A physical surgical simulator, the McGill Inanimate System for Training and Evaluation of Laparoscopic Skills (MISTELS) is used to examine the acquisition of laparoscopic skills, as well as to determine a summative evaluation of these skills. The cumulative summation method (CUSUM) is used to characterize individual and group learning curves for a MISTELS task. To examine transfer of learning in laparoscopy, novice laparoscopists were randomized to either practice a basic psychomotor task (peg board transfer) or to a no-practice control group. After forty iterations, the novices performed a more complex task (suturing); those who practiced the basic task significantly improved their complex task performance. Finally, using the receiver operator curve (ROC), the summative evaluation score for MISTELS was determined by maximizing the sensitivity and specificity of this training instrument. Using these findings, individualized training programs can be developed to teach essential laparoscopic skills prior to entering the operating room.

Sutural distraction osteogenesis (SDO) has been proposed as a novel approach for cleft palate closure in an effort to avoid the shortcomings of traditional surgical repair. In this thesis, we present data that confirms that attempted distraction of the palatomaxillary suture (PMS) achieves cleft closure preferentially by alveolar arch collapse, and not by intended SDO. To that end, we have designed a novel custom-fit intraoral splint that successfully prevents maxillary collapse while facilitating cleft defect approximation via sutural distraction. Preservation of maxillary dimensions was confirmed via intraoral measurements and craniometrics. New bone deposition secondary to SDO was quantified with histomorphometry and microCT, while the effects of distraction on the PMS and palatal bone were assessed with histology and Dual-energy Xray Absorptiometry (DXA). In summary, approximation of palatal defects via SDO in a canine model without maxillary collapse is possible, and may be a promising therapeutic approach for the repair of cleft palates in human infants.

The biggest challenge to islet transplantation is preserving cell mass and function. It is known that the stresses encountered during islet isolation have deleterious effects on beta-cell physiology. The nature of these effects, however, are incompletely known, partly due to the heterogeneity of islet preparations. Using a combination of laser capture microdissection and microarray technology, we therefore sought to determine the beta-cell specific events that occur as a result of islet isolation and in vitro culture. Our data shows that islet isolation and in vitro culture induce a large inflammatory response that is NF-kB dependent and involves the upregulation of several pro-inflammatory cytokines such as IL-8, IL-1 and MCP-1. Furthermore, several transcription factors involved in ß-cell differentiation, such as NeuroD1, NKX2.2, and MafA were decreased, providing insight into mechanisms of beta-cell dedifferentiation. Therefore, therapies aimed at targeting NF-kB and re-expressing transcription factors necessary to beta-cell function should be explored further. / Le stress subi durant l'isolation des îlots de Langerhans a des effets négatifs sur la physiologie des cellules bêta. Nous avons tenté de déterminer les événements survenant suite à une isolation d'îlots et de leur culture in vitro grâce à la capture et découpage laser et la puce à gènes. Nos résultats démontrent que l'isolation d'îlots et leur culture in vitro produisent une importante réponse inflammatoire. Cette réponse dépend de la protéine NF-kB et implique une augmentation de plusieurs cytokines pro-inflammatoires, incluant IL-8, IL-1, et MCP-1. Aussi, plusieurs facteurs de transcription essentiels dans la différenciation des cellules bêta comme NeuroD1, NKX2.2, et MafA ont diminué, suggérant que les cellules bêta se dédifférencient après leur isolation et culture in vitro. Par conséquent, les thérapies visant NF-kB et la réexpression des facteurs de transcription nécessaires à la fonction des cellules bêta devraient être explorées plus en détails.

Mutant quaking viable mice (qkV) develop a tremor phenotype in their hind limbs 10 days after birth, likely resulting from severe myelination defects. Genetically, quaking viable mice contain a deletion in the promoter/enhancer region of the quaking gene. The quaking gene is alternatively spliced, producing QUAKING isoforms that differ in their C-terminal amino acid sequence. The QKI-5 isoform is nuclear, whereas the QKI-6 and QKI-7 isoforms are predominantly cytoplasmic. The QKI isoforms contain a single KH RNA-binding domain, which suggests a role in RNA metabolism. Although the dysmyelinating phenotype of the mutant mice suggests a role in myelination, the function of the protein remains largely unknown. The objective of this thesis is to characterize the role of the RNA binding proteins QKI in the differentiation of glial cells and their involvement in the process of myelination. Moreover, this study describes the quaking viable defects and how the isoforms contribute to the observed phenotype. [...] / Les protéines liant l’ARN jouent un rôle central afin de contrôler l’expression génique, l’épissage alternatif et la localisation des ARN messagers. Pour qu’une cellule se différencie, les gènes doivent être régulés au niveau de leur expression et de la localisation de leurs ARNm. Un des phénomènes physiologique de différentiation au niveau du système nerveux est la myélinisation des axones. En vulgarisant, la gaine de myéline serait l’isolant entourant le fil électrique étant l’axone. [...]

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.