Hypoxia is a common feature of solid tumors and one of the hallmarks of tumor microenvironment. Tumor hypoxia plays an important role in angiogenesis, malignant progression, metastatic development, chemo-radio resistance and favours immune evasion by the emergence of tumor variants with increased survival and anti-apoptotic potential. There is very little work done on the impact of tumor hypoxia on the regulation of tumor susceptibility to the lysis induced by cytotoxic antitumor response. Therefore, we asked whether hypoxia confers tumor resistance to cytotoxic T lymphocyte (CTL)-mediated killing. We demonstrated that exposure of target cells to hypoxia has an inhibitory effect on the CTL-mediated autologous target cell lysis. Such inhibition was not associated with an alteration of CTL reactivity and tumor target recognition. We also showed that the concomitant hypoxic induction of Signal transducer and activator of transcription 3 (STAT3) phosphorylation on tyrosine 705 residue (pSTAT3) and hypoxia inducible factor 1 alpha (HIF-1α) is functionally linked to the alteration of Non small cell lung carcinoma (NSCLC) target susceptibility to CTL-mediated killing. We also showed that hypoxia-induced resistance of lung tumor to CTL-mediated lysis was associated with autophagy induction in target cells. Inhibition of autophagy resulted in impairment of pSTAT3 (via inhibition Src kinase) and restoration of hypoxic tumor cell susceptibility to CTL-mediated lysis. Moreover, in vivo inhibition of autophagy by hydroxychloroquine (HCQ) in B16F10 tumor bearing mice and mice vaccinated with TRP2 peptide dramatically increased tumor growth inhibition. Collectively, the current study establishes a novel functional link between hypoxia-induced autophagy and the regulation of antigen specific T cell lysis and points to a major role of autophagy in the control of in vivo tumor growth.Finally, as resistance of tumor targets to killer cells is likely to be regulated by multiple factors, we further aimed to identify the microRNA's regulated by hypoxia in NSCLC and melanoma and their putative involvement in the regulation of tumor susceptibility to antigen-specific CTL-mediated killing. MicroRNA-210 (miR-210) was significantly induced in a HIF-1α dependent manner in NSCLC and melanoma cells and miR-210 was expressed in hypoxic zones of human NSCLC tissues. Moreover, we demonstrated that hypoxia-induced miR-210 regulates tumor cell susceptibility to CTL-mediated lysis in part by suppressing PTPN, HOXA1 and TP53I11 expression indicating that miR-210 plays a potential role in the regulation of anti-tumor immune response.

Cardiovascular disease (CVD) is a major cause of adult morbidity and mortality in developed as well as in developing countries. In black population groups, stroke is more prominent than ischaemic heart disease. This may be attributed to a combination of risk factors seen in this population group inter alia raised haemostatic markers, which favour the development of stroke since it is well known that a disturbance in the haemostatic balance (a hypercoagulable and a hypofibrinolytic state) predisposes to CVD. It is generally accepted that childhood genetic, environmental and behavioural factors lay the groundwork for the manifestation of adult CVD. Therefore, one of the studies that form part of this dissertation was a cross-sectional study to determine whether haemostatic abnormalities are already present in black African adolescents and to determine whether high risk groups exist [in relation to the following haemostatic markers: fibrinogen, factor VIII (FVIII), plasminogen activator inhibitor type 1 activity (PAI-Iact), and thrombin anti-thrombin complex (TAT)] for the development of CVD later in life. The population subdivisions were made according to gender, body fat %, maturity status, height for age Z-score, and habitual PA levels. Since behavioural factors [diet, physical activity (PA), smoking and drinking habits] are controllable determinants, it could be possible to improve CVD risk to a certain degree. Therefore, the second study that forms part of this dissertation attempted to establish whether a PA programme will successfully reduce haemostatic variables in a subset of the study population used in the first study. The reader is