Modelización matemática y simulación de los efectos de la lidocaína sobre la actividad eléctrica cardíaca en tejido ventricular

Hoy resulta más complejo que nunca abordar el estudio de los fármacos antiarrítmicos, en virtud de los vuelcos experimentados por la aparición de diferentes trabajos donde se ha comprobado la acción proarrítmica de este tipo de fármacos. Estos resultados han obligado a un replanteamiento en la terapia antiarrítmica actual. Por tal motivo, como objetivo principal de esta tesis se planteó la realización de un modelo matemático capaz de simular la acción de la lidocaína, para determinar las razones de la acción antiarrítmica o pro-arrítmica de este fármaco cuando es administrado bajo condiciones patológicas como la isquemia. En este trabajo se planteó y validó el modelo del efecto de la lidocaína, donde como aportación original se logró modelizar el efecto de la dependencia del pH a través de la utilización de los algoritmos genéticos para el ajuste de las constantes de asociación y disociación de las ecuaciones diferenciales. De esta forma, este modelo nos proporciona una herramienta útil a la hora de estudiar el efecto del fármaco en diferentes patologías. En nuestros resultados se observó como la lidocaína redujo parámetros como la corriente de sodio, la derivada máxima del potencial de acción y la velocidad de conducción. Estos efectos se incrementaron cuando la frecuencia de estimulación aumentó y el valor de pH disminuyó. Adicionalmente, se mostró como el período refractario se incrementó significativamente sólo para altas frecuencias de estimulación y concentración del fármaco. Al estudiar el efecto del fármaco bajo condiciones de isquemia aguda, se observó como la vulnerabilidad a reentradas se incrementó a medida que aumentaba la concentración del fármaco, proporcionando un efecto pro-arrítmico de la lidocaína bajo estas condiciones. Este efecto se atribuyó a la reducción de la velocidad de conducción en las diferentes zonas del tejido isquémico ocasionado por la lidocaína. Adicionalmente, se estudió la acción de la lidocaína en combinación con fármacos antiCardona Urrego, KE. (2008). Modelización matemática y simulación de los efectos de la lidocaína sobre la actividad eléctrica cardíaca en tejido ventricular [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/2934Palanci

Pro-arrhythmic Effects of Low Plasma [K+] in Human Ventricle: An Illustrated Review

[EN] Potassium levels in the plasma, [Kþ]o, are regulated precisely under physiological conditions. However, increases (from approx. 4.5 to 8.0 mM) can occur as a consequence of, e.g., endurance exercise, ischemic insult or kidney failure. This hyperkalemic modulation of ventricular electrophysiology has been studied extensively. Hypokalemia is also common. It can occur in response to diuretic therapy, following renal dialysis, or during recovery from endurance exercise. In the human ventricle, clinical hypokalemia (e.g., [Kþ]o levels of approx. 3.0 mM) can cause marked changes in both the resting potential and the action potential waveform, and these may promote arrhythmias. Here, we provide essential background information concerning the main Kþ-sensitive ion channel mechanisms that act in concert to produce prominent short-term ventricular electrophysiological changes, and illustrate these by implementing recent mathematical models of the human ventricular action potential. Even small changes (~1 mM) in [Kþ]o result in significant alterations in two different Kþ currents, IK1 and HERG. These changes can markedly alter in resting membrane potential and/or action potential waveform in human ventricle. Specifically, a reduction in net outward transmembrane Kþ currents (repolarization reserve) and an increased substrate input resistance contribute to electrophysiological instability during the plateau of the action potential and may promote pro-arrhythmic early after-depolarizations (EADs). Translational settings where these insights apply include: optimal diuretic therapy, and the interpretation of data from Phase II and III trials for anti-arrhythmic drug candidates.In Valencia, this work was supported by: (i) the “Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016” from the Ministerio de Economía, Industria y Competitividad of Spain (DPI2016-75799-R) and AEI/FEDER, UE, and by the “Programa Prometeu (PROMETEU/2016/088) de la Conselleria d'Educació, Formació I Ocupació, Generalitat Valenciana”. and (v) GileadSciences, Ltd. Wayne Giles acknowledges receipt of financial support in the form of a salary award (Medical Scientist) from Alberta Innovates-Health Solutions, and operating funding from the Canadian Institutes for Health Research and the Heart and Stroke Foundation of Alberta.Trénor Gomis, BA.; Cardona-Urrego, KE.; Romero Pérez, L.; Gómez García, JF.; Saiz Rodríguez, FJ.; Rajamani, S.; Belardinelli, L.... (2018). Pro-arrhythmic Effects of Low Plasma [K+] in Human Ventricle: An Illustrated Review. Trends in Cardiovascular Medicine. 28(4):233-242. https://doi.org/10.1016/j.tcm.2017.11.002S23324228

In silico assessment of drug safety in human heart applied to late sodium current blockers

