Le système opioïde contrôle la douleur et la récompense, et le récepteur opioïde mu est la cible moléculaire de l’analgésie et de la dépendance aux opiacés. Dans la première partie de la thèse, nous avons montré que ce récepteur est également nécessaire au développement de l’hyperalgie se développant lors d’une administration chronique de morphine. Dans la seconde partie de thèse, nous avons étudié l’impact des interactions entre systèmes opioïde et cannabinoïde sur les effets associés à l’administration chronique de morphine. Nous avons exploré les effets d’un prétraitement avec un agoniste sélectif du récepteur cannabinoïde CB1, l’arachidonyl-2-chloroethylamide (ACEA) sur le développement de réponses nociceptives morphiniques, le sevrage, la récompense et des comportements naturels. L’étude comportementale a été complétée par des analyses transcriptionnelles et fonctionnelles afin d’identifier les processus neuroadaptatifs mis en jeu. Nos travaux montrent que l’activation des récepteurs CB1 et Mu présentent des effets bénéfiques sur les paramètres comportementaux associés à l’addiction, suggérant un intérêt thérapeutique potentiel à associer ces composés en clinique. / The opioid system controls pain and reward, and the Mu opioid receptor plays a central role in these effects. In the first part of the thesis, we showed that Mu receptor is also involved in the development of hyperalgesia induced by chronic opiate exposure. In the second part of the thesis, we studied the impact of opioid and cannabinoid interactions on effects associated to chronic morphine administration. We explored the effects of a pretreatment with a CB1 cannabinoid receptor selective agonist, arachidonyl-2-chloroethylamide (ACEA), on morphine-associated nociceptive, withdrawal, reward and naturalistic behaviors. To complete this behavioral study, we performed transcriptional and functional analyses to identify the neuroadaptative processes involved. Our study demonstrates that dual activation of CB1 and Mu receptors has a beneficial effect on behavioral parameters related to addiction, pointing to potential usefulness of combining both medications for therapeutic interventions.

The researcher is concerned about the lack of attention given to withdrawn early adolescents (WEAs) at school. During early adolescence, the foundations for lasting character, personality traits and social interaction are laid. Learners exhibiting withdrawal behaviour are described as being quiet, reserved, removed or distant. Attempts by educators to get them involved in lessons often end in failure and this causes educators to become frustrated and confused about how to deal with these learners. The aim of this study is therefore to establish the factors that contribute to withdrawal behaviour in early adolescents. The researcher devised an identification instrument that makes the identification of WEAs much easier for educators. He also established the deep seated fears and anxieties of WEAs and ascertained how they would like to be treated by their educators. / Psychology of Education / M. Ed. (Psychology of Education)