referred to the abstracts at the beginning of each separate study manuscript (Chapters 3 and 4), for a description of the subjects, study design and methods used in each study. The results of the cross-sectional study showed that in African adolescents (a) gender independently contributed to the variability in PAI-Iact, but that the gender difference in fibrinogen and TAT could be explained by the significant differences in fat mass and PA levels observed between the genders; (b) fibrinogen was significantly higher in the stunted compared to the non-stunted children indicating that childhood chronic malnutrition may possibly predispose independently to CVD; (c) fitness influences TAT concentrations positively and that (d) no significant differences in FVIII could be found between any of the subdivisions. As these determinants seem to be modifiable through behavioural changes and optimal nutrition status through early life, it raises a sense of urgency to develop strategies for the prevention and treatment of these risk factors. The results of the intervention study showed that an 11-week outdoor PA intervention programme had no significant effect on the haemostatic markers of African adolescents, but the results of this study should be interpreted with caution since (a) seasonal variations could have clouded the effect of the PA intervention as baseline measurements were taken in the summer and end measurements in the winter; (b) attendance of the PA sessions does not necessarily implicate compliance to the exercises given; (c) baseline values seem to play a prominent role in the changes that could be expected during an intervention and, therefore, improvements in the haemostatic profile would most likely be more significant in individuals with raised baseline levels. Similar research on African children is warranted since studies investigating PA's effect on haemostatic variables remain a topic of debate and speculation and data on African population groups are scanty. / Thesis (M.Sc. (Nutrition))--North-West University, Potchefstroom Campus, 2007

Snake venoms are a complex mixture of polypeptide and other molecules that adversely affect multiple homeostatic systems within their prey in a highly specific and targeted manner. Amongst the most potently toxic venoms in the world are those of the Australian venomous snakes, which belong almost exclusively to the elapid family. Their venoms posses a number of unique properties by which they target the mammalian cardiovascular and neuromuscular systems and are the focus for the identification of novel pharmacologically interesting compounds which may be of diagnostic or therapeutic benefit. Although much is known about the biochemical properties of Australia snake venoms as a whole, little research attention has focused upon individual components at the molecular level. This thesis describes the cloning, characterisation and comparative analysis of a number of unique toxins from the venom gland of the coastal taipan (Oxyuranus scutellatus) and a total of seven other related Australian snakes. These include the factor X- and factor V-like components of a prothrombin activator that causes a highly coagulable state in mammals. Comparative analysis of the sequences identified in this study, along with recombinant expression of an active form of the factor X-like component, provides important information on the structural, functional and evolutionary relationships of these molecules. Numerous other toxins were similarly identified and characterised including a pseudechetoxin-like protein, multiple phospholipase A2 enzymes and neurotoxin isoforms as well as vasoactive venom natriuretic peptides. Identified transcripts included not only toxin sequences but also other cellular peptides implicated in toxin processing, including a calglandulin-like protein. This thesis is the first description of the majority of these molecules at either the cDNA or protein level, and provides a means to study the activity of individual components from snake venoms and probe their function within the systems they specifically target. This study represents the most detailed and comprehensive description to date of the cloning and characterisation of different genes associated with envenomation from Australian snakes.