Drug-induced action potential (AP) prolongation leading to Torsade de Pointes is a major concern for the development of anti-arrhythmic drugs. Nevertheless the development of improved anti-arrhythmic agents, some of which may block different channels, remains an important opportunity. Partial block of the late sodium current (INaL) has emerged as a novel anti-arrhythmic mechanism. It can be effective in the settings of free radical challenge or hypoxia. In addition, this approach can attenuate pro-arrhythmic effects of blocking the rapid delayed rectifying K+ current (IKr). The main goal of our computational work was to develop an in-silico tool for preclinical anti-arrhythmic drug safety assessment, by illustrating the impact of IKr/INaL ratio of steady-state block of drug candidates on “torsadogenic” biomarkers. The O’Hara et al. AP model for human ventricular myocytes was used. Biomarkers for arrhythmic risk, i.e., AP duration, triangulation, reverse rate-dependence, transmural dispersion of repolarization and electrocardiogram QT intervals, were calculated using single myocyte and one-dimensional strand simulations. Predetermined amounts of block of INaL and IKr were evaluated. “Safety plots” were developed to illustrate the value of the specific biomarker for selected combinations of IC50s for IKr and INaL of potential drugs. The reference biomarkers at baseline changed depending on the “drug” specificity for these two ion channel targets. Ranolazine and GS967 (a novel potent inhibitor of INaL) yielded a biomarker data set that is considered safe by standard regulatory criteria. This novel in-silico approach is useful for evaluating pro-arrhythmic potential of drugs and drug candidates in the human ventricle.This work was supported by (1) Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica, (2) Plan Avanza en el marco de la Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion del Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), (3) Programa de Apoyo a la Investigacion y Desarrollo (PAID-06-11-2002) de la Universidad Politecnica de Valencia, (4) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana and (5) Gilead Sciences, Ltd.Trenor Gomis, BA.; Gomis-Tena Dolz, J.; Cardona Urrego, KE.; Romero Pérez, L.; Rajamani, S.; Belardinelli, L.; Giles, WR.... (2013). In silico assessment of drug safety in human heart applied to late sodium current blockers. Channels. 7(4):1-14. doi:10.4161/chan.24905S11474Maltsev, V. A., Silverman, N., Sabbah, H. N., & Undrovinas, A. I. (2007). Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability. European Journal of Heart Failure, 9(3), 219-227. doi:10.1016/j.ejheart.2006.08.007Zaza, A., Belardinelli, L., & Shryock, J. C. (2008). Pathophysiology and pharmacology of the cardiac «late sodium current». Pharmacology & Therapeutics, 119(3), 326-339. doi:10.1016/j.pharmthera.2008.06.001Song, Y., Shryock, J. C., Wagner, S., Maier, L. S., & Belardinelli, L. (2006). Blocking Late Sodium Current Reduces Hydrogen Peroxide-Induced Arrhythmogenic Activity and Contractile Dysfunction. Journal of Pharmacology and Experimental Therapeutics, 318(1), 214-222. doi:10.1124/jpet.106.101832Milberg, P., Pott, C., Fink, M., Frommeyer, G., Matsuda, T., Baba, A., … Eckardt, L. (2008). Inhibition of the Na+/Ca2+ exchanger suppresses torsades de pointes in an intact heart model of long QT syndrome-2 and long QT syndrome-3. Heart Rhythm, 5(10), 1444-1452. doi:10.1016/j.hrthm.2008.06.017Jia, S., Lian, J., Guo, D., Xue, X., Patel, C., Yang, L., … Yan, G.-X. (2011). Modulation of the late sodium current by ATX-II and ranolazine affects the reverse use-dependence and proarrhythmic liability of IKrblockade. British Journal of Pharmacology, 164(2), 308-316. doi:10.1111/j.1476-5381.2010.01181.xUNDROVINAS, A. I., BELARDINELLI, L., UNDROVINAS, N. A., & SABBAH, H. N. (2006). Ranolazine Improves Abnormal Repolarization and Contraction in Left Ventricular Myocytes of Dogs with Heart Failure by Inhibiting Late Sodium Current. Journal of Cardiovascular Electrophysiology, 17(s1), S169-S177. doi:10.1111/j.1540-8167.2006.00401.xWu, L., Shryock, J. C., Song, Y., Li, Y., Antzelevitch, C., & Belardinelli, L. (2004). Antiarrhythmic Effects of Ranolazine in a Guinea Pig in Vitro Model of Long-QT Syndrome. Journal of Pharmacology and Experimental Therapeutics, 310(2), 599-605. doi:10.1124/jpet.104.066100MOSS, A. J., ZAREBA, W., SCHWARZ, K. Q., ROSERO, S., MCNITT, S., & ROBINSON, J. L. (2008). Ranolazine Shortens Repolarization in Patients with Sustained Inward Sodium Current Due to Type-3 Long-QT Syndrome. Journal of Cardiovascular Electrophysiology, 19(12), 1289-1293. doi:10.1111/j.1540-8167.2008.01246.xSong, Y., Shryock, J. C., Wu, L., & Belardinelli, L. (2004). Antagonism by Ranolazine of the Pro-Arrhythmic Effects of Increasing Late INa in Guinea Pig Ventricular Myocytes. Journal of Cardiovascular Pharmacology, 44(2), 192-199. doi:10.1097/00005344-200408000-00008Belardinelli, L., Liu, G., Smith-Maxwell, C., Wang, W.-Q., El-Bizri, N., Hirakawa, R., … Shryock, J. C. (2012). A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias. Journal of Pharmacology and Experimental Therapeutics, 344(1), 23-32. doi:10.1124/jpet.112.198887Banyasz, T., Koncz, R., Fulop, L., Szentandrassy, N., Magyar, J., & Nanasi, P. (2004). Profile of IKs During the Action Potential Questions the Therapeutic Value of IKs Blockade. Current Medicinal Chemistry, 11(1), 45-60. doi:10.2174/0929867043456304Hopenfeld, B. (2006). A mathematical analysis of the action potential plateau duration of a human ventricular myocyte. Journal of Theoretical Biology, 240(2), 311-322. doi:10.1016/j.jtbi.2005.09.021Maleckar, M. M., Greenstein, J. L., Giles, W. R., & Trayanova, N. A. (2009). Electrotonic Coupling between Human Atrial Myocytes and Fibroblasts Alters Myocyte Excitability and Repolarization. Biophysical Journal, 97(8), 2179-2190. doi:10.1016/j.bpj.2009.07.054Nygren, A., Fiset, C., Firek, L., Clark, J. W., Lindblad, D. S., Clark, R. B., & Giles, W. R. (1998). Mathematical Model of an Adult Human Atrial Cell. Circulation Research, 82(1), 63-81. doi:10.1161/01.res.82.1.63Viswanathan, P. (1999). Pause induced early afterdepolarizations in the long QT syndrome: a simulation study. Cardiovascular Research, 42(2), 530-542. doi:10.1016/s0008-6363(99)00035-8Wu, R., & Patwardhan, A. (2007). Effects of rapid and slow potassium repolarization currents and calcium dynamics on hysteresis in restitution of action potential duration. Journal of Electrocardiology, 40(2), 188-199. doi:10.1016/j.jelectrocard.2006.01.001Zaniboni, M. (2011). 3D current–voltage–time surfaces unveil critical repolarization differences underlying similar cardiac action potentials: A model study. Mathematical Biosciences, 233(2), 98-110. doi:10.1016/j.mbs.2011.06.008Zaniboni, M. (2012). Late Phase of Repolarization is Autoregenerative and Scales Linearly with Action Potential Duration in Mammals Ventricular Myocytes: A Model Study. IEEE Transactions on Biomedical Engineering, 59(1), 226-233. doi:10.1109/tbme.2011.2170987Zaniboni, M., Riva, I., Cacciani, F., & Groppi, M. (2010). How different two almost identical action potentials can be: A model study on cardiac repolarization. Mathematical Biosciences, 228(1), 56-70. doi:10.1016/j.mbs.2010.08.007Belardinelli, L., Antzelevitch, C., & Vos, M. A. (2003). Assessing predictors of drug-induced torsade de pointes. Trends in Pharmacological Sciences, 24(12), 619-625. doi:10.1016/j.tips.2003.10.002Shah, R. R., & Hondeghem, L. M. (2005). Refining detection of drug-induced proarrhythmia: QT interval and TRIaD. Heart Rhythm, 2(7), 758-772. doi:10.1016/j.hrthm.2005.03.023Hondeghem, L. M., Carlsson, L., & Duker, G. (2001). Instability and Triangulation of the Action Potential Predict Serious Proarrhythmia, but Action Potential Duration Prolongation Is Antiarrhythmic. Circulation, 103(15), 2004-2013. doi:10.1161/01.cir.103.15.2004Mirams, G. R., Cui, Y., Sher, A., Fink, M., Cooper, J., Heath, B. M., … Noble, D. (2011). Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk. Cardiovascular Research, 91(1), 53-61. doi:10.1093/cvr/cvr044Obiol-Pardo, C., Gomis-Tena, J., Sanz, F., Saiz, J., & Pastor, M. (2011). A Multiscale Simulation System for the Prediction of Drug-Induced Cardiotoxicity. Journal of Chemical Information and Modeling, 51(2), 483-492. doi:10.1021/ci100423zSuzuki, S., Murakami, S., Tsujimae, K., Findlay, I., & Kurachi, Y. (2008). In silico risk assessment for drug-induction of cardiac arrhythmia. Progress in Biophysics and Molecular Biology, 98(1), 52-60. doi:10.1016/j.pbiomolbio.2008.05.003Mirams, G. R., Davies, M. R., Cui, Y., Kohl, P., & Noble, D. (2012). Application of cardiac electrophysiology simulations to pro-arrhythmic safety testing. British Journal of Pharmacology, 167(5), 932-945. doi:10.1111/j.1476-5381.2012.02020.xSarkar, A. X., & Sobie, E. A. (2011). Quantification of repolarization reserve to understand interpatient variability in the response to proarrhythmic drugs: A computational analysis. Heart Rhythm, 8(11), 1749-1755. doi:10.1016/j.hrthm.2011.05.023CHANG, C., ACHARFI, S., WU, M., CHIANG, F., WANG, J., SUNG, T., & CHAHINE, M. (2004). A novel SCN5A mutation manifests as a malignant form of long QT syndrome with perinatal onset of tachycardia/bradycardia. Cardiovascular Research, 64(2), 268-278. doi:10.1016/j.cardiores.2004.07.007Weirich, J., & Antoni, H. (1998). Rate-dependence of antiarrhythmic and proarrhythmic properties of class I and class III antiarrhythmic drugs. Basic Research in Cardiology, 93(0), s125-s132. doi:10.1007/s003950050236O’Hara, T., Virág, L., Varró, A., & Rudy, Y. (2011). Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation. PLoS Computational Biology, 7(5), e1002061. doi:10.1371/journal.pcbi.1002061Wu, L., Ma, J., Li, H., Wang, C., Grandi, E., Zhang, P., … Belardinelli, L. (2011). Late Sodium Current Contributes to the Reverse Rate-Dependent Effect of I Kr Inhibition on Ventricular Repolarization. Circulation, 123(16), 1713-1720. doi:10.1161/circulationaha.110.000661Banyasz, T., Barandi, L., Harmati, G., Virag, L., Szentandrassy, N., Marton, I., … P. Nanasi, P. (2011). Mechanism of Reverse Rate-Dependent Action of Cardioactive Agents. Current Medicinal Chemistry, 18(24), 3597-3606. doi:10.2174/092986711796642355Noble D, Tsien RW. The repolarization process of heart cells. In: DeMello WC, ed. Electrical Phenomena in the Heart. New York: Academic Press, 1972:133-161.Fink, M., Noble, D., Virag, L., Varro, A., & Giles, W. R. (2008). Contributions of HERG K+ current to repolarization of the human ventricular action potential. Progress in Biophysics and Molecular Biology, 96(1-3), 357-376. doi:10.1016/j.pbiomolbio.2007.07.011Goineau, S., Castagné, V., Guillaume, P., & Froget, G. (2012). The comparative sensitivity of three in vitro safety pharmacology models for the detection of lidocaine-induced cardiac effects. Journal of Pharmacological and Toxicological Methods, 66(1), 52-58. doi:10.1016/j.vascn.2012.06.001Wu, L., Guo, D., Li, H., Hackett, J., Yan, G.-X., Jiao, Z., … Belardinelli, L. (2008). Role of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine. Heart Rhythm, 5(12), 1726-1734. doi:10.1016/j.hrthm.2008.09.008Diness, J. G., Hansen, R. S., Nissen, J. D., Jespersen, T., & Grunnet, M. (2009). Antiarrhythmic effect of IKr activation in a cellular model of LQT3. Heart Rhythm, 6(1), 100-106. doi:10.1016/j.hrthm.2008.10.020Laursen, M., Olesen, S.-P., Grunnet, M., Mow, T., & Jespersen, T. (2011). Characterization of cardiac repolarization in the Göttingen minipig. Journal of Pharmacological and Toxicological Methods, 63(2), 186-195. doi:10.1016/j.vascn.2010.10.001HONDEGHEM, L. M. (2006). Thorough QT/QTc Not So Thorough: Removes Torsadogenic Predictors from the T-Wave, Incriminates Safe Drugs, and Misses Profibrillatory Drugs. Journal of Cardiovascular Electrophysiology, 17(3), 337-340. doi:10.1111/j.1540-8167.2006.00347.xHondeghem, L. M., & Snyders, D. J. (1990). Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation, 81(2), 686-690. doi:10.1161/01.cir.81.2.686Bril, A. (1998). Combined potassium and calcium channel antagonistic activities as a basis for neutral frequency dependent increase in action potential duration: comparison between BRL-32872 and azimilide. Cardiovascular Research, 37(1), 130-140. doi:10.1016/s0008-6363(97)00216-2Jurkiewicz, N. K., & Sanguinetti, M. C. (1993). Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide. Circulation Research, 72(1), 75-83. doi:10.1161/01.res.72.1.75O’Hara, T., & Rudy, Y. (2012). Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species. American Journal of Physiology-Heart and Circulatory Physiology, 302(5), H1023-H1030. doi:10.1152/ajpheart.00785.2011Stengl, M., Volders, P. G. A., Thomsen, M. B., Spatjens, R. L. H. M. G., Sipido, K. R., & Vos, M. A. (2003). Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes. The Journal of Physiology, 551(3), 777-786. doi:10.1113/jphysiol.2003.044040Shah, R. R. (2002). The significance of QT interval in drug development. British Journal of Clinical Pharmacology, 54(2), 188-202. doi:10.1046/j.1365-2125.2002.01627.xNuyens, D., Stengl, M., Dugarmaa, S., Rossenbacker, T., Compernolle, V., Rudy, Y., … Carmeliet, P. (2001). Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nature Medicine, 7(9), 1021-1027. doi:10.1038/nm0901-1021Gautier, M., Zhang, H., & Fearon, I. M. (2008). Peroxynitrite formation mediates LPC-induced augmentation of cardiac late sodium currents. Journal of Molecular and Cellular Cardiology, 44(2), 241-251. doi:10.1016/j.yjmcc.2007.09.007Fearon, I. M., & Brown, S. T. (2004). Acute and chronic hypoxic regulation of recombinant hNav1.5 α subunits. Biochemical and Biophysical Research Communications, 324(4), 1289-1295. doi:10.1016/j.bbrc.2004.09.188Ward, C. A., & Giles, W. R. (1997). Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes. The Journal of Physiology, 500(3), 631-642. doi:10.1113/jphysiol.1997.sp022048Saint, D. A. (2009). The cardiac persistent sodium current: an appealing therapeutic target? British Journal of Pharmacology, 153(6), 1133-1142. doi:10.1038/sj.bjp.0707492Zygmunt, A. C., Eddlestone, G. T., Thomas, G. P., Nesterenko, V. V., & Antzelevitch, C. (2001). Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle. American Journal of Physiology-Heart and Circulatory Physiology, 281(2), H689-H697. doi:10.1152/ajpheart.2001.281.2.h689Trenor, B., Cardona, K., Gomez, J. F., Rajamani, S., Ferrero, J. M., Belardinelli, L., & Saiz, J. (2012). Simulation and Mechanistic Investigation of the Arrhythmogenic Role of the Late Sodium Current in Human Heart Failure. PLoS ONE, 7(3), e32659. doi:10.1371/journal.pone.0032659Martin, R. L., McDermott, J. S., Salmen, H. J., Palmatier, J., Cox, B. F., & Gintant, G. A. (2004). The Utility of hERG and Repolarization Assays in Evaluating Delayed Cardiac Repolarization: Influence of Multi-Channel Block. Journal of Cardiovascular Pharmacology, 43(3), 369-379. doi:10.1097/00005344-200403000-00007Antzelevitch, C., Belardinelli, L., Zygmunt, A. C., Burashnikov, A., Di Diego, J. M., Fish, J. M., … Thomas, G. (2004). Electrophysiological Effects of Ranolazine, a Novel Antianginal Agent With Antiarrhythmic Properties. Circulation, 110(8), 904-910. doi:10.1161/01.cir.0000139333.83620.5dNoble, D. (2006). Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload. Heart, 92(suppl_4), iv1-iv5. doi:10.1136/hrt.2005.078782Scirica, B. M., Morrow, D. A., Hod, H., Murphy, S. A., Belardinelli, L., Hedgepeth, C. M., … Braunwald, E. (2007). Effect of Ranolazine, an Antianginal Agent With Novel Electrophysiological Properties, on the Incidence of Arrhythmias in Patients With Non–ST-Segment–Elevation Acute Coronary Syndrome. Circulation, 116(15), 1647-1652. doi:10.1161/circulationaha.107.724880Hoefen, R., Reumann, M., Goldenberg, I., Moss, A. J., O-Uchi, J., Gu, Y., … Lopes, C. M. (2012). In Silico Cardiac Risk Assessment in Patients With Long QT Syndrome. Journal of the American College of Cardiology, 60(21), 2182-2191. doi:10.1016/j.jacc.2012.07.053Silva, J. R., Pan, H., Wu, D., Nekouzadeh, A., Decker, K. F., Cui, J., … Rudy, Y. (2009). A multiscale model linking ion-channel molecular dynamics and electrostatics to the cardiac action potential. Proceedings of the National Academy of Sciences, 106(27), 11102-11106. doi:10.1073/pnas.0904505106STARMER, C. (1991). Lidocaine blockade of continuously and transiently accessible sites in cardiac sodium channels*1. Journal of Molecular and Cellular Cardiology, 23, 73-83. doi:10.1016/0022-2828(91)90026-iRudy, Y., & Silva, J. R. (2006). Computational biology in the study of cardiac ion channels and cell electrophysiology. Quarterly Reviews of Biophysics, 39(1), 57-116. doi:10.1017/s0033583506004227Clancy, C. E., Zhu, Z. I., & Rudy, Y. (2007). Pharmacogenetics and anti-arrhythmic drug therapy: a theoretical investigation. American Journal of Physiology-Heart and Circulatory Physiology, 292(1), H66-H75. doi:10.1152/ajpheart.00312.2006Zygmunt, A. C., Nesterenko, V. V., Rajamani, S., Hu, D., Barajas-Martinez, H., Belardinelli, L., & Antzelevitch, C. (2011). Mechanisms of atrial-selective block of Na+ channels by ranolazine: I. Experimental analysis of the use-dependent block. American Journal of Physiology-Heart and Circulatory Physiology, 301(4), H1606-H1614. doi:10.1152/ajpheart.00242.2011Nesterenko, V. V., Zygmunt, A. C., Rajamani, S., Belardinelli, L., & Antzelevitch, C. (2011). Mechanisms of atrial-selective block of Na+ channels by ranolazine: II. Insights from a mathematical model. American Journal of Physiology-Heart and Circulatory Physiology, 301(4), H1615-H1624. doi:10.1152/ajpheart.00243.2011Zemzemi, N., Bernabeu, M. O., Saiz, J., Cooper, J., Pathmanathan, P., Mirams, G. R., … Rodriguez, B. (2013). Computational assessment of drug-induced effects on the electrocardiogram: from ion channel to body surface potentials. British Journal of Pharmacology, 168(3), 718-733. doi:10.1111/j.1476-5381.2012.02200.xHille B. Ionic Channels of Excitable Membranes. 2nd ed. Sunderland, MA: Sinauer Associates, 1992.Rajamani, S., Shryock, J. C., & Belardinelli, L. (2008). Rapid Kinetic Interactions of Ranolazine With HERG K+ Current. Journal of Cardiovascular Pharmacology, 51(6), 581-589. doi:10.1097/fjc.0b013e3181799690Rajamani, S., El-Bizri, N., Shryock, J. C., Makielski, J. C., & Belardinelli, L. (2009). Use-dependent block of cardiac late Na+ current by ranolazine. Heart Rhythm, 6(11), 1625-1631. doi:10.1016/j.hrthm.2009.07.042Bassingthwaighte, J., Hunter, P., & Noble, D. (2009). The Cardiac Physiome: perspectives for the future. Experimental Physiology, 94(5), 597-605. doi:10.1113/expphysiol.2008.044099Quinn, T. A., Granite, S., Allessie, M. A., Antzelevitch, C., Bollensdorff, C., Bub, G., … Delmar, M. (2011). Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): Standardised reporting for model reproducibility, interoperability, and data sharing. Progress in Biophysics and Molecular Biology, 107(1), 4-10. doi:10.1016/j.pbiomolbio.2011.07.001Glukhov, A. V., Fedorov, V. V., Lou, Q., Ravikumar, V. K., Kalish, P. W., Schuessler, R. B., … Efimov, I. R. (2010). Transmural Dispersion of Repolarization in Failing and Nonfailing Human Ventricle. Circulation Research, 106(5), 981-991. doi:10.1161/circresaha.109.204891MALTSEV, V., & UNDROVINAS, A. (2006). A multi-modal composition of the late Na+ current in human ventricular cardiomyocytes. Cardiovascular Research, 69(1), 116-127. doi:10.1016/j.cardiores.2005.08.015Drouin, E., Charpentier, F., Gauthier, C., Laurent, K., & Le Marec, H. (1995). Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: Evidence for presence of M cells. Journal of the American College of Cardiology, 26(1), 185-192. doi:10.1016/0735-1097(95)00167-xBerecki, G., Zegers, J. G., Bhuiyan, Z. A., Verkerk, A. O., Wilders, R., & Van Ginneken, A. C. G. (2006). Long-QT syndrome-related sodium channel mutations probed by the dynamic action potential clamp technique. The Journal of Physiology, 570(2), 237-250. doi:10.1113/jphysiol.2005.096578Maltsev, V. A., Silverman, N., Sabbah, H. N., & Undrovinas, A. I. (2007). Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variability. European Journal of Heart Failure, 9(3), 219-227. doi:10.1016/j.ejheart.2006.08.007Valdivia, C. R., Chu, W. W., Pu, J., Foell, J. D., Haworth, R. A., Wolff, M. R., … Makielski, J. C. (2005). Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. Journal of Molecular and Cellular Cardiology, 38(3), 475-483. doi:10.1016/j.yjmcc.2004.12.012Belardinelli, L. (2006). Inhibition of the late sodium current as a potential cardioprotective principle:

Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Carbon monoxide (CO) that is produced in a number of different mammalian tissues is now known to have significant effects on the cardiovascular system. These include: (i) vasodilation, (ii) changes in heart rate and strength of contractions, and (iii) modulation of autonomic nervous system input to both the primary pacemaker and the working myocardium. Excessive CO in the environment is toxic and can initiate or mediate life threatening cardiac rhythm disturbances. Recent reports link these ventricular arrhythmias to an increase in the slowly inactivating, or “late” component of the Na+ current in the mammalian heart. The main goal of this paper is to explore the basis of this pro-arrhythmic capability of CO by incorporating changes in CO-induced ion channel activity with intracellular signaling pathways in the mammalian heart. To do this, a quite well-documented mathematical model of the action potential and intracellular calcium transient in the human ventricular myocyte has been employed. In silico iterations based on this model provide a useful first step in illustrating the cellular electrophysiological consequences of CO that have been reported from mammalian heart experiments. Specifically, when the Grandi et al. model of the human ventricular action potential is utilized, and after the Na+ and Ca2+ currents in a single myocyte are modified based on the experimental literature, early after-depolarization (EAD) rhythm disturbances appear, and important elements of the underlying causes of these EADs are revealed/illustrated. Our modified mathematical model of the human ventricular action potential also provides a convenient digital platform for designing future experimental work and relating these changes in cellular cardiac electrophysiology to emerging clinical and epidemiological data on CO toxicity.In Valencia, this work was supported by: (i) VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica from the Ministerio de Economia y Competitividad of Spain (TIN2012-37546-0O3-01) and the European Commission (European Regional Development Funds-ERDF-FEDER)., (ii) Plan Avanza en el marco de la Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion del Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), (iii) Programa deApoyo a la Investigacion y Desarrollo (PAID-06-11-2002) de la Universitat Politecnica de Valencia, (iv) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana, and (v) GileadSciences, Ltd. Wayne Giles acknowledges receipt of financial support in the form of a salary award (Medical Scientist) from Alberta Innovates-Health Solutions, and operating funding from the Canadian Institutes for Health Research and the Heart and Stroke Foundation of Alberta.Trénor Gomis, BA.; Cardona-Urrego, KE.; Saiz Rodríguez, FJ.; Rajamani, S.; Belardinelli, L.; Giles, WR. (2013). Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations. Frontiers in Physiology. 4:1-11. https://doi.org/10.3389/fphys.2013.00282S111

