Polymorphisms of the Flavin containing monooxygenase 3 (FMO3) gene do not predispose to essential hypertension in Caucasians.

BACKGROUND: The recessive disorder trimethylaminuria is caused by defects in the FMO3 gene, and may be associated with hypertension. We investigated whether common polymorphisms of the FMO3 gene confer an increased risk for elevated blood pressure and/or essential hypertension. METHODS: FMO3 genotypes (E158K, V257M, E308G) were determined in 387 healthy subjects with ambulatory systolic and diastolic blood pressure measurements, and in a cardiovascular disease population of 1649 individuals, 691(41.9%) of whom had a history of hypertension requiring drug treatment. Haplotypes were determined and their distribution noted. RESULTS: There was no statistically significant association found between any of the 4 common haplotypes and daytime systolic blood pressure in the healthy population (p = 0.65). Neither was a statistically significant association found between the 4 common haplotypes and hypertension status among the cardiovascular disease patients (p = 0.80). CONCLUSION: These results suggest that the variants in the FMO3 gene do not predispose to essential hypertension in this population

Maternal Allopurinol Prevents Cardiac Dysfunction in Adult Male Offspring Programmed by Chronic Hypoxia During Pregnancy.

Integrating functional and molecular levels, we investigated the effects of maternal treatment with a xanthine oxidase inhibitor on the programming of cardiac dysfunction in adult offspring using an established rat model of hypoxic pregnancy. Female Wistar rats were divided into normoxic or hypoxic (13% O2) pregnancy±maternal allopurinol treatment (30 mg kg-1 d-1). At 4 months, hearts were isolated from 1 male per litter per outcome variable to determine cardiac function and responses to ischemia-reperfusion in a Langendorff preparation. Sympathetic dominance, perfusate CK (creatine kinase) and LDH (lactate dehydrogenase) and the cardiac protein expression of the β1-adrenergic receptor, the M2 Ach receptor (muscarinic type-2 acetylcholine receptor), and the SERCA2a (sarcoplasmic reticulum Ca2+ ATPase 2a) were determined. Relative to controls, offspring from hypoxic pregnancy showed elevated left ventricular end diastolic pressure (+34.7%), enhanced contractility (dP/dtmax, +41.6%), reduced coronary flow rate (-21%) and an impaired recovery to ischemia-reperfusion (left ventricular diastolic pressure, area under the curve recovery -19.1%; all P<0.05). Increased sympathetic reactivity (heart rate, +755.5%; left ventricular diastolic pressure, +418.9%) contributed to the enhanced myocardial contractility ( P<0.05). Perfusate CK (+431%) and LDH (+251.3%) and the cardiac expression of SERCA2a (+71.4%) were also elevated ( P<0.05), further linking molecular markers of cardiac stress and injury to dysfunction. Maternal allopurinol restored all functional and molecular indices of cardiac pathology. The data support a link between xanthine oxidase-derived oxidative stress in hypoxic pregnancy and cardiac dysfunction in the adult offspring, providing a target for early intervention in the developmental programming of heart disease.British Heart Foundatio

Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease.

Aging and developmental programming are both associated with oxidative stress and endothelial dysfunction, suggesting common mechanistic origins. However, their interrelationship has been little explored. In a rodent model of programmed cardiovascular dysfunction we determined endothelial function and vascular telomere length in young (4 mo) and aged (15 mo) adult offspring of normoxic or hypoxic pregnancy with or without maternal antioxidant treatment. We show loss of endothelial function [maximal arterial relaxation to acetylcholine (71 ± 3 vs. 55 ± 3%) and increased vascular short telomere abundance (4.2-1.3 kb) 43.0 ± 1.5 vs. 55.1 ± 3.8%) in aged vs. young offspring of normoxic pregnancy (P < 0.05). Hypoxic pregnancy in young offspring accelerated endothelial dysfunction (maximal arterial relaxation to acetylcholine: 42 ± 1%, P < 0.05) but this was dissociated from increased vascular short telomere length abundance. Maternal allopurinol rescued maximal arterial relaxation to acetylcholine in aged offspring of normoxic or hypoxic pregnancy but not in young offspring of hypoxic pregnancy. Aged offspring of hypoxic allopurinol pregnancy compared with aged offspring of untreated hypoxic pregnancy had lower levels of short telomeres (vascular short telomere length abundance 35.1 ± 2.5 vs. 48.2 ± 2.6%) and of plasma proinflammatory chemokine (24.6 ± 2.8 vs. 36.8 ± 5.5 pg/ml, P < 0.05). These data provide evidence for divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease, and aging being decelerated by antioxidants even prior to birth.-Allison, B. J., Kaandorp, J. J., Kane, A. D., Camm, E. J., Lusby, C., Cross, C. M., Nevin-Dolan, R., Thakor, A. S., Derks, J. B., Tarry-Adkins, J. L., Ozanne, S. E., Giussani, D. A. Divergence of mechanistic pathways mediating cardiovascular aging and developmental programming of cardiovascular disease.The work was supported by The British Heart Foundation, The Wellcome Trust, The Perinatal Centre Wilhelmina Children’s Hospital Utrecht, The Royal Dutch Academy of Sciences (Ter Meulen Fonds), The Dutch Institute for Scientific Research (NWO) and The Dutch Society of Obstetrics and Gynecology (NVOG).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by the Federation of American Societies for Experimental Biology

