Adverse childhood experiences, bullying, inflammation and BMI in 10-year-old children: The biological embodiment

Exposure to adversity during the first years of life might already be biologically embedded well before adult life. Thus, the impact of different stressful experiences needs to be explored. This study aims to examine if the association between being victimized (adverse childhood experiences—ACEs and bullying) and (hs-) C-Reactive Protein (CRP) is explained by the influence of adversity on the body mass index (BMI) of the child. We included children from the Portuguese birth cohort Generation XXI (n = 3712) that at 10 years of age completed a questionnaire on the exposure to ACEs and bullying victimization, assessed by an adaptation from the original ACEs study and an adaptation of The Bully Scale Survey, respectively. Following an overnight fast, a venous blood sample was collected by trained nurses and hs-CRP was assayed in fresh blood samples. Weight and height were measured with the child in underwear and bare feet. Weight was measured to the nearest one-tenth of a kilogram with the use of a digital scale (Tanita), and height was measured to the nearest one-tenth of a centimetre with the use of a wall stadiometer (seca®). BMI was calculated as the value of weight (kg) over squared height (m), and computed as an age- and sex-specific BMI standard deviation (SD) score (z-score), according to the World Health Organization Child Growth Standards (5–19 years). Regression coefficients and respective 95% Confidence Interval [β(95%CI)] were computed using path analysis. We observed that ACEs had a positive total effect on hs-CRP at the age of 10 years (β = 0.06; 95%CI: -0.02; 0.15). A direct effect (β = 0.02; 95%CI: -0.01; 0.06) accounted for 66.1% of the association between ACEs and hs-CRP. A positive total effect of bullying victimization on hs-CRP (β = 0.20; 95%CI: 0.06; 0.34) was observed. A direct effect (β = 0.08; 95%CI: -0.05; 0.21) accounted for 40.0% of the association, while an indirect effect through BMI (β = 0.12; 95%CI: 0.06; 0.18) explained 60.0% of the pathway between bullying victimization and hs-CRP. Results suggest that there might be different mechanisms involved in the biological embedding of childhood experiences. BMI seems to explain a great part of the association between exposure to bullying victimization and hs-CRP at 10 years of age. Further research is still needed to better understand the mechanisms explaining the emergence and persistence of health poorer outcomes later in life for victims of abuse. © 2022 Soares et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This work was supported by the European Regional Development Fund (ERDF) through the Operational Programme Competitiveness and Internationalization and national funding from the Foundation for Science and Technology (FCT), Portuguese Ministry of Science, Technology and Higher Education under the projects “BioAdversity: How childhood social adversity shapes health: The biology of social adversity” (POCI-01- 0145-FEDER-016838; PTDC/ DTP-EPI/1687/2014), “HIneC: When do health inequalities start? Understanding the impact of childhood social adversity on health trajectories from birth to early adolescence” (POCI-01-0145-FEDER-029567; PTDC/SAU-PUB/29567/2017). It is also supported by the Unidade de Investigação em Epidemiologia - Instituto de Saúde Pública da Universidade do Porto (EPIUnit) (UIDB/04750/ 2020) and Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (ITR) (LA/P/0064/2020), Administração Regional de Saúde Norte (Regional Department of Ministry of Health) and Fundação Calouste Gulbenkian; PhD Grant SFRH/BD/108742/2015 (to SS) co-funded by FCT and the Human Capital Operational Programme (POCH/FSE Program); FCT Investigator contracts CEECIND/01516/2017 (to SF) and IF/01060/2015 (to ACS). This study is also a result of the project DOCnet (NORTE-01-0145FEDER-000003), supported by the Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement. The funders had no role in study design, data collection and analysis, publication decision, or manuscript preparation. The authors gratefully acknowledge the families enrolled in Generation XXI for their kindness, all members of the research team for their enthusiasm and perseverance and the participating hospitals and their staff for their help and support

Early socioeconomic circumstances and cardiometabolic health in 10-year-old children

