Bifurcations and Slow-Fast Analysis in a Cardiac Cell Model for Investigation of Early Afterdepolarizations

In this study, we teased out the dynamical mechanisms underlying the generation of arrhythmogenic early afterdepolarizations (EADs) in a three-variable model of a mammalian ventricular cell. Based on recently published studies, we consider a 1-fast, 2-slow variable decomposition of the system describing the cellular action potential. We use sweeping techniques, such as the spike-counting method, and bifurcation and continuation methods to identify parametric regions with EADs. We show the existence of isolas of periodic orbits organizing the different EAD patterns and we provide a preliminary classification of our fast-slow decomposition according to the involved dynamical phenomena. This investigation represents a basis for further studies into the organization of EAD patterns in the parameter space and the involved bifurcations

Controls on space–time distribution of soft-sediment deformation structures: Applying palaeomagnetic dating to approach the apparent recurrence period of paleoseisms at the Concud Fault (eastern Spain)

This work describes soft-sediment deformation structures (clastic dykes, load structures, diapirs, slumps, nodulizations or mudcracks) identified in three sections (Concud, Ramblillas and Masada Cociero) in the Iberian Range, Spain. These sections were logged from boreholes and outcrops in Upper Pliocene-Lower Pleistocene deposits of the Teruel-Concud Residual Basin, close to de Concud normal fault. Timing of the succession and hence of seismic and non-seismic SSDSs, covering a time span between ~ 3.6 and ~ 1.9 Ma, has been constrained from previous biostratigraphic and magnetostratigraphic information, then substantially refined from a new magnetostratigraphic study at Masada Cociero profile. Non-seismic SSDSs are relatively well-correlated between sections, while seismic ones are poorly correlated except for several clusters of structures. Between 29 and 35 seismic deformed levels have been computed for the overall stratigraphic succession. Factors controlling the lateral and vertical distribution of SSDSs are their seismic or non-seismic origin, the distance to the seismogenic source (Concud Fault), the sedimentary facies involved in deformation and the observation conditions (borehole core vs. natural outcrop). In the overall stratigraphic section, seismites show an apparent recurrence period of 56 to 108 ka. Clustering of seismic SSDSs levels within a 91-ka-long interval records a period of high paleoseismic activity with an apparent recurrence time of 4.8 to 6.1 ka, associated with increasing sedimentation rate and fault activity. Such activity pattern of the Concud Fault for the Late Pliocene-Early Pliocene, with alternating periods of faster and slower slip, is similar to that for the most recent Quaternary (last ca. 74 ka BP). Concerning the research methods, time occurrence patterns recognized for peaks of paleoseismic activity from SSDSs in boreholes are similar to those inferred from primary evidence in trenches. Consequently, apparent recurrence periods calculated from SSDS inventories collected in borehole logs close to seismogenic faults are comparable to actual recurrence times of large paleoearthquakes

Cinemática rotacional del cabalgamiento basal surpirenaico en las Sierras Exteriores Aragonesas: Datos magnetotectónicos

The magnetotectonic analysis of 32 sites located along the External Sierras (mainly in Middle Eocene marls) shows the primary character of the magnetisation and pennits the differences between the paleovectors obtained to be interpreted as a result of the rotational kinematics of the southpyrenean floor thrust in the study area. The constancy of the directions of the defined unblocking intervals (300"-425°C for the thermal treatment) and the homogeneity of the magnetic carriers (these were always low coercitivity phases, probably sulphides andlor magnetite) prove the stability of the magnetisation. On the other hand, the primary character of the magnetisation (Middle Eocene) can be demonstrated by: a) the constancy of the magnetic inclination (47.3 +/- 1.7) and its similarity with the reference direction; b) the occurrence of reversals, and the positive result of the fold-test made in the Pico del Águila anticline; c) the consistency between the reference direction (DEC = 005", INC = 51°, a95=6 ") and the direction obtained for the authocthonous footwall (DEC = 005", INC = 38", a95= 8") which crops out in the western sector of the Sierras Exteriores thrust front. The interpretation of the paleomagnetic data within the External Sierras structural framework clearly shows that the kinematics of individual thrust sheets involves a clockwise component, at least during a period of their evolution. The maximum rotation values were found in the western and central sectors (42" and 30" respectively). The age of the rotation decreases towards the west along with the age of deformation of the cover rocks. Starting in late Priabonian the kinematics of the thrust front resulted in a lack of rotation in the central sector of the Sierras, while the western sector undenvent a clockwise rotation. The differential movement between both sectors gave rise to the development or reactivation of structures (i. e. Rasal-Anzáñigo anticlines) that articulated the deformation of adjacent zones with different rotational components

Remagnetización alpina en la Serra del Cadí (Pirineo Oriental)

The eastern Pyrenees, particularly the Cadi Range, displays the less density and quality of paleomagnetic data of the chain. This paper revisited one of the central sections (Pobla de Lillet) where we have resampled Permian, Maastrichtian and Paleocene rocks. Best results were attained in the Permian red sandstones and in the Cretaceous limestones. In the Permian, two components with paleomagnetic meaning were identified. The high temperature component (up to 670 ° C) is similar to that defined in pioneering works, it appears to be primary and does not show significant rotations. The intermediate temperature component (up to 500 ° C), not identified in previous works, seems to be a syntectonic remagnetization with Alpine age. The characterization of rotations and the extension of this remagnetization (as an additional source of kinematics information) should be addressed in Permian rocks in future works since the paleomagnetic signal of Cenozoic rocks is of lower qualityTrabajo financiado con los Proyectos Pmag3Drest-CGL2009-14214 y DR3AM- CGL2014-55118 del MINECO y del 3DR3- PI165/09 del Gobierno de Aragón.Peer Reviewe

