This chapter discusses psychopharmacological treatment for children's emotional and psychiatric disorders. It considers approaches to the selection of pharmacological agents. It then reviews the current state of psychopharmacological treatment with children and adolescents, focusing on pharmacological agents for the treatment of established psychiatric diagnoses and psychopharmacological agents selected to control or treat behaviors experienced by the child regardless of the presence of a clear diagnosis.

Dissertation submitted in partial compliance with the requirements for a Masters Degree in Tehcnology: Chiropractic, Durban University of Technology, 2009. / Background: The aim of this study was to determine the knowledge, perception and utilisation of vitamins and minerals, natural medicines and pharmacological agents as adjuncts to Chiropractic practice in South Africa. Method: This study was a population based cross sectional survey utilising a descriptive, quantitative questionnaire study design. The questionnaire was distributed to all practicing qualified Chiropractors (n=388) and masters Chiropractic students (n=102) in South Africa. Results: The results obtained (30.4% response rate), indicated that the majority of the respondents (62.8%) felt qualified to advise patients on vitamins and mineral supplements and had a positive view of the use of vitamins and minerals as part of Chiropractic patient management (86.6%). The majority of the practitioners were aware that topical substances are part of the scope of practice and males were nearly twice as likely as females to use them. The majority thought biopuncture should be available to Chiropractors (82%) and felt that Chiropractors should challenge the legislation to incorporate biopuncture as part of the scope of practice (77.5%). Most respondents agreed with the statement indicating that NSAIDS should be part of Chiropractic scope of practice and 71% of respondents felt that being able to use NSAIDS in non-emergency situations would enhance patient retention. This study revealed that amongst the student population the majority, if allowed, would consider administering pharmacological agents in practice (55.1%). Conclusion: A correlation exists between the perception, knowledge and utilisation of vitamins and minerals, natural medicines and pharmacological agents in the Chiropractic profession with respect to the demographic data and there is a significant difference in opinion between qualified Chiropractors and Chiropractic masters students regarding perception, knowledge and utilisation of these adjuncts to practice.

Dissertation submitted in partial compliance with the requirements for a Masters Degree in Tehcnology: Chiropractic, Durban University of Technology, 2009. / Background: The aim of this study was to determine the knowledge, perception and utilisation of vitamins and minerals, natural medicines and pharmacological agents as adjuncts to Chiropractic practice in South Africa. Method: This study was a population based cross sectional survey utilising a descriptive, quantitative questionnaire study design. The questionnaire was distributed to all practicing qualified Chiropractors (n=388) and masters Chiropractic students (n=102) in South Africa. Results: The results obtained (30.4% response rate), indicated that the majority of the respondents (62.8%) felt qualified to advise patients on vitamins and mineral supplements and had a positive view of the use of vitamins and minerals as part of Chiropractic patient management (86.6%). The majority of the practitioners were aware that topical substances are part of the scope of practice and males were nearly twice as likely as females to use them. The majority thought biopuncture should be available to Chiropractors (82%) and felt that Chiropractors should challenge the legislation to incorporate biopuncture as part of the scope of practice (77.5%). Most respondents agreed with the statement indicating that NSAIDS should be part of Chiropractic scope of practice and 71% of respondents felt that being able to use NSAIDS in non-emergency situations would enhance patient retention. This study revealed that amongst the student population the majority, if allowed, would consider administering pharmacological agents in practice (55.1%). Conclusion: A correlation exists between the perception, knowledge and utilisation of vitamins and minerals, natural medicines and pharmacological agents in the Chiropractic profession with respect to the demographic data and there is a significant difference in opinion between qualified Chiropractors and Chiropractic masters students regarding perception, knowledge and utilisation of these adjuncts to practice.

