Cardiac sodium channel, its mutations and their spectrum of arrhythmia phenotypes

The mechanisms of cellular excitability and propagation of electrical signals in the cardiac muscle are very important functionally and pathologically. The heart is constituted by three types of muscle: atrial, ventricular, and specialized excitatory and conducting fi bers. From a physiological and pathophysiological point of view, the conformational states of the sodium channel during heart function constitute a signifi cant aspect for the diagnosis and treatment of heart diseases. Functional states of the sodium channel (closed, open, and inactivated) and their structure help to understand the cardiac regulation processes. There are areas in the cardiac muscle with anatomical and functional differentiation that present automatism, thus subjecting the rest of the fi bers to their own rhythm. The rate of these (pacemaker) areas could be altered by modifi cations in ions, temperature and especially, the autonomic system. Excitability is a property of the myocardium to react when stimulated. Another electrical property is conductivity, which is characterized by a conduction and activation process, where the action potential, by the all-or-nothing law, travels throughout the heart. Heart relaxation also stands out as an active process, dependent on the energetic output and on specificion and enzymatic actions, with the role of sodium channel being outstanding in the functional process. In the gene mutation aspects that encode the rapid sodium channel (SCN5A gene), this channel is responsible for several phenotypes, such as Brugada syndrome, idiopathic ventricular fibrillation, dilated cardiomyopathy, early repolarization syndrome, familial atrial fibrillation, variant 3 of long QT syndrome, multifocal ectopic ventricular contractions originating in Purkinje arborizations, progressive cardiac conduction defect (Lenègre disease), sudden infant death syndrome, sick sinus syndrome, sudden unexplained nocturnal death syndrome, among other sodium channel alterations with clinical overlapping. Finally, it seems appropriate to consider the “sodium channel syndrome” (mutations in the gene of the α subunit of the sodium channel, SCN5A gene) as a single clinical entity that may manifest in a wide range of phenotypes, to thus have a better insight on these cardiac syndromes and potential outcomes for their clinical treatment

Vectocardiographic analysis of right ventricular electrical conduction delay

Introduction: The electrocardiographic interpretation of end conduction delay (ECD) in the right ventricular branch of the heart has already generated some hypotheses that this right branch is not single, as anatomically demonstrated, and can be divided into distinct terminal branches when we analyze tracings through the vectorcardiogram. Methods: There were 227 electrocardiograms selected, with typical characteristics defined as ECD of patients from the electrocardiography service of the Centro Universitário Saúde ABC, of both sexes, in the age range of 18 to 87 years, with varied ethnicities, weight and height, with cardiovascular risk factors or without them. We performed vectorcardiograms in these patients to observe the behavior of the final portion of electrical conduction. Results: Analyzing the vectorcardiographic tracings of patients who presented ECD in electrocardiogram, we confirmed in the recording by the frontal plane, the presence of ECD but recorded in three distinct regions; 103 patients in the right upper quadrant between -120° and -150°, 45 patients in the right lower quadrant between +170° and -170°, and medial, and 79 patients in the right lower quadrant between +110° and + 140°. Conclusion: Electrical depolarization of the heart in the right ventricle in electrocardiographic tracings apparently records typical alterations that we can diagnose as depolarization of a single bundle; but when we performed vectorcardiograms, we recorded three distinct zones of right ventricular depolarization with delay; i.e., three distinct sectors of right ventricle free wall delay, such as type I (upper), type II (lower) and type III (medial).publishedVersionPeer reviewe

Study of light-induced formation of photodimers in the i-motif nucleic acid structure by rapid-scan FTIR difference spectroscopy and hybrid hard- and soft-modelling

The i-motif is a DNA structure formed by cytosine-rich sequences, very relevant from a biochemical point of view and potentially useful in Nanotechnology as pH-sensitive nanodevices or nanomotors. To provide a different view on the structural changes and dynamics of direct excitation processes involving i-motif structures, the use of rapid scan FTIR spectroscopy is proposed. Hybrid hard- and soft-modelling based on the Multivariate Curve Resolution by Alternating least squares (MCR-ALS) algorithm has been used for the resolution of rapid-scan FTIR spectra and the interpretation of the photochemically induced time-dependent conformational changes of i-motif structures. The hybrid hard- and soft-modelling version of MCR-ALS (HS-MCR), which allows the introduction of kinetic models to describe the process behavior, provides also rate constants associated with the transitions modeled. The results show that i-motif structures formed by short DNA sequences present higher structural changes upon UV irradiation than those formed by long sequences with additional structural stabilizing elements, such as hairpins

i-motif structures in long cytosine-rich sequences found upstream of the promoter region of the SMARCA4 gen

