Planning functional neurosurgical procedures to minimize the effects of movement disorders requires the accurate localization of small subcortical structures for the creation of lesions (in the thalamus or the globus pallidus) or the implantation of deep brain stimulating electrodes (in structures such as the thalamus, globus pallidus, and the subthalamic nucleus). Standard computed tomography (CT) and magnetic resonance imaging techniques (MRI) have limited signal, resolution, and contrast in subcortical regions, thereby complicating target localization. Modern imaging and image processing techniques have demonstrated that targets are better identified using digital atlases which can be customized to each patients unique anatomy. In this thesis, multi-modal techniques for targeting subcortical nuclei in neurosurgical interventions are presented. Chapter 3 describes the development of a new atlas of the subcortical anatomy developed from a set of manually segmented high-resolution serial histological data using novel reconstruction techniques. The atlas was warped to fit a high-resolution, high-contrast MRI template and all versions of the atlas can be viewed in register to allow enhanced visualization of the subcortical anatomy and contains 105 structures. To accurately target subcortical structures on pre-operative MRI data, the atlas must be customized to each patient. Chapter 4 contains a validation of warping techniques for atlas-to-patient warping. An overlap metric is used to compare the atlas definition of three subcortical structures with a silver standard derived from the agreement of manual segmentations of five manual raters. A functional validation was also performed to compare the coordinates locations of positive intra-operative stimulations and the atlas definition of the sensory thalamus. The manual segmentations of the clinical data were also used to compare two linear, two piecewise linear, and four nonlinear registration based atlas warping / Le planning des procedures fonctionnelles neurochirurgicales pour minimiser les troubles du mouvement demande une localisation précise des petites structures subcorticales pour la creation de lesions (dans le thalamus ou le globus pallidus) ou pour l'implementation d'electrodes profondes (dans des structures comme le thalamus, le globus pallidus ou le noyau subthalamique). Le scanner a rayons X (CT) ou l'imagerie par resonance magnétique (IRM) ont un signal, une resolution et un contraste limites dans les regions subcorticales, compliquant ainsi la localisation de la cible. Les techniques modernes d'imagerie et de traitement d'images ont demontre que les cibles sont mieux identifiees en utilisant des atlas digitaux ajuste a l'anatomie de chaque patient. Dans cette these, sont presentees des techniques multi-modales pour cibler les noyaux subcorticaux dans les interventions neurochirurgicales. Le chapitre 3 décrit la creation d'un nouvel atlas de l'anatomie subcorticale, développe a partir d'une serie de coupes histologiques consecutives, utilisant des techniques de reconstruction innovantes. Cet atlas a ete deforme pour s'ajuster a un modele IRM de haute resolution et de fort contraste. Toutes les versions de l'atlas peuvent etre recale pour permettre une visualisation amelioree de l'anatomie subcorticale contenant 105 structures. Pour cibler precisement les structures subcorticales sur les donnees IRM preopreratoires, l'atlas doit etre s'ajuster a la conformation individuelle du cerveau du patient. Le chapitre 4 contient une validation des techniques de déformations pour les déformations allant d'un atlas vers l'anatomie du patient. Une mesure de recouvrement est utilisee pour comparer trois structures subcorticales definies par l'atlas et des segmentations manuelles de ces structures utilises comme reference (silver standard) et definiees par consensus entre cinq opérateurs. Une validation fonctionnelle a egalement ete realisee afin de comparer le pos

This observational study compared the value of physician-administered Advanced Life Support (MD-ALS) to Basic Life Support (BLS) in the treatment of penetra1mg trauma in an urban setting. / Patients were identified in Montreal and Quebec City between 1993 to 1997 Prehospital care is provided exclusively by Urgences Sante in Montreal. Patients in Montreal are randomly allocated to either ALS or BLS due to an insufficient number of MD-ALS units. The south shore of Montreal and Quebec City are serviced by a separate emergency medical system (EMS) which provides only BLS. / Differences were not statistically significant in terms of age and ISS between treatment groups. Mortality, when examined using both the Intent to Treat and Efficacy approaches, did not differ between ALS and BLS patients. Prehospital treatment type was not a significant predictor of mortality, or length of hospital stay. Patients treated by MD-ALS required home-care services more often than BLS patients once discharged, and spent significantly more time at the injury scene.

