Risk factors for executive function impairment in adolescence: 2004 Pelotas Birth Cohort study

Objective: To investigate risk factors associated with impaired attention-related executive functions (EFs) at age 11 and working memory at age 15. Methods: Data from the population-based 2004 Pelotas Birth Cohort was analyzed at ages 11 (N=3,582) and 15 (N=1,950). The study measured attentional control, cognitive flexibility, and selective attention using the Daily Attention Test for Children. Spatial working memory was assessed by the Cambridge Automated Neuropsychological Test Battery. Logistic regression was employed to explore the relationship between perinatal and childhood exposures and EF impairment. Results: Low maternal education had a significant negative impact on EFs. At age 11, it was associated with decreased attentional control (OR=3.04; CI95% 2.09-4.43), and at age 15, it was linked to impaired spatial working memory (OR=2.21; CI95% 1.58-3.09). Additional risk factors included low family income, black or brown maternal skin color, high parity, prematurity, low birth weight, and a high number of siblings. Breastfeeding, regardless of duration, was found to be a protective factor against impaired cognitive flexibility (OR=0.38; CI95% 0.22-0.65). Conclusion: This study underscores the lasting impact of perinatal exposures on EFs development. Policies that mitigate the negative effects of risk factors and promote EF development, especially among vulnerable populations, are needed

DRD4 rare variants in attention-deficit/hyperactivity disorder (ADHD) : further evidence from a birth cohort study

The dopamine receptor D4 (DRD4) is one of the most studied candidate genes for Attention-Deficit/Hyperactivity Disorder (ADHD). An excess of rare variants and non-synonymous mutations in the VNTR region of 7R allele in ADHD subjects was observed in previous studies with clinical samples. We hypothesize that genetic heterogeneity in the VNTR is an important factor in the pathophysiology of ADHD. The subjects included in the present study are members of the 1993 Pelotas Birth Cohort Study (N=5,249). We conducted an association study with the 4,101 subjects who had DNA samples collected. The hyperactivity-inattention scores were assessed through the parent version of the Strengths and Difficulties Questionnaire at 11 and 15 years of age. The contribution of allele’s length and rare variants to high hyperactivity/inattention scores predisposition was evaluated by multivariate logistic regression. No effect of allele length was observed on high scores of hyperactivity-inattention. By contrast, when resequencing/haplotyping was conducted in a subsample, all 7R rare variants as well as non-synonymous 7R rare variants were associated with high hyperactivity/inattention scores (OR=2.561; P=0.024 and OR=3.216; P=0.008 respectively). A trend for association was observed with 4R rare variants. New coding mutations covered 10 novel motifs and many of them are previously unreported deletions leading to different stop codons. Our findings suggest a contribution of DRD4 7R rare variants to high hyperactivity-inattention scores in a population-based sample from a large birth cohort. These findings provide further evidence for an effect of DRD4 7R rare variants and allelic heterogeneity in ADHD genetic susceptibility

General and abdominal obesity in adults living in a rural area in Southern Brazil

