Characterizing the phenotypic manifestations of MFN2 R104W mutation in Charcot-Marie-Tooth type 2

Mutations of the mitofusin 2 (MFN2) gene have been reported to be the most common cause of the axonal form of Charcot Marie Tooth disease (CMT). The aim of this study was to describe a de novo MFN2 p.R104W mutation and characterize the associated phenotype. We screened the entire coding region of MFN2 gene and characterized its clinical phenotype, nerve conduction studies and sural nerve biopsy. Neuropsychological tests and brain MRI were also performed. A de nova mutation was found in exon 4 (c.310C > T; p.R104W). In addition to a severe and early onset axonal neuropathy, the patient presented learning problems, obesity, glucose intolerance, leukoencephalopathy, brain atrophy and evidence of myelin involvement and mitochondrial structural changes on sural nerve biopsy. These results suggest that MFN2 p.R104W mutation is as a hot-spot for MFN2 gene associated to a large and complex range of phenotypes. (C) 2011 Elsevier B.V. All rights reserved.

Mechanical, electrical and electro-mechanical properties of thermoplastic elastomer styrene–butadiene–styrene/multiwall carbon nanotubes composites

Composites of styrene–butadiene–styrene (SBS) block copolymer with multiwall carbon nanotubes were processed by solution casting to investigate the influence of filler content, the different ratios of styrene/butadiene in the copolymer and the architecture of the SBS matrix on the electrical, mechanical and electro-mechanical properties of the composites. It was found that filler content and elastomer matrix architecture influence the percolation threshold and consequently the overall composite electrical conductivity. The mechanical properties are mainly affected by the styrene and filler content. Hopping between nearest fillers is proposed as the main mechanism for the composite conduction. The variation of the electrical resistivity is linear with the deformation. This fact, together with the gauge factor values in the range of 2–18, results in appropriate composites to be used as (large) deformation sensors.

Temperature dependence of the electrical conductivity of vapor grown carbon nanofiber/epoxy composites with different filler dispersion levels

The influence of the dispersion of vapor grown carbon nanofibers (VGCNF) on the electrical properties of VGCNF/epoxy composites has been studied. A homogeneous dispersion of the VGCNF does not imply better electrical properties. The presence of well distributed clusters appears to be a key factor for increasing composite conductivity. It is also shown that the main conduction mechanism has an ionic nature for concentrations below the percolation threshold, while above the percolation threshold it is dominated by hopping between the fillers. Finally, using the granular system theory it is possible to explain the origin of conduction at low temperatures.

Bias-dependent photocurrent collection in p-i-n a-Si : H/SiC : H heterojunction

A series of large area single layers and glass/ZnO:AVp(SixC1-x:H)/i(Si:H)/n(SixC1-x:H)/AI (0 < x < 1) heterojunction cells were produced by plasma-enhanced chemical vapour deposition (PE-CVD) at low temperature. Junction properties, carrier transport and photogeneration are investigated from dark and illuminated current-voltage (J-V) and capacitance-voltage (C-V) characteristics. For the heterojunction cells atypical J-V characteristics under different illumination conditions are observed leading to poor fill factors. High series resistances around 106 Q are also measured. These experimental results were used as a basis for the numerical simulation of the energy band diagram, and the electrical field distribution of the structures. Further comparison with the sensor performance gave satisfactory agreement. Results show that the conduction band offset is the most limiting parameter for the optimal collection of the photogenerated carriers. As the optical gap increases and the conductivity of the doped layers decreases, the transport mechanism changes from a drift to a diffusion-limited process.

a-SiH p-i-n structures with extreme i-layer thickness

We present measurements and numerical simulation of a-Si:H p-i-n detectors with a wide range of intrinsic layer thickness between 2 and 10 pm. Such a large active layer thickness is required in applications like elementary particle detectors or X-ray detectors. For large thickness and depending on the applied bias, we observe a sharp peak in the spectral response in the red region near 700 nm. Simulation results obtained with the program ASCA are in agreement with the measurement and permit the explanation of the experimental data. In thick samples holes recombine or are trapped before reaching the contacts, and the conduction mechanism is fully electron dominated. As a consequence, the peak position in the spectral response is located near the optical band gap of the a-Si:H i-layer. (C) 2009 Elsevier B.V. All rights reserved.

Hopping conduction and persistent photoconductivity in Cu2ZnSnS4 thin films

The temperature dependence of electrical conductivity and the photoconductivity of polycrystalline Cu2ZnSnS4 were investigated. It was found that at high temperatures the electrical conductivity was dominated by band conduction and nearest-neighbour hopping. However, at lower temperatures, both Mott variable-range hopping (VRH) and Efros–Shklovskii VRH were observed. The analysis of electrical transport showed high doping levels and a large compensation ratio, demonstrating large degree of disorder in Cu2ZnSnS4. Photoconductivity studies showed the presence of a persistent photoconductivity effect with decay time increasing with temperature, due to the presence of random local potential fluctuations in the Cu2ZnSnS4 thin film. These random local potential fluctuations cannot be attributed to grain boundaries but to the large disorder in Cu2ZnSnS4.