Definitive repair of complex congenital cardiac defects in early life has become the recent trend in pediatric cardiac surgery. This early aggressive surgical approach is to avoid the detrimental effects on the heart of chronic cyanosis, hypertrophy and volume overload which are the consequences of unrepaired congenital malformations. Adequate protection of the heart, not only during the period of corrective surgery, but also certain pre-ischemic events remain of paramount importance to the success of these operations. Profound systemic hypothermia followed by total circulatory arrest is widely used for the correction of congenital cardiac defects in the newborn. It involves a period of cold systemic perfusion on cardiopulmonary bypass before circulatory arrest is established. Using an isolated perfused piglet heart model, the first study demonstrated that prolonged cold perfusion of the immature heart could be detrimental in itself. When followed by a period of ischemic arrest, it further potentiated the myocardial injury and induced severe irreversible contracture. Further extension of this study showed that verapamil administered prior to prearrest cold perfusion could indeed minimize the functional and ultrastructural damage of prolonged myocardial cooling. This shed some light to the pathophysiology of prolonged prearrest cooling contracture of the newborn myocardium.

The current generation of small caliber artificial vascular grafts occlude within a short period of time due to various problems involving blood-biomaterial interactions. One way of circumventing this is to introduce a monolayer of endothelial cells (EC) onto the graft before implantation to mimic a natural human vascular state. In this way, a hemostatic-thrombotic equilibrium can be maintained. Current methods used to transplant cells onto grafts include the pre-coating of grafts with extracellular matrix proteins like fibronectin and fibrin, as well as other methods like ammonia plasma surface modification of grafts. But little is known about the effects of surface modifications on ECs' ability to secrete prostacyclin (PGI2, anti-platelet thrombomodulators), tissue plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAM, both fibrinolytic proteins). Our studies show that uncoated and fibronectin (fn) coated ammonia plasma modified poly(tetrafluoroethylene)(PTFE) are capable of secreting high amounts of PGI2. Furthermore, these surfaces secrete highly active t-PA proteins but relatively low amounts of PAI-1. Thus, uncoated and Fn coated modified PTFE support optimal conditions that provide for a non-thrombogenic surface, and may be suitable to further develop protocols and other strategies for arterial and venous reconstruction. Another strategy that we implemented was to further enhance the secretion of t-PA by EC. In this approach, we established a retroviral-mediated transfection protocol wherein human t-PA sequences encoded in a plasmid (PB2NSt) were stably integrated into the EC genome.

Previous studies have shown that mortality reduction with thrombolysis in acute myocardial infarction depends in part on time to thrombolysis, which can be shortened by administering these drugs in the Emergency Department (ED). This study was undertaken to determine the appropriateness of thrombolytic use by Emergency Physicians, and to determine complication rates of ED thrombolysis. / The charts of 137 patients admitted from a tertiary care hospital ED with acute coronary syndromes were assessed for concordance with standard Canadian thrombolytic guidelines, based on a blinded review by two independent assessors. The adjusted Kappa statistic for the overall concordance with the guidelines was 0.85 (95% CI 0.76-0.94). Hierarchical modeling was used to estimate the distribution of physician-specific concordance rates. Complication rates for thrombolysis in the ED were similar to previously reported rates. A logistic regression was also carried out to identify other independent predictors of thrombolysis after controlling for eligibility for thrombolysis; none were found. / The results indicate excellent agreement between Emergency Physicians' clinical decisions regarding thrombolysis and standard Canadian thrombolysis guidelines.

