Actividad física, hábitos sedentarios, condición física, y biomarcadores inflamatorios en niños y adolescentes

Cardiovascular diseases (CVD) are the main cause of mortality in the world(1). Episodes of CVD are found mainly during or after the fifth decade of life. However there are evidences indicating that precursors of CVD have their origins during childhood and adolescence(2,3). In fact, it has been shown that levels of CVD during childhood are predictors of CVD risk during adulthood(4-7). Between the main conventional CVD risk factors we found, obesity, hypertension, insulin resistance and dyslipidemia(8). A better understanding of the mechanism that affect risk factors for CVD during childhood and adolescence would contribute to the development of effective prevention programs, a better counseling and a shift towards correct public health policies. In the last decades, numerous studies have found the existence of new CVD risk factors, among which are the inflammatory biomarkers(9). The overall objective of the present doctoral thesis was to study the influence of the physical activity, sedentary behaviour and physical fitness levels as well as the neck circumference on emerging CVD risk factors in children and adolescents. To address these aims 3 studies were conducted from data gathered in the UP&DOWN study. Study I was conducted in a population of 481 participants (229 children; 252 adolescents) from the UP&DOWN study. Study II was performed with 503 participants (230 children; 273 adolescents) from the UP&DOWN study. In the study III 2198 participants were included, (1179 children; 1019 adolescents) belonging to the UP&DOWN study. The main findings of this Doctoral Thesis were: i) Physical activity and sedentary behaviour levels were inversely and positively associated, respectively, with levels of inflammatory biomarkers in children and adolescents; however, when physical fitness levels were taken into account, almost all associations disappeared. ii) Physical fitness, mainly cardiorespiratory fitness and upper body muscular fitness, were inversely associated with inflammatory biomarkers in children and adolescents independently of body mass index. iii) Neck circumference was positively associated with other anthropometric and body composition indexes, as well as with independent cardiovascular risk factors grouped in children and adolescents. The results of this doctoral thesis have helped broaden the knowledge about the relationship between physical activity levels, sedentary behaviour, physical fitness and neck circumference with emerging cardiovascular risk factors in children and adolescents. The results suggest that a regular practice of physical activity in order to improve physical fitness levels, as well as a shorter time invested in sedentary behaviour, could contribute to an improvement in the inflammatory profile and reduce the risk of CVD in children and adolescents. In addition, cut-off values to classify children and adolescents as normal weight and overweight/obese have been identified, based on prediction equations using body mass index, waist circumference and body fat percentage.Las enfermedades cardiovasculares (ECV) son la principal causa de mortalidad mundial(1). Los casos de ECV se presentan con mayor frecuencia durante o después de la quinta década de la vida. Sin embargo hay evidencias que indican que los precursores de ECV tienen su origen en la infancia y la adolescencia(2,3). De hecho, se ha demostrado que los niveles de riesgo de ECV durante la infancia son predictores de los niveles de riesgo en edad adulta(4-7). Entre los principales factores de riesgo de padecer ECV convencionales se encuentran la obesidad, hipertensión, resistencia a la insulina y la dislipemia(8). Un mayor conocimiento de los mecanismos que afectan a los factores de riesgo de padecer ECV en la juventud contribuiría al desarrollo de programas de prevención eficaces, a un mejor asesoramiento y a un cambio hacia políticas correctas de salud pública. En las últimas décadas, numerosos estudios han encontrado la existencia de nuevos factores de riesgo de padecer ECV, entre los que se encuentran los biomarcadores inflamatorios(9). El objetivo general de la presente tesis doctoral ha sido estudiar la influencia de los niveles de actividad física, hábitos sedentarios, condición física así como el perímetro de cuello sobre factores emergentes de riesgo de enfermedad cardiovascular en niños y adolescentes. Para responder a estos objetivos se realizaron 3 estudios a partir de los datos recogidos en el estudio UP&DOWN. El estudio I se realizó en una población de 481 participantes (229 niños; 252 adolescentes) pertenecientes al estudio UP&DOWN. El estudio II, se llevó a cabo con 503 participantes (230 niños; 273 adolescentes) del estudio UP&DOWN). En el estudio III se incluyeron 2198 participantes, (1179 niños; 1019 adolescentes) pertenecientes al estudio UP&DOWN. Los principales hallazgos de esta Tesis Doctoral fueron: i) Los niveles de actividad física y los hábitos sedentarios se asociaron inversa y positivamente, de forma respectiva, con los niveles de biomarcadores inflamatorios en niños y adolescentes; sin embargo, cuando se tuvieron en cuenta los niveles de condición física desaparecieron casi todas las asociaciones. ii) La condición física, principalmente la capacidad cardiorrespiratoria y la fuerza muscular del tren superior, se asociaron negativamente con los niveles de biomarcadores inflamatorios en niños y adolescentes independientemente del índice de masa corporal iii) El perímetro de cuello se asoció positivamente con otros índices antropométricos y de composición corporal, así como con factores de riesgo cardiovasculares individuales y agrupados en niños y adolescentes. Los resultados de esta tesis doctoral han ayudado a ampliar los conocimientos acerca de la relación entre los niveles de actividad física, hábitos sedentarios, condición física y el perímetro de cuello con factores emergentes de riesgo cardiovascular en poblaciones de niños y adolescentes. Los resultados sugieren que la práctica regular de actividad física con el fin de mejorar los niveles de condición física, así como un menor tiempo invertido en hábitos sedentarios, podrían contribuir a una mejora del perfil inflamatorio y a reducir el riesgo de padecer ECV en niños y adolescentes. Además, se han identificado puntos de corte del perímetro del cuello según edad y sexo, para clasificar a los niños y adolescentes dentro de los grupos de normopeso y sobrepeso/obesidad, basados en ecuaciones de predicción que usan el índice de masa corporal, perímetro de cintura y porcentaje de grasa corporal

