In Turkey, the majority of the historic city centres have been continuously occupied since early ages onwards and where still occupation exists. The multi-layered structure of historic centres both can indicate the historical continuity of cities and enhance urban consciousness, if urban archaeological resources are handled effectively into planning process. However, the recent policies and strategies don&amp / #8217 / t allow the handling of urban archaeological resources, especially invisible sub-soil resources, into planning and decision-making process. In this thesis, it is aimed to formulate a basic methodological framework for the handling of urban archaeological resources into planning process of historic city centres in Turkey. Therefore, the study is handled in two parts / a conceptual methodological framework part and an exploratory case study.In the conceptual part, a basic equation is studied to research the factors on the conservation and evaluation of real urban archaeological potential. Then, the methodological framework is examined in detail in izmir Historic City Centre that has been inhabited since 324 B.C. Consequently, the terms of equi-property areas, which are used to define ideal potential of archaeological resources, and urban archaeological character zones, which are described as the basic units of planning and conservation policies, are developed to determine exact management strategies for urban archaeological resources.

This thesis examines deindustrialisation, the declining contribution of industrial activities to economic output and employment, in Lanarkshire, Scotland’s largest coalfield between the early nineteenth and mid-twentieth century. It focuses on contraction between the National Coal Board’s (NCB) vesting in 1947 and the closure of Lanarkshire’s last colliery, Cardowan, in 1983. Deindustrialisation was not the natural outcome of either market forces or geological exhaustion. Colliery closures and falling coal employment were the result of policy-makers’ decisions. The thesis consists of four thematic chapters: political economy, moral economy, class and community, and generation and gender. The analysis is based on archival sources including Scottish Office reports and correspondence relating to regional policy, and NCB records. These are supported by National Union of Mineworkers Scottish Area and STUC meeting minutes, and oral history testimonies from over 30 men and women with Lanarkshire coalfield backgrounds, as well as two focus groups. The first two chapters analyse the process of deindustrialisation, with the first offering a top-down perspective and the second a bottom-up viewpoint. In chapter one deindustrialisation is analysed through changes in political economy. Shifts in labour market structure are examined through the development of regional policy and its administration by the Scottish Office. The analysis centres upon a policy network of Scottish business elites and civil servants who shaped a vision of modernisation via industrial diversification through attracting inward investment. In chapter two the perspective shifts to community and workforce. It analyses responses to coalfield contraction through a moral economy of customary rights to colliery employment. A detailed investigation of Lanarkshire colliery closures between the 1940s and 1980s emphasises the protracted nature of deindustrialisation. Chapters three and four consider the social and cultural structures which shaped the moral economy but were heavily altered by deindustrialisation. Chapter three focuses on the dense networks that linked occupation, community, and class consciousness. Increasing coalfield centralisation and remote control of pits from NCB headquarters in London, and mounting hostility to coal closures, contributed to an accentuated sense of Scottish-ness. Chapter four illuminates gender and generational dimensions. The differing experiences of cohorts of men who faced either early retirement, redundancy or transfer to alternative sectors, or those who never attained anticipated industrial employment due to final closures, are analysed in terms of constructions of masculinity and the endurance of cultural as well as material losses. This is counterpoised to women who gained industrial work in assembly plants and the perceived gradual attainment of an improved economic and social position whilst continuing to navigate structures of patriarchy.

