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The forecasting of electricity consumption and demand plays a pivotal role in electric power systems planning. This paper proposes the combination of forecasts from two approaches with the aim of improving the forecasting accuracy, in order to make the best use of the installed transmission and generating capacity. In the first approach, the consumption time series is decomposed by wavelet analysis and a Box-Jenkins model is fitted to each wavelet component, following which the individual components forecasts are added to compute the total consumption forecast. The alternative approach, uses the Singular Spectrum Analysis technique to model the consumption time series in order to shrink the noise level. Thereafter, the Box-Jenkins model is used to forecast the filtered time series, producing a second forecast for the consumption series. Eventually, the two forecasts are combined geometrically in order to minimize the mean square error. The proposed methodology is illustrated by a computational experiment with the time series of residential consumption of electricity in Brazil.

Patinha D, Fasching A, Pinho D, Albino-Teixeira A, Morato M, Palm F. Angiotensin II contributes to glomerular hyperfiltration in diabetic rats independently of adenosine type I receptors. Am J Physiol Renal Physiol 304: F614-F622, 2013. First published January 2, 2013; doi:10.1152/ajprenal.00285.2012.-Increased angiotensin II (ANG II) or adenosine can potentiate each other in the regulation of renal hemodynamics and tubular function. Diabetes is characterized by hyperfiltration, yet the roles of ANG II and adenosine receptors for controlling baseline renal blood flow (RBF) or tubular Na+ handling in diabetes is presently unknown. Accordingly, the changes in their functions were investigated in control and 2-wk streptozotocin-diabetic rats after intrarenal infusion of the ANG II AT(1) receptor antagonist candesartan, the adenosine A(1) receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), or their combination. Compared with controls, the baseline blood pressure, RBF, and renal vascular resistance (RVR) were similar in diabetics, whereas the glomerular filtration rate (GFR) and filtration fraction (FF) were increased. Candesartan, DPCPX, or the combination increased RBF and decreased RVR similarly in all groups. In controls, the GFR was increased by DPCPX, but in diabetics, it was decreased by candesartan. The FF was decreased by candesartan and DPCPX, independently. DPCPX caused the most pronounced increase in fractional Na+ excretion in both controls and diabetics, whereas candesartan or the combination only affected fractional Li+ excretion in diabetics. These results suggest that RBF, via a unifying mechanism, and tubular function are under strict tonic control of both ANG II and adenosine in both control and diabetic kidneys. Furthermore, increased vascular AT(1) receptor activity is a contribution to diabetes-induced hyperfiltration independent of any effect of adenosine A(1) receptors.

In the prediction of (stochastic) time series, it has been common to suppose that an individual predictive method – for instance, an Auto-Regressive Integrated Moving Average (ARIMA) model – produces residuals like a white noise process. However, mainly due to the structures of auto-dependence not mapped by a given individual predictive method, this assumption may easily be violated, in practice, as pointed out in Firmino et al. (2015). In order to correct it (and accordingly to produce more forecasts with more accuracy power), this paper puts forward a Wavelet Hybrid Forecaster (WHF) that integrates the following numerical techniques: wavelet decomposition; ARIMA models; Artificial Neural Networks (ANNs); and linear combination of forecasts. Basically, the proposed WHF can map simultaneously linear – by means of a linear combination of ARIMA forecasts – and non-linear – through a linear combination of ANN forecasts – auto-dependence structures exhibited by a given time series. Differently of other hybrid methodologies existing in literature, the WHF forecasts are produced carrying into account implicitly the information from the frequency presenting in the underlying time series by means of the Wavelet Components (WCs) obtained by the wavelet decomposition approach. All numerical results show that WHF method has achieved remarkable accuracy gains, when comparing with other competitive forecasting methods already published in specialized literature, in the prediction of a well-known annual time series of sunspot.

The information provided by accurate forecasts of solar energy time series are considered essential for performing an appropriate prediction of the electrical power that will be available in an electric system, as pointed out in Zhou et al. (2011). However, since the underlying data are highly non-stationary, it follows that to produce their accurate predictions is a very difficult assignment. In order to accomplish it, this paper proposes an iterative Combination of Wavelet Artificial Neural Networks (CWANN) which is aimed to produce short-term solar radiation time series forecasting. Basically, the CWANN method can be split into three stages: at first one, a decomposition of level p, defined in terms of a wavelet basis, of a given solar radiation time series is performed, generating r+1 Wavelet Components (WC); at second one, these r+1 WCs are individually modeled by the k different ANNs, where k>5, and the 5 best forecasts of each WC are combined by means of another ANN, producing the combined forecasts of WC; and, at third one, the combined forecasts WC are simply added, generating the forecasts of the underlying solar radiation data. An iterative algorithm is proposed for iteratively searching for the optimal values for the CWANN parameters, as we will see. In order to evaluate it, ten real solar radiation time series of Brazilian system were modeled here. In all statistical results, the CWANN method has achieved remarkable greater forecasting performances when compared with a traditional ANN (described in Section 2.1).