Changes in and the mediating role of physical activity in relation to active school transport, fitness and adiposity among Spanish youth: the UP&DOWN longitudinal study

Background Longitudinal changes in child and adolescent active school transport (AST), and the mediating role of different intensities of daily physical activity (PA) levels in relation to AST and physical fitness and adiposity indicators is unclear. This study aimed to: 1) describe longitudinal changes in AST, light PA (LPA), moderate- to vigorous-intensity PA (MVPA), physical fitness and adiposity indicators over three time-points; and 2) investigate the mediating role of LPA and MVPA levels on associations between AST and physical fitness and adiposity indicators over three time-points among children and adolescents. Methods This longitudinal study comprised 1646 Spanish children and adolescents (48.8% girls, mean age 12.5 years +/- 2.5) at baseline, recruited from schools in Cadiz and Madrid. Mode of commuting to school was self-reported at baseline (T0, 2011-12), 1-year (T1) and 2-year follow-up (T2). PA was assessed using accelerometers. Handgrip strength, standing long jump and cardiorespiratory fitness (CRF) assessed physical fitness. Height, weight, body mass index, waist circumference, and triceps and subscapular skinfold thickness were measured. Multilevel linear regression analyses assessed changes in AST, PA levels, physical fitness and adiposity indicators over three time-points (T0-T1-T2). Additionally, longitudinal path analysis (n = 453; mean age [years] 12.6 +/- 2.4) was used to test the mediating effects of LPA and MVPA levels on the association between AST and physical fitness and adiposity indicators. Results Multilevel analyses observed decreases in LPA between T0-T1 (beta = - 11.27; p < 0.001) and T0-T2 (beta = - 16.27; p < 0.001) and decreases in MVPA between T0-T2 (beta = - 4.51; p = 0.011). Moreover, changes over time showed increases in handgrip between T0-T1 (beta = 0.78; p = 0.028) and T0-T2 (beta = 0.81; p = 0.046). Path analyses showed that AST was directly positively associated with MVPA at T1 (all, beta approximate to 0.33; p < 0.001). MVPA at T1 mediated associations between AST and CRF at T2 (beta = 0.20; p = 0.040), but not the other outcomes. LPA did not mediate any associations. Conclusions Results from longitudinal path analysis suggest that participation in more AST may help attenuate declines in MVPA that typically occur with age and improve CRF. Therefore, we encourage health authorities to promote AST, as a way to increase MVPA levels and CRF among youth

