No / Purpose: Evidence exists for an additional inhibitory accommodative control system mediated by the sympathetic branch of the autonomic nervous system (ANS). This work aims to show the relative prevalence of sympathetic inhibition in young emmetropic and myopic adults, and to evaluate the effect of sympathetic facility on accommodative and oculomotor function. Methods: Profiling of ciliary muscle innervation was carried out in 58 young adult subjects (30 emmetropes, 14 early onset myopes, 14 late onset myopes) by examining post-task open-loop accommodation responses, recorded continuously by a modified open-view infrared optometer. Measurements of amplitude of accommodation, tonic accommodation, accommodative lag at near, AC/A ratio, and heterophoria at distance and near were made to establish a profile of oculomotor function. Results: Evidence of sympathetic inhibitory facility in ciliary smooth muscle was observed in 27% of emmetropes, 21% of early-onset myopes and 29% of late-onset myopes. Twenty-six percent of all subjects demonstrated access to sympathetic facility. Closed-loop oculomotor function did not differ significantly between subjects with sympathetic facility, and those with sympathetic deficit. Conclusions: Emmetropic and myopic groups cannot be distinguished in terms of the relative proportions having access to sympathetic inhibition. Presence of sympathetic innervation does not have a significant effect on accommodative function under closed-loop viewing conditions.

Maturity-onset diabetes of the young (MODY), due to hepatocyte nuclear factor 1 alpha mutations (HNF1A-MODY), is the most common form of monogenic diabetes presenting in young adults. An accurate genetic diagnosis of HNF1A-MODY has therapeutic implications for the patients and their family members. However, the majority of people with HNF1A-MODY are not referred for genetic testing and remain misdiagnosed as type 1 or type 2 diabetes. As part of measures to address this misdiagnosis, over the last few years there have been efforts to define clinical features and biomarkers that can be used to identify those at high risk of HNF1A-MODY. Secreted hepatic proteins regulated by HNF1A are attractive candidates for diagnostic biomarkers that would be specific for this form of diabetes. Apolipoprotein M (apoM), C-reactive protein (CRP) and plasma glycan profile have all been investigated as biomarkers to improve selection of suspected MODY cases for genetic testing. In my thesis, I have addressed questions about the variation in apoM between different forms of diabetes and assessed the performance of hsCRP and plasma glycan profile to identify HNF1A-MODY in previously uninvestigated individuals with young-onset diabetes and in a non-European population. Additionally because CRP and plasma glycans are both important components of an acute inflammatory response, I examined the effect of haploinsufficiency of HNF1A in a standardised model of inflammation. When investigating apoM, I showed that serum apoM levels are lower in HNF1A-MODY than controls, and have demonstrated for the first time that serum apoM provides good discrimination between HNF1A-MODY and type 1 diabetes. CRP and plasma glycan profile both performed well in identifying HNF1A-MODY cases in unselected young adults with diabetes. The results also suggested that both biomarkers have value for assessing the functional impact of novel HNF1A variants. I went on to examine the use of a low CRP for selecting those at risk of HNF1A-MODY in South Asian subjects with young-onset diabetes. This study suggests that the overall population prevalence of HNF1A-MODY is similar in South Asians to Europeans, but that MODY represents a lower proportion of those with diabetes (due to the higher prevalence of type 2 diabetes in South Asians). The specific selection strategy employed in this study was not successful in identifying subjects at high risk of HNF1A-MODY (only 3% of those sequenced had mutations), suggesting that additional clinical and biochemical features will be required in addition to CRP to distinguish South Asians at high risk of HNF1A-MODY. Lastly, using endotoxaemia as a standardised model of acute inflammation for the first time in HNF1A-MODY, I have shown that despite low baseline levels, subjects with HNF1A-MODY had peak stimulated CRP levels comparable to non-diabetic controls. An attenuated cytokine response was observed in HNF1A-MODY, which requires further investigation. This is also the first report of inflammation-associated changes in plasma and white cell membrane glycan profile in diabetes. This research work adds substantially to current understanding of performance of HNF1A-MODY biomarkers, a critical step before their clinical translation. The work presented also provides novel insights into the regulation of the acute inflammatory response in HNF1A-MODY.

Voice onset time (VOT) är en akustisk tidsparameter som reflekterar den tidsmässiga samordningen av talmotoriken. VOT betraktas som det mest pålitliga akustiska kännetecknet på huruvida en klusil är tonlös eller tonande. Föreliggande studies syfte var att studera och jämföra VOT hos svenska barn (8, 9, 10, 11 år) och vuxna för att se hur utvecklingen sker samt för att ta fram svenska normvärden. Ljudinspelningar genomfördes på 150 barn och 36 vuxna vid uttal av de svenska klusilerna i minimala par. Akustiska analyser av materialet utfördes sedan. Resultatet visade att de tonlösa klusilerna föreföll produceras med vuxenlika VOT-värden från och med cirka nio års ålder. De tonande motsvarigheterna producerades med vuxenlik VOT omkring tio års ålder. I tioårsåldern förekom dessutom förton i helt vuxenlik utsträckning. Resultaten tyder dock på att svenska vuxna ej nödvändigtvis behöver producera tonande klusiler med förton. Inga tydliga könsskillnader erhölls. De normvärden för VOT som har tagits fram i föreliggande studie kan nyttjas som referensmaterial vid utredning av barn med talstörningar. / Voice onset time (VOT) is a temporal acoustic parameter, which reflects the timing of speech motor control. VOT is said to be the most reliable acoustic cue of whether a plosive is voiceless or voiced. The aim of the present study was to investigate and compare VOT among Swedish children (8, 9, 10, 11 years) and adults to examine the development of VOT and to obtain Swedish normative data. Audio recordings were performed on 150 children and 36 adults when pronouncing the Swedish plosives in minimal pairs. Acoustic analyses were then carried out. The results indicated that the voiceless plosives seemed to be produced with adult like VOT-values around the age of nine. The voiced plosives in turn, appeared to be produced with adult like values at approximately ten years of age. By the age of ten, also prevoicing was found in a fully adult like extent. Though, the results indicate that not all Swedish adults produce voiced plosives with prevoicing. No evident gender differences were found. The normative data for VOT that have been obtained in the present study can be used as normative data when assessing children with speech disorders.

Die klinische Erfahrung zeigt, dass sich depressive Episoden sehr schnell innerhalb weniger Stunden bis Tage oder sehr langsam innerhalb mehrerer Wochen bis Monate entwickeln können. Hauptziel dieser Arbeit war es, die zeitliche Entwicklung depressiver Episoden bei Patienten mit einer unipolaren oder bipolaren affektiven Störung zu untersuchen. Mithilfe des dafür entwickelten und im Rahmen dieser Studie weiter modifizierten strukturierten Patienteninterview ODI (Onset of Depression Inventory) wurde die Geschwindigkeit des Depressionsbeginns bei 223 konsekutiven Patienten erfasst, von denen 129 in die Auswertung eingeschlossen werden konnten. Es zeigte sich, dass sich depressive Episoden bei Patienten mit bipolarer affektiver Störung signifikant schneller manifestieren als bei Patienten mit unipolarer affektiver Störung. Somit kann die Geschwindigkeit des Depressionsbeginns, gemessen mit dem ODI, als Differenzierungsmerkmal zwischen unipolarer und bipolarer affektiver Störung gewertet werden und im klinischen Alltag helfen, zwischen den beiden Störungsbildern zu unterscheiden.