Este artigo propoe a combinacao linear das previsoes obtidas por tres metodos de previsao (a saber, ARIMA,Amortecimento Exponencial e Redes Neurais Artificiais) cujos pesos adaptativos determinados por meio deum problema de programacao nao linear multiobjetivo, em que se busca minimizar, simultaneamente, asestatisticas: MAE, MAPE e MSE. Os resultados alcancados pela combinacao proposta sao comparados coma abordagem tradicional de combinacao linear de previsoes, onde os pesos adaptativos otimos sao determinadossomente pela minimizacao do MSE; com o metodo de combinacao por media aritmetica; e com osmetodos individuais.

Introduction Myeloperoxidase (MPO), an enzyme linking obesity and cardiovascular (CV) risk in adults, has rarely been studied in young children and no studies assessed its association with renal function. We sought to explore a possible association between serum MPO levels, obesity, CV risk factors and renal function in prepubertal children. Materials/Methods Cross-sectional evaluation of 309 children aged 8–9 years (161 normal weight, 148 overweight/obese), members of the birth cohort Generation I (Portugal). Anthropometrics (body mass index (BMI), waist-to-height ratio (WHtR) and % body fat mass (%BFM) by bioelectrical impedance analysis), 24-h ambulatory blood pressure monitoring and pulse wave velocity (PWV) were measured. Insulin resistance was estimated by the HOMA index (considering serum fasting glucose and insulin determinations). Serum MPO levels were assessed by immunoenzymatic assay. Results MPO levels were positively associated with obesity indices (BMI z-score, WHtR and %BFM). Higher MPO levels were associated with higher 24-h and night-time mean arterial pressure, with nondipping and with higher values of insulin resistance. In normal weight children, the endothelial function, as evaluated indirectly by PWV, was an independent predictor of MPO levels. In overweight/obese children, estimated glomerular filtration rate increased significantly across tertiles of MPO (Ptrend = 0·031) and this association held after adjustment for age, sex, neutrophil and monocyte counts and CV risk factors. Conclusions Our results reinforce the role of MPO as a risk marker in obesity and related CV morbidities in young children. MPO levels associate with the dipping pattern and PWV and, among overweight/obese children, an association exists between MPO and renal function.

Oxidative stress and nitric oxide (NO) appear to represent important links between obesity and cardiovascular, metabolic and/or renal disease. We investigated whether oxidative stress and NO production/metabolism are increased in overweight and obese prepubertal children and correlate with cardiometabolic risk and renal function. We performed a cross-sectional evaluation of 313 children aged 8–9 years. Anthropometrics, 24-h ambulatory blood pressure, pulse wave velocity (PWV), insulin resistance (homoeostasis model assessment index (HOMA-IR)), inflammatory/metabolic biomarkers, estimated glomerular filtration rate (eGFR), plasma total antioxidant status (TAS), plasma and urinary isoprostanes (P-Isop, U-Isop), urinary hydrogen peroxide (U-H2O2), and plasma and urinary nitrates and nitrites (P-NOx, U-NOx) were compared among normal weight, overweight and obese groups, according to WHO BMI z-score reference. U-Isop were increased in the obese group, whereas U-NOx were increased in both overweight and obese children. U-Isop were positively correlated with U-H2O2, myeloperoxidase (MPO), high-sensitivity C-reactive protein, HOMA-IR and TAG. TAS correlated negatively with U-Isop and MPO and positively with PWV. HOMA-IR and U-H2O2 were associated with higher U-Isop, independently of BMI and eGFR, and total cholesterol and U-H2O2 were associated with U-NOx, independently of BMI, eGFR values and P-NOx concentration. In overweight and obese children, eGFR decreased across P-NOx tertiles (median: 139·3 (25th, 75th percentile 128·0, 146·5), 128·0 (25th, 75th percentile 121·5, 140·4), 129·5 (25th, 75th percentile 119·4, 138·3), Pfor linear trend=0·003). We conclude that oxidant status and NO are increased in relation to fat accumulation and, even in young children, they translate into higher values of cardiometabolic risk markers and affect renal function.

BACKGROUND AND PURPOSE Activation of the intrarenal renin-angiotensin system (RAS) and increased renal medullary hydrogen peroxide (H2O2) contribute to hypertension. We examined whether H2O2 mediated hypertension and intrarenal RAS activation induced by angiotensin II (Ang II). EXPERIMENTAL APPROACH Ang II (200 ng·kg−1·min−1) or saline were infused in Sprague Dawley rats from day 0 to day 14. Polyethylene glycol (PEG)-catalase (10 000 U·kg−1·day−1) was given to Ang II-treated rats, from day 7 to day 14. Systolic blood pressure was measured throughout the study. H2O2, angiotensin AT1 receptor and Nox4 expression and nuclear factor-κB (NF-κB) activation were evaluated in the kidney. Plasma and urinary H2O2 and angiotensinogen were also measured. KEY RESULTS Ang II increased H2O2, AT1 receptor and Nox4 expression and NF-κB activation in the renal medulla, but not in the cortex. Ang II raised plasma and urinary H2O2 levels, increased urinary angiotensinogen but reduced plasma angiotensinogen. PEG-catalase had a short-term antihypertensive effect and transiently suppressed urinary angiotensinogen. PEG-catalase decreased renal medullary expression of AT1 receptors and Nox4 in Ang II-infused rats. Renal medullary NF-κB activation was correlated with local H2O2 levels and urinary angiotensinogen excretion. Loss of antihypertensive efficacy was associated with an eightfold increase of plasma angiotensinogen. CONCLUSIONS AND IMPLICATIONS The renal medulla is a major target for Ang II-induced redox dysfunction. H2O2 appears to be the key mediator enhancing intrarenal RAS activation and decreasing systemic RAS activity. The specific control of renal medullary H2O2 levels may provide future grounds for the treatment of hypertension.

