A implantação do Sistema Único de Assistência Social no município de Ourinhos-SP: a contribuição do Serviço Social

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Aeroelastic Analysis of a Typical Section Using of Shape memory wire actuator

Shape memory alloys (SMAs) provide a compact and effective actuation for a variety of mechanical systems. In this paper, a numerical simulation study of a three degree of-freedom airfoil, subjected to two-dimensional incompressible inviscid flow using a SMA is presented. SMA wire actuators are used to control the flap movement of a wing section. Through the thermo-mechanical constitutive equation of the SMA proposed by Brison, we simulate numerically the behavior of a double SMA wire actuator. Two SMA actuators are used: one to move the flap down and the other to move the flap up. Through the numerical results conducted in the present study, the behavior and characteristics of an SMA actuator with two SMA wires are shown the effectiveness of the SMA actuator. In conclusion, this paper shows the feasibility of using SMA wire actuators for flap movement, with success

Multimodal (EEG-fMRI) functional connectivity study of levodopa effect in Parkinson’s disease

Aim: To assess if the intake of levodopa in patients with Parkinson’s Disease (PD) changes cerebral connectivity, as revealed by simultaneous recording of hemodynamic (functional MRI, or fMRI) and electric (electroencephalogram, EEG) signals. Particularly, we hypothesize that the strongest changes in FC will involve the motor network, which is the most impaired in PD. Methods: Eight patients with diagnosis of PD “probable”, therapy with levodopa exclusively, normal cognitive and affective status, were included. Exclusion criteria were: moderate-severe rest tremor, levodopa induced dyskinesia, evidence of gray or white matter abnormalities on structural MRI. Scalp EEG (64 channels) were acquired inside the scanner (1.5 Tesla) before and after the intake of levodopa. fMRI functional connectivity was computed from four regions of interest: right and left supplementary motor area (SMA) and right and left precentral gyrus (primary motor cortex). Weighted partial directed coherence (w-PDC) was computed in the inverse space after the removal of EEG gradient and cardioballistic artifacts. Results and discussion: fMRI group analysis shows that the intake of levodopa increases hemodynamic functional connectivity among the SMAs / primary motor cortex and: sensory-motor network itself, attention network and default mode network. w-PDC analysis shows that EEG connectivity among regions of the motor network has the tendency to decrease after the intake the levodopa; furthermore, regions belonging to the DMN have the tendency to increase their outflow toward the rest of the brain. These findings, even if in a small sample of patients, suggest that other resting state physiological functional networks, beyond the motor one, are affected in patients with PD. The behavioral and cognitive tasks corresponding to the affected networks could benefit from the intake of levodopa.

Block of the hERG channel by bupivacaine: Electrophysiological and modeling insights towards stereochemical optimization

The hERG voltage-gated potassium channel mediates the cardiac I(Kr) current, which is crucial for the duration of the cardiac action potential. Undesired block of the channel by certain drugs may prolong the QT interval and increase the risk of malignant ventricular arrhythmias. Although the molecular determinants of hERG block have been intensively studied, not much is known about its stereoselectivity. Levo-(S)-bupivacaine was the first drug reported to have a higher affinity to block hERG than its enantiomer. This study strives to understand the principles underlying the stereoselectivity of bupivacaine block with the help of mutagenesis analyses and molecular modeling simulations. Electrophysiological measurements of mutated hERG channels allowed for the identification of residues involved in bupivacaine binding and stereoselectivity. Docking and molecular mechanics simulations for both enantiomers of bupivacaine and terfenadine (a non-stereoselective blocker) were performed inside an open-state model of the hERG channel. The predicted binding modes enabled a clear depiction of ligand-protein interactions. Estimated binding affinities for both enantiomers were consistent with electrophysiological measurements. A similar computational procedure was applied to bupivacaine enantiomers towards two mutated hERG channels (Tyr652Ala and Phe656Ala). This study confirmed, at the molecular level, that bupivacaine stereoselectively binds the hERG channel. These results help to lay the foundation for structural guidelines to optimize the cardiotoxic profile of drug candidates in silico.

Patient with syncope and LQTS carrying a mutation in the PAS domain of the hERG1 channel

We report the case of a woman with syncope and persistently prolonged QTc interval. Screening of congenital long QT syndrome (LQTS) genes revealed that she was a heterozygous carrier of a novel KCNH2 mutation, c.G238C. Electrophysiological and biochemical characterizations unveiled the pathogenicity of this new mutation, displaying a 2-fold reduction in protein expression and current density due to a maturation/trafficking-deficient mechanism. The patient's phenotype can be fully explained by this observation. This study illustrates the importance of performing genetic analyses and mutation characterization when there is a suspicion of congenital LQTS. Identifying mutations in the PAS domain or other domains of the hERG1 channel and understanding their effect may provide more focused and mutation-specific risk assessment in this population.

