The etiology of acute liver failure (ALF) remains elusive in almost half of affected children. We hypothesized that inherited mitochondrial and fatty acid oxidation disorders were occult etiological factors in patients with idiopathic ALF and impaired energy metabolism.

Alterations of the innate immunity contribute to the development of spontaneous bacterial peritonitis (SBP) in liver cirrhosis. Given its role in immune signaling, antimicrobial function, and macrophage differentiation, we hypothesized that genetic polymorphisms of TRAF6 modulate the risk of SBP. Thus, we determined theTRAF6 haplotype in 432 patients with cirrhosis and ascites using the haplotype-tagging single nucleotide polymorphisms rs331457 and rs5030419. In addition, peritoneal macrophages were immunomagnetically isolated and characterized. Overall, 122 (28%) patients had an episode of SBP. In the combined prospective-retrospective analysis the frequency of SBP differed between the four haplotypes (P = 0.014) and was the highest in 102 patients carrying the rs331457 but not the rs5030419 variant, when compared to other haplotypes (odds ratio 1.95 [1.22-3.12]) or to the wild-type (odds ratio 1.71 [1.04-2.82]). This association was confirmed in multivariate logistic regression (adjusted odds ratio 2.00 [1.24-3.22]) and in prospective sensitivity analysis (hazard ratio 2.09 [1.08-4.07]; P = 0.03). The risk haplotype was associated with lower concentrations of the immune activation marker soluble CD87 in ascitic fluid and with a decreased expression of IL-6 and CXCL8 in isolated peritoneal macrophages. In conclusion, genetic polymorphisms of TRAF6 are associated with decreased peritoneal immune activation and an increased risk of SBP.

Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Incidence rates of cardiomyopathies, which are a common cause of heart failure in young people, have increased during the last decades. An association between body weight in adolescence and future cardiomyopathy among men was recently identified. Whether or not this holds true also for women is unknown. The aim was therefore to determine whether for young women being overweight or obese is associated with a higher risk of developing cardiomyopathy.

G protein-coupled receptors (GPCRs) are key regulatory proteins of immune cell function inducing signaling in response to extracellular (pathogenic) stimuli. Although unrelated, hydroxycarboxylic acid receptor 3 (HCA3) and GPR84 share signaling via Gαi/o proteins and the agonist 3-hydroxydecanoic acid (3HDec). Both receptors are abundantly expressed in monocytes, macrophages and neutrophils but have opposing functions in these innate immune cells. Detailed insights into the molecular mechanisms and signaling components involved in immune cell regulation by GPR84 and HCA3 are still lacking. Here, we report that GPR84-mediated pro-inflammatory signaling depends on coupling to the hematopoietic cell-specific Gα15 protein in human macrophages, while HCA3 exclusively couples to Gαi protein. We show that activated GPR84 induces Gα15-dependent ERK activation, increases intracellular Ca2+ and IP3 levels as well as ROS production. In contrast, HCA3 activation shifts macrophage metabolism to a less glycolytic phenotype, which is associated with anti-inflammatory responses. This is supported by an increased release of anti-inflammatory IL-10 and a decreased secretion of pro-inflammatory IL-1β. In primary human neutrophils, stimulation with HCA3 agonists counteracts the GPR84-induced neutrophil activation. Our analyses reveal that 3HDec acts solely through GPR84 but not HCA3 activation in macrophages. In summary, this study shows that HCA3 mediates hyporesponsiveness in response to metabolites derived from dietary lactic acid bacteria and uncovers that GPR84, which is already targeted in clinical trials, promotes pro-inflammatory signaling via Gα15 protein in macrophages.

Overweight and obesity have been identified as risk factors for severe COVID-19; however, prospective cohort studies investigating the association between overweight early in life and severity of COVID-19 are lacking.

Urbanization may influence physical activity (PA) levels, although little evidence is available for low- and middle- income countries where urbanization is occurring fastest. We evaluated associations between urbanization and total PA, as well as work-, leisure-, home-, and transport-specific PA, for 138,206 adults living in 698 communities across 22 countries within the Prospective Urban and Rural Epidemiology (PURE) study. The 1-week long-form International PA Questionnaire was administered at baseline (2003-2015). We used satellite-derived population density and impervious surface area estimates to quantify baseline urbanization levels for study communities, as well as change measures for 5- and 10-years prior to PA surveys. We used generalized linear mixed effects models to examine associations between urbanization measures and PA levels, controlling for individual, household and community factors. Higher community baseline levels of population density (- 12.4% per IQR, 95% CI - 16.0, - 8.7) and impervious surface area (- 29.2% per IQR, 95% CI - 37.5, - 19.7), as well as the rate of change in 5-year population density (- 17.2% per IQR, 95% CI - 25.7, - 7.7), were associated with lower total PA levels. Important differences in the associations between urbanization and PA were observed between PA domains, country-income levels, urban/rural status, and sex. These findings provide new information on the complex associations between urbanization and PA.

To examine the association between social isolation and mortality and incident diseases in middle-aged adults in urban and rural communities from high-income, middle-income and low-income countries.

Comprehensive proteomics profiling may offer new insights into the dysregulated metabolic milieu of type 2 diabetes, and in the future, serve as a useful tool for personalized medicine. This calls for a better understanding of circulating protein patterns at the early stage of type 2 diabetes as well as the dynamics of protein patterns during changes in metabolic status.