Introduction. The mechanism by which transmyocardial revascularization (TMR) exerts a beneficial effect remains unknown. This thesis hypothesizes that myocardial punctures for TMR cause a myocardial injury, leading to an angiogenic response mediated by a number of growth factors. / Methods. Fifty-three rats underwent ligation of the left coronary artery. Group I (n = 25) served as controls, while Group II (n = 28) underwent concomitant TMR by creating six transmural channels with a 25-gauge needle in the ischemic zone. Surviving animals in both groups were sacrificed at intervals of 1, 2, 4, and 8 weeks (n = 5 in each subgroup). Immunohistochemistry in the infarct areas was performed for factor VIII to assess vascular density. Immunohisto-chemistry using specific antibodies was also performed for transforming growth factor-beta (TGFbeta), basic-fibroblast growth factor (b-FGF), and vasoendothelial growth factor (VEGF). Growth factor expression was quantitated by comparing areas of staining (in mm2) using computerized morphometric analysis. / Results. Mortality was similar in both groups (5/25 vs. 8/28, p = NS). Group II had significantly greater vascular density than Group I (5.65 vs. 4.06 vessels/HPF, p < 0.001), with a peak at 1 week post-operatively (9.12 vs. 5.56 vessels/HPF, p < 0.0001) in both groups. Overall, both TGFbeta and bFGF were significantly higher in the TMR group compared to the control group (0.207 mm2/mm2 vs. 0.141 mm2/mm 2, p < 0.05 and 0.125 mm2/mm2 vs. 0.099 mm2/mm2, p < 0.05). / Conclusions. This model of TMR is associated with a significant angiogenic response, which appears to be mediated by the release of certain angiogenic growth factors such as TGFbeta and bFGF. With the long term patency of laser-created myocardial channels in clinical TMR increasingly in doubt, its mechanism of myocardial revascularization may be similar to that observed in our model.

This doctoral thesis includes four projects. The first project explored the role of innate HIV genetic polymorphisms in drug-selected mutations. By means of drug selection experiments, we comparatively evaluated emergent mutations in protease and reverse transcriptase in HIV-1 and HIV-2 subtypes. Genotypic and phenotypic analyses were used to determine time to appearance of resistance mutations and the levels of drug resistance, respectively. Natural polymorphisms in HIV-2 seemed to facilitate selection of protease inhibitor (PI) resistance: The acquisition of the I54M, I84V, L90M and L99F mutations resulted in multi-PI-resistant viruses. Nucleoside reverse transcriptase inhibitor (NRTI) combinations preferentially selected for the K65R mutation in HIV-1 subtype C, while in HIV-1 subtype B, and HIV-2 cultures favored the development of M184I. The K65R mutation was not detected in HIV-2 selections. These results underscore potential differences in emergent drug resistance pathways in HIV-1 and HIV-2 and the role that innate polymorphisms may have in dictating antiretroviral resistance pathways. In the second project, we studied the relationship between mutations in the RNase H domain on viral susceptibility to nucleoside analogues. Our results showed that although some mutations were observed in the connection domain, the presence of the L74V and M184V mutations was the most significant determinant of phenotypic resistance to ZDV in patients with thymidine analog-associated mutations. The third project performed a near full-length genomic analysis of a novel HIV-1 recombinant involving subtypes A1 and C in Quebec. The fourth project evaluated the genetic diversity of an / Cette thèse de doctorat comprend 4 projets. Le premier explore le rôle du polymorphisme génétique du VIH dans la sélection des mutations de résistance. Au cours des tests de sélection, nous avons évalué comparativement le délai dans lequel les mutations de résistance émergent dans la protéase et la transcriptase inverse des sous-types de VIH-1 et de VIH-2. Des analyses génotypiques et phénotypiques ont été utilisées pour déterminer le délai d'émergence et le niveau de résistance des mutations, respectivement. Le polymorphisme naturel du VIH-2 semble faciliter la sélection des mutations de résistance aux inhibiteurs de protéase (IPs). L'acquisition des mutations de résistance I54M, I84V, L90M et L99F entraine une résistance croisée à plusieurs IPs. Les combinaisons d'inhibiteurs nucléosidiques de la transcriptase inverse (INTI) sélectionnent préférentiellement la mutation K65R chez le VIH-1 de sous-type C alors que les cultures du sous-type B et le VIH-2 favorisent le développement de M184I. La mutation K65R n'a jamais été détectée dans les sélections de VIH-2. Ces résultats mettent en évidence des différences dans les mécanismes de résistance du VIH-1 et du VIH-2 et le rôle que certain polymorphisme jouent dans les voies génétiques de résistance. Dans le second projet, nous avons étudié la relation existante entre le polymorphisme dans la RNAse H et la sensibilité aux analogues nucléosidiques. Nos résultats montrent que bien que certaines mutations soient observées dans le domaine de connection, la présence des mutations L74V et M184V était le facteur déterminant de la résistance phénotypique à la ZDV chez les

