Comparative degradation of ZnO- and SnO(2)-based polycrystalline non-ohmic devices by current pulse stress

The degradation behaviour of SnO(2)-based varistors (SCNCr) due to current pulses (8/20 mu s) is reported here for the first time in comparison with the ZnO-based commercial varistors (ZnO). Puncturing and/or cracking failures were observed in ZnO-based varistors possessing inferior thermo-mechanical properties in comparison with that found in a SCNCr system free of failures. Both systems presented electric degradation related to the increase in the leakage current and decrease in the electric breakdown field, non-linear coefficient and average value of the potential barrier height. However, it was found that a more severe degradation occurred in the ZnO-based varistors concerning their non-ohmic behaviour, while in the SCNCr system, a strong non-ohmic behaviour remained after the degradation. These results indicate that the degradation in the metal oxide varistors is controlled by a defect diffusion process whose rate depends on the mobility, the concentration of meta-stable defects and the amount of electrically active interfaces. The improved behaviour of the SCNCr system is then inferred to be associated with the higher amount of electrically active interfaces (85%) and to a higher energy necessary to activate the diffusion of the specific defects.

A general threshold stress hybrid hazard model for lifetime data

In this paper we propose a hybrid hazard regression model with threshold stress which includes the proportional hazards and the accelerated failure time models as particular cases. To express the behavior of lifetimes the generalized-gamma distribution is assumed and an inverse power law model with a threshold stress is considered. For parameter estimation we develop a sampling-based posterior inference procedure based on Markov Chain Monte Carlo techniques. We assume proper but vague priors for the parameters of interest. A simulation study investigates the frequentist properties of the proposed estimators obtained under the assumption of vague priors. Further, some discussions on model selection criteria are given. The methodology is illustrated on simulated and real lifetime data set.

Oxidative Stress and Modification of Renal Vascular Permeability Are Associated with Acute Kidney Injury during P. berghei ANKA Infection

Malaria associated-acute kidney injury (AKI) is associated with 45% of mortality in adult patients hospitalized with severe form of the disease. However, the causes that lead to a framework of malaria-associated AKI are still poorly characterized. Some clinical studies speculate that oxidative stress products, a characteristic of Plasmodium infection, as well as proinflammatory response induced by the parasite are involved in its pathophysiology. Therefore, we aimed to investigate the development of malaria-associated AKI during infection by P. berghei ANKA, with special attention to the role played by the inflammatory response and the involvement of oxidative stress. For that, we took advantage of an experimental model of severe malaria that showed significant changes in the renal pathophysiology to investigate the role of malaria infection in the renal microvascular permeability and tissue injury. Therefore, BALB/c mice were infected with P. berghei ANKA. To assess renal function, creatinine, blood urea nitrogen, and ratio of proteinuria and creatininuria were evaluated. The products of oxidative stress, as well as cytokine profile were quantified in plasma and renal tissue. The change of renal microvascular permeability, tissue hypoxia and cellular apoptosis were also evaluated. Parasite infection resulted in renal dysfunction. Furthermore, we observed increased expression of adhesion molecule, proinflammatory cytokines and products of oxidative stress, associated with a decrease mRNA expression of HO-1 in kidney tissue of infected mice. The measurement of lipoprotein oxidizability also showed a significant increase in plasma of infected animals. Together, our findings support the idea that products of oxidative stress, as well as the immune response against the parasite are crucial to changes in kidney architecture and microvascular endothelial permeability of BALB/c mice infected with P. berghei ANKA.