A Comparative Study of Vaginal Labor and Caesarean Section Postpartum Uterine Myoelectrical Activity

[EN] Postpartum hemorrhage (PPH) is one of the major causes of maternal mortality and morbidity worldwide, with uterine atony being the most common origin. Currently there are no obstetrical techniques available for monitoring postpartum uterine dynamics, as tocodynamometry is not able to detect weak uterine contractions. In this study, we explored the feasibility of monitoring postpartum uterine activity by non-invasive electrohysterography (EHG), which has been proven to outperform tocodynamometry in detecting uterine contractions during pregnancy. A comparison was made of the temporal, spectral, and non-linear parameters of postpartum EHG characteristics of vaginal deliveries and elective cesareans. In the vaginal delivery group, EHG obtained a significantly higher amplitude and lower kurtosis of the Hilbert envelope, and spectral content was shifted toward higher frequencies than in the cesarean group. In the non-linear parameters, higher values were found for the fractal dimension and lower values for Lempel-Ziv, sample entropy and spectral entropy in vaginal deliveries suggesting that the postpartum EHG signal is extremely non-linear but more regular and predictable than in a cesarean. The results obtained indicate that postpartum EHG recording could be a helpful tool for earlier detection of uterine atony and contribute to better management of prophylactic uterotonic treatment for PPH prevention.This work was supported by the Spanish Ministry of Economy and Competitiveness, the European Regional Development Fund (MCIU/AEI/FEDER, UE RTI2018-094449-A-I00-AR) and the Generalitat Valenciana (GV/2018/104 and AICO/2019/220).Díaz-Martínez, MDA.; Mas-Cabo, J.; Prats-Boluda, G.; Garcia-Casado, J.; Cardona-Urrego, K.; Monfort-Ortiz, R.; Lopez-Corral, A.... (2020). A Comparative Study of Vaginal Labor and Caesarean Section Postpartum Uterine Myoelectrical Activity. Sensors. 20(11):1-14. https://doi.org/10.3390/s20113023S1142011Ngwenya, S. (2016). Postpartum hemorrhage: incidence, risk factors, and outcomes in a low-resource setting. International Journal of Women’s Health, Volume 8, 647-650. doi:10.2147/ijwh.s119232Carroli, G., Cuesta, C., Abalos, E., & Gulmezoglu, A. M. (2008). Epidemiology of postpartum haemorrhage: a systematic review. Best Practice & Research Clinical Obstetrics & Gynaecology, 22(6), 999-1012. doi:10.1016/j.bpobgyn.2008.08.004Souza, J. P., Gülmezoglu, A. M., Carroli, G., Lumbiganon, P., & Qureshi, Z. (2011). The world health organization multicountry survey on maternal and newborn health: study protocol. BMC Health Services Research, 11(1). doi:10.1186/1472-6963-11-286Knight, M., Callaghan, W. M., Berg, C., Alexander, S., Bouvier-Colle, M.-H., Ford, J. B., … Walker, J. (2009). Trends in postpartum hemorrhage in high resource countries: a review and recommendations from the International Postpartum Hemorrhage Collaborative Group. BMC Pregnancy and Childbirth, 9(1). doi:10.1186/1471-2393-9-55Callaghan, W. M., Kuklina, E. V., & Berg, C. J. (2010). Trends in postpartum hemorrhage: United States, 1994–2006. American Journal of Obstetrics and Gynecology, 202(4), 353.e1-353.e6. doi:10.1016/j.ajog.2010.01.011Marshall, A. L., Durani, U., Bartley, A., Hagen, C. E., Ashrani, A., Rose, C., … Pruthi, R. K. (2017). The impact of postpartum hemorrhage on hospital length of stay and inpatient mortality: a National Inpatient Sample–based analysis. American Journal of Obstetrics and Gynecology, 217(3), 344.e1-344.e6. doi:10.1016/j.ajog.2017.05.004Prick, B. W., Duvekot, J. J., van der Moer, P. E., van Gemund, N., van der Salm, P. C. M., Jansen, A. J. G., … Uyl-de Groot, C. A. (2014). Cost-effectiveness of red blood cell transfusion vs. non-intervention in women with acute anaemia after postpartum haemorrhage. Vox Sanguinis, 107(4), 381-388. doi:10.1111/vox.12181Castiel, D., Bréchat, P.-H., Benoît, B., Nguon, B., Gayat, E., Soyer, P., … Barranger, E. (2008). Coût total des actes chirurgicaux dans la prise en charge des hémorragies de la délivrance. Gynécologie Obstétrique & Fertilité, 36(5), 507-515. doi:10.1016/j.gyobfe.2008.03.009Fukami, T., Koga, H., Goto, M., Ando, M., Matsuoka, S., Tohyama, A., … Tsujioka, H. (2019). Incidence and risk factors for postpartum hemorrhage among transvaginal deliveries at a tertiary perinatal medical facility in Japan. PLOS ONE, 14(1), e0208873. doi:10.1371/journal.pone.0208873Vogel, J. P., Williams, M., Gallos, I., Althabe, F., & Oladapo, O. T. (2019). WHO recommendations on uterotonics for postpartum haemorrhage prevention: what works, and which one? BMJ Global Health, 4(2), e001466. doi:10.1136/bmjgh-2019-001466Lutomski, J., Byrne, B., Devane, D., & Greene, R. (2012). Increasing trends in atonic postpartum haemorrhage in Ireland: an 11-year population-based cohort study. BJOG: An International Journal of Obstetrics & Gynaecology, 119(9), 1150-1151. doi:10.1111/j.1471-0528.2012.03370.xWilmink, F. A., Wilms, F. F., Heydanus, R., Mol, B. W. J., & Papatsonis, D. N. M. (2008). Fetal complications after placement of an intrauterine pressure catheter: A report of two cases and review of the literature. The Journal of Maternal-Fetal & Neonatal Medicine, 21(12), 880-883. doi:10.1080/14767050802220508Hadar, E., Biron-Shental, T., Gavish, O., Raban, O., & Yogev, Y. (2014). A comparison between electrical uterine monitor, tocodynamometer and intra uterine pressure catheter for uterine activity in labor. The Journal of Maternal-Fetal & Neonatal Medicine, 28(12), 1367-1374. doi:10.3109/14767058.2014.954539Alberola-Rubio, J., Prats-Boluda, G., Ye-Lin, Y., Valero, J., Perales, A., & Garcia-Casado, J. (2013). Comparison of non-invasive electrohysterographic recording techniques for monitoring uterine dynamics. Medical Engineering & Physics, 35(12), 1736-1743. doi:10.1016/j.medengphy.2013.07.008Euliano, T. Y., Nguyen, M. T., Darmanjian, S., McGorray, S. P., Euliano, N., Onkala, A., & Gregg, A. R. (2013). Monitoring uterine activity during labor: a comparison of 3 methods. American Journal of Obstetrics and Gynecology, 208(1), 66.e1-66.e6. doi:10.1016/j.ajog.2012.10.873Euliano, T. Y., Nguyen, M. T., Marossero, D., & Edwards, R. K. (2007). Monitoring Contractions in Obese Parturients. Obstetrics & Gynecology, 109(5), 1136-1140. doi:10.1097/01.aog.0000258799.24496.93Benalcazar Parra, C., Tendero, A. I., Ye-Lin, Y., Alberola-Rubio, J., Perales Marin, A., Garcia-Casado, J., & Prats-Boluda, G. (2018). Feasibility of Labor Induction Success Prediction based on Uterine Myoelectric Activity Spectral Analysis. Proceedings of the 11th International Joint Conference on Biomedical Engineering Systems and Technologies. doi:10.5220/0006649400700077Euliano, T., Skowronski, M., Marossero, D., Shuster, J., & Edwards, R. (2006). Prediction of intrauterine pressure waveform from transabdominal electrohysterography. The Journal of Maternal-Fetal & Neonatal Medicine, 19(12), 803-808. doi:10.1080/14767050601023657Benalcazar-Parra, C., Garcia-Casado, J., Ye-Lin, Y., Alberola-Rubio, J., Lopez, Á., Perales-Marin, A., & Prats-Boluda, G. (2019). New electrohysterogram-based estimators of intrauterine pressure signal, tonus and contraction peak for non-invasive labor monitoring. Physiological Measurement, 40(8), 085003. doi:10.1088/1361-6579/ab37dbRooijakkers, M. J., Rabotti, C., Oei, S. G., Aarts, R. M., & Mischi, M. (2014). Low-complexity intrauterine pressure estimation using the Teager energy operator on electrohysterographic recordings. Physiological Measurement, 35(7), 1215-1228. doi:10.1088/0967-3334/35/7/1215Schlembach, D., Maner, W. L., Garfield, R. E., & Maul, H. (2009). Monitoring the progress of pregnancy and labor using electromyography. European Journal of Obstetrics & Gynecology and Reproductive Biology, 144, S33-S39. doi:10.1016/j.ejogrb.2009.02.016Fele-Žorž, G., Kavšek, G., Novak-Antolič, Ž., & Jager, F. (2008). A comparison of various linear and non-linear signal processing techniques to separate uterine EMG