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During the last decade, substantial advances have been made in the understanding of the complex molecular, immunological and cellular disturbances involved in the initiation as well as evolution of myelodysplastic syndromes (MDS). In 85% of the mainly frail and older patient population, anemia is present at the time of diagnosis and is thus a major therapeutic challenge. High rates of primary resistance to erythropoiesis-stimulating agents (ESAs), the currently only approved standard therapy to treat anemia in lower-risk MDS, demand the development of novel and effcient drugs with a good safety profile. Luspatercept, a ligand trap of activin receptor II, is able to promote late stage erythropoiesis even in patients failing prior ESA treatment. The presence of ring sideroblastic phenotype defines a subgroup of patients with higher response rates. Additionally, recent developments in clinical research using HIF-1 or telomerase modulation by roxadustat or imetelstat are promising. Other areas of translational research involve targeting the inflammasome by anti-inflammatory drugs in order to improve anemia. These efforts will hopefully pave the way for new targeted treatment options for anemic low-risk MDS patients.

Objetivo: identificar o risco cardiovascular (RCV) e sua associação com fase do climatério, idade, grau de instrução, paridade, nível de atividade física, hábito de fumar e terapia hormonal da menopausa, em mulheres de 40 a 65 anos atendidas em ambulatórios públicos da cidade de São Paulo. Métodos: as variáveis dependentes foram RCV segundo obesidade global, identificada pelo índice de massa corporal (IMC) e pelo percentual de gordura corporal (%GC), e RCV segundo obesidade abdominal, identificada pela relação cintura/quadril (RCQ) e pela circunferência da cintura (CC). A variável explanatória principal foi fase do climatério e as variáveis de controle foram: idade, grau de instrução, paridade, nível de atividade física, hábito de fumar e terapia hormonal da menopausa (THM). As análises de regressão logística múltipla foram executadas no programa STATA 9.0, utilizando o processo \"stepwise\". Resultados: constatou-se RCV aumentado, segundo obesidade global, em 32,0% (IMC) e 24,7% (%GC) das mulheres; e, segundo obesidade abdominal em 49,0% (RCQ) e 64,0% (CC) das mulheres. Nos modelos finais, permaneceram associadas ao RCV aumentado, segundo obesidade global (IMC): fase do climatério, nível de atividade física, paridade e grau de instrução e, de acordo com o %GC: nível de atividade física e paridade. Segundo obesidade abdominal (RCQ) permaneceram associadas: nível de atividade física, grau de instrução e idade e, de acordo com a CC: nível de atividade física, paridade e idade. Conclusão: a fase do climatério só foi importante para explicar o RCV aumentado, segundo obesidade global, identificada pelo IMC. A variável explanatória mais importante para explicar o RCV aumentado, tanto segundo obesidade global como abdominal, foi o nível de atividade física; enquanto a paridade foi importante para explicar o RCV aumentado segundo obesidade global e a idade, segundo obesidade abdominal. / Purpose: to identify cardiovascular risk (CVR) and its relationship to climacteric period, age, educational level, parity, physical activity level, tobacco smoking and hormone therapy, in women aged 40-65 years old, attended in outpatient clinics from São Paulo, Brazil. Methods: the dependent variables were: CVR, according to body obesity, assessed by body mass index (BMI) and by body fat percentage (%BF), and CVR, according to abdominal obesity, assessed by waist/hip ratio (WHR) and by waist circumference (WC). The main explanatory variable was climacteric period and the control variables were: age, educational level, parity, physical activity level, tobacco smoking and hormone therapy. The multiple regression analysis were performed at software STATA 9.0, by the stepwise process. Results: higher CVR assessed by body obesity prevalence was 32,0% (BMI) and 24,7% (%GC); according to abdominal obesity, was 49,0% (WHR) and 64,0% (WC). In the final models, the variables associated with higher CVR, assessed by body obesity, were climacteric period, physical activity level, parity and educational level (BMI) and physical activity level and parity (%BF). According to abdominal obesity, the variables associated with higher CVR were physical activity level, educational level and age (WHR) and physical activity level, parity and age (WC). Conclusion: the most important variable to explain higher CVR was physical activity level, according to body and abdominal obesity, while the parity was important to explain higher CVR according to body obesity and the age to explain higher CVR according to abdominal obesity.

