Despite major advances in our understanding of the biology of childhood acute myeloid leukemia (AML) and the development of new cytotoxic drugs, the prognosis of long-term survival is still only 60-65 %. In the present research, we studied the pharmacokinetics of drugs used in the induction therapy of childhood AML and performed in vitro drug sensitivity testing of leukemic cells from children with AML. The aims of the studies were to correlate the results of the analysis to biological and clinical parameters and to identify subgroups of AML with specific drug sensitivity profiles in order to better understand why treatment fails in some patients and how therapy may be improved. Blood samples were analysed to study the pharmacokinetics of doxorubicin (n=41), etoposide (n=45) and 6-thioguanine (n=50). Doxorubicin plasma concentration and total body clearance were correlated to the effect of induction therapy, and doxorubicin plasma concentration was an independent factor for complete remission, both in univariate and multivariate analysis including sex, age, and white blood cell count at diagnosis. For etoposide and 6-thioguanine no correlation was found between pharmacokinetics and clinical effect. Children with Down syndrome (DS) tended to reach higher blood concentrations of etoposide and thioguanine nucleotides, indicating that dose reduction may be reasonable to reach the same drug exposure as in children without DS. Leukemic cells from 201 children with newly diagnosed AML, 15 of whom had DS, were successfully analysed for in vitro drug sensitivity by the fluorometric microculture cytotoxicity assay (FMCA). We found that samples from children with DS were highly sensitive to most drugs used in AML treatment. In non-DS children, the t(9;11) samples were significantly more sensitive to cytarabine (p=0.03) and doxorubicin (p=0.035) than other samples. The findings might explain the very favorable outcome reported in children with DS and t(9;11)-positive AML. A specific drug resistance profile was found for several other genetic subgroups as well. A detailed study of MLL-rearranged leukemia showed that cellular drug sensitivity is correlated both to partner genes and cell lineage, findings that support the strategy of contemporary protocols to include high-dose cytarabine in the treatment of patients with MLL-rearrangement, both in AML and acute lymphoblastic leukemia (ALL). Our results indicate that drug resistance and pharmacokinetic studies may yield important information regarding drug response in different sub-groups of childhood AML, helping us to optimize future chemotherapy in childhood AML.

The purpose of this study is to examine how two educators at a preschool that is located in a neighborhood south of Stockholm works with TAKK with children who has Down syndrome in a language promotion purposes. The aim is also to investigate what teachers think about using TAKK with children without special needs and children with Down syndrome. In this study, I used qualitative research methods. I've used both observations and interviews to get answers to my questions. The theories which I have used in this thesis is, socio-cultural perspective, including integration and segregated integration. In order to find out how the educators work with TAKK I have asked these questions: How do the educators work with TAKK with children with Down syndrome from a language development perspective? What do the educators express about using TAKK with children without special needs and with children who has Down syndrome? My conclusions to these questions are that the literatures I have read in many ways are consistent with how they work. They told me, among other things, that the use of TAKK is good for both the children with and without Down syndrome. Regarding to how they use TAKK in their everyday work I could see that they used TAKK on a daily basis in the routines at the preschool.

