Text in Afrikaans / The purpose of this study is to identify the role of the parents in the continuous inclusion of learners with Down’s syndrome in inclusive education. The study was conducted in the South African context with the parents of children with Down’s syndrome and who are currently included in inclusive education in Gauteng. The roles that these parents play in the inclusion of their children were identified by means of semi-structured interviews. This was done according to a qualitative phenomenological research design within the theoretical framework of the bio-ecological model of Brunfenbrenner. Results from this study indicated that parents will have to fulfil specific roles in a multi-faceted manner to ensure continuous inclusion for these learners with Down’s syndrome in inclusive education. The primary contribution of this study is towards the expansion of the theoretical knowledge of the role of the parents in continuous inclusive education of learners with Down’s syndrome. / Die doel van hierdie studie is om die ouers se rol by die kontinue insluiting van leerders met Downsindroom in inklusieweonderwys te bepaal. Die studie is binne die Suid-Afrikaanse milieu onderneem met die ouers van leerders met Downsindroom wat tans gewone inklusieweonderwys in Gauteng ontvang. Semi-gestruktureerdeonderhoude is gebruik om die ouers se rol in die kontinue insluiting van hul kinders in gewone inklusiewe onderwys te identifiseer. Hierdie studie is volgens’n kwantitatiewefenomenologiesenavorsingsontwerp binne die teoretiese raamwerk van die bio-ekosistemiesebenaderingsmodel van Bronfenbrenner uitgevoer.Die bevindings van hierdie studie toon dat ouers spesifieke rolle behoort te vervul om hierdie leerders se kontinue insluiting in inklusiewe onderwys te verseker. Die primêre bydrae wat hierdie studie sal lewer, is tot die uitbreiding van teoretiese kennis aangaande die ouers se rol in die insluiting van leerders met Downsindroom in inklusiewe onderwys. / Inclusive Education / M. Ed. (Inklusiewe Onderwys)

La présente thèse par articles aborde différentes facettes du dépistage prénatal de certaines aneuploïdies au premier trimestre de la grossesse. L’introduction retrace l’historique du dépistage prénatal et énonce les différents marqueurs biochimiques et échographiques associés aux aneuploïdies. La première publication démontre que le tabagisme maternel abaisse significativement les niveaux sanguins maternels de PAPP-A et de la fraction libre de la β-hCG et augmente significativement la clarté nucale, confirmant la nécessité de contrôler cette co-variable dans le calcul de risque final, du moins pour la trisomie 18. Le deuxième article identifie des seuils de clarté nucale au-delà desquels la biochimie génétique n’apporte aucune valeur additionnelle au dépistage prénatal de la trisomie 21 et de la trisomie 18. Pour les fœtus avec clarté nucale supérieure aux seuils établis, un diagnostic prénatal intrusif devrait être offert sans délai. Le troisième et dernier article porte sur la première détermination des niveaux plasmatiques maternels de la protéine FLRG (follistatin-related gene) au premier trimestre de grossesse et sur son rôle potentiel à titre de marqueur biochimique dans le dépistage prénatal de la trisomie 21. Bien que détectables, les niveaux plasmatiques maternels de FLRG ne sont pas significativement altérés en présence de fœtus avec syndrome de Down. Dans la discussion générale, les trois articles sont abordés sous un angle plus spécifique au Québec. Des données complémentaires et originales y sont présentées. Une discussion sur l’évolution future du dépistage prénatal est entamée et des axes de recherche sont proposés. / In this thesis by articles, we explore different facets of first trimester prenatal screening of aneuploidy. Introduction retraces the origin of prenatal screening and enunciates current biochemical and ultrasound markers associated with aneuploidy. In the first article, impact of maternal smoking on first-trimester prenatal screening results is assessed for Down syndrome and trisomy 18. Both maternal blood levels of PAPP-A and free β-hCG are significantly decreased by maternal smoking while fetal nuchal translucency (NT) thickness is significantly increased. Without adjustment, this results in an increase of false positives, at least for trisomy 18. Based on these results, adjustment for smoking should be mandatory in first-trimester prenatal screening. In the second article, we identify NT threshold values above which biochemical screening provides no additional benefit. In pregnancies in which NT is above the proposed upper cut-offs, invasive prenatal screening should be offered without undue delay. In the third and last article, maternal plasma levels of follistatin- related gene protein (FLRG) are determined for the first time in first trimester of pregnancy. Its potential role as a new marker for Down syndrome is assessed. Although FLRG can be successfully detected in maternal plasma, its levels are not significantly altered by the presence of Down syndrome fetuses. In the general discussion, articles are mainly addressed under a Quebec standpoint. Additional and complementary original data are presented and different clinical research avenues are proposed.