Objetivo: identificar o risco cardiovascular (RCV) e sua associação com fase do climatério, idade, grau de instrução, paridade, nível de atividade física, hábito de fumar e terapia hormonal da menopausa, em mulheres de 40 a 65 anos atendidas em ambulatórios públicos da cidade de São Paulo. Métodos: as variáveis dependentes foram RCV segundo obesidade global, identificada pelo índice de massa corporal (IMC) e pelo percentual de gordura corporal (%GC), e RCV segundo obesidade abdominal, identificada pela relação cintura/quadril (RCQ) e pela circunferência da cintura (CC). A variável explanatória principal foi fase do climatério e as variáveis de controle foram: idade, grau de instrução, paridade, nível de atividade física, hábito de fumar e terapia hormonal da menopausa (THM). As análises de regressão logística múltipla foram executadas no programa STATA 9.0, utilizando o processo \"stepwise\". Resultados: constatou-se RCV aumentado, segundo obesidade global, em 32,0% (IMC) e 24,7% (%GC) das mulheres; e, segundo obesidade abdominal em 49,0% (RCQ) e 64,0% (CC) das mulheres. Nos modelos finais, permaneceram associadas ao RCV aumentado, segundo obesidade global (IMC): fase do climatério, nível de atividade física, paridade e grau de instrução e, de acordo com o %GC: nível de atividade física e paridade. Segundo obesidade abdominal (RCQ) permaneceram associadas: nível de atividade física, grau de instrução e idade e, de acordo com a CC: nível de atividade física, paridade e idade. Conclusão: a fase do climatério só foi importante para explicar o RCV aumentado, segundo obesidade global, identificada pelo IMC. A variável explanatória mais importante para explicar o RCV aumentado, tanto segundo obesidade global como abdominal, foi o nível de atividade física; enquanto a paridade foi importante para explicar o RCV aumentado segundo obesidade global e a idade, segundo obesidade abdominal. / Purpose: to identify cardiovascular risk (CVR) and its relationship to climacteric period, age, educational level, parity, physical activity level, tobacco smoking and hormone therapy, in women aged 40-65 years old, attended in outpatient clinics from São Paulo, Brazil. Methods: the dependent variables were: CVR, according to body obesity, assessed by body mass index (BMI) and by body fat percentage (%BF), and CVR, according to abdominal obesity, assessed by waist/hip ratio (WHR) and by waist circumference (WC). The main explanatory variable was climacteric period and the control variables were: age, educational level, parity, physical activity level, tobacco smoking and hormone therapy. The multiple regression analysis were performed at software STATA 9.0, by the stepwise process. Results: higher CVR assessed by body obesity prevalence was 32,0% (BMI) and 24,7% (%GC); according to abdominal obesity, was 49,0% (WHR) and 64,0% (WC). In the final models, the variables associated with higher CVR, assessed by body obesity, were climacteric period, physical activity level, parity and educational level (BMI) and physical activity level and parity (%BF). According to abdominal obesity, the variables associated with higher CVR were physical activity level, educational level and age (WHR) and physical activity level, parity and age (WC). Conclusion: the most important variable to explain higher CVR was physical activity level, according to body and abdominal obesity, while the parity was important to explain higher CVR according to body obesity and the age to explain higher CVR according to abdominal obesity.

Cardiovascular diseases (CVD) are the leading cause of death, and the underlying atherosclerotic process has its origin in youth. Physical activity lowers future CVD risk, however few adolescents achieve the recommended minimum amount of daily activity and interventions fail to meaningfully increase activity levels in this group. It is therefore essential to identify how small volumes of exercise can be optimised for the primary prevention of CVD. The purpose of this thesis is to identify the influence of exercise intensity on vascular health outcomes in adolescents, and to assess the efficacy of 2 weeks of low volume, high-intensity interval training on CVD risk factors in this population. Chapter 4 demonstrates that a single bout of high-intensity interval exercise (HIIE) performed one hour before a high fat meal elicits comparable reductions in postprandial lipaemia as a work-matched bout of moderate-intensity exercise (MIE) in girls. However, neither exercise attenuated postprandial lipaemia in the boys. Additionally, HIIE elicited a superior increase in postprandial fat oxidation and decrease in blood pressure, and this was sex independent. These findings are furthered in Chapter 5, which identified that accumulating HIIE, but not MIE, favourably modulates glycaemic control, postprandial blood pressure and fat oxidation in adolescents irrespective of sex. A high fat meal was included in Chapter 6 in order to impair vascular function via oxidative stress. Postprandial vascular function was preserved following MIE, but improved after HIIE, and these changes were not related to changes in postprandial lipaemia or total antioxidant status. Chapter 7 addressed the time course of the changes in vascular function post exercise, and identified that HIIE promotes superior changes in vascular function than MIE. Finally, Chapter 8 identified that 2 weeks of high-intensity interval training improved novel (endothelial function and heart rate variability), but not traditional CVD factors in adolescent boys and girls. However, most of these favourable changes were lost 3 days after training cessation. Thus, this thesis demonstrates that vascular health outcomes are positively associated with exercise intensity. Given that HIIE was perceived to be more enjoyable than MIE in Chapters 4, 6 and 7, performing HIIE appears to be an effectual and feasible alternative to MIE for the primary prevention of CVD.