Cytosine-rich oligonucleotides are capable of forming complex structures known as i-motif with increasingly studied biological properties. The study of sequences prone to form i-motifs located near the promoter region of genes may be difficult because these sequences not only contain repeats of cytosine tracts of disparate length but also these may be separated by loops of varied nature and length. In this work, the formation of an intramolecular i-motif structures by a long sequence located upstream of the promoter region of the SMARCA4 gene has been demonstrated. Nuclear Magnetic Resonance, Circular Dichroism, Gel Electrophoresis, Size-Exclusion Chromatography, and multivariate analysis have been used. Not only the wild sequence (5'-TC3T2GCTATC3TGTC2TGC2TCGC3T2G2TCATGA2C4-3') has been studied but also several other truncated and mutated sequences. Despite the apparent complex sequence, the results showed that the wild sequence may form a relatively stable and homogeneous unimolecular i-motif structure, both in terms of pH or temperature. The model ligand TMPyP4 destabilizes the structure, whereas the presence of 20% (w/v) PEG200 stabilized it slightly. This finding opens the door to the study of the interaction of these kind of i-motif structures with stabilizing ligands or proteins

The CIM-UVigo plug-in hybrid propulsion vessel for coastal oceanographic research: a tool for the ecological transition

Peer Reviewe

Study of conformational transitions of i-motif DNA using time-resolved fluorescence and multivariate analysis methods

Recently, the presence of i-motif structures at C-rich sequences in human cells and their regulatory functions have been demonstrated. Despite numerous steady-state studies on i-motif at neutral and slightly acidic pH, the number and nature of conformation of this biological structure are still controversial. In this work, the fluorescence lifetime of labelled molecular beacon i-motif-forming DNA sequences at different pH values is studied. The influence of the nature of bases at the lateral loops and the presence of a Watson-Crick-stabilized hairpin are studied by means of time-correlated single-photon counting technique. This allows characterizing the existence of several conformers for which the fluorophore has lifetimes ranging from picosecond to nanosecond. The information on the existence of different i-motif structures at different pH values has been obtained by the combination of classical global decay fitting of fluorescence traces, which provides lifetimes associated with the events defined by the decay of each sequence and multivariate analysis, such as principal component analysis or multivariate curve resolution based on alternating least squares. Multivariate analysis, which is seldom used for this kind of data, was crucial to explore similarities and differences of behaviour amongst the different DNA sequences and to model the presence and identity of the conformations involved in the pH range of interest. The results point that, for i-motif, the intrachain contact formation and its dissociation show lifetimes ten times faster than for the open form of DNA sequences. They also highlight that the presence of more than one i-motif species for certain DNA sequences according to the length of the sequence and the composition of the bases in the lateral loop

Três necessidades urgentes na batalha contra COVID-19: medicamentos específicos, informações e aceitação da Pandemia

The first confirmed case of COVID-19 was notified to the Brazilian Ministry of Health on February 26, 2020. On November 20, 2021, by the end of Epidemiological Week-46 (EW-46) 257,168,692 confirmed cases of COVID-19 reported worldwide. Among the countries with the highest number of accumulated cases the United States of America ranks number one (47,701,872), followed by India (34,510,413), Brazil (22,012,150), the United Kingdom (9,857,658), and Russia (9,135,149). Concerning deaths, 5,146,467 were confirmed worldwide until November 20, 2021. The United States was the country with the highest accumulated number of deaths (771,013), followed by Brazil (612,587), India (465,662), Mexico (292,145), and Russia (257,891).ResumoO primeiro caso confirmado de COVID-19 foi notificado ao Ministério da Saúde (MS) do Brasil em 26 de fevereiro de 2020. Até o final da Semana Epidemiológica (SE) 46 de 2021, no dia 20 de novembro de 2021, foram confirmados 257.168.692 casos de covid-19 no mundo. Os Estados Unidos foram o país com o maior número de casos acumulados (47.701.872), seguido pela Índia (34.510.413), Brasil (22.012.150), Reino Unido (9.857.658) e Rússia (9.135.149). Em relação aos óbitos, foram confirmados 5.146.467 no mundo até o dia 20 de novembro de 2021. Os Estados Unidos foram o país com maior número acumulado de óbitos (771.013), seguido do Brasil (612.587), Índia (465.662), México (292.145) e Rússia (257.891

