Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

The aim of this work is design of system for wireless data collection from energy meters. The work shows issues of smart metering and explains meters communication. There is designed and described concept of the system composed of RF modules connected to data concentrator. Designed RF module uses SoC radio CC430F5137 and it is connected to a data concentrator via RS485 bus. For the purposes of communication as well as firmware update, the communication protocol is designed. In the next part the work focuses on design and creation of RF module frmware, bootloader for RF module and software application for energy meter data processing.

<div>My PhD thesis evolves around the potential protective effects of sex hormones progesterone and testosterone against drug-induced QT interval prolongation in premenopasual women and older men.<br></div>

The mechanical contraction of the heart is tightly coupled to rapid and concerted electrical excitation of the cardiac muscle. This electrical activity is facilitated by a highly synchronized conduction system consisting of channels, pumps, and transporters that facilitate the flow of charged ions between cellular compartments, the cytoplasm, and the interstitial fluid between cells. The biophysical properties of these membrane proteins have been studied for many years, but their role in the generation of potentially lethal cardiac arrhythmias and their interactions with drugs remains an important field of research. The cardiac isoform of the voltage-gated Na+-channel, Nav1.5, has garnered widespread interest because of its role in the generation of electrical impulses in the cardiac myocyte, its association with congenital conduction disorders and acquired cardiac arrhythmias, and its unique pharmacological properties. The Congenital Long QT Syndrome Type 3 (LQT3) arises from heritable mutations in SCN5A - the gene encoding Nav1.5 - that disrupt the inactivation process responsible for imparting a refractory period and that often cause a sustained depolarizing late current (INaL). The gain of function depolarizing currents arising from LQT3 mutant channels cause a prolongation of the ventricular action potential and leave patients susceptible to asynchronous electrical activity, ventricular arrhythmias, and sudden cardiac death. The disruption of channel inactivation can arise through a wide range of modalities, including changes in inactivation voltage-dependence and kinetics, and has been shown to occur with varying degrees of severity. Because of this range of phenotypes there is heterogeneity in the risk factors for arrhythmia and sudden cardiac death and in the utility of Na+-channel blocking antiarrhythmic drugs. Moreover, INaL has been implicated as a proarrhythmic and potentiating factor in several acquired cardiac ailments including heart failure, ischemia, and hypertrophy. There is therefore a large unmet need for improved understanding of INaL and mechanisms of its selective inhibition, and LQT3 mutant channels provide a reliable experimental model for this class of cardiac arrhythmias. This study will employ a combination of electrophysiological and computational methods to unravel mechanisms by which mutant Nav1.5 produces pro-arrhythmic currents and the interactions of different disease-causing mutant channels with a set of clinically relevant antiarrhythmic drugs. Chapter 1 of this study presents a functional characterization of one LQT3 mutation, F1473C, that was discovered in a patient with severe QT prolongation, frequent ventricular arrhythmias, and a poor response to pharmacological intervention. This mutation gives rise to INaL by a mechanism that is functionally distinct from the mechanism discovered previously in the canonical LQT3 mutation, ΔKPQ (1505-1507del), and causes a unique response to channel inhibitors. In order to better understand the mechanisms of this divergent pharmacology, Chapter 2 presents the development of a series of computational models which explore the gating dysfunctions that cause INaL and how these pathological changes can influence the predicted safety and efficacy of pharmacological intervention. These models predict that the majority of mutation- specific drug effects can be attributed to differential mutant channel gating, but raise the possibility that mutations may directly alter the physical chemical interaction between drugs and channels. Finally, Chapter 3 presents an attempt to explore this possibility using an innovative chemical biology technique - the site-specific incorporation of unnatural amino acids - that allows for the measurement of precise chemical interactions hypothesized to vary in a mutation-dependent manner. The findings presented in this work promote the need for patient-specific screening of antiarrhythmic agents and lay the groundwork for the use of in silico systems analysis of cardiovascular pharmacology.