OBJETIVO: Avaliar a prevalência de obesidade geral, abdominal e concomitância de ambos os desfechos e seus determinantes em adultos residentes na zona rural. MÉTODOS: Este estudo transversal de base populacional foi conduzido em município de médio porte da região Sul do Brasil. Três desfechos foram avaliados: obesidade geral (índice de massa corporal ≥ 30 kg/m²), abdominal (circunferência da cintura ≥ 102 cm e ≥ 88 cm em homens e mulheres, respectivamente) e concomitância de ambas, classificada em: sem risco; apenas um fator de risco; e fatores agregados. Foram realizadas análises brutas e ajustadas por regressão de Poisson para cada desfecho de obesidade e regressão logística multinomial para o risco metabólico. Características demográficas e socioeconômicas foram consideradas como variáveis independentes. RESULTADOS: Foram incluídos no estudo 1.433 indivíduos. Desses, 29,5% apresentaram obesidade geral e 37,8%, abdominal. A presença de um fator de risco foi observada em 15,8% da amostra, enquanto 25,8% apresentaram fatores agregados. O risco de obesidade geral, abdominal e a concomitância dos desfechos aumentaram significativamente com a idade, em ambos os sexos. Homens mais ricos apresentaram risco aumentado para obesidade geral (RP = 1,7; IC95% 1,0–2,9), abdominal (RP = 1,8; IC95% 1,1–2,9) e fatores agregados (RO = 1,9; IC95% 1,4–5,8). Ter 12 anos ou mais de estudo se mostrou fator de proteção para mulheres em relação à obesidade abdominal (RP=0,4; IC95% 0,2–0,8) e fatores agregados (RO = 0,2; IC95% 0,05–0,7). Realizar atividade rural reduziu o risco de obesidade geral (RP = 0,6; IC95% 0,5–0,8) e fatores agregados (RO = 0,5; IC95% 0,3–0,8) em mulheres, e de obesidade abdominal (RP = 0,6; IC95% 0,5–0,8) e presença de um fator de risco (RO = 0,5; IC95% 0,3–0,7), em homens. Cor da pele e tempo de vida residido na zona rural não foram estatisticamente associados aos desfechos estudados. CONCLUSÕES: Altas prevalências de obesidade geral e abdominal foram observadas nessa população, condizentes com os valores encontrados em populações urbanas. Entretanto, a realização de atividades rurais mostrou-se um fator de proteção para os desfechos de obesidade.OBJECTIVE: To evaluate the prevalence of general and abdominal obesity and the concomitant presence of both outcomes and their determinants among adults living in a rural area. METHODS: This cross-sectional, population-based study was carried out in a medium-sized city in the southern region of Brazil. We evaluated three outcomes: general obesity (body mass index ≥ 30 kg/m²), abdominal obesity (waist circumference ≥ 102 cm and ≥ 88 cm in men and women, respectively), and concomitant obesities, classified as: no risk, only one risk factor, and aggregate factors. We performed crude and adjusted Poisson regression analyses for each obesity outcome and multinomial logistic regression for metabolic risk. We considered demographic and socioeconomic characteristics as independent variables. RESULTS: A total of 1,433 individuals were included in the study. Of them, 29.5% presented general obesity and 37.8% presented abdominal obesity. We observed the presence of a risk factor in 15.8% of the sample, while 25.8% presented aggregate factors. The risk of general and abdominal obesity and concomitant outcomes increased significantly with age in both sexes. Richer men were at increased risk for general obesity (PR = 1.7; 95%CI 1.0–2.9), abdominal obesity (PR = 1.8; 95%CI 1.1–2.9), and aggregate factors (OR = 1.9; 95%CI 1.4–5.8). An education level of twelve years or more was a protective factor for women in relation to abdominal obesity (PR = 0.4; 95%CI 0.2–0.8) and aggregate factors (OR = 0.2; 95%CI 0.05–0.7). Rural activity reduced the risk of general obesity (PR = 0.6; 95%CI 0.5–0.8) and aggregate factors (OR = 0.5; 95%CI 0.3–0.8) in women, and the risk of abdominal obesity (PR = 0.6; 95%CI 0.5–0.8) and presence of a risk factor (OR = 0.5; 95%CI 0.3–0.7) in men. Skin color and time lived in rural areas were not statistically associated with the outcomes studied. CONCLUSIONS: We observed high prevalences of general and abdominal obesity in this population, which is consistent with the values found in urban populations. However, rural activities were a protective factor for obesity outcome

New findings in eNOS gene and thalidomide embryopathy suggest pre-transcriptional effect variants as susceptibility factors

Antiangiogenic properties of thalidomide have created an interest in the use of the drug in treatment of cancer. However, thalidomide is responsible for thalidomide embryopathy (TE). A lack of knowledge regarding the mechanisms of thalidomide teratogenesis acts as a barrier in the aim to synthesize a safer analogue of thalidomide. Recently, our group detected a higher frequency of alleles that impair the pro-angiogenic mechanisms of endothelial nitric oxide synthase (eNOS), coded by the NOS3 gene. In this study we evaluated variable number tandem repeats (VNTR) functional polymorphism in intron 4 of NOS3 in individuals with TE (38) and Brazilians without congenital anomalies (136). Haplotypes were estimated for this VNTR with previously analyzed polymorphisms, rs2070744 (−786C>T) and rs1799983 (894T>G), in promoter region and exon 7, respectively. Haplotypic distribution was different between the groups (p=0.007). Alleles −786C (rs2070744) and 4b (VNTR), associated with decreased NOS3 expression, presented in higher frequency in TE individuals (p=0.018; OR=2.57; IC=1.2–5.8). This association was not identified with polymorphism 894T>G (p=0.079), which influences eNOS enzymatic activity. These results suggest variants in NOS3, with pre-transcriptional effects as susceptibility factors, influencing the risk TE development. This finding generates insight for a new approach to research that pursues a safer analogue

FOXP in tetrapoda : intrinsically disordered regions, short linear motifs and their evolutionary significance

The FOXP subfamily is probably the most extensively characterized subfamily of the forkhead superfamily, playing important roles in development and homeostasis in vertebrates. Intrinsically disorder protein regions (IDRs) are protein segments that exhibit multiple physical interactions and play critical roles in various biological processes, including regulation and signaling. IDRs in proteins may play an important role in the evolvability of genetic systems. In this study, we analyzed 77 orthologous FOXP genes/proteins from Tetrapoda, regarding protein disorder content and evolutionary rate. We also predicted the number and type of short linear motifs (SLIMs) in the IDRs. Similar levels of protein disorder (approximately 70%) were found for FOXP1, FOXP2, and FOXP4. However, for FOXP3, which is shorter in length and has a more specific function, the disordered content was lower (30%). Mammals showed higher protein disorders for FOXP1 and FOXP4 than non-mammals. Specific analyses related to linear motifs in the four genes showed also a clear differentiation between FOXPs in mammals and non-mammals. We predicted for the first time the role of IDRs and SLIMs in the FOXP gene family associated with possible adaptive novelties within Tetrapoda. For instance, we found gain and loss of important phosphorylation sites in the Homo sapiens FOXP2 IDR regions, with possible implication for the evolution of human speech

