In anesthesia practice, consciousness is often equated with the waking state and with the ability to respond to stimuli in the integrated manner. The reversible loss of consciousness is induced by the general anesthetic, which have a wide range of molecular structure and physicochemical characteristics. The mechanisms of unconsciousness induced by anesthetic agents are not well understood. The studies I have conducted for my Ph.D. have focused on how anesthetic drugs produce unconsciousness in human subjects. In two separate PET studies, receptor imaging and regional CBF analysis were used to examine the unconsciousness induced by propofol, a popular general anesthetic. The first study evaluated kinetic analysis methods for estimation of the receptor availability of the muscarinic receptor using dynamic positron emission tomography (PET) studies with [N-11C-methyl]-benztropine. The study also investigated the effect of propofol on central muscarinic receptor availability during general anesthesia. The results of this study suggested the propofol-related reductions in muscarinic receptor availability. The second study identified the brain function changes specifically linked to the difference in levels of consciousness. We used physostigmine (an anticholinestherase) to restore consciousness in the subjects anesthetized with a constant concentration of propofol. The results revealed that the thalamus and precuneus/cuneus jointly play a critical role in controlling the changes in the level of consciousness during general anesthesia. / Together, these two studies support a hypothesis that the joint deactivations of a Common Midline Core, which includes the medial thalamus, midline precuneus/cuneus, prefrontal cortex and other related cortical areas, contribute to the unconsciousness induced by general anesthetics. These deactivations are mediated, at least partially, by a reduction in the central cholinergic transmission.

First recognized in 1981, human immunodeficiency virus type 1 (HIV-1) continues to foster considerable medical and ethical debate among physicians with regards to treatment options in reproductive medicine. During the first decade of the HIV/AIDS epidemic, fear of viral transmission prompted many physicians to refuse to treat non-HIV-related conditions in infected individuals. In the last decade, long-term prognosis for HIV-infected individuals has risen dramatically, fuelled by the development of potent antiretroviral therapies. Given their improved state of health, an increasing number of infected individuals, many of whom are heterosexual adults of reproductive age, are requesting the use of assisted reproductive technologies (ARTs) to achieve pregnancy, either as a result of infertility factors, or as a means to diminish the risk of transmission to the uninfected partner. Although the medical community now considers HIV a chronic, manageable illness, many practitioners, citing the potential transmission of the virus to the uninfected partner and/or to the couple’s offspring, as well as concerns for the psychosocial well-being of the child-to-be, continue to strongly discourage such couples from proceeding with reproductive care, even denying access in certain circumstances. However, continual advances in the treatment and prognosis of infected individuals, as well as a considerable decrease in the risk of vertical transmission, have called into question the systematic medical recommendation against the provision of ART services to HIV-affected individuals. This research examines the medical, ethical and legal aspects regarding the use of ARTs by HIV-affected couples, focusing on the professional role obligations of the providing physician. Although the risk remains that any child of such a couple could be born with or become infected with HIV, an ethical and legal analysis of this debate demonstrates that such a practice violates respect for patients / Depuis plus de vingt-cinq ans, le virus d’immunodéficience humaine type 1 (VIH-1) provoque de nombreux débats médicaux et éthiques parmi les médecins, particulièrement en ce qui concerne les traitements potentiels de la médecine reproductive. Au cours de la première décennie de l’épidémie du VIH/SIDA, une forte inquiétude vis-à-vis la possibilité de transmission virale incita plusieurs médecins à refuser de traiter les conditions non reliées au VIH chez les personnes atteintes du virus. Au cours des dix dernières années, le pronostic à long terme pour les personnes infectées s’est amélioré de façon significative, en raison du développement de thérapies antirétrovirales puissantes. Un nombre croissant d’individus, en relativement bonne santé même s’ils sont infectés par le virus, dont un bon nombre sont des adultes hétérosexuels en âge d’avoir des enfants, demandent d’avoir accès aux techniques de reproduction assistées (TRA) pour établir une grossesse, en raison d’une incapacité de concevoir ou pour diminuer le risque de transmission au partenaire non infecté. Bien que la communauté médicale considère maintenant le VIH comme une maladie chronique et «gérable», plusieurs médecins, préoccupés par la potentielle de transmission au partenaire non infecté et/ou au fétus, ainsi que par le bien-être psychosocial de l’enfant, continuent à décourager fortement ces couples d’avoir recours aux soins reproductifs, allant jusqu'à leur en refuser catégoriquement l’accès dans certains cas. Cependant, des progrès continus dans le traitement et pronostic d’individus infectés, ainsi qu’une diminution considérable du risque de transmission verticale, mettent en question la recommandation médicale systématique de ne pas offrir les services TRA aux personnes infectées. Ce mémoire examine les aspects médicaux, éthiques et légaux liés à l’utilisation des TRA par les couples atteints du