HARP (Heparin Affin regulatory peptide) est un facteur de croissance qui constitue avec la midkine une sous-famille des Heparin Binding Growth Factors (HBGFs). HARP est impliqué dans de nombreux processus physiologiques comme la neurogenèse et la vasculogenèse mais aussi dans des processus physiopathologiques comme l’angiogenèse et la progression tumorale. HARP interagit avec différents récepteurs (N-syndécan, RPTPβ/ζ, et ALK). Plus récemment, il a été montré au laboratoire que la nucléoline, protéine navette entre le noyau, le cytoplasme, et la surface cellulaire est un nouveau récepteur à HARP. Malgré les avancées dans ce domaine, l’interaction de HARP avec ses récepteurs n’est pas totalement élucidée. L'objectif de ce projet de thèse était la recherche de nouveaux partenaires moléculaires qui interagissent avec HARP, de comprendre le mécanisme de leurs interaction et d’analyser les effets biologiques. A ce titre, j’ai participé à l’étude de l’interaction de HARP avec le facteur de croissance des fibroblastes, le FGF-2. Ce facteur liant l’héparine est également mitogène et angiogène. En utilisant des techniques de biocapteurs optiques et d’interaction protéine-protéine, nous avons montré une interaction directe entre HARP et le FGF-2 et qui implique les domaines C-TSR-I et C-terminale de HARP. De plus, cette interaction inhibe la migration et la prolifération des cellules endothéliales, induites par le FGF-2 ou par HARP seuls. En parallèle, j’ai mis en évidence l’interaction entre HARP et la NRP-1. NRP-1 est une protéine transmembranaire, ayant comme ligands principaux, les sémaphorines de classe 3 (SEMA 3A), le facteur de croissance endothélial vasculaire (VEGF) et le FGF-2. En plus de son rôle crucial dans le développement des systèmes nerveux et cardiovasculaires, la NRP-1 est impliquée dans les processus physiopathologiques tels que l’angiogenèse et l’invasion tumorale. Ainsi, la NRP-1 présente un profil biologique similaire à HARP. En utilisant des tests d’ELISA, d’immunoprécipitation et de « pull-down », nous avons montré que HARP interagit avec la NRP-1. Cette interaction semble être directe et s’effectue via les domaines de liaison à l’héparine TSR-I. HARP induit l’internalisation de la NRP-1 au bout de 15 minutes et son recyclage partiel à la surface cellulaire au bout d’une heure. L’internalisation de la NRP-1 s’accompagne par la phosphorylation des voies MAPK (ERK1/2), Akt et FAK. L’interaction HARP/NRP-1 est cruciale pour la migration des cellules endothéliales et l’invasion des cellules tumorales. En conclusion, ces résultats apportent de nouvelles avancées concernant les partenaires moléculaires de HARP en particulier et montrent également la complexité des interactions des facteurs de croissance entre eux et avec leurs récepteurs. Plus généralement, cette étude permet d'envisager des stratégies thérapeutiques ciblant l’interaction de la NRP-1 avec HARP et aussi les autres facteurs de croissance. / HARP (Heparin Affin regulatory peptide) is a growth factor that constitutes with midkine a subfamily of Heparin Binding Growth Factors (HBGFs). HARP is involved in many physiological processes such as neurogenesis and vasculogenesis but also in pathophysiological processes such as angiogenesis and tumor progression. HARP interacts with different receptors (N-syndecan, RPTPβ / ζ and ALK). More recently, it has been shown in the laboratory that nucleolin, a protein shuttle between the nucleus, cytoplasm, and cell surface, is a new HARP receptor. Despite the advances in this field, the interaction of HARP with its receptors is not fully understood. The aim of this thesis was the search for new molecular partners that interact with HARP, to understand the mechanism of their interaction and analyze the biological effects. My work was firstly to participate to the study of the interaction of HARP with the fibroblast growth factor-2, FGF-2. This factor is also an heparin-binding factor, with mitogenic and angiogenic activities. Using techniques of optical biosensors and protein-protein interaction, we have shown a direct interaction between HARP and FGF-2 that involves C-TSR-I and C-terminus domains of HARP. In addition, HARP inhibits the migration and proliferation of endothelial cells induced by FGF-2. In parallel, I highlighted the interaction between HARP and NRP-1. NRP-1 is a transmembrane protein having as main ligands, semaphorins class 3 (SEMA 3A), the vascular endothelial growth factor (VEGF) and FGF-2. In addition to its crucial role in the development of the nervous and cardiovascular systems, the NRP-1 is involved in physiopathological processes such as angiogenesis and tumor invasion. Thus, NRP-1 has a biological profile similar to HARP. Using ELISA, immunoprecipitation and "pull-down" tests, we have shown that HARP interacts with NRP-1. This interaction appears to be direct and occurs via heparin binding domains of HARP: TSR-I. HARP induces internalization of NRP-1 after 15 minutes and partial recycling to the cell surface after one hour. The internalization of the NRP-1 is accompanied by the phosphorylation of MAPK pathways (ERK1 / 2), Akt and FAK. HARP/NRP-1 interaction is crucial for endothelial cell migration and invasion of tumor cells. In conclusion, these results provide new advances on molecular partners of HARP in particular and also show the complexity of the interactions between these growth factors and their receptors. More generally, this study allows considering therapeutic strategies targeting the interaction of NRP-1 with HARP as well as other growth factors.