records of term and pre-term delivery groups. Medical & Biological Engineering & Computing, 46(9), 911-922. doi:10.1007/s11517-008-0350-yHassan, M., Terrien, J., Marque, C., & Karlsson, B. (2011). Comparison between approximate entropy, correntropy and time reversibility: Application to uterine electromyogram signals. Medical Engineering & Physics, 33(8), 980-986. doi:10.1016/j.medengphy.2011.03.010Mas-Cabo, J., Prats-Boluda, G., Perales, A., Garcia-Casado, J., Alberola-Rubio, J., & Ye-Lin, Y. (2018). Uterine electromyography for discrimination of labor imminence in women with threatened preterm labor under tocolytic treatment. Medical & Biological Engineering & Computing, 57(2), 401-411. doi:10.1007/s11517-018-1888-yLemancewicz, A., Borowska, M., Kuć, P., Jasińska, E., Laudański, P., Laudański, T., & Oczeretko, E. (2016). Early diagnosis of threatened premature labor by electrohysterographic recordings – The use of digital signal processing. Biocybernetics and Biomedical Engineering, 36(1), 302-307. doi:10.1016/j.bbe.2015.11.005Mas-Cabo, J., Prats-Boluda, G., Garcia-Casado, J., Alberola-Rubio, J., Perales, A., & Ye-Lin, Y. (2019). Design and Assessment of a Robust and Generalizable ANN-Based Classifier for the Prediction of Premature Birth by means of Multichannel Electrohysterographic Records. Journal of Sensors, 2019, 1-13. doi:10.1155/2019/5373810Acharya, U. R., Sudarshan, V. K., Rong, S. Q., Tan, Z., Lim, C. M., Koh, J. E., … Bhandary, S. V. (2017). Automated detection of premature delivery using empirical mode and wavelet packet decomposition techniques with uterine electromyogram signals. Computers in Biology and Medicine, 85, 33-42. doi:10.1016/j.compbiomed.2017.04.013Fergus, P., Cheung, P., Hussain, A., Al-Jumeily, D., Dobbins, C., & Iram, S. (2013). Prediction of Preterm Deliveries from EHG Signals Using Machine Learning. PLoS ONE, 8(10), e77154. doi:10.1371/journal.pone.0077154Ren, P., Yao, S., Li, J., Valdes-Sosa, P. A., & Kendrick, K. M. (2015). Improved Prediction of Preterm Delivery Using Empirical Mode Decomposition Analysis of Uterine Electromyography Signals. PLOS ONE, 10(7), e0132116. doi:10.1371/journal.pone.0132116Benalcazar-Parra, C., Ye-Lin, Y., Garcia-Casado, J., Monfort-Ortiz, R., Alberola-Rubio, J., Perales, A., & Prats-Boluda, G. (2019). Prediction of Labor Induction Success from the Uterine Electrohysterogram. Journal of Sensors, 2019, 1-12. doi:10.1155/2019/6916251Sammali, F., Kuijsters, N. P. M., Schoot, B. C., Mischi, M., & Rabotti, C. (2018). Feasibility of Transabdominal Electrohysterography for Analysis of Uterine Activity in Nonpregnant Women. Reproductive Sciences, 25(7), 1124-1133. doi:10.1177/1933719118768700Ye-Lin, Y., Bueno-Barrachina, J. M., Prats-boluda, G., Rodriguez de Sanabria, R., & Garcia-Casado, J. (2017). Wireless sensor node for non-invasive high precision electrocardiographic signal acquisition based on a multi-ring electrode. Measurement, 97, 195-202. doi:10.1016/j.measurement.2016.11.009Maul, H., Maner, W., Olson, G., Saade, G., & Garfield, R. (2004). Non-invasive transabdominal uterine electromyography correlates with the strength of intrauterine pressure and is predictive of labor and delivery. The Journal of Maternal-Fetal & Neonatal Medicine, 15(5), 297-301. doi:10.1080/14767050410001695301Shukla, S., Singh, S. K., & Mitra, D. (2020). An efficient heart sound segmentation approach using kurtosis and zero frequency filter features. Biomedical Signal Processing and Control, 57, 101762. doi:10.1016/j.bspc.2019.101762Ye-Lin, Y., Alberola-Rubio, J., Prats-boluda, G., Perales, A., Desantes, D., & Garcia-Casado, J. (2014). Feasibility and Analysis of Bipolar Concentric Recording of Electrohysterogram with Flexible Active Electrode. Annals of Biomedical Engineering, 43(4), 968-976. doi:10.1007/s10439-014-1130-5Vrhovec, J., Macek-Lebar, A., & Rudel, D. (s. f.). Evaluating Uterine Electrohysterogram with Entropy. IFMBE Proceedings, 144-147. doi:10.1007/978-3-540-73044-6_36Zhang, X.-S., Roy, R. J., & Jensen, E. W. (2001). EEG complexity as a measure of depth of anesthesia for patients. IEEE Transactions on Biomedical Engineering, 48(12), 1424-1433. doi:10.1109/10.966601Aboy, M., Hornero, R., Abasolo, D., & Alvarez, D. (2006). Interpretation of the Lempel-Ziv Complexity Measure in the Context of Biomedical Signal Analysis. IEEE Transactions on Biomedical Engineering, 53(11), 2282-2288. doi:10.1109/tbme.2006.883696Katz, M. J. (1988). Fractals and the analysis of waveforms. Computers in Biology and Medicine, 18(3), 145-156. doi:10.1016/0010-4825(88)90041-8De Lau, H., Yang, K. T., Rabotti, C., Vlemminx, M., Bajlekov, G., Mischi, M., & Oei, S. G. (2016). Toward a new modality for detecting a uterine rupture: electrohysterogram propagation analysis during trial of labor after cesarean. The Journal of Maternal-Fetal & Neonatal Medicine, 30(5), 574-579. doi:10.1080/14767058.2016.1178227Benalcazar-Parra, C., Ye-Lin, Y., Garcia-Casado, J., Monfort-Orti, R., Alberola-Rubio, J., Perales, A., & Prats-Boluda, G. (2018). Electrohysterographic characterization of the uterine myoelectrical response to labor induction drugs. Medical Engineering & Physics, 56, 27-35. doi:10.1016/j.medengphy.2018.04.002Garcia-Casado, J., Ye-Lin, Y., Prats-Boluda, G., Mas-Cabo, J., Alberola-Rubio, J., & Perales, A. (2018). Electrohysterography in the diagnosis of preterm birth: a review. Physiological Measurement, 39(2), 02TR01. doi:10.1088/1361-6579/aaad56Fisch, G. S., Cohen, I. L., Jenkins, E. C., & Brown, W. T. (1988). Screening developmentally disabled male populations for fragile X: The effect of sample size. American Journal of Medical Genetics, 30(1-2), 655-663. doi:10.1002/ajmg.1320300166Ye-Lin, Y., Garcia-Casado, J., Prats-Boluda, G., Alberola-Rubio, J., & Perales, A. (2014). Automatic Identification of Motion Artifacts in EHG Recording for Robust Analysis of Uterine Contractions. Computational and Mathematical Methods in Medicine, 2014, 1-11. doi:10.1155/2014/470786Alberola-Rubio, J., Garcia-Casado, J., Prats-Boluda, G., Ye-Lin, Y., Desantes, D., Valero, J., & Perales, A. (2017). Prediction of labor onset type: Spontaneous vs induced; role of electrohysterography? Computer Methods and Programs in Biomedicine, 144, 127-133. doi:10.1016/j.cmpb.2017.03.018Maner, W. L., MacKay, L. B., Saade, G. R., & Garfield, R. E. (2006). Characterization of abdominally acquired uterine electrical signals in humans, using a non-linear analytic method. Medical & Biological Engineering & Computing, 44(1-2), 117-123. doi:10.1007/s11517-005-0011-3Marchini, G., Lagercrantz, H., Winberg, J., & Uvnäs-Moberg, K. (1988). Fetal and maternal plasma levels of gastrin, somatostatin and oxytocin after vaginal delivery and elective cesarean section. Early Human Development, 18(1), 73-79. doi:10.1016/0378-3782(88)90044-8Pickering, K., Gallos, I. D., Williams, H., Price, M. J., Merriel, A., Lissauer, D., … Roberts, T. E. (2018). Uterotonic Drugs for the Prevention of Postpartum Haemorrhage: A Cost-Effectiveness Analysis. PharmacoEconomics - Open, 3(2), 163-176. doi:10.1007/s41669-018-0108-xMorfaw, F., Fundoh, M., Pisoh, C., Ayaba, B., Mbuagbaw, L., Anderson, L. N., & Thabane, L. (2019). Misoprostol as an adjunct to oxytocin can reduce postpartum-haemorrhage: a propensity score–matched retrospective chart review in Bamenda-Cameroon, 2015–2016. BMC Pregnancy and Childbirth, 19(1). doi:10.1186/s12884-019-2407-3Grotegut, C. A., Paglia, M. J., Johnson, L. N. C., Thames, B., & James, A. H. (2011). Oxytocin exposure during labor among women with postpartum hemorrhage secondary to uterine atony. American Journal of Obstetrics and Gynecology, 204(1), 56.e1-56.e6. doi:10.1016/j.ajog.2010.08.023Shen, Y., Oda, T., Tamura, N., Kohmura‐Kobayashi, Y., Furuta‐Isomura, N., Yaguchi, C., … Kanayama, N. (2019). Elevated bradykinin receptor type 1 expression in postpartum acute myometritis: Possible involvement in augmented interstitial edema of the atonic gravid uterus. Journal of Obstetrics and Gynaecology Research, 45(8), 1553-1561. doi:10.1111/jog.1401