BDNF/TrkB são descritos em diversas neoplasias onde iniciam sinais mitogênicos, facilitam o crescimento tumoral, previnem apoptose e regulam angiogênese e metástase. Outros fatores de crescimento também são importantes para tumorigênese, como GRP/GRPR e EGF/EGFR. O objetivo geral deste trabalho foi investigar o papel de BDNF/TrkB em câncer colorretal avaliando possíveis interações com GRPR e EGFR. Verificamos que BDNF e seu receptor, TrkB, estão presentes em amostras de pacientes com câncer colorretal esporádico, e os níveis de BDNF encontram-se mais elevados no tecido neoplásico que no tecido adjacente ao tumor. O tratamento com RC- 3095, um antagonista de GRPR, na linhagem celular de câncer colorretal humana, HT-29, causa diminuição nos níveis de NGF secretados pelas células e aumento de BDNF em relação ao controle não tratado. RC-3095 inibe a proliferação e viabilidade celular das linhagens HT-29 (EGFR positiva) e SW-620 (EGFR negativa), embora apenas em HT-29 ocorra um aumento significativo na expressão de mRNA de BDNF. Por isso, um anticorpo monoclonal anti-EGFR, cetuximabe, foi combinado a RC-3095, nas células HT-29, sendo capaz de prevenir tal aumento, sugerindo que este efeito seja mediado por EGFR. Os tratamentos com um inibidor de Trks, K252a (1000 nM) ou com cetuximabe (10 nM) também inibem a proliferação celular. Entretanto, a combinação de BDNF a cetuximabe previne este efeito, enquanto que a combinação de doses não efetivas de K252a (10 nM) à cetuximabe (1 nM) inibe a proliferação celular de HT- 29. Além disso, cetuximabe também causa aumento na expressão de mRNA de TrkB e BDNF, após 600 minutos de tratamento. Nossos resultados sugerem que a inibição da proliferação celular in vitro ou do crescimento tumoral in vivo devem acontecer através do bloqueio combinado entre GRPR e TrkB em células de câncer colorretal EGFR positivas, e que BDNF também esteja envolvido em mecanismos de resistência a fármacos. Por isso, o bloqueio de BDNF / TrkB pode emergir como potencial alvo antitumoral. / BDNF / TrkB are described in various cancers where they participate in tumor growth, apoptosis, angiogenesis and metastasis. Furthermore, other growth factors are also important to tumorigenesis as GRP/GRPR and EGF/EGFR. Therefore, the aim of this study was to investigate the role of BDNF/TrkB in colorectal cancer evaluating the interactions with GRPR and EGFR. We found that BDNF and its receptor, TrkB, are present in samples from patients diagnosed with sporadic colorectal cancer, and BDNF levels were higher in tumor tissue compared to adjacent tumor tissue. Treatment with RC-3095, GRPR antagonist, in human colorectal cancer cell line, HT-29 caused a decrease in NGF levels secreted by cells, and generated increase of BDNF when compared to untreated control. RC-3095 inhibited the proliferation and cell viability in HT-29 (EGFR positive) and SW-620 (EGFR negative), but only HT-29 cells showed a significant increase in BDNF mRNA expression. Therefore, a monoclonal anti-EGFR antibody, cetuximab was combined with RC-3095 in HT-29 cells, and was able to prevent such an increase, suggesting that this effect is mediated by EGFR. The treatment with a Trk inhibitor, K252a (1000 nM) or cetuximab (10 nM), inhibited cell proliferation. However, the combination of BDNF with cetuximab prevented this effect, whereas the combination of ineffective doses of K252a (10 nM) with cetuximab (1 nM) still inhibited cell proliferation of HT-29. Furthermore, cetuximab also caused an increase in BDNF and TrkB mRNA expression, 600 minutes after treatment. In summary, our results suggest that inhibition of cell proliferation in vitro or tumor growth in vivo must occur between the combination of GRPR and TrkB in EGFR positive colorectal cancer cells, and that BDNF is also involved in drug resistance mechanisms. Therefore, blockage of BDNF / TrkB may emerge as potential antitumor target.

