Disassembly and Mislocalization of AQP4 in Incipient Scar Formation after Experimental Stroke.

There is an urgent need to better understand the mechanisms involved in scar formation in the brain. It is well known that astrocytes are critically engaged in this process. Here, we analyze incipient scar formation one week after a discrete ischemic insult to the cerebral cortex. We show that the infarct border zone is characterized by pronounced changes in the organization and subcellular localization of the major astrocytic protein AQP4. Specifically, there is a loss of AQP4 from astrocytic endfoot membranes that anchor astrocytes to pericapillary basal laminae and a disassembly of the supramolecular AQP4 complexes that normally abound in these membranes. This disassembly may be mechanistically coupled to a downregulation of the newly discovered AQP4 isoform AQP4ex. AQP4 has adhesive properties and is assumed to facilitate astrocyte mobility by permitting rapid volume changes at the leading edges of migrating astrocytes. Thus, the present findings provide new insight in the molecular basis of incipient scar formation.

Cortical thickness, gray-white matter contrast, and intracortical myelin in first-episode schizophrenia patients treated with long-acting paliperidone palmitate versus oral antipsychotics.

This longitudinal study evaluated the cortical thickness, gray-to-white matter contrast (GWC), and frontal lobe intracortical myelin (ICM) volume in first-episode schizophrenia (FES) patients treated with oral antipsychotics (OAP) versus a long-acting injectable antipsychotic, paliperidone palmitate (PP). 2D proton density and inversion recovery images, and 3D T1-weighted MPRAGE images were acquired at 3T from 68 FES patients in a randomized clinical trial with PP vs OAP. At baseline, no differences in GWC and ICM were observed between FES patients and HCs, but the thickness of the left precuneus, the right transverse temporal gyrus, and the bilateral superior temporal gyri was found to be thinner in FES patients relative to HCs. Following 9 months of antipsychotics, OAP treatment, compared to PP treatment, resulted in a more widespread cortical thickness reduction including the right lateral occipital and orbitofrontal gyri. No significant ICM and GWC changes were observed in the PP group, whereas OAP treatment led to a significant ICM volume decrease and GWC increase. A negative correlation was found between ICM changes and GWC changes within multiple frontal regions after 9 months of OAP treatment. These preliminary findings suggest that PP treatment might aid preservation of brain morphology.

[Prehospital ultrasound and cardiological emergencies]. / Échographie préhospitalière et urgences cardiologiques.

Technological advances over the past two decades have paved the way for the prehospital use of ultrasound. This practice was first developed in traumatology and then in a multitude of other indications, including cardiology. The development of pulmonary ultrasound is certainly the most visible illustration of this. Firstly, because it is an extra-cardiac examination that provides the answer to a cardiac question. Secondly because from a theoretical point of view this ultrasound indication was a bad indication for the use of ultrasound due to the air contained in the thorax. Thirdly, because this indication has become a 'standard of care' when caring for a patient with dyspnea - a practice that has become widespread during the COVID epidemic. In patients with heart failure, ultrasound has a high diagnostic power (including for alternative diagnoses) which is all the more precise since the technique is non-invasive, the response is obtained quickly, the examination can be repeated at desire to follow the evolution of the patient. The main other indications for prehospital ultrasound are cardiac arrest to search for a curable cause, identification of residual mechanical cardiac activity, monitoring of cerebral perfusion; chest pain, for both positive and negative diagnoses; shock for the search for an etiology and therapeutic follow-up or even pulmonary embolism or ultrasound for the search for dilation of the right ventricle which is now at the forefront of the recommendation algorithm.