Problème. L'administration de médicaments aux propriétés sédatives pour la gestion des symptômes comportementaux, aussi appelée contention chimique, est une intervention complexe dont les finalités de contrôle, de protection, de traitement et d'alternative à d'autres coercitions entrent en conflit et sèment le désaccord chez les acteurs en établissements de santé. Tous s'entendent toutefois sur la nécessité d'en mesurer l'usage et d'évaluer la conformité des pratiques des soignants aux normes de qualité applicable. Or, à l'heure actuelle, aucune définition opérationnelle de la contention chimique, aucun outil ni indicateur de qualité des soins valide ne permet d'évaluer l'usage des contentions chimiques. But. Cette étude métrologique a pour but de développer et de valider un outil d'évaluation réflexive de la qualité des soins en matière de contention chimique de la perspective de l'infirmière. Méthodologie. Quatre questions de recherche rassemblées en deux grandes phases de l'étude ont permis de poursuivre ce but, lors desquelles des méthodes qualitatives et quantitatives ont été utilisées. La phase de développement de l'outil d'évaluation réflexive impliquait la conduite d'une revue réaliste pour rassembler, à l'intérieur d'un modèle théorique, un inventaire d'items potentiels. Cette méthode systématique de synthèse des connaissances suggère une étape préliminaire destinée à clarifier la nature et les contextes de déploiement de l'intervention d'intérêt, ici l'usage des contentions chimiques. Pour ce faire, un examen de la portée a été réalisé. Puis, une technique Delphi a permis la validation du contenu des items recensés, lesquels ont ensuite été intégrés dans une plateforme virtuelle d'évaluation réflexive qui permet de mesurer les perceptions des professionnelles en charge de la décision d'administrer la contention chimique, soit les infirmières. L'outil d'évaluation au format innovant, appelé E-value-action, a ensuite été pré-testé pour une appréciation de la validité apparente (face validity) auprès de futurs- utilisateurs d'un Centre intégré universitaire de santé et de services sociaux (CIUSSS) du Québec, Canada, lesquels ont offert une rétroaction qualitative suite à une simulation d'évaluation. Résultats. L'examen de la portée basé sur 33 articles de provenance internationale a fait ressortir la nécessité d'élargir le concept à définir et à mesurer pour aborder la contention chimique comme une notion synonyme à la sédation des symptômes comportementaux. Ensuite, par le biais de la revue réaliste, 28 normes de pratique répertoriées dans 45 articles scientifiques ou textes de lignes directrices ont pu être insérées au modèle théorique puis libellés sous forme d'items à intégrer à l'outil d'évaluation. Ces normes, appuyées d'exemples concrets, reflètent la qualité des soins infirmiers en trois contextes principaux : les soins en santé mentale, les soins aigus à l'adulte et les soins de longue durée à la clientèle âgée. Au niveau de la validité de contenu, les items de l'outil ont présenté un degré d'accord sur la clarté des items de 90% et de 95% sur la pertinence, témoignant d'un consensus (>70%) chez le panel d'experts chercheurs, gestionnaires et cliniciens (n = 20) de différentes régions administratives du Québec, Canada. L'adéquation de la plateforme virtuelle d'évaluation et l'intérêt pour son implantation en contextes cliniques ressortent de l'analyse des données de la validité apparente auprès d'infirmières en soins directs (n = 7) d'un CIUSSS québécois. Discussion. L'usage de cet outil d'évaluation réflexive devrait favoriser l'intégration des normes de pratique en soins infirmiers en plus de promouvoir une culture de réduction des mesures de contrôle favorable à des soins plus sécuritaires, efficaces et centrés sur la personne. Une validation ultérieure à plus grande échelle et la traduction du contenu d'E-value-action avec validations transculturelles sont recommandées pour soutenir les nombreux états/provinces et pays anglophones qui possèdent, comme le Québec, une règlementation sur la réduction ou l'usage d'exception des mesures de contrôle dont la substance chimique. / Background. The administration of sedative agents for the management of behavioral symptoms, also called chemical restraint, is a complex intervention of which the various goals of control, protection, treatment and alternative to other coercion inspire vigorous debate among professionals within the health care field. There is general consensus, however, on the necessity to reduce the application and to evaluate professional practices against relevant quality standards. Despite this clear recommendation, there is currently no operational definition of chemical restraint, and there is no valid measurement tool or indicator available for the evaluation of chemical restraint interventions in healthcare. Aim. This metrological study aims to develop and validate an instrument to assess the quality of chemical restraint practices from the perspective of nurses. Methods. This goal has been pursued through the formulation of four research questions organized into two large phases of study, involving both qualitative and quantitative methods. The development phase was based on a realist review of existing quality standards in order to gather, within a theoretical model, an inventory of potential items. This systematic method of knowledge synthesis requires, as a preliminary step, the clarification of the nature and various contexts of the intervention of interest, in this case, chemical restraint. This was accomplished through a scoping review. Following this, the Delphi method enabled the