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Statins are drugs used in dislipidemias treatment. These agents are reversible inhibitors of the rate-limiting enzyme in cholesterol biosynthesis,the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and preventing de conversion of HMG-CoA to mevalonate. Besides reducing the plasma cholesterol, statins also present effects which seem cholesterol-independent, the so-called pleiotropic effects of statins. Date in literature has been shown that HMG-CoA inhibitors display neuroprotective properties, mainly related to improvement in vascular function due to increase in nitric oxide production, in this context, this class of drugs has proven usefull in treatment and prevention of neurodegenerative disorders such as Alzheimer´s and Parkinson´s. On the other hand, studies based on clinical data have shown that after abrupt discontinuation of statin therapy occurs a period in which the protective properties are lost, and deleterious effects are activated, leading to the appearance of rebound deterioration of vasculature which seems to be associated with alterations in enzymes activities endhotelial nitric oxide synthase and NADPH oxidase. However, little is known about whether these effects of statin withdrawal syndrome in the central nervous system. Therefore, this study aimed to investigate the effect of atorvastatin treatment withdrawal in the rat cerebral cortex. For this purpose, different parameters of oxidative/nitrosative stress were measured, including nitric oxide levels, the immunoreactivity for damage markers 3-nitrotyrosine, 4-hydroxynonenal and carbonyl, the activity of pro-oxidant enzymes NADPH oxidase and xanthine oxidase and the activity of antioxidant enzymes mitochondrial and citoplasmatic superoxide dismutase, catalase and glutathione-S-transferase. The results indicate that atorvastatin withdrawal decreases mitochondrial superoxide dismutase activity and increases NADPH oxidase activity, which may increase superoxide radical levels. Associated with this was seen a decreased in the level of nitric oxide ans increased in 3-nitrotyrosine immunoreactivity, suggesting that superoxide is reacting with nitric oxide leading the formation of peroxinitrite, which leads to proteins nitration. Increasing in the 3-NT/MnSOD ratio, and enzyme expression seen by western blot confirms the assumption that MnSOD is being nitrated, that nitration leads to lower superoxide detoxification. In conclusion, withdrawal of atorvastatin treatment occasioned oxidative/nitrosative damage in the rat cerebral cortex due to alterations in pro-oxidant and antioxidant enzymes activities. / As estatinas são fármacos utilizados no tratamento das dislipidemias. Esses agentes são inibidores reversíveis da enzima limitante da via de biossíntese do colesterol, a 3-hidróxi-3-metilglutaril-coenzima A redutase, e impedem a conversão do HMG-CoA a mevalonato. Além da capacidade de diminuir o colesterol plasmático, as estatinas também possuem efeitos que são independentes da inibição da via de biossíntese do colesterol, são os chamados efeitos pleiotrópicos. Dados da literatura tem demonstrado que os inibidores da HMG-CoA redutase possuem propriedades neuroprotetoras, relacionadas à melhora na função vascular devido ao aumento da produção de óxido nítrico, neste contexto, essa classe de fármacos tem se mostrado útil no tratamento e na prevenção de doenças neurodegenerativas tais como, Alzheimer e Parkinson. Por outro lado, estudos baseados em dados clínicos mostram que a após a interrupção abrupta do tratamento com estatinas ocorre um período em que as propriedades protetoras geradas são perdidas, e efeitos deletérios são ativados, levando ao aparecimento de uma deterioração rebote na vasculatura, o qual parece estar associado a alterações na atividade das enzimas óxido nítrico sintase endotelial e NADPH oxidase. Contudo, até o momento, pouco se sabe sobre esse feito da síndrome da retirada da estatina no sistema nervoso central. Sendo assim, esse estudo teve por objetivo verificar o efeito da retirada do tratamento com atorvastatina no córtex cerebral de ratos. Para isso, diferentes parâmetros do estresse oxidativo/nitrosativo foram medidos, tais como a imunoreatividade para os marcadores de dano 3-nitrotirosina, 4-hidroxinonenal e carbonil, a atividade das enzimas pró-oxidantes NADPH oxidase e xantina oxidase e das enzimas antioxidantes superóxido dismutase mitocondrial e citoplasmática, catalase e glutationa-S-transferase, bem como, o nível de óxido nítrico medido através do nitrito e nitrato. Os resultados obtidos mostram que a retirada do tratamento provoca diminuição na atividade da superóxido dismutase mitocondrial aumento na atividade da NADPH oxidase, o que sugere estar ocorrendo aumento na quantidade de radical superóxido. Associado a isso, foi visto diminuição no nível de óxido nítrico e aumento na imunoreatividade para 3-nitrotirosina, o que sugere que o superóxido está reagindo com o óxido nítrico levando a formação de peroxinitrito. Este último provoca a nitração de proteínas. O aumento da razão 3-NT/MnSOD, e da expressão da enzima visto por western blot, comprova a suposição de que a superóxido dismutase mitocondrial está sendo nitrada, essa nitração leva a uma menor detoxificação do superóxido, de modo que assim, é formado um ciclo. Assim, conclui-se que a retirada do tratamento com atorvastatina provoca dano oxidativo/nitrosativo no córtex cerebral de ratos devido a alterações na atividade das enzimas pró e anti-oxidantes.