The impact of the initial COVID-19 outbreak on young adults’ mental health: a longitudinal study of risk and resilience factors

Few studies assessing the effects of COVID-19 on mental health include prospective markers of risk and resilience necessary to understand and mitigate the combined impacts of the pandemic, lockdowns, and other societal responses. This population-based study of young adults includes individuals from the Neuroscience in Psychiatry Network (n = 2403) recruited from English primary care services and schools in 2012–2013 when aged 14–24. Participants were followed up three times thereafter, most recently during the initial outbreak of the COVID-19 outbreak when they were aged between 19 and 34. Repeated measures of psychological distress (K6) and mental wellbeing (SWEMWBS) were supplemented at the latest assessment by clinical measures of depression (PHQ-9) and anxiety (GAD-7). A total of 1000 participants, 42% of the original cohort, returned to take part in the COVID-19 follow-up; 737 completed all four assessments [mean age (SD), 25.6 (3.2) years; 65.4% female; 79.1% White]. Our findings show that the pandemic led to pronounced deviations from existing mental health-related trajectories compared to expected levels over approximately seven years. About three-in-ten young adults reported clinically significant depression (28.8%) or anxiety (27.6%) under current NHS guidelines; two-in-ten met clinical cut-offs for both. About 9% reported levels of psychological distress likely to be associated with serious functional impairments that substantially interfere with major life activities; an increase by 3% compared to pre-pandemic levels. Deviations from personal trajectories were not necessarily restricted to conventional risk factors; however, individuals with pre-existing health conditions suffered disproportionately during the initial outbreak of the COVID-19 pandemic. Resilience factors known to support mental health, particularly in response to adverse events, were at best mildly protective of individual psychological responses to the pandemic. Our findings underline the importance of monitoring the long-term effects of the ongoing pandemic on young adults’ mental health, an age group at particular risk for the emergence of psychopathologies. Our findings further suggest that maintaining access to mental health care services during future waves, or potential new pandemics, is particularly crucial for those with pre-existing health conditions. Even though resilience factors known to support mental health were only mildly protective during the initial outbreak of the COVID-19 pandemic, it remains to be seen whether these factors facilitate mental health in the long term

Brain-behaviour modes of covariation in healthy and clinically depressed young people

Abstract: Understanding how variations in dimensions of psychometrics, IQ and demographics relate to changes in brain connectivity during the critical developmental period of adolescence and early adulthood is a major challenge. This has particular relevance for mental health disorders where a failure to understand these links might hinder the development of better diagnostic approaches and therapeutics. Here, we investigated this question in 306 adolescents and young adults (14–24 y, 25 clinically depressed) using a multivariate statistical framework, based on canonical correlation analysis (CCA). By linking individual functional brain connectivity profiles to self-report questionnaires, IQ and demographic data we identified two distinct modes of covariation. The first mode mapped onto an externalization/internalization axis and showed a strong association with sex. The second mode mapped onto a well-being/distress axis independent of sex. Interestingly, both modes showed an association with age. Crucially, the changes in functional brain connectivity associated with changes in these phenotypes showed marked developmental effects. The findings point to a role for the default mode, frontoparietal and limbic networks in psychopathology and depression

Stress among parents of children with and without autism spectrum disorder: a comparison involving physiological indicators and parent self-reports