Exhaled Acetone as a New Biomarker of Heart Failure Severity

Background: Heart failure (HF) is associated with poor prognosis, and the identification of biomarkers of its severity could help in its treatment. In a pilot study, we observed high levels of acetone in the exhaled breath of patients with HF. The present study was designed to evaluate exhaled acetone as a biomarker of HF diagnosis and HF severity. Methods: Of 235 patients with systolic dysfunction evaluated between May 2009 and September 2010, 89 patients (HF group) fulfilled inclusion criteria and were compared with sex- and age-matched healthy subjects (control group, n = 20). Patients with HF were grouped according to clinical stability (acute decompensated HF [ADHF], n = 59; chronic HF, n = 30) and submitted to exhaled breath collection. Identification of chemical species was done by gas chromatography-mass spectrometry and quantification by spectrophotometry. Patients with diabetes were excluded. Results: The concentration of exhaled breath acetone (EBA) was higher in the HF group (median, 3.7 mu g/L; interquartile range [IQR], 1.69-10.45 mu g/L) than in the control group (median, 0.39 mu g/L; IQR, 0.30-0.79 mu g/L; P < .001) and higher in the ADHF group (median, 7.8 mu g/L; IQR, 3.6-15.2 mu g/L) than in the chronic HF group (median, 1.22 mu g/L; IQR, 0.68-2.19 P < .001). The accuracy and sensitivity of this method in the diagnosis of HF and ADHF were about 85%, a value similar to that obtained with B-type natriuretic peptide (BNP). EBA levels differed significantly as a function of severity of HF (New York Heart Association classification, P < .001). There was a positive correlation between EBA and BNP (r = 0.772, P < .001). Conclusions: EBA not only is a promising noninvasive diagnostic method of HF with an accuracy equivalent to BNP but also a new biomarker of HF severity. CHEST 2012; 142(2):457-466

Protein Oxidative Stress and Dyslipidemia in Dialysis Patients

Our aim was to investigate and determine the associations between oxidative stress (OS), dyslipidemia and inflammation in patients treated with continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) using observational cross-sectional study. Twenty patients in CAPD and 48 in HD for at least 8 weeks and aged =18 years were included in the study. Individuals with malignant or acute inflammatory disease were excluded. A control group of 17 healthy individuals was also recruited. The biochemical parameter evaluations were analyzed using colorimetric kits for albumin, serum glucose, total cholesterol (TC) and lipid fractions. To determine the inflammatory status, CRP, IL-6 and TNF-a were analyzed by automated chemiluminescence kits. Plasma advanced oxidation protein products (AOPP) were determined by spectrophotometry. Mean AOPP levels were significantly higher for the HD group compared to the control, and there was no difference in AOPP concentrations between the control and CAPD groups. Dialysis patients had levels of inflammatory parameters higher than controls, and showed a high prevalence of patients with dyslipidemia, especially in CAPD. In the HD group, AOPP was positively correlated with triglycerides (TG) and inversely associated with HDL. Also the HD group was observed to have negative associations between TNF-a and HDL, LDL and TC. In the CAPD group, CRP was inversely correlated with HDL. Hemodialysis patients had increased protein OS and associations of inflammation and dyslipidemia were also observed in these dialysis groups. A more detailed characterization of the relations between oxidative stress and other more traditional risk factors has therapeutic importance, since cardiovascular diseases are the leading cause of death among dialysis patients.

Increased vascular contractility and oxidative stress in beta(2)-adrenoceptor knockout mice: the role of NADPH oxidase

Background/Aims: beta(2)-adrenoceptor (beta(2)-AR) activation induces smooth muscle relaxation and endothelium-derived nitric oxide (NO) release. However, whether endogenous basal beta(2)-AR activity controls vascular redox status and NO bioavailability is unclear. Thus, we aimed to evaluate vascular reactivity in mice lacking functional beta(2)-AR (beta 2KO), focusing on the role of NO and superoxide anion. Methods and Results: Isolated thoracic aortas from beta 2KO and wild-type mice (WT) were studied. beta 2KO aortas exhibited an enhanced contractile response to phenylephrine compared to WT. Endothelial removal and L-NAME incubation increased phenylephrine-induced contraction, abolishing the differences between beta 2KO and WT mice. Basal NO availability was reduced in aortas from beta 2KO mice. Incubation of beta 2KO aortas with superoxide dismutase or NADPH inhibitor apocynin restored the enhanced contractile response to phenylephrine to WT levels. beta 2KO aortas exhibited oxidative stress detected by enhanced dihydroethidium fluorescence, which was normalized by apocynin. Protein expression of eNOS was reduced, while p47(phox) expression was enhanced in beta 2KO aortas. Conclusions: The present results demonstrate for the first time that enhanced NADPH-derived superoxide anion production is associated with reduced NO bioavailability in aortas of beta 2KO mice. This study extends the knowledge of the relevance of the endogenous activity of beta(2)-AR to the maintenance of the vascular physiology. Copyright (C) 2012 S. Karger AG, Basel

Mechanisms of blunted muscle vasodilation during peripheral chemoreceptor stimulation in heart failure patients