Thesis (PhD)--University of Stellenbosch, 2002. / Page ii of digitised copy missing due to the condition of the original hard copy. / ENGLISH ABSTRACT: no abstract available / AFRIKAANSE OPSOMMING: Hierdie studie bestudeer die rol wat die opvoedkundige sielkundige kan speel in die ondersteuning van leerders met Downsindroom tydens die insluiting tot hoofstroomonderwys. Die studie vind plaas in 'n tydperk waar postmoderne denke en demokratisering van onderwys in Suid-Afrika te voorskyn kom. Hierdie tipe studie is relevant. aangesien huidige beleidsdokumente klem Ie op die demokratisering van onderwys en die transformasie na inklusiewe onderwys. Die Universiteit van Pretoria het in samewerking met die Universiteit van Stellenbosch 'n lootsprojek geinisieer waarin inklusiewe onderwys bestudeer is. Die projek het bestaan uit 'n gevallestudie van tien leerders met Downsindroom wat gedurende 1996 in verskillende hoofstroom kleuterskole geplaas is, waartydens hulle 'n leergereedheidsprogram gevolg het. Gedurende 1997 is die leerders in graad eenklasse in die hoofstroom geplaas. Die leerders se agtergrond was divers ten aansien van hul onderrig, maar die meeste van hulle was eers in spesiale skole. Die doel van die studie was om die leerders, ouers en onderwysers te ondersteun en verdere ondersteuning in a trans-disslplinere span te koordineer. Die waarneming en temas wat in hierdie studie na yore gekom het, beklemtoon dat diagnose, evaluasie en terapeutiese ondersteuning binne 'n ekosistemiese raamwerk belangrik is vir leerders met Downsindroom wat in die hoofstroom geplaas word. Die konsep van holistiese gesondheidsontwikkeling word beklemtoon in die transformasie van onderwys in Suid-Afrika. Opvoedkundige sielkundiges moet hulself dus ook strategies posisioneer. Gedurende die studie is die volgende rolle vir die opvoedkundige sielkundige ge"identifiseer: psigoterapeut, assessor/evalueerder, fasiliteerder, navorser/reflektiewe praktisyn, vakspesialis, konsultant, bestuurder en administratiewe rol en laastens die rol van ontwikkelingsfasiliteerder. Dit is ook belangrik dat die opvoedkundige sielkundige die rol as fasiliteerder van geestesgesondheid vertolk.

Abstract The primary focus of this research project was an evaluation of the Group Stepping Stones Triple P parenting program for parents of a child with a disability. In addition there was an investigation into the similarities and differences in child behaviour and parenting experience, and program outcomes, for families of children with different developmental disabilities. While the Triple P Positive Parenting Program has an impressive evidence base (Sanders, 1999; Sanders, Markie-Dadds, Tully & Bor, 2000) and research indicates that the standard Stepping Stones Triple P Program is efficacious for different disability groups (Roberts, Mazzucchelli, Studman & Sanders, 2006) and for parents of children with Autistic Spectrum Disorders (Whittingham, Sofronoff, Sheffield & Sanders, 2009), to date the group version of Stepping Stones Triple P has not been comprehensively evaluated, nor the efficacy of the program evaluated when administered concurrently to parents of children with different developmental disabilities. Currently, there is a lack of participant-friendly, evidence-based group parenting programs that can be utilised in a cost-effective manner with all parents of children with disabilities. Many interventions have been designed specifically to cater to the requirements of a particular disability group. While there is some divergence in disability characteristics and in the experience of families of children with different disabilities, there is compelling evidence that many of the most challenging experiences faced by parents of disabled children (such as emotional and behavioural disturbance and delays in skill development) are shared by many disability populations (Raina et al., 2005; Bourke et al., 2008). Consequently there is empirical support for the implementation of a broad, skill-based parenting program for all parents of children with disabilities. The first study in this research project was a randomised controlled trial the Group Stepping Stones Triple P program for parents of children with Autism Spectrum Disorders (ASD), Down syndrome, other intellectual disabilities and Cerebral Palsy. Fifty-two families were included in this trial and were randomly allocated to treatment and wait-list control groups. The results demonstrate significant improvements in child behaviour and parenting difficulties that were maintained at follow-up six months later. For over a third of participants the change in child behaviour and parenting styles was clinically reliable (Jacobsen & Truax, 1991; Evans, Margison & Barkham, 1998). In addition, the majority of parents reported the attainment of their program goals following the intervention. The second study was a comparison