In experimental asthma, allergen challenges cause airway structural changes, termed remodeling, including an increase in smooth muscle (SM) mass and goblet cell metaplasia. These changes are substantially mediated via the epidermal growth factor receptor (EGFR) and its axis of ligands. The causal relationship between remodeling and another key asthmatic feature, airway hyperresponsiveness (AHR) has not been clearly established. The first objective was to investigate the site of airway narrowing in response to a single allergen challenge. We used two approaches, a morphometric assessment and an analysis of respiratory mechanics, using the constant phase model to partition the site of responses. We snap froze lungs during the early allergic airway response (EAR) and performed a morphometric analysis of airway luminal areas. Interestingly, the EAR response demonstrated an initial, transient response in the large airways yet, a more sustained response in the peripheral lung. We reasoned that in peripheral airways, the perturbation of the surface tension of the airway lining fluid by protein leak from the vasculature may have contributed to the response. The role of exogenous, natural surfactant in the EAR has not been explored extensively. The surfactant used largely contained surfactant protein (SP)-B but lacked SP-A and SP-D, both of which confer immunomodulatory properties on surfactant. We confirmed that effects of the surfactant may not have been purely via physical properties but also by immunomodulation. This notion was confirmed as surfactant inhibited the mast cell mediators, cysteinyl-leukotrienes and amphiregulin, in vivo.We next investigated the relationship between allergen-induced AHR and airway remodeling. We induced airway remodeling using the Brown Norway rat undergoing three multiple challenges with the sensitizing antigen ovalbumin. We used the constant phase model to evaluate mechanical responses to inhaled aerosols of methacholine. AHR in the peripheral lung compartment and airway remodeling across all airway sizes were observed 48 h after the last of three allergen challenges. The corticosteroid budesonide (0.1mg/kg), used to further probe the relationship between airway remodeling and AHR, was sufficient to inhibit remodeling but not AHR. At one week, AHR did not persist despite the remodeling. Finally we examined the contractile SM properties 48 h after the last allergen challenge and studied whether inhibition of the EGFR modulated the SM phenotype and AHR. We used laser capture microdissection to harvest SM and epithelial cells for the assessment of mRNA expression. As earlier observed, AHR was induced, but only in the periphery despite increases in SM-myosin heavy chain (sm-MHC) gene expression and growth of SM in the larger airways. EGFR inhibition decreased all these outcomes in addition to SM growth across all airways and inflammation.In conclusion, the site of allergic airway narrowing is initially located in the central airways and over time develops in the lung periphery. Modulation of surface tension influences the magnitude of airway narrowing during the EAR. After multiple allergen challenges, AHR is placed in the peripheral airways exclusively despite airway remodeling in the central airways and increased sm-MHC gene expression in the muscle in these airways, all of which were reduced by EGFR inhibition. Our studies show that the relationship between airway remodeling and AHR is not a simple one and the two phenomena seem to be dissociated in the rat model of allergic asthma. / L'exposition chronique aux allergènes provoque des changements structurels des voies respiratoires qualifiés de remodelage. Ces changements sont substantiellement véhiculés par le récepteur du facteur de croissance épidermique (EGFR) et de ses ligands. La relation entre le remodelage et l'hyperréactivité bronchique (HRB), un autre élément clé de l'asthme, n'a pas été clairement établie. Le premier objectif de ce travail était de définir le site de l'obstruction des voies aériennes, induite par une exposition allergénique. Nous avons utilisés deux approches, l'analyse morphométrique des voies aériennes et la mesure des mécaniques respiratoires en utilisant le modèle de phase constante. L'analyse morphométrique indique que les voies aériennes périphériques sont responsables de l'HRB induite par l'allergène. La réponse allergique immédiate (RAI) était associée à une bronchoconstriction transitoire dans les larges voies respiratoires, suivi d'une réponse dans le compartiment périphérique du poumon. Nous avons émis l'hypothèse que cette réponse pourrait résulter d'une perturbation des tensions de surface des voies aériennes périphériques due à une extravasation de protéines plasmatiques. La stabilité des voies aériennes périphériques peut être influencée par les protéines du surfactant. L'apport exogène de protéines de surfactant naturel a été exploré. Le surfactant utilisé était majoritairement composé de protéines B du surfactant, SP-B, mais ne contenait ni SP-A ni SP-D aux propriétés immunomodulatrices. Nous avons démontré que le surfactant avait des effets physiques mais aussi pouvait être immunomodulateur. La réduction des concentrations des médiateurs mastocytaires, les leukotriènes et l'amphiréguline, dans les lavages broncho-alvéolaires confirme cette notion. Dans le but de mieux comprendre la relation entre remodelage et HRB, nous avons induit le remodelage