (16–17%, p < 0.001) and systemic vascular resistance (7–9%, p ≤ 0.026), and upright cardiac output (6–11%, p ≤ 0.008) were higher in both MS groups than controls. Elevation of supine aortic characteristic impedance was higher in women than in men with MS (16% vs. 8%, p = 0.026), and in contrast to men, no upright impedance reduction was observed in women. When upright, women but not men with MS showed faster return of reflected pressure wave (p = 0.036), and smaller decrease in left cardiac work (p = 0.035) versus controls. The faster upright return of reflected pressure, lower upright decrease in left cardiac work, and higher elevation of aortic characteristic impedance may contribute to the greater increase in MS-related cardiovascular risk in women than in men. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (apoE) is the key regulator of plasma lipids, mediating altered functionalities in lipoprotein metabolism - affecting the risk of coronary artery (CAD) and Alzheimer's diseases, as well as longevity. Searching pathways influenced by apoE prior to adverse manifestations, we utilized a metabolome dataset of 228 nuclear-magnetic-resonance-measured serum parameters with a 10-year follow-up from the population-based Young Finns Study cohort of 2,234 apoE-genotyped (rs7412, rs429358) adults, aged 24-39 at baseline. At the end of our follow-up, by limiting FDR-corrected p < 0.05, regression analyses revealed 180/228 apoE-polymorphism-related associations with the studied metabolites, in all subjects - without indications of apoE x sex interactions. Across all measured apoE- and apoB-containing lipoproteins, ε4 allele had consistently atherogenic and ε2 protective effect on particle concentrations of free/esterified cholesterol, triglycerides, phospholipids and total lipids. As novel findings, ε4 associated with glycoprotein acetyls, LDL-diameter and isoleucine - all reported biomarkers of CAD-risk, inflammation, diabetes and total mortality. ApoE-subgroup differences persisted through our 10-year follow-up, although some variation of individual metabolite levels was noticed. In conclusion, apoE polymorphism associate with a complex metabolic change, including aberrations in multiple novel biomarkers related to elevated cardiometabolic and all-cause mortality risk, extending our understanding about the role of apoE in health and disease. [ABSTRACT FROM AUTHOR]

Using targeted NMR spectroscopy of 227 fasting serum metabolic traits, we searched for novel metabolic signatures of renal function in 926 type 2 diabetics (T2D) and 4838 non-diabetic individuals from four independent cohorts. We furthermore investigated longitudinal changes of metabolic measures and renal function and associations with other T2D microvascular complications. 142 traits correlated with glomerular filtration rate (eGFR) after adjusting for confounders and multiple testing: 59 in diabetics, 109 in non-diabetics with 26 overlapping. The amino acids glycine and phenylalanine and the energy metabolites citrate and glycerol were negatively associated with eGFR in all the cohorts, while alanine, valine and pyruvate depicted opposite association in diabetics (positive) and non-diabetics (negative). Moreover, in all cohorts, the triglyceride content of different lipoprotein subclasses showed a negative association with eGFR, while cholesterol, cholesterol esters (CE), and phospholipids in HDL were associated with better renal function. In contrast, phospholipids and CEs in LDL showed positive associations with eGFR only in T2D, while phospholipid content in HDL was positively associated with eGFR both cross-sectionally and longitudinally only in non-diabetics. In conclusion, we provide a wide list of kidney function-associated metabolic traits and identified novel metabolic differences between diabetic and non-diabetic kidney disease. [ABSTRACT FROM AUTHOR]

α-melanocyte-stimulating hormone (α-MSH) is processed from pro-opiomelanocortin (POMC) and mediates anti-inflammatory actions in leukocytes. α-MSH also promotes macrophage reverse cholesterol transport by inducing ATP-binding cassette transporters ABCA1 and ABCG1. Here we investigated the regulation of POMC and α-MSH expression in atherosclerosis. First, transcript levels of POMC and its processing enzymes were analyzed in human arterial plaques (n = 68) and non-atherosclerotic controls (n = 24) as well as in whole blood samples from coronary artery disease patients (n = 55) and controls (n = 45) by microarray. POMC expression was increased in femoral plaques compared to control samples as well as in unstable advanced plaques. α-MSH-producing enzyme, carboxypeptidase E, was down-regulated, whereas prolylcarboxypeptidase, an enzyme inactivating α-MSH, was up-regulated in unstable plaques compared to stable plaques, suggesting a possible reduction in intraplaque α-MSH levels. Second, immunohistochemical analyses revealed the presence of α-MSH in atherosclerotic plaques and its localization in macrophages and other cell types. Lastly, supporting the role of α-MSH in reverse cholesterol transport, POMC expression correlated with ABCA1 and ABCG1 in human plaque and whole blood samples. In conclusion, α-MSH is expressed in atherosclerotic plaques and its processing enzymes associate with plaque stability, suggesting that measures to enhance the local bioavailability of α-MSH might protect against atherosclerosis. [ABSTRACT FROM AUTHOR]