Objective measurement of the subglottic lumen is still lacking in clinical practice. The objective of this study is to evaluate the accuracy of ultrasound and video-bronchoscopy in measuring the subglottic diameter in the pediatric population. This was a blind, prospective clinical study. Ten children undergoing non-life threatening bronchoscopy had their subglottic diameters measured with ultrasound, video-bronchoscopy and endotracheal tube sizing. / Ultrasound and video-bronchoscopy strongly correlated with endotracheal tube sizing in measuring the subglottic diameter. Ultrasound had measurements that were always smaller while video-bronchoscopy had measurements that were slightly larger than endotracheal tube sizing. Video-bronchoscopy may be more accurate than endotracheal tube sizing as the latter method will often underestimate the size of the lumen due to its own limitations. The smaller values obtained by ultrasound suggest it is not ideal to give absolute measurements in this area, but rather a potential tool to detect change of lumen size on follow-up.

Background. Up to 1600 Canadians/yr suffer a serious complication due to the diagnostic test ERCP (endoscopic retrograde cholangiopancreatography) used in the management of patients with suspected biliary obstruction. MRCP (magnetic resonance cholangiopancreatography) is a new highly accurate noninvasive alternative that is not associated with any significant complications. / Aims. To assess the real-life effectiveness and costs of MRCP versus ERCP in a planned interim analysis of a randomized clinical trial, in intermediate risk patients. To assist in the decision regarding study continuation versus termination. / Methods. 200 patients with a clinical and/or ultrasonographic (US) suspicion of obstruction were randomized to MRCP or ERCP, using block allocation stratified by level of obstruction. The primary endpoint was the occurrence of a negative outcome attributable to the biliopancreatic disease or procedures within 12 months of randomization. Secondary outcomes included complication-related length of stay (CRLOS), number of procedures, costs, mortality and accuracy. / Results. 102 patients were randomized to MRCP and 98 to ERCP with mean ages of 56.4 +/- 18 (SD) and 51.8 +/- 19 yrs, respectively. Median follow-up was 12 months. According to intention-to-treat analysis, 18 (17.6%) MRCP patients had a complication (CRLOS = 0.80 d/patient (excluding 1 outlier with CRLOS = 157d) versus 14 (14.3%) ERCP patients (CRLOS = 0.68d/patient); difference = 3.3% (95%CI: -7 to 13%). There were 45 fewer ERCPs but 90 extra MRCPs in the MRCP arm. ERCP was "dominant", with both marginally lower complications and lower costs by $1411/person (ITT). There was neither evidence for confounding nor effect modification. / Conclusions. In this interim analysis, it appears that a strategy that involves a screening MRCP in this group of patients is not cost-effective. The results of this primary analysis are unlikely to change with the recruitment of 200 additional patients into the trial.