Made available in DSpace on 2016-08-03T16:31:14Z (GMT). No. of bitstreams: 1 Paginas 1-61.pdf: 4698640 bytes, checksum: 9e9fdc2cc379239aa56927f2d6ef0ba3 (MD5) Previous issue date: 2010-04-16 / The objective of this retrospective study was to compare the occlusal efficiency of orthopedic treatments using the Fränkel-2 regulator (RF 2) and Balters Bionator functional appliances, treated during different dental development stages, and compare them to a control group. The sample consisted of 45 documented records, belonging to the Dental School graduate program with a concentration area in orthodontics at the Methodist University of São Paulo. All records featured an initial Class II division 1 bilateral malocclusion. Of these, 15 patients were treated with the Bionator (group 1), with average initial age of 8.56 years and 80% of cases in dental development stage-2 (DS 2); 15 patients were treated with RF 2 (group 2), with average initial age of 10.71 years and 80% of cases in dental development stage -3 (DS 3); and a control group with 15 patients (group 3), with average initial age of 10.03 years and with dental development stage compatible both with groups 1 and 2. The groups were divided into two phases, according to the evaluation period: T1: beginning of treatment, and T2: final treatment, totaling 90 pairs of models. The occlusal evaluations were performed in plaster models, using the PAR index with the aid of the PAR ruler and a properly calibrated digital micrometer caliper. For intergroup comparison, ANOVA and Tukey test were used. The severity of the malocclusions (INITIAL PAR) was similar in all groups; however, the final PAR index showed a statistically significant difference, in which the percentile reduction for the PAR index was 20.72% for group 1, 60.06% for group 2, and no significant difference in the final PAR index for group 3. The present study concludes that the treatment for Class II division 1 malocclusion is more efficient when is begins during dental development stage-3 (DS 3) than in dental development stage-2 (DS 2). Moreover, importance is given to a more prolonged use of the dental appliance, as patients in group 2 showed better occlusal results.(AU) / O objetivo deste estudo retrospectivo foi comparar a eficiência oclusal do tratamento ortopédico com os aparelhos funcionais Regulador de Função Fränkel-2 e Bionator de Balters em um estágio de desenvolvimento dental diferente e comparar com um grupo controle. A amostra constituiu-se de 45 registros de documentações, pertencentes ao arquivo do programa de pós-graduação em Odontologia, área de concentração Ortodontia, da Universidade Metodista de São Paulo, com má oclusão inicial de Classe II bilateral, divisão 1, sendo 15 pacientes provenientes do grupo tratados com Bionator (grupo 1) com média de idade incial de 8,56 anos e com 80% dos casos em um estágio de desenvolvimento dental-2 (DS 2), 15 pacientes tratados com RF-2 (grupo 2) com média de idade inicial de 10,71 anos e com 80% dos casos em um estágio de desenvolvimento dental-3 (DS 3), e 15 pacientes controle (grupo 3) com media de idade incial de 10,03 anos e com estágio de desenvolvimento dental compatível com os grupos 1 e 2. Os grupos foram divididos em duas fases, de acordo com o período de avaliação: T1:início de tratamento e T2: final de tratamento, totalizando 90 pares de modelos. As avaliações oclusais foram realizadas em modelos de gesso, utilizando o Índice PAR com auxílio da régua PAR e de um paquímetro digital devidamente calibrado. Para comparação entre os três grupos foi utilizado Análise de Variância a um critério e em seguida o Teste de Tukey. A severidade da má oclusão (PAR Inicial) foi semelhante em ambos os grupos, porém, o PAR final apresentou uma diferença estatisticamente significante onde o percentual de redução do índice PAR para o grupo 1 foi de 20,72%, para o grupo 2 foi de 60,06% e no grupo 3 não houve alteração significante do valor do Índice PAR. O presente estudo conclui que o tratamento da má oclusão de Classe II, 1a divisão é mais eficiente quando iniciado no estágio de desenvolvimento dental 3 (DS 3) do que no estágio de desenvolvimento dental 2 (DS2). Além disso, ressalta-se a importância do uso mais prolongado do aparelho ortopédico, já que os pacientes do grupo 2 apresentaram melhores resultados oclusais.(AU)