DOI: 10.12957/cadest.2015.18510ResumoBarragens de usinas hidrelétricas são avaliadas por inspeções visuais e por instrumentos de monitoramento. As leituras periódicas de um instrumento podem ser interpretadas como uma série temporal estocástica cujos valores passados fornecem informações relevantes para construção de predições acerca de seus valores futuros, além de indicar tendências do comportamento futuro da barragem como um todo. Desta forma, é fundamental produzir previsões mais acuradas possíveis, de modo que sirvam de alerta confiável para predição de eventuais anormalidades no comportamento da barragem, permitindo a realização precoce de obras e ações de intervenção. Assim, este artigo propõe uma metodologia na qual é feita uma avaliação do desempenho por meio da previsão de séries temporais das leituras de um instrumento da barragem da usina hidrelétrica de Itaipu usando uma combinação híbrida dos previsores ARIMA-GARCH e redes neurais artificiais, com a utilização da decomposição wavelet. Os resultados mostram que a combinação híbrida proposta alcançou desempenho, em termos de acurácia, bastante superior quando comparado com o uso individual dos métodos preditivos tradicionais e de suas combinações.Palavras-chave: Segurança de barragem; Séries Temporais Estocásticas; Modelos ARIMA-GARCH; Redes Neurais Artificiais; Decomposição Wavelet.

N-methyl-D-aspartate receptors (NMDAR) have a role in cardiovascular control at the nucleus tractus solitarii (NTS), eliciting increases or decreases in blood pressure (BP), depending on the area injected with the agonists. In spite of the association between cardiovascular control and pain modulation, the effects of manipulating NMDAR in pain responses have never been evaluated. In this study, we decreased the expression of NMDAR in the NTS using gene transfer to target receptor subunits and evaluate long-term effects. Seven days after the injection of lentiviral vectors containing the NR1a subunit cDNA of NMDAR, in antisense orientation, into the intermediate NTS of Wistar rats, BP was measured, and the formalin test of nociception was performed. The antisense vector induced a decrease of NR1 expression in the NTS and elicited BP rises and hypoalgesia. Antisense vectors inhibited formalin-evoked c-Fos expression in the spinal cord, indicating decreased nociceptive activity of spinal neurons. Using a time-course approach, we verified that the onset of both the increases in BP and the hypoalgesia was at 4 days after vector injection into the NTS. The injection of NMDA into the NTS reversed the effects of antisense vectors in pain behavioral responses and spinal neuronal activation and decreased BP and heart rate. The present study shows that the NR1 subunit of the NMDAR at the NTS is critical in the regulation of tonic cardiovascular and nociceptive control and shows an involvement of the nucleus in the modulation of sustained pain. © 2011Wiley Periodicals, Inc.

Background: Participation in phase I studies of experimental pharmaceuticals depends on informed consent; thus the personality and psychological characteristics of the recruited subjects may have an influence on their decision to volunteer. Here, we report a study aiming to assess whether ‘interpersonal values’ (conditioning the direct interactions with others) of healthy subjects who volunteer for phase I studies are different from the general population. Methods: The study population consisted of 138 consecutive healthy subjects who volunteered for phase I studies. The subjects’ interpersonal values were assessed using the Survey of Interpersonal Values (SIV) and were compared with the general population. SIV contains six scales that characterize the following values: Support (being treated with understanding, receiving encouragement from other people, being treated with kindness and consideration); Conformity (doing what is socially correct, following regulations closely, doing what is accepted and proper, being a conformist); Recognition (being looked up to and admired, being considered important, attracting favourable notice, achieving recognition); Independence (being free to make one’s own decisions, having the right to do whatever one wants to do, being able to do things in one’s own way); Benevolence (doing things for other people, sharing with others, helping the unfortunate, being generous) and Leadership (being in charge of other people, having authority over others). Results: As compared with the general population, phase I study participants reported higher levels of importance on the values of support (p < 0.001), independence (p < 0.001) and benevolence (p < 0.001), and significantly lower levels of importance on the values of conformity (p < 0.001) and leadership (p < 0.001). Conclusion: Interpersonal values of participants in phase I studies differed from the general population. Further studies are needed to assess the possible influence of the personality and psychological characteristics of healthy volunteers on the study outcomes and on the interpretation and generalizability of the results.