Test–Retest Reliability of Functional Electromechanical Dynamometer on Five Sit-to-Stand Measures in Healthy Young Adults

Background: The purpose of this study was to determine the reliability for the strength and movement velocity of the concentric phase from the five Sit-to-Stand (5STS), using three incremental loads measured by a functional electromechanical dynamometer (FEMD) in healthy young adults. Methods: The average and peak strength and velocity values of sixteen healthy adults (mean ± standard deviation (SD): age = 22.81 ± 2.13 years) were recorded at 5, 10 and 15 kg. To evaluate the reliability of FEMD, the intraclass correlation coefficient (ICC), standard error of measurement (SEM) and coefficient of variation (CV) were obtained. Results: Reliability was high for the 10 kg (CV range: 3.70–4.18%, ICC range: 0.95–0.98) and 15 kg conditions (CV range: 1.64–3.02%, ICC: 0.99) at average and peak strength, and reliability was high for the 5 kg (CV range: 1.71–2.84%, ICC range: 0.96–0.99), 10 kg (CV range: 0.74–1.84%, ICC range: 0.99–1.00) and 15 kg conditions (CV range: 0.79–3.11%, ICC range: 0.99–1.00) at average and peak velocity. Conclusions: The findings of this study demonstrate that FEMD is a reliable instrument to measure the average and peak strength and velocity values during the five STS in healthy young adults.FEDER/Ministry of Science, Innovation and Universities—State Research Agency (Dossier number: RTI2018-099723-B-I00

Neck circumference and clustered cardiovascular risk factors in children and adolescents: Cross-sectional study.

OBJECTIVE: Early detection of cardiovascular disease (CVD) risk factors, such as obesity, is crucial to prevent adverse long-term effects on individuals' health. Therefore, the aims were: (1) to explore the robustness of neck circumference (NC) as a predictor of CVD and examine its association with numerous anthropometric and body composition indices and (2) to release sex and age-specific NC cut-off values to classify youths as overweight/obese. DESIGN: Cross-sectional study. SETTING: 23 primary schools and 17 secondary schools from Spain. PARTICIPANTS: 2198 students (1060 girls), grades 1-4 and 7-10. MEASURES: Pubertal development, anthropometric and body composition indices, systolic and diastolic blood pressure (SBP and DBP, respectively), cardiorespiratory fitness, blood sampling triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), glucose and inflammatory markers. Homoeostasis model assessment (HOMA-IR) and cluster of CVD risk factors were calculated. RESULTS: NC was negatively associated with maximum oxygen consumption (R2=0.231, P<0.001 for boys; R2=0.018, P<0.001 for girls) and adiponectin (R2=0.049, P<0.001 for boys; R2=0.036, P<0.001 for girls); and positively associated with SBP, DBP, TC/HDL-c, TG, HOMA, complement factors C-3 and C-4, leptin and clustered CVD risk factor in both sexes (R2 from 0.035 to 0.353, P<0.01 for boys; R2 from 0.024 to 0.215, P<0.001 for girls). Moreover, NC was positively associated with serum C reactive protein and LDL-c only in boys (R2 from 0.013 to 0.055, P<0.05). CONCLUSION: NC is a simple, low-cost and practical screening tool of excess of upper body obesity and CVD risk factors in children and adolescents. Paediatricians can easily use it as a screening tool for overweight/obesity in children and adolescents. For this purpose, sex and age-specific thresholds to classify children and adolescents as normal weight or overweight/obese are provided.This work was supported by the DEP 2010 21662 C04 00 (DEP 2010 21662 C04 01: DEP 2010 21662 C04 02: DEP 2010 21662 C04 03: DEP 2010 21662 C04 04) grant from the National Plan for Research: Development and Innovation (R+D+i) MICINN

Improving the effect of incubation and oxidative stress on thawed spermatozoa from red deer by using different antioxidant treatments