BDNF/TrkB são descritos em diversas neoplasias onde iniciam sinais mitogênicos, facilitam o crescimento tumoral, previnem apoptose e regulam angiogênese e metástase. Outros fatores de crescimento também são importantes para tumorigênese, como GRP/GRPR e EGF/EGFR. O objetivo geral deste trabalho foi investigar o papel de BDNF/TrkB em câncer colorretal avaliando possíveis interações com GRPR e EGFR. Verificamos que BDNF e seu receptor, TrkB, estão presentes em amostras de pacientes com câncer colorretal esporádico, e os níveis de BDNF encontram-se mais elevados no tecido neoplásico que no tecido adjacente ao tumor. O tratamento com RC- 3095, um antagonista de GRPR, na linhagem celular de câncer colorretal humana, HT-29, causa diminuição nos níveis de NGF secretados pelas células e aumento de BDNF em relação ao controle não tratado. RC-3095 inibe a proliferação e viabilidade celular das linhagens HT-29 (EGFR positiva) e SW-620 (EGFR negativa), embora apenas em HT-29 ocorra um aumento significativo na expressão de mRNA de BDNF. Por isso, um anticorpo monoclonal anti-EGFR, cetuximabe, foi combinado a RC-3095, nas células HT-29, sendo capaz de prevenir tal aumento, sugerindo que este efeito seja mediado por EGFR. Os tratamentos com um inibidor de Trks, K252a (1000 nM) ou com cetuximabe (10 nM) também inibem a proliferação celular. Entretanto, a combinação de BDNF a cetuximabe previne este efeito, enquanto que a combinação de doses não efetivas de K252a (10 nM) à cetuximabe (1 nM) inibe a proliferação celular de HT- 29. Além disso, cetuximabe também causa aumento na expressão de mRNA de TrkB e BDNF, após 600 minutos de tratamento. Nossos resultados sugerem que a inibição da proliferação celular in vitro ou do crescimento tumoral in vivo devem acontecer através do bloqueio combinado entre GRPR e TrkB em células de câncer colorretal EGFR positivas, e que BDNF também esteja envolvido em mecanismos de resistência a fármacos. Por isso, o bloqueio de BDNF / TrkB pode emergir como potencial alvo antitumoral. / BDNF / TrkB are described in various cancers where they participate in tumor growth, apoptosis, angiogenesis and metastasis. Furthermore, other growth factors are also important to tumorigenesis as GRP/GRPR and EGF/EGFR. Therefore, the aim of this study was to investigate the role of BDNF/TrkB in colorectal cancer evaluating the interactions with GRPR and EGFR. We found that BDNF and its receptor, TrkB, are present in samples from patients diagnosed with sporadic colorectal cancer, and BDNF levels were higher in tumor tissue compared to adjacent tumor tissue. Treatment with RC-3095, GRPR antagonist, in human colorectal cancer cell line, HT-29 caused a decrease in NGF levels secreted by cells, and generated increase of BDNF when compared to untreated control. RC-3095 inhibited the proliferation and cell viability in HT-29 (EGFR positive) and SW-620 (EGFR negative), but only HT-29 cells showed a significant increase in BDNF mRNA expression. Therefore, a monoclonal anti-EGFR antibody, cetuximab was combined with RC-3095 in HT-29 cells, and was able to prevent such an increase, suggesting that this effect is mediated by EGFR. The treatment with a Trk inhibitor, K252a (1000 nM) or cetuximab (10 nM), inhibited cell proliferation. However, the combination of BDNF with cetuximab prevented this effect, whereas the combination of ineffective doses of K252a (10 nM) with cetuximab (1 nM) still inhibited cell proliferation of HT-29. Furthermore, cetuximab also caused an increase in BDNF and TrkB mRNA expression, 600 minutes after treatment. In summary, our results suggest that inhibition of cell proliferation in vitro or tumor growth in vivo must occur between the combination of GRPR and TrkB in EGFR positive colorectal cancer cells, and that BDNF is also involved in drug resistance mechanisms. Therefore, blockage of BDNF / TrkB may emerge as potential antitumor target.

Les couches catalytiques avec une structure ordonnée à base de nanoparticules de Pt supportées sur des nanofilaments de carbone verticalement alignés ont montré des performances intéressantes grâce à l’amélioration des propriétés du transport de matière et à une meilleure utilisation du Pt. Des études électrochimiques combinées à une modélisation mathématique ont mis en évidence l’influence du transport de protons sur les processus d’oxydo-réduction, la cinétique et le mécanisme de réduction de l’O2 (ORR), et sur H2O2 qui s’échappe des couches pendant l’ORR. Nous avons montré que (i) les protons sont impliqués dans l’étape limitante de la réaction, (ii) pour un pH ≥ 3, un plateau de courant limité par la diffusion des protons est observé et, (iii) pour un pH ≥ 3, le mécanisme de l’ORR implique non seulement les ions hydroniums mais aussi les molécules d’eau. L’intégration de ces couches catalytiques dans des PEMFCs haute température a ensuite été étudiée. Les performances obtenues sont légèrement plus basses que celles des couches conventionnelles. Un travail d’optimisation reste donc à accomplir pour améliorer les performances. / Ordered catalytic layers based on vertically aligned carbon nanofilaments with Pt nanoparticles demonstrate high efficiency for oxygen transport and Pt utilization in the catalytic layer. Electrochemical studies combined with mathematical modeling confirm the influence of the proton transport on surface red-ox processes, the kinetics and the mechanism of the O2 reduction (ORR), and on the H2O2 escape. We show that (i) protons are involved in the rate-determining step of the O2 reduction, (ii) for pH ≥ 3, a plateau corresponding to the diffusion-limited current of protons is observed and, (iii) for pH ≥ 3, the mechanism of the ORR involves not only the hydronium ions but also water molecules. The integration of these catalytic layers in high temperature PEMFCs was then studied. The performance is slightly lower than that for conventional layers. An optimization work is required to improve the performance.