Aim: To assess the role of socioeconomic conditions and psychological factors in the decision of healthy subjects to participate in a phase I study. Methods: Subjects (n = 117) were given information about a phase I study and asked to participate. Subjects were assessed regarding their demographic and socioeconomic characteristics, and evaluated using the Curiosity and Exploration Inventory (CEI-T), Self-Efficacy Scale (SES), State-Trait Anxiety Inventory (STAI), Fear of Negative Evaluation (FNE) and Social Avoidance and Distress (SAD) scales, and the Beck Depression Inventory-II (BDI-II). Results: In a univariate analysis, a significant positive correlation (Spearman’s rho) was found between willingness to participate in the proposed phase I study and CEI-T exploratory tendencies (R = 0.338; p < 0.001) and total scores (R = 0.276; p < 0.01), SES total scores (R = 0.299; p < 0.01) and SES subscales for initiative and persistence (R = 0.290; p < 0.01), planning/goal setting (R = 0.189; p < 0.05) and social self-efficacy (R = 0.294; p < 0.01). A significant negative correlation was found between willingness to participate and STAI anxiety-state (R = −0.229; p < 0.05), STAI anxiety-trait (R = −0.260; p < 0.01) and SAD (R = −0.204; p < 0.05) scores. In a logistic regression model, CEI-T exploratory tendencies, SES initiative and persistence, and STAI anxiety-trait were the only unique significant predictors of willingness to participate in the proposed phase I study (all p < 0.05). Yet, although subjects who refused and those who were willing to participate were significantly different in these personality traits, they showed no marked differences in their demographic or socioeconomic characteristics, including monthly income. A significant positive correlation was found between CEI-T exploration scores and willingness to participate without financial reward (R = 0.269; p < 0.05). There was an inverse correlation between perceived risk of participation and willingness to participate (R = −0.236; p < 0.05). Conclusion: Subjects higher in initiative, persistence and exploratory tendencies, and lower in anxiety-traits were more willing to accept participation in a phase I study. These personality traits had a more decisive influence on the subjects’ willingness to volunteer for a phase I study than socioeconomic conditions, such as monthly income.

Background and Objective An assessment of clinically important change is useful in interpreting clinical trial outcomes. The 4-point Ashworth Scale (AS) is a widely accepted measure of muscle tone, and the 9-point Physician Global Assessment Score (PGAS) is a global measure of post-treatment change as evaluated by the physician. The quantitative relationship between AS and PGAS has not previously been described in spasticity. Methods Data from three clinical trials of botulinum toxin type A (BOTOX; Allergan, Irvine, CA) in poststroke spasticity were analyzed ( n = 442). Mean change from baseline in AS score was plotted as a function of PGAS and correlations were calculated. Receiver–operator curve (ROC) analyses with the wrist flexor AS change from baseline as the independent variable and PGAS as the dependent variable were performed using the following criteria: PGAS of ≥1 (mild improvement or better) and PGAS of ≥2 (moderate improvement or better). Results In pooled data, the Pearson's correlation coefficient r between the change in wrist Ashworth Score and the PGAS was −0.44 ( p = 0, t = −26.5). Pearson correlations by individual study were also statistically significant. By ROC analysis, a PGAS of ≥1 was associated with 33% reduction of wrist AS and a PGAS of ≥2 was associated with approximately 50% reduction. In a well-powered phase 3 study, the Pearson's correlation coefficient was even higher ( r = −0.76, p = 0, t = −28.5). Conclusions Changes in disease-specific scales that correlate significantly with changes in physician global assessments are considered clinically meaningful. In clinical trials of chronic spasticity, we found that 33% and 50% changes in the Ashworth Scale scores correlate with 1-point or 2-point changes in PGAS. This is similar to findings from pooled chronic pain studies, in which 30% and 50% changes on the pain numeric rating scale were considered clinically important (Farrar et al., Pain 2001;94:149–158). Study supported by Allergan, Irvine, CA.

Objective To investigate the influence of anxiety, social anxiety and depressive symptoms on the willingness of healthy subjects to volunteer for phase I studies and to report adverse events. Materials and methods A group of healthy subjects who had never participated in a clinical trial (“Naive Subjects” )w ere invited to participate in a phase I study. All subjects were assessed for trait anxiety (State-Trait Anxiety Inventory, STAIT), social anxiety (Social Avoidance and Distress, SAD, and Fear of Negative Evaluation, FNE) and depressive symptomatology (Beck Depression Inventory, BDI-II). Subjects who accepted the invitation to participate were compared with those who refused. The personality traits of a group of “Actual Participants” were examined, and the relation of these traits to adverse events reported during participation was evaluated. Results A significant inverse correlation was found between the STAI-T (R=−0.203, p

