Electrical and network neuronal properties are preferentially disrupted in dorsal, but not ventral, medial entorhinal cortex in a mouse model of Tauopathy

The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal-ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC-SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30-80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia. SIGNIFICANCE STATEMENT: The medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia

The Einstein-Vlasov sytem/Kinetic theory

The main purpose of this article is to guide the reader to theorems on global properties of solutions to the Einstein-Vlasov system. This system couples Einstein's equations to a kinetic matter model. Kinetic theory has been an important field of research during several decades where the main focus has been on nonrelativistic- and special relativistic physics, e.g. to model the dynamics of neutral gases, plasmas and Newtonian self-gravitating systems. In 1990 Rendall and Rein initiated a mathematical study of the Einstein-Vlasov system. Since then many theorems on global properties of solutions to this system have been established. The Vlasov equation describes matter phenomenologically and it should be stressed that most of the theorems presented in this article are not presently known for other such matter models (e.g. fluid models). The first part of this paper gives an introduction to kinetic theory in non-curved spacetimes and then the Einstein-Vlasov system is introduced. We believe that a good understanding of kinetic theory in non-curved spacetimes is fundamental in order to get a good comprehension of kinetic theory in general relativity.Comment: 31 pages. This article has been submitted to Living Rev. Relativity (http://www.livingreviews.org

The role of experience in echocardiographic identification of location and extent of mitral valve prolapse with 2D and 3D echocardiography

Contradiction exists on the incremental value of two-dimensional (2D) and 3D transoesophageal echocardiography (TOE) over 2D transthoracic echocardiography (TTE) for the detection of mitral valve (MV) prolapse in readers with different echocardiographic experience. Twenty patients and five healthy persons were retrospectively identified who had undergone 2D-TTE, 2D-TOE and 3D-TOE. Fifteen (75 %) patients had surgical evidence of prolapse of the posterior MV leaflet and five patients (25 %) had a dilated MV annulus without prolapse. Three reader groups with different echocardiographic expertise (novice, trainees, cardiologists) scored thus in total 675 posterior scallops. Overall there was an improvement in agreement and Kappa values from novice to trainees to cardiologists. Diagnostic accuracies of 2D-TOE were higher than those of 2D-TTE mainly in novice readers. The incremental value of 3D-TOE over 2D-TOE was mainly seen in specificities. Time to diagnosis was dramatically reduced from 2D to 3D-TEE in all reader groups (all P < 0.001). 3D-TOE also improved the agreement (+12 to +16 %) and Kappa values (+0.14 to +0.21) in all reader groups for the exact description of P2 prolapse. Differences between readers with variable experience in determining the precise localization and extent of the prolapsing posterior MV scallops exist in particular in 2D-TTE analysis. 3D-TOE analysis was extremely fast compared to the 2D analysis methods and showed the best diagnostic accuracy (mainly driven by specificity) with identification of P1 and P3 prolapse still improving from novice to trainees to cardiologists and provided optimal description of P2 prolapse extent

Hemodynamic deterioration precedes onset of ventricular tachyarrhythmia after Heartmate II implantation

Background: Early postoperative ventricular tachyarrhythmia (PoVT) after left ventricular assist device (LVAD) implantation are common and associated with higher mortality-rates. At present, there is no data on initiation of these PoVT and the role of alterations in cardiac hemodynamics. Case Presentation: A LVAD was implanted in a patient with end-stage heart failure due to a ischemic cardiomyopathy. Alterations in cardiac rhythm and hemodynamics preceding PoVT-episodes during the first five postoperative days were examined by using continuous recordings of cardiac rhythm and various hemodynamic parameters. All PoVT (N=120) were monomorphic, most often preceded by short-long-short-sequences or regular SR and initiated by ventricular runs. Prior to PoVT, mean arterial pressure decreased; heart rate and ST-segments deviations increased. Conclusions: PoVT are caused by different underlying electrophysiological mechanisms. Yet, they are all monomorphic and preceded by hemodynamic deterioration due to myocardial ischemia

QUest for the Arrhythmogenic Substrate of Atrial fibRillation in Patients Undergoing Cardiac Surgery (QUASAR Study): Rationale and Design

The heterogeneous presentation and progression of atrial fibrillation (AF) implicate the existence of different pathophysiological processes. Individualized diagnosis and therapy of the arrhythmogenic substrate underlying AF may be required to improve treatment outcomes. Therefore, this single-center study aims to identify t

Intraoperative inducibility of atrial fibrillation does not predict early postoperative atrial fibrillation