O objetivo deste estudo foi mensurar o fluxo salivar, pH, capacidade tampão, concentrações de proteína total e ácido siálico, atividades das enzimas amilase e peroxidase e concentração dos íons sódio, potássio, cálcio, fósforo, zinco e magnésio em saliva total de indivíduos síndrome de Down com idade entre 1 e 25 anos. Nos indivíduos com idade entre 1 e 5 anos a saliva total foi coletada através de uma leve sucção, enquanto que nos outros indivíduos com idade entre 6 e 10, 11 e 15, 15 e 20, 21 e 25 a saliva total foi coletada com estimulação mecânica através da mastigação de parafilm, durante 10 minutos. O pH e a capacidade tampão foramdeterminadas usando um pHmetro digital. A capacidade tampão foi mensurada através de titulação com HCl a 0,01N. A concentração de eletrólitos foi determinada através de um espectrofotômetro de emissão atômica com fonte de excitação de argônio induzido. A proteína total foi mensurada através do reagente de Folin. A atividade da amilase foi mensurada através da produção de maltose e a atividade da peroxidase foi mensurada através da utilização de orto-dianisidina. Para a analise estatística os dados foram apresentados em media ± desvio padrão. Foi utilizado o teste “t" de Student para determinar as diferenças entre as medias dos indivíduos síndrome de Down e o grupo controle. Nenhuma diferença significante foi observada na concentração de ácido siálico, fósforo, zinco, magnésio e cálcio entre os indivíduos síndrome de Down e o grupo controle. A concentração de sódio, proteína total e a capacidade tampão demonstraram ser maior nos indivíduos com síndrome de Down em comparação ao grupo controle. Por outro lado, o fluxo salivar, a concentração de potássio, e a atividade das enzimas amilase e peroxidase foram menores no grupo síndrome de Down quando comparado ao grupo controle. Estes resultados sugerem que as pessoas com síndrome de Down apresentam alterações no metabolismo do ducto e/ou das células acinares das glândulas salivares. / The aim of this study was to measure the flow rate, pH, buffer capacity, sialic acid, total protein concentrations, amylase and peroxidase activities and sodium, potassium, calcium, phosphorus, zinc and magnesium concentration whole saliva of individuals with Down syndrome aged 1 - 25 years. In individuals aged 1-5 years the whole saliva was collected under slight suction, while in the others individuals aged 6-10, 11-15, 15-20, 21-25 the whole saliva was collected with stimulation by chewing a piece of parafilm, for 10 minutes. The pH and the buffer capacity were determined using a digital pHmeter. The buffer capacity was measured by titration with 0.01 N HCl. Electrolyte concentrations were determined by inductively coupled argon plasma with atomic emission spectrometry. Sialic acid was determined by thiobarbituric acid assay. Protein was determined by the folin’s phenol reagent. Amylase was assayed measuring the maltose produced by the breakdown of starch and peroxidase with ortho dianisidine. For statistical analysis the date are presented as mean ± SD. Student’s “t" test was used to determine differences between the mean of the Down syndrome and control groups. No statistically significant differences were observed in sialic acid, phosphorus, zinc, magnesium and calcium concentration between the individuals with Down syndrome and control group. The sodium and total protein concentration and buffer capacity showed higher in the Down syndrome than in the control group. On the other hand the flow rate and potassium concentration, amylase and peroxidase activities were lower in the Down syndrome than in the control group. These results suggest that the Down syndrome persons present alteration in the metabolism of the duct and/or acinar cells of salivary glands.