P. 856-870Antioxidants could improve sperm media, extending the viability of spermatozoa and protecting their DNA. The protective ability of lipoic acid, melatonin, Trolox and crocin was tested on red deer spermatozoa incubated at 37°C. Cryopreserved spermatozoa were thawed and incubated with 1 mM or 0.1 mM of each antioxidant, with or without oxidative stress (100 μM Fe2+). Motility (CASA), viability, mitochondrial membrane potential and acrosomal status were assessed. Lipoperoxidation (malondialdehyde production), intracellular reactive oxygen species (ROS) and DNA status (TUNEL) were checked at 4 h. Incubation alone increased ROS and decreased motility. Oxidative stress intensified these effects, increasing lipoperoxidation and DNA damage. Lipoic acid had little protective effect, whereas 1 mM melatonin showed limited protection. Trolox lowered ROS and lipoperoxidation both in oxidised and non-oxidised samples. In oxidised samples, Trolox prevented DNA and acrosomal damage, and ameliorated motility. Crocin at 1 mM showed similar results to Trolox, but noticeably stimulated motility and had no effect on lipoperoxidation. In a second experiment, a broader range of crocin and melatonin concentrations were tested, confirming the effects of crocin (positive effects noticeable at 0.5–0.75 mM), but showing an increase in lipoperoxidation at 2 mM. Melatonin was increasingly effective at 2.5 and 5 mM (ROS, lipoperoxidation and DNA status). Crocin seems a promising new antioxidant, but its particular effects on sperm physiology must be further studied, especially the consequences of motility stimulation and confirming its effect on lipoperoxidation. Melatonin might be useful at relatively high concentrations, compared to Trolox.S

Prefrontal reactivity to TMS perturbation as a toy model of mental health outcomes during the COVID-19 pandemic

Psychosocial hardships associated with the COVID-19 pandemic led many individuals to suffer adverse mental health consequences, however, others show no negative effects. We hypothesized that the electroencephalographic (EEG) response to transcranial magnetic stimulation (TMS) could serve as a toy-model of an individual's capacity to resist psychological stress, in this case linked to the COVID-19 pandemic. We analyzed data from 74 participants who underwent mental health monitoring and concurrent electroencephalography with transcranial magnetic stimulation of the left dorsolateral prefrontal cortex (L-DLPFC) and left inferior parietal lobule (L-IPL). Within the following 19 months, mental health was reassessed at three timepoints during lock-down confinement and different phases of de-escalation in Spain. Compared with participants who remained stable, those who experienced increased mental distress showed, months earlier, significantly larger late EEG responses locally after L-DLPFC stimulation (but not globally nor after L-IPL stimulation). This response, together with years of formal education, was significantly predictive of mental health status during the pandemic. These findings reveal that the effect of TMS perturbation offers a predictive toy model of psychosocial stress response, as exemplified by the COVID-19 pandemic

Long-interval intracortical inhibition in primary motor cortex related to working memory in middle-aged adults

Excitability of the primary motor cortex measured with TMS has been associated with cognitive dysfunctions in patient populations. However, only a few studies have explored this relationship in healthy adults, and even fewer have considered the role of biological sex. Ninety-seven healthy middle-aged adults (53 male) completed a TMS protocol and a neuropsychological assessment. Resting Motor Threshold (RMT) and Long-Interval Intracortical Inhibition (LICI) were assessed in the left motor cortex and related to attention, episodic memory, working memory, reasoning, and global cognition composite scores to evaluate the relationship between cortical excitability and cognitive functioning. In the whole sample, there was a significant association between LICI and cognition; specifically, higher motor inhibition was related to better working memory performance. When the sample was broken down by biological sex, LICI was only associated with working memory, reasoning, and global cognition in men. No associations were found between RMT and cognitive functions. Greater intracortical inhibition, measured by LICI, could be a possible marker of working memory in healthy middle-aged adults, and biological sex plays a critical role in this association

Local Prefrontal Cortex TMS-Induced Reactivity Is Related to Working Memory and Reasoning in Middle-Aged Adults