BACKGROUND:Fibrogenic cytokines are recognized as putative drivers of disease activity and histopathological deterioration in various kidney diseases. We compared urinary transforming growth factor β1 (U-TGF-β1) and endothelin 1 (U-ET-1) levels across body mass index classes and assessed their association with the level of urinary angiotensinogen (U-AGT), a biomarker of intrarenal renin-angiotensin-aldosterone system (RAAS). METHODS:The was a cross-sectional evaluation of 302 children aged 8-9 years. Ambulatory blood pressure (BP), insulin resistance (HOMA-IR), aldosterone level and renal function were evaluated. U-ET-1, U-TGF-β1 and U-AGT levels were determined by immunoenzymatic methods. RESULTS:Obese children presented with the lowest levels of U-ET-1 and U-TGF-β1, but the difference was only significant for U-ET-1. In obese children, the median levels of both U-ET-1 and U-TGF-β1 tended to increase across tertiles (T1-T3) of U-AGT (U-ET-1: T1, 19.9 (14.2-26.3); T2, 32.5 (23.3-141.6); T3, 24.8 (18.7-51.5) ng/g creatinine, p = 0.007; U-TGF-β1: T1, 2.2 (1.8-4.0); T2, 4.3 (2.7-11.7); T3, 4.9 (3.8-10.1) ng/g creatinine, p = 0.004]. In multivariate models, in the obese group, U-ET-1 was associated with HOMA-IR and aldosterone and U-AGT levels, and U-TGF-β1 was associated with U-AGT levels and 24 h-systolic BP. CONCLUSIONS:Whereas the initial hypothesis of higher levels of urinary fibrogenic cytokines in obese children was not confirmed in our study, both TGF-β1 and U-ET-1 levels were associated with U-AGT level, which likely reflects an early interplay between tissue remodeling and RAAS in obesity-related kidney injury.

PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO COORDENAÇÃO DE APERFEIÇOAMENTO DO PESSOAL DE ENSINO SUPERIOR CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO PROGRAMA DE EXCELENCIA ACADEMICA PROGRAMA DE DOUTORADO SANDUÍCHE NO EXTERIOR Nesta tese de doutorado, é proposta uma combinação híbrida de métodos preditivos que agrega cinco abordagens distintas e genéricas, do ponto de vista de modelagem: método SSA; decomposição wavelet; redes neurais artificiais; programação matemática multiobjetivo MINIMAX, com abordagem de programação por metas; e método de simulação de quase Monte-Carlo. Para exemplificar e demonstrar a eficiência da combinação híbrida proposta, são mostrados, no Capítulo 7, os principais resultados de uma aplicação computacional, no qual é possível verificar que o seu desempenho, em termos de modelagem, foi consideravelmente superior, em relação a todas as estatísticas de aderência consideradas. In this thesis, we propose a hybrid combination of predictive methods that aggregates five distinct and general approaches, from the viewpoint of modeling: SSA method; wavelet decomposition, artificial neural networks, multiobjective mathematical programming MINIMAX, with goal programming approach; quasi- Monte-Carlo simulation method. To exemplify and demonstrate the efficiency of the proposed hybrid combination are shown, in Section 7, the main results of a computer application in which you can verify that their performance, in terms of modeling, was significantly higher, compared to all considered adherence statistics.

Statins are the most commonly prescribed drugs for the treatment of dyslipidemia. They are also recommended in primary and secondary prevention of cardiovascular disease. In addition to decreasing cholesterol synthesis, statins interfere with the synthesis of isoprenoid intermediates, which may explain many of their pleiotropic properties, including their antioxidant effects.Oxidative stress is defined as an imbalance between the synthesis of reactive oxygen species and their elimination by antioxidant defense systems, with a prevailing pro-oxidant status that results in macromolecular damage and disruption of cellular redox signaling. Reactive oxygen species interfere with various processes that affect cardiac structure and function, contributing to the contractile dysfunction, myocardial hypertrophy and fibrosis observed in the pathophysiology of heart failure. By regulating several molecular pathways that control nicotinamide adenine dinucleotide phosphate oxidase and endothelial nitric oxide synthase activity, statins help restore redox homeostasis. These drugs also contribute to the control of inflammation and appear to have a protective role in various diseases. The results of observational studies and clinical trials with statins in heart failure have not been consensual.This review aims to analyze the role of oxidative stress in heart failure and the molecular mechanisms underlying statins’ antioxidant properties. It also examines current scientific evidence on the use of these drugs as a specific treatment for heart failure. Resumo: As estatinas são os fármacos mais prescritos no tratamento da dislipidemia, estando recomendadas na prevenção primária e secundária das doenças cardiovasculares. Para além de diminuírem a síntese de colesterol, interferem com a síntese de intermediários isoprenoides, o que poderá explicar muitos dos seus efeitos pleiotrópicos, incluindo a ação antioxidante.O stresse oxidativo é definido como um desequilíbrio entre a formação de espécies reativas de oxigénio e a sua eliminação por sistemas de defesa antioxidantes, com prevalência de um estado pró-oxidante com efeitos deletérios nas macromoléculas orgânicas e na sinalização redox celular. As espécies reativas de oxigénio podem interferir com vários processos que afetam a estrutura e função cardíacas, contribuindo para a disfunção contráctil, fibrose e hipertrofia do miocárdio observadas na fisiopatologia da insuficiência cardíaca. As estatinas promovem a restauração do equilíbrio redox pela regulação de várias vias moleculares responsáveis pelo controlo da atividade de enzimas como a NADPH oxídase e a sintetase endotelial de monóxido de azoto. Estes fármacos contribuem também para o controlo de processos inflamatórios e parecem desempenhar um papel protetor em várias patologias. Os resultados de estudos observacionais e ensaios clínicos, realizados com o objetivo de esclarecer o efeito das estatinas na insuficiência cardíaca, não têm sido consensuais. Esta revisão tem como principal objetivo analisar o papel do stresse oxidativo na insuficiência cardíaca e os mecanismos moleculares inerentes às propriedades antioxidantes das estatinas. Pretende ainda reunir a evidência científica atual relativa à utilização destes fármacos como terapêutica específica da insuficiência cardíaca. Keywords: Statins, Heart failure, Oxidative stress, Endothelial nitric oxide synthase, Nicotinamide adenine dinucleotide phosphate oxidases, Antioxidant/anti-inflammatory effects, Clinical trials, Palavras-chave: Estatinas, Insuficiência cardíaca, Stresse oxidativo, Sintetase endotelial de monóxido de azoto, Nicotinamida adenina dinucleótido fosfato oxidase, Efeitos antioxidantes/anti-inflamatórios, Ensaios clínicos