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O tratamento para a Síndrome da Apnéia Obstrutiva do Sono (SAOS) mostra-se necessário devido às co-morbidades associadas ao quadro da síndrome. Fatores como problemas cardiovasculares, e aumento das chances de acidentes automobilísticos e de trabalho, além da diminuição da qualidade de vida, fazem dessa condição um sério problema a ser tratado. Dentre os tratamentos clínicos têm recebido especial atenção os aparelhos intra-orais por se tratar de um método simples e não invasivo. Os objetivos deste trabalho foram avaliar através dos índices polissinográficos as melhoras produzidas por um aparelho experimental e um aparelho placebo, e através de radiografias cefalométricas analisar fatores anatômicos relacionados com a severidade inicial do quadro e com as alterações do quadro da síndrome decorrentes do uso do aparelho experimental (Twin Block). Dezenove pacientes participaram deste estudo que foi prospectivo, com acompanhamento médio de 10,5 meses, cruzado, randomizado e duplo-cego. Foram feitas polissonografias iniciais e em uso dos aparelhos, após em média 6,47 (d.p.=2,01) meses do uso do Twin Block e 3,8 (d.p.=0,84) meses do uso do placebo e radiografias cefalométricas inicial e com o aparelho Twin Block em posição. Os dados pareados foram avaliados pelo teste de Wilcoxon, os não pareados pelos testes t de Student e Mann-Whitney e a comparação de proporções com o teste z, todos com 5% de significância (p<0.05). Os resultados mostraram tendências, embora não comprovadas estatisticamente, nas quais o grupo com SAOS moderada apresentou medidas de faringe menores e posição do osso hióide menos caudal quando comparados com o grupo com SAOS leve; que houve melhor resposta à terapia com o Twin-Block do que com o placebo, considerando-se o índice de apnéias mais hipopnéias por hora de sono (IAH), o índice de apnéias por hora de sono (IA), e a percentagem de sono REM; que a posição do osso hióide vertical diminuiu mais nos pacientes que melhoraram, tanto para o IAH quanto para o IA, que a maioria das medidas de faringe sofreram maior aumento nos pacientes que melhoraram em comparação com os que não melhoraram.Também foi possível estabelecer-se correlação positiva entre hipofaringe (HF) e os pacientes que melhoraram (avaliando pelo IAH), entre distância do osso hióide a terceira vértebra cervical (DHTV), faringe na altura do plano oclusal [NF(2)], largura do palato mole (PM) e os pacientes que melhoraram (avaliando pelo IA), além de entre NF (2) e os pacientes que não melhoraram (avaliando pelo IA). Conclui-se que o Twin Block mostrou-se clinicamente mais efetivo que o aparelho placebo no controle da SAOS, que algumas medições cefalométricas podem estar relacionadas com a severidade da síndrome medida inicialmente e que há variações de alterações anatômicas entre os pacientes que responderam e não responderam à terapia com aparelho intra-oral. / The treatment for the Obstructive Sleep Apnea Syndrome (OSAS) is necessary due to the co-morbidities associated with the syndrome. Factors such as cardiovascular problems, higher risk of automobile and work accidents, in addition to the decreased quality of life, makes the condition a serious problem to be treated. Among the treatments, clinicians have given special attention to the intra-oral appliances because it is simple and noninvasive. The objectives of this study were to evaluate by polysomnographyc indexes the improvements produced by both experimental and placebo units, and by cephalometric radiographs examine anatomical factors related with the initial severity of the syndrome and with the changes resulting from the use of the experimental appliance (Twin Block). Nineteen patients participated in this crossover, randomized, double-blind and prospective study, with monitoring average of 10.5 months. Polysomnographys were made in the initial use of the devices, after an average of 6.47 months (s.d. = 2.01) of Twin Block use and 3.8 months (s.d. = 0.84) of placebo use, along with cephalometric radiographs taken initially and with the Twin Block in position. Paired data were analyzed by the Wilcoxon test, non-paired by the Student t test and Mann-Whitney and compared proportions with the test z, all with 5% of significance (p <0.05). The results showed trends, though not statistically proven, that the group with moderate OSAS presented lower measures for the pharynx and higher hyoid bone position when compared to the group with mild OSAS; that the patients were more responsive to therapy with Twin-Block than with placebo, considering the index of more apnea hypopnea per hour of sleep (AHI), the index of sleep apnea per hour (AI), and the percentage of REM sleep; that the position of the vertical hyoid bone decreased more in patients who improved, both for the AHI and for the AI; that most pharyngeal measures suffered greater increase in patients who improved in comparison with those who did not get better. It could also be established a positive correlation between hypopharynx (HF) and patients who improved (by assessing AHI), distance between the hyoid bone and the third cervical vertebra (DHTV), pharynx in the occlusal plain [NF (2)], the width of the soft palate (PM) and patients that improved (by assessing AI), and between NF (2) and patients who had not improved (by assessing AI). It is concluded that the Twin Block was clinically more effective than the placebo unit in the control of OSAS, that some cephalometric measurements may be related to the severity of the syndrome measure initially and that there are variations in anatomic changes among patients who responded and not responded to therapy with intra-oral device.