Introduction: The prefrontal cortex (PFC) plays a crucial role in cognition, particularly in executive functions. Cortical reactivity measured with Transcranial Magnetic Stimulation combined with Electroencephalography (TMS-EEG) is altered in pathological conditions, and it may also be a marker of cognitive status in middle-aged adults. In this study, we investigated the associations between cognitive measures and TMS evoked EEG reactivity and explored whether the effects of this relationship were related to neurofilament light chain levels (NfL), a marker of neuroaxonal damage. Methods: Fifty two healthy middle-aged adults (41-65 years) from the Barcelona Brain Health Initiative cohort underwent TMS-EEG, a comprehensive neuropsychological assessment, and a blood test for NfL levels. Global and Local Mean-Field Power (GMFP/LMFP), two measures of cortical reactivity, were quantified after left prefrontal cortex (L-PFC) stimulation, and cognition was set as the outcome of the regression analysis. The left inferior parietal lobe (L-IPL) was used as a control stimulation condition. Results: Local reactivity was significantly associated with working memory and reasoning only after L-PFC stimulation. No associations were found between NfL and cognition. These specific associations were independent of the status of neuroaxonal damage indexed by the NfL biomarker and remained after adjusting for age, biological sex, and education. Conclusion: Our results demonstrate that TMS evoked EEG reactivity at the L-PFC, but not the L-IPL, is related to the cognitive status of middle-aged individuals and independent of NfL levels, and may become a valuable biomarker of frontal lobe-associated cognitive function. Keywords: Electroencephalography; TMS-EEG; cognition; cortical reactivity; prefrontal cortex (PFC); transcranial magnetic stimulation (TMS)

Osteoprotegerin CGA Haplotype Protection against Cerebrovascular Complications in Anti-CCP Negative Patients with Rheumatoid Arthritis

INTRODUCTION: Rheumatoid arthritis is an inflammatory disease with high incidence of cardiovascular disease due to accelerated atherosclerosis. Osteoprotegerin (OPG) has been associated with increased risk of atherosclerotic disease in the general population. Several polymorphisms in the OPG gene with functional effects on cardiovascular disease in non-rheumatic individuals have been described. Therefore, we aimed to analyze the effect of three of these functional OPG polymorphisms on the risk of cardiovascular disease in a large and well-characterized cohort of Spanish patients with rheumatoid arthritis. METHODS: Three OPG gene variants (rs3134063, rs2073618 and rs3134069) were genotyped by TaqMan assays in 2027 Spanish patients with rheumatoid arthritis. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing was positive in 997 of 1714 tested. Also, 18.3% of the whole series had experienced cardiovascular events, including 5.4% with cerebrovascular accidents. The relationship between OPG variants and cardiovascular events was assessed using Cox regression. RESULTS: No association between OPG gene variants and cardiovascular disease was observed in the whole group of rheumatoid arthritis patients or in anti-CCP positive patients. Nevertheless, a protective effect of CGA haplotype on the risk of cardiovascular disease in general, and specifically in the risk of cerebrovascular complications after adjusting for sex, age at disease diagnosis and traditional cardiovascular risk factors was disclosed in anti-CCP negative patients (HR = 0.54; 95%CI: 0.31-0.95; p = 0.032 and HR = 0.17; 95%CI: 0.04-0.78; p = 0.022, respectively). CONCLUSION: Our results indicate a protective effect of the OPG CGA haplotype on cardiovascular risk, mainly due to a protective effect against cerebrovascular events in anti-CCP negative rheumatoid arthritis patients

A Somatostatin Receptor Subtype-3 (SST3) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors

[Purpose] Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST2 and SST5. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST2. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST3 and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST3-agonists and characterize their effects on experimental NFPT models.[Experimental Design] Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST3-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST3-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST3-agonist. [Results] We successfully identified the first SST3-agonist peptides. SST3-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis in vitro, and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST3-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST3 than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST3-agonist treatments. Concurrently, SSTR3 silencing increased cell viability in a subset of NFPTs. [Conclusions] This study demonstrates that SST3-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST3, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.This work has been funded by the following grants: Junta de Andalucía [CTS-1406 (R.M. Luque), BIO-0139 (J.P. Castaño)]; Ministerio de Ciencia, Innovación y Universidades [BFU2016-80360-R (J.P. Castaño)] and Instituto de Salud Carlos III, co-funded by European Union [ERDF/ESF, “Investing in your future”: PI16/00264 (R.M. Luque), CP15/00156 (M.D. Gahete) and CIBERobn]. CIBER is an initiative of Instituto de Salud Carlos III