Proof That Lower Is Better--LDL Cholesterol and IMPROVE-IT

The so-called LDL hypothesis is the concept that excess low-density lipoprotein (LDL) cholesterol is a causal factor in the development of atherosclerotic vascular disease. By extension, this hypothesis also assumes that reducing LDL cholesterol levels, regardless of the means, should produce a corresponding reduction in cardiovascular events. Considerable evidence supports the LDL hypothesis, including animal studies and epidemiologic studies involving humans, as well as clinical trials of both statins and nonstatin lipid-modifying agents. In a meta-analysis that included more than 90,000 participants in 14 randomized trials of statins, the Cholesterol Treatment Trialists’ (CTT) collaborators found that, on average, a reduction of 1 mmol per liter (38.7 mg per deciliter) in LDL cholesterol levels yields a consistent 23% reduction in the risk of major coronary events over 5 years

A psychosocial exploration of bereaved children’s experiences of exclusion from school: what understanding can be gained from a psychoanalytic perspective?

According to the Childhood Bereavement network, a parent dies every 22 minutes in the U.K. Despite this, there is little research into the impact of parental death on children and young people. This psychosocial study explores the experiences of children and young people who have been bereaved of a parent and who are subsequently excluded from school. Three participants of school age were interviewed about their experiences of these two events and the data obtained from the interviews was analysed using an individual, psychoanalytically informed case study approach, allowing for an in-depth exploration of the affect generated by the existence of dynamic, intersubjective, unconscious processes during the interviews. The data emerging from the transference and counter transference was explored and it was found that the ongoing presence of an attachment figure might mitigate some of the risk factors associated with the experience of parental death. It also seems possible that this population of children and young people are likely to be under identified in schools and when they are known to have experienced parental bereavement, school professionals struggle to understand and respond to their emotional needs. Consideration is given to the implications for the role of the Educational Psychologist in working with this vulnerable population of children and young people. The wider potential of psychoanalytically informed approaches to working with pupils and staff in schools is also considered

Short-Term Exposure to Air Pollution and Biomarkers of Oxidative Stress: The Framingham Heart Study

BACKGROUND: Short-term exposure to elevated air pollution has been associated with higher risk of acute cardiovascular diseases, with systemic oxidative stress induced by air pollution hypothesized as an important underlying mechanism. However, few community-based studies have assessed this association. METHODS AND RESULTS: Two thousand thirty-five Framingham Offspring Cohort participants living within 50 km of the Harvard Boston Supersite who were not current smokers were included. We assessed circulating biomarkers of oxidative stress including blood myeloperoxidase at the seventh examination (1998-2001) and urinary creatinine-indexed 8-epi-prostaglandin F2alpha (8-epi-PGF2alpha) at the seventh and eighth (2005-2008) examinations. We measured fine particulate matter (PM2.5), black carbon, sulfate, nitrogen oxides, and ozone at the Supersite and calculated 1-, 2-, 3-, 5-, and 7-day moving averages of each pollutant. Measured myeloperoxidase and 8-epi-PGF2alpha were loge transformed. We used linear regression models and linear mixed-effects models with random intercepts for myeloperoxidase and indexed 8-epi-PGF2alpha, respectively. Models were adjusted for demographic variables, individual- and area-level measures of socioeconomic position, clinical and lifestyle factors, weather, and temporal trend. We found positive associations of PM2.5 and black carbon with myeloperoxidase across multiple moving averages. Additionally, 2- to 7-day moving averages of PM2.5 and sulfate were consistently positively associated with 8-epi-PGF2alpha. Stronger positive associations of black carbon and sulfate with myeloperoxidase were observed among participants with diabetes than in those without. CONCLUSIONS: Our community-based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress

Sexual selection can partly explain low frequencies of Segregation Distorter alleles