Repeated high blood pressure at 6 and 11 years at the Pelotas 2004 birth cohort study

Background: We evaluated the prevalence and the factors associated with repeated high systolic (SBP) and diastolic blood pressure (DBP) at 6- and 11-year follow-ups of children from the Pelotas (Brazil) 2004 Birth Cohort. Methods: All live births to mothers living in the urban area of Pelotas were enrolled in the cohort. Blood pressure (BP) values were transformed into Z-scores by sex, age, and height. High SBP and DBP were defined as repeated systolic and diastolic BP Z-scores on the ≥95th percentile at the two follow-ups. Prevalence (95% confidence interval) of repeated high SBP, DBP, and both (SDBP) were calculated. Associations with maternal and child characteristics were explored in crude and adjusted logistic regression analyses. Results: A total of 3182 cohort participants were analyzed. Prevalence of repeated high SBP, DBP and SDBP was 1.7% (1.2–2.1%), 2.3% (1.8–2.9%) and 1.2% (0.9–1.6%), respectively. Repeated high SBP was associated with males, gestational diabetes mellitus (2.92; 1.13–7.58) and obesity at 11 years (2.44; 1.29–4.59); while repeated high DBP was associated with females, family history of hypertension from both sides (3.95; 1.59–9.85) and gestational age < 34 weeks (4.08; 1.52–10.96). Repeated high SDBP was not associated with any of the characteristics investigated. Conclusion: Prevalence of repeated high SBP, DBP, and SDBP were within the expected distribution at the population level. Nonetheless, gestational diabetes mellitus, obesity, family history of hypertension, and prematurity increased the risk of repeated high blood pressure measured at two occasions 5 years apart

The effects of two early parenting interventions on child aggression and risk for violence in Brazil (The PIÁ Trial): protocol for a randomised controlled trial

Background Children in many low- and middle-income countries (LMICs) are at high risk for exposure to violence and later violent behaviour. The World Health Organization has declared an urgent need for the evaluation and implementation of low-cost parenting interventions in LMICs to prevent violence. Two areas of significant early risk are harsh parenting and poor child cognitive and socio-emotional development. Parenting interventions suitable for LMIC contexts have been developed targeting these risk factors and have been shown to have promising effects. However, their impact on child aggression, a key precursor of violence, has yet to be determined. The Pelotas Trial of Parenting Interventions for Aggression (PIÁ) has been designed to address this issue. Methods We are conducting a randomised controlled trial to evaluate two early parenting interventions for mothers of children aged between 30 and 42 months in a Brazilian city. The first of these, dialogic book-sharing (DBS), aims to promote child cognitive and socio-emotional development; and the second, the ACT Raising Safe Kids Program (ACT), is designed to reduce harsh parenting. These interventions are being compared with a control group receiving neither intervention. Three hundred and sixty-nine families in a birth cohort are being randomly allocated to one of the three groups (DBS, ACT, Control). Facilitators deliver the interventions to groups of five to 10 mothers at weekly sessions for 8 weeks in DBS and 9 weeks in ACT. Independent assessments of parenting and child development are being made before the interventions, shortly afterwards, and at follow-up 6 months later. The primary outcome is child aggression, and the two main secondary outcomes are: (1) child cognitive and socio-emotional development and (2) harsh parenting. Longer-term outcomes will be investigated as the birth cohort is followed into late childhood, adolescence, and adulthood. Discussion The Pelotas Trial of Parenting Interventions for Aggression (PIÁ) aims to evaluate the impact of two early parenting interventions on child aggression and several other key risk factors for the development of violence, including aspects of parenting and child cognition and socio-emotional functioning. The study is being carried out in a LMIC context where violence constitutes a major social and health burden. Since the two interventions are brief and, with modest levels of training, readily deliverable in LMIC settings, a demonstration that they benefit parenting and reduce risk factors for violence would be of major significance

CLOCK polymorphisms in attention-deficit/hyperactivity disorder (ADHD) : further evidence linking sleep and circadian disturbances and ADHD

Circadian and sleep disorders, short sleep duration, and evening chronotype are often present in attention-deficit/hyperactivity disorder (ADHD). CLOCK, considered the master gene in the circadian rhythm, has been explored by few studies. Understanding the relationship between ADHD and CLOCK may provide additional information to understand the correlation between ADHD and sleep problems. In this study, we aimed to explore the association between ADHD and CLOCK, using several genetic markers to comprehensively cover the gene extension. A total of 259 ADHD children and their parents from a Brazilian clinical sample were genotyped for eight single nucleotide polymorphisms (SNPs) in the CLOCK locus. We tested the individual markers and the haplotype effects using binary logistic regression. Binary logistic and linear regressions considering ADHD symptoms among ADHD cases were conducted as secondary analysis. As main result, the analysis showed a risk effect of the G-A-T-G-G-C-G-A (rs534654, rs1801260, rs6855837, rs34897046, rs11931061, rs3817444, rs4864548, rs726967) haplotype on ADHD. A suggestive association between ADHD and rs534654 was observed. The results suggest that the genetic susceptibility to circadian rhythm attributed to the CLOCK gene may play an important role on ADHD