A rat model of a focal mosaic expression of PCDH19 replicates human brain developmental abnormalities and behaviours.

Protocadherin 19 gene-related epilepsy or protocadherin 19 clustering epilepsy is an infantile-onset epilepsy syndrome characterized by psychiatric (including autism-related), sensory, and cognitive impairment of varying degrees. Protocadherin 19 clustering epilepsy is caused by X-linked protocadherin 19 protein loss of function. Due to random X-chromosome inactivation, protocadherin 19 clustering epilepsy-affected females present a mosaic population of healthy and protocadherin 19-mutant cells.

Deficient adaptation to centrosome duplication defects in neural progenitors causes microcephaly and subcortical heterotopias.

Congenital microcephaly (MCPH) is a neurodevelopmental disease associated with mutations in genes encoding proteins involved in centrosomal and chromosomal dynamics during mitosis. Detailed MCPH pathogenesis at the cellular level is still elusive, given the diversity of MCPH genes and lack of comparative in vivo studies. By generating a series of CRISPR/Cas9-mediated genetic KOs, we report here that - whereas defects in spindle pole proteins (ASPM, MCPH5) result in mild MCPH during development - lack of centrosome (CDK5RAP2, MCPH3) or centriole (CEP135, MCPH8) regulators induces delayed chromosome segregation and chromosomal instability in neural progenitors (NPs).

Single-cell transcriptomics of the early developing mouse cerebral cortex disentangle the spatial and temporal components of neuronal fate acquisition.

In the developing cerebral cortex, how progenitors that seemingly display limited diversity end up producing a vast array of neurons remains a puzzling question. The prevailing model suggests that temporal maturation of progenitors is a key driver in the diversification of the neuronal output. However, temporal constraints are unlikely to account for all diversity, especially in the ventral and lateral pallium where neuronal types significantly differ from their dorsal neocortical counterparts born at the same time.

Modelling genetic mosaicism of neurodevelopmental disorders in vivo by a Cre-amplifying fluorescent reporter.

Genetic mosaicism, a condition in which an organ includes cells with different genotypes, is frequently present in monogenic diseases of the central nervous system caused by the random inactivation of the X-chromosome, in the case of X-linked pathologies, or by somatic mutations affecting a subset of neurons. The comprehension of the mechanisms of these diseases and of the cell-autonomous effects of specific mutations requires the generation of sparse mosaic models, in which the genotype of each neuron is univocally identified by the expression of a fluorescent protein in vivo. Here, we show a dual-color reporter system that, when expressed in a floxed mouse line for a target gene, leads to the creation of mosaics with tunable degree.

Influence of heart rate on FFR measurements: An experimental and clinical validation study.

Background: Functional lesion assessment in stable coronary disease is considered the gold standard. The result of fractional flow reserve (FFR) in stable coronary disease is often a decision-maker for patient qualification. Taking into account the paramount position of FFR, it is crucial to acknowledge and reduce all potential bias.

A Localized Scaffold for cGMP Increase Is Required for Apical Dendrite Development.

Studies in cultured neurons have established that axon specification instructs neuronal polarization and is necessary for dendrite development. However, dendrite formation in vivo occurs when axon formation is prevented. The mechanisms promoting dendrite development remain elusive.

Evolutionary Gain of Dbx1 Expression Drives Subplate Identity in the Cerebral Cortex.

Changes in transcriptional regulation through cis-regulatory elements are thought to drive brain evolution. However, how this impacts the identity of primate cortical neurons is still unresolved. Here, we show that primate-specific cis-regulatory sequences upstream of the Dbx1 gene promote human-like expression in the mouse embryonic cerebral cortex, and this imparts cell identity.

Synaptogenesis Stimulates a Proteasome-Mediated Ribosome Reduction in Axons.