This study contributes to the current literature on time, gender, migration, culture and identity by bringing insights into how time is perceived and experienced by Syrian women who are settled and working in the UK. It is a topic that is little known in the extant literature, and that differs in its dynamics form the western literature. The notion of time has been widely debated but with little reference to its impact on the perceptions and individual experiences of migrant women, who engage with culturally different time structures and different time schedules. The spatial experiences of those women represented by their mobility across cultural boundaries seem to be affecting how migrant women perceive and organise time. Throughout the study, the Heideggerian interpretive phenomenological perspective has been adopted to make sense of and interpret the meanings and experiences provided by the participants of this study. This has been selected to allow space for considering and acknowledging the impact of the personal experience and prior knowledge of both the researcher and the researched subjects. Perceptions of time and time experiences have been found to be much diversified across personal, social and cultural contexts which are marked by spatial or geographical boundaries. Also, time structures and time schedules have been institutionally gendered across the cultures of both countries: Syria and the UK, but with varying degrees. Empirically, this study can help work organisations and agencies interested in working with migrant people to understand the diversity of perceptions and experiences of migrant female workers in the UK to enable them offering the care and services tailored to the needs of those migrants. In doing so, this research is hoped to improve the quality of work and social contributions of migrant women in the UK. Methodologically, this phenomenological inquiry contributes to the field of empirical and socio-political knowledge as well as the understanding of moral, aesthetic, and personal welfare debated in the migration literature. It contributes to the understanding of human experiences in relation to the notion of time, in isolation of any concern to predicting or prescribing any theory.

This study is concerned with the sexual abuse of enslaved women and girls by white men in the antebellum South. Interviews conducted by the Federal Writers’ Project in the 1930s are studied alongside nineteenth-century narratives of the formerly enslaved in order to make calculations of the scale of abuse in the South, but also to discover which conditions, social spaces and situations were, and possibly still are, most conducive to the sexual abuse of women and girls. This thesis is separated into two parts. Part One establishes a methodology for working with testimony of the formerly enslaved and determines the scale of sexual abuse using all available 1930s interviews with people who had lived in Louisiana and Texas under slavery. This systematic quantitative analysis is a key foundation from which to interpret the testimony of abuse that is explored according to different forms of sexual violence in Part Two. It is argued that abuse was endemic in the South, and occurred on a scale that was much higher than has been argued in previous studies. Enslaved people could experience a range of white male sexually abusive behaviours: rape, sexual slavery and forced breeding receive particular attention in this study due to the frequency with which they were mentioned by the formerly enslaved. These abuses are conceptualised as existing on a continuum of sexual violence that, alongside other less frequently mentioned practices, pervaded the lives of all enslaved people. Common features existed along the continuum. Abuse was intergenerational in nature for both the abusers and the abused. Light-skinned enslaved children born of rape were far more likely to become victims of abuse themselves and young enslaved girls were prematurely sexualised. Sexual abuse was brought into the white domestic space through the institution of sexual slavery, white children were thus unconsciously schooled in the abusive sexual mores of southern society from an early age. Abuse was quite open among white male family members. Other institutions existed that normalised and legitimised abuse, such as the fancy-girl trade and sexual interference through forced breeding practices that included eugenic manipulation and the use of ‘studs’. Despite this, enslaved women showed remarkable levels of emotional survival and initial reflections are made on the ways in which women could resist and cope with sexual abuse. Testimony suggests that abuse was discussed amongst the black community, support was rarely denied to victims, and there was no stigma was attached to children born of rape. With recent revelations on the scale of the institutionalised sexual abuse of women and children, as well as vast modern sex-trafficking networks, there are special opportunities presented through the current cultural climate in order to understand the southern experience. The South is reframed as a ‘culture of abuse’ where sexual violence against enslaved people was naturalised and culturally reproduced.