bronchique chez des rats BN provoqués chroniquement à l'ovalbumine. Les mesures de mécanique respiratoire ont été réalisées en appliquant le modèle de phase constante afin de distinguer les sites pulmonaires impliqués dans la bronchoconstriction induite par des doses croissantes de métacholine. Deux jours après la dernière des trois provocations L'HRB était présente dans le compartiment périphérique du poumon alors que le remodelage était présent dans toutes les voies aériennes. Le budésonide, un anti-inflammatoire corticostéroïdien utilisé pour mettre en évidence la relation entre l'HRB et le remodelage, a inhibé le remodelage sans affecter l'HRB. A l'inverse du remodelage, L'HRB n'a pas persistée après une semaine. Finalement le phénotype contractile du muscle lisse (ML) et le rôle du récepteur EGFR ont été étudiés dans le modèle de provocations allergénique répétées. Nous avons utilisé la capture par microdissection laser pour évaluer l'expression génique dans le ML et l'épithélium. Comme précédemment observé L'HRB a été induite uniquement dans les voies aériennes périphériques bien que l'expression du gène de la chaîne lourde de myosine et l'hyperplasie du ML aient été observées dans les larges voies aériennes. L'inhibition du récepteur EGFR a réduit l'expression de la chaine lourde de myosine, l'HRB et le remodelage du ML ainsi que l'inflammation.En conclusion le site de l'obstruction bronchique est initialement localisé dans les voies aériennes centrales avant de se développer en périphérie. La modulation de la tension de surface influence l'amplitude de l'obstruction bronchique durant la RAI. Les provocations allergéniques répétées entraine une HRB exclusivement périphérique malgré l'apparition d'un remodelage du ML et d'une augmentation d'expression de la chaine lourde de myosine dans les voies aériennes centrales. Toutes ces dernières manifestations ont été réduites par l'inhibition du récepteur EGFR. Nos travaux démontrent une relation complexe entre HRB et remodelage, deux phénomènes dissociés dans le modèle d'asthme allergique chez le rat.

Rationale. Hypertension occurs in 10% of pregnancies. Snoring is a marker for sleep apnea, and is a newly identified risk factor for gestational hypertension. Moreover, sleep apnea is an independent risk factor for hypertension in the non-pregnant population. I hypothesized that sleep apnea was associated with gestational hypertension. / Hypothesis. The prevalence of sleep apnea is higher among pregnant women with hypertensive pregnancies than among those without hypertension during pregnancy. / Design. Case-control study of 17 pregnant women with gestational hypertension and 33 pregnant women without hypertension, with matching by gestational age. Sleep apnea was ascertained by polysomnography. / Results. The crude odds ratio for the presence of obstructive sleep apnea, given the presence of gestational hypertension, was 5.6. The odds ratio was 7.5 (95% CI 3.5-16), based on a logistic regression model with adjustment for maternal age, gestational age, nulliparity, first pregnancy, and body mass index. / Conclusion. Gestational hypertension was strongly associated with the presence of obstructive sleep apnea.

Despite much advancement in our understanding of its pathobiology, there is no cure for Alzheimer's disease (AD), a devastating neurodegenerative disorder affecting more than 35 million people world-wide. At diagnosis, the brains of AD patients are already severely damaged and display massive accumulation of intraneuronal neurofibrillary tangles and extracellular amyloid plaques. Amyloid plaques are composed of aggregated, insoluble amyloid beta peptide (Abeta), which is known to be highly neurotoxic. At this stage, AD drugs can only delay, but not arrest, the progression of the disease, likely because the neuronal damage is already beyond rescue.It is currently accepted that, for any pharmacological agent to achieve efficacy, the treatment should be initiated prior to extensive central nervous system (CNS) damage, possibly in pre-clinical stages. A better understanding of the earliest events occurring in the pre-clinical phase of the disease is therefore a priority. Unfortunately, the study of pre-clinical stages in AD is complicated by the lack of biomarkers signalling the conversion from non cognitive impairment to AD. On the other hand, transgenic (Tg) models of the AD-like amyloid pathology represent a very suitable model to investigate the progression of the disease.In these studies, we took advantage of our newly generated Tg model of AD-like amyloid pathology, coded McGill-Thy1-APP mice to identify early pathological events preceding plaque deposition. We first examined the cognitive status of the animals and demonstrated that cognitive impairments occur prior to plaque deposition. Such deficits were associated with a paradoxical up-regulation of cholinergic pre-synaptic boutons. Prior to plaque deposition we also described the occurrence of intraneuronal Abeta-immunoreactive material. Furthermore, using oligomeric specific antibodies, we found that the intraneuronal Abeta material was in large part composed of Abeta-oligomers. To further elucidate the mechanisms involved in the early neuronal dysfunction, we characterized the occurrence of inflammation in young, pre-plaque mice. We started by confirming the occurrence of the well known, plaque-associated microglial activation in old, 13-14 months old Tg mice. In