of program outcomes for parents from different disability groups. The sample was divided into two groups; parents of children with ASD and parents of children with intellectual and physical disabilities. The results demonstrated significant improvements in child behaviour and parenting difficulties from pre- to post-intervention for both the ASD group and the Intellectual and Physical disability group. For a third of parents in the ASD group and over a third of parents in the Intellectual and Physical disability group, the changes were clinically reliable (Jacobsen & Truax, 1991; Evans et al., 1998). In addition, the means for both groups on the child behaviour, parenting style and parental psychological functioning variables were compared. The results indicated that there were some differences in child behaviour, parenting styles and parent distress between the two groups, and in the program goals set by parents. However, overall the results revealed no systematic differences in treatment outcomes across disability groups, demonstrating that the program was effective for families of children with ASD and families of children with Intellectual and Physical disabilities. Finally, a series of three case evaluations were conducted to examine program outcomes and differences in child behaviour and parenting experiences for the families of a child with ASD, Down syndrome and Cerebral palsy. The results of the case studies revealed significant improvements in child behaviour and parenting styles for all three families, along with high levels of program satisfaction and successful attainment of parenting goals. For all three families these changes in child behaviour and parenting style were clinically reliable (Jacobsen & Truax, 1991; Evans et al., 1998) and maintained at six-month follow up. The results also provided information about the similarities and differences in parenting experiences, child behaviour and program goals across the three disabilities. Overall, this research project has demonstrated that the Group Stepping Stones Triple P program is an effective parenting intervention for challenging behaviour and dysfunctional parenting in families of children with a range of developmental disabilities. The results of this research provide evidence to suggest that mixed disability group format used in the administration of the Group Stepping Stones Triple P program did not preclude positive program outcomes. Finally, the results of this research project indicate that there are many shared parenting experiencing across families of children with different disabilities and that regardless of observed differences in disability characteristics and family experiences, the Group Stepping Stones Triple P program is sufficiently flexible and comprehensive in its scope to meet the needs of families from different disability populations.

Made available in DSpace on 2014-06-11T19:23:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-03-12Bitstream added on 2014-06-13T18:09:52Z : No. of bitstreams: 1 tanaka_mh_me_arafo.pdf: 647421 bytes, checksum: 7aca1036f8801f2b3143929ea57d6d5c (MD5) / A doença periodontal (DP) em indivíduos com Síndrome de Down (SD) se desenvolve com alta prevalência, precocemente, de modo rápido e generalizado em comparação com indivíduos não-sindrômicos. Foi demonstrado que portadores da SD apresentam resposta imune diminuída em relação aos cromossomicamente normais. O objetivo desta pesquisa foi investigar diferenças nos parâmetros clínicos periodontais e níveis de expressão dos genes Interferon-gama (IFNG), Interferon-gama receptor 1 (IFNGR1), Interferon-gama receptor 2 (IFNGR2), Interferon-alfa (IFNA), Interferon-alfa receptor 1 (IFNAR1), Interferon-alfa receptor 2 (IFNAR2), Janus-quinase 1 (JAK1), Transdutor de sinal e ativador da transcrição 1 (STAT1) e Fator de regulação de interferon 1 (IRF1) em indivíduos com SD que apresentam ou não DP e em indivíduos cromossomicamente normais. Fizeram parte deste estudo 80 indivíduos entre 7 e 57 anos de idade subdivididos em 4 grupos: SD com DP (A); indivíduos com SD sem DP (B); indivíduos não-sindrômicos (Controle) com DP (C) e indivíduos Controle sem DP (D). A expressão gênica foi investigada por meio de quantificação relativa utilizando a técnica da Reação em Cadeia da Polimerase (PCR) em Tempo Real. Para o índice sangramento à sondagem (SS) não houve diferença entre os grupos A e 21 C. A periodontite crônica localizada foi o tipo prevalente tanto entre indivíduos com SD como Controle. Considerando os parâmetros clínicos, não foram encontradas diferenças na periodontite crônica localizada entre os indivíduos com SD e Controle, assim como para a periodontite crônica generalizada. Com relação à análise genética, observou-se que indivíduos dos grupos com SD em relação aos grupos cromossomicamente normais (A+B-C+D) tiveram uma expressão de IFNG semelhante ao observado