Metabolomic Profiling of Statin Use and Genetic Inhibition of HMG-CoA Reductase

Background Statins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized. Objectives This study sought to determine the molecular effects of statin therapy on multiple metabolic pathways. Methods Metabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts. Results Starting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R2 = 0.94, slope 1.00 ± 0.03). Conclusions Statin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms

Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892

Metabolic profiling of alcohol consumption in 9778 young adults

Background: High alcohol consumption is a major cause of morbidity, yet alcohol is associated with both favourable and adverse effects on cardiometabolic risk markers. We aimed to characterize the associations of usual alcohol consumption with a comprehensive systemic metabolite profile in young adults. Methods: Cross-sectional associations of alcohol intake with 86 metabolic measures were assessed for 9778 individuals from three population-based cohorts from Finland (age 24-45 years, 52% women). Metabolic changes associated with change in alcohol intake during 6-year follow-up were further examined for 1466 individuals. Alcohol intake was assessed by questionnaires. Circulating lipids, fatty acids and metabolites were quantified by high-throughput nuclear magnetic resonance metabolomics and biochemical assays. Results: Increased alcohol intake was associated with cardiometabolic risk markers across multiple metabolic pathways, including higher lipid concentrations in HDL subclasses and smaller LDL particle size, increased proportions of monounsaturated fatty acids and decreased proportion of omega-6 fatty acids, lower concentrations of glutamine and citrate (P<0.001 for 56 metabolic measures). Many metabolic biomarkers displayed U-shaped associations with alcohol consumption. Results were coherent for men and women, consistent across the three cohorts and similar if adjusting for body mass index, smoking and physical activity. The metabolic changes accompanying change in alcohol intake during follow-up resembled the cross-sectional association pattern (R-2 = 0.83, slope = 0.7260.04). Conclusions: Alcohol consumption is associated with a complex metabolic signature, including aberrations in multiple biomarkers for elevated cardiometabolic risk. The metabolic signature tracks with long-term changes in alcohol consumption. These results elucidate the double-edged effects of alcohol on cardiovascular risk.Peer reviewe

Effects of hormonal contraception on systemic metabolism : cross-sectional and longitudinal evidence

Background: Hormonal contraception is commonly used worldwide, but its systemic effects across lipoprotein subclasses, fatty acids, circulating metabolites and cytokines remain poorly understood. Methods: A comprehensive molecular profile (75 metabolic measures and 37 cytokines) was measured for up to 5841 women (age range 24-49 years) from three population-based cohorts. Women using combined oral contraceptive pills (COCPs) or progestin-only contraceptives (POCs) were compared with those who did not use hormonal contraception. Metabolomics profiles were reassessed for 869 women after 6 years to uncover the metabolic effects of starting, stopping and persistently using hormonal contraception. Results: The comprehensive molecular profiling allowed multiple new findings on the metabolic associations with the use of COCPs. They were positively associated with lipoprotein subclasses, including all high-density lipoprotein (HDL) subclasses. The associations with fatty acids and amino acids were strong and variable in direction. COCP use was negatively associated with albumin and positively associated with creatinine and inflammatory markers, including glycoprotein acetyls and several growth factors and interleukins. Our findings also confirmed previous results e.g. for increased circulating triglycerides and HDL cholesterol. Starting COCPs caused similar metabolic changes to those observed cross-sectionally: the changes were maintained in consistent users and normalized in those who stopped using. In contrast, POCs were only weakly associated with metabolic and inflammatory markers. Results were consistent across all cohorts and for different COCP preparations and different types of POC delivery. Conclusions: Use of COCPs causes widespread metabolic and inflammatory effects. However, persistent use does not appear to accumulate the effects over time and the metabolic perturbations are reversed upon discontinuation. POCs have little effect on systemic metabolism and inflammation.Peer reviewe

Polyelectrolyte stabilized nanodiamond dispersions

Colloidal stability of negatively charged nanodiamonds (ND) has been realized with the help of double hydrophilic block copolymers poly(ethylene oxide)-block-poly(dimethylaminoethyl methacrylate)-dodecyl (PEO-bPDMAEMA-C12). The polymers were synthesized through RAFT polymerization of DMAEMA with a PEO macromonomer carrying trithiocarbonate and dodecyl end-groups. The NDs and the polymers were complexed by mixing them in different ratios. In addition to the amount of polymers, the effect of the detailed structure of the polymer was of interest and thus, also polymers with different lengths of the PEO-block were synthesized, as well as a block copolymer without the dodecyl end-group. The composition of the polymer, as well as the complexation conditions were varied to find the route to stable nanoparticles. The optimized complexation method gave colloidally stable ND particles with positively charged PDMAEMA coronas. The colloids were stable at room temperature and also in saline solutions up to 0.154 M NaCl.Peer reviewe

