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The primary cardiotoxic action of doxorubicin when used as antitumor drug is attributed to the generation of reactive oxygen species (ROS) therefore effective cardioprotection therapies are needed. In this sense, the antianginal drug nicorandil has been shown to be effective in cardioprotection from ischemic conditions but the underlying molecular mechanism to cope with doxorubicin-induced ROS is unclear. Our in vitro study using the HL-1 cardiomyocyte cell line derived from mouse atria reveals that the endogenous nitric oxide (NO) production was stimulated by nicorandil and arrested by NO synthase inhibition. Moreover, while the NO synthase activity was inhibited by doxorubicin-induced ROS, the NO synthase inhibition did not affect doxorubicin-induced ROS. The inhibition of NO synthase activity by doxorubicin was totally prevented by preincubation with nicorandil. Nicorandil also concentration-dependently (10 to 100 μM) decreased doxorubicin-induced ROS and the effect was antagonized by 5-hydroxydecanoate. The inhibition profile of doxorubicin-induced ROS by nicorandil was unaltered when an L-arginine derivative or a protein kinase G inhibitor was present. Preincubation with pinacidil mimicked the effect of nicorandil and the protection was eliminated by glibenclamide. Quantitative colocalization of fluorescence indicated that the mitochondrion was the target organelle of nicorandil and the observed response was a decrease in the mitochondrial inner membrane potential. Interference with H+ movement across the mitochondrial inner membrane, leading to depolarization, also protected from doxorubicin-induced ROS. The data indicate that activation of the mitochondrial ATP-sensitive K+ channel by nicorandil causing mitochondrial depolarization, without participation of the NO donor activity, was responsible for inhibition of the mitochondrial NADPH oxidase that is the main contributor to ROS production in cardiomyocytes. Impairment of the cytosolic Ca2+ signal induced by caffeine and the increase in lipid peroxidation, both of which are indicators of doxorubicin-induced oxidative stress, were also prevented by nicorandil. [ABSTRACT FROM AUTHOR]

In atrial-derived HL-1 cells, ryanodine receptor and Na + /Ca 2+ -exchanger were altered early by 5 μM doxorubicin. The observed effects were an increase of cytosolic Ca 2+ at rest, ensuing ryanodine receptor phosphorylation, and the slowing of Ca 2+ transient decay after caffeine addition. Doxorubicin triggered a linear rise of reactive oxygen species (ROS) with no early effect on mitochondrial inner membrane potential. Doxorubicin and ROS were both detected in mitochondria by colocalization with fluorescence probes and doxorubicin-induced ROS was totally blocked by mitoTEMPO. The NADPH oxidase activity in the mitochondrial fraction was sensitive to inhibition by GKT137831, and doxorubicin-induced ROS decreased gradually as the GKT137831 concentration added in preincubation was increased. When doxorubicin-induced ROS was prevented by GKT137831, the kinetic response revealed a permanent degree of protection that was consistent with mitochondrial NADPH oxidase inhibition. In contrast, the ROS induction by doxorubicin after melatonin preincubation was totally eliminated at first but the effect was completely reversed with time. Limiting the source of ROS production is a better alternative for dealing with oxidative damage than using ROS scavengers. The short-term effect of doxorubicin on Ca 2+ transporters involved in myocardiac contractility was dependent on oxidative damage, and so the impairment was subsequent to ROS production. [ABSTRACT FROM AUTHOR]