entre indivíduos do grupo... / Periodontal disease (PD) in individuals with Down Syndrome (DS) has an early, quickly and widespread onset and high prevalence when compared with individuals without the Syndrome. Only poor oral hygiene does not explain the severe periodontal destruction seen in DS patients. It has been shown that DS patients have a weaker immune response than people with normal number of chromosomes. The aim of this study was to investigate differences in periodontal clinical parameters and the expression levels of the genes Interferon-gamma (IFNG), Interferon-gamma receptor 1 (IFNGR1), Interferon-gamma receptor 2 (IFNGR2), interferon-alpha (IFNA), interferon-alpha receptor 1 (IFNAR1), Interferon-alpha receptor 2 (IFNAR2), Janus-kinase 1 (JAK1), Signal transducers and activators of transcription 1 (STAT1) and Interferon regulatory factor 1 (IRF1) in DS patients with and without periodontal disease in comparison with chromossomically normal individuals. A total of 80 individuals aged 7 to 57 years participated in this study and were divided into 4 groups: DS with PD (A); DS without PD (B); individuals without DS (control) with PD (C) and individuals without DS (control) and without PD (D). A quantitative RT-qPCR was used to investigate gene expression. There was no difference between groups A and C regarding the bleeding on probing 25 (BOP) index. The most prevalent type of periodontitis seen in this study was the localized chronic periodontitis, both in individuals with and without DS. Considering the clinical parameters, localized and generalized chronic periodontitis did not differ between individuals with and without DS. Regarding genetic analysis, individuals of the groups with DS in relation to the groups without DS (A+B-C+D) showed an IFNG expression similar to that seen among the individuals of groups control with PD (C-D). However, individuals... (Complete abstract click electronic access below)

Submitted by Noeme Timbo (noeme.timbo@metodista.br) on 2017-06-27T14:35:36Z No. of bitstreams: 1 Danielle Lueth Assaf.pdf: 1674732 bytes, checksum: bc8e2ad44b421c8f851b66f2aea6ba89 (MD5) / Made available in DSpace on 2017-06-27T14:35:36Z (GMT). No. of bitstreams: 1 Danielle Lueth Assaf.pdf: 1674732 bytes, checksum: bc8e2ad44b421c8f851b66f2aea6ba89 (MD5) Previous issue date: 2017-03-23 / This research aims to expand the understanding about a theme that is gaining prominence in our society, day after day: the inclusion of people with disabilities. With the new public policies, a constant updating is necessary, aiming at the improvement of the quality of the experience of disabled people in the school environment and the expansion of their learning capacity. Although the theme is not new, with the advent of the Magna Carta, and the fundamental rights and guarantees of the citizen, a new systematics has been inevitable to deal with this issue. It is a controversial topic and therefore specific field research was required. There is great divergence among professionals: in favor, against or partially against total or partial inclusion. There are, therefore, those who stand up for the insertion of these children into specialized institutions or the presence of specific classrooms for all students who have some type of disability. Thus, the present work aimed at the following objectives: to reflect on the public policies of inclusive education and its applicability in the reality of Brazilian education; Understand aspects inherent to Down Syndrome, such as etiology and characteristics, as well as aspects of development and learning; To seek, understand and reflect on pedagogical practices that aim to aid in the learning process of students with Down Syndrome; And reflecting on the learning conditions offered to these students by regular education and how specialized education can contribute. For the development of the following work, it was necessary a bibliographic review in the desired area, field research in a specialized school, collection of historical data, collection of data through interviews and testimonies and, finally, the analysis of the data obtained in the research with the school, emphasizing that the methodology used was the qualitative method, through interviews conducted with semi-structured questionnaire and observation of the context, as mentioned above. It is important to mention that the montessorian pedagogy was investigated, bringing significant benefits to the learning of the students with Down's syndrome, through the adaptation of the method. / A pesquisa realizada visa ampliar a compreensão a respeito de um tema que, dia a dia, ganha força em nossa sociedade: a inclusão de pessoas com deficiência. Com as novas políticas públicas, é necessária uma constante atualização, visando o aprimoramento, a melhoria da qualidade da experiência de pessoas deficientes no ambiente escolar e a ampliação