This thesis questions the generally accepted view that mechanics’ institutes made little contribution to adult working-class education from their foundation in the 1820s to the last decade of the nineteenth century when, finally, government recognised the importance of adult and further education with the passing of the Technical Instructions Acts of 1889 and 1891. It addresses the issue of what impact the mechanics’ institutes exerted upon the adult working classes in a regional context. It has also questioned research previously carried out by a number of historians who hold the view that by 1850 the mechanics’ institutes’ movement was in decline. This thesis argues that in Yorkshire the movement, through no small contribution made by the Yorkshire Union of Mechanics’ Institutes, went from strength to strength and responded to the need for relevant curricula throughout the period of study. It establishes that mechanics’ institutes of the Yorkshire Union (1838 – 1891) were not only to be found in the urban and industrialising towns, but many were also located in the rural and semi-rural areas of the Dales and Pennines. Across the Yorkshire Union as a whole there were similar patterns in growth and development. This thesis establishes that not only did mechanics' institutes support the working classes but they also provided a firm foundation for technical and further education, which was built on through the passing of the 1889 and 1891 Technical Instruction Acts. Several institutes either became technical schools or had established a tradition of adult education which was taken up by the new technical colleges of the early twentieth century. Many smaller institutes either became satellite centres for local colleges or became public libraries and museums. The nineteenth century success of the mechanics’ institutes foreshadowed the later development of adult education.

Brain tumors are the second leading cause of cancer deaths in young adults ages 20- 39. (Armstrong et al., 2004) According to the South African Medical Research Council, there was an estimate 801 deaths because of brain cancer in South Africa in 2000. If these statistics are compared to other types of cancers like breast-, lung- and prostate cancers, is the prevalence of the diagnoses of brain tumors, a very small percentage. According to the Mayo clinic in South Africa, the estimate number of brain tumor incidences was 3% in 2007. Despite of these statistics with regards Brain tumors, one in six South African men and one in seven South African women will be diagnosed with cancer during their life times. Despite this small percentage, the diagnoses of brain tumors have escalated the last few years. The reason for these new statistics is still unknown. With exercise that is becoming one of the most important adjuvant therapies for most diseases or illnesses, we may sustain this idea of using exercise intervention as an adjuvant therapy for brain tumor cancers we can prove this through many researches that has been done in the last few years. (Schwartz, 2003) Studies done by different researchers they found that exercise intervention is becoming increasingly recognized as a safe, feasible and beneficial supportive therapy for cancer patients both during and after the cessation of adjuvant therapy. (Jones et al., 2006) Exercise influences a lot of different systems in the body, to the advantage of the cancer patient (Schwartz, 2003) and emerging new research shows that physical exercise may boost brain function, which include improve mood. (Kong, 1999) Exercise, according to Cotman and Berchtold (2002) is commonly believed to be a behavioral strategy to relieve stress, and reduce depression and anxiety in humans. Exercise intervention further influence following aspects of the human body, namely brain deprived neurotrophic factor (BDNF) and 5-HT (Serotonin). Improvement of these could, in fact, lead to a better quality of life (QoL) of a brain tumor patient (Cotman&Berchtold, 2002). Fatigue that sets in, due to the different cancer therapies, is also a factor that has an affect on depression and anxiety of the patient. Keeping still and rest to prevent fatigue were followed in previous regiment when working with cancer patients was followed. This approach, in fact, has a very negative effect on the patient. Being diagnosed with a brain tumor the patient will never be emotionally prepared for this type of information and it usually shatters their sense of well being and their personal security. All of these factors, especially depression, affect the patient’s