Background Social adversity is thought to become biologically embedded during sensitive periods of development, setting children on a trajectory of increased risk for later chronic diseases. Thus, social differences are expected to be expressed as biological alterations and might have their origins in early life. Therefore, we aim to estimate the association between early socioeconomic position (SEP) and cardiometabolic health during childhood. Methods Data from 2962 participants in the population-based birth cohort Generation XXI, from Porto, Portugal, was collected following standardized procedures at all study waves. Early SEP definition included household income, parental education and occupation at child’s birth. Cardiometabolic health was characterized at the age of 7 and 10, considering the triglycerides, cholesterol, fasting glucose, body mass index, systolic and diastolic blood pressure. Logistic regression was used to estimate the association between early SEP and a favorable cardiometabolic health profile. Results A favorable cardiometabolic profile was observed in almost half of participants at both ages, particularly among high SEP children who remain more frequently without alterations. For girls, higher paternal education at 7 years (OR:1.49;95%CI:1.03-2.15) and higher SEP at 10 were associated with better cardiometabolic health profile. In boys, a better cardiometabolic health profile was observed with increasing levels in maternal and paternal education and occupation, but at the age of 10, social differences were more evident according to parental education. Conclusions We provide evidence that children from more advantaged SEP at birth have an increased likelihood of presenting better cardiometabolic health at early ages. Social differences in cardiometabolic health biomarkers are already found in childhood, suggesting that the short-term impact of early life SEP on the physiology dysregulation takes place already in the first decade of life

Prevalence of Adverse Childhood Experiences in the First Decade of Life: A Study in the Portuguese Cohort, Generation XXI

Adverse childhood experiences (ACEs) are a modifiable risk factor for diseases throughout life. This study estimates the prevalence of ACEs in children, addressing associated sociodemographic characteristics and examining the relationship of ACEs with the child’s health and behaviors. We used information on 5295 participants at 10 years old, of the birth cohort Generation XXI, established in Porto, Portugal. Children answered a self-administered questionnaire on ACEs, based on the original ACEs study. Principal component analysis was used to group correlated ACEs, and a score was computed to assess their cumulative effect. Overall, 96.2% of children reported having been exposed to at least one ACE. The most prevalent ACE was a household member shouting, yelling, or screaming at the child (57.7%). Boys were more likely than girls to report “abuse”, “school problems”, and “death/severe disease”. Low parental education, income, and unemployment were associated with an increased risk of “school problems”, “death/severe disease”, and “household dysfunction”. We observed that the dimensions of ACEs could be identified at 10 years of age. A disadvantaged socioeconomic environment was associated with dimensions of ACEs. These data illustrate the natural history of dimensions of ACEs and their potential social patterning.This work was supported by the European Regional Development Fund (ERDF) through the Operational Programme Competitiveness and Internationalization and national funding from the Foundation for Science and Technology (FCT), Portuguese Ministry of Science, Technology and Higher Education under the projects “BioAdversity: How childhood social adversity shapes health: The biology of social adversity” (POCI-01-0145-FEDER-016838; PTDC/DTP-EPI/1687/2014), “HIneC: When do health inequalities start? Understanding the impact of childhood social adversity on health trajectories from birth to early adolescence” (POCI-01-0145-FEDER-029567; PTDC/SAU-PUB/29567/2017) and “STEPACHE: The pediatric roots of amplified pain: from contextual influences to risk stratification” (POCI-01-0145-FEDER-029087; PTDC/SAU-EPI/29087/2017). It is also supported by the Unidade de Investigação em Epidemiologia—Instituto de Saúde Pública da Universidade do Porto (EPIUnit) (UIDB/04750/2020) and Laboratório para a Investigação Integrativa e Translacional em Saúde Populacional (ITR) (LA/P/0064/2020), Administração Regional de Saúde Norte (Regional Department of Ministry of Health) and Fundação Calouste Gulbenkian; PhD Grant SFRH/BD/144503/2019 (to AA) funded by FCT through Fundo Social Europeu (FSE) and CEECIND/01516/2017 (to SF)

Early socioeconomic circumstances and adverse childhood experiences in 10-year-old children