de sua capacidade de aprendizado. Embora a temática não seja nova, com o advento da Carta Magna, e os direitos e garantias fundamentais do cidadão, fez-se inevitável uma nova sistemática para lidar com essa questão. É uma temática controversa e por isso foi necessária pesquisa de campo específica. Existe grande divergência entre os profissionais: a favor, contra ou parcialmente contra a inclusão total ou parcial. Há, portanto, aqueles que defendem a inserção dessas crianças em instituições especializadas ou a presença de salas de aula específicas para todos os alunos que possuem algum tipo de deficiência. Assim, o presente trabalho pretendeu os seguintes objetivos: refletir acerca das políticas públicas de educação inclusiva e sua aplicabilidade na realidade da educação brasileira; compreender aspectos inerentes à Síndrome de Down, tais como etiologia e características, bem como aspectos do desenvolvimento e aprendizagem; buscar, compreender e refletir acerca de práticas pedagógicas que visem auxiliar no processo de aprendizagem dos alunos com Síndrome de Down; e refletir acerca das condições de aprendizagem oferecidas a esses alunos pelo ensino regular e de que maneira o ensino especializado pode contribuir. Para o desenvolvimento do trabalho que se segue, foi necessária uma revisão bibliográfica na área pretendida, pesquisa de campo em escola especializada, levantamento de dados históricos, coleta de dados através de entrevistas e depoimentos e, por fim, a análise dos dados obtidos na pesquisa junto à escola, ressaltando que a metodologia empregada foi o método qualitativo, por meio de entrevistas realizadas com questionário semiestruturado e observação do contexto, como mencionado acima. Importante mencionar que a pedagogia montessoriana foi investigada, trazendo benefícios significativos à aprendizagem do aluno com Síndrome de Down, por meio de adaptação do método.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Este trabalho explora as possibilidades de contribuição da psicanálise para a compreensão do processo de construção de identidade e busca de autonomia de adultos com limitação intelectual moderada. Parte da ideia de que estas pessoas apresentam formas diversas de subjetivação e que, como todos, ao longo da vida são passíveis de encontros e desencontros provocadores dos mais diversos sentimentos. Reconhece a importância dos aspectos orgânicos, e afastando-se dos mesmos, desenvolve a ideia de que, para além do substrato orgânico, os aspectos emocionais são fatores fundamentais para a construção da autonomia. A hipótese básica é a de que os limites e as possibilidades de aquisição da autonomia são variáveis e que os aspectos emocionais são importantes neste processo. Há aspectos da dependência ambiental que são insuperáveis nestes casos, o que não quer dizer que sejam fixos ou imutáveis. Mesmo levando-se em consideração as restrições impostas pela base orgânica dos quadros estudados, as ligações familiares, primordialmente representadas pela relação da mãe com seu filho, colocam-se como fator importante quando se propõe a compreender e trabalhar com estas pessoas. O trabalho aborda a articulação possível entre a dependência e a autonomia levantando algumas consequências: nas práticas sociais, na construção da subjetividade e nos tratamentos. Pretende desenvolver a ideia de que a teoria do desenvolvimento emocional primitivo de Winnicott traz uma importante contribuição para a compreensão deste processo. / This paper explores some possible psychoanalytical contributions in understanding the process of identity construction and autonomy of adults with moderate intellectual limitations. This work is based on the idea that this group shows different forms of subjectivity and, like all of us, has its share of encounters and disencounters experienced in life with every kind of feelings about this. Although recognizing the importance of the organic aspects, it searches further than those looking for the emotional aspects which are essential to the construction of autonomy. The basic concept adopted is that the limits and possibilities of the conquest of autonomy vary from person to person and the emotional aspects embedded are crucial in the process. There are aspects of enviromental dependency that are insuperable in those cases, although it doesnt mean that they are fixed or that they cannot change. Even considering the organic restrictions of the studied cases, the family connections (essentialy represented by mother and son relationship) are very important in understanding and working with those cases. This work aims a possible articulation between dependency and autonomy enlightening some consequences in social practices, in the construction of subjectivity and in treatment. It intends to develop the idea that Winnicotts primitive emotional development concepts offer an important contribution to this process.