QoL. (Vaynman et al., 2004) An exercise regiment for brain tumor patients has not yet been developed properly, because exercise intervention for familiar cancers could be problematic and not suitable for brain tumor patients. (Schwartz, 2003) Therefore, the purpose of this study is to further the knowledge and the field of expertise of exercise as an adjuvant therapy in brain tumor patients to better QoL over a larger period of time. AFRIKAANS : Die tweede grootste leier in siektes tussen die ouderdomme van 20-39 jaar wat lewens eis is Brein gewasse (brein kanker). (Armstrong et al., 2004) Volgens die Suid- Afrikaanse Mediese Navorsingraad, is daar tot 801 gevalle van breingewas sterftes in die jaar 2000 aangemeld. As hierdie statistieke vergelyk word met statistieke van kanker wat meer prominent voorkom soos byvoorbeeld bors-, long-, en protaatkanker, lyk die voorkoms van breinkanker diagnosis maar na ‘n baie klein persentasie. Die Mayo Kliniek in Suid-Afrika het in 2007 bevind dat die voorkoms van breinkanker in Suid-Afrika ‘n persentasie van 3% uitgemaak het. Ten spyte van hierdie statistieke betreffende breingewasse, sal een uit elke ses mans en een uit elke sewe vroue, gediagnoseer word met een of ander kanker gedurende hulle leeftyd. Alhoewel die persentasie wat reeds genoem is maar na ‘n klein hoeveelheid lyk, het die voorkoms van breingewasse baie toegeneem in die laaste paar jaar en selfs maande. Die rede vir hierdie aansienlike toename is steeds onbekend. Oefening word al hoe belangriker en word al hoe meer deur verskeie dokters voorgeskryf om te dien as ‘n bykomende behandeling vir verskeie siekte toestande. Dit word veral ook vir kanker pasiënte voorgeskryf. Oefen intervensie kan dus gebruik word vir breinkanker pasiënte, hierdie stelling gestaaf kan word, aangesien daar verskeie navorsings reeds bewys het dat oefening as bykomende terapie gebruik is vir kanker pasiënte. (Schwartz, 2003) Hierdie studies het bevind dat oefening as ‘n veilige, uitvoerbare en voordelige bykomende intervensie vir kanker pasiënte erken word. Hierdie intervensie kan tydens en na hoof kanker behandeling gebruik word (Jones et al., 2006). Oefening beinvloed verskeie sisteme in die liggaam, tot voordeel van die kanker pasiënt. (Schwartz, 2003) Nuwe navorsing het ook aan die lig laat kom dat fisieke aktiwiteit ‘n persoon se breinfunksie bevorder, wat onder andere ‘n baie groot invloed het om die pasiënt se gemoedstoestand. (Kong, 1999) Volgens, Cotman and Berchtold (2002), is daarvolgens studies bewys dat oefenterapie ‘n manier is om stres te verlig, sowel as depressie en angstigheid in meeste mense. Oefenterapie beinvloed ook die volgende aspekte positief in die menslike liggaam naamlik, Brein ontnemende neurtrofiese-faktor (BDNF) en 5-HT (Serotonien). Verbetering van hierdie faktore, kan ly tot ‘n beter kwaliteit van lewe van ‘n pasiënt wat met ‘n breingewas gediagnoseer is (Cotman&Berchtold, 2002). Uitputting (moegheid) wat gewoonlik intree as gevolg van kanker terapie, is ook ‘n faktor wat ‘n effek het op die depressie- en angsvlakke van ‘n pasiënt. In vroeë behandelingsprotokol van kankerpasiënte, moes die pasiënt so stil as moontlik verkeer om sodoende uitputting of moegheid te voorkom. Hierdie benadering het in die uiteinde ‘n baie negatiewe effek op die pasiënte tot gevolg gehad. ‘n Persoon wat met ‘n breingewas gediagnoseer word sal nooit emosioneel voorbereid wees op hierdie diagnose nie en sodoende kan dit lei tot ‘n ineenstorting van die persoon se geestestoestand en persoonlike sekuriteit. Hierdie “ineenstorting” kan ‘n groot invloed hê op die kwaliteit van lewe van hierdie pasiënt (Vaynman et al., 2004). ‘n Oefenintervensie protokol vir breinkanker pasiënte is nog nie voldoende vasgestel nie, aangesien oefenterapie intervensies wat vir bekende kankers problematies en selfs gevaarlik kan wees vir breingewas pasiënte nie. (Schwartz, 2003) Daarom is die doel van die studie, om inligting te verkry en kennis in te samel om die veld van deskundiges uit te brei om sodoende ‘n oefenterapie protokol neer te lê vir breinkanker pasiënte. Hierdie protokol sal dus dien as ‘n bevordering van kwaliteit van lewe van hierdie pasiente deur middel van oefen intervensie as bykomende behandeling. Copyright / Dissertation (MA)--University of Pretoria, 2012. / Biokinetics, Sport and Leisure Sciences / unrestricted