We described recently that systemic hypoxia provokes vasoconstriction in heart failure (HF) patients. We hypothesized that either the exaggerated muscle sympathetic nerve activity and/or endothelial dysfunction mediate the blunted vasodilatation during hypoxia in HF patients. Twenty-seven HF patients and 23 age-matched controls were studied. Muscle sympathetic nerve activity was assessed by microneurography and forearm blood flow (FBF) by venous occlusion plethysmography. Peripheral chemoreflex control was evaluated through the inhaling of a hypoxic gas mixture (10% O-2 and 90% N-2). Basal muscle sympathetic nerve activity was greater and basal FBF was lower in HF patients versus controls. During hypoxia, muscle sympathetic nerve activity responses were greater in HF patients, and forearm vasodilatation in HF was blunted versus controls. Phentolamine increased FBF responses in both groups, but the increase was lower in HF patients. Phentolamine and N-G-monomethyl-L-arginine infusion did not change FBF responses in HF but markedly blunted the vasodilatation in controls. FBF responses to hypoxia in the presence of vitamin C were unchanged and remained lower in HF patients versus controls. In conclusion, muscle vasoconstriction in response to hypoxia in HF patients is attributed to exaggerated reflex sympathetic nerve activation and blunted endothelial function (NO activity). We were unable to identify a role for oxidative stress in these studies. (Hypertension. 2012; 60: 669-676.) . Online Data Supplement

N-Acetylcysteine Protects Rats with Chronic Renal Failure from Gadolinium-Chelate Nephrotoxicity

The aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC). Male Wistar rats were submitted to 5/6 nephrectomy (Nx) to induced CRF. An ionic - cyclic Gd (Gadoterate Meglumine) was administrated (1.5 mM/KgBW, intravenously) 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd-chelate administration: 1 - Nx (n = 7); 2 - Nx+NAC (n = 6); 3 - Nx+Gd (n = 7); 4 - Nx+NAC+Gd (4.8 g/L in drinking water), initiated 2 days before Gd-chelate administration and maintained during 4 days (n = 6). This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW), proteinuria (mg/24 hs), serum iron (mu g/dL); serum ferritin (ng/mL); transferrin saturation (%), TIBC (mu g/dL) and TBARS (nmles/ml). Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd-chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure.

Exercise Training Restores Cardiac Protein Quality Control in Heart Failure

Exercise training is a well-known coadjuvant in heart failure treatment; however, the molecular mechanisms underlying its beneficial effects remain elusive. Despite the primary cause, heart failure is often preceded by two distinct phenomena: mitochondria dysfunction and cytosolic protein quality control disruption. The objective of the study was to determine the contribution of exercise training in regulating cardiac mitochondria metabolism and cytosolic protein quality control in a post-myocardial infarction-induced heart failure (MI-HF) animal model. Our data demonstrated that isolated cardiac mitochondria from MI-HF rats displayed decreased oxygen consumption, reduced maximum calcium uptake and elevated H2O2 release. These changes were accompanied by exacerbated cardiac oxidative stress and proteasomal insufficiency. Declined proteasomal activity contributes to cardiac protein quality control disruption in our MI-HF model. Using cultured neonatal cardiomyocytes, we showed that either antimycin A or H2O2 resulted in inactivation of proteasomal peptidase activity, accumulation of oxidized proteins and cell death, recapitulating our in vivo model. Of interest, eight weeks of exercise training improved cardiac function, peak oxygen uptake and exercise tolerance in MI-HF rats. Moreover, exercise training restored mitochondrial oxygen consumption, increased Ca2+-induced permeability transition and reduced H2O2 release in MI-HF rats. These changes were followed by reduced oxidative stress and better cardiac protein quality control. Taken together, our findings uncover the potential contribution of mitochondrial dysfunction and cytosolic protein quality control disruption to heart failure and highlight the positive effects of exercise training in re-establishing cardiac mitochondrial physiology and protein quality control, reinforcing the importance of this intervention as a nonpharmacological tool for heart failure therapy.

No effect of creatine supplementation on oxidative stress and cardiovascular parameters in spontaneously hypertensive rats