Background: Hypertrophic Cardiomyopathy (HCM) and Long QT Syndrome (LQTS) are genetic cardiovascular diseases that cause sudden cardiac death. When an individual is diagnosed with an inherited disease such as HCM/LQTS it is critical that their biological relatives are notified of their increased risk. Newly diagnosed individuals in turn notify other at-risk family members through a successive process called cascade screening. This facilitates screening of at-risk biological relatives through genetic testing and/or clinical testing, and treatment for HCM/LQTS prior to development of life-threatening complications. However, for cascade screening to detect all potential cases the disease risk must be effectively communicated to all at-risk relatives. The responsibility for notifying family members of this risk largely falls to the first person diagnosed in the family (proband). Empiric evidence suggests that around half of at-risk relatives are not screened in accordance with cascade screening recommendations, potentially due to information about HCM/LQTS risk not being communicated effectively in their families. Factors have been identified that influence communication about genetic risk in families with non-cardiac disease; however, it is not known if or how these factors apply in families with genetic cardiac disease. These include network factors, which describe characteristics of relationships between family members and non-network factors, which describe characteristics of individuals including individual factors, disease factors, and sociocultural factors. There is a critical need to understand communication in families with HCM/LQTS in order to facilitate effective genetic risk communication in families, improve adherence to cascade screening recommendations, and prevent death and complications from cardiovascular diseases. Objectives: The purpose of this study was to improve our understanding of the relationships among network and non-network factors and communication of genetic risk for HCM/LQTS between probands and their relatives. I proposed the following aims: Aim 1: Describe family social network structures and communication paths about risk for HCM/LQTS from probands to their relatives. Aim 2: Identify which network and non-network factors are associated with who is told about risk for HCM/LQTS. Methods: The sample for this study included individuals with HCM or LQTS recruited through the University of Iowa Cardiology Clinics (UI) and the University of Wisconsin Inherited Arrhythmia Clinic (UW). Data were collected using a structured interview, family pedigree, and survey. Analysis included egocentric social network analysis, descriptive, bivariate, and multilevel logit regression modeling. Results: Participants in this study had an average of 24 living at-risk relatives in their families. Overall, just over half (52%) of these at-risk relatives had been reported to have been told about their risk. However, within families, the percentage of relatives told about their risk ranged from 0%-100%. Ninety percent of first-degree relatives were told about their risk, 61% of second-degree relatives were told and 33% of third-degree relatives were told. Recruitment site affiliation was determined to be a confounder and so analyses were calculated separately for UI and UW. In both the UI and UW samples, network factors including closer geographic distance, increased emotional closeness, increased relationship quality, increased frequency of communication, higher betweenness centrality, and closer degree of biological relation were independently associated with increased odds of communication of risk. In the UI sample, non-network factors that were independently associated with increased odds of communication of risk included younger age at diagnosis; having LQTS; having positive genetic test results; having an ICD; younger current age; being female; having increased role limitations due to physical functioning; feeling anxious about telling family members about risk; feeling communication was a burden; feeling that communication was a responsibility or duty; being happy to be able to share important information; and identifying financial issues, pregnancies, or upcoming marriages as playing a role in communication. In a multivariate model, increased frequency of communication, closer degree of biological relation, having an ICD, and identifying financial issues and pregnancies as contributors to communication were significantly associated with communication of genetic risk information. In the UW sample, non-network factors that were independently associated with increased odds of communication of risk included younger age, decreased emotional wellbeing, increased role limitations due to emotional wellbeing, and decreased energy and fatigue. In a multivariate model, increased frequency of communication and closer degree of biological relation were significantly associated with communication. Although over half of at-risk relatives were told about their risk, just over half of those (53.8%) were reported to have screened for disease, which represents 27% of all at-risk relatives. Of those tested, 35% were reported as diagnosed with HCM/LQTS. Conclusion: Communication of genetic risk for HCM/LQTS in families is inadequate and contributes to the problem of relatives not being screened for disease. Insight on the factors that influence communication in families at risk of sudden cardiac death can guide development of interventions, policies, and future research aimed at improving genetic risk communication and cascade screening, and preventing death and complications from inherited cardiac diseases. This research is applicable for genetic conditions where population based screening methods are not effective and rely on families to communicate risk and need for screening.

Traditional SPICE simulation tools and applications of circuit theory lack real-time interaction and feedback. The goal of this thesis was to create an interactive physical environment to allow the manipulation and simulation of discrete electrical components in near-real-time while optimizing and streamlining the human-computer interaction (HCI) elements to make the user experience as positive and transparent as possible. This type of HCI and near-real-time simulation feedback would allow for the instant realization of how the parameters of each discrete component or hardware module affect the overall simulation and response of the circuit. The scope of this thesis is to research, design and develop two real-time interactive SPICE simulation tools and analyze the real-time benefits and HCI elements of both simulators, principally the user interface design itself. The first real-time interactive simulator (TouchSPICE) uses multiple embedded processors (touchscreen hardware blocks) and a host computer to build and simulate a circuit. The second real-time interactive simulator (ReActive-SPICE) uses a single host computer with integrated software to build and simulate a circuit, much like LTspice™ and PSpice™ without the real-time aspects. As part of the study, 20 students were asked to create circuits utilized in undergraduate-level labs using TouchSPICE and ReActive-SPICE for the sole purpose of providing feedback on the two user interfaces. Students were asked to complete a survey before, during and after circuit creation to provide a basis for judging the intuitiveness, efficiency and overall effectiveness of the HCIs. Conclusions based-off the surveys support the hypothesis that both TouchSPICE and ReActive-SPICE were more intuitive and overall simpler than traditional SPICE simulation tools. Feedback collected showed TouchSPICE to have a more intuitive user interface while ReActive-SPICE proved to be more efficient. ReActive-SPICE was further developed and enhanced to improve the user interface as well as the overall circuit creation and real-time simulation processes.