A debate is presently taking place about the respective training and roles of general internists and medical subspecialists in the provision of speciallized care in Canada. However, very little evidence is available in the literature to document expected differences in the impact of generalized and subspecialized internal medicine care on utilization of health care resources and on outcomes of care. / Our goal was to describe and compare the number of subsequent referrals for consultation to specialists, between patients referred initially to general internists, in comparison to patients referred initially to cardiologists, pneumologists, gastroenterologists, endocrinologists, or rheumatologists. We also compared measures of continuity of care and of professionnal charges between these two groups of patients, following their initial referral. / Administrative databases from the "Regie de l'assurance maladie du Quebec" were used to identify the study population and to measure the outcomes. Information on known determinants of referral, including case-mix characteristics, was gathered and included in the multivariate analysis.

Background. Deep vein thrombosis (DVT) is a common condition with significant mortality and morbidity. Proximal DVT is more often associated with pulmonary embolism and the post-phlebitic syndrome than calf DVT. Identifying which clinical variables predict DVT and proximal DVT could be useful for the effective targeting of diagnostic tests for DVT. / Purpose. To determine, in patients presenting with leg symptoms, which clinical variables best predict (1) DVT and (2) proximal DVT. To estimate the probability of DVT in an individual presenting with a particular grouping of these variables. / Results. Male sex, orthopedic surgery, and warmth and superficial venous dilation on exam were independent predictors of DVT (adjusted odds ratios and 95% confidence intervals 2.8 (1.5, 5.1), 5.4 (2.2, 13.6), 2.1 (1.2, 3.9) and 2.9 (1.4, 5.7), respectively) and proximal DVT (adjusted odds ratios 2.4 (1.2, 4.8), 4.1 (1.4, 12.3), 2.3 (1.2, 4.7) and 3.4 (1.6, 7.0), respectively). A clinical prediction index that categorized patients into different levels of DVT risk was created, and its ROC curve showed moderate predictive ability. No single cutoff point was ideal in terms of desired sensitivity and specificity, however the index was useful in a strategy aimed to limit the need for contrast venography in patients with suspected DVT. Using this strategy, 78% of study patients could have avoided contrast venography. (Abstract shortened by UMI.)

Urinary Incontinence (UI) is a major cause of disability and lost autonomy in older individuals. Most incontinent elderly individuals exhibit involuntary bladder contractions, detrusor overactivity (DO). Ultrastructural studies of the overactive detrusor have revealed changes in contact between myocytes involving decreased numbers of adherens junctions, and the de novo appearance ofjunctions proposed to be aberrant gap junctions. Remarkably, former junctions has never been studied in bladder muscle cells, while, until recently, bladder muscle cells were felt not express gap junctions. We developed a primary culture system using rat bladder smooth muscle cells, and found that these formed typical N-cadherin positive junctions more typical of those formed between fibroblasts as opposed to epithelial cells. We also studied detrusor needle biopsies obtained from elderly subjects and discovered the presence of several known Connexin mRNA sequences in both individuals with DO and age-matched controls. In addition, we observed an apparent up regulation of connexin 43 mRNA in DO subjects.