The Segregation Distorter (SD) allele found in Drosophila melanogaster distorts Mendelian inheritance in heterozygous males by causing developmental failure of non-SD spermatids, such that greater than 90% of the surviving sperm carry SD. This within-individual advantage should cause SD to fix, and yet SD is typically rare in wild populations. Here, we explore whether this paradox can be resolved by sexual selection, by testing if males carrying three different variants of SD suffer reduced pre- or post-copulatory reproductive success. We find that males carrying the SD allele are just as successful at securing matings as control males, but that one SD variant (SD-5) reduces sperm competitive ability and increases the likelihood of female remating. We then used these results to inform a theoretical model; we found that sexual selection could limit SD to natural frequencies when sperm competitive ability and female remating rate equalled the values observed for SD-5. However, sexual selection was unable to explain natural frequencies of the SD allele when the model was parameterized with the values found for two other SD variants, indicating that sexual selection alone is unlikely to explain the rarity of SD

Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes

Tobacco smoking is a leading cause of non-communicable disease globally and is a major risk factor for cardiovascular disease (CVD) and lung disease. Importantly, recent data by the World Health Organizations (WHO) indicate that in the last two decades global tobacco use has significantly dropped, which was largely driven by decreased numbers of female smokers. Despite such advances, the use of e-cigarettes and waterpipes (shisha, hookah, narghile) is an emerging trend, especially among younger generations. There is growing body of evidence that e-cigarettes are not a harm-free alternative to tobacco cigarettes and there is considerable debate as to whether e-cigarettes are saving smokers or generating new addicts. Here, we provide an updated overview of the impact of tobacco/waterpipe (shisha) smoking and e-cigarette vaping on endothelial function, a biomarker for early, subclinical, atherosclerosis from human and animal studies. Also their emerging adverse effects on the proteome, transcriptome, epigenome, microbiome, and the circadian clock are summarized. We briefly discuss heat-not-burn tobacco products and their cardiovascular health effects. We discuss the impact of the toxic constituents of these products on endothelial function and subsequent CVD and we also provide an update on current recommendations, regulation and advertising with focus on the USA and Europe. As outlined by the WHO, tobacco cigarette, waterpipe, and e-cigarette smoking/vaping may contribute to an increased burden of symptoms due to coronavirus disease 2019 (COVID-19) and to severe health consequences

The development of a novel Wellness Assessment Instrument and its use in the assessment of wellness status in patients with chronic obstructive pulmonary disease

Aims:Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disorder that affects health outcomes on multiple levels including overall wellbeing. More specifically, factors such as spiritual wellbeing, and psychological, mental and motivational status which may be at least as important as others, have been rarely studied. This article reports the method of validating a new wellness assessment questionnaire and the status of several wellness domains in patients with COPD.Methods:The study consisted of two phases: first, the development of a new Wellness Questionnaire with the help of focus groups; second, the validation and use of the questionnaire in a cohort of patients with COPD. For focus groups, healthy people ⩾45 years of age with no known comorbidity as well as people with a clinical diagnosis of COPD were invited to participate in the study.Results:Thematic analysis of findings from focus groups and original cohort respondents highlighted some factors that appear to influence wellness status. Five domains were explored as potential markers of wellness in patients with COPD. Quantitative analysis with Spearman correlation demonstrated a significant correlation between Physical/Personal Wellness and other markers of COPD progression such as Global Initiative Obstructive Lung Disease (GOLD; 0.006), force expiratory volume in 1 s (FEV1%; 0.01), health-related quality of life (0.009), multidimensional BOD score and quartile (0.003 and 0.02).Conclusion:The findings suggest that a combination of personal, physical, emotional, mental and other psychological factors is responsible for negative COPD outcomes. While there is a need to validate this new wellness questionnaire in further research, it incorporates new markers of wellness that could benefit management of COPD