Background: Exacerbated oxidative stress is thought to be a mediator of arterial hypertension. It has been postulated that creatine (Cr) could act as an antioxidant agent preventing increased oxidative stress. The aim of this study was to investigate the effects of nine weeks of Cr or placebo supplementation on oxidative stress and cardiovascular parameters in spontaneously hypertensive rats (SHR). Findings: Lipid hydroperoxidation, one important oxidative stress marker, remained unchanged in the coronary artery (Cr: 12.6 +/- 1.5 vs. Pl: 12.2 +/- 1.7 nmol.mg(-1); p = 0.87), heart (Cr: 11.5 +/- 1.8 vs. Pl: 14.6 +/- 1.1 nmol.mg(-1); p = 0.15), plasma (Cr: 67.7 +/- 9.1 vs. Pl: 56.0 +/- 3.2 nmol.mg(-1); p = 0.19), plantaris (Cr: 10.0 +/- 0.8 vs. Pl: 9.0 +/- 0.8 nmol.mg(-1); p = 0.40), and EDL muscle (Cr: 14.9 +/- 1.4 vs. Pl: 17.2 +/- 1.5 nmol.mg(-1); p = 0.30). Additionally, Cr supplementation affected neither arterial blood pressure nor heart structure in SHR (p > 0.05). Conclusions: Using a well-known experimental model of systemic arterial hypertension, this study did not confirm the possible therapeutic effects of Cr supplementation on oxidative stress and cardiovascular dysfunction associated with arterial hypertension.

Issues on the mean stress effect in fretting fatigue of a 7050-T7451 Al alloy posed by new experimental data

The aims of this work are: (i) to produce new experimental data for fretting fatigue considering the presence of a mean bulk stress and (ii) to assess two design methodologies against failure by fretting fatigue. Tests on a cylinder–flat contact configuration were conducted using a fretting apparatus mounted on a servo-hydraulic machine. The material used for both the pads and fatigue specimen was an aeronautical 7050-T7451 Al alloy. The experimental program was designed with all relevant parameters, apart from the mean bulk load (always applied before the contact loads), kept constant. The mean bulk stress varied from compressive to tensile values while maintaining a high peak pressure in order to encourage crack initiation. Two methodologies against fretting fatigue are proposed and confronted against the experimental data. The non-local stress-based methodology considers the evaluation of a critical plane fatigue criterion at the center of a process zone located beneath the contacting surfaces. The results showed that it correctly predicts crack initiation, but was not capable to provide successful prediction of the integrity of the specimens. Alternatively, we considered a crack arrest criterion which has the potential to provide a more complete description about the integrity of the specimens.

Slow Strain Rate Testing and Stress Corrosion Cracking of Ultra-Fine Grained and Conventional Al-Mg Alloy

Stress corrosion cracking susceptibility was investigated for an ultra-fine grained (UFG) AI-7.5Mg alloy and a conventional 5083 H111 alloy in natural seawater using slow strain rate testing (SSRT) at very slow strain rates between 1E(-5) s(-1), 1E(-6) s(-1) and 1E(-7) s(-1). The UFG Al-7.5Mg alloy was produced by cryomilling, while the 5083 H111 alloy is considered as a wrought manufactured product. The response of tensile properties to strain rate was analyzed and compared. Negative strain rate sensitivity was observed for both materials in terms of the elongation to failure. However, the UFG alloy displayed strain rate sensitivity in relation to strength while the conventional alloy was relatively strain rate insensitive. The mechanical behavior of the conventional 5083 alloy was attributed to dynamic strain aging (DSA) and delayed pit propagation while the performance of the UFG alloy was related to a diffusion-mediated stress relaxation mechanism that successfully delayed crack initiation events, counteracted by exfoliation and pitting which enhanced crack initiation. (C) 2014 Elsevier B.V. All rights reserved.

Coronary artery disease, nitric oxide and oxidative stress: the "Yin-Yang" effect--a Chinese concept for a worldwide pandemic

Prevention of coronary artery disease (CAD) and reduction of its mortality and morbidity remains a major public health challenge throughout the "Western world". Recent evidence supports the concept that the impairment of endothelial function, a hallmark of insulin resistance states, is an upstream event in the pathophysiology of insulin resistance and its main corollaries: atherosclerosis and myocardial infarction. Atherosclerosis is currently thought to be the consequence of a subtle imbalance between pro- and anti-oxidants that produces favourable conditions for lesion progression towards acute thrombotic complications and clinical events. Over the last decade, a remarkable burst of evidence has accumulated, offering the new perspective that bioavailable nitric oxide (NO) plays a pivotal role throughout the CAD-spectrum, from its genesis to the outcome after acute events. Vascular NO is a critical modulator of coronary blood flow by inhibiting smooth muscle contraction and platelet aggregation. It also acts in angiogenesis and cytoprotection. Defective endothelial nitric oxide synthase (eNOS) driven NO synthesis causes development of major cardiovascular risk factors (insulin resistance, arterial hypertension and dyslipidaemia) in mice, and characterises CAD-prone insulin-resistant humans. On the other hand, stimulation of inducible nitric oxide synthase (iNOS) and NO overproduction causes metabolic insulin resistance and characterises atherosclerosis, heart failure and cardiogenic shock in humans, suggesting a "Yin-Yang" effect of NO in the cardiovascular homeostasis. Here, we will present a concise overview of the evidence for this novel concept, providing the conceptual framework for developing a potential therapeutic strategy to prevent and treat CAD.