© The Author 2015. Published by Oxford University Press. All rights reserved., Abnormal accumulation of aggregated α-synuclein (aSyn) is a hallmark of sporadic and familial Parkinson's disease (PD) and related synucleinopathies. Recent studies suggest a neuroprotective role of adenosine A2A receptor (A2AR) antagonists in PD. Nevertheless, the precise molecular mechanisms underlying this neuroprotection remain unclear. We assessed the impact of A2AR blockade or genetic deletion (A2AR KO) on synaptic plasticity and neuronal cell death induced by aSyn oligomers. We found that impairment of LTP associated with aSyn exposure was rescued in A2AR KO mice or upon A2AR blockade, through an NMDA receptor-dependent mechanism. The mechanisms underlying these effects were evaluated in SH-SY5Y cells overexpressing aSyn and rat primary neuronal cultures exposed to aSyn. Cell death in both conditions was prevented by selective A2AR antagonists. Interestingly, blockade of these receptors did not interfere with aSyn oligomerization but, instead, reduced the percentage of cells displaying aSyn inclusions. Altogether, our data raise the possibility that the well-documented effects of A2AR antagonists involve the control of the latter stages of aSyn aggregation, thereby preventing the associated neurotoxicity. These findings suggest that A2AR represent an important target for the development of effective drugs for the treatment of PD and related synucleinopathies., T.F.O. and L.V.L. were supported by a grant from the Fritz Thyssen Stiftung (Az. 10.12.2.165), Germany. L.V.L. is an Investigator FCT, funded by Fundação para a Ciência e Tecnologia, Portugal. T.F.O. is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB; Germany).

[resumo] [abstract]

A comparison was made of the influence of candesartan, ZD7155, losartan and eprosartan on angiotensin II effects at pre- and postjunctional AT(1) receptors of the rat tail artery. To study the anti-angiotensin II effect at prejunctional receptors, the tissues were preincubated with [(3)H]noradrenaline and then superfused and electrically stimulated (1 Hz, 2 ms, 50 mA, during 5 min); to study the angiotensin II effect at postjunctional receptors, non-cumulative concentration-response curves to angiotensin II were determined in the absence and in the presence of the antagonist. p A(2) values were calculated for competitive antagonists and p D'(2) values for insurmountable antagonists. At the prejunctional level, losartan and eprosartan displayed competitive antagonism with p A(2) values of 6.50 and 8.08, respectively, whereas candesartan and ZD7155 displayed non-competitive antagonism with p D'(2) values of 8.71 and 7.98, respectively. At the postjunctional level, the four antagonists displayed the same kind of antagonism as prejunctionally with p A(2) values for losartan and eprosartan of 8.52 and 8.22, respectively, and p D'(2) values of 10.62 and 9.01, for candesartan and ZD7155, respectively. The ratios between post- and prejunctional potencies were: losartan 101, candesartan 81, ZD7155 11, and eprosartan 1.4. We conclude that, at least functionally, pre- and postjunctional angiotensin II AT(1) receptors are different and propose that the prejunctional receptors in this tissue belong to the AT(1B)-subtype.

Singular Spectrum Analysis (SSA) is a non-parametric technique to decompose a time series into signal and noise. In this article, the Box-Jenkins and Holt-Winters models are tested with and without SSA approach for modeling a time series of monthly residential electricity consumption from a dealership in Rio de Janeiro. Three different methodologies are used in the SSA approach: Analysis of Main Components (ACP), ACP associated with Cluster Analysis and Graphical Analysis of Singular Vectors. MAPE, MAE, RMSE and R2 statistics are used to test the predictive power of the models. The results show a greater predictive power of the model when applied in conjunction with the filtered technique SSA series.