Ribosomes and a subset of cellular mRNAs are trafficked into axons of developing neurons. The axonal localization of translational machinery allows new proteins to be rapidly and locally synthesized during axonal growth and pathfinding. However, in mature neurons, axonal ribosomes are significantly reduced or even absent.

The development of synaptic transmission is time-locked to early social behaviors in rats.

The development of functional synapses is a sequential process preserved across many brain areas. Here, we show that glutamatergic postsynaptic currents anticipated GABAergic currents in Layer II/III of the rat neocortex, in contrast to the pattern described for other brain areas. The frequencies of both glutamatergic and GABAergic currents increased abruptly at the beginning of the second postnatal week, supported by a serotonin upsurge.

In vivo methods for acute modulation of gene expression in the central nervous system.

Accurate and timely expression of specific genes guarantees the healthy development and function of the brain. Indeed, variations in the correct amount or timing of gene expression lead to improper development and/or pathological conditions. Almost forty years after the first successful gene transfection in in vitro cell cultures, it is currently possible to regulate gene expression in an area-specific manner at any step of central nervous system development and in adulthood in experimental animals in vivo, even overcoming the very poor accessibility of the brain.

Freedom from pulmonary vein stenosis after multiple applications of epicardial ablation energy.

Objectives: In patients undergoing cardiac surgical procedures, pulmonary vein isolation may be easily accomplished, and it is important to achieve bidirectional conduction block across created lesions. The primary aim of this study was to assess the risk of pulmonary vein stenosis (PVS) after multiple applications of epicardial bipolar radiofrequency energy.

Methods: Thirty-five consecutive patients who were referred for off-pump coronary revascularization with concomitant pulmonary vein isolation and left atrial appendage occlusion were prospectively included in the study.

The female epilepsy protein PCDH19 is a new GABAAR-binding partner that regulates GABAergic transmission as well as migration and morphological maturation of hippocampal neurons.

The PCDH19 gene (Xp22.1) encodes the cell-adhesion protein protocadherin-19 (PCDH19) and is responsible for a neurodevelopmental pathology characterized by female-limited epilepsy, cognitive impairment and autistic features, the pathogenic mechanisms of which remain to be elucidated. Here, we identified a new interaction between PCDH19 and GABAA receptor (GABAAR) alpha subunits in the rat brain.

Intraoperative epicardial focal pulmonary venous electrocardiography in patients with atrial fibrillation.

Objectives: In patients referred to off-pump coronary artery bypass grafting, pulmonary vein isolation (PVI) may be used for those with persistent atrial fibrillation (AF), an alternative to the Maze procedure. However, the success rate of PVI in persistent AF is limited. The study assesses the prognostic value of focal epicardial electrocardiography of the pulmonary veins (PVs) for surgical ablation results.

The X-Linked Intellectual Disability Protein IL1RAPL1 Regulates Dendrite Complexity.

Mutations and deletions of the () gene, located on the X chromosome, are associated with intellectual disability (ID) and autism spectrum disorder (ASD). IL1RAPL1 protein is located at the postsynaptic compartment of excitatory synapses and plays a role in synapse formation and stabilization. Here, using primary neuronal cultures and -KO mice, we characterized the role of IL1RAPL1 in regulating dendrite morphology.

Left Atrial Ganglionated Plexi Detection is Related to Heart Rate and Early Recurrence of Atrial Fibrillation after Surgical Ablation.

Introduction:: Left atrial ganglionated plexi ablation is an adjuvant technique used to increase the success rate of surgical ablation of atrial fibrillation. Ganglionated plexi ablation requires previous detection. We aimed to assess determinants of successful ganglionated plexi detection and to correlate range of ganglionated plexi ablation with risk of early atrial fibrillation recurrence.

Right atrium positioning for exposure of right pulmonary veins during off-pump atrial fibrillation ablation.