content validation of the identified items, which were then integrated into a virtual reflexive assessment tool within which the perceptions of the nurses in charge of administering chemical restraints could be measured. In order to gain an appreciation of the face validity of this innovative assessment tool, called E-value- action, it was then pre-tested among future users at one of Quebec's Integrated University Health and Social Services Centers (CIUSSS), Canada. After completing this simulated evaluation, participants were invited to provide a qualitative description of their experience. Results. The scoping review, based on 33 internationally sourced articles, highlighted the necessity to expand the concept being defined and measured to include chemical restraint or behavioral sedation. The realist review method was then used to identify 28 quality standards, inventoried within 45 scientific articles or practical guidelines, which were then integrated into the theoretical model and itemized to facilitate their inclusion within the quality assessment tool. These items, supported by concrete examples, reflect nursing practices in three principal contexts: mental health care, acute care for adults and long- term elder care. As concerns the content validity, the items within the theoretical model presented an agreement of 90% for the clarity, and of 95% for the relevance, demonstrating a consensus (>70%) among the panel of expert researchers, managers and clinicians (n = 20) from different administrative regions of Quebec, Canada. The alignment between the virtual self-evaluation platform and the interest for its implementation within clinical contexts is palpable from the analysis of the face validity data gathered from direct care nurses (n = 7) in the Quebec CIUSSS. Discussion. The application of this reflexive self-evaluation tool should engender a deeper integration of nursing standards in addition to promoting a diminished utilization of coercive measures leading to care that is more secure, effective and patient-centered. A subsequent large-scale pilot testing of the E-value-action platform is recommended, including the translation and adaptation for cross-cultural analysis, in order to support the numerous English-speaking jurisdictions which, like Quebec, have developed regulations concerning the reduction or exceptional application of coercive measures such as pharmacological agents.

Les cardiopathies congénitales (CC) représentent l’une des anomalies congénitales les plus communes. Près de la moitié des nouveau-nés atteints nécessitent une chirurgie cardiaque au cours de leur premier mois de vie, ce qui les expose à un risque accru d’atteintes cérébrales et a été associé à un développement neurologique altéré. Il est donc nécessaire de trouver des stratégies neuroprotectrices efficaces pour améliorer leur évolution neurologique. Ce mémoire décrit l’influence des doses d’agents pharmacologiques administrées en période périopératoire sur la récupération de l’EEG en postopératoire, ainsi que sur les résultats neurodéveloppementaux évalués à 12 et 24 mois. Nous avons émis l'hypothèse que l’administration de certains agents pharmacologiques de sédation, d’anesthésie et d’analgésie en période intra- et postopératoire pourrait avoir un effet bénéfique au niveau de la récupération cérébrale à court- et long-terme, soit en réduisant la discontinuité observée sur l’EEG postopératoire et/ou en améliorant la performance obtenue lors de divers tests neurodéveloppementaux standardisés. Nos résultats semblent préconiser l’administration de plus fortes doses d’opioïdes en période périopératoire pour réduire la douleur et le stress induit par la chirurgie cardiaque, ce qui serait associé avec une amélioration du pronostic neurodéveloppemental. L’administration de plus fortes doses de dexmédétomidine et de midazolam était marquée par une récupération retardée de l’activité cérébrale après la chirurgie cardiaque sans aucun impact remarquable sur les résultats neurodéveloppementaux dans notre cohorte. Similairement, les doses de kétamine n’ont eu aucun impact sur la récupération cérébrale post-opératoire ou les bilans neurodéveloppementaux. / Congenital heart disease (CHD) is one of the most common congenital defects. Almost half of neonates affected require heart surgery during their first month of life, which exposes them to an increased risk of brain damage and has been associated with impaired neurodevelopment. It is therefore important to identify effective neuroprotective strategies to improve their neurological outcomes. This thesis describes the influence of the administration of pharmacological agents during the perioperative period on postoperative EEG recovery and neurodevelopmental outcomes at 12 and 24 months. We hypothesized that the administration of certain pharmacological agents for sedation, anesthesia and analgesia given during the intra- and post-operative period could have a beneficial effect on cerebral recovery, by decreasing the postoperative EEG discontinuity and/or improving neurodevelopmental outcomes. Our results suggest that the administration of higher doses of opioids during the perioperative period could reduce the pain and stress induced by cardiac surgery and are thus associated with improved neurodevelopmental outcomes. The administration of higher doses of dexmedetomidine and midazolam was marked by a delayed recovery of brain activity after cardiac surgery without any noticeable impact on neurodevelopmental outcomes in our cohort. Similarly, the doses of ketamine had no impact on postoperative brain recovery and on their long-term development.