The purpose of this study was to determine if islets of Langerhans transplanted into the submucosal compartment of the duodenum survive after implantation, and to establish their replication rate. Our goal was also to evaluate both the number of islets needed to achieve normoglycemia in diabetes and the potential of the implant to maintain glucose homeostasis. Experiments were performed using Syrian hamsters. Islets of Langerhans were obtained by collagenase digestion of pancreata and purified on a BSA gradient. Following transplantation, islet morphology and insulin synthesis were maintained. Normoglycemia was not achieved in hyperglycemic animals transplanted with $<$800 islets, but was achieved in 8/11 diabetic animals transplanted with $ ge$800 islets. Reversal of hyperglycemia occurred over 2-5 weeks. The $ beta$-cells remained well-granulated in recipients of $ ge$800 islets and euglycemia was maintained until sacrifice up to 20 weeks post-transplantation. Glucose utilization was similar in normoglycemic controls and in recipients of $ ge$800 islets, but was significantly impaired in all diabetic animals. / In conclusion, (1) the submucosal space supports islet graft viability at least up to 20 weeks post-implantation, (2) the grafts function to reverse the diabetic state, but (3) a critical islet cell mass is necessary to reverse hyperglycemia and maintain normal glucose homeostasis. The submucosal space of the duodenum appears to be an effective site for islet implantation, but additional studies are required to further evaluate the benefits.

Ethical decisions about medical care of infants is based on the by proxy evaluation of the infants' best interests. Since parents and physicians may have different points of reference, conflicts may arise during the decision-making process. The decision about the infant's well being becomes even more complex when high risk treatment with an uncertain long-term outcome is considered. Surgical palliation of hypoplastic left heart syndrome (HLHS) is an example of such a treatment. I use this example in my discussion on the relevant ethical issues and possible roots of conflicts between the decision-makers. / I argue that as long as long-term survival rates are variable, and the survivors' quality of life remains uncertain, palliative surgery for HLHS should not be obligatory. Rather, the parents should be informed not only about the existing treatments but also about the non-treatment option, and what each option may imply for the infant, parents and the family.

The aim of this study was to: (a) identify risk factors for the development of venothromboembolism in a trauma population, (b) evaluate whether risk factors vary with increasing Injury Severity Score (ISS), and (c) assess the predictive ability of the Risk Assessment Profile for Thromboembolism (RAPT) in this trauma population. There were 7532 admissions for trauma between 1993 and 1998 to the Montreal General Hospital trauma center. A nested case-control design was used. Cases were defined as all patients with radiological evidence of either a deep venous thrombosis or pulmonary embolus during their admission. Controls were patients satisfying the same inclusion criteria who did not suffer a symptomatic deep venous thrombosis or pulmonary embolism while in hospital, did not have evidence of deep venous thrombosis prior to the traumatic event, and found to be free of any symptomatic thromboembolic events on consequent follow up. Patients were divided into three categories, ISS 1--24 (mild-moderate injuries), ISS 25--59 (moderate-severe injuries), and ISS 60--75 (severe-fatal injuries). (Abstract shortened by UMI.)

Objective. To compare the prognostic ability of first available measurements of CD4 cell count and viral load with that of the most recent measurements and to assess the additional prognostic ability of the values of past measurements of these markers. / Methods. Demographic and clinical information on 965 HIV-1 infected adults followed at a university-based HIV clinic in Montreal, Quebec were extracted from a clinical database. The prognostic ability of initial and most recent CD4 cell count and viral load measurements were assessed in a series of Cox models. The added prognostic ability of past values of measurements of these markers was explored by calculating; (i) the unweighted mean values of all previous measurements and (ii) a time-weighted mean. The differences between these mean levels and the most recent values were included as time-dependent covariates in Cox models adjusted for the value of the most recent measurements. / Conclusion. The most recent measurements of CD4 cell count and viral load are more powerful predictors of clinical disease progression than initial measurements. (Abstract shortened by UMI.)