Acute effects of vasoactive drug treatment on brachial artery reactivity

AbstractObjectivesThe goal of this study was to investigate whether concomitant therapy with vasoactive medications alters the results of noninvasive assessment of endothelial function.BackgroundUltrasound assessment of brachial artery flow-mediated dilation is emerging as a useful clinical tool. The current practice of withholding cardiac medications before ultrasound studies has unknown utility and would limit the clinical use of the methodology.MethodsTo determine whether a single dose of a vasoactive drug influences brachial reactivity, we examined flow-mediated dilation and nitroglycerin-mediated dilation in 73 healthy subjects (age 27 ± 6 years). Studies were completed at baseline and 3 h after randomized treatment with a single oral dose of placebo, felodipine (5 mg), metoprolol (50 mg), or enalapril (10 mg). To determine if holding vasoactive therapy for 24 h before study yields different results than continuation of clinically prescribed medications, we examined vascular function in 72 patients (age 57 ± 10 years) with coronary artery disease. Ultrasound studies were performed 24 h after the last dose and again 3 h after patients took their clinically prescribed medications.ResultsIn healthy subjects one dose of all three drugs lowered blood pressure, and metoprolol also lowered heart rate. However, there was no significant effect of treatment on brachial artery dilation. In patients with coronary artery disease on chronic treatment, taking prescribed medications reduced blood pressure and heart rate, but had no significant effect on brachial artery dilation.ConclusionsRecent administration of commonly used nonnitrate vasoactive drugs has no significant effect on brachial reactivity. These findings suggest that current practice of withholding cardiac medications before testing endothelial function may not be necessary, making this methodology more practical for clinical use

Genome-Wide Association with Select Biomarker Traits in the Framingham Heart Study

BACKGROUND: Systemic biomarkers provide insights into disease pathogenesis, diagnosis, and risk stratification. Many systemic biomarker concentrations are heritable phenotypes. Genome-wide association studies (GWAS) provide mechanisms to investigate the genetic contributions to biomarker variability unconstrained by current knowledge of physiological relations. METHODS: We examined the association of Affymetrix 100K GeneChip single nucleotide polymorphisms (SNPs) to 22 systemic biomarker concentrations in 4 biological domains: inflammation/oxidative stress; natriuretic peptides; liver function; and vitamins. Related members of the Framingham Offspring cohort (n = 1012; mean age 59 ± 10 years, 51% women) had both phenotype and genotype data (minimum-maximum per phenotype n = 507–1008). We used Generalized Estimating Equations (GEE), Family Based Association Tests (FBAT) and variance components linkage to relate SNPs to multivariable-adjusted biomarker residuals. Autosomal SNPs (n = 70,987) meeting the following criteria were studied: minor allele frequency ≥ 10%, call rate ≥ 80% and Hardy-Weinberg equilibrium p ≥ 0.001. RESULTS: With GEE, 58 SNPs had p < 10-6: the top SNPs were rs2494250 (p = 1.00*10-14) and rs4128725 (p = 3.68*10-12) for monocyte chemoattractant protein-1 (MCP1), and rs2794520 (p = 2.83*10-8) and rs2808629 (p = 3.19*10-8) for C-reactive protein (CRP) averaged from 3 examinations (over about 20 years). With FBAT, 11 SNPs had p < 10-6: the top SNPs were the same for MCP1 (rs4128725, p = 3.28*10-8, and rs2494250, p = 3.55*10-8), and also included B-type natriuretic peptide (rs437021, p = 1.01*10-6) and Vitamin K percent undercarboxylated osteocalcin (rs2052028, p = 1.07*10-6). The peak LOD (logarithm of the odds) scores were for MCP1 (4.38, chromosome 1) and CRP (3.28, chromosome 1; previously described) concentrations; of note the 1.5 support interval included the MCP1 and CRP SNPs reported above (GEE model). Previous candidate SNP associations with circulating CRP concentrations were replicated at p < 0.05; the SNPs rs2794520 and rs2808629 are in linkage disequilibrium with previously reported SNPs. GEE, FBAT and linkage results are posted at . CONCLUSION: The Framingham GWAS represents a resource to describe potentially novel genetic influences on systemic biomarker variability. The newly described associations will need to be replicated in other studies.National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC25195); National Institutes of Health National Center for Research Resources Shared Instrumentation grant (1S10RR163736-01A1); National Institutes of Health (HL064753, HL076784, AG028321, HL71039, 2 K24HL04334, 1K23 HL083102); Doris Duke Charitable Foundation; American Diabetes Association Career Developement Award; National Center for Research Resources (GCRC M01-RR01066); US Department of Agriculture Agricultural Research Service (58-1950-001, 58-1950-401); National Institute of Aging (AG14759

Current research into brain barriers and the delivery of therapeutics for neurological diseases: a report on CNS barrier congress London, UK, 2017.

This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers