Atualmente os profissionais de saúde se confrontam com o cuidar de pacientes com talassemia maior que chegaram à fase adulta, devido ao avanço do conhecimento sobre a doença e dos efeitos das terapêuticas, principalmente da transfusão sangüínea e dos quelantes. A literatura médica destaca a problemática da irregularidade da adesão ao tratamento, pelo paciente, principalmente o da quelação, fundamental para a sua sobrevivência. No presente estudo, a análise dos sentidos dados pelos talassêmicos adultos à sua experiência com o regime terapêutico é o objetivo, desenvolvido pela antropologia médica e método qualitativo. Foi realizado com usuários do Hemocentro de Ribeirão Preto do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP. Para a coleta de dados foi empregado o relato oral, por entrevistas semi-estruturadas, obtendo-se narrativas sobre a experiência. Participaram do estudo onze adultos jovens, seis do sexo masculino, com idades entre 22 a 32 anos, com níveis educacionais e profissões distintas. As entrevistas foram transcritas e organizadas em textos individuais. Seguimos as etapas da análise temática indutiva para a análise dos dados. Os resultados são discutidos em dois núcleos temáticos: \"O início da doença e do tratamento\" e \"A vida do portador de talassemia com o tratamento\". No primeiro, são descritas as lembranças do início do tratamento. As narrativas demonstram que eles estão bem informados sobre a doença e tratamentos, e que tiveram contato com a morte de familiares com a talassemia. Subjetivamente eles destacam a sua identidade de diferença por terem o traço da doença. No segundo tema, descrevemos o longo itinerário terapêutico vivenciado; o reconhecimento da importância da adesão ao tratamento; as mudanças e adequações dos quelantes usados; a convivência com o estigma social pelas alterações corporais, reações da transfusão e do quelante; as dificuldades em manterem suas funções sociais; os episódios de irregularidade do seguimento terapêutico e suas justificativas. Pelos temas apreendemos que os adultos jovens com talassemia maior sob o regime terapêutico estão resignados com a sua condição, que a doença e tratamentos não os excluem da vida cotidiana, mas estão no centro das suas relações sociais. Para reduzirem o peso do sofrimento e do estigma, eles empregam a estratégia de normalização, elaborada no grupo social. Esta possibilita terem a sensação de ordem da vida, de controle da doença e do tratamento. Assim, as interrupções no tratamento ocorrem pela necessidade de normalização do corpo e da vida, mas que traz conseqüências graves para a sobrevivência. Ao final da discussão, fazemos uma reflexão sobre o conceito médico de adesão confrontado com o de concordância, e suas implicações para o contexto de cuidado com o talassêmico adulto. / Currently health professionals are faced with assisting patients with thalassemia major who reached adulthood, due to the advance of knowledge about the disease and the effects of therapies, especially the blood transfusion and chelation. The literature highlights the problem of irregular treatment adhesion by patients, especially the chelation, essential to their survival. In this study, the analysis of the sense given by thalassemic adults to their experience with the drug regimen is the goal, developed by medical anthropology and qualitative method. It was conducted with patients at the Blood Center of Ribeirão Preto, Hospital das Clínicas da Faculdade de Medicina de Ribeirao Preto - USP. To collect the data it was used oral report, by semi-structured interviews, obtaining narratives about the experience. Eleven young adults, six males, aged 22-32 years, with different educational levels and occupations attended the study. The interviews were transcribed and organized in individual texts. We followed the steps of inductive thematic analysis to analyze the data. The results are discussed in two themes: \"The onset of disease and treatment\" and \"The life of thalassemic patients with treatment.\" In the first one we describe the memories of the beginning of treatment. The narratives show that they are well informed about the disease and treatments, and had contact with the death of a family member with thalassemia. Subjectively they highlight the difference of their identity by having the disease trait. In the second theme, we describe the long-lived therapeutic itinerary; the recognition of the importance of adhering to the treatment; changes and adaptations of the chelating agents used; the social stigma of living with the body changes; adverse effects of transfusion and chelation; the difficulties in maintaining their social functions; episodes of irregularity in following therapeutic treatment and its justifications. Through the themes we could observe that young adults with thalassemia major under the therapeutic regimen are resigned to their condition, that the disease and treatment do not exclude them from everyday life, but are in the center of their social relations. To reduce the suffering and stigma, they employ the normalization strategy, elaborated in the social group. This enables them to have a sense of order in life, of disease and treatment control. Thus, disruptions in treatment occur by the need for normalization of body and life, but that brings severe consequences for survival. At the end of the discussion, we reflect on the medical concept of adhesion confronting with the agreement and its implications for the care context with the thalassemic adult.