Parents of children with Autism Spectrum Disorder (ASD) have been reported as experiencing higher levels of stress and poorer physical health than parents of typically developing children. However, most of the relevant literature has been based on parental self-reports of stress and health. While research on physiological outcomes has grown in recent years, gaps still exist in our understanding of the physiological effects, if any, of stress related to parenting a child with ASD. The present study compared parent-reported stress, anxiety, and depression, as well as selected physiological measures of stress (i.e., cortisol, alpha-amylase, and ambulatory blood pressure and heart rate) between matched groups of parents of children with (N = 38) and without (N = 38) ASD. Participants completed questionnaires, collected saliva samples for the purpose of measuring cortisol and alpha-amylase, and wore an ambulatory blood pressure monitor for 24 h. Parents of children with ASD reported significantly higher levels of parental distress, anxiety, and depression than parents of typically developing children. Parent-reported distress, anxiety, depression, and health were not correlated with physiological measures. With the exception that parents of children with ASD had significantly lower cortisol levels 30 min after waking, no other significant group differences were found for physiological measures. Parents of children with ASD reported significantly higher use of a number of adaptive coping strategies (e.g., emotional support) in comparison to parents of typically developing children. Results are discussed in the context of implications for future research directions, stress research, and practical implications for parental support

An expanding manifold in transmodal regions characterizes adolescent reconfiguration of structural connectome organization

Funder: Canada Research Chairs; FundRef: http://dx.doi.org/10.13039/501100001804Funder: Fonds de la Recherche du Quebec – SantéFunder: Autism Research TrustFunder: Canadian Institutes of Health Research; FundRef: http://dx.doi.org/10.13039/501100000024Funder: BrainCanadaFunder: MNI-Cambridge collaborative awardAdolescence is a critical time for the continued maturation of brain networks. Here, we assessed structural connectome development in a large longitudinal sample ranging from childhood to young adulthood. By projecting high-dimensional connectomes into compact manifold spaces, we identified a marked expansion of structural connectomes, with strongest effects in transmodal regions during adolescence. Findings reflected increased within-module connectivity together with increased segregation, indicating increasing differentiation of higher-order association networks from the rest of the brain. Projection of subcortico-cortical connectivity patterns into these manifolds showed parallel alterations in pathways centered on the caudate and thalamus. Connectome findings were contextualized via spatial transcriptome association analysis, highlighting genes enriched in cortex, thalamus, and striatum. Statistical learning of cortical and subcortical manifold features at baseline and their maturational change predicted measures of intelligence at follow-up. Our findings demonstrate that connectome manifold learning can bridge the conceptual and empirical gaps between macroscale network reconfigurations, microscale processes, and cognitive outcomes in adolescent development

Empathy, social values and civic behaviour among early adolescents in Ireland: Composite report

This new century is indeed one of pressing global issues, from climate change to large-scale migration and displacement – issues that challenge us to exercise our capacity for empathy, to feel for the plight of those we have never met as we do for those with whom we share a city or a country. (Michael D. Higgins, President of Ireland, 2016)1 Although there are many definitions available in the literature, empathy is typically understood as a person’s ability to feel and understand the emotions and feelings of others. Empathy is widely seen as the foundation for broader societal attitudes and behaviours, such as social responsibility and prosocial or civic behaviour. Research has shown that empathy and related ‘other-oriented’ values and behaviours are associated with a wide range of positive outcomes in the areas of personal development, interpersonal relationships, and societal well-being. As highlighted in the quote by Michael D. Higgins above, we are living in an era of great social change, where people’s capacity for empathy remains critical but can be challenged by a range of forces or influences. The emergence of populist politics which have cultivated divisions between groups in society could be seen as a challenge to empathic and civic values. Concerns have been expressed that the increasing individualisation of society over recent decades is leading to declining levels of empathy, social concern, and civic engagement among younger generations. The accelerated advancement of information and communication technology has raised questions as to whether increased online activity among young people will reduce their capacity to empathise with others and change perceptions of what constitutes acceptable behaviour. Others have disputed claims that the current generation is less empathetic than their predecessors, arguing that young people’s civic behaviour is different from previous generations and that technology and social media have facilitated greater social understanding between people. Given the importance of empathy and related social values to social cohesion and democracy, it can be argued that it is of societal importance that values of empathy and care towards others be given due attention in research and policy. In particular, because the empathic or civic processes that individuals experience in childhood and youth have been found to influence their social values and civic behaviour into adulthood, it is important to explore these issues as they pertain to young people. To date, however, there has been little research conducted on this topic among youth in Ireland. This study aims to generate empirical evidence regarding the values and experiences of youth in Ireland towards a range of issues which reflect a sense of social responsibility towards others, including an analysis of factors that influence the development of social values and empathy. It also aims to review the degree to which national policy and curriculum supports the promotion of such values.non-peer-reviewe