Abstract A large body of animal studies indicates that reinforcement from alcohol is associated with dopaminergic neurotransmission in the mesocorticolimbic pathway. However, as most psychiatric phenomena cannot be studied with animals, human studies are needed. Furthermore, because of the fluctuating nature of phenomena regarding the status of abuse and withdrawal, repeated observations of the same study subjects under different situations can elucidate a variety of pathophysiological mechanisms. In this study 42 alcoholics were monitored during withdrawal and 30 alcoholics after four weeks of abstinence. 123I-β-CIT SPET was used as a method for the semi quantification of their striatal dopamine transporter (DAT) densities reflecting the function and structure of the dopaminergic system. DAT density was markedly lower during withdrawal among alcoholics as compared to control subjects, but it elevated during abstinence to the level of healthy volunteers. This increases in DAT density during withdrawal and afterwards correlated with the depression scores of alcoholics. DAT density correlated with the Novelty Seeking (NS) personality trait, especially among abstinent alcoholics. After four weeks of controlled abstinence alcoholics with an A1 allele of dopamine receptor D2 were found to have higher DAT densities than alcoholics without it. The results indicate that striatal DAT density is associated with mood, personality, A1 genotype and the length of the abstinence period after heavy alcohol drinking.

Pain and movement are intimately connected and nearly universal human experiences. However, our understanding of the extent, significance, and mechanisms of pain-movement relationships is limited. While pain is a normal, protective response to injury and potentially harmful stimuli, prolonged or dysfunctional neuromuscular adaptions in response to pain can contribute to a variety of pain conditions. Alternatively, movement (in the form of global physical activity, individual exercise programs, and/or specific motor learning/functional tasks) is often prescribed to help decrease pain and improve function. While attempts have been made to show an effect of movement on pain or to better understand altered movement strategies in response to pain, much of the research has been limited to animal models or to those with specific persistent or chronic pain conditions limiting generalizability and interpretability. Therefore, this research sought to advance current understanding of the relationships between physical activity and normal variability in centrally- and peripherally-mediated pain in healthy adults. Additionally, we sought to characterize changes in reflexive motor responses in the upper extremity to an endogenous, naturally-occurring, long-lasting acute muscle pain. The results of these investigations indicate that greater, self-reported intense (i.e. vigorous) and leisure activity are more strongly associated with decreased pain sensitivity than is pain modulation or measured activity (via accelerometry). Future research is needed to determine directionality of these relationships. Further, reflexive motor responses to endogenous, acute muscle pain in the upper extremity were not significantly altered indicating that changes in pain-related, movement strategies may be more strongly influenced by supraspinal adaptations. These results may have value in improving understanding of pain-related, movement sequelae and directing future research in this area.

The topic of this thesis is the Irish issue in the light of the Brexit debates. British people decided to leave the European Union in referendum in June 2016. Article 50 of the Lisbon Treaty was activated 29th of March 2017. Two years long negotiating period started from that date. The withdrawal agreement proposal which was approved by all 27 members of the European Union was rejected three times by British parliament. Brexit was postponed until the end of October of 2019. Future relationship on the island of Ireland with Irish backstop became the main barrier of Brexit negotiations. Both sides of negotiations agree on no possibility of hard border between Republic of Ireland and Northern Ireland. Both of them want to follow The Good Friday Agreement of 1998. On the other hand none of them is willing to step aside from their earlier requirements. Theresa May, British prime minister, decided to leave the EU Custom Union and the European Single Market resolutely. The EU rejected to renegotiate the withdrawal agreement proposal that includes the Irish backstop. The Irish backstop guarantee maintaining an open border on the island of Ireland in the event that the UK leaves the EU without securing an all-encompassing deal. Great Britain is afraid to lost control over its territory. Based on the...