Background Evidence showed that adverse childhood experiences (ACEs) are associated with the development of disease later in life and premature death. Examining the occurrence of these experiences at early ages would contribute to intervene and therefore to reduce health inequalities. This study aimed to assess the prevalence of ACEs among 10-year-children and to examine its association with early socioeconomic circumstances. Methods At the fourth wave of the population-based birth cohort Generation XXI, from Porto, Portugal, 5153 children completed a self-report questionnaire on 9 experiences related to household dysfunction and physical and emotional abuse. Socioeconomic circumstances included household income, maternal and paternal education, and history of parental unemployment. Logistic regression was performed to calculate the Odds Ratios (OR) and 95% Confidence Intervals (95%CI). Results A high prevalence of physical and emotional abuse was reported by children from low socioeconomic circumstances. A graded relationship between socioeconomic circumstances and cumulative ACEs was observed, for instance, low household income was associated with increased number of ACEs (one event [OR = 1.10; 95%CI: 0.89-1.36], two events [OR = 1.41; 95%CI: 1.15-1.73], three events [OR = 1.67; 95%CI: 1.34-2.06], and four or more events [OR = 2.05; 95%CI: 1.64-2.55]). Also, living with one parent or none of them increased the likelihood of reporting multiple ACEs (OR = 5.50; 95%CI: 4.23-7.13). Conclusions Children from low socioeconomic circumstances were more likely to report multiple adverse experiences in the first decade of life. These findings support that children from less advantaged environments might be at a higher risk of co-occurrence of adverse experiences during their childhood

Genetic topography and cortical cell loss in Huntington's disease link development and neurodegeneration

Cortical cell loss is a core feature of Huntington Disease (HD), beginning many years before clinical motor diagnosis, during the premanifest stage. However, it is unclear how genetic topography relates to cortical cell loss. Here, we explore the biological processes and cell types underlying this relationship and validate this using cell-specific post-mortem data. Eighty premanifest participants on average 15 years from disease onset and 71 controls were included. Using volumetric and diffusion MRI we extracted HD-specific whole brain maps where lower grey matter volume and higher grey matter mean diffusivity, relative to controls, were used as proxies of cortical cell loss. These maps were combined with gene expression data from the Allen Human Brain Atlas (AHBA) to investigate the biological processes relating genetic topography and cortical cell loss. Cortical cell loss was positively correlated with the expression of developmental genes (i.e. higher expression correlated with greater atrophy and increased diffusivity) and negatively correlated with the expression of synaptic and metabolic genes that have been implicated in neurodegeneration. These findings were consistent for diffusion MRI and volumetric HD-specific brain maps. As wild type Huntingtin is known to play a role in neurodevelopment, we explored the association between wild type Huntingtin (HTT) expression and developmental gene expression across the AHBA. Co-expression network analyses in 134 human brains free of neurodegenerative disorders was also performed. HTT expression was correlated with the expression of genes involved in neurodevelopment while co-expression network analyses also revealed that HTT expression was associated with developmental biological processes. Expression weighted cell-type enrichment (EWCE) analyses were used to explore which specific cell-types were associated with HD cortical cell loss and these associations were validated using cell specific single nucleus RNAseq (snRNAseq) data from post-mortem HD brains. The developmental transcriptomic profile of cortical cell loss in preHD was enriched in astrocytes and endothelial cells, while the neurodegenerative transcriptomic profile was enriched for neuronal and microglial cells. Astrocyte-specific genes differentially expressed in HD post-mortem brains relative to controls using snRNAseq were enriched in the developmental transcriptomic profile, while neuronal and microglial-specific genes were enriched in the neurodegenerative transcriptomic profile Our findings suggest that cortical cell loss in preHD may arise from dual pathological processes, emerging as a consequence of neurodevelopmental changes, at the beginning of life, followed by neurodegeneration in adulthood, targeting areas with reduced expression of synaptic and metabolic genes. These events result in age-related cell death across multiple brain cell types

Progressive alterations in white matter microstructure across the timecourse of Huntington's disease