Abstract: Doxorubicin is a wide-spectrum chemotherapeutic agent, although a cumulative dose may cause cardiac damage and lead to heart failure. Doxorubicin cardiotoxicity is dependent on the intracellular iron pool and manifests itself by increasing oxidative stress. Our group has recently shown the ability of metformin, an oral antidiabetic with cardiovascular benefits, to protect cardiomyocytes from doxorubicin-induced damage. This work aimed to study whether metformin is able to modulate the expression of ferritin, the major intracellular iron storage protein, in cardiomyocytes and whether it is involved in their protection. The addition of metformin to adult mouse cardiomyocytes (HL-1 cell line) induced both gene and protein expression of the ferritin heavy chain (FHC) in a time-dependent manner. The silencing of FHC expression with siRNAs inhibited the ability of metformin to protect cardiomyocytes from doxorubicin-induced damage, in terms of the percentage of cell viability, the levels of reactive oxygen species, and the activity of antioxidant enzymes (catalase, glutathione peroxidase, and superoxide dismutase). In addition, metformin induced the activation of NF-κB in HL-1 cells, whereas preincubation with SN50, an inhibitor of NF-κB, blocked the upregulation of the FHC and the protective effect mediated by metformin. Taken together, these results provide new knowledge on the protective actions of metformin against doxorubicin-induced cardiotoxicity by identifying FHC and NF-κB as the major mediators of this beneficial effect. [Copyright &y& Elsevier]

Abstract: Doxorubicin has cardiotoxic effects that limit its clinical benefit in cancer patients. Metformin exerts cardioprotective actions via AMP-activated protein kinase (AMPK) and increases the expression of adiponectin and its receptors (adipoR1 and adipoR2) in skeletal muscle and adipose tissue, but its effect on cardiac tissue is still unknown. This work aimed to study whether metformin exerts any protective action against the cardiotoxicity of doxorubicin and whether the cardiac system of adiponectin is involved in any such action. The addition of doxorubicin (5μM) to adult mouse cardiomyocytes (HL-1 cell line) induced apoptosis, which was characterized by a loss of cell viability, activation of caspases, and fragmentation of the genetic material. Doxorubicin treatment also caused a decrease in the activity of the antioxidant enzymes catalase, glutathione peroxidase, and superoxide dismutase. Pretreatment with metformin (4mM, 24h) provided protection against doxorubicin-induced damage. This pretreatment significantly increased cell viability, attenuated the activation of caspases and the fragmentation of genetic material, and restored the antioxidant activity. In addition, metformin up-regulated the expression of adiponectin and its receptors, adipoR1 and adipoR2, in cardiomyocytes. In contrast, silencing either adipoR1 or adipoR2 with siRNA inhibited the AMPK activation and the protective effects of metformin. Taken together, these results demonstrate that metformin protects cardiomyocytes from doxorubicin-induced damage and that the cardiac adiponectin system plays an important role in this protective action. [Copyright &y& Elsevier]

Power millimetre-wave band transmitters are commonly formed by a chain of MESFET or HEMT GaAs MMIC power amplifiers. Under large-signal conditions the reverse gate output current, which appears at the gate port of those devices due to drain-gate breakdown mechanisms, causes a drop in the power amplifier's power added efficiency (PAE) figure, thus affecting the entire transmitter reliability. Additionally, it is desirable to obtain a stable performance from the transmitters for different ambient temperatures. In particular, millimetre-wave wireless systems, such as the local multipoint distribution system (LMDS), require constant small signal gain for a wide range of temperatures. In this paper, an active bias network is used to compensate for both effects. The performance of the active bias network is shown to be superior, in terms of the power amplifier's PAE and the compensation of the power amplifier's small signal gain drifts due to temperature, to a conventional resistive divider when used for biasing the power amplifier. © 2003 Wiley Periodicals, Inc. Microwave Opt Technol Lett 38: 389–392, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.11069 [ABSTRACT FROM AUTHOR]

This paper proposes a method to obtain the isothermal static DC curves of microwave FET power amplifiers, avoiding the use of pulsed measurements and accounting for the self-heating problem in this type of device. The method requires the determination of the thermal resistance of the device under test and the measurement of its static DC curves under different ambient temperatures. © 2004 Wiley Periodicals, Inc. Microwave Opt Technol Lett 43: 378–380, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.20475 [ABSTRACT FROM AUTHOR]

A new continuous-wave linear frequency modulated radar scheme, which allows the accomplishment of high resolution radar images independently of the target position, is presented. Range resolutions around 15 cm can be achieved transmitting a gigahertz of bandwidth with a maximum distance of 15 km. [ABSTRACT FROM AUTHOR]

A response to a letter to the editor in response to the remarks on pae improvement and compensation of small-signall gain drift due to temperature on power amplifiers through active biasing.