To describe and to analyze the use of repair strategies in the syllable constituents of coda and complex onset used by children with normal phonological acquisition and phonological deviation, in order to examine the similarities as well as the differences between the studied groups. Besides this, specifically in relation to the coda constituent and based on the Non-Linear Gerative Phonology, we aimed at examining if the application of the adopted resources provides evidences of phonological knowledge. Methods: The analysis included speech data from 60 children with normal acquisition, 30 female and 30 male, in addition to 84 children with deviation, 31 female and 53 male. The age in the normal group was between 1:0 and 4:0, whereas in the deviation group it was between 3:0 and 11:0. In the analysis of the strategies used in complex onset position, the variables: age, gender, preceding and following context, obstruent of complex onset, kind of liquid of complex onset, tonicity, number of syllables and position in the word were considered. In relation to the resources used in the coda, the variables were: age, gender, preceding and following context, kind of phoneme in the coda, tonicity, number of syllables and position in the word. Then, the data were submitted to statistical analysis using the VARBRUL program. Results: The analysis of the complex onset showed that the strategies used by the children considering normal phonological development and deviation were, respectively: simplification for C1V (93%; 77%), alteration of the obstruent feature (5%; 17%), alteration of the liquid feature (1%; 5%), epenthesis (1%; 0%) and metathesis (0%; 1%). In the coda constituent, the children with normal development and deviation used the following resources, respectively: omission of target segment (71%; 71%), omission of target segment with a change in the quality of the preceding vowel (1%; 4%), omission of target syllable (6%; 1%), 14 semivocalization (11%; 14%), substitution for liquid (1%; 3%), palatalization (2%; 3%), metathesis (1%; 2%), epenthesis (1%; 1%), compensatory lengthening (5%; 0%) and other realizations (1%; 1%). In terms of the strategies used in the complex onset, the variables tonicity, preceding context and position in the word were not relevant, whereas considering the resources applied in coda, all the variables were important. Conclusion: The study of repair strategies in both constituents showed more similarities than differences in relation to the kind of repair strategies that children with normal phonological development and phonological deviation use during the acquisition process. In the complex onset constituent, there is less diversity among the resources, while the use of simplification for C1V is predominant in both studied groups. In the coda syllabic position, we found a greater variety of strategies, and the omission of the target segment was the most used by children with normal phonological acquisition and deviation. Besides this, the other strategies applied in the coda position became important due to their evidences in terms of phonological knowledge. / Descrever e analisar o uso das estratégias de reparo nos constituintes coda e onset complexo, empregados por crianças com aquisição fonológica normal e desviante, a fim de verificar as semelhanças e as diferenças existentes entre os grupos estudados. Além disso, em relação especificamente ao constituinte coda, pretendeu-se, através da Fonologia Gerativa Não-Linear, verificar se a aplicação dos recursos empregados fornece indícios de conhecimento fonológico. Método: Foram utilizados dados de fala de 60 crianças com aquisição normal, 30 do sexo feminino e 30 do sexo masculino, e 84 crianças com aquisição desviante, 31 do sexo feminino e 53 do sexo masculino. A idade do grupo normal variou de 1:0 a 4:0, enquanto que a do grupo desviante variou de 3:0 a 11:0 anos. Para a análise das estratégias empregadas na posição de onset complexo foram consideradas as variáveis: idade, sexo, contexto precedente e seguinte, obstruinte do onset complexo, tipo de líquida do onset complexo, tonicidade, número de sílabas e posição na palavra. Para os recursos utilizados em coda foram consideradas: idade, sexo, contexto precedente e seguinte, tipo de fonema em coda, tonicidade, número de sílabas e posição na palavra. Posteriormente, os dados foram submetidos à análise estatística através do programa VARBRUL. Resultados: A análise do onset complexo revelou que as estratégias que as crianças lançaram mão, considerando o desenvolvimento 12 fonológico normal e desviante, foram, respectivamente: simplificação para C1V (93%; 77%), alteração do traço da obstruinte (5%; 17%), alteração do traço da líquida (1%; 5%), epêntese (1%; 0%) e metátese (0%, 1%). No constituinte coda, as crianças com desenvolvimento normal e desviante utilizaram os seguintes recursos, respectivamente: omissão do fonema alvo (71%; 71%), omissão do fonema alvo com mudança da qualidade da vogal precedente (1%; 4%), omissão da sílaba alvo (6%; 1%), semivocalização (11%; 14%), substituição por líquida (1%; 3%), palatalização (2%; 3%), metátese (1%; 2%), epêntese (1%; 1%), alongamento compensatório (5%; 0%) e outras realizações (1%; 1%). Para as estratégias empregadas em onset complexo as variáveis tonicidade, contexto precedente e posição na palavra não foram relevantes no estudo, enquanto que, para os recursos aplicados em coda, todas as variáveis foram relevantes. Conclusão: O estudo das estratégias de reparo em ambos os constituintes revelou mais similaridades que diferenças quanto ao tipo de estratégias de reparo que as crianças com desenvolvimento fonológico normal e desviante lançam mão ao longo do percurso de aquisição. No constituinte onset complexo há menos diversidade entre os recursos, predominando o uso de simplificação para C1V para ambos os grupos estudados. Já na posição silábica de coda, constata-se uma maior variedade de estratégias, sendo o recurso de omissão do fonema alvo o preferido pelas crianças com aquisição fonológica normal e desviante. Além disso, as outras estratégias aplicadas na posição de coda se mostraram importantes pelo que evidenciaram em termos de conhecimento fonológico.

La thèse a pour objectifs d'identifier les besoins et les difficultés des conjoints aidants de personnesprésentant une maladie d'Alzheimer. Elle vise également à mettre en évidence les points communs etles spécificités de la situation d’aide en fonction de l’âge d’apparition de la maladie. L’axe 1 porte sur l’analyse du vécu de couples dont l'un des partenaires présente une démence précoce. Les résultats mettent en évidence une évolution dans le rapport au savoir des aidants et des personnes malades. Ils passent d'un besoin de comprendre les changements occasionnés par l’arrivée de la maladie à une mise à distance après l'annonce du diagnostic. De plus, avec l'avancée des troubles, les aidants éprouvent des difficultés à ajuster leur niveau d’aide, ce qui est source de conflits entre les deux partenaires. Les deux études de l'axe 2 ont pour objectif d’établir une comparaison entre les aidants de personnes malades jeunes et de personnes malades âgées à la fois sur leurs besoins et sur leurs modes d’ajustement. La majorité des besoins et des stratégies est commune à tous les aidants. Néanmoins, les aidants de personnes malades jeunes expriment plus de besoins en termes de maintien de contact, d'adaptation des structures de soins et d'accompagnement dans les démarches administratives. Les aidants de personnes malades âgées utilisent plus l'humour, l'aménagement et la mise à distance de l'entourage comme stratégies d'ajustement. L’axe 3 vise à investiguer l'influence des caractéristiques de la situation d'aide sur la détresse du conjoint aidant à l’aide d’une modélisation structurale. Les paramètres de ce modèle général ont été comparés en fonction de l'âge de début de la maladie et du genre de l'aidant. Cette étude met en évidence 4 facteurs influençant le sentiment de détresse des conjoints aidants : le sentiment d'être préparé, la qualité du support familial, l’évaluation de sa santé et la qualité d’ajustement du couple. Ce dernier facteur est plus important pour les conjoints aidants de personnes malades jeunes. L’analyse de ces résultats permet de spécifier le contenu de programmes d’accompagnement en faveur de modules communs à tous les aidants et de modules spécifiques en fonction de l'âge d'apparition de la maladie. / This thesis aims to identify needs and difficulties of the spouse caregivers of persons with dementia. We also investigate similarities and specificities related to the caregiving situation regarding the age atonset of the disease.The first axis examines the experience of couples in which one member received a diagnosis of earlyon setdementia. The results show an evolution in the relation to knowledge of the caregivers and the persons with dementia. They oscillate between the need to understand the changes caused by the disease and a distancing after the diagnosis. Moreover, with the progression of the disease, the caregivers are not able to adapt their level of assistance, which increases tensions between the two partners. The two studies of the second axis aim to compare needs and coping strategies of spouse caregivers of persons with early and late onset dementia. The majority of needs and strategies are the same for all spouse caregivers. However, the spouse caregivers of persons with early-onset dementia express the greatest number of needs related to maintaining contacts, more need of adapted care structures and more need to be assisted in administrative procedures. The spouse caregivers of persons with late-onset dementia use more humor, re-arranging, and getting away from the entourage. The third axis investigates the influence of the characteristics of the caregiving context on spousal caregiver distress with a structural modelisation. The sittings of this general model were compared regarding the age at onset of the disease and the gender of caregiver. This study demonstrated that 4 factors contribute to spousal caregiver distress: preparedness, family support, self-rated health and the quality of the couple relationship. Dyadic determinants were more important for caregivers of PEOD. The analysis of these results permits to specify the content of support for a common core and specific modules depending on the age at onset of the disease.

Submitted by Vanessa Rocha Ribeiro null (va_rocharibeiro@aluno.ibb.unesp.br) on 2017-03-08T15:02:28Z No. of bitstreams: 1 Dissertação Vanessa Rocha Ribeiro.pdf: 3324263 bytes, checksum: c662d084e05ff3055723d93ba4f2eee2 (MD5) / Approved for entry into archive by LUIZA DE MENEZES ROMANETTO (luizamenezes@reitoria.unesp.br) on 2017-03-13T14:49:32Z (GMT) No. of bitstreams: 1 ribeiro_vr_me_bot.pdf: 3324263 bytes, checksum: c662d084e05ff3055723d93ba4f2eee2 (MD5) / Made available in DSpace on 2017-03-13T14:49:32Z (GMT). No. of bitstreams: 1 ribeiro_vr_me_bot.pdf: 3324263 bytes, checksum: c662d084e05ff3055723d93ba4f2eee2 (MD5) Previous issue date: 2017-02-22 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Introdução: A pré-eclâmpsia (PE) é uma patologia obstétrica e uma das principais causas de morbimortalidade materna e fetal. Na PE ocorre um estado de má adaptação da tolerância imunológica, caracterizada por ativação anormal do sistema imune inato e adaptativo. As células T reguladoras (Treg) representam uma população de linfócitos T responsáveis pela manutenção da tolerância e controle da inflamação, enquanto células Th17 medeiam diferentes tipos de reações inflamatórias. Portanto, o balanço entre células Treg e Th17 pode ser crítico para a tolerância ao feto e prevenção da PE. Objetivo: Avaliar as subpopulações de células T CD4+ (Th1, Th2, Th17 e Treg) e o perfil de citocinas produzido por essas células, em gestantes portadoras de pré-eclâmpsia, classificadas em PE precoce e PE tardia. Métodos: Foram estudadas 60 gestantes, sendo 20 normotensas e 40 portadoras de PE, pareadas pela idade gestacional. As gestantes com PE foram classificadas de acordo com o aparecimento das manifestações clínicas em PE precoce (< 34 semanas de gestação; n=20) e PE tardia (≥ 34 semanas de gestação; n=20). Células mononucleares do sangue periférico (PBMCs), obtidas das gestantes foram avaliadas quanto à produção de citocinas pró e anti-inflamatórias e à expressão de fatores de transcrição envolvidos na caracterização das subpopulações de células T CD4+. A expressão dos fatores de transcrição intracitoplasmáticos de células Th1 (T-bet), Th2 (GATA-3), Th17 (RORc) e Treg (FoxP3) foi avaliada por citometria de fluxo e a expressão gênica desses fatores de transcrição foi determinada por PCR em tempo real com transcrição reversa (RT-qPCR), logo após a colheita de sangue para avaliação da expressão endógena dessas diferentes subpopulações de células T. A determinação das citocinas de perfil Th1 (IFN-γ e TNF-α), Th2 (IL-4), Th17 (IL-6, IL-17 e IL-22) e Treg (IL-10 e TGF-β1) foi realizada no plasma das gestantes pela técnica de ELISA. Os resultados foram analisados por meio de testes paramétricos ou não paramétricos com nível de significância de 5%. Resultados: Os perfis inflamatórios Th1 e Th17 foram identificados por aumento significativo da média de intensidade de fluorescência (MIF) e da percentagem de células expressando os fatores de transcrição específicos nas gestantes portadoras de PE precoce e PE tardia em relação aos grupos de gestantes normotensas com idade gestacional correspondente. A percentagem de células Th17 foi significativamente maior nas gestantes com PE precoce do que nas com PE tardia. Por outro lado, a análise dos perfis anti-inflamatórios Th2 e Treg mostrou que a percentagem de células expressando GATA-3 e FoxP3 foi significativamente menor nos grupos de PE precoce e PE tardia comparados aos grupos de normotensas, enquanto a comparação entre gestantes pré-eclâmpticas mostrou percentagem de células Treg significativamente menor nas gestantes portadoras de PE precoce. A expressão gênica do fator de transcrição T-bet por PBMCs não mostrou diferenças significativas entre os grupos de gestantes pré-eclâmpticas e de normotensas. Aumento significativo da expressão gênica do fator de transcrição RORc e diminuição da expressão dos genes GATA-3 e FoxP3 foram observados nos grupos de gestantes pré-eclâmpticas em relação aos grupos de normotensas de idade gestacional correspondente. Entre as gestantes pré-eclâmpticas, encontrou-se menor nível transcricional do fator de transcrição GATA-3 na PE precoce. Os níveis plasmáticos das citocinas IFN-γ, IL-6, IL-17 e TNF-α foram significativamente maiores nas gestantes portadoras de PE, enquanto as concentrações de IL-10 e TGF-β1 foram significativamente menores em comparação aos grupos de gestantes normotensas correspondentes. Observaram-se ainda, maiores níveis de IL-6, IL-17, TGF-β1 e TNF-α na PE precoce do que na PE tardia. A expressão proteica de IL-4 (perfil Th2) e IL-22 (perfil Th17), não apresentou diferença significativa entre os grupos estudados. Conclusão: Os resultados demonstram que o balanço entre células Treg e Th17 é deficiente na PE, havendo polarização para perfil Th17 na PE precoce. Esse desbalanço pode ser atribuído ao predomínio de citocinas pró-inflamatórias sobre as anti-inflamatórias, presentes na circulação de gestantes portadoras de pré-eclâmpsia. / Introduction: Preeclampsia (PE) is an obstetric pathology and one of the main causes of maternal and fetal morbidity and mortality. In PE there is a state of maladaptation of immunological tolerance, characterized by abnormal activation of the innate and adaptive immune system. Regulatory T cells (Treg) represent a population of T lymphocytes responsible for tolerance maintenance and inflammation control, whereas Th17 cells mediate different types of inflammatory reactions. Therefore, the balance between Treg and Th17 cells may be critical for fetal tolerance and PE prevention. Objective: To evaluate the subpopulations of CD4+ T cells (Th1, Th2, Th17 and Treg) and the cytokine profile produced by these cells in pregnant women with PE, classified in early-onset PE and late-onset PE. Methods: Sixty pregnant women, 20 normotensive and 40 preeclamptic women, matched by gestational age, were studied. Pregnant women with PE were classified according to clinical manifestations in early-onset PE (<34 weeks gestation; n = 20) and late-onset PE (≥ 34 weeks gestation; n = 20). Peripheral blood mononuclear cells (PBMCs) obtained from pregnant women were evaluated for the production of pro and anti-inflammatory cytokines and expression of transcription factors involved in the characterization of CD4+ T cell subpopulations. Expression of the intracytoplasmic transcription factors of Th1 (T-bet), Th2 (GATA-3), Th17 (RORc) and Treg (FoxP3) cells was assessed by flow cytometry and the gene expression of these transcription factors was determined by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) shortly after blood collection to evaluate the endogenous expression of these different T-cell subpopulations. The cytokine profile of Th1 cells (IFN-γ and TNF-α), Th2 (IL -4), Th17 (IL-6, IL-17 and IL-22) and Treg (IL-10 and TGF-β1) were measured in the plasma of the pregnant women by the ELISA. The results were analyzed using parametric or non-parametric tests with a significance level of 5%. Results: Th1 and Th17 inflammatory profiles were identified by a significant increase in mean fluorescence intensity (FMI) and by the percentage of cells expressing specific transcription factors in pregnant women with early-onset PE and late-onset PE in relation to the normotensive groups with corresponding gestational age. The percentage of Th17 cells was significantly higher in early-onset PE than in late-onset PE group. On the other hand, analysis of Th2 and Treg anti-inflammatory profiles showed percentages of cells expressing GATA-3 and FoxP3 significantly lower in the early- and late-onset PE groups compared to the normotensive groups, whereas the comparison between preeclamptic groups showed significantly lower percentage of Treg cells in pregnant women with early-onset PE. The gene expression of the T-bet transcription factor by PBMCs did not show significant differences between the preeclamptic and normotensive pregnant groups. Significant increase in the gene expression of RORc and decrease in the expression of the GATA-3 and FoxP3 genes