Congreso Internacional de Responsabilidad Social Apuestas para el desarrollo regional.

Congreso Internacional de Responsabilidad Social: apuestas para el desarrollo regional [Edición 1 / Nov. 6 - 7: 2019 Bogotá D.C.]El Congreso Internacional de Responsabilidad Social “Apuestas para el Desarrollo Regional”, se llevó a cabo los días 6 y 7 de noviembre de 2019 en la ciudad de Bogotá D.C. como un evento académico e investigativo liderado por la Corporación Universitaria Minuto de Dios -UNIMINUTO – Rectoría Cundinamarca cuya pretensión fue el fomento de nuevos paradigmas, la divulgación de conocimiento renovado en torno a la Responsabilidad Social; finalidad adoptada institucionalmente como postura ética y política que impacta la docencia, la investigación y la proyección social, y cuyo propósito central es la promoción de una “sensibilización consciente y crítica ante las situaciones problemáticas, tanto de las comunidades como del país, al igual que la adquisición de unas competencias orientadas a la promoción y al compromiso con el desarrollo humano y social integral”. (UNIMINUTO, 2014). Dicha postura, de conciencia crítica y sensibilización social, sumada a la experiencia adquirida mediante el trabajo articulado con otras instituciones de índole académico y de forma directa con las comunidades, permitió establecer como objetivo central del evento la reflexión de los diferentes grupos de interés, la gestión de sus impactos como elementos puntuales que contribuyeron en la audiencia a la toma de conciencia frente al papel que se debe asumir a favor de la responsabilidad social como aporte seguro al desarrollo regional y a su vez al fortalecimiento de los Objetivos de Desarrollo Sostenible

Congreso Internacional de Responsabilidad Social Apuestas para el desarrollo regional.