young, pre-plaque mice we observed a moderate, but significant up-regulation of inflammatory enzymes (iNOS, inducible nitric oxide synthase) and membrane bound receptors (CD40 and MHC-II); the neuronal marker COX-2 was also found to be up-regulated. Furthermore, we observed that microglial cells at this age display an activated morphology and are specifically associated with Abeta-oligomers burdened neurons. Finally, the anti-inflammatory drug minocycline was administered to 2-month old mice for one month, till the age of 3 months, thus in the absence of any amyloid plaque deposition. This protocol allowed us to investigate the role of inflammation in the early, pre-plaque stage of the disease. We found that, besides correcting neuroinflammation, minocycline significantly reduced the levels of amyloid precursor protein and APP-immunoreactive fragments, including C-terminus fragments (CTF). Furthermore, we observed that minocycline reduced the levels and activity of BACE, which were up-regulated in Tg animals compared to Non Tg.Taken together, our results showed that intracellular accumulation of Abeta-oligomers per se, prior to plaque deposition, is sufficient to trigger a number of CNS alterations. Amongst these, microglial activation appears to be, at least in its earliest manifestation, a key player in APP processing. We suggest that neuroinflammation in pre-clinical stages of AD might represent a suitable target for the discovery of novel preventive agents and/or early diagnostic markers. / Il n'existe aucun remède pour la maladie de Alzheimer (MA), une condition neurodégénérative dévastatrice, qui attaque plus de 35 millions de personnes dans le monde entier. Lorsque cette maladie est diagnostiquée, le cerveau des patients est déjà gravement endommagé et montre l'accumulation d'enchevêtrements neurofibrillaires intracellulaires et des plaques amyloïdes extracellulaires. Les plaques amyloïdes sont composées d'agrégats insolubles de la protéine beta amyloïde (Abeta) qui est neurotoxique. Il est actuellement admis que, pour obtenir un résultat thérapeutique, il faudrait commencer le traitement pharmacologique dans les premiers stades de la maladie, lors de la période pré-clinique, avant que les dommages neuronaux deviennent irrécupérables. Une meilleure compréhension des événements survenant dans ces premiers stades de la maladie est donc une priorité. Malheureusement, l'étude de ces stades pré-cliniques est compliquée par l'absence de biomarqueurs indiquant la conversion du stade sans troubles cognitifs à MA. Ainsi, les modèles transgéniques (Tg) de la pathologie amyloïde similaires à MA représentent des modèles très appropriés pour étudier l'évolution de la maladie.Afin d'étudier les premiers événements pathologiques survenant avant l'accumulation des plaques, nous avons profité d'un modèle Tg nouvellement généré dans notre laboratoire et nommé McGill-Thy1-APP. Nous avons d'abord examiné l'état cognitif des souris Tg et nous avons démontré que les troubles cognitifs précèdent l'accumulation des plaques. Nous avons aussi démontré qu'une augmentation paradoxale de boutons cholinergiques accompagnait les troubles cognitifs chez ces animaux. Avant l'apparition des plaques, nous avons décrit la survenance de matériel intraneuronal immunoréactif pour l'Abeta. Par ailleurs, en utilisant des anticorps spécifiques pour les formes oligomériques, nous avons constaté que le matériel intraneuronal est en grande partie composé d'oligomères de l'Abeta.Pour élucider si les mécanismes impliqués dans la dysfonction neuronale précèdent l'accumulation de plaques, nous avons caractérisé l'apparition de l'inflammation chez les jeunes souris Tg, avant qu'elles montrent des plaques. Nous avons d'abord confirmé l'apparition de l'activation microgliale associée avec les plaques amyloïdes chez les vieilles souris Tg de 13-14 mois. Chez les jeunes souris pré-plaques, nous avons observé une augmentation modérée mais significative des enzymes (iNOS et COX-2) et des récepteurs de membranaires (CD40 et CMH-II) inflammatoires. Par ailleurs, nous avons observé que les cellules microglies à cet âge affichent une morphologie activée et sont spécifiquement associées à des neurones contenant des oligomères de l'Abeta.Enfin, la minocycline (un médicament anti-inflammatoire) a été administrée à des souris âgées de deux mois pour un mois (jusqu'à l'âge de 3 mois) donc en l'absence de tout dépôt de plaques amyloïde. Ce protocole nous a permis d'étudier le rôle de l'inflammation dans les premiers stades de la maladie, avant le dépôt de plaques. Nous avons constaté que, outre la correction de la neuroinflammation, la minocycline réduit considérablement les niveaux de la protéine précurseur de l'amyloïde (APP) et les fragments connexes avec l'APP, y compris les fragments du carboxy terminaux. Par ailleurs, nous avons observé que la minocycline réduit les niveaux et l'activité de BACE.Ensemble, nos résultats montrent que l'accumulation intracellulaire des oligomères de l'Abeta en soi, avant le dépôt de plaques, est suffisante pour déclencher des modifications du SNC. Parmi ces derniers, l'activation microgliale semble avoir, du moins dans sa première manifestation, un rôle fondamental dans le métabolism de l'APP. Nous suggérons que la neuroinflammation dans les stades pré-cliniques de la MA pourrait représenter une cible appropriée pour la découverte de nouveaux agents préventifs et/ou de marqueurs diagnostiques.

Hypertension and antihypertensive drugs have been linked to the risk of cancer for over 3 decades. In this thesis, we address some of the weaknesses of studies to date by conducting a population based observational study using the Saskatchewan Health databases. We followed 77887 subjects initiating antihypertensives between 1980 and 1987 until the end of 2004. A case-control analysis nested within this cohort revealed a small decrease in the risk of cancers at all sites combined in ß-blocker users compared to thiazide diuretic users (OR incident 0.9; 95% CI 0.85-0.96, fatal 0.91; 0.83-0.99) driven in large part by a decrease in the risk of colon cancer (OR incident 0.79; 0.67-0.93, fatal 0.74; 0.57-0.97). No other differences in risk were observed between users of commonly prescribed classes of antihypertensives for all cause and common cancers. In a sub-cohort of 42270 subjects who started using antihypertensive drugs on a regular basis for hypertension, those who started regular use under the age of 60 years had an increased risk of cancer at all sites combined (RR incident 1.34; 1.18-1.52, fatal 1.21; 1.08-1.36) compared to the general population while those who started when they were 60 years and older had a decreased risk (RR incident 0.88; 0.78-0.98, fatal 0.88; 0.80-0.97). Rate ratios were elevated or diminished across most sites of cancer and remained unchanged after excluding cancers in the first 10 years of follow up. However, neglecting minor differences between how cancer rates are derived in the general population versus an exposed cohort of interest led to substantial bias that may explain some of the discrepancies in the literature to date. We conclude that essential hypertension is associated with a modest increase risk of cancer but isolated systolic hypertension appears to be associated with a modest decreased risk. The former association is not due to protopathic or detection bias but may be, at least in part, due to residual confo / L'hypertension et les médicaments antihypertenseurs ont été reliés au risque de cancer depuis plus de 3 décennies. Dans cette thèse, nous abordons certaines des faiblesses des études menées jusqu'ici en réalisant une étude de population observationnelle à l'aide la base de données de santé de Saskatchewan. Nous avons suivi 77887 sujets dont le traitement antihypertenseurs avait été initié entre 1980 et 1987 jusqu'à fin 2004. Une analyse cas-témoin nichée dans cette cohorte a indiqué une petite diminution du risque de cancer (toutes causes confondues) chez les utilisateurs de bétabloquants comparativement aux utilisateurs de diurétiques thiazidiques (OR incident 0.9; IC 95% 0.85-0.96, décès 0.91; 0.83-0.99) due en grande partie à une diminution du risque de cancer du colon (OR incident 0.79 ; 0.67-0.93, décès 0.74 ; 0.57-0.97). Nous n'avons observé aucune autre différence de risque entre les utilisateurs des classes d'antihypertenseurs les plus communément prescrites, toute cause de cancer confondue et concernant les cancers les plus fréquents. Dans une sous-cohorte de 42270 sujets qui ont commencé à employer des médicaments antihypertenseurs de façon régulière pour l'hypertension, ceux qui ont commencée utilisation régulière sous l'âge de 60 ans ont eu un plus grand risque de cancer (RR incident 1.34 ; 1.18-1.56, décès 1.21; 1.08-1.36) comparativement à la population générale tandis que les sujets plus âgés avaient un risque diminué (RR incident 0.88; 0.78-0.98, décès 0.88; 0.80-0.97). Les rapports de taux étaient élevés ou diminués selon le site du cancer considéré et restaient inchangés après exclusion des cancers survenus lors des 10 premières années de suivi. Cependant, l'absence de prise en compte des différences, quoique mineures, d'estimation des taux de cancer entre la population générale et une cohorte exposée a entrainé un biais substantiel qui peut expliquer certaines des divergences t

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.