Obstructive sleep apnea intensifies stroke severity following middle cerebral artery occlusion.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a sleep disorder caused by transient obstruction of the upper airway and results in intermittent hypoxia, sleep fragmentation, sympathetic nervous system activation, and arousal which can have an adverse effect on cardiovascular disease. It is theorized that OSA might intensify stroke injury. Our goal here was to develop a new model of experimental OSA and test its ability to aggravate behavioral and morphological outcomes following transient brain ischemia/reperfusion. METHODS: We used a 3D printed OSA device to expose C57BL6 mice to 3 h of OSA (obstructive apnea index of 20 events per hour) for three days. These mice were then subjected to ischemia/reperfusion using the middle cerebral artery occlusion model (MCAO) stroke and examined for overall survival, infarct size and neurological scoring. RESULTS: We found that OSA transiently decreased respiration and reduced oxygen saturation with bradycardia and tachycardia typical of human responses during apneic events. Brain injury from MCAO was significantly increased by OSA as measured by infarct size and location as well as by intensification of neurological deficits; mortality following MCAO was also increased in OSA animals. CONCLUSIONS: Our findings suggest that our new model of OSA alters respiratory and cardiovascular physiological functions and is associated with enhanced ischemia/reperfusion mediated injury in our non-invasive, OSA intensified model of stroke.

Insights into Cell Surface Expression, Supramolecular Organization, and Functions of Aquaporin 4 Isoforms in Astrocytes.

Aquaporin 4 (AQP4) is the most abundant water channel in the central nervous system (CNS). Its expression is confined to non-neuronal glial cells, predominantly to astrocytes that represent a heterogeneous glial cell type in the CNS. The membrane of astrocyte processes, which align brain capillaries and pia, is particularly rich in AQP4. Several isoforms of AQP4 have been described; however, only some (AQP4a (M1), AQP4 c (M23), AQP4e, and AQP4ex) have been identified in the plasma membrane assemblies of astrocytes termed orthogonal arrays of particles (OAPs). Intracellular splicing isoforms (AQP4b, AQP4d, AQP4f, AQP4-Δ4) have been documented, and most of them are postulated to have a role in the cell surface distribution of the plasma membrane isoforms and in the formation of OAPs in murine and human astrocytes. Although OAPs have been proposed to play various roles in the functioning of astrocytes and CNS tissue as a whole, many of these still need to be described. OAPs are studied primarily from the perspective of understanding water permeability regulation through the plasma membrane and of their involvement in cell adhesion and in the dynamics of astrocytic processes. This review describes the cellular distribution of various AQP4 isoforms and their implications in OAP assembly, which is regulated by several intracellular and extracellular proteins.

International expert consensus on the management of allergic rhinitis (AR) aggravated by air pollutants: Impact of air pollution on patients with AR: Current knowledge and future strategies.

Allergic rhinitis affects the quality of life of millions of people worldwide. Air pollution not only causes morbidity, but nearly 3 million people per year die from unhealthy indoor air exposure. Furthermore, allergic rhinitis and air pollution interact. This report summarizes the discussion of an International Expert Consensus on the management of allergic rhinitis aggravated by air pollution. The report begins with a review of indoor and outdoor air pollutants followed by epidemiologic evidence showing the impact of air pollution and climate change on the upper airway and allergic rhinitis. Mechanisms, particularly oxidative stress, potentially explaining the interactions between air pollution and allergic rhinitis are discussed. Treatment for the management of allergic rhinitis aggravated by air pollution primarily involves treating allergic rhinitis by guidelines and reducing exposure to pollutants. Fexofenadine a non-sedating oral antihistamine improves AR symptoms aggravated by air pollution. However, more efficacy studies on other pharmacological therapy of coexisting AR and air pollution are currently lacking.

Impact of hyperoxia on patients hospitalized in an intensive care unit for acute heart failure.

