Kir2.1 mutations differentially increase the risk of flecainide proarrhythmia in Andersen Tawil Syndrome.

Background: Flecainide and other class-Ic antiarrhythmic drugs (AADs) are widely used in Andersen-Tawil syndrome type 1 (ATS1) patients. However, class-Ic drugs might be proarrhythmic in some cases. We investigated the molecular mechanisms of class-I AADs proarrhythmia and whether they might increase the risk of death in ATS1 patients with structurally normal hearts.

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Arrhythmia refers to irregularities in the rate and rhythm of the heart, with symptoms spanning from mild palpitations to life-threatening arrhythmias and sudden cardiac death (SCD). The complex molecular nature of arrhythmias complicates the selection of appropriate treatment. Current therapies involve the use of antiarrhythmic drugs (class I-IV) with limited efficacy and dangerous side effects and implantable pacemakers and cardioverter-defibrillators with hardware-related complications and inappropriate shocks.

Extracellular Kir2.1 Mutant Upsets Kir2.1-PIP Bonds and Is Arrhythmogenic in Andersen-Tawil Syndrome.

Background: Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K channel Kir2.1. The extracellular Cys (cysteine)-to-Cys disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane.

The Kir2.1E299V mutation increases atrial fibrillation vulnerability while protecting the ventricles against arrhythmias in a mouse model of short QT syndrome type 3.

Aims: Short QT syndrome type 3 (SQTS3) is a rare arrhythmogenic disease caused by gain-of-function mutations in KCNJ2, the gene coding the inward rectifier potassium channel Kir2.1. We used a multidisciplinary approach and investigated arrhythmogenic mechanisms in an in-vivo model of de-novo mutation Kir2.

Extracellular cysteine disulfide bond break at Cys122 disrupts PIP-dependent Kir2.1 channel function and leads to arrhythmias in Andersen-Tawil Syndrome.

Background: Andersen-Tawil Syndrome Type 1 (ATS1) is a rare heritable disease caused by mutations in the strong inwardly rectifying K channel Kir2.1. The extracellular Cys122-to-Cys154 disulfide bond in the Kir2.

Energy substrate metabolism, mitochondrial structure and oxidative stress after cardiac ischemia-reperfusion in mice lacking UCP3.

Myocardial ischemia-reperfusion (IR) injury may result in cardiomyocyte dysfunction. Mitochondria play a critical role in cardiomyocyte recovery after IR injury. The mitochondrial uncoupling protein 3 (UCP3) has been proposed to reduce mitochondrial reactive oxygen species (ROS) production and to facilitate fatty acid oxidation.

Molecular stratification of arrhythmogenic mechanisms in the Andersen Tawil syndrome.

Andersen-Tawil syndrome (ATS) is a rare inheritable disease associated with loss-of-function mutations in KCNJ2, the gene coding the strong inward rectifier potassium channel Kir2.1, which forms an essential membrane protein controlling cardiac excitability. ATS is usually marked by a triad of periodic paralysis, life-threatening cardiac arrhythmias and dysmorphic features, but its expression is variable and not all patients with a phenotype linked to ATS have a known genetic alteration.

The Role of Context in Language Development for Children With Autism Spectrum Disorder.

Parent and preschool teacher ratings of the 10 noun categories of MacArthur-Bates Communication Development Inventory (CDI) were used to study expressive language in 2-4-year-old children with autism spectrum disorder (ASD) ( = 58) across the home and preschool context. There was no significant difference in the total number of words the children said in the two contexts, but the children said significantly more words in the noun categories "Furniture and rooms" and "People" at home. Only one third of the words the children said were said both at home and in the preschool, while the other two thirds were said only at home or only in preschool.

Antioxidant responses and cellular adjustments to oxidative stress.

Redox biological reactions are now accepted to bear the Janus faceted feature of promoting both physiological signaling responses and pathophysiological cues. Endogenous antioxidant molecules participate in both scenarios. This review focuses on the role of crucial cellular nucleophiles, such as glutathione, and their capacity to interact with oxidants and to establish networks with other critical enzymes such as peroxiredoxins.

4-Hydroxynonenal induces Nrf2-mediated UCP3 upregulation in mouse cardiomyocytes.

4-Hydroxy-2-nonenal (HNE) is a highly cytotoxic product of lipid peroxidation. Nevertheless, at low concentrations, it is able to mediate cell signaling and to activate protective pathways, including that of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2). In addition, HNE activates uncoupling proteins (UCPs), mitochondrial inner membrane proteins that mediate uncoupling of oxidative phosphorylation and have been proposed to protect against oxidative stress.