Les travaux de la thèse se sont articulés autour de la synthèse totale d’un composé naturel isolé à partir de la plante Scorzoneraradiata, la RCZ. Lors d’un criblage sur un panel de kinases, dont la kinase DYRK1A, les résultats ont montré la très grande sélectivité de ce composé avec une action d’inhibition sur DYRK1A (IC50 = 220 nM). De nombreuses études disponibles dans la littérature ont établi le lien entre la dérégulation de la protéine DYRK1A avec le syndrome de Down (trisomie 21) et certaines maladies neurodégénératives tel que la maladie d’Alzheimer. En vue de l’obtention de ce composé prometteur présentant un squelette dihydrostilbène porteur d’une fonction cétone et d’un groupement osidique. Trois voies d’approche ont été successivement mises en œuvre. Le groupement cétone est construit par le biais d’une réaction de Sonogashira suivit par une hydratation en présence d’un sel mercurique. La réaction de Wittig permet l’assemblage du squelette stilbène. Lors de la première approche, un isomère de position du composé final avec un pouvoir inhibiteur divisé par dix par rapport à RCZ a été obtenu. L’utilisation de différents groupements protecteurs a permis l’obtention du composé final RCZ en seulement 15 étapes. Ce travail ouvre de nouvelles perspectives dans le développement d’analogues par des pharmacomodulations en se basant sur les informations fournies par le co-cristal de RCZ avec la protéine DYRK2. / This thesis focuses on the synthesis of RCZ, a natural compound isolated from the plant Scorzonera radiata. During a high-throughput screening, this compound has demonstrated, on a large panel of kinases, a high and unusual degree of selectivity against the kinase DYRK1A. On a structural point of view, the compound is a glycosylated dihydrostlibene, which also bears two phenols and an acetyl group. Recently, a link between the deregulation of the kinase DYRK1A with Down syndrom and some neurodegenerative diseases such as Alzheimer disease has been established. In order to perform the synthesis of this compound, three approaches were undertaken. In these approaches, the acetyl group was built through a Sonogashira coupling followed by a mercury salt catalyzed hydration of the acetylenic group. Also, the stilbene scaffold was always obtained by Wittig condensdation. In the first approach, an isomer was obtained with approximately a ten times less potent inhibitory activity against DYRK1A than RCZ. By the use of different protective groups the final compound RCZ was successfully obtained. In conclusion, a total and efficient synthesis of RCZ has been constructed in 15 steps. This work opens future perspective in the design of new inhibitors based on the determination of the crystal structure of the RCZ-DYRK2 complex.

Les fonctions cardiovasculaires doivent répondre à des stimulations physiologiques importantes et différentes lors de l'exercice physique, de l'exposition à la haute altitude ou de tests de stimulation spécifiques du système nerveux autonome. Nous avons dans ce travail de thèse, étudié les modulations autonomiques consécutives à l'exercice (entraînements / compétition ou réentraînement), à l'hypoxie ou à des tests de stimulation adrénergiques afin de faire le lien avec la fatigue et/ou la limitation à l'effort. Le suivi de coureurs à pieds séniors nous a permis d'observer une majoration de l'activité sympathique ainsi qu'une diminution du tonus parasympathique sous l'effet de l'entraînement, et plus encore de la compétition. Dans un second temps, nous avons analysé les réponses adaptatives de sujets exposés à une hypoxie brutale par le biais de tests d'orthostatisme, et mis en évidence une dysautonomie transitoire les deux premiers jours d'exposition à l'altitude, suivie d'un retour vers des valeurs basales le quatrième jour. Notre troisième protocole a montré que les fibromyalgiques présentent une qualité de vie et une capacité d'exercice altérées ainsi que des réponses autonomiques à l'orthostatisme émoussées comparées à des sujets témoins. Cependant, un entraînement en endurance de 12 semaines à intensité modérée, semble bénéfique sur la qualité de vie des patientes, et améliore les paramètres d'exercice et de modulation de l'activité du système nerveux. Enfin, nous avons confirmé que les sujets trisomiques présentaient une capacité d'exercice ainsi qu'une fonction cardio-respiratoire altérées par rapport à des sujets contrôles appariés en âge. Les tests de stimulations du système nerveux autonome montrent aussi une dysautonomie marquée, avec des réponses autonomiques émoussées qui peuvent