Innovations in the practice of pediatric cardiology and cardiovascular surgery have resulted in significant improvements in the survival of children born with congenital heart disease. This has resulted in a growing population of adults with repaired or palliated congenital heart disease. However, these patients are at increased risk of impaired cardiovascular health, including mortality, particularly under conditions of physiological stress, such as operative reintervention, in later life. We hypothesized that neonatal hypoxia engenders lasting changes in cardiovascular structure and function which may adversely influence myocardial and vascular responses to physiological stress at maturity. To test this hypothesis, Sprague-Dawley rats reared initially in hypoxic conditions (FiO2 = 0.12) for days 1 to 10 of life were compared to rats reared only in ambient air. Neonatal hypoxia was associated with significant changes in the left ventricular expression of 1945 and 422 genes in 10- and 90-day-old animals, respectively. Functional annotation revealed several genes involved in adaptive vascular remodeling and energy metabolism, as well as the regulation of apoptosis. Trends in gene expression suggested a proapoptotic paradigm which was corroborated by data showing decreased survival, following an ischemia-reperfusion insult, of cardiomyocytes isolated from adult animals exposed to neonatal hypoxia. Based on the above observations, we next sought to characterize additional changes in cardiovascular structure and function, induced by neonatal hypoxia, which might enhance cardiomyocyte vulnerability to physiological stress in the adult animal. Hypoxic animals had significant left ventricular hypertrophy, as well as impaired cardiomyocte calcium homeostasis and sarcomere relaxation, observations which were consistent with in vivo echocardiographic evidence of severe diastolic dysfunction. Neonatal hypoxia was also associated with the development of significant remodeling of left ventricular arterioles resulting in decreased lumen area. Significant reduction in agonist-induced activation of Akt and ERK1/2 survival signalling, as well as decreased mitochondrial hexokinase 2 expression, were observed. Finally, the left ventricular protein expression of Gαi3, Gαi2, and HIF-1α was significantly increased in adult animals following neonatal hypoxia.The above observations were evaluated in the context of the clinical challenges associated with the care of adult patients with congenital heart disease, and the potential clinical implications of these data are discussed. / Les innovations dans la pratique de la cardiologie et de la chirurgie cardio-vasculaire pédiatrique ont entraîné des améliorations importantes dans la survie des enfants nés avec une cardiopathie congénitale. Cela a mené à une population croissante d'adultes ayant une maladie cardiaque congénitale réparée ou palliée. Cependant, ces patients sont à risque de santé cardio-vasculaire affaiblie, y compris la mortalité, en particulier dans des conditions de stress physiologique, tel que la réintervention opératoire. Notre hypothèse est que l'hypoxie néonatale engendre des changements durables dans la structure et la fonction cardio-vasculaire qui peuvent influencer négativement les réponses du myocarde au stress physiologique.Pour vérifier cette hypothèse, des rats Sprague-Dawley élevés initialement dans des conditions hypoxiques (FiO2 = 0,12) pour les jours 1 à 10 de vie ont été comparés à des rats élevés dans l'air ambiant. L'hypoxie néonatale a été associée à des changements significatifs dans l'expression, au niveau du ventricule gauche, de 1945 et de 422 gènes chez les animaux âgés de 10 et de 90 jours, respectivement. L'annotation fonctionnelle a révélé plusieurs gènes impliqués dans le remodelage vasculaire adaptatif et le métabolisme énergétique, ainsi que dans la régulation de l'apoptose. Les tendances dans l'expression des gènes ont suggéré un paradigme proapoptotique qui a été corroboré par des résultats montrant une diminution de la survie, suite à une insulte ischémie-reperfusion, de cardiomyocytes isolés chez les animaux adultes exposés à l'hypoxie néonatale.Sur la base des observations ci-dessus, nous avons ensuite cherché à caractériser les changements dans la structure et la fonction cardio-vasculaire, induits par l'hypoxie néonatale, qui pourraient accroître la vulnérabilité des cardiomyocytes au stress physiologique chez l'animal adulte. Les animaux hypoxiques avaient une hypertrophie ventriculaire gauche significative, ainsi que des altérations de l'homéostasie du calcium dans le cardiomyocyte et de la détente des sarcomères, des observations compatibles avec des observations échocardiographiques montrant une dysfonction diastolique sévère. L'hypoxie néonatale a également été associée au développement du remodelage des artérioles du ventricule gauche. Nous avons observé une réduction significative de l'activation d'Akt et ERK1/2 induite par l'isoproterenol, ainsi qu'une diminution de l'expression mitochondriale de hexokinase 2. Enfin, l'expression des protéines Gαi3, Gαi2, et HIF-1α a été significativement augmentée, au niveau du ventricule gauche, chez les animaux adultes suivant l'hypoxie néonatale.Les observations ci-dessus ont été évaluées dans le contexte des défis cliniques associés aux soins des patients adultes atteints de cardiopathies congénitales, et les implications cliniques potentielles sont discutées.