Introdução: A Síndrome de Down (SD) é uma doença genética de alta prevalência, com várias alterações imunológicas decorrentes da disfunção tímica associada à doença. Neste estudo, avaliou-se a associação entre presença de autoimunidade e disfunção do timo em pacientes com SD. Métodos: Foram avaliados 22 pacientes com SD (11 com autoimunidade e 11 sem), que preenchiam os critérios de inclusão: diagnóstico clinico e genético, idade > a 10 anos e sem uso de drogas imunossupressoras. Estes pacientes foram comparados a um grupo controle formado por adolescentes saudáveis (n=11) e outro de pacientes com doenças autoimunes, caracterizados por manifestações clínicas e presença de autoanticorpos (n=11). Todos os grupos foram pareados por idade e sexo. Os parâmetros laboratoriais avaliados foram: número de leucócitos, linfócitos CD3+, CD4+, CD8+, CD19+, CD21+, CD4+CD28null , células T reguladoras (CD4+CD25+Foxp3+), linfócitos T naive (CD4+CD45RA+CD62L+) e linfócitos T de memória (CD4+CD45RO+CD62L- ) e célula NK (CD3-CD16+, CD56+) por citometria de fluxo, Foi também avaliada a concentração de sjTREC (T receptor excision circles) em sangue total por qRT-PCR .Resultados: Nos pacientes com SD, observou-se redução das concentrações séricas de sjTREC, do número de linfócitos B e aumento do número de células CD4+CD28null. Na análise concomitante entre os grupos formados (SD com e sem autoimunidade, controle e autoimunidade sem SD), após correção de Bonferroni, observou-se que o grupo SD com autoimunidade apresentou redução de linfócitos T CD4, linfócitos naive e linfócitos B. Quando comparados os grupos SD com e sem autoimunidade observou-se redução significativa das concentrações de TREC no primeiro grupo. Não houve alterações das Células NK. Em valores percentuais, os pacientes com SD e autoimunidade apresentaram elevação da subpopulação de células T reguladoras. Conclusões: Este estudo mostra que pacientes com SD apresentam disfunção tímica quando avaliados pela quantificação de concentrações de TREC, sendo esta última mais expressiva nos pacientes com SD e autoimunidade. A redução dos linfócitos T naive associada a número normal de linfócitos T de memória sugere disfunção tímica primária, não compatível com processo de senescência. A observação do aumento do número de linfócitos CD4+CD28null poderia ser consequência de múltiplos estímulos celulares provavelmente em consequência da linfopenia observada. A elevação de células Treg em pacientes com SD e autoimunidade poderia ser decorrente de alterações funcionais destas células bem como de alterações nos processos de homeostase / Introduction: Down syndrome (DS) is a genetic disease of high prevalence, with many immunological alterations as a consequence of thymic disfunction associated to this disease. In this study, it was evaluated the association between the presence of thymic disfunction and autoimmunity in patients with DS. Methods: It was evaluated 22 patients with DS (11 with and 11 without autoimmunity) who fulfilled the inclusion criteria: clinical and genetic diagnosis, and age >10 years and no use of immunosuppressive drugs. These patients were compared to a control group composed by health adolescents (n=11) and patients with autoimmune diseases, characterized by clinical manifestations and autoantibodies (n=11). All groups were matched for age and sex. The laboratory parameters evaluated were: number of leukocytes, CD3+, CD4+, CD8+, CD19+, CD4+CD28null lymphocytes, regulatory T cells (CD4+CD25+Foxp3+), naive T lymphocytes (CD4+CD45RA+CD62L+), memory T lymphocytes (CD4+CD45RO+CD62L-) and NK cells (CD3-CD16+CD56+). The subpopulations of lymphocytes were determined by flow cytometry. It was also evaluated whole blood sjTREC (T receptor excision circles) concentrations by PCR. Results: In DS patients, there was reduction of sjTREC concentration, B lymphocytes number and increase of CD4+CD28null cells number. When compared all the groups formed (SD with and without autoimmunity, autoimmunity without SD and control group), after Bonferroni correction, the SD group with autoimmunity showed a reduction of T CD4+lymphocytes, naïve