O estudo teve como objetivo avaliar a razão de custo-efetividade, sob a perspectiva do Sistema Único de Saúde SUS, do tratamento da anemia de pacientes em Terapia Renal Substitutiva. Duas alternativas foram comparadas: um novo medicamento recentemente registrado no Brasil, o Ativador Contínuo de Receptor de Eritropoetina (Continuous Erythropoietin Receptor Activator), CERA, e outro, atualmente disponível no sistema de saúde brasileiro, a Eritropoetina Recombinante Humana - Epo-rHu. Métodos: Um modelo de Markov simulou o curso de uma coorte de pacientes em Terapia Renal Substitutiva tratados com CERA e Epo-rHu por quatro anos. A qualidade de vida associada ao uso dos medicamentos foi estimada de forma indireta, por meio de entrevista qualificada com os profissionais cuidadores, previamente submetida e aprovada pelo Comitê de Ética em Pesquisa local. Foi realizada análise de sensibilidade no modelo proposto através da variação dos parâmetros: dose dos medicamentos, custo das estratégias, taxa de desconto e efetividade utilizados para sua construção. Resultados: A média da qualidade de vida atribuída aos pacientes tratados foi 6,3 para a Epo-rHu, 7,8 para o CERA e 9,3 para os pacientes transplantados. O modelo demonstrou que a estratégia mais custo-efetiva é a terapêutica com a Epo-rHu, com um custo por QALY de R$ 21.052,00. O custo incremental por QALY ganho associado ao CERA foi de R$ 72.974,00. Conclusão: A utilização mensal do medicamento CERA está associada à maior qualidade de vida quando comparada a Epo-rHu. No entanto, a terapia com o novo medicamento não se mostrou mais custo-efetiva frente ao tratamento com Epo-rHu / This study sought to determine the cost-effectiveness of anemia treatment in dialysis patients for Brazilian Public Health System. Two alternatives were compared: a new drug, the Continuous Erythropoietin Receptor Activator, CERA, recently registred in Brazil, and another one, provided nowadays by the National Health System, Epo-rHu (Recombinant Human Eythropoietin). Methods: A Markov cohort of dialysis patients treated with CERA and Epo-rHu for four years was used to perform the base case analysis. The model outputs were QALYs and costs. The quality of life associated with each drug was measured by interviews applied to health care professionals. These interviews were previously submitted and approved by the local ethics committee. A sensitivity analysis was applied to the model to test it, varying the values of drugs dosage, costs, discount rate and effectiveness. Results: The average quality of life assigned by health care professionals to the patients treated with Epo-rHu, CERA and to kidney transplant receptors were respectively 6,3, 7,8 and 9,3. The model showed that Epo-rHu treatment was more cost-effective than CERA treatment. The cost-effectiveness ratio of Epo-rHu therapy was R$ 21.052,00. In addition, the cost per QALY gained of CERA therapy was R$ 72.974,00. Conclusion: Anemia treatment with CERA is associated with improvement in quality of life compared to Epo-rHu therapy. However, the new drug is not more cost-effective than the drug provided by the Brazilian Public Health System

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Sulfate ions found in seawater, groundwater and wastewater are aggressive agents that can result in severe concrete degradation. They react with cement hydration products and depending on the associated cations present (magnesium, calcium, potassium, sodium, ammonium), their concentrations and the conditions of the environment, this can result in the formation of ettringite, gypsum or thaumasite, decalcification of C-S-H, processes which may cause expansion, cracking and loss of mass and strength.When high sulfate resistance is required, national and international standards prescribe the use of cement with high concentrations of granulated blast furnace slag (GBFS). By substituting GBFS for cement, lower amounts of clinker are required. In addition, the pozzolanic activity of GBFS takes up the CH released by the hydration of silicates (C3S e C2S), which then is not available to react with sulfate ions to form gypsum, resulting in a more dense paste with lower penetrability. GBFS is one of the few mineral admixtures that can be added to white Portland cement (WPC), a material with widespread usage in civil construction, particularly in cases