While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2 Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.
Jacques Derrida (b. 1930–d. 2004) was one of the most famous philosophers of the 20th century, and he has remained so since his death in 2004. Derrida’s work was described by Hélène Cixous as the greatest ethico-political warning of our time, and he was remarkably prolific. It is unlikely that anyone has read all of Derrida’s work, and there are around fifty books still to be published in both French and English from his lecture notes, which are almost all completed prose of philosophical subtlety (for more on this, see the Derrida Seminars Translation Project). He was especially indebted to philosophers such as Edmund Husserl, Martin Heidegger, and Emmanuel Levinas, along with various literary figures (e.g., Mallarmé, Joyce, Celan, etc.), and he developed a manner of reading and engaging with texts and ideas that came to be known as “deconstruction,” which was infamous throughout the 1980s and 1990s, especially in Anglo-American countries, where Derrida was arguably most influential. Derrida deliberately resisted any simple definition of deconstruction, instead preferring pithy and enigmatic remarks such as “deconstruction is justice.” Nonetheless, deconstruction is standardly thought to involve a scholarly reading of texts according to traditional standards, while also attempting to reveal dimensions of the text that resist or problematize the overt argument. These points may occur in apparently marginal and peripheral places but still destabilize both the author’s stated intentions and the textual system in question. The singularity of each text, however, precludes deconstruction being a neutral “method” that might be taken up and robotically deployed upon any and all texts. Derrida’s later philosophy is less textually embedded, instead becoming increasingly concerned with ethico-political concepts, such as democracy, responsibility, justice, friendship, forgiveness, hospitality, and the gift. Here his concern was with an aporetic or paradoxical logic to these concepts and to the experience of them, which leaves them open and incomplete. Without doing the disservice of offering further such short and ultimately unsatisfactory summaries of Derrida’s immense corpus, this bibliography aims to introduce the reader to some of the most influential of Derrida’s own texts, as well as provide a means for navigating the vast secondary literature that is out there. With regard to Derrida’s own texts, it has not been possible to provide summaries of all of them. Instead, this bibliography highlights just some of the most significant of those texts in regard to a given area or theme with which Derrida was concerned, while also having annotated entries on some of the most significant secondary literature that is about Derrida’s work, even if it extends or transforms it. While this article is primarily focused on texts in the English language, also included are some of the most significant writings on Derrida in French.
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