cells and B lymphocytes. When SD with and without autoimmunity groups were compared it was observed significant reduction in the TREC concentrations in the first group. There were no changes in NK cells. Patients with DS and autoimmune diseases had huge percentages of T reg cells comparing different groups. Conclusions: This study showed that DS patients presented thymic disfunction by reduced levels of whole blood sjTREC, and this condition is more expressive to patients with DS and autoimmune disease associated. The reduction of TCD4+ naïve cells with normal TCD4+ memory cells is suggestive of primary thymic disfunction against a senescent process. The elevated number of CD4+CD28null in DS patients probably was a consequence of reduced T cell numbers. The elevation of Treg cells remains unclear, and coud be a result of ineffective cells or deregulation of Thymus dependent immunity

Grâce aux progrès de la génétique moléculaire qui ont permis d’identifier de nouveaux gènes de déficience intellectuelle liée à l’X, il nous a été possible de travailler sur des groupes homogènes de malades présentant une mutation dans le même gène. Nous avons d’une part, pu mettre en évidence un dysfonctionnement du circuit cérébello-thalamo-préfrontal grâce à une étude en IRM morphométrique réalisée chez des patients ayant une mutation dans le gène Rab-GDI. D’autre part, nous avons identifié un phénotype tout à fait spécifique lié aux mutations du gène ARX, tant clinique que neuropsychologique, et cinématique, associant une atteinte très particulière de la motricité distale des membres supérieurs et du langage. La préhension des patients est pathognomonique, avec une préférence pour la pince pouce-majeur, une difficulté accrue pour l’utilisation du bord cubital de la main, et un trouble de la pronosupination. Sur le plan neuroanatomique, il existe une diminution de volume des noyaux gris centraux et des épaisseurs corticales des régions contrôlant la motricité, bien corrélées au paramètres de cinématique. Enfin, nous avons exploré les stratégies de raisonnement des patients déficients intellectuels atteints du syndrome de l’X fragile, d’une mutation du gène ARX ou de trisomie 21 en élaborant un paradigme de raisonnement visuel analogique issu des matrices de Raven. Nous en avons établi la trajectoire développementale. Les stratégies utilisées par les patients (étude en eyetracking) sont différentes de celles des contrôles y compris de même âge mental, avec un défaut d’inhibition majeur, encore plus franc chez les patients X fragiles que ceux porteurs de trisomie 21 / Thanks to progress in molecular genetics, that allowed identification of new genes responsible for X linked intellectual disability, we studied on homogeneous groups of patients presenting with a mutation in one or the other gene. In the first section, we showed dysfunction of cerebello-thalamo-prefrontal networks, thanks to morphological MRI study performed on patients with a mutation in the Rab-GDI gene. In the second section, we highlighted a very specific phenotype related to ARX gene mutations, clinically, neuropsychologically, and kinematically, with a very peculiar impairment of upper limbs distal motricity, and language disorder. Patients hand-grip is pathognomonic, with a preference for the middle finger instead of the index for the grip of object, major impairment of fourth finger use, and lack of pronation movements. Neuroimaging study showed decreased volume of basal ganglia, and cortical thickness of motor regions, well correlated to kinematic parameters. In the third section, we explored reasoning strategies in three groups of patients with intellectual deficiency: fragile X, ARX mutated and Down syndrome patients and controls (both chronological and mental age-matched subjects). We notably elaborated a visual analogical reasoning paradigm, inspired from Raven’s matrices. We established a developmental trajectory of this paradigm. The strategy used by patients (eyetracking study) was different from the one used by controls, with a huge lack of inhibition, even greater for fragile X patients than for Down syndrome patients