were observed in both groups of preeclamptic women compared with the normotensive ones of corresponding gestational age. Among the preeclamptic pregnant women lower transcriptional level of GATA-3 transcription factor was detected in early-onset PE. Plasma levels of the cytokines IFN-γ, IL-6, IL-17 and TNF-α were significantly higher in pregnant women with PE, whereas IL-10 and TGF-β1 concentrations were significantly lower than in the normotensive corresponding groups. It was also observed higher levels of IL-6, IL-17, TGF-β1 and TNF-α in early-onset than in late-onset PE group. Protein expression of IL-4 (Th2 profile) and IL-22 (Th17 profile), did not show significant differences between the groups studied. Conclusion: The results show that the balance between Treg and Th17 cells is deficient in PE, with polarization to the Th17 profile in early-onset PE. This imbalance can be attributed to the predominance of pro-inflammatory cytokines over the anti-inflammatory ones present in the circulation of pregnant women with preeclampsia. / FAPESP: 2014/25124-7 / FAPESP: 2012/24697-8

Orientador: Maria Terezinha Serrão Peraçoli / Resumo: Introdução: A pré-eclâmpsia (PE) é uma patologia obstétrica e uma das principais causas de morbimortalidade materna e fetal. Na PE ocorre um estado de má adaptação da tolerância imunológica, caracterizada por ativação anormal do sistema imune inato e adaptativo. As células T reguladoras (Treg) representam uma população de linfócitos T responsáveis pela manutenção da tolerância e controle da inflamação, enquanto células Th17 medeiam diferentes tipos de reações inflamatórias. Portanto, o balanço entre células Treg e Th17 pode ser crítico para a tolerância ao feto e prevenção da PE. Objetivo: Avaliar as subpopulações de células T CD4+ (Th1, Th2, Th17 e Treg) e o perfil de citocinas produzido por essas células, em gestantes portadoras de pré-eclâmpsia, classificadas em PE precoce e PE tardia. Métodos: Foram estudadas 60 gestantes, sendo 20 normotensas e 40 portadoras de PE, pareadas pela idade gestacional. As gestantes com PE foram classificadas de acordo com o aparecimento das manifestações clínicas em PE precoce (< 34 semanas de gestação; n=20) e PE tardia (≥ 34 semanas de gestação; n=20). Células mononucleares do sangue periférico (PBMCs), obtidas das gestantes foram avaliadas quanto à produção de citocinas pró e anti-inflamatórias e à expressão de fatores de transcrição envolvidos na caracterização das subpopulações de células T CD4+. A expressão dos fatores de transcrição intracitoplasmáticos de células Th1 (T-bet), Th2 (GATA-3), Th17 (RORc) e Treg (FoxP3) foi avaliada por c... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

OBJECTIVES: The aim of our study was to assess clinical presentation of early-onset schizophrenia spectrum disoders (EO-SSD), the time to first improvement and efficacy associated with selected atypical (AAPs) and typical (TAPs) antipsychotics, as well as two main side effects - weight gain and treatment-emergent extrapyramidal symptoms (EPSs) during the treatment in patients with EO-SSD. METHODS: This was a systematic chart review of all patients receiving routine clinical care in our department, with selected AAPs (risperidone, olanzapine, ziprasidone, quetiapine and clozapine) and TAPs (haloperidol, perphenazine and sulpiride), for schizophrenic psychoses, between 1997 and 2007. During this period, our review identified 173 patients (85 males, 88 females; mean age 15.8±1.6 years); their treatment included 297 treatment trials. Data on premorbid adjustment, prodromal symptoms and psychopathology at admission, as well as comorbidity were evaluated based on the patients' medical records. The time to first improvement could be estimated in 258 treatment trials; of these, 195 (76%) comprised AAPs and 63 (24%) TAPs. The time to first improvement was assessed in agreement with the methodology established for retrospective studies as the number of treatment days prior to the first record of improvement...