Nedd4-2-dependent ubiquitylation and regulation of the cardiac potassium channel hERG1

The voltage-gated cardiac potassium channel hERG1 (human ether-à-gogo-related gene 1) plays a key role in the repolarization phase of the cardiac action potential (AP). Mutations in its gene, KCNH2, can lead to defects in the biosynthesis and maturation of the channel, resulting in congenital long QT syndrome (LQTS). To identify the molecular mechanisms regulating the density of hERG1 channels at the plasma membrane, we investigated channel ubiquitylation by ubiquitin ligase Nedd4-2, a post-translational regulatory mechanism previously linked to other ion channels. We found that whole-cell hERG1 currents recorded in HEK293 cells were decreased upon neural precursor cell expressed developmentally down-regulated 4-2 (Nedd4-2) co-expression. The amount of hERG1 channels in total HEK293 lysates and at the cell surface, as assessed by Western blot and biotinylation assays, respectively, were concomitantly decreased. Nedd4-2 and hERG1 interact via a PY motif located in the C-terminus of hERG1. Finally, we determined that Nedd4-2 mediates ubiquitylation of hERG1 and that deletion of this motif affects Nedd4-2-dependent regulation. These results suggest that ubiquitylation of the hERG1 protein by Nedd4-2, and its subsequent down-regulation, could represent an important mechanism for modulation of the duration of the human cardiac action potential.

Stereoselective Inhibition of the hERG1 Potassium Channel

A growing number of drugs have been shown to prolong cardiac repolarization, predisposing individuals to life-threatening ventricular arrhythmias known as Torsades de Pointes. Most of these drugs are known to interfere with the human ether à-gogo related gene 1 (hERG1) channel, whose current is one of the main determinants of action potential duration. Prolonged repolarization is reflected by lengthening of the QT interval of the electrocardiogram, as seen in the suitably named drug-induced long QT syndrome. Chirality (presence of an asymmetric atom) is a common feature of marketed drugs, which can therefore exist in at least two enantiomers with distinct three-dimensional structures and possibly distinct biological fates. Both the pharmacokinetic and pharmacodynamic properties can differ between enantiomers, as well as also between individuals who take the drug due to metabolic polymorphisms. Despite the large number of reports about drugs reducing the hERG1 current, potential stereoselective contributions have only been scarcely investigated. In this review, we present a non-exhaustive list of clinically important molecules which display chiral toxicity that may be related to hERG1-blocking properties. We particularly focus on methadone cardiotoxicity, which illustrates the importance of the stereoselective effect of drug chirality as well as individual variations resulting from pharmacogenetics. Furthermore, it seems likely that, during drug development, consideration of chirality in lead optimization and systematic assessment of the hERG1 current block with all enantiomers could contribute to the reduction of the risk of drug-induced LQTS.

Barreras que dificultan la procuracion de organos y tejidos para trasplantes en la provincia de Misiones. 16H221

La temática transplantológica ha tenido avances sin precedentes en la ciencia médica, y la medicina de nuestro país ha acompañado de cerca esta evolución del conocimiento, al punto de colocar a nuestros especialistas en el tema y al INCUCAI en una posición de liderazgo en Latinoamérica. Así, el implante de órganos, tejidos y células se ha vuelto una práctica cada vez más frecuente en nuestro sistema de salud. Además, debido a la eficacia de sus resultados, se transforma día a día en una terapéutica cuya indicación se multiplica para todos los casos. Sin embargo, lejos está el sistema de salud de la Argentina, y especialmente el de las Provincias, de poder convertir a estos progresos científicos en una práctica médica masiva, al alcance de todos aquellos que la necesitan, en tiempos razonables de acceso. Entre otras razones, por la insuficiente cantidad de donaciones de órganos y tejidos que se materializan. La enorme brecha que existe actualmente entre el número de personas diagnosticadas para un trasplante (Lista de Espera) y el de las donaciones que efectivamente se concretan (Procuración) se ha convertido en el principal problema a resolver por el sistema sanitario. Los siguientes datos proporcionados por el SINTRA (Sistema Nacional de Información de Procuración y Trasplante) son indicativos de la situación a nivel de todo el País y en nuestra Provincia (datos referidos a órganos y tejidos):

Músculos Inteligentes en Robots Biológicamente Inspirados: Modelado, Control y Actuación

Las aleaciones metálicas que exhiben una propiedad conocida como efecto de memoria de forma, pertenecen a la clase de materiales inteligentes cuya aplicación más notable en el campo de la robótica se refleja en el uso de actuadores musculares artificiales, ó músculos inteligentes. Estos materiales tienen una estructura cristalina uniforme que cambia radicalmente en función de su temperatura de transición, causando su deformación. Se les denomina materiales inteligentes por la capacidad de recordar su configuración inicial después de recibir dicho estímulo térmico. Este artículo presenta la implementación de un actuador muscular inteligente aplicado en un micro-robot aéreo bio-inspirado tipo murciélago. Esto mamíferos voladores desarrollaron poderosos músculos que se extienden a lo largo de la estructura ósea de las alas, adquiriendo una asombrosa capacidad de maniobra gracias a la capacidad de cambiar la forma del ala durante el vuelo. Replicar este tipo de alas mórficas en un prototipo robótico requiere el análisis de nuevas tecnologías de actuación, abordando los problemas de modelado y control que garanticen la aplicabilidad de este actuador compuesto por fibras musculares de SMAs