Load-Bearing Biomedical Applications of Diamond-Like Carbon Coatings - Current Status

The current status of diamond-like carbon (DLC) coatings for biomedical applications is reviewed with emphasis on load-bearing coatings. Although diamond-like carbon coating materials have been studied for decades, no indisputably successful commercial biomedical applications for high load situations exist today. High internal stress, leading to insufficient adhesion of thick coatings, is the evident reason behind this delay of the break-through of DLC coatings for applications. Excellent adhesion of thick DLC coatings is of utmost importance for load-bearing applications. According to this review superior candidate material for articulating implants is thick and adherent DLC on both sliding surfaces. With the filtered pulsed arc discharge method, all the necessary requirements for the deposition of thick and adherent DLC are fulfilled, provided that the substrate material is selected properly

Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk

Pediatricians and nutritionists knowledge about treatment of cow milk allergy in infants

OBJECTIVE: Evaluate the knowledge of pediatricians and nutritionists regarding the exclusion diet of cow milk and derivates, with emphasis on questions related to the nutrition of children submitted to such diet. METHODS: Cross-sectional study that enrolled pediatricians (n=53) and nutritionists (n=29) from public hospitals in São Paulo, Brazil, during 2005. Data was collected through self-administered questionnaires. RESULTS: The age of the professionals varied from 21 to 50 years old. Regarding professional experience, 41.2% were graduated for less than five years and 91.6% had a specialization course, masters and/or PhD degree. The vast majority of professionals (97.5%) confirmed that they regularly evaluated the diet of children that needed exclusion of cow milk. However, only 48% of the professionals conducted a more detailed evaluation of the diet, including calculations of food ingestion. Only 38.7% of the professionals compared child s food ingestion with some recommended pattern. Recommendations for daily ingestion of calcium by children up to the age of 36 months were properly mentioned by 22% of the pediatricians and 60.7% of the nutritionists (p=0.001). Inadequate cow milk substitute products were recommended by 66% of the pediatricians and by 48.3% of the nutritionists. Regarding labels of industrialized products, 81.6% of the pediatricians and 96.4% of the nutritionists advised the parents to look for all terms that could indicate the presence of cow milk protein. CONCLUSIONS: Pediatricians and nutritionists made conceptual errors in their main recommendations regarding the treatment of cow milk protein allergy.OBJETIVO: Avaliar o conhecimento de pediatras e nutricionistas sobre a dieta de exclusão do leite de vaca e seus derivados, com ênfase em questões relacionadas à nutrição da criança. MÉTODOS: Estudo transversal descritivo, do qual participaram pediatras (n=53) e nutricionistas (n=29), vinculados a hospitais públicos do Município de São Paulo, no ano de 2005. Os dados foram coletados por questionário auto-administrado. RESULTADOS: A idade dos profissionais variou de 21 a 50 anos. Quanto ao tempo de graduação, 41,2% eram formados a menos de cinco anos e 91,6% possuíam especialização, mestrado e/ou doutorado. A maioria (97,5%) afirmou avaliar a dieta de crianças submetidas à exclusão do leite de vaca, entretanto, somente 48% o faziam de forma mais detalhadas, incluindo o cálculo da ingestão alimentar. Apenas 38,7% comparam a ingestão alimentar da criança com algum padrão de recomendação. A recomendação diária da ingestão de cálcio para crianças com até 36 meses foi corretamente assinalada por 22% dos pediatras e 60,7% dos nutricionistas (p=0,001). Produtos não adequados como substitutos do leite de vaca seriam recomendados por 66% dos pediatras e 48,3% dos nutricionistas. Com relação à leitura de rótulos de produtos industrializados, 81,6% dos pediatras e 96,4% dos nutricionistas orientam os pais a ler todos os termos que indicam a presença das proteínas do leite de vaca. CONCLUSÕES: Os pediatras e nutricionista demonstraram erro conceitual no que se refere às principais recomendações terapêuticas na alergia às proteínas do leite de vaca.Universidade Federal de São Paulo (UNIFESP)UNIFESPUNIFESPSciEL