Morphine is extensively metabolized to neurotoxic morphine-3-glucuronide (M3G) and opioid agonist morphine-6-glucuronide (M6G). Due to these different roles, interindividual variability and co-administration of drugs that interfere with metabolism may affect analgesia. The aim of the study was to investigate the repercussions of administration of an inducer (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD) and an inhibitor (ranitidine) of glucuronidation in morphine metabolism and consequent analgesia, using the Guinea pig as a suitable model.Thirty male Dunkin-Hartley guinea pigs were divided in six groups: control, morphine, ranitidine, ranitidine+morphine, TCDD and TCDD+morphine. After previous exposure to TCDD and ranitidine, morphine effect was assessed by an increasing temperature hotplate (35-52.5°C), during 60min after morphine administration. Then, blood was collected and plasma morphine and metabolites were quantified.Animals treated with TCDD presented faster analgesic effect and 75% reached the cut-off temperature of 52.5°C, comparing with only 25% in morphine group. Animals treated with ranitidine presented a significantly lower analgesic effect, compared with morphine group (p0.05). Moreover, significant differences between groups were found in M3G levels and M3G/morphine ratio (p0.001 and p0.0001), with TCDD animals presenting the highest values for M3G, M6G, M3G/morphine and M6G/morphine, and the lowest value for morphine. The opposite was observed in the animals treated with ranitidine.Our results indicate that modulation of morphine metabolism may result in variations in metabolite concentrations, leading to different analgesic responses to morphine, in an animal model that may be used to improve morphine effect in clinical practice.

Background Lipoxins (LXs) are proresolving and anti-inflammatory eicosanoids whose role in chronic heart failure (CHF) pathogenesis has never been investigated. This study evaluated levels of LXs in CHF patients, its relationship with disease severity and correlation with established CHF biomarkers. The effect of low-dose aspirin [acetylsalicylic acid (ASA)] on the levels of LXs was also studied. Materials and methods Lipoxin A4 (LXA4), 15-epi-lipoxin A4 (15-epi-LXA4) and myeloperoxidase (MPO) concentration and activity were evaluated by immunoenzymatic and spectrophotometric assays in 34 CHF patients [New York Heart Association (NYHA) functional class I to IV]. B-type natriuretic peptide (BNP), troponin, myoglobin, C-reactive protein (CRP) and uric acid (UA) were also analyzed. Results Patients were stratified into mild-to-moderate CHF (NYHA, classes I and II) and severe CHF (NYHA classes III and IV). Severe patients had lower plasma LXA4 (0·262 ± 0·034 vs. 0·362 ± 0·039 ng/mL, P

The study was undertaken to test the endothelium-mediated vascular responses in rats rendered hypertensive by chronic administration of 1,3-dipropyl-8-sulphophenylxanthine (DPSPX). The relaxant effect of carbachol (an endothelium-dependent relaxing drug) and of sodium nitroprusside (an endothelium-independent relaxing drug) as well as the potentiation of the contractile effect of noradrenaline by NG-nitro-l-arginine methyl ester (l-NAME) were compared in aortic rings from normotensive and DPSPX-hypertensive rats. Carbachol and sodium nitroprusside caused concentration-dependent relaxations in aortic rings precontracted by 1 μM noradrenaline. The relaxant effect of carbachol was significantly reduced in tissues of DPSPX-hypertensive rats: the maximal relaxant effect being 86 ± 3% and 64 ± 4% (of the pre-existing tone) in normal and hypertensive rats, respectively, while there were no significant differences in the relaxant effect of sodium nitroprusside. l-NAME (100 μM) significantly reduced the EC50 values of noradrenaline (3.71 ± 0.28 times, n = 8 and 2.96 ± 0.27 times, n = 7, in normal and hypertensive rats, respectively) and significantly enhanced the maximal contractile effect of noradrenaline (46 ± 8%, n = 8 and 35 ± 6%, n = 7, in normal and hypertensive rats respectively): the factors of reduction of EC50 values and the percentages of enhancement of the maximal contractile effect in the aorta of normal and hypertensive rats were not significantly different. The results obtained provide evidence of functional impairment of the endothelium in DPSPX-hypertensive rats.

Background Diabetes and hypertension independently contribute to renal injury, and the major mechanisms involved are increased reactive oxygen species (ROS) bioavailability and renin-angiotensin system (RAS) activation. We investigated the role of adenosine in controlling ROS production and RAS activation associated with renal dysfunction in hypertension and diabetes. Methods Fourteen days after induction of diabetes with streptozotocin in 12-week-old male Wistar and spontaneously hypertensive (SHR) rats, animals were treated during 7 days with 2-chloroadenosine (CADO group, 5 mg/kg/d), a stable analogue of adenosine, or underwent a sham operation procedure. At the end of the study (day 21), intra-arterial systolic blood pressure (SBP) was measured, and 24-h urine and plasma samples and renal tissue were collected. Results CADO treatment decreased the plasma glucose concentration and glucose and protein excretion by more than 30% in both strains. CADO treatment decreased SBP in diabetic SHR rats (143 ± 8 versus 114 ± 4 mmHg, p < 0.05), but not in diabetic Wistar rats. The hypotensive effect of CADO was associated to a ∼70% increase in plasma angiotensinogen (AGT) concentration and a ∼50% decrease in urinary AGT excretion. CADO also caused a decrease in medullary and cortical hydrogen peroxide production of about 40%, which was associated with a proportional increase in glutathione peroxidase (GPx) activity in diabetic Wistar but not in diabetic SHR animals. Conclusions These results suggest that activation of adenosine receptors improves renal antioxidant capacity in diabetic Wistar but not SHR rats, although it improves glucose metabolism in both strains. Furthermore, activation of adenosine receptors does not seem to be directly influencing AGT production.

