Chronic treatment with ivabradine does not affect cardiovascular autonomic control in rats

A low resting heart rate (HR) would be of great benefit in cardiovascular diseases. Ivabradine-a novel selective inhibitor of hyperpolarization-activated cyclic nucleotide gated (HCN) channels- has emerged as a promising HR lowering drug. Its effects on the autonomic HR control are little known. This study assessed the effects of chronic treatment with ivabradine on the modulatory, reflex and tonic cardiovascular autonomic control and on the renal sympathetic nerve activity (RSNA). Male Wistar rats were divided in 2 groups, receiving intraperitoneal injections of vehicle (VEH) or ivabradine (IVA) during 7 or 8 consecutive days. Rats were submitted to vessels cannulation to perform arterial blood pressure (AP) and HR recordings in freely moving rats. Time series of resting pulse interval and systolic AP were used to measure cardiovascular variability parameters. We also assessed the baroreflex, chemoreflex and the Bezold-Jarish reflex sensitivities. To better evaluate the effects of ivabradine on the autonomic control of the heart, we performed sympathetic and vagal autonomic blockade. As expected, ivabradine-treated rats showed a lower resting (VEH: 362 \ufffd 16 bpm vs. IVA: 260 \ufffd 14 bpm, p = 0.0005) and intrinsic HR (VEH: 369 \ufffd 9 bpm vs. IVA: 326 \ufffd 11 bpm, p = 0.0146). However, the chronic treatment with ivabradine did not change normalized HR spectral parameters LF (nu) (VEH: 24.2 \ufffd 4.6 vs. IVA: 29.8 \ufffd 6.4; p > 0.05); HF (nu) (VEH: 75.1 \ufffd 3.7 vs. IVA: 69.2 \ufffd 5.8; p > 0.05), any cardiovascular reflexes, neither the tonic autonomic control of the HR (tonic sympathovagal index; VEH: 0.91\ufffd 0.02 vs. IVA: 0.88 \ufffd 0.03, p = 0.3494). We performed the AP, HR and RSNA recordings in urethane-anesthetized rats. The chronic treatment with ivabradine reduced the resting HR (VEH: 364 \ufffd 12 bpm vs. IVA: 207 \ufffd 11 bpm, p < 0.0001), without affecting RSNA (VEH: 117 \ufffd 16 vs. IVA: 120 \ufffd 9 spikes/s, p = 0.9100) and mean arterial pressure (VEH: 70 \ufffd 4 vs. IVA: 77 \ufffd 6 mmHg, p = 0.3293). Our results suggest that, in health rats, the long-term treatment with ivabradine directly reduces the HR without changing the RSNA modulation and the reflex and tonic autonomic control of the heart

Patterns of Growth in Childhood in Relation to Adult Schooling Attainment and Intelligence Quotient in 6 Birth Cohorts in Low- and Middle-Income Countries: Evidence from the Consortium of Health-Oriented Research in Transitioning Societies (COHORTS)

BACKGROUND: Growth faltering has been associated with poor intellectual performance. The relative strengths of associations between growth in early and in later childhood remain underexplored. OBJECTIVES: We examined the association between growth in childhood and adult human capital in 5 low- and middle-income countries (LMICs). METHODS: We analyzed data from 9503 participants in 6 prospective birth cohorts from 5 LMICs (Brazil, Guatemala, India, the Philippines, and South Africa). We used linear and quasi-Poisson regression models to assess the associations between measures of height and relative weight at 4 age intervals [birth, age ∼2 y, midchildhood (MC), adulthood] and 2 dimensions of adult human capital [schooling attainment and Intelligence Quotient (IQ)]. RESULTS: Meta-analysis of site- and sex-specific estimates showed statistically significant associations between size at birth and height at ∼2 y and the 2 outcomes (P < 0.001). Weight and length at birth and linear growth from birth to ∼2 y of age (1 z-score difference) were positively associated with schooling attainment (β: 0.13; 95% CI: 0.08, 0.19, β: 0.17; 95% CI: 0.07, 0.32, and β: 0.25, 95% CI: 0.10, 0.40, respectively) and adult IQ (β: 0.74, 95% CI: 0.35, 1.14, β: 0.73, 95% CI: 0.35, 1.10, and β: 1.52, 95% CI: 0.96, 2.08, respectively). Linear growth from age 2 y to MC and from MC to adulthood was not associated with higher school attainment or IQ. Change in relative weight in early childhood, MC, and adulthood was not associated with either outcome. CONCLUSIONS: Linear growth in the first 1000 d is a predictor of schooling attainment and IQ in adulthood in LMICs. Linear growth in later periods was not associated with either of these outcomes. Changes in relative weight across the life course were not associated with schooling and IQ in adulthood

Symptom variability over the course of the day in patients with stable COPD in Brazil: a real-world observational study