Distraction osteogenesis (DO) is a surgical technique used to treat limb length discrepancies, limb deformities, long bone non-unions and bone loss due to trauma, infection or malignancies. In this surgical method a transverse osteotomy is performed and the fractured bone is stabilized using the Ilizarov fixation system. After a short latency period, the two ends of the fractured bone are slowly pulled apart, stimulating new bone formation within the distracted gap. After the distraction is completed, the newly formed bone is allowed to fully consolidate. One of the main limitations of DO is the long consolidation period required for the bone to heal. Different methods have been researched to accelerate the consolidation phase of DO, including the exogenous application of bone morphogenetic proteins (BMPs). BMPs are growth factors that are required in the bone developmental pathway. Although numerous studies have tested pharmacological doses of BMP2 and BMP7 using different animal models of DO, the physiological role of BMPs during DO still remains poorly understood. Hence, in this study we investigated the physiological role of BMP2 in a heterozygous conditional BMP2 knockout model of distraction osteogenesis. Distraction osteogenesis was performed on the right tibia of forty wild-type BMP2 fl/+ mice and heterozygous BMP2 fl/+ cre mice using a miniature version of the Ilizarov fixator. Mice underwent a latency period of 5 days, a distraction period of 12 days (distraction rate of 0.2 mm every 12 hours) and a consolidation period of 34 days. Distracted samples were collected from four time points: 11 days (mid-distraction phase), 17 days (end of distraction phase), 34 days (mid-consolidation phase) and 51 days (end of consolidation phase). Samples were studied using µCT, Faxitron x-ray, immunohistochemistry, histology, Real Time-quantitative PCR and biomechanical testing. Results from this study showed that reducing BMP2 expression through gene d / L’ostéogenèse par distraction (OD) est une technique chirurgicale utilisée pour traiter des dissymétries des membres et des défauts osseux suite à un traumatisme, une infection ou une maladie. Dans cette méthode, une ostéotomie est faite et l'os fracturé est stabilisé par un fixateur externe de type Ilizarov. Durant la période de distraction, les extrémités de l'os sont tirées lentement l'une de l'autre, ce qui stimule la nouvelle formation d'os dans la zone de distraction. Ensuite, la phase de consolidation permet l’ossification de tissu nouvellement formé.Le problème principal de l’OD est que la période de consolidation est très longue. De recherches ont été faites afin d’accélérer la phase de consolidation de l’OD tel que l'application des protéines de la morphogenèse osseuse (BMP). Les BMP sont nécessaires pour le développement osseux. Bien que beaucoup d’études ont analysé les effets de doses pharmacologiques de BMP2 et BMP7 en utilisant des modèles animaux de l’OD, le rôle physiologique des BMP est encore inconnu. Donc, pour cette étude nous avons analysé le rôle physiologique de BMP2 durant l’OD chez des souris ayant une déficience en BMP2 localisée dans les membres. Nous avons soumis le tibia droit de souris contrôle-BMP2 fl/+ et de souris hétérozygotes-BMP2 fl/+ cre à l’ostéogenèse par distraction en utilisant un fixateur Ilizarov miniaturisé. Les souris ont subi une période de latence de 5 jours, une période de distraction de 12 jours (avec un taux de distraction de 0.2 mm chaque 12 heures), et une période de consolidation de 34 jours. Les échantillons ont été recueillis à 11, 17, 34 et 51 jours, et analysés par µCT, rayons X, immunohistochimie, histologie, par PCR en temps réel, et par un examen biomécanique.Les résultats de cette étude ont montré que la diminution de l’expression de BMP2 dans les membres hétérozygotes avait pour effet de ralentir le processus de con