Background--Early postoperative atrial fibrillation (EPoAF) is associated with thromboembolic events, prolonged hospitalization, and development of late PoAF (LPoAF). It is, however, unknown if EPoAF can be predicted by intraoperative AF inducibility. The aims of this study are therefore to explore (1) the value of intraoperative inducibility of AF for development of both EPoAF and LPoAF and (2) the predictive value of de novo EPoAF for recurrence of LPoAF. Methods and Results--Patients (N=496, 75% male) undergoing cardiothoracic surgery for coronary and/or valvular heart disease were included. AF induction was attempted by atrial pacing, before extracorporeal circulation. All patients were on continuous rhythm monitoring until discharge to detect EPoAF. During a follow-up period of 2 years, LPoAF was detected by ECGs and Holter recordings. Sustained AF was inducible in 56% of patients. There was no difference in patients with or without AF before surgery (P=0.159), or between different types of surgery (P=0.687). In patients without a history of AF, incidence of EPoAF and LPoAF was 37% and 2%, respectively. EPoAF recurred in 58% patients with preoperative AF, 53% developed LPoAF. There were no correlations between intraoperative inducibility and EPoAF or LPoAF (P > 0.05). EPoAF was not correlated with LPoAF in patients without a history of AF (P=0.116), in contrast to patients with AF before surgery (P < 0.001). Conclusions--Intraoperative AF inducibility does not predict development of either EPoAF or LPoAF. In patients with AF before surgery, EPoAF is correlated with LPoAF recurrences. This correlation is absent in patients without AF before surgery

Impact of ischemic and valvular heart disease on atrial excitation

Background--The influence of underlying heart disease or presence of atrial fibrillation (AF) on atrial excitation during sinus rhythm (SR) is unknown. We investigated atrial activation patterns and total activation times of the entire atrial epicardial surface during SR in patients with ischemic and/or valvular heart disease with or without AF. Methods and Results--Intraoperative epicardial mapping (N=128/192 electrodes, interelectrode distances: 2 mm) of the right atrium, Bachmann's bundle (BB), left atrioventricular groove, and pulmonary vein area was performed during SR in 253 patients (186 male [74%], age 66±11 years) with ischemic heart disease (N=132, 52%) or ischemic valvular heart disease (N=121, 48%). As expected, SR origin was located at the superior intercaval region of the right atrium in 232 patients (92%). BB activation occurred via 1 wavefront from right-to-left (N=163, 64%), from the central part (N=18, 7%), or via multiple wavefronts (N=72, 28%). Left atrioventricular groove activation occurred via (1) BB: N=108, 43%; (2) pulmonary vein area: N=9, 3%; or (3) BB and pulmonary vein area: N=136, 54%; depending on which route had the shortest interatrial conduction time (P < 0.001). Ischemic valvular heart disease patients more often had central BB activation and left atrioventricular groove activation via pulmonary vein area compared with ischemic heart disease patients (N=16 [13%] versus N=2 [2%]; P=0.009 and N=86 [71%] versus N=59 [45%]; P < 0.001, respectively). Total activation times were longer in patients with AF (AF: 136±20 [92-186] ms; no AF: 114±17 [74-156] ms; P < 0.001), because of prolongation of right atrium (P=0.018) and BB conduction times (P < 0.001). Conclusions--Atrial excitation during SR is affected by underlying heart disease and AF, resulting in alternative routes for BB and left atrioventricular groove activation and prolongation of total activation times. Knowledge of atrial excitation patterns during SR and its electropathological variations, as demonstrated in this study, is essential to further unravel the pathogenesis of AF

Epicardium-derived cells are important for correct development of the Purkinje fibers in the avian heart

During embryonic development, the proepicardial organ (PEO) grows out over the heart surface to form the epicardium. Following epithelial-mesenchymal transformation, epicardium-derived cells (EPDCs) migrate into the heart and contribute to the developing coronary arteries, to the valves, and to the myocardium. The peripheral Purkinje fiber network develops from differentiating cardiomyocytes in the ventricular myocardium. Intrigued by the close spatial relationship between the final destinations of migrating EPDCs and Purkinje fiber differentiation in the avian heart, that is, surrounding the coronary arteries and at subendocardial sites, we investigated whether inhibition of epicardial outgrowth would disturb cardiomyocyte differentiation into Purkinje fibers. To this end, epicardial development was inhibited mechanically with a membrane, or genetically, by suppressing epicardial epithelial-to-mesenchymal transformation with antisense retroviral vectors affecting Ets transcription factor levels (n = 4, HH39-41). In both epicardial inhibition models, we evaluated Purkinje fiber development by EAP-300 immunohistochemistry and found that restraints on EPDC development resulted in morphologically aberrant differentiation of Purkinje fibers. Purkinje fiber hypoplasia was observed both periarterially and at subendocardial positions. Furthermore, the cells were morphologically abnormal and not aligned in orderly Purkinje fibers. We conclude that EPDCs are instrumental in Purkinje fiber differentiation, and we hypothesize that they coo