Les effets pro-arythmiques des médicaments

RésuméLes effets pro-arythmiques des médicaments sont fréquents et graves, et sont associés à une surmortalité non négligeable. La polymédication augmente le nombre d’effets indésirables et d’interactions graves voire mortelles. Certains sont facilement évitables. Cependant, au-delà de l’allongement de l’intervalle QT, d’autres mécanismes peuvent avoir un rôle majeur comme les dysfonctions du RyR2, responsable d’arythmie calcium-dépendantes par surcharge calcique intracellulaire, avec apparition de post-dépolarisations tardives, sans modifications de l’intervalle QT. Les bloqueurs des canaux sodiques sont également un problème sérieux de part le risque de démasquer ou d’aggraver une dysfonction du canal sodique chez des patients atteints de syndrome de Brugada asymptomatique ou non. Leur dépistage à un stade précoce du développement des médicaments peut avoir un intérêt majeur.SummaryThe cardiac safety of new and marketed drugs is a major concern for public authorities, patients, physicians as well as pharmaceutical companies. Letal adverse drug reactions are indeed a leading cause of death worldwide and increase at a greater rate than the increase in total hospital admission. The increasing use of polypharmacy in current clinical practice is also associated to a growing number of side effects and interactions leading to fatal adverse events. Measurement of the QT interval is an established, albeit incomplete, approach to assess the proarrhythmic risk of a drug. Ventricular arrhythmia (VA) can be caused by a QT-prolonging drug inducing abnormal repolarization of the action potential (AP) of ventricular cardiomyocytes. Emerging evidence, derived from recent understanding of these mechanisms and of similar mechanisms reported for heart failure (HF), suggest that diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) related to RyR2 dysfunction can induce Ca2+ dependent arrhythmia. In this report, we review mechanisms underlying drug-induced arrhythmogenic effects and Ca2+ dependent arrhythmia, and, for the latter, we discuss some of the issues associated to worsening of cardiac arrhythmias

Історія радянської України в бібліографічних покажчиках англомовних праць другої половини ХХ століття

У статті проаналізовано бібліографічні покажчики англомовної слов’янознавчої та радянознавчої літератури, видрукувані в англомовних країнах протягом другої половини ХХ ст. Зроблено спробу визначити місце, яке у них займали праці з історії України, зокрема ті, що стосуватися пізньосталінського та хрущовського періодів.В статье анализируются библиографические указатели англоязычной славяноведческой и советологической литературы, опубликованные в англоязычных странах во второй половине ХХ века. Сделана попытка охарактеризовать положение, которое в них занимала история Советской Украины, особенно ее позднесталинский и хрущевский периоды.In the article, the bibliographic guides to the English-language publications in Slavic, East European and Soviet Studies that were published in the second half of the 20th century are analyzed. The special attention is given to history of Ukraine from the second half of the 1940s till the mid-1960s as a particular subject in those guides

Multimodal assessment of painful peripheral neuropathy induced by chronic oxaliplatin-based chemotherapy in mice

<p>Abstract</p> <p>Background</p> <p>A major clinical issue affecting 10-40% of cancer patients treated with oxaliplatin is severe peripheral neuropathy with symptoms including cold sensitivity and neuropathic pain. Rat models have been used to describe the pathological features of oxaliplatin-induced peripheral neuropathy; however, they are inadequate for parallel studies of oxaliplatin's antineoplastic activity and neurotoxicity because most cancer models are developed in mice. Thus, we characterized the effects of chronic, bi-weekly administration of oxaliplatin in BALB/c mice. We first studied oxaliplatin's effects on the peripheral nervous system by measuring caudal and digital nerve conduction velocities (NCV) followed by ultrastructural and morphometric analyses of dorsal root ganglia (DRG) and sciatic nerves. To further characterize the model, we examined nocifensive behavior and central nervous system excitability by <it>in vivo </it>electrophysiological recording of spinal dorsal horn (SDH) wide dynamic range neurons in oxaliplatin-treated mice</p> <p>Results</p> <p>We found significantly decreased NCV and action potential amplitude after oxaliplatin treatment along with neuronal atrophy and multinucleolated DRG neurons that have eccentric nucleoli. Oxaliplatin also induced significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment, and a significant increase in the activity of wide dynamic range neurons in the SDH.</p> <p>Conclusions</p> <p>Our findings demonstrate that chronic treatment with oxaliplatin produces neurotoxic changes in BALB/c mice, confirming that this model is a suitable tool to conduct further mechanistic studies of oxaliplatin-related antineoplastic activity, peripheral neurotoxicity and pain. Further, this model can be used for the preclinical discovery of new neuroprotective and analgesic compounds.</p