L’érythropoïèse inefficace joue un rôle central dans la physiopathologie de l’anémie des β-TM. Ses caractéristiques sont triple: accélération de la différenciation érythroïde, arrêt de maturation au stade d’érythroblaste polychromatophile et mort par apoptose à ce stade de différenciation. Les mécanismes précis de cette apoptose et de l’arrêt de la maturation n’ont pas encore été élucidés. Il a été montré, au cours de l’érythropoïèse physiologique, que la protéine chaperonne Hsp70, en se localisant dans le noyau des érythroblastes en cours de différenciation, protège GATA-1 (facteur de transcription érythroïde majeur) de sa destruction par la caspase-3. Cette enzyme clé de l’apoptose est en effet activée physiologiquement au cours de la différenciation érythroïde et peut cliver GATA-1. Notre travail se base sur l’hypothèse suivante : Hsp70 pourrait, au cours de l’érythropoïèse des β-TM, être séquestrée dans le cytoplasme des érythroblastes matures (stade d’une intense hémoglobinisation) afin d’exercer son rôle de chaperonne des chaînes d’α-globine libres. Cela aurait comme conséquence néfaste l’absence de localisation nucléaire d’Hsp70 et, en conséquence, la destruction de GATA-1 à l’origine de l’arrêt de maturation et de la mort cellulaire. Nous avons montré dans ce travail qu’Hsp70 était localisée principalement dans le cytoplasme des érythroblastes matures dans la moelle de patients β-TM, avec un défaut d’expression nucléaire. Par ailleurs, GATA-1 n’est plus exprimé dans ces cellules. Nous avons confirmé ces résultats dans un système de culture cellulaire érythroïde humaine en milieu liquide reproduisant les étapes de la différenciation érythroïde terminale. Une intéraction physique directe entre Hsp70 et l’α-globine a été identifiée par techniques de microscopie confocale, d’immunoprécipitation et de double hybride. Enfin, la transduction dans les érythroblastes de β-TM d’un mutant d’Hsp70-S400A, principalement nucléaire, ou d’un mutant de GATA-1 non clivable par la caspase-3 corrige l’érythropoïèse inefficace.Une modélisation mathématique du complexe Hsp70/α-globine nous a permis de préciser les domaines impliqués dans l’intéraction, ce qui ouvre la voie à une possibilité de criblage de petites molécules permettant la rupture de ce complexe afin de ramener Hsp70 dans le noyau avec un espoir thérapeutique pour améliorer l’érythropoïèse inefficace des β-TM. / Β-TM is an inherited hemoglobinopathy caused by a quantitative defect in the synthesis of the β-globin chains of hemoglobin, leading to the accumulation of free α-globin chains that form toxic aggregates. Despite extensive knowledge on the molecular defects causing β-TM, little is known about the mechanisms responsible for ineffective erythropoiesis (IE), which is characterised by accelerated erythroid differentiation, maturation arrest and apoptosis at the polychromatophilic stage. We have previously demonstrated that normal human erythroid cell maturation requires a transient activation of caspase-3. Although GATA-1, the master transcriptional factor of erythropoiesis, is a caspase-3 target, we have shown that during human erythroid differentiation, it is protected from cleavage through its association with the chaperone Hsp70 in the nucleus. Hsp70 is constitutively highly expressed in normal human erythroid cells. The best-known role of this ubiquitous chaperone is to participate in proteins folding and refolding of proteins denatured by cytoplasmic stress, thus preventing their aggregation.In this study, we have evidenced that during the maturation of human β-TM erythroblasts, Hsp70 is sequestrated in the cytoplasm by the excess of free α-globin chains, resulting in nuclear GATA-1 cleavage and, in turn, end-stage maturation arrest and apoptosis. A molecular modeling shows that α-globin binds to a highly electronegative cavity formed by all Hsp70 domains. Additionally, the transduction of a nuclear-targeted Hsp70 mutant (Hsp70-S400A) or caspase-3 uncleavable GATA-1 mutant (µGATA-1) corrects β-TM ineffective erythropoiesis in human cultured β-TM cells. Our data indicate that cytosolic Hsp70 sequestration by α-globin chains prevents its nuclear localization and is a key mechanism of the β-TM IE. In order to increase nuclear Hsp70 translocation, developing small molecules that could increase Hsp70 expression or disrupt the Hsp70/α-globin complex could be a novel approach of targeted therapies to improve erythropoiesis in β-TM.