Introdução: A Síndrome de Down (SD) é uma doença genética de alta prevalência, com várias alterações imunológicas decorrentes da disfunção tímica associada à doença. Neste estudo, avaliou-se a associação entre presença de autoimunidade e disfunção do timo em pacientes com SD. Métodos: Foram avaliados 22 pacientes com SD (11 com autoimunidade e 11 sem), que preenchiam os critérios de inclusão: diagnóstico clinico e genético, idade > a 10 anos e sem uso de drogas imunossupressoras. Estes pacientes foram comparados a um grupo controle formado por adolescentes saudáveis (n=11) e outro de pacientes com doenças autoimunes, caracterizados por manifestações clínicas e presença de autoanticorpos (n=11). Todos os grupos foram pareados por idade e sexo. Os parâmetros laboratoriais avaliados foram: número de leucócitos, linfócitos CD3+, CD4+, CD8+, CD19+, CD21+, CD4+CD28null , células T reguladoras (CD4+CD25+Foxp3+), linfócitos T naive (CD4+CD45RA+CD62L+) e linfócitos T de memória (CD4+CD45RO+CD62L- ) e célula NK (CD3-CD16+, CD56+) por citometria de fluxo, Foi também avaliada a concentração de sjTREC (T receptor excision circles) em sangue total por qRT-PCR .Resultados: Nos pacientes com SD, observou-se redução das concentrações séricas de sjTREC, do número de linfócitos B e aumento do número de células CD4+CD28null. Na análise concomitante entre os grupos formados (SD com e sem autoimunidade, controle e autoimunidade sem SD), após correção de Bonferroni, observou-se que o grupo SD com autoimunidade apresentou redução de linfócitos T CD4, linfócitos naive e linfócitos B. Quando comparados os grupos SD com e sem autoimunidade observou-se redução significativa das concentrações de TREC no primeiro grupo. Não houve alterações das Células NK. Em valores percentuais, os pacientes com SD e autoimunidade apresentaram elevação da subpopulação de células T reguladoras. Conclusões: Este estudo mostra que pacientes com SD apresentam disfunção tímica quando avaliados pela quantificação de concentrações de TREC, sendo esta última mais expressiva nos pacientes com SD e autoimunidade. A redução dos linfócitos T naive associada a número normal de linfócitos T de memória sugere disfunção tímica primária, não compatível com processo de senescência. A observação do aumento do número de linfócitos CD4+CD28null poderia ser consequência de múltiplos estímulos celulares provavelmente em consequência da linfopenia observada. A elevação de células Treg em pacientes com SD e autoimunidade poderia ser decorrente de alterações funcionais destas células bem como de alterações nos processos de homeostase / Introduction: Down syndrome (DS) is a genetic disease of high prevalence, with many immunological alterations as a consequence of thymic disfunction associated to this disease. In this study, it was evaluated the association between the presence of thymic disfunction and autoimmunity in patients with DS. Methods: It was evaluated 22 patients with DS (11 with and 11 without autoimmunity) who fulfilled the inclusion criteria: clinical and genetic diagnosis, and age >10 years and no use of immunosuppressive drugs. These patients were compared to a control group composed by health adolescents (n=11) and patients with autoimmune diseases, characterized by clinical manifestations and autoantibodies (n=11). All groups were matched for age and sex. The laboratory parameters evaluated were: number of leukocytes, CD3+, CD4+, CD8+, CD19+, CD4+CD28null lymphocytes, regulatory T cells (CD4+CD25+Foxp3+), naive T lymphocytes (CD4+CD45RA+CD62L+), memory T lymphocytes (CD4+CD45RO+CD62L-) and NK cells (CD3-CD16+CD56+). The subpopulations of lymphocytes were determined by flow cytometry. It was also evaluated whole blood sjTREC (T receptor excision circles) concentrations by PCR. Results: In DS patients, there was reduction of sjTREC concentration, B lymphocytes number and increase of CD4+CD28null cells number. When compared all the groups formed (SD with and without autoimmunity, autoimmunity without SD and control group), after Bonferroni correction, the SD group with autoimmunity showed a reduction of T CD4+lymphocytes, naïve