Congreso Internacional de Responsabilidad Social: apuestas para el desarrollo regional [Edición 1 / Nov. 6 - 7: 2019 Bogotá D.C.]El Congreso Internacional de Responsabilidad Social “Apuestas para el Desarrollo Regional”, se llevó a cabo los días 6 y 7 de noviembre de 2019 en la ciudad de Bogotá D.C. como un evento académico e investigativo liderado por la Corporación Universitaria Minuto de Dios -UNIMINUTO – Rectoría Cundinamarca cuya pretensión fue el fomento de nuevos paradigmas, la divulgación de conocimiento renovado en torno a la Responsabilidad Social; finalidad adoptada institucionalmente como postura ética y política que impacta la docencia, la investigación y la proyección social, y cuyo propósito central es la promoción de una “sensibilización consciente y crítica ante las situaciones problemáticas, tanto de las comunidades como del país, al igual que la adquisición de unas competencias orientadas a la promoción y al compromiso con el desarrollo humano y social integral”. (UNIMINUTO, 2014). Dicha postura, de conciencia crítica y sensibilización social, sumada a la experiencia adquirida mediante el trabajo articulado con otras instituciones de índole académico y de forma directa con las comunidades, permitió establecer como objetivo central del evento la reflexión de los diferentes grupos de interés, la gestión de sus impactos como elementos puntuales que contribuyeron en la audiencia a la toma de conciencia frente al papel que se debe asumir a favor de la responsabilidad social como aporte seguro al desarrollo regional y a su vez al fortalecimiento de los Objetivos de Desarrollo Sostenible

El Centro Infantil “Estrellitas de Niquitao” de la Fundación de Atención a la Niñez (FAN) como ambiente potenciador de los lenguajes expresivos de los niños y las niñas de 4 a 5 años

The purpose of this degree project was to present how the "Estrellitas de Niquitao" Children's Learning Center promotes the expressive languages of the children from 4 to 5 years old who attend there, through observation, identification and systematization of different aspects such as physical space, human relations and pedagogical strategies used by educational agents. The methodology used for the development of this research was of a qualitative nature, from a hermeneutic approach, since it allows to interpret reality at a specific time and under an exact event; In this sense, 4 techniques were used for the collection of information (interview, info-photography, and participant observation), which allowed explaining why the learning environment of the children's center is significant and favors the expression of boys and girls through different expressive languages. This is how in the course of this research it was possible to deepen into concepts such as Children's Center, development of children from 4 to 5 years old, learning environments and expressive languages, themes that support from the theoretical, analyzed and systematized in the conclusions and resultsEste trabajo de grado tuvo como finalidad develar cómo el ambiente de aprendizaje del Centro Infantil “Estrellitas de Niquitao” potencia los lenguajes expresivos de los niños y las niñas de 4 a 5 años que allí asisten, a través de la observación, la identificación y sistematización de diferentes aspectos como el espacio físico, las relaciones humanas y las estrategias pedagógicas utilizadas por las agentes educativas. La metodología utilizada para el desarrollo de esta investigación fue de carácter cualitativo, desde un enfoque hermenéutico, ya que este permite interpretar la realidad en un tiempo específico y bajo un suceso exacto; en este sentido se utilizaron 4 técnicas para la recolección de información (entrevista, fotografía info-fotografía y observación participante), las cuales permitieron explicar por qué el ambiente de aprendizaje del Centro Infantil es significativo y favorece la expresión de los niños y las niñas a través de diferentes lenguajes expresivos. Es así como en el transcurso de esta investigación se logró profundizar en conceptos como Centro Infantil, desarrollo de los niños y niñas de 4 a 5 años, ambientes de aprendizaje y lenguajes expresivos, temáticas que sustentan desde lo teórico, lo analizado y sistematizado en las conclusiones y resultado

Incursion process of silver telecom sas to the market of construction of optical fiber networks in Florida - United States

Esta investigación tiene como propósito el estudio del proceso de internacionalización en la Florida por parte de Silver Telecom, que está en el sector de las telecomunicaciones como un fabricante de soluciones para las telecomunicaciones. Esto es relevante por la naturaleza única de Silver Telecom, que es la única compañía en Colombia que diseña, desarrolla, fabrica y comercializa soluciones para redes activas y pasivas de fibra óptica. Silver Telecom ha entrado en otros mercados en Latino América como Perú o Bolivia, pero nunca en un país como Estados Unidos o un estado como Florida.This investigation has as a purpose the study of the internationalization process in Florida as performed by Silver Telecom SAS, which is in the telecommunications sector as a manufacturer of telecommunication solutions. This is relevant due to Silver’s unique nature, as it is the only company in Colombia that designs, develops, manufactures and commercializes solutions for active and passive fiber optic networks. Silver has also gained entry to other Latin American markets such as Peru or Bolivia, but never in a country like the United States, in a state like Florida.Especialista en Administración Financier

Reverberate: Art and Event

Libro resultado de investigación, de la convocatoria Invitación a presentar proyectos de Investigación-Creación en Artes InvestigARTE 2019. Línea temática de Artes Visuales del Programa Nacional de Ciencia, Tecnología e Innovación en Ciencias Humanas, Sociales y Educación del Ministerio de Ciencia, Tecnología e Innovación, MinCiencias, República de Colombia. Este libro reúne una serie de escritos, producto de los encuentros del Colectivo Reverberar que se llevaron a cabo durante los años 2020 y 2021 en modalidad virtual, en el marco del proyecto de Investigación-creación Reverberar: Arte y Acontecimiento (2020-2022). La distribución de los mismos responde a cuatro grandes temáticas, o sensaciones, que suscitaron la lectura de los textos ante la tarea de encontrar una narrativa que permitiera contar la experiencia del Colectivo para llevar a cabo sus procesos creativos e investigativos en torno al acontecimiento, el cuerpo, el arte y la performance; en medio de una situación de pandemia de orden mundial y de protesta social nacional.Book resulting from research, from the call Invitation to present Research-Creation projects in the Arts InvestigARTE 2019. Thematic line of Visual Arts of the National Program for Science, Technology and Innovation in Human, Social and Education Sciences of the Ministry of Science, Technology and Innovation , Ministry of Science, Republic of Colombia. This book brings together a series of writings, the product of the meetings of the Reverberar Collective that took place during the years 2020 and 2021 in virtual mode, within the framework of the Research-creation project Reverberar: Art and Event (2020-2022). Their distribution responds to four major themes, or sensations, that aroused the reading of the texts before the task of finding a narrative that would allow telling the experience of the Collective to carry out its creative and investigative processes around the event, the body, art and performance; in the midst of a global order pandemic situation and national social protest.Bogot