être mises en lien avec une capacité d'effort limitée et/ou l'apparition d'une fatigue précoce à l'effort chez les trisomiques 21. Notre travail, par l'analyse de la variabilité cardiaque, a donc permis de mettre en évidence des altérations de l'activité autonomique qui peuvent être durables ou transitoires, selon l'environnement, selon le niveau d'activité ou l'existence de pathologies. / Cardiovascular functions have to answer to important physiological stimulations during physical activity, high altitude exposure, or specific stimulation tests of the autonomic nervous system. In this thesis work, we studied autonomic modulations after exercise (training/competition or retraining), hypoxia or adrenergic stimulation tests in order to link them with fatigue and/or effort limitation. Senior runners' follow-up allowed us to observe an increase in sympathetic activity and also a decrease in parasympathetic tone with training and particularly competition. In a second time, we analyzed the adaptive responses of subjects exposed to rough hypoxia through orthostatic tests and we highlighted a transitional dysautonomia during the first two days of altitude exposure followed by a return to basal values on the fourth day. Our third protocol has demonstrated that fibromyalgic patients show altered life quality and exercise capacity and also blunted autonomic responses to orthostatism compared to control subjects. However, twelve weeks of endurance training in moderate intensity seems to be beneficial on patients' life quality and improves exercise parameters and modulation of the activity of the nervous system. Finally, we have confirmed that subjects with Down syndrome showed altered exercise capacity and cardio-respiratory function in comparison to aged matched control subjects. Stimulation tests of the autonomic nervous system also show a marked dysautonomia with blunted autonomic responses, which can be linked to a limited effort capacity and/or to the appearance of an early fatigue to exercise in subjects with Down syndrome. Our work, thanks to cardiac variability analysis highlighted alterations in autonomic activity, which could be lasting or transient, depending on the environment, the activity level or the existence of pathologies.

La trisomie 21 (T21) résulte de la présence d’une extra-copie du chromosome 21 (Chr21). Parmi les gènes candidats impliqués dans les déficits cognitifs liés à la T21, DYRK1A est un des plus pertinents. Des études ont montré une corrélation entre l’augmentation de son activité kinase avec les déficits mnésiques observés dans les modèles murins de T21. Afin de comprendre les mécanismes sous-jacents aux altérations cognitives causées par son surdosage, nous avons utilisé des modèles murins sur-exprimant DYRK1A seule ou en plus d’autres gènes orthologues au Chr21, ainsi que des inhibiteurs spécifiques de DYRK1A (Leucettines) synthétisés par ManRos Therapeutics. Ici sont présentées les conséquences d’un traitement chronique avec ces Leucettines sur la cognition de ces animaux. Des analyses du phosphoprotéome de ces souris traitées ou non avec une des Leucettines, la L41, a mis en lumière des cibles et mécanismes biologiques impliqués dans les perturbations mnésiques de ces animaux. Enfin, ce projet a surtout permis de mettre en évidence un nouvel inhibiteur plus sélectif pour DYRK1A comme candidat-médicament pour l’amélioration des fonctions cognitives des porteurs de la T21. / Down Syndrome (DS), is due to the presence of an extra copy of chromosome 21 (Ch21). Among the candidates implicated in DS intellectual disabilities, DYRK1A is one of the most relevant. Several studies have shown a correlation between an increase of its kinase activity and the intellectual defects observed in DS models. In order to understand the mechanisms underlying the impact of DYRK1A overdosage on cognitive alterations, we used several trisomic mouse models expressing DYRK1A alone or with additional Hsa21 orthologous genes and specific DYRK1A inhibitors (Leucettines) from ManRos Therapeutics. We will present here the consequence of the Leucettines treatment following repetitive administration to several DS mouse models on the behavior and cognition. Further analysis of the phosphoproteome of DS mouse models treated or not with one of the Leucettine, the L41, unravels a few targets and pathways which are involved in the cognitive alterations observed in these trisomic mice. These results support the potential of more selective DYRK1A inhibitor as a therapeutic approach to improve cognitive functions in DS patients.