Influence of water immersion, water gymnastics and swimming on cardiac output in patients with heart failure

Background Whole-body water immersion leads to a significant shift of blood from the periphery into the intra-thoracic circulation, followed by an increase in central venous pressure and heart volume. In patients with severely reduced left ventricular function, this hydrostatically in-duced volume shift might overstrain the cardiovascular adaptive mechanisms and lead to cardiac decompensation. The aim of this study is to assess the hemodynamic response to water immer-sion, gymnastics and swimming in patients with heart failure (CHF). Methods We examined 10 patients with compensated CHF (62.9 +/- 6.3 years, EF 31.5 +/- 4.1%, peak VO2 19.4 +/- 2.8 ml/kg/min.), 10 patients with coronary artery disease (CAD) but preserved left ventricular function (57.2 +/- 5.6 years, EF 63.9 +/- 5.5%, peak VO2 28.0 +/- 6.3 ml/kg/min.) and 10 healthy subjects (32.8 +/- 7.2 years, peak VO2 45.6 +/- 6.0 ml/kg/min.). Hemodynamic response to thermo-neutral (32 degrees C) water immersion and exercise was measured using a non-invasive foreign gas rebreathing method during stepwise water immersion, water gymnastics and swimming. Results Water immersion up to the chest increased cardiac index by 19% in healthy subjects, by 21% in CAD patients and 16% in CHF patients. While some CHF patients showed a decrease of stroke volume during immersion, all subjects were able to increase cardiac index (by 87% in healthy subjects, 77% in CAD patients and 53% in CHF patients). Oxygen uptake during swim-ming was 9.7 +/- 3.3 ml/kg/min. in CHF patients, 12.4 +/- 3.5 ml/kg/min. in CAD patients and 13.9 +/- 4.0 ml/kg/min. in healthy subjects. Conclusions Patients with severely reduced left ventricular function but stable clinical conditions and a minimal peak VO2 of at least 15 ml/kg/min. during a symptom-limited exercise stress test tolerate water immersion and swimming in thermo-neutral water well. Although cardiac in-dex and oxygen uptake are lower compared with CAD patients with preserved left ventricular function and healthy controls, these patients are able to increase cardiac index adequately during water immersion and swimming.

Neuregulin-1 beta attenuates doxorubicin-induced alterations of excitation-contraction coupling and reduces oxidative stress in adult rat cardiomyocytes

Treatment of metastatic breast cancer with doxorubicin (Doxo) in combination with trastuzumab, an antibody targeting the ErbB2 receptor, results in an increased incidence of heart failure. Doxo therapy induces reactive oxygen species (ROS) and alterations of calcium homeostasis. Therefore, we hypothesized that neuregulin-1 beta (NRG), a ligand of the cardiac ErbB receptors, reduces Doxo-induced alterations of EC coupling by triggering antioxidant mechanisms. Adult rat ventricular cardiomyocytes (ARVM) were isolated and treated for 18-48 h. SERCA protein was analyzed by Western blot, EC coupling parameters by fura-2 and video edge detection, gene expression by RT-PCR, and ROS by DCF-fluorescence microscopy. At clinically relevant doses Doxo reduced cardiomyocytes contractility, SERCA protein and SR calcium content. NRG, similarly as the antioxidant N-acetylcystein (NAC), did not affect EC coupling alone, but protected against Doxo-induced damage. NRG and Doxo showed an opposite modulation of glutathione reductase gene expression. NRG, similarly as NAC, reduced peroxide- or Doxo-induced oxidative stress. Specific inhibitors showed, that the antioxidant action of NRG depended on signaling via the ErbB2 receptor and on the Akt- and not on the MAPK-pathway. Therefore, NRG attenuates Doxo-induced alterations of EC coupling and reduces oxidative stress in ARVM. Inhibition of the ErbB2/NRG signaling pathway by trastuzumab in patients concomitantly treated with Doxo might prevent beneficial effects of NRG in the myocardium.