1. The study was undertaken to compare the beta-adrenoceptor-mediated facilitation of noradrenaline release in the tail artery of vehicle-treated rats and of rats rendered hypertensive by chronic administration of 1,3-dipropyl-8-sulphophenylxanthine (DPSPX). Artery rings were loaded with [3H]-noradrenaline, and five periods of electrical stimulation (1 Hz for 2 min) were applied. To eliminate the influence of prejunctional alpha 2-adrenoceptors, the tissues were pre-exposed to 1 microM phenoxybenzamine. 2. Isoprenaline caused a concentration-dependent increase of tritium overflow elicited by electrical stimulation. It was more effective in arteries from DPSPX-treated than in those from vehicle-treated rats; isoprenaline (27.8 nM) increased by 30% tritium overflow in vessels from vehicle-treated rats whereas isoprenaline (7.0 nM) produced a 30% increase in vessels from DPSPX-treated animals. Furthermore, the maximal effect of isoprenaline was a 32.6% increase in control rats but a 48.6% increase in DPSPX-treated rats. 3. These results show that the sympathetic nerve endings of the rat tail artery are endowed with prejunctional beta-adrenoceptors which mediate facilitation of noradrenaline release elicited by electrical stimulation. They also suggest that adenosine receptors and beta-adrenoceptors interact at the prejunctional level and that impairment of this 'talk' may lead to the development of a hypertensive state.

Chronic treatment of rats with 90 mg/kg/day DPSPX (1,3-dipropyl-8-sulphophenylxanthine) during seven days leads to a hypertensive state which is characterized by marked morphological changes of the blood vessel walls as well as by important functional alterations. While the angiotensin-converting enzyme (ACE) inhibitor captopril and the antagon- ist of angiotensin II AT 1 receptors losartan prevent the development of both hypertension and morphological changes, the selective b1-adrenoceptor antagonist atenolol could prevent only the increase in blood pressure. It is concluded that at least two factors are involved in the development of the hypertensive state. It is well established that long-term treatment of male adult Wistar rats with 1,3-dipropyl-8-sulphophenylxanthine (DPSPX), a non-selective antagonist of adenosine receptors causes a hypertensive state which lasts for at least one month after the administration of the drug had been stopped (Albino-Teixeira et al. 1991; Guimaraes & Albino- Teixeira 1996) (for methodological details see Albino-Teixei- ra 1990). From the second day of treatment on, the blood pressure increases regularly, reaching a maximum value of about 40 mmHg for the systolic and 35 mmHg for the diastolic press- ure at about the 6th day. This increase in blood pressure is accompanied by important morphological changes of the blood vessel walls and by functional alterations as well.

This chapter aims at giving a critical overview of the major oxidant and antioxidant changes in arterial hypertension, summarizing the experimental and clinical evidence about the involvement of oxidative stress in the pathophysiology of hypertension, either as a cause or a consequence of this disease. This review also provides a description of the biomarkers commonly used to evaluate lipid peroxidation and antioxidant defenses in experimental and human hypertension. Finally, we review the strategies (antioxidants, antihypertensive drugs) known to prevent or ameliorate oxidative damage, both in animal models of hypertension and hypertensive patients.

Activation of the intrarenal renin-angiotensin system (RAS) and increased renal medullary hydrogen peroxide (H(2) O(2) ) contribute to hypertension. We examined whether H(2) O(2) mediated hypertension and intrarenal RAS activation induced by angiotensin II (Ang II).Ang II (200 ng·kg(-1) ·min(-1) ) or saline were infused in Sprague Dawley rats from day 0 to day 14. Polyethylene glycol (PEG)-catalase (10 000 U·kg(-1) ·day(-1) ) was given to Ang II-treated rats, from day 7 to day 14. Systolic blood pressure was measured throughout the study. H(2) O(2) , angiotensin AT(1) receptor and Nox4 expression and nuclear factor-κB (NF-κB) activation were evaluated in the kidney. Plasma and urinary H(2) O(2) and angiotensinogen were also measured.Ang II increased H(2) O(2) , AT(1) receptor and Nox4 expression and NF-κB activation in the renal medulla, but not in the cortex. Ang II raised plasma and urinary H(2) O(2) levels, increased urinary angiotensinogen but reduced plasma angiotensinogen. PEG-catalase had a short-term antihypertensive effect and transiently suppressed urinary angiotensinogen. PEG-catalase decreased renal medullary expression of AT(1) receptors and Nox4 in Ang II-infused rats. Renal medullary NF-κB activation was correlated with local H(2) O(2) levels and urinary angiotensinogen excretion. Loss of antihypertensive efficacy was associated with an eightfold increase of plasma angiotensinogen.The renal medulla is a major target for Ang II-induced redox dysfunction. H(2) O(2) appears to be the key mediator enhancing intrarenal RAS activation and decreasing systemic RAS activity. The specific control of renal medullary H(2) O(2) levels may provide future grounds for the treatment of hypertension.

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