Le syndrome du QT long (SQTL) est une anomalie du coeur caractérisée par une prolongation de l'intervalle de repolarisation entre les ondes Q et T sur l'électrocardiogramme. Ce syndrome pouvant provoquer de l'arythmie et même la mort peut être causé par des mutations génétiques, ou par la prise de certains médicaments. Plusieurs médicaments vendus sous ordonnance qui induisaient le syndrome du QT long ont été retirés du marché au cours de la dernière décennie et plusieurs autres ont échoué les tests de contrôle avant même leur sortie en pharmacie. La plupart de ces médicaments provoquent le SQTL à des doses thérapeutiques et dans pratiquement tous les cas, le syndrome est causé par une interaction du médicament avec le canal potassique transmembranaire du human ether-à-go-go-related-gene (hERG). Selon plusieurs études, la majorité des molécules qui bloquent le canal hERG se lieraient à des sites localisés dans la partie intracellulaire de la région du pore (hélice transmembranaire S5 et/ou S6) ou dans la région extracellulaire qui connecte S5 et S6. Dans la présente recherche, le rôle du segment extracellulaire (lIe583 -Tyr597 ) dans le fonctionnement du canal hERG et dans le mécanisme du SQTL fut étudié. Pour ce faire, l'interaction de ce segment avec quatre médicaments cardiotoxiques (bépridil, cétirizine, diphenhydramine, pentamidine) fut analysée en plus de vérifier l'interaction de ce segment et des médicaments avec des membranes modèles. Une approche combinant la RMN de l'état liquide et de l'état solide jumelée avec des analyses de dichroïsme circulaire a permis d'obtenir les conclusions suivantes. Tout d'abord, les résultats des interactions peptide-médicaments étudiées par RMN de l'état liquide du ¹H par des mesures de diffusion à l'aide de gradients de champ pulsés suggèrent une faible interaction du peptide avec chacun des médicaments dans un environnement aqueux. Cependant, une très forte interaction des médicaments et du peptide avec la membrane a été observée, suggérant un rôle potentiel de cette dernière dans la cardiotoxicité des médicaments provoquant le SQTL. Ensuite, les résultats des interactions médicaments-membranes et peptide-membrane étudiées par RMN de l'état solide du ²H et du ³¹P suggèrent une importante perturbation de la membrane (tant au niveau des têtes polaires que des chaînes acyle) par le segment extracellulaire lIe583 -Tyr597 . Finalement, les analyses de dichroïsme circulaire ont permis de démontrer que ce segment n'adopte pas une structure secondaire bien définie malgré sa forte interaction avec la membrane. Cependant, la conformation de ce segment varie en fonction de la nature et de la charge de la membrane modèle, ce qui prouve sa grande flexibilité structurale. Ces résultats suggèrent que la membrane joue un rôle important dans le fonctionnement du canal hERG, probablement en stabilisant des conformations transitoires durant les processus d'ouverture et de fermeture contrôlés par voltage. En terminant, les expériences biochimiques réalisées ont permis d'exprimer avec succès le segment S5. Des expériences sont toujours en cours pour purifier ce segment. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Syndrome du QT long, hERG, Médicaments cardiotoxiques, Membrane modèle, RMN de l'état liquide, RMN de l'état solide, Interaction médicaments-membranes, Interaction peptide-membranes.

¡@¡@An embedded system has improved quickly in recent years and now functions like a small computer. Equipped with operating systems (OS), graphic user interfaces (GUI), and software developed for various platforms, an embedded system provides users with services more powerful and friendlier than ever. Qt/Embedded and OpenGL ES are an OS and a GUI developed for embedded systems. In this thesis, We integrated Qt/Embedded with OpenGL ES on a Versatile PB 92EJ-S and conducted various tests. ¡@¡@The Versatile PB 92EJ-S was equipped with ARM926EJ-S, an onboard chip capable of performing VFP9 vector floating operation. However, not all embedded systems are powered by a floating coprocessor. To make the test results applicable to all systems, We performed only fixed-point operations, a practice also improving the overall performance. In addition, to provide communications between OpenGL ES and Windows and interfaces for OpenGL ES to draw, We implemented EGL, a platform interface layer defined in OpenGL ES. Furthermore, We developed GLUT ES, a modification of GLUT, to make the embedded system compatible with Windows of different versions. Finally, We benchmarked the platform with programs developed by GLUT ES interfaces and OpenGL ES.

<p>The paper deals with the development of a remote management solution for embedded audio devices. The creation of a development environment for the embedded ARM target is discussed as well as several available solutions for remote system management. The creation of a service for stream and system management using SNMP is discussed as well as several changes to the SNMP standard to improve performance using multicast. The implementation of a proof-of-concept cross-platform user interface for the client side is described as well.</p>