<p> Exposure to chronic low oxygen (hypoxia) leads to a series of adaptive responses involving changes in gene expression that are critical for cell, tissue, and organismal survival. These changes are mediated by an important set of regulators belonging to the hypoxia inducible factor (HIF) family of transcription factors (e.g. HIF-lα, HIF-2α, HIF3α) which undergo rapid degradation during normal oxygen (normoxia) but are rapidly stabilized during hypoxia. While the role of HIF-1α has been extensively studied in many cell types, there have been relatively few studies on the role of HIF-2α, though recent evidence suggests its function maybe tissue specific. This thesis examined the hypothesis that HIF-2α plays a central role in the development and function of catecholaminergic cells of the sympathoadrenal (SA) lineage. The study was aided by use of an immortalized line of rat adrenomedullary chromaffin cells (i.e. MAH cells), derived from fetal SA progenitors, which express several hypoxia-sensitive properties characteristic of native cells in the adrenal gland. In Chapter 2, I investigated the potential contributions of mitochondrial reactive oxygen species (ROS) and 0 2 consumption to HIF-2α induction in MAH cells exposed to chronic hypoxia (2% O(2); 24 hr). In MAH cells, chronic hypoxia caused an increase in HIF-2α induction which was blocked by inhibition of any of the mitochondrial complexes using pharmacological agents, or by specific inhibition of complexes III and IV using RNAi techniques. It was found that in this 0 2-sensitive chromaffin cell line mitochondrial O(2) consumption, rather than changes in ROS, regulated HIF-2α induction during hypoxia. In Chapter 3, I investigated the hypothesized role of HIF-2α in the development of the catecholaminergic phenotype in cells of the SA lineage using the MAH cell line as a model. Mutant MAH cells, with depleted HIF-2α due to siRNA knock-down, showed dramatically lower levels of dopamine and noradrenaline compared to untransfected and scrambled control cells, regardless of whether the cells were cultured under normoxia or chronic hypoxia. This was correlated with a marked reduction in the expression of DOPA decarboxylase (DDC) and dopamine B hydroxylase (DBH), though the expression of tyrosine hydroxylase (TH) was unaffected. Moreover, HIF-2α was able to bind to a region of the DDC gene promoter which contains two putative hypoxia response elements (HREs). These data suggest that a basal level of HIF-2α function is required for the normal developmental expression of DDC and DBH in SA progenitor cells, and that loss of this function leads to impaired catecholamine (CA) biosynthesis. In Chapter 4, I investigated genes regulated by chronic hypoxia in MAH cells, with a focus on those involved in CA metabolism, storage, and secretion. Using microarray analysis combined with QPCR and RNAi knock-down methodology I uncovered several genes, involved in amine vesicular packaging, trafficking and secretion, which were upregulated during chronic hypoxia. One gene specifically, the adenosine A(2A) receptor (A(2A)R) gene, which appears to modulate CA secretion via autocrine or paracrine actions of extracellular adenosine, was dramatically upregulated in chronic hypoxia. Interestingly, this effect was completely abolished in HIF-2α knockdown MAH cells, suggesting a critical involvement of HIF-2α. Chromatin immunoprecipitation (ChIP) assays revealed that HIF-2α bound to the promoter region of the A(2A)R gene which contains a putative hypoxia response element (HRE) immediately upstream of exon 1. Ratiometric fluorescence measurements of intracellular Ca(2+) revealed that adenosine (50 μM) potentiated the high K(+)-evoked rise in [Ca(2+)]i in MAH cells. This effect of adenosine was further enhanced after chronic hypoxia, but was abolished in HIF-2α knock-down cells. In conclusion, these data suggest that HIF-2α is a key regulator of several genes involved in CA biosynthesis, and of others that mediate the facilitatory effects of chronic hypoxia on CA secretion in sympathoadrenal derivatives. / Thesis / Doctor of Philosophy (PhD)