Effect of ionic liquid anion type in the performance of solid polymer electrolytes based on Poly(Vinylidene fluoride-trifluoroethylene)

The effect of different anions within the ionic liquid in the characteristics of solid polymer electrolytes (SPEs) based on P(VDF-TrFE) has been investigated. 1-ethyl-3-methylimidazolium acetate, [C2mim][OAc], 1-ethyl-3-methylimidazolium triflate, [C2mim][(CF3SO3)3], 1-ethyl-3-methylimidazolium lactate, [C2mim][Lactate], 1-ethyl-3-methylimidazolium thiocyanate, [C2mim][SNC] and 1-ethyl-3-methylimidazolium hydrogen sulphate [C2mim][HSO4] have been used in SPE prepared by thermally induced phase separation (TIPS). The polymer phase, thermal and electrochemical properties of the SPE have been determined. The thermal and electrical properties of the SPEs strongly depend on the selected IL, as determined by their different interactions with the polymer matrix. The room temperature ionic conductivity increases in the following way for the different anions: [SNC] > [CF3SO3)3] > [HSO4] > [Lactate] > [OAc], which is mainly dependent on the viscosity of the ionic liquid.

Weak-type estimates for Haar shift operators: Sharp power on the A(p) characteristic

"Vegeu el resum a l'inici del document del fitxer adjunt."

The L-Type Ca+ and KATP channels may contribute to pacing-induced protection against anoxia-reoxygenation in the embryonic heart model.

L-Type Ca(2+) and K(ATP) Channels in Pacing-Induced Cardioprotection. AIMS: The L-type Ca(2+) channel, the sarcolemmal (sarcK(ATP)), and mitochondrial K(ATP) (mitoK(ATP)) channels are involved in myocardial preconditioning. We aimed at determining to what extent these channels can also participate in pacing-induced cardioprotection. METHODS: Hearts of 4-day-old chick embryos were paced in ovo during 12 hour using asynchronous intermittent ventricular stimulation at 110% of the intrinsic rate. Sham operated and paced hearts were then submitted in vitro to anoxia (30 minutes) and reoxygenation (60 minutes). These hearts were exposed to L-type Ca(2+) channel agonist Bay-K-8644 (BAY-K) or blocker verapamil, nonselective K(ATP) channel antagonist glibenclamide (GLIB), mitoK(ATP) channel agonist diazoxide (DIAZO), or antagonist 5-hydroxydecanoate. Electrocardiogram, electromechanical delay (EMD) reflecting excitation-contraction (E-C) coupling, and contractility were determined. RESULTS: Under normoxia, heart rate, QT duration, conduction, EMD, and ventricular shortening were similar in sham and paced hearts. During reoxygenation, arrhythmias ceased earlier and ventricular EMD recovered faster in paced hearts than in sham hearts. In sham hearts, BAY-K (but not verapamil), DIAZO (but not 5-hydroxydecanoate) or GLIB accelerated recovery of ventricular EMD, reproducing the pacing-induced protection. By contrast, none of these agents further ameliorated recovery of the paced hearts. CONCLUSION: The protective effect of chronic asynchronous pacing at near physiological rate on ventricular E-C coupling appears to be associated with subtle activation of L-type Ca(2+) channel, inhibition of sarcK(ATP) channel, and/or opening of mitoK(ATP) channel.

Intermittent atrial tachycardia promotes repolarization alternans and conduction slowing during rapid rates, and increases susceptibility to atrial fibrillation in a free-behaving sheep model.

INTRODUCTION: Paroxysmal atrial fibrillation (AF) may be triggered by intermittent atrial tachycardia, and ultimately lead to persistent AF. However, the mechanisms by which intermittent atrial tachycardia promotes sustained AF are not well understood. METHODS AND RESULTS: Eight sheep were chronically implanted with 2 pacemakers for the recording of broadband right atrial unipolar electrograms, and for the delivery of electrophysiological stimulation protocols and intermittent right atrial tachycardia. Right atrial kinetics of activation recovery interval (ARI) as a surrogate for action potential duration, of conduction time and velocity, and of repolarization alternans were analyzed at incremental pacing rates during the remodeling process induced by weeks of intermittent atrial tachycardia until the development of sustained AF. Intermittent atrial tachycardia decreased ARI and blunted its rate adaptation, facilitated atrial capture, and slowed conduction at high rates, and increased susceptibility to pacing-induced AF. In spite of blunted ARI rate adaptation, right atrial repolarization alternans was maintained during remodeling, and further increased in magnitude just before rapid pacing-induced AF. CONCLUSION: This study suggests that weeks of intermittent right atrial tachycardia result in a gradual electrical remodeling favorable for wavebreaks and reentry that may facilitate fibrillation.

Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome.