cells and B lymphocytes. When SD with and without autoimmunity groups were compared it was observed significant reduction in the TREC concentrations in the first group. There were no changes in NK cells. Patients with DS and autoimmune diseases had huge percentages of T reg cells comparing different groups. Conclusions: This study showed that DS patients presented thymic disfunction by reduced levels of whole blood sjTREC, and this condition is more expressive to patients with DS and autoimmune disease associated. The reduction of TCD4+ naïve cells with normal TCD4+ memory cells is suggestive of primary thymic disfunction against a senescent process. The elevated number of CD4+CD28null in DS patients probably was a consequence of reduced T cell numbers. The elevation of Treg cells remains unclear, and coud be a result of ineffective cells or deregulation of Thymus dependent immunity

La présente thèse par articles aborde différentes facettes du dépistage prénatal de certaines aneuploïdies au premier trimestre de la grossesse. L’introduction retrace l’historique du dépistage prénatal et énonce les différents marqueurs biochimiques et échographiques associés aux aneuploïdies. La première publication démontre que le tabagisme maternel abaisse significativement les niveaux sanguins maternels de PAPP-A et de la fraction libre de la β-hCG et augmente significativement la clarté nucale, confirmant la nécessité de contrôler cette co-variable dans le calcul de risque final, du moins pour la trisomie 18. Le deuxième article identifie des seuils de clarté nucale au-delà desquels la biochimie génétique n’apporte aucune valeur additionnelle au dépistage prénatal de la trisomie 21 et de la trisomie 18. Pour les fœtus avec clarté nucale supérieure aux seuils établis, un diagnostic prénatal intrusif devrait être offert sans délai. Le troisième et dernier article porte sur la première détermination des niveaux plasmatiques maternels de la protéine FLRG (follistatin-related gene) au premier trimestre de grossesse et sur son rôle potentiel à titre de marqueur biochimique dans le dépistage prénatal de la trisomie 21. Bien que détectables, les niveaux plasmatiques maternels de FLRG ne sont pas significativement altérés en présence de fœtus avec syndrome de Down. Dans la discussion générale, les trois articles sont abordés sous un angle plus spécifique au Québec. Des données complémentaires et originales y sont présentées. Une discussion sur l’évolution future du dépistage prénatal est entamée et des axes de recherche sont proposés. / In this thesis by articles, we explore different facets of first trimester prenatal screening of aneuploidy. Introduction retraces the origin of prenatal screening and enunciates current biochemical and ultrasound markers associated with aneuploidy. In the first article, impact of maternal smoking on first-trimester prenatal screening results is assessed for Down syndrome and trisomy 18. Both maternal blood levels of PAPP-A and free β-hCG are significantly decreased by maternal smoking while fetal nuchal translucency (NT) thickness is significantly increased. Without adjustment, this results in an increase of false positives, at least for trisomy 18. Based on these results, adjustment for smoking should be mandatory in first-trimester prenatal screening. In the second article, we identify NT threshold values above which biochemical screening provides no additional benefit. In pregnancies in which NT is above the proposed upper cut-offs, invasive prenatal screening should be offered without undue delay. In the third and last article, maternal plasma levels of follistatin- related gene protein (FLRG) are determined for the first time in first trimester of pregnancy. Its potential role as a new marker for Down syndrome is assessed. Although FLRG can be successfully detected in maternal plasma, its levels are not significantly altered by the presence of Down syndrome fetuses. In the general discussion, articles are mainly addressed under a Quebec standpoint. Additional and complementary original data are presented and different clinical research avenues are proposed.