Bilateral Internuclear Ophthalmoplegia in a Patient with Devic's Neuromyelitis Optica

An unusual presentation of Devic's neuromyelitis optica (NMO) disease associated with bilateral internuclear ophthalmoplegia (INO) is described. A 32-year-old pregnant patient was diagnosed with NMO. First symptoms were headache and sudden visual loss in her right eye (RE). Eighteen months ago, she reported other neurologic symptoms such as paresthesia. Based on her visual field, fundoscopy and Ishihara test, she was diagnosed with retrobulbar neuritis of the RE. After delivery, new neurologic symptoms resembling transverse myelitis appeared. She was treated with methylprednisolone and plasmapheresis, which improved her visual acuity; however, a sudden bilateral INO appeared, with adduction defect and nystagmus with abduction in both eyes. No improvement was obtained after treatment with azathioprine and rituximab. Paresis of the legs and the right arm persisted, but double vision and OIN gradually disappeared. At the end, the patient had a residual exophoria in the RE and nystagmus with abduction in the left eye. Prevalence of NMO is lower than one case per one million inhabitants, and it is not likely to affect the encephalic trunk; furthermore, bilateral INO in NMO is rare. Two major criteria and at least two of the three minor ones are required to confirm a NMO diagnosis, and our patient fulfilled these diagnosis criteria

Datación magnetostratigráfica de la molasa Surpirenaica (Fm Uncastillo, Oligoceno-Mioceno)

The Uncastillo Fm crops out along the southern boundary of the External Sierras, which represents the southernmost limit of the Pyrenean Range. Three tectosedimentary units related to tectonic pulses have been previously differentiated in this formation. The sedimentary evolution of the Uncastillo Fm is mainly related to the tightening of the WNW-ESE Santo Domingo anticline in the External Sierras during Chattian-Aquitanian times and records the younger tectonic movement of the south Pyrenean sole thrust. The Uncastillo Fm represents the change to overall southwardflowing alluvial and fluvial systems from overall west-northwest-flowing fluvial systems (Campodarbe Fm). Recent magnetostratigraphic results from the underlying Campodarbe Fm shift to younger ages (from chron 10r to 7r) the top of the Campodarbe Fm in the proximal area of the fluvial system (Luesia fan). In order to check that reassignment and refine the age of the Uncastillo Fm, a new magnetostratigraphic study has been conducted in laterally equivalent deposits that represent middle-distal areas located to the east of the Luesia fan. These deposits consist of mudstones with interbedded sandstones. These finer grain size sediments allow for a magnetostratigraphic sampling in the Fuencalderas section of ~1300 m, which complete the chronostratigraphic frame of the last tectonic pulses of the Pyrenean Range.Trabajo financiado por los proyectos SEROS (CGL 2014-55900-PL), DR3AM (CGL2015- CGL2014-55118) y Grupos Geotransfer y Análisis de Cuencas de la Universidad de Zaragoza. Es una contribución del Institut de Recerca Geomodels y del Grup de Geodinàmica i Anàlisi de Conques (2014SGR467).Peer Reviewe

Electrocardiographic biomarkers for detection of drug-induced late sodium current block

Background Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Thus, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the ''CiPA'' initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans. Methods and Results In this study we assess the ability of eight ECG morphology biomarkers to detect late sodium current block in the presence of QTc prolongation by analyzing a clinical trial where a selective hERG potassium channel blocker (dofetilide) was administered alone and then in combination with two late sodium current blockers (lidocaine and mexiletine). We demonstrate that late sodium current block has the greatest effect on the heart-rate corrected JTpeak interval (J-Tpeakc), followed by QTc and then T-wave flatness. Furthermore, J-Tpeakc is the only biomarker that improves detection of the presence of late sodium current block compared to using QTc alone (AUC: 0.83 vs. 0.72 respectively, p<0.001). Conclusions Analysis of the J-Tpeakc interval can differentiate drug-induced multichannel block involving the late sodium current from selective hERG potassium channel block. Future methodologies assessing drug effects on cardiac ion channel currents on the ECG should use J-Tpeakc to detect the presence of late sodium current block

Sex differences in drug-induced changes in ventricular repolarization

Introduction: Heart rate corrected QT (QTc) interval prolongation is a predictor of drug-induced torsade de pointes, a potentially fatal ventricular arrhythmia that disproportionately affects women. This study assesses whether there are sex differences in the ECG changes induced by four different hERG potassium channel blocking drugs. Methods and results: Twenty-two healthy subjects (11 women) received a single oral dose of dofetilide, quinidine, ranolazine, verapamil and placebo in a double-blind 5-period crossover study. ECGs and plasma drug concentrations were obtained at pre-dose and at 15 time-points post-dose. Dofetilide, quinidine and ranolazine prolonged QTc. There were no sex differences in QTc prolongation for any drug, after accounting for differences in exposure. Sex differences in any ECG biomarker were observed only with dofetilide, which caused greater J-Tpeakc prolongation (p=0.045) but lesser Tpeak-Tend prolongation (p=0.006) and lesser decrease of T wave amplitude (p=0.003) in women compared to men. Conclusions: There were no sex differences in QTc prolongation for any of the studied drugs. Moreover, no systematic sex differences in other drug-induced ECG biomarker changes were observed in this study. This study suggests that the higher torsade risk in women compared to men is not due to a larger concentration-dependent QTc prolongation