Transiting exoplanets from the CoRoT space mission VIII. CoRoT-7b: the first Super-Earth with measured radius

We report the discovery of very shallow (DF/F = 3.4 10-4), periodic dips in the light curve of an active V = 11.7 G9V star observed by the CoRoT satellite, which we interpret as due to the presence of a transiting companion. We describe the 3-colour CoRoT data and complementary ground-based observations that support the planetary nature of the companion. Methods. We use CoRoT color information, good angular resolution ground-based photometric observations in- and out- of transit, adaptive optics imaging, near-infrared spectroscopy and preliminary results from Radial Velocity measurements, to test the diluted eclipsing binary scenarios. The parameters of the host star are derived from optical spectra, which were then combined with the CoRoT light curve to derive parameters of the companion. We examine carefully all conceivable cases of false positives, and all tests performed support the planetary hypothesis. Blends with separation larger than 0.40 arcsec or triple systems are almost excluded with a 8 10-4 risk left. We conclude that, as far as we have been exhaustive, we have discovered a planetary companion, named CoRoT-7b, for which we derive a period of 0.853 59 +/- 3 10-5 day and a radius of Rp = 1.68 +/- 0.09 REarth. Analysis of preliminary radial velocity data yields an upper limit of 21 MEarth for the companion mass, supporting the finding. CoRoT-7b is very likely the first Super-Earth with a measured radius.Comment: Accepted in Astronomy and Astrophysics; typos and language corrections; version sent to the printer w few upgrade

Microparticles induce pulmonary artery contraction through activation of acid sphingomyelinase and inhibition of Kv currents

National audienc

Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer

BACKGROUND: New chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity. METHODS: A detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity. RESULTS: Eighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients. CONCLUSION: Oxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity

Dose Effects of Oxaliplatin on Persistent and Transient Na+ Conductances and the Development of Neurotoxicity

BACKGROUND: Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+) channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+) channel dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: Specifically the function of transient and persistent Na(+) currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na(+) channel inactivation) was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001) and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), strength-duration time constant (marker of persistent Na(+) conductances) was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS). However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = -.65; P<.05; Sensory correlation coefficient = .67; P<.05). CONCLUSIONS/SIGNIFICANCE: It is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na(+) conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies

Transiting exoplanets from the CoRoT space mission. VIII. CoRoT-7b: the first super-Earth with measured radius

Copyright © The European Southern Observatory (ESO)Aims. We report the discovery of very shallow (ΔF/F ≈ 3.4×10−4), periodic dips in the light curve of an active V = 11.7 G9V star observed by the CoRoT satellite, which we interpret as caused by a transiting companion. We describe the 3-colour CoRoT data and complementary ground-based observations that support the planetary nature of the companion. Methods. We used CoRoT colours information, good angular resolution ground-based photometric observations in- and out- of transit, adaptive optics imaging, near-infrared spectroscopy, and preliminary results from radial velocity measurements, to test the diluted eclipsing binary scenarios. The parameters of the host star were derived from optical spectra, which were then combined with the CoRoT light curve to derive parameters of the companion. Results. We examined all conceivable cases of false positives carefully, and all the tests support the planetary hypothesis. Blends with separation >0.40'' or triple systems are almost excluded with a 8 × 10−4 risk left. We conclude that, inasmuch we have been exhaustive, we have discovered a planetary companion, named CoRoT-7b, for which we derive a period of 0.853 59 ± 3 × 10−5 day and a radius of Rp = 1.68 ± 0.09 REarth. Analysis of preliminary radial velocity data yields an upper limit of 21 MEarth for the companion mass, supporting the finding. Conclusions. CoRoT-7b is very likely the first Super-Earth with a measured radius. This object illustrates what will probably become a common situation with missions such as Kepler, namely the need to establish the planetary origin of transits in the absence of a firm radial velocity detection and mass measurement. The composition of CoRoT-7b remains loosely constrained without a precise mass. A very high surface temperature on its irradiated face, ≈1800–2600 K at the substellar point, and a very low one, ≈50 K, on its dark face assuming no atmosphere, have been derived

Determinants of Unlawful File Sharing: A Scoping Review

We employ a scoping review methodology to consider and assess the existing evidence on the determinants of unlawful file sharing (UFS) transparently and systematically. Based on the evidence, we build a simple conceptual framework to model the psychological decision to engage in UFS, purchase legally or do nothing. We identify social, moral, experiential, technical, legal and financial utility sources of the decision to purchase or to file share. They interact in complex ways. We consider the strength of evidence within these areas and note patterns of results. There is good evidence for influences on UFS within each of the identified determinants, particularly for self-reported measures, with more behavioral research needed. There are also indications that the reasons for UFS differ across media; more studies exploring media other than music are required