Text in Afrikaans / The purpose of this study is to identify the role of the parents in the continuous inclusion of learners with Down’s syndrome in inclusive education. The study was conducted in the South African context with the parents of children with Down’s syndrome and who are currently included in inclusive education in Gauteng. The roles that these parents play in the inclusion of their children were identified by means of semi-structured interviews. This was done according to a qualitative phenomenological research design within the theoretical framework of the bio-ecological model of Brunfenbrenner. Results from this study indicated that parents will have to fulfil specific roles in a multi-faceted manner to ensure continuous inclusion for these learners with Down’s syndrome in inclusive education. The primary contribution of this study is towards the expansion of the theoretical knowledge of the role of the parents in continuous inclusive education of learners with Down’s syndrome. / Die doel van hierdie studie is om die ouers se rol by die kontinue insluiting van leerders met Downsindroom in inklusieweonderwys te bepaal. Die studie is binne die Suid-Afrikaanse milieu onderneem met die ouers van leerders met Downsindroom wat tans gewone inklusieweonderwys in Gauteng ontvang. Semi-gestruktureerdeonderhoude is gebruik om die ouers se rol in die kontinue insluiting van hul kinders in gewone inklusiewe onderwys te identifiseer. Hierdie studie is volgens’n kwantitatiewefenomenologiesenavorsingsontwerp binne die teoretiese raamwerk van die bio-ekosistemiesebenaderingsmodel van Bronfenbrenner uitgevoer.Die bevindings van hierdie studie toon dat ouers spesifieke rolle behoort te vervul om hierdie leerders se kontinue insluiting in inklusiewe onderwys te verseker. Die primêre bydrae wat hierdie studie sal lewer, is tot die uitbreiding van teoretiese kennis aangaande die ouers se rol in die insluiting van leerders met Downsindroom in inklusiewe onderwys. / Inclusive Education / M. Ed. (Inklusiewe Onderwys)

O objetivo deste estudo foi mensurar o fluxo salivar, pH, capacidade tampão, concentrações de proteína total e ácido siálico, atividades das enzimas amilase e peroxidase e concentração dos íons sódio, potássio, cálcio, fósforo, zinco e magnésio em saliva total de indivíduos síndrome de Down com idade entre 1 e 25 anos. Nos indivíduos com idade entre 1 e 5 anos a saliva total foi coletada através de uma leve sucção, enquanto que nos outros indivíduos com idade entre 6 e 10, 11 e 15, 15 e 20, 21 e 25 a saliva total foi coletada com estimulação mecânica através da mastigação de parafilm, durante 10 minutos. O pH e a capacidade tampão foramdeterminadas usando um pHmetro digital. A capacidade tampão foi mensurada através de titulação com HCl a 0,01N. A concentração de eletrólitos foi determinada através de um espectrofotômetro de emissão atômica com fonte de excitação de argônio induzido. A proteína total foi mensurada através do reagente de Folin. A atividade da amilase foi mensurada através da produção de maltose e a atividade da peroxidase foi mensurada através da utilização de orto-dianisidina. Para a analise estatística os dados foram apresentados em media ± desvio padrão. Foi utilizado o teste “t” de Student para determinar as diferenças entre as medias dos indivíduos síndrome de Down e o grupo controle. Nenhuma diferença significante foi observada na concentração de ácido siálico, fósforo, zinco, magnésio e cálcio entre os indivíduos síndrome de Down e o grupo controle. A concentração de sódio, proteína total e a capacidade tampão demonstraram ser maior nos indivíduos com síndrome de Down em comparação ao grupo controle. Por outro lado, o fluxo salivar, a concentração de potássio, e a atividade das enzimas amilase e peroxidase foram menores no grupo síndrome de Down quando comparado ao grupo controle. Estes resultados sugerem que as pessoas com síndrome de Down apresentam alterações no metabolismo do ducto e/ou das células acinares das glândulas salivares. / The aim of this study was to measure the flow rate, pH, buffer capacity, sialic acid, total protein concentrations, amylase and peroxidase activities and sodium, potassium, calcium, phosphorus, zinc and magnesium concentration whole saliva of individuals with Down syndrome aged 1 - 25 years. In individuals aged 1-5 years the whole saliva was collected under slight suction, while in the others individuals aged 6-10, 11-15, 15-20, 21-25 the whole saliva was collected with stimulation by chewing a piece of parafilm, for 10 minutes. The pH and the buffer capacity were determined using a digital pHmeter. The buffer capacity was measured by titration with 0.01 N HCl. Electrolyte concentrations were determined by inductively coupled argon plasma with atomic emission spectrometry. Sialic acid was determined by thiobarbituric acid assay. Protein was determined by the folin’s phenol reagent. Amylase was assayed measuring the maltose produced by the breakdown of starch and peroxidase with ortho dianisidine. For statistical analysis the date are presented as mean ± SD. Student’s “t” test was used to determine differences between the mean of the Down syndrome and control groups. No statistically significant differences were observed in sialic acid, phosphorus, zinc, magnesium and calcium concentration between the individuals with Down syndrome and control group. The sodium and total protein concentration and buffer capacity showed higher in the Down syndrome than in the control group. On the other hand the flow rate and potassium concentration, amylase and peroxidase activities were lower in the Down syndrome than in the control group. These results suggest that the Down syndrome persons present alteration in the metabolism of the duct and/or acinar cells of salivary glands.