The aim of the thesis is to investigate the readiness characteristics that determine risk for either failure or withdrawal before students enter university. These relationships are investigated and explained with a literature discussion that includes readiness for university education, student transition, retention and withdrawal theory. The motivation for this research emanates against the challenges that the South African Higher Education in general faces as well as the demands placed on the Faculty of Economic and Management Sciences to supply for the high demand for well equipped financial service professionals. The research project was completed in three phases. In the first phase a structured questionnaire was developed to measure the non-cognitive factors relating to readiness for university education. The purpose of the ‘Academic Readiness Questionnaire’ is to function as a screening test for first-year students that enter university. The Academic Readiness Questionnaire went through a scientific process of test development and standardisation. The overall Cronbach’s alpha for the questionnaire is 0.87, which indicates good internal consistency reliability for the scale with this sample. In the second phase the Academic Readiness Questionnaire was administered to the 2008 cohort of first-time entering students from the faculty of Economic and Management Sciences during the first-year orientation week. The total number of students in the sample is 829 students. In the third phase the students who withdrew from their studies were interviewed telephonically. A total of 42 students were interviewed to determine the salient reasons for withdrawal. Quantitative data were analysed using various descriptive and inferential statistical methods. These include factor analysis, regression analysis and multiway frequency analysis. The telephonic interviews were analysed with content analysis. The main findings reveal that the readiness characteristics show a direct relationship with academic success and intention to withdraw. The number of variables able to predict risk for either failure or withdrawal differ. More variables show a significant relationship with risk for failure than for withdrawal. Furthermore, the research results show that African students have higher academic achievement and are less likely to withdraw, when compared to white students. African students also tend to have higher academic success, compared to white students. The differences in academic success and withdrawal rates among African and white students are due to high school achievement and the number of credits the students register for. White students are also more likely to withdraw voluntarily, mostly within the first couple of weeks or months mainly due to choosing an incorrect study choice. / Thesis (PhD)--University of Pretoria, 2010. / Psychology / unrestricted

Built-up timber beams consist of individual lumber laminations connected together using mechanical fasteners such as nails, bolts and screws. Lateral torsional buckling (LTB) is an important failure mode that needs to be considered in deep beams with long spans and insufficient lateral supports. Due to the mechanical connectors, built-up beams are expected to have a lower moment capacity compared with solid beams with similar dimensions. The behaviour of built-up beams is greatly affected by the stiffness of the fasteners joining the individual laminations and determining the level of partial composite action attained in the beam. The current research aims to investigate the buckling behaviour of timber built-up beams. This is done by initially investigating the important parameters that play a role in the behaviour through an extensive sensitivity analysis. The focus of the analysis is on the contribution of the connections, since the buckling behaviour of individual solid timber beam element has been relatively well-established. Input parameters for the connection properties are obtained from joint level experimental tests. Finally, recommendations for specific fastener patterns and accompanying reduction factors on the buckling capacity relative to equivalent solid sections are developed and proposed.

School attendance problems experienced by children are a concern across Canadian educational systems. Higher rates of attendance issues exist among children who experience emotional and behavioural difficulties, which places them at heightened risk for poor educational outcomes. Frequently explored in educational research are variables related to school attendance problems among the general child population, however, a shortage of literature exists that explores these elements among children with emotional and behavioral difficulties. To address this void, this mixed-methods study explored child and educational elements that surrounded the school attendance problems of a sample of children receiving mental health services at a community clinic. Together, analyses of data gathered from the CANS, SDQ, and client files indicated that dynamic and reciprocal relationships existed among children’s emotional, behavioural, social, and academic difficulties which contributed to their attendance and overall educational experiences. These results corroborate existing research related to school attendance problems, however, provide unique insights into the profiles of this particular population and how their needs can be better met to promote more positive school experiences.

A state college in the mid-Atlantic United States requires a music theory course for 4 of its undergraduate music programs. In the 6 years prior to this study, students had difficulty with the course, with many failing or withdrawing. Tinto's theory of student retention served as the foundation of the conceptual framework for this study, the purpose of which was to identify challenges to successfully completing the course. This purpose was reflected in the study's driving research question focused on students' experiences regarding challenges to success. In this instrumental case study, 12 students and 2 instructors participated in individual interviews, and 7 students participated in a focus group. Initial coding was used for the 1st-cycle coding phase. Axial coding was used for the 2nd cycle. Seven themes emerged through an iterative categorization protocol: 3 student-related themes, 3 college-related themes, and 1 theme relating to solutions for overcoming challenges to success in Music Theory I. Although data indicated that students experienced diverse challenges to success, the need for additional help was most evident. Thus, a logical project for this study was a music theory lab designed using best practices for course redesign and adult learning found in the literature and developed to support student learning of the concepts presented in Music Theory I. This study may contribute to positive social change by providing an opportunity for students at the college to receive academic support structured to meet their learning needs and improve their performance in Music Theory I, which may prevent students from withdrawing from or failing the course.