Objetivo: Analisar os sintomas em diferentes momentos do dia em pacientes com DPOC. Métodos: Estudo observacional multicêntrico de corte transversal em oito centros brasileiros. Foram avaliados os sintomas matinais, diurnos e noturnos em pacientes com DPOC estável. Resultados: Foram incluídos 593 pacientes em tratamento regular, sendo 309 (52,1%) do sexo masculino e 92 (15,5%) fumantes ativos. A média de idade foi de 67,7 anos, e a média de VEF1 foi de 49,4% do valor previsto. Os pacientes com sintomas mais graves (n = 183; 30,8%), em comparação com aqueles com sintomas leves e moderados, apresentaram pior nível de atividade física (p = 0,002), maior limitação ao fluxo aéreo (p < 0,001), exacerbações ambulatoriais (p = 0,002) e hospitalares (p = 0,043) mais frequentemente e piores resultados em instrumentos específicos. Os sintomas matinais e noturnos mais frequentes foram dispneia (em 45,2% e 33,1%, respectivamente), tosse (em 37,5% e 33,3%, respectivamente) e chiado (em 24,4% e 27,0%, respectivamente). Houve forte correlação da intensidade dos sintomas diurnos com sintomas matinais (r = 0,65, p < 0,001), sintomas noturnos (r = 0,60, p < 0,001), bem como com o escore do COPD Assessment Test (r = 0,62; p < 0,001); porém, houve uma correlação fraca com VEF1 (r = −0,205; p < 0,001). Conclusões: A dispneia foi mais frequente no período matinal do que no período noturno. Ter sintomas matinais e/ou noturnos foi associado à pior gravidade dos sintomas diurnos. A intensidade dos sintomas foi fortemente associada a pior qualidade de vida e frequência de exacerbações, mas fracamente associada à limitação ao fluxo aéreo.463Objective: To analyze symptoms at different times of day in patients with COPD. Methods: This was a multicenter, cross-sectional observational study conducted at eight centers in Brazil. We evaluated morning, daytime, and nighttime symptoms in patients with stable COPD. Results: We included 593 patients under regular treatment, of whom 309 (52.1%) were male and 92 (15.5%) were active smokers. The mean age was 67.7 years, and the mean FEV1 was 49.4% of the predicted value. In comparison with the patients who had mild or moderate symptoms, the 183 (30.8%) with severe symptoms were less physically active (p = 0.002), had greater airflow limitation (p < 0.001), had more outpatient exacerbations (p = 0.002) and more inpatient exacerbations (p = 0.043), as well as scoring worse on specific instruments. The most common morning and nighttime symptoms were dyspnea (in 45.2% and 33.1%, respectively), cough (in 37.5% and 33.3%, respectively), and wheezing (in 24.4% and 27.0%, respectively). The intensity of daytime symptoms correlated strongly with that of morning symptoms (r = 0.65, p < 0.001) and that of nighttime symptoms (r = 0.60, p < 0.001), as well as with the COPD Assessment Test score (r = 0.62; p < 0.001), although it showed only a weak correlation with FEV1 (r = −0.205; p < 0.001). Conclusions: Dyspnea was more common in the morning than at night. Having morning or nighttime symptoms was associated with greater daytime symptom severity. Symptom intensity was strongly associated with poor quality of life and with the frequency of exacerbations, although it was weakly associated with airflow limitation

The Brazilian Developments On The Regional Atmospheric Modeling System (brams 5.2): An Integrated Environmental Model Tuned For Tropical Areas

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)We present a new version of the Brazilian developments on the Regional Atmospheric Modeling System (BRAMS), in which different previous versions for weather, chemistry, and carbon cycle were unified in a single integrated modeling system software. This new version also has a new set of state-of-the-art physical parameterizations and greater computational parallel and memory usage efficiency. The description of the main model features includes several examples illustrating the quality of the transport scheme for scalars, radiative fluxes on surface, and model simulation of rainfall systems over South America at different spatial resolutions using a scale aware convective parameterization. Additionally, the simulation of the diurnal cycle of the convection and carbon dioxide concentration over the Amazon Basin, as well as carbon dioxide fluxes from biogenic processes over a large portion of South America, are shown. Atmospheric chemistry examples show the model performance in simulating near-surface carbon monoxide and ozone in the Amazon Basin and the megacity of Rio de Janeiro. For tracer transport and dispersion, the model capabilities to simulate the volcanic ash 3-D redistribution associated with the eruption of a Chilean volcano are demonstrated. The gain of computational efficiency is described in some detail. BRAMS has been applied for research and operational forecasting mainly in South America. Model results from the operational weather forecast of BRAMS on 5km grid spacing in the Center for Weather Forecasting and Climate Studies, INPE/Brazil, since 2013 are used to quantify the model skill of near-surface variables and rainfall. The scores show the reliability of BRAMS for the tropical and subtropical areas of South America. Requirements for keeping this modeling system competitive regarding both its functionalities and skills are discussed. Finally, we highlight the relevant contribution of this work to building a South American community of model developers. © Author(s) 2017.1011892222014/01563-1, FAPESP, Fundação de Amparo à Pesquisa do Estado de São Paulo2014/01564-8, FAPESP, Fundação de Amparo à Pesquisa do Estado de São Paulo2015/10206-0, FAPESP, Fundação de Amparo à Pesquisa do Estado de São Paulo306340/2011-9, Conselho Nacional de Desenvolvimento Científico e TecnológicoFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq