Carvedilol Protects against Doxorubicin-Induced Mitochondrial Cardiomyopathy

Several cytopathic mechanisms have been suggested to mediate the dose-limiting cumulative and irreversible cardiomyopathy caused by doxorubicin. Recent evidence indicates that oxidative stress and mitochondrial dysfunction are key factors in the pathogenic process. The objective of this investigation was to test the hypothesis that carvedilol, a nonselective [beta]-adrenergic receptor antagonist with potent antioxidant properties, protects against the cardiac and hepatic mitochondrial bioenergetic dysfunction associated with subchronic doxorubicin toxicity. Heart and liver mitochondria were isolated from rats treated for 7 weeks with doxorubicin (2 mg/kg sc/week), carvedilol (1 mg/kg ip/week), or the combination of the two drugs. Heart mitochondria isolated from doxorubicin-treated rats exhibited depressed rates for state 3 respiration (336 ± 26 versus 425 ± 53 natom O/min/mg protein) and a lower respiratory control ratio (RCR) (4.3 ± 0.6 versus 5.8 ± 0.4) compared with cardiac mitochondria isolated from saline-treated rats. Mitochondrial calcium-loading capacity and the activity of NADH-dehydrogenase were also suppressed in cardiac mitochondria from doxorubicin-treated rats. Doxorubicin treatment also caused a decrease in RCR for liver mitochondria (3.9 ± 0.9 versus 5.6 ± 0.7 for control rats) and inhibition of hepatic cytochrome oxidase activity. Coadministration of carvedilol decreased the extent of cellular vacuolization in cardiac myocytes and prevented the inhibitory effect of doxorubicin on mitochondrial respiration in both heart and liver. Carvedilol also prevented the decrease in mitochondrial Ca2+ loading capacity and the inhibition of the respiratory complexes of heart mitochondria caused by doxorubicin. Carvedilol by itself did not affect any of the parameters measured for heart or liver mitochondria. It is concluded that this protection by carvedilol against both the structural and functional cardiac tissue damage may afford significant clinical advantage in minimizing the dose-limiting mitochondrial dysfunction and cardiomyopathy that accompanies long-term doxorubicin therapy in cancer patients.http://www.sciencedirect.com/science/article/B6WXH-47G34FR-7/1/591ea3d1072dcf2971b640191c05679

GPUVerify: A Verifier for GPU Kernels

We present a technique for verifying race- and divergence-freedom of GPU kernels that are written in mainstream ker-nel programming languages such as OpenCL and CUDA. Our approach is founded on a novel formal operational se-mantics for GPU programming termed synchronous, delayed visibility (SDV) semantics. The SDV semantics provides a precise definition of barrier divergence in GPU kernels and allows kernel verification to be reduced to analysis of a sequential program, thereby completely avoiding the need to reason about thread interleavings, and allowing existing modular techniques for program verification to be leveraged. We describe an efficient encoding for data race detection and propose a method for automatically inferring loop invari-ants required for verification. We have implemented these techniques as a practical verification tool, GPUVerify, which can be applied directly to OpenCL and CUDA source code. We evaluate GPUVerify with respect to a set of 163 kernels drawn from public and commercial sources. Our evaluation demonstrates that GPUVerify is capable of efficient, auto-matic verification of a large number of real-world kernels

Foundational extensible corecursion: a proof assistant perspective

This paper presents a formalized framework for defining corecursive functions safely in a total setting, based on corecursion up-to and relational parametricity. The end product is a general corecursor that allows corecursive (and even recursive) calls under “friendly” operations, including constructors. Friendly corecursive functions can be registered as such, thereby increasing the corecursor’s expressiveness. The metatheory is formalized in the Isabelle proof assistant and forms the core of a prototype tool. The corecursor is derived from first principles, without requiring new axioms or extensions of the logic

Robustness Testing of Intermediate Verifiers

Program verifiers are not exempt from the bugs that affect nearly every piece of software. In addition, they often exhibit brittle behavior: their performance changes considerably with details of how the input program is expressed-details that should be irrelevant, such as the order of independent declarations. Such a lack of robustness frustrates users who have to spend considerable time figuring out a tool's idiosyncrasies before they can use it effectively. This paper introduces a technique to detect lack of robustness of program verifiers; the technique is lightweight and fully automated, as it is based on testing methods (such as mutation testing and metamorphic testing). The key idea is to generate many simple variants of a program that initially passes verification. All variants are, by construction, equivalent to the original program; thus, any variant that fails verification indicates lack of robustness in the verifier. We implemented our technique in a tool called "mugie", which operates on programs written in the popular Boogie language for verification-used as intermediate representation in numerous program verifiers. Experiments targeting 135 Boogie programs indicate that brittle behavior occurs fairly frequently (16 programs) and is not hard to trigger. Based on these results, the paper discusses the main sources of brittle behavior and suggests means of improving robustness

Creating nanoporous graphene with swift heavy ions

This article has an erratum: DOI 10.1016/j.carbon.2017.03.065We examine swift heavy ion-induced defect production in suspended single layer graphene using Raman spectroscopy and a two temperature molecular dynamics model that couples the ionic and electronic subsystems. We show that an increase in the electronic stopping power of the ion results in an increase in the size of the pore-type defects, with a defect formation threshold at 1.22–1.48 keV/layer. We also report calculations of the specific electronic heat capacity of graphene with different chemical potentials and discuss the electronic thermal conductivity of graphene at high electronic temperatures, suggesting a value in the range of 1 Wm−1 K−1. These results indicate that swift heavy ions can create nanopores in graphene, and that their size can be tuned between 1 and 4 nm diameter by choosing a suitable stopping power.Peer reviewe

Congruence between perceived and theoretical knowledge before and after an internet-based continuing education program about VLU nursing care

Background: Previous research has revealed nurses' knowledge gaps in venous leg ulcer (VLU) nursing care, and continuing education is needed. The closer nurses' perceived knowledge is to their evidence-based theoretical knowledge, the better possibilities they have to conduct evidence-based VLU nursing care.Objectives: To assess the congruence between nurses' perceived and theoretical knowledge about VLU nursing care before and after an internet-based education about VLU nursing care (eVLU).Design: Quasi-experimental study with intervention and comparison groups and pre- and post-measurements.Setting: Home health care in two Finnish municipalities.Participants: Nurses (n = 946) working in home health care were invited to participate. In the intervention group, 239 nurses and 229 nurses in the comparison group met the inclusion criteria, and they were all recruited to the study.Method: Nurses were divided into intervention and comparison groups with lottery between the municipalities. Nurses in both groups took care of patients with VLU according to their organizations' instructions. In addition to this, nurses in the intervention group received a 6-week eVLU while those in the comparison group did not. Data were collected with a questionnaire about perceived and theoretical knowledge before education, at six weeks, and at 10 weeks. The percentages of congruence were calculated at every measurement point, and the McNemar test was used to detect statistical significance of changes between measurements.Results: The increase of congruence was more often statistically significant in the intervention group than in the comparison group.Conclusion: The results support the hypothesis that the congruence between perceived and theoretical knowledge will be higher among nurses receiving eVLU. Because of the low participation and drop-outs, the results should be interpreted with caution.</p

Guiding Dynamic Symbolic Execution Toward Unverified Program Executions

Most techniques to detect program errors, such as testing, code reviews, and static program analysis, do not fully verify all possible executions of a program. They leave executions unverified when they do not check certain properties, fail to verify properties, or check properties under certain unsound assumptions such as the absence of arithmetic overflow. In this paper, we present a technique to complement partial verification results by automatic test case generation. In contrast to existing work, our technique supports the common case that the verification results are based on unsound assumptions. We annotate programs to reflect which executions have been verified, and under which assumptions. These annotations are then used to guide dynamic symbolic execution toward unverified program executions. Our main technical contribution is a code instrumentation that causes dynamic symbolic execution to abort tests that lead to verified executions, to prune parts of the search space, and to prioritize tests that cover more properties that are not fully verified. We have implemented our technique for the .NET static analyzer Clousot and the dynamic symbolic execution tool Pex. It produces smaller test suites (by up to 19.2%), covers more unverified executions (by up to 7.1%), and reduces testing time (by up to 52.4%) compared to combining Clousot and Pex without our technique

First observation of excited states in 173Hg

The neutron-deficient nucleus 173Hg has been studied following fusion-evaporation reactions. The observation of gamma rays decaying from excited states are reported for the first time and a tentative level scheme is proposed. The proposed level scheme is discussed within the context of the systematics of neighbouring neutron-deficient Hg nuclei. In addition to the gamma-ray spectroscopy, the alpha decay of this nucleus has been measured yielding superior precision to earlier measurements.Comment: 5 pages, 4 figure

On the equivalence of pairing correlations and intrinsic vortical currents in rotating nuclei

The present paper establishes a link between pairing correlations in rotating nuclei and collective vortical modes in the intrinsic frame. We show that the latter can be embodied by a simple S-type coupling a la Chandrasekhar between rotational and intrinsic vortical collective modes. This results from a comparison between the solutions of microscopic calculations within the HFB and the HF Routhian formalisms. The HF Routhian solutions are constrained to have the same Kelvin circulation expectation value as the HFB ones. It is shown in several mass regions, pairing regimes, and for various spin values that this procedure yields moments of inertia, angular velocities, and current distributions which are very similar within both formalisms. We finally present perspectives for further studies.Comment: 8 pages, 4 figures, submitted to Phys. Rev.