Background Interleukin (IL)-33 and sST2 are molecules with an opposite pathophysiologic implications in the myocardial response after acute myocardial infarction (AMI). Both may be a target for therapeutic interventions. The kinetics of IL-33 and sST2 expression in infarcted myocardium and their correlation with the ongoing processes of fibrosis, inflammation and apoptosis remains poorly defined. Materials and methods Fifty Wistar rats underwent left anterior descending coronary artery surgical ligation and were sacrificed at 1, 2, 4, 12 or 24 weeks post-AMI. A sham-operated group was also included. The mRNA cardiac expression levels of IL-33, sST2, fibrosis markers, inflammatory markers and apoptosis markers were assessed by RT-PCR. The protein expression of IL-33 was also measured by Western blotting. Results The mRNA levels of IL-33 and sST2 were upregulated in the infarcted myocardium during the first week after AMI. However, while IL-33 levels remained elevated during the first 12 weeks post-AMI, sST2 levels showed a marked drop at 4 weeks. IL-33 protein expression showed a similar kinetic than mRNA expression. The expression of sST2 positively correlated with cardiac gene expression of inflammatory and fibrosis markers. However, the IL-33 level did not correlate with these cardiac remodelling markers. No correlation of sST2 with apoptosis markers was observed. Conclusion After AMI, expression of sST2 is rapidly upregulated during the first 4 weeks and, in contrast to IL-33, its levels correlated with the ongoing processes of fibrosis and inflammation. These findings suggest differential regulation of IL33 and sST2. Therapeutic modulation of early sST2 expression may be of greater importance to prevent adverse remodelling after AMI. [ABSTRACT FROM AUTHOR]

The authors present a novel and heuristic approach for the detection of low radar cross-section targets in high-resolution sea clutter. The proposed technique is based on the application of the Radon transform to range–time matrices formed by column-wise storage of consecutive range profiles. The objective of this paper is 2-fold: to analyse the effect of the transform on real high-resolution sea clutter and to describe a detection scheme based on the insight obtained. The proposed technique emulates the behaviour of traditional motion target detection algorithms without the need for reliable Doppler information. It also constitutes a powerful non-coherent integration strategy of the target's energy along its specific path on the range–time plot. The performance of the detection technique has been tested against real high-resolution sea clutter data, acquired at the south coast of Spain with an in-house developed continuous wave linear frequency modulated millimetre-wave radar system. Monte Carlo simulations show a significant improvement over the conventional cell averaging constant false alarm rate schemes. [ABSTRACT FROM AUTHOR]

Background: Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown.Objectives: The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology.Methods: The study cohort comprised 62 patients with HF and LVEF <45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization.Results: CHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology.Conclusions: Somatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology. [ABSTRACT FROM AUTHOR]

This paper presents the statistical analysis of an experimental high-resolution sea-clutter database, collected with a high-resolution Ka-band radar at the south coast of Spain. The main motivation of this paper has been to check the validity of the available theoretical models for high-resolution sea-clutter against data corresponding to a range resolution of centimeters. The overall amplitude probability density function (pdf), the compatibility with a compound representation, and the average spectral behavior of the data are analyzed in detail. Results clearly show the suitability of the compound Gaussian model and, more precisely, that the empirical pdf is well modeled by the generalized K distribution with log-normal texture. A close agreement has also been found between the estimated clutter spectral density and a power-law model. [ABSTRACT FROM AUTHOR]

Traffic surveillance is an important civilian application of radars. The current high-resolution radars give new opportunities so that the traffic application may be redefined. In this paper, a traffic scenario with a high-resolution radar is presented. A range-bin alignment method, the Global Range Alignment, which comes from the focusing techniques in inverse synthetic aperture radar, is applied to obtain further capabilities than the usual velocity measurement: distinction between vehicle types via length estimation and adequate management in situations with simultaneous targets. Preliminary results from a real scenario using a high-resolution linear frequency-modulated continuous-wave millimeter-wave radar are shown. [ABSTRACT FROM AUTHOR]