Objectives: Concomitant surgical ablation of atrial fibrillation (AF) is recommended for patients undergoing off-pump coronary revascularization in the presence of this arrhythmia. Achievement of optimal visualization of pulmonary veins while maintaining stable haemodynamic conditions is crucial for proper completion of the ablation procedure. This study evaluates the safety and feasibility of right atrial positioning using a suction-based cardiac positioner as opposed to compressive manoeuvres for exposure during off-pump surgical ablation for AF.

Association of Central Sleep Apnea with Impaired Heart Structure and Cardiovascular Hemodynamics in Patients with Chronic Heart Failure.

BACKGROUND Advanced heart failure (HF) is commonly accompanied by central sleep apnea (CSA) with Cheyne-Stokes respiration (CSR). The aim of this study was to evaluate the relationship between CSA/CSR and other clinical features of HF, with particular emphasis on cardiovascular hemodynamics. MATERIAL AND METHODS In 161 stable HF patients with left ventricular ejection fraction (LVEF) ≤45% (NYHA class I-III; mean LVEF 32.

Pulmonary artery aneurysm in an adult patient with idiopathic dilatation of the pulmonary artery.

Idiopathic dilatation of the pulmonary artery (IDPA) is a rare congenital heart disease. It has been described for almost one hundred years, and numerous definitions have been proposed. The IDPA diagnostic criteria have not been updated for years.

Targeted in vivo genetic manipulation of the mouse or rat brain by in utero electroporation with a triple-electrode probe.

This protocol is an extension to:Nat. Protoc. 1, 1552-1558 (2006); doi:10.

Comparison of safety of radial and femoral approaches for coronary catheterization in interventional cardiology.

Background: The femoral approach has been the preferably used access in interventional cardiology as well for coronary diagnostics as for percutaneous coronary intervention, being perceived as easy and facilitating quick access with relatively low risk. Due to the results of the latest studies, however, the radial approach has become increasingly popular. The aim of this study was a safety analysis of cardiological interventional procedures (i.

Apaf1-deficient cortical neurons exhibit defects in axonal outgrowth.

The establishment of neuronal polarity and axonal outgrowth are key processes affecting neuronal migration and synapse formation, their impairment likely leading to cognitive deficits. Here we have found that the apoptotic protease activating factor 1 (Apaf1), apart from its canonical role in apoptosis, plays an additional function in cortical neurons, where its deficiency specifically impairs axonal growth. Given the central role played by centrosomes and microtubules in the polarized extension of the axon, our data suggest that Apaf1-deletion affects axonal outgrowth through an impairment of centrosome organization.

[The current pharmacotherapy of pulmonary arterial hypertension].

Pulmonary arterial hypertension (PAH) is a chronic, serious disease caused by remodeling of small pulmonary vessels, which leads to increase of pulmonary resistance, right heart failure and death. The 1990ths of XX century are the beginning of dynamic research into the pathophysiology and treatment of this disease. Actually, the goal oriented therapy based on three main metabolic pathways includes: prostacyclin's analogues, endothelin receptor antagonists and phosphodiesterase-5 inhibitors.

[New directions in the therapy of pulmonary arterial hypertension].

Recent years are the time of dynamic development of pulmonary arterial pressure pharmacotherapy. By introducing the goal oriented therapy the survival in this group of patients has significantly increased. Apart from the pharmacotherapy used according to the ESC guidelines, new attempts of interventional treatment based on denervation of pulmonary artery have also been taken.

Minimizing right ventricular pacing in patients with sinus node disease and prolonged PQ interval: The impact on exercise capacity.

Background: Several clinical and experimental studies have shown that unnecessary right ventricular pacing in sinus node disease can be detrimental. Inter- and intra-ventricular asynchrony imposed by right ventricular pacing may cause reduction in contractility and relaxation of left ventricle, worsening mitral regurgitation, regional redistribution of myocardial perfusion and oxygen consumption, and asymmetrical hypertrophy of left ventricular wall. In some patients, sinus node disease coexists with impaired atrioventricular conduction.