BACKGROUND: Whole-brain longitudinal diffusion studies are crucial to examine changes in structural connectivity in neurodegeneration. Here, we investigated the longitudinal alterations in white matter (WM) microstructure across the timecourse of Huntington's disease (HD). METHODS: We examined changes in WM microstructure from premanifest to early manifest disease, using data from two cohorts with different disease burden. The TrackOn-HD study included 67 controls, 67 premanifest, and 10 early manifest HD (baseline and 24-month data); the PADDINGTON study included 33 controls and 49 early manifest HD (baseline and 15-month data). Longitudinal changes in fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity, and radial diffusivity from baseline to last study visit were investigated for each cohort using tract-based spatial statistics. An optimized pipeline was employed to generate participant-specific templates to which diffusion tensor imaging maps were registered and change maps were calculated. We examined longitudinal differences between HD expansion-carriers and controls, and correlations with clinical scores, including the composite UHDRS (cUHDRS). RESULTS: HD expansion-carriers from TrackOn-HD, with lower disease burden, showed a significant longitudinal decline in FA in the left superior longitudinal fasciculus and an increase in MD across subcortical WM tracts compared to controls, while in manifest HD participants from PADDINGTON, there were significant widespread longitudinal increases in diffusivity compared to controls. Baseline scores in clinical scales including the cUHDRS predicted WM microstructural change in HD expansion-carriers. CONCLUSION: The present study showed significant longitudinal changes in WM microstructure across the HD timecourse. Changes were evident in larger WM areas and across more metrics as the disease advanced, suggesting a progressive alteration of WM microstructure with disease evolution

Integrated analysis of climate, soil, topography and vegetative growth in Iberian viticultural regions

The Iberian viticultural regions are convened according to the Denomination of Origin (DO) and present different climates, soils, topography and management practices. All these elements influence the vegetative growth of different varieties throughout the peninsula, and are tied to grape quality and wine type. In the current study, an integrated analysis of climate, soil, topography and vegetative growth was performed for the Iberian DO regions, using state-of-the-art datasets. For climatic assessment, a categorized index, accounting for phenological/thermal development, water availability and grape ripening conditions was computed. Soil textural classes were established to distinguish soil types. Elevation and aspect (orientation) were also taken into account, as the leading topographic elements. A spectral vegetation index was used to assess grapevine vegetative growth and an integrated analysis of all variables was performed. The results showed that the integrated climate-soil-topography influence on vine performance is evident. Most Iberian vineyards are grown in temperate dry climates with loamy soils, presenting low vegetative growth. Vineyards in temperate humid conditions tend to show higher vegetative growth. Conversely, in cooler/warmer climates, lower vigour vineyards prevail and other factors, such as soil type and precipitation acquire more important roles in driving vigour. Vines in prevailing loamy soils are grown over a wide climatic diversity, suggesting that precipitation is the primary factor influencing vigour. The present assessment of terroir characteristics allows direct comparison among wine regions and may have great value to viticulturists, particularly under a changing climate

Stabilization of angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid

Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system (RAAS), is a promising candidate as a treatment for cancer that reflects its antiproliferative and anti-angiogenic properties. However, the peptide’s therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer

Children at danger: injury fatalities among children in San Diego County

External causes of death are important in the pediatric population worldwide. We performed an analysis of all injury-fatalities in children between ages zero and 17 years, between January 2000 and December 2006, in San Diego County, California, United States of America. Information was obtained from the County of San Diego Medical Examiner’s database. External causes were selected and grouped by intent and mechanism. Demographics, location of death and relation between the injury mechanism and time of death were described. There were 884 medico-legal examinations, of which 480 deaths were due to external causes. There majority were males (328, 68.3%) and whites (190, 39.6%). The most prevalent mechanism of injury leading to death was road traffic accidents (40.2%), followed by asphyxia (22.7%) and penetrating trauma (17.7%). Unintentional injuries occurred in 65.8% and intentional injuries, including homicide and suicide, occurred in 24.2 and 9.4%, respectively. Death occurred at the scene in 196 cases (40.9%). Most deaths occurred in highways (35.3%) and at home (28%). One hundred forty-six patients (30.4%) died in the first 24 h. Seven percent died 1 week after the initial injury. Among the cases that died at the scene, 48.3% were motor vehicle accidents, 20.9% were victims of firearms, 6.5% died from poisoning, 5% from hanging, and 4% from drowning. External causes remain an important cause of death in children in San Diego County. Specific strategies to decrease road-traffic accidents and homicides must be developed and implemented to reduce the burden of injury-related deaths in children