La phosphorylation des protéines par les kinases est l’une plus importantes modification post-traductionnelle dans les processus cellulaires tels que la division, la différenciation, la prolifération et l’apoptose. Due à leur rôle clef, un dérèglement des protéines kinases peut entrainer de nombreuses pathologies proliférative telles que le cancer et non prolifératives telles que les maladies neurodégénératives. Le travail de thèse s’est construit autour de 2 séries d’inhibiteurs de protéine kinases comportant les noyaux imidazo[1,2-b]pyridazine et imidazo[4,5-b]pyridine. L’objectif est d’inhiber sélectivement les protéines kinases choisies, pour leurs implications dans les pathologies visées au laboratoire. Les imidazo[1,2-b]pyridazines ont été préparées pour identifier des inhibiteurs de CLK1 et DYRK1A, cibles potentielles dans la maladie d’Alzheimer. Parmi les imidazo[1,2-b]pyridazines synthétisées, plusieurs molécules se sont révélées particulièrement sélectives de DYRKs et CLKs, avec des IC50 < 100 nM. Une relation structure-activité basée sur la synthèse de 70 molécules, a permis de dégager des éléments structuraux de la sélectivité des molécules. L’évaluation des produits a également été portée sur les kinases de parasites. Il a ainsi été possible d’identifier quelques inhibiteurs actifs sur PfCLK1. La seconde partie de cette thèse avait pour objectif l’optimisation du protocole de synthèse imidazo[4,5-b]pyridines, analogue de la roscovitine. Des dérivés s’étaient révélés capables d’inhiber la formation de kystes, dans un modèle cellulaire de polykystose rénale. Une synthèse en sept étapes a conduit à plusieurs grammes d’imidazo[4,5-b]pyridine 3,5,7 trisubstitués, qui sont ainsi disponibles pour l’évaluation in vivo. / Phosphorylation by protein kinases is one of the most important post-translational modification in cellular processes such as division, differentiation, proliferation and apoptosis. Kinase deregulation is associated with numerous diseases such as cancer or neurodegenerative diseases. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine were prepared to inhibit protein kinases involved in diseases targeted in the laboratory. The imidazo[1,2-b]pyridazines were synthesized to identify inhibitors of CLK1 and DYRK1A, potential targets in Alzheimer's disease. Among the imidazo[1,2-b]pyridazines synthesized, several molecules were found selective of DYRKs and CLKs, with IC50 < 100 nM. A structure-activity relationship based on the synthesis of 70 molecules, led to the identification of the structural bases of the selectivity. Products were also evaluated against parasite kinases. It was possible to identify some highly potent inhibitors on PfCLK1. The aim of second part of this thesis was to optimize the synthetic process to obtain imidazo[4,5-b]pyridines, which are close analogues of roscovitine. Derivatives had proved capable of inhibiting the formation of cysts in a cellular model of polycystic kidney disease. A seven-step synthesis has led to several grams of 3,5,7-trisubstituted imidazo[4,5-b]pyridine which is now available for evaluation in vivo.