AIMS: Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is caused, in part, by mutations in the SCN5A gene, which encodes the sodium channel alpha-subunit Na(v)1.5. Here, we aimed to characterize the biophysical properties and consequences of a novel BrS SCN5A mutation. METHODS AND RESULTS: SCN5A was screened for mutations in a male patient with type-1 BrS pattern ECG. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. Sodium currents (I(Na)) were analysed using the whole-cell patch-clamp technique at 37 degrees C. The electrophysiological effects of the mutation were simulated using the Luo-Rudy model, into which the transient outward current (I(to)) was incorporated. A new mutation (C1850S) was identified in the Na(v)1.5 C-terminal domain. In HEK293 cells, mutant I(Na) density was decreased by 62% at -20 mV. Inactivation of mutant I(Na) was accelerated in a voltage-dependent manner and the steady-state inactivation curve was shifted by 11.6 mV towards negative potentials. No change was observed regarding activation characteristics. Altogether, these biophysical alterations decreased the availability of I(Na). In the simulations, the I(to) density necessary to precipitate repolarization differed minimally between the two genotypes. In contrast, the mutation greatly affected conduction across a structural heterogeneity and precipitated conduction block. CONCLUSION: Our data confirm that mutations of the C-terminal domain of Na(v)1.5 alter the inactivation of the channel and support the notion that conduction alterations may play a significant role in the pathogenesis of BrS.

[Portrait de la reine Olga de Grèce (même type que Wc 218) non signé, 2 phot. de types grecs par Rubellin, phot. à Smyrne, le tout donné par P.P. Potagos en 1887]

Donateur : Potagos, Panagiotes (1839-1903)

A Heterozygous Deletion Mutation in the Cardiac Sodium Channel Gene SCN5A with Loss- and Gain-of-Function Characteristics Manifests as Isolated Conduction Disease, without Signs of Brugada or Long QT Syndrome.

BACKGROUND: The SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome. METHOD AND RESULTS: In a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na(+) currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation). CONCLUSION: In a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na(+) current and depolarization force.

The L-Type Ca2+ and KATP channels may contribute to pacing-induced protection against anoxia-reoxygenation in the embryonic heart model

Rapport de synthèse : Implication des canaux Ca2+ de type L et des canaux KATP dans la protection induite par pacing dans un modèle de coeur embryonnaire soumis à l'anoxieréoxygénation. Contexte et but : le canal Ca2+ de type L, les canaux K+ du sarcolemme (sarcKatp) et de la mitochondrie (mitoKatp) interviennent dans le préconditionnement ischémique ou pharmacologique du myocarde. La présente étude cherche à déterminer dans quelle mesure ces canaux peuvent aussi jouer un rôle dans la cardioprotection induite par pacing. Méthodes :des coeurs d'embryons de poulet âgés de 4 jours ont été soumis in ovo à un pacing durant 12 heures, en pratiquant une stimulation électrique ventriculaire asynchrone intermittente à 110% de la fréquence cardiaque intrinsèque. Les coeurs contrôles (sham) et les coeurs stimulés ont ensuite été soumis in vitro à une période d'anoxie de 30 minutes, suivie d'une réoxygénation de 60 minutes. Les coeurs ont été exposés à l'agoniste du canal Ca2+ de type L (Bay-K-8644, BAY-K) ou à son bloqueur (vérapamil, VERAP), à l'antagoniste non sélectif des canaux KATP (glibenclamide, GLIB), ainsi qu'à l'agoniste du canal mitoKATP (diazoxide, DIAZO), ou à son antagoniste (5-hydroxydécanoate, 5-HD). L'électrocardiogramme, le délai électro-mécanique (DEM) reflétant le couplage excitation-contraction, ainsi que la contractilité myocardique ont été systématiquement déterminés pendant l'anoxieréoxygénation. Résultats : en normoxie, la fréquence cardiaque, l'intervalle QT, la conduction atrioventriculaire, le DEM et le raccourcissement ventriculaires étaient identiques dans les coeurs sham et les coeurs stimulés. Par contre, au cours de la réoxygénation post-anoxique, les arythmies cessaient plus précocément et le DEM ventriculaire retrouvait plus rapidement son niveau initial dans les coeurs stimulés, comparés aux sham. Dans les coeurs sham, BAY-K (mais pas le VERAP), DIAZO (mais pas le 5HD) ou GLIB accéléraient la récupération du DEM ventriculaire, reproduisant ainsi la protection induite par le pacing. En revanche, aucun de ces agents n'affectait la récupération des cceurs stimulés. Conclusion : un pacing ventriculaire chronique et intermittent délivré à une fréquence quasi physiologique améliore la tolérance myocardique à une anoxie-réoxygénation ultérieure. L'approche pharmacologique amontré qu'une activation discrète du canal Ca2+ de type L, une inhibition du canal sarcKATP et/ou une ouverture du canal mitoKATP peuvent contribuer à la cardioprotection induite par le pacing.