L'encéphalopathie hypoxique ischémique néonatale (EHI) reste la cause principale de mortalité chez le nouveau-né à terme. Un tiers des survivants vont développer des séquelles neurologiques, dont la paralysie cérébrale (PC), l'épilepsie et un retard intellectuel. Afin d'améliorer leur pronostic, ces nouveau-nés sont soumis à l'hypothermie thérapeutique (HT) qui débute au plus tard 6 heures après la naissance, pour une durée totale de 72 heures, suivie d'un réchauffement graduel (0.5°C/h). Il a été démontré que cette thérapie à effet neuroprotecteur diminue considérablement l'étendue des lésions cérébrales et la fréquence des séquelles neurologiques. Or, des études animales suggèrent que l'hypothermie sans sédation avec opioïdes n'est pas bénéfique. Selon les observations qui ont été réalisées, les porcelets traités avec la thérapie, mais sans l’administration d’analgésique ont manifesté des signes d’instabilités et de tremblements exagérés. On ignorait jusqu’à présent dans quelle mesure ces résultats tirés des expérimentations animales pouvaient être généralisables au nouveau-né. Ainsi, mon projet de maîtrise vise à mieux comprendre les facteurs qui risquent de compromettre les effets bénéfiques de la thérapie de refroidissement, dans le but d’optimiser la neuroprotection et d’améliorer le développement des nourrissons atteints d’EHI. Nous avons comme objectif principal d’évaluer l’association entre les doses d’opioïdes consommées pendant l’HT, le degrée de tremblement, et l’évolution de l’index de discontinuité à l’EEG au fil des 72h de l’HT, du réchauffement et jusqu’à 12 heures post-HT. Pour répondre à l’objectif, nous avons conduit une étude chez 21 nouveau-nés avec EHI soumis à l’HT, et dont les principaux résultats ont montré des associations significatives entre les fortes doses d’opioïdes administrés à l’enfant (r = - 0.493, p = 0.023), les frissons réduits pendant l’HT (r = 0.513, p = 0.017) et l’amélioration du rythme cérébrale d’EEG. Ces résultats sont décrits de manière plus approfondie dans le Chapitre 2 qui présente la version de l’article soumis à la revue Journal of Pediatrics, et le Chapitre 3 qui présente un retour sur la littérature à la lumière de nos trouvailles. Quant au Chapitre 4, nous y élaborons les possibilités de perspectives futures et les retombées cliniques de nos résultats. À long terme, nous espérons que nos travaux permettront l’ouverture d’une nouvelle piste d’amélioration de la neuroprotection, en favorisant systématiquement une meilleure prise en charge de la douleur et du stress induit par le refroidissement. / Neonatal hypoxic-ischemic encephalopathy (HIE) remains the leading cause of death and mortality in the term infant. A third of the survivors will develop neurological sequelae including cerebral palsy (CP), epilepsy and mental retardation. In order to improve their prognosis, these newborns undergo therapeutic hypothermia (TH), which begins no later than 6 hours after birth, maintained for a total duration of 72 hours and followed by gradual rewarming (0.5°C/h). This neuroprotective therapy has been shown to significantly decrease the extent of brain injury and the frequency of neurological sequelae. Results from animal studies revealed that ongoing hypothermia without proper anesthesia is not beneficial. Based on the observations that have been reported, piglets treated with TH with no analgesics have shown signs of instability and excessive tremors. Until now, the extent to which these results from animal experiments could be generalized to the newborn remained unknown. Thus, the purpose of my master’s project was to better understand the clinical factors that may compromise the beneficial effects of TH, in an attempt to optimize neuroprotection and improve the neurological outcome of HIE infants. Our main objective was to assess the associations between opioid doses consumed during TH, shivering recorded during TH, and the evolution of EEG discontinuity index over the course of TH, rewarming and up to 12 hours post-TH. To meet the objective, we conducted a study in 21 newborns with HIE undergoing TH, and the results have shown significant associations between high doses of opioid administered (r = - 0.493, p = 0.023), reduced shivering stress (r = 0.513, p = 0.017) and improved EEG background activity. The key findings of the study are described in more detail in Chapter 2, which presents the original manuscript submitted for publication to the “Journal of Pediatrics”, and Chapter 3, which presents a review of the literature in light of our results. In Chapter 4, we discuss future perspectives and the clinical significance of our results. At last, we hope that our study will open up new avenues for improving neuroprotection, by systematically promoting a better management of pain and cooling-induced stress.