Summary: In this cross-sectional study, peripheral bone traits were examined relative to total daily steps measured with pedometer. Higher number of steps was associated with greater bone values at the calcaneus and tibia in women, but not in men. In women, dose-dependent associations at the radius were congruent with the weight-bearing bones.Introduction: Habitual physical activity measured as daily steps may contribute to bone density and strength at the calcaneus and other weight-bearing bones.Methods: Subgroups of 705-837 women and 480-615 men aged 31-46 years from the Cardiovascular Risk in Young Finns Study participated in the present study. Participants were instructed to use pedometer for 1 week, and the total daily steps, divided into tertiles, were evaluated relative to quantitative ultrasound-measured bone traits at the calcaneus and peripheral quantitative computed tomography-measured bone traits at the tibia and radius. Analysis of covariance was used to examine the between-group differences.Results: In women, significant dose-dependent between-group differences were found in the weight-bearing bones and in non-weight-bearing radius. The differences in broadband ultrasound attenuation and speed of sound at the calcaneus were 3.8 and 0.5% greater in women within the highest tertile of daily steps compared to the lowest tertile (p values for trend ≤ 0.04). In tibia, women in the highest tertile (> 8765 steps/day) had on average 1-5.4% greater bone cross-sectional area, bone mineral content (BMC), trabecular density, and bone strength index at the distal site and 1.6-2.7% greater bone areas, BMC and strength strain index (SSI) at the shaft compared to women with less daily steps (p values for trend ≤ 0.02). Similarly, in radius, BMC and BSI at the distal site, and bone cross-sectional areas, BMC and SSI at the shaft were 1.7-3.4% greater in women within the highest tertile of daily steps compared to their peers (p values for trend ≤ 0.04). In men, the differences in calcaneal, tibial, and radial bone traits were mainly non-significant between the tertiles of daily steps.Conclusion: Observed significant positive associations between daily steps and various bone traits at the calcaneus, tibia, and radius in women suggest that habitual physical activity may benefit skeletal health in adulthood. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases due to atherosclerosis are the leading cause of death globally. We aimed to investigate the potentially altered gene and pathway expression in advanced peripheral atherosclerotic plaques in comparison to healthy control arteries. Gene expression analysis was performed (Illumina HumanHT-12 version 3 Expression BeadChip) for 68 advanced atherosclerotic plaques (15 aortic, 29 carotid and 24 femoral plaques) and 28 controls (left internal thoracic artery (LITA)) from Tampere Vascular Study. Dysregulation of individual genes was compared to healthy controls and between plaques from different arterial beds and Ingenuity pathway analysis was conducted on genes with a fold change (FC) > ±1.5 and false discovery rate (FDR) < 0.05. 787 genes were significantly differentially expressed in atherosclerotic plaques. The most up-regulated genes were osteopontin and multiple MMPs, and the most down-regulated were cell death-inducing DFFA-like effector C and A (CIDEC, CIDEA) and apolipoprotein D (FC > 20). 156 pathways were differentially expressed in atherosclerotic plaques, mostly inflammation-related, especially related with leukocyte trafficking and signaling. In artery specific plaque analysis 50.4% of canonical pathways and 41.2% GO terms differentially expressed were in common for all three arterial beds. Our results confirm the inflammatory nature of advanced atherosclerosis and show novel pathway differences between different arterial beds. [ABSTRACT FROM AUTHOR]

MicroRNAs are involved in disease development and may be utilized as biomarkers. We investigated the association of blood miRNA levels and a) fatty liver (FL), b) lipoprotein and lipid pathways involved in liver lipid accumulation and c) levels of predicted mRNA targets in general population based cohort. Blood microRNA profiling (TaqMan OpenArray), genome-wide gene expression arrays and nuclear magnetic resonance metabolomics were performed for Young Finns Study participants aged 34-49 years (n = 871). Liver fat status was assessed ultrasonographically. Levels of hsa-miR-122-5p and -885-5p were up-regulated in individuals with FL (fold change (FC) = 1.55, p = 1.36 * 10−14 and FC = 1.25, p = 4.86 * 10−4, respectively). In regression model adjusted with age, sex and BMI, hsa-miR-122-5p and -885-5p predicted FL (OR = 2.07, p = 1.29 * 10−8 and OR = 1.41, p = 0.002, respectively). Together hsa-miR-122-5p and -885-5p slightly improved the detection of FL beyond established risk factors. These miRNAs may be associated with FL formation through the regulation of lipoprotein metabolism as hsa-miR-122-5p levels associated with small VLDL, IDL, and large LDL lipoprotein subclass components, while hsa-miR-885-5p levels associated inversely with XL HDL cholesterol levels. Hsa-miR-885-5p levels correlated inversely with oxysterol-binding protein 2 (OSBPL2) expression (r = −0.143, p = 1.00 * 10−4) and suppressing the expression of this lipid receptor and sterol transporter could link hsa-miR-885-5p with HDL cholesterol levels. [ABSTRACT FROM AUTHOR]