BACKGROUND: Oxygen therapy remains a cornerstone of treatment for acute heart failure in patients with pulmonary congestion. While avoiding hypoxaemia has long been a goal of critical care practitioners, less attention has been paid to the potential hazard related to excessive hyperoxia. AIM: To evaluate the impact of early hyperoxia exposure among critically ill patients hospitalized in an intensive care unit for acute heart failure. METHODS: In this preliminary study conducted in a Parisian intensive care unit, we assessed patients with acute heart failure admitted with pulmonary congestion and treated with oxygen therapy from 1 January 2015 to 31 December 2016. The hyperoxia group was defined by having at least one partial pressure of oxygen measurement>100mmHg on the first day following admission to the intensive care unit. The primary endpoint was 30-day all-cause mortality. Secondary endpoints were 30-day unplanned hospital admissions, occurrence of infections and intensive care unit and hospital lengths of stay. RESULTS: Seventy-five patients were included. Forty-three patients (57.3%) presented hyperoxia, whereas 32 patients (42.7%) did not (control group). The baseline clinical characteristics did not differ between the two groups. The primary endpoint was not statistically different between the two groups (14.0% in the hyperoxia group vs 18.8% in the control group; P=0.85). The secondary endpoints were also not significantly different between the two groups. In the multivariable analysis, hyperoxia was not associated with increased 30-day mortality (odds ratio 0.77, 95% confidence interval 0.24-2.41). CONCLUSION: In patients referred to an intensive care unit for acute heart failure, we did not find any difference in outcomes according to the presence of hyperoxia.

Application of optical action potentials in human induced pluripotent stem cells-derived cardiomyocytes to predict drug-induced cardiac arrhythmias.

INTRODUCTION: Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as new and human-relevant source in vitro model for cardiac safety assessment that allow us to investigate a set of 20 reference drugs for predicting cardiac arrhythmogenic liability using optical action potential (oAP) assay. METHODS: Here, we describe our examination of the oAP measurement using a voltage sensitive dye (Di-4-ANEPPS) to predict adverse compound effects using hiPS-CMs and 20 cardioactive reference compounds. Fluorescence signals were digitized at 10kHz and the records subsequently analyzed off-line. Cells were exposed to 30min incubation to vehicle or compound (n=5/dose, 4 doses/compound) that were blinded to the investigating laboratory. Action potential parameters were measured, including rise time (Trise) of the optical action potential duration (oAPD). RESULTS: Significant effects on oAPD were sensitively detected with 11 QT-prolonging drugs, while oAPD shortening was observed with ICa-antagonists, IKr-activator or ATP-sensitive K+ channel (KATP)-opener. Additionally, the assay detected varied effects induced by 6 different sodium channel blockers. The detection threshold for these drug effects was at or below the published values of free effective therapeutic plasma levels or effective concentrations by other studies. DISCUSSION: The results of this blinded study indicate that OAP is a sensitive method to accurately detect drug-induced effects (i.e., duration/QT-prolongation, shortening, beat rate, and incidence of early after depolarizations) in hiPS-CMs; therefore, this technique will potentially be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase.

Anterior inferior petrosectomy: defining the role of endonasal endoscopic techniques for petrous apex approaches.

OBJECT: Historically, surgery to the petrous apex has been addressed via craniotomy and open microscopic anterior petrosectomy (OAP). However, with the popularization of endoscopic approaches, the petrous apex can further be approached endonasally by way of an endoscopic endonasal anterior petrosectomy (EAP). Endonasal anterior petrosectomy is a relatively new procedure and has not been compared anatomically with OAP. The authors hypothesized that the EAP and OAP techniques approach different portions of the petrous apex and therefore may have different applications. METHODS: Four cadaveric heads were used. An OAP was performed on one side and an EAP was performed on the contralateral side; the limits of bony resection were defined. The extent of bony resection was then evaluated using predissection and postdissection thin-slice CT scans. The comparative resection was then reconstructed using 3D modeling on Brainlab workstations. RESULTS: The average resection volumes for EAP and OAP were 0.297 cm(3) and 0.649 cm(3), respectively, representing a comparative percentage of 46% (EAP/OAP). An EAP and OAP achieved resection of 29% and 64% of the total petrous apex volume, respectively. Indeed, EAP addressed the inferior portion of the petrous apex located adjacent to the petroclival suture more completely than OAP, where 45% of the bone overlying the petroclival suture (petroclival angle to the jugular foramen) was resected with the EAP, while 0% was resected with the OAP. CONCLUSIONS: In anatomically normal cadavers, OAP achieved nearly a 50% larger volumetric resection than EAP. Furthermore, while OAP appears to completely address the superior portion of the petrous apex, EAP appears to have a niche in approaches to lesions in the inferior petrous apex. Given these results, the authors propose that OAP be redefined as the "superior anterior petrosectomy," while EAP be referred to as the "inferior anterior petrosectomy," which more clearly defines the role of each approach in anterior petrosectomy.