Background The association between common carotid artery intima-media thickness (CCA-IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA-IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta-analysis of 20 prospective studies from the Proof-ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA-IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA-IMT was 0.71 mm (SD, 0.17 mm). Over a median follow-up of 5.9 years (5th-95th percentile, 1.9-19.0 years), 8278 individuals developed first-ever carotid plaque. We combined study-specific odds ratios (ORs) for incident carotid plaque using random-effects meta-analysis. Baseline CCA-IMT was approximately log-linearly associated with the odds of developing carotid plaque. The age-, sex-, and trial arm-adjusted OR for carotid plaque per SD higher baseline CCA-IMT was 1.40 (95% CI, 1.31-1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low- and high-density lipoprotein cholesterol, and lipid-lowering and antihypertensive medication was 1.34 (95% CI, 1.24-1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29-1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large-scale individual participant data meta-analysis demonstrated that CCA-IMT is associated with the long-term risk of developing first-ever carotid plaque, independent of traditional cardiovascular risk factors.

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.

Like in other vertebrates, the anterior part of the telencephalon of amphibians mainly consists of the olfactory bulb (OB), but different from higher vertebrates, the lateral telencephalic ventricles of larval Xenopus laevis expand deep into the anterior telencephalon. The neurogenic periventricular zone (PVZ) of the lateral ventricles generates new OB neurons throughout the animal's lifetime. We investigated the ultrastructural organization of the PVZ and found that within a time period of 24 h, 42.54 ± 6.65% of all PVZ cells were actively proliferating. Functional purinergic receptors are widespread in the central nervous system and their activation has been associated with many critical physiological processes, including the regulation of cell proliferation. In the present study we identified and characterized the purinergic system of the OB and the PVZ. ATP and 2MeSATP induced strong [Ca(2+)](i) increases in cells of both regions, which could be attenuated by purinergic antagonists. However, a more thorough pharmacological investigation revealed clear differences between the two brain regions. Cells of the OB almost exclusively express ionotropic P2X purinergic receptor subtypes, whereas PVZ cells express both ionotropic P2X and metabotropic P1 and P2Y receptor subtypes. The P2X receptors expressed in the OB are evidently not involved in the immediate processing of olfactory information.

Previous studies on the relation between lifestyle and the metabolic syndrome lack one or several aspects of the physical activity pattern in the analyses or cardiorespiratory fitness. Likewise, both uni- and triaxial accelerometry have been used, though, the predictive validity of these two modes has not been compared.

Unexplained chest pain (UCP) is a common reason for emergency hospital admission and generates considerable health-care costs for society. Even though prior research indicates that psychological problems and impaired quality of life are common among UCP patients, there is lack of knowledge comparing UCP patients with a reference group from the general population. The aim of this study was to analyse differences between men and women with UCP and a reference group in terms of psychosocial factors as depression, anxiety, stress, social interaction and health-related quality of life (HRQOL).

This study investigates how the excess risk of lower extremity amputations (amputations) in people with type 1 diabetes mellitus (DM) differs from the general population by diabetes duration, glycemic control, and renal complications.

The prevalence of stroke is expected to increase partly because of prolonged life expectancy in the general population. The objective of this study was to investigate trends in the prevalence of patients hospitalized with ischemic stroke (IS) in Sweden from 1995-2010.

The aim of this study was to investigate associations between psychosocial work exposure and the presence of biological and imaging biomarkers of cardiovascular disease.

The present study aims to describe accelerometer-assessed physical activity (PA) patterns and fulfillment of PA recommendations in a large sample of middle-aged men and women, and to study differences between subgroups of socio-demographic, socio-economic, and lifestyle-related variables. A total of 27 890 (92.5% of total participants, 52% women, aged 50-64 years) middle-aged men and women with at least four days of valid hip-worn accelerometer data (Actigraph GT3X+, wGT3X+ and wGT3X-BT) from the Swedish CArdioPulmonary bioImage Study, SCAPIS, were included. In total, 54.5% of daily wear time was spent sedentary, 39.1% in low, 5.4% in moderate, and only 0.1% in vigorous PA. Male sex, higher education, low financial strain, born in Sweden, and sedentary/light working situation were related to higher sedentary time, but also higher levels of vigorous PA. High BMI and having multiple chronic diseases associated strongly with higher sedentary time and less time in all three PA intensities. All-year physically active commuters had an overall more active PA pattern. The proportion fulfilling current PA recommendations varied substantially (1.4% to 92.2%) depending on data handling procedures and definition used. Twenty-eight percent was defined as having an "at-risk" behavior, which included both high sedentary time and low vigorous PA. In this large population-based sample, a majority of time was spent sedentary and only a fraction in vigorous PA, with clinically important variations between subgroups. This study provides important reference material and emphasizes the importance of a comprehensive assessment of all aspects of the individual PA pattern in future research and clinical practice.

To develop a healthy diet score that is associated with health outcomes and is globally applicable using data from the Prospective Urban Rural Epidemiology (PURE) study and replicate it in five independent studies on a total of 245 000 people from 80 countries.

The adaptation of cellular metabolism is considered a hallmark of cancer. Oncogenic signaling pathways support tumorigenesis and cancer progression through the induction of certain metabolic phenotypes associated with altered regulation of key metabolic enzymes. Hydroxycarboxylic acid receptor 2 (HCA2) is a G protein-coupled receptor previously shown to act as a tumor suppressor. Here, we aimed to unveil the connection between cellular metabolism and HCA2 in BT-474 cells. Moreover, we intend to clarify how well this metabolic phenotype is reflected in transcriptional changes and metabolite levels as determined by global metabolomics analyses.