Os efeitos do exercício aeróbico sobre os parâmetros bioquímicos em indivíduos com DRC em hemodiálise: Um estudo longitudinal

Background: Chronic kidney disease is directly related to cardiovascular disorders. Guided physical exercises significantly improve the adverse effects of dialytic treatment. Objective: To analyze changes in biochemical parameters of subjects with chronic kidney disease undergoing moderate exercise during hemodialysis. Methods: This is an experimental study composed of 54 subjects submitted to hemodialysis, split into a control group and a group with intervention. The experimental group underwent three weekly sessions of aerobic exercise, performed during hemodialysis sessions, with a duration of 30 minutes, for 12 weeks. The blood parameters of both groups were compared. Results: Statistically significant differences were observed between pre (p=0.001) and post-exercise protocol for urea (p=0.006), calcium (p=0.001), alanine aminotransferase (p=0.020) and sodium (p=<0.001). In the control group, we observed significant differences for the calcium variable (p<0.001), alanine aminotransferase (p=0.024), hematocrit (p=0.015), calcium vs phosphorus (p=0.018), and sodium (p=0.023), before and after the period. Conclusion: Aerobic training during hemodialysis was able to maintain blood level stability in patients with chronic kidney disease, both during and at the end of the protocol, even considering increased blood flow. This trial is registered in the Brazilian registry of clinical Trials - number RBR-7354r6. Registration date: July 5, 2018 at 12:59 PM. Last Update: July 24, 2018 at 10:24 AM. Identification of the test - UTN Number: U1111-1216-8272.Introdução: A doença renal crônica está diretamente relacionada a distúrbios cardiovasculares. Exercícios físicos guiados melhoram significativamente os efeitos adversos do tratamento dialítico. Objetivo: Analisar as alterações nos parâmetros bioquímicos de indivíduos com doença renal crônica submetidos a exercícios moderados durante a hemodiálise. Método: Este é um estudo experimental composto por 54 indivíduos submetidos à hemodiálise, divididos em um grupo controle e um grupo com intervenção. O grupo experimental passou por três sessões semanais de exercício aeróbico, realizadas durante as sessões de hemodiálise, com duração   de 30 minutos, por 12 semanas. Os parâmetros sanguíneos de ambos os grupos foram comparados. Resultados: Diferenças estatisticamente significativas foram observadas entre o protocolo pré (p=0,001) e pós-exercício para urea (p=0,006), cálcio (p=0,001), alanina aminotransferase (p=0,020) e sódio (p=&0.001). No grupo controle, observamos diferenças significativas para a variável cálcio (p<0.001), alanina aminotransferase (p=0,024), hematócrito (p=0,015), cálcio vs fósforo (p=0,018) e sódio (p=0,023), antes e depois do período. Conclusão: O treinamento aeróbico durante a hemodiálise foi capaz de manter a estabilidade do nível sanguíneo em pacientes com doença renal crônica, tanto durante quanto no final do protocolo, considerando mesmo o aumento do fluxo sanguíneo. Este ensaio está registrado no registro brasileiro de Ensaios Clínicos - número RBR-7354r6. Data de inscrição: 5 de julho de 2018 às 12h59. Última atualização: 24 de julho de 2018 às 10h24. Identificação do teste - UTN Número: U1111-1216-8272

Fractalidade e comportamento caótico da variabilidade da frequência cardíaca como preditores de hipotensão após raquianestesia: protocolo de ensaio clínico randomizado