Multistage electrotherapy delivered through chronically-implanted leads terminates atrial fibrillation with lower energy than a single biphasic shock.

OBJECTIVES: The goal of this study was to develop a low-energy, implantable device-based multistage electrotherapy (MSE) to terminate atrial fibrillation (AF). BACKGROUND: Previous attempts to perform cardioversion of AF by using an implantable device were limited by the pain caused by use of a high-energy single biphasic shock (BPS). METHODS: Transvenous leads were implanted into the right atrium (RA), coronary sinus, and left pulmonary artery of 14 dogs. Self-sustaining AF was induced by 6 ± 2 weeks of high-rate RA pacing. Atrial defibrillation thresholds of standard versus experimental electrotherapies were measured in vivo and studied by using optical imaging in vitro. RESULTS: The mean AF cycle length (CL) in vivo was 112 ± 21 ms (534 beats/min). The impedances of the RA-left pulmonary artery and RA-coronary sinus shock vectors were similar (121 ± 11 Ω vs. 126 ± 9 Ω; p = 0.27). BPS required 1.48 ± 0.91 J (165 ± 34 V) to terminate AF. In contrast, MSE terminated AF with significantly less energy (0.16 ± 0.16 J; p < 0.001) and significantly lower peak voltage (31.1 ± 19.3 V; p < 0.001). In vitro optical imaging studies found that AF was maintained by localized foci originating from pulmonary vein-left atrium interfaces. MSE Stage 1 shocks temporarily disrupted localized foci; MSE Stage 2 entrainment shocks continued to silence the localized foci driving AF; and MSE Stage 3 pacing stimuli enabled consistent RA-left atrium activation until sinus rhythm was restored. CONCLUSIONS: Low-energy MSE significantly reduced the atrial defibrillation thresholds compared with BPS in a canine model of AF. MSE may enable painless, device-based AF therapy.

Optic neuritis in neuromyelitis optica.

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease associated with recurrent episodes of optic neuritis and transverse myelitis, often resulting in permanent blindness and/or paralysis. The discovery of autoantibodies (AQP4-IgG) that target aquaporin-4 (AQP4) has accelerated our understanding of the cellular mechanisms driving NMO pathogenesis. AQP4 is a bidirectional water channel expressed on the plasma membranes of astrocytes, retinal Müller cells, skeletal muscle, and some epithelial cells in kidney, lung and the gastrointestinal tract. AQP4 tetramers form regular supramolecular assemblies at the cell plasma membrane called orthogonal arrays of particles. The pathological features of NMO include perivascular deposition of immunoglobulin and activated complement, loss of astrocytic AQP4, inflammatory infiltration with granulocyte and macrophage accumulation, and demyelination with axon loss. Current evidence supports a causative role of AQP4-IgG in NMO, in which binding of AQP4-IgG to AQP4 orthogonal arrays on astrocytes initiates complement-dependent and antibody-dependent cell-mediated cytotoxicity and inflammation. Immunosuppression and plasma exchange are the mainstays of therapy for NMO optic neuritis. Novel therapeutics targeting specific steps in NMO pathogenesis are entering the development pipeline, including blockers of AQP4-IgG binding to AQP4 and inhibitors of granulocyte function. However, much work remains in understanding the unique susceptibility of the optic nerves in NMO, in developing animal models of NMO optic neuritis, and in improving therapies to preserve vision.