Contexte : Autisme, trouble du spectre autistique, schizophrénies précoces voire même très précoces (SDTP)... autant de termes utilisés de nos jours! Même si les classifications restent aujourd'hui catégorielles, les travaux sont cependant croissants pour approfondir et comprendre un éventuel lien entre les troubles du spectre autistique et schizophrénique, et notamment un lien entre les troubles du spectre autistique (TSA) et les schizophrénies précoces. Objectif : Clarifier les liens cliniques et biologiques entre TSA et schizophrénies à début précoce (avant 18 ans) et même très précoce (avant 13 ans). Méthodologie: Population de 62 sujets, divisés en trois groupes selon l'âge de début de la pathologie schizophrénique : strictement avant 13 ans (Very Early Onset Schizophrenia, VEOS), entre 13 et 18 ans (Early Onset Schizophrenia, EOS) et supérieur ou égal à 18 ans (Adult Onset Schizophrenia, AOS). Pour chaque groupe, 2 évaluations cliniques sont effectuées : recherche d'antécédents prémorbides autistiques avec l'ADI-R (Autism Diagnostic Interview-Revised); l'autre phénotypique avec MINI (Mini International Neuropsychiatric Interview), BPRS (Brief Psychiatric Rating Scale), PANSS (Positive And Negative Symptoms Scale for schizophrenia), STAI (State Trait Anxiety Inventory), TAS (Toronto Alexithymia Scale) et NSS (Neurological Soft Signs). L'analyse biologique est basée sur des mesures du cycle du cortisol salivaire (jour 1: 8h00; 11h00; 16h00; 24h00 et jour 2 :8h00), afin d'évaluer la réponse au stress de l'axe hypothalamo-hypophyso-surrenalien. Résultats: un gradient des troubles VEOS > EOS > AOS apparaît. Plus la schizophrénie semble débuter tôt et plus sont retrouvés des antécédents prémorbides autistiques et une réactivité au stress, réponse également exacerbée chez les apparentés. Conclusion: Un lien clinico-biologique apparaît donc entre SDTP et TSA, avec notamment des troubles cliniques déjà présents avant trois ans et des anomalies de la réponse au stress. Les schizophrénies à début très précoce sont-elles ainsi à distinguer dans le grand ensemble des schizophrénies? En tout cas, un diagnostic à mieux connaître, afin de mieux le prendre en charge et de mieux accompagner patients et famille. / Context : Autism spectrum disorders (ASD) , early onset schizophrenia (EOS) or even very early onset schizophrenia (VEOS)... so many terms used these days! Although today, classifications are categorical, work is however increasing to deepen and understand a possible link between ASD and schizophrenia spectrum disorders, and especially a link between ASD and early onset schizophrenia. Objective : To clarify clinical and biological links between ASD and EOS (before age 18) and especially links between ASD and VEOS (before age 13). Méthod: 62 subjects, divided into three groups according to age at onset of schizophrenia : strictly before age 13 (VEOS ), between age 13 and 18 (EOS) and after 18 (Adult Onset Schizophrenia, AOS). For each group, two clinical evaluations are assessed: search early symptoms of autism with the ADI-R (Autism Diagnostic Interview-Revised) and phenotypic evaluation with MINI (Mini International Neuropsychiatric Interview), BPRS (Brief Psychiatric Rating Scale), PANSS (Positive And Negative Symptoms Scale for schizophrenia), STAI (State Trait Anxiety Inventory), TAS (Toronto Alexithymia Scale) et NSS (Neurological Soft Signs). Biological analysis is based on salivary cortisol measurements, collected during a 24-h period (0800h-day 1, 1100h, 1600h, 2400h, 0800h-day2), in order to evaluate the stress response of the hypothalamic-pituitary-adrenal axis. Résults: VEOS symptoms > EOS symptoms > AOS symtoms. The earlier the schizophrenia is and the more present premorbid history of autism is and the more abnormal stress response is (abnormal stress response also present in relatives). Conclusion: A clinico-biological link appears between VEOS and ASD, with early symtoms of autism before thirty six months and stress response abnormalities. Are VEOS different from schizophrenia? Anyway, a diagnosis to know better in order to improve patients and families cares.