Introduction: All drugs and techniques that induce the anesthetic state act in some way in the Autonomic Nervous System (ANS). The administration of local anesthetics in the subarachnoid space produces motor, sensitive and sympathetic block, with latencies and variable and independent block levels. The motor block is the first to install, followed by the sympathetic and the sensitive. Sympathetic blockage affects 2 to 6 dermatomes above the sensory block. The recovery of spinal anesthesia is assessed through a scale defined in 1979 by Bromage and is based exclusively on the return of motor function and does not take into account the recovery of ANS activity. The persistence of sympathetic block may imply a higher incidence of urinary retention, bradycardia and hypotension. Objective: To assess cardiac autonomic modulation during perioperative hypotension caused by subarachnoid anesthesia. Methods: A randomised, double-blind clinical trial will be performed in a large hospital located in the southern region of Ceará, Brazil and at the HUJB in Cajazeiras, Paraíba. Sixty patients from the anaesthesia outpatient clinic were enrolled. Patients were divided into two groups: one group received Bupivacaine with clonidine, and the other group received only bupivacaine at a dose of 15 mg. The sample consisted of 60 ASA patients I to III, submitted to orthopedic surgery of lower limbs and lower abdomen under spinal anesthesia. The Heart Rate Variability will be evaluated in three moments: rest, before anesthesia; 20 min after the blockade was installed, and at the time of motor function recovery according to the Bromage criteria and prognostic indices will be evaluated in the development of perioperative hypotension in two groups. Linear methods will be used in the frequency domain and nonlinear in chaos domain, Poincaré plot, approximate entropy, Detrended Fluctuation Analysis (DFA) and Correlation Dimension. The data will be collected through a Polar V800® heart rate meter and properly submitted for analysis and filtering by Kubios 3.0® software. Discussion: In the literature we find data evaluating the installation of sympathetic block through HRV using linear methods however, there is a lack of studies using methods based on the domain of chaos. Some studies address the value of HRV as a predictor of hypotension following subarachnoid anesthesia, mainly using linear methods in the frequency domain. It is understood to be important to analyze these factors using methods already validated in the domain of chaos, complexity and fractality, more compatible with the complexity of the behavior of biological systems, in the characterization of the autonomic function during the subarachnoid anesthesia. Registry: The clinical trial was registered in the Brazilian Registry of Clinical Trials (ReBEC) under the number RBR-4Q53D6.Introdução: Todas as drogas e técnicas que induzem o estado anestésico atuam de alguma forma no SNA. A administração de anestésicos locais no espaço subaracnóideo produz bloqueio motor, sensitivo e simpático, com latências e níveis de bloqueio variáveis e independentes. O bloqueio motor é o primeiro a ser instalado, seguido pelo simpático e sensitivo. O bloqueio simpático afeta de 2 a 6 dermátomos acima do bloqueio sensitivo. A recuperação da raquianestesia é avaliada através de uma escala definida em 1979 por Bromage e baseia-se exclusivamente no retorno da função motora e não leva em conta a recuperação da atividade da SNA. A persistência do bloqueio simpático pode implicar em maior incidência de retenção urinária, bradicardia e hipotensão. Objetivo: Caracterizar a variabilidade da frequência cardíaca durante anestesia subaracnóidea por meio de métodos lineares no domínio da frequência e métodos não lineares no domínio caos e definir a duração do bloqueio autonômico em raquianestesia através desses parâmetros, bem como identificar índices de variabilidade da frequência cardíaca (VFC) que podem ser usados como preditores de hipotensão perioperatória. Método: Um ensaio clínico randomizado, duplo-cego será realizado em um hospital de grande porte localizado na região sul do Ceará, no Brasil, e no HUJB em Cajazeiras, na Paraíba. Sessenta pacientes do ambulatório de anestesia serão incluídos. Os pacientes serão divididos em dois grupos: um grupo receberá Bupivacaína com clonidina e o outro grupo receberá apenas bupivacaína na dose de 15 mg. A amostra será composta por 60 pacientes ASA I a III, a serem submetidos a cirurgia ortopédica de membros inferiores e abdome inferior sob raquianestesia. A Variabilidade da Frequência Cardíaca será avaliada em três momentos: repouso, antes da anestesia; 20 min após a instalação do bloqueio, e no momento da recuperação da função motora, de acordo com os critérios de Bromage. Será avaliada a incidência de hipotensão perioperatória nos dois grupos. Métodos lineares serão utilizados no domínio da freqüência e não-lineares no domínio do caos: plot de Poincaré, entropia aproximada, Análise de Flutuação Destendenciada (DFA) e Dimensão de Correlação. Os dados serão recolhidos através de um cardiofrequencímetro Polar V800® e devidamente submetidos para análise e filtragem pelo software Kubios 3.0®.  Discussão: Na literatura encontramos dados avaliando a instalação do bloqueio simpático através da VFC utilizando métodos lineares, no entanto, faltam estudos utilizando métodos baseados no domínio do caos. Alguns estudos abordam o valor da VFC como um preditor de hipotensão após a anestesia subaracnóidea, principalmente usando métodos lineares no domínio da frequência. Entende-se ser importante analisar esses fatores utilizando métodos já validados no domínio do caos, complexidade e fractalidade, mais compatíveis com a complexidade do comportamento dos sistemas biológicos, na caracterização da função autonômica durante a anestesia subaracnóidea. Registro: O ensaio clínico foi registrado no Registro Brasileiro de Ensaios Clínicos (ReBEC) sob o número RBR-4Q53D6