Atualmente os profissionais de saúde se confrontam com o cuidar de pacientes com talassemia maior que chegaram à fase adulta, devido ao avanço do conhecimento sobre a doença e dos efeitos das terapêuticas, principalmente da transfusão sangüínea e dos quelantes. A literatura médica destaca a problemática da irregularidade da adesão ao tratamento, pelo paciente, principalmente o da quelação, fundamental para a sua sobrevivência. No presente estudo, a análise dos sentidos dados pelos talassêmicos adultos à sua experiência com o regime terapêutico é o objetivo, desenvolvido pela antropologia médica e método qualitativo. Foi realizado com usuários do Hemocentro de Ribeirão Preto do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP. Para a coleta de dados foi empregado o relato oral, por entrevistas semi-estruturadas, obtendo-se narrativas sobre a experiência. Participaram do estudo onze adultos jovens, seis do sexo masculino, com idades entre 22 a 32 anos, com níveis educacionais e profissões distintas. As entrevistas foram transcritas e organizadas em textos individuais. Seguimos as etapas da análise temática indutiva para a análise dos dados. Os resultados são discutidos em dois núcleos temáticos: \"O início da doença e do tratamento\" e \"A vida do portador de talassemia com o tratamento\". No primeiro, são descritas as lembranças do início do tratamento. As narrativas demonstram que eles estão bem informados sobre a doença e tratamentos, e que tiveram contato com a morte de familiares com a talassemia. Subjetivamente eles destacam a sua identidade de diferença por terem o traço da doença. No segundo tema, descrevemos o longo itinerário terapêutico vivenciado; o reconhecimento da importância da adesão ao tratamento; as mudanças e adequações dos quelantes usados; a convivência com o estigma social pelas alterações corporais, reações da transfusão e do quelante; as dificuldades em manterem suas funções sociais; os episódios de irregularidade do seguimento terapêutico e suas justificativas. Pelos temas apreendemos que os adultos jovens com talassemia maior sob o regime terapêutico estão resignados com a sua condição, que a doença e tratamentos não os excluem da vida cotidiana, mas estão no centro das suas relações sociais. Para reduzirem o peso do sofrimento e do estigma, eles empregam a estratégia de normalização, elaborada no grupo social. Esta possibilita terem a sensação de ordem da vida, de controle da doença e do tratamento. Assim, as interrupções no tratamento ocorrem pela necessidade de normalização do corpo e da vida, mas que traz conseqüências graves para a sobrevivência. Ao final da discussão, fazemos uma reflexão sobre o conceito médico de adesão confrontado com o de concordância, e suas implicações para o contexto de cuidado com o talassêmico adulto. / Currently health professionals are faced with assisting patients with thalassemia major who reached adulthood, due to the advance of knowledge about the disease and the effects of therapies, especially the blood transfusion and chelation. The literature highlights the problem of irregular treatment adhesion by patients, especially the chelation, essential to their survival. In this study, the analysis of the sense given by thalassemic adults to their experience with the drug regimen is the goal, developed by medical anthropology and qualitative method. It was conducted with patients at the Blood Center of Ribeirão Preto, Hospital das Clínicas da Faculdade de Medicina de Ribeirao Preto - USP. To collect the data it was used oral report, by semi-structured interviews, obtaining narratives about the experience. Eleven young adults, six males, aged 22-32 years, with different educational levels and occupations attended the study. The interviews were transcribed and organized in individual texts. We followed the steps of inductive thematic analysis to analyze the data. The results are discussed in two themes: \"The onset of disease and treatment\" and \"The life of thalassemic patients with treatment.\" In the first one we describe the memories of the beginning of treatment. The narratives show that they are well informed about the disease and treatments, and had contact with the death of a family member with thalassemia. Subjectively they highlight the difference of their identity by having the disease trait. In the second theme, we describe the long-lived therapeutic itinerary; the recognition of the importance of adhering to the treatment; changes and adaptations of the chelating agents used; the social stigma of living with the body changes; adverse effects of transfusion and chelation; the difficulties in maintaining their social functions; episodes of irregularity in following therapeutic treatment and its justifications. Through the themes we could observe that young adults with thalassemia major under the therapeutic regimen are resigned to their condition, that the disease and treatment do not exclude them from everyday life, but are in the center of their social relations. To reduce the suffering and stigma, they employ the normalization strategy, elaborated in the social group. This enables them to have a sense of order in life, of disease and treatment control. Thus, disruptions in treatment occur by the need for normalization of body and life, but that brings severe consequences for survival. At the end of the discussion, we reflect on the medical concept of adhesion confronting with the agreement and its implications for the care context with the thalassemic adult.

Bone marrow mesenchymal stem cells (BM-MSCs) are pluripotent cells that can differentiate into a variety of non-hematopoietic tissues. They also maintain healthy heamatopoiesis by providing supportive cellular microenvironment into BM. In this thesis, MSCs were characterized in terms of their morphological, immunophenotypical and differentiation properties. Then, they were examined by attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy together with hierarchical clustering, and FTIR microspectroscopy. In the first part of this study, global structural and compositional changes in BM-MSCs during beta thallasemia major (

Bone marrow mesenchymal stem cells (BM-MSCs) are pluripotent cells that can differentiate into a variety of non-hematopoietic tissues. They also maintain healthy heamatopoiesis by providing supportive cellular microenvironment into BM. In this thesis, MSCs were characterized in terms of their morphological, immunophenotypical and differentiation properties. Then, they were examined by attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy together with hierarchical clustering, and FTIR microspectroscopy. In the first part of this study, global structural and compositional changes in BM-MSCs during beta thallasemia major (

Text in English / This research explores the meaning of the first and second-order therapeutic stances with reference to the therapist's professional and personal development. The dominant positivist paradigm was reflected in the therapist's initial position of expert observer, outside of the observed. The observed phenomena were a group of children suffering from thalassemia major, a terminal genetic disease, and their mothers. The initial idea of short-term intervention and focus on the observed evolved into six-year journey where the observer and the observed became an interconnected unit of observation, understanding and change. A first-order stance led to therapeutic stuckness, where the therapist's confrontation with her therapeutic failure and the limitations of the dominant paradigm provoked a deconstruction of the expert position and promoted a self-reflexive therapeutic stance. The author's self-searching process took her back to her personal self, her family of origin and the ''wounded healer". The researcher moved from an initial disconnection between her professional and personal selves to an awareness of the interface between the two and, ultimately, to a unification of her professional and personal selves. Such development involved an individuation process moving from a narcissistic belief in her objective stance towards a therapeutic stance where she sees herself less as a powerful agent of change and moves to an increasingly higher order of integration of the professional and personal selves (Skovholt & Ronnestad, 1992). The process with the children and mothers shifted from a focus on compliance and medical issues to more personal and emotional stories. The therapist's participation and collaborative stance created a context for change, where greatly improved medical compliance was just one of the many transformations experienced by all the participants. The researcher speculates that development of a second-order stance requires second-order change, which comes "at the end of long, often frustrating mental and emotional labor" (Watzlawick et al., 1974, p. 23), promoting integration between the professional and personal selves of the therapist. The researcher therefore contends that this process has important implications for psychotherapy training, supervision and continuing education. / Psychology / D. Litt. et Phil. (Psychology)

Text in English / This research explores the meaning of the first and second-order therapeutic stances with reference to the therapist's professional and personal development. The dominant positivist paradigm was reflected in the therapist's initial position of expert observer, outside of the observed. The observed phenomena were a group of children suffering from thalassemia major, a terminal genetic disease, and their mothers. The initial idea of short-term intervention and focus on the observed evolved into six-year journey where the observer and the observed became an interconnected unit of observation, understanding and change. A first-order stance led to therapeutic stuckness, where the therapist's confrontation with her therapeutic failure and the limitations of the dominant paradigm provoked a deconstruction of the expert position and promoted a self-reflexive therapeutic stance. The author's self-searching process took her back to her personal self, her family of origin and the ''wounded healer". The researcher moved from an initial disconnection between her professional and personal selves to an awareness of the interface between the two and, ultimately, to a unification of her professional and personal selves. Such development involved an individuation process moving from a narcissistic belief in her objective stance towards a therapeutic stance where she sees herself less as a powerful agent of change and moves to an increasingly higher order of integration of the professional and personal selves (Skovholt & Ronnestad, 1992). The process with the children and mothers shifted from a focus on compliance and medical issues to more personal and emotional stories. The therapist's participation and collaborative stance created a context for change, where greatly improved medical compliance was just one of the many transformations experienced by all the participants. The researcher speculates that development of a second-order stance requires second-order change, which comes "at the end of long, often frustrating mental and emotional labor" (Watzlawick et al., 1974, p. 23), promoting integration between the professional and personal selves of the therapist. The researcher therefore contends that this process has important implications for psychotherapy training, supervision and continuing education. / Psychology / D. Litt. et Phil. (Psychology)