where concrete is used as a finished surface for architectural impact. The substitution of GBFS for WPC offers technical and environmental gains as well as economic advantages due to the higher cost of WPC. This study investigated the sulfate resistance of WPC with 0%, 50% and 70% GBFS as a substitution for cement. A mix with 50% GBFS that was chemically activated with Na2SO4 (4% b/w of binder) was also studied. The performance of the blended cements was monitored by exposing the prepared mortar specimens to a solution of Na2SO4 (5%) for 2 years according to ASTM C1012/04 and using TG/DTA, DRX and SEM/EDX analyses of the paste samples. For comparison, the same blends prepared with high early strength Portland cement (PC) were also used. The results showed the benefits of the use of GBFS in both types of cement, with higher concentrations of slag resulting in improved sulfate resistance. The use of chemical activation reduced expansion when compared with mixtures without activation. For long-term exposure, all WPC blends showed lower expansion than the corresponding blends with PC. Microstructural analysis identified ettringite and gypsum as the main degradation products of the sulfate attack. / Os íons sulfato, encontrados na água do mar, em águas subterrâneas e em águas residuárias são agentes agressivos que podem levar a uma severa degradação do concreto. Ao reagirem com os produtos de hidratação do cimento, dependendo do tipo de cátion a que estão associados (magnésio, cálcio, potássio, sódio, amônio, etc.), da concentração e das condições do meio, podem levar à formação de etringita secundária, sulfato de cálcio, taumasita, descalcificação do C-S-H, podendo ocorrer expansão, fissuração, perda de massa e de resistência. Quando se faz necessário assegurar uma elevada resistência ao sulfato, a normalização nacional e internacional, dentre outras recomendações, especifica o uso de cimento com elevados teores de escória de alto-forno. Além da redução da quantidade de clínquer ocasionada pela substituição do cimento por escória, a atividade pozolânica da mesma consome o CH liberado pela hidratação dos silicatos (C3S e C2S), que não fica disponível para reagir com os sulfatos e formar sulfato de cálcio, e promove a densificação da matriz, reduzindo a penetrabilidade do meio. A escória é também uma das poucas adições que podem ser incorporadas no cimento Portand branco (CPB), que vem se tornando uma nova tendência dentro do contexto da construção civil, quando se opta por concreto aparente em obras com forte apelo arquitetônico. Além das vantagens técnicas e ambientais, a substituição do cimento branco por escória possibilita a redução do custo bastante elevado do CPB. Neste estudo, investigou-se a resistência ao sulfato de sódio do CPB com teores de substituição de escória de alto-forno de 0%, 50% e 70%. Também foi investigada uma mistura com 50% de escória ativada quimicamente por Na2SO4 (em teor de 4% em massa do material aglomerante). O desempenho dos cimentos foi avaliado pela exposição de argamassas em solução de 5% de Na2SO4 por dois anos, de acordo com a ASTM C1012/04 e através de análise de DRX, TG/DTA e MEV/EDS em pastas. Para comparação foram investigadas as mesmas misturas compostas com cimento Portland de alta resistência inicial, CPV-ARI. Os resultados mostraram os benefícios do uso da escória em ambos os cimentos, sendo que o acréscimo do seu teor aumentou a resistência ao ataque por sulfatos. A ativação química reduziu a expansão comparativamente às misturas sem ativador. A longo prazo, todas as misturas com o CPB apresentaram menor expansão do que aquelas com CPV-ARI. A análise da microestrutura identificou a etringita e o sulfato de cálcio como os principais produtos de degradação por sulfato de sódio.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O tratamento para a Síndrome da Apnéia Obstrutiva do Sono (SAOS) mostra-se necessário devido às co-morbidades associadas ao quadro da síndrome. Fatores como problemas cardiovasculares, e aumento das chances de acidentes automobilísticos e de trabalho, além da diminuição da qualidade de vida, fazem dessa condição um sério problema a ser tratado. Dentre os tratamentos clínicos têm recebido especial atenção os aparelhos intra-orais por se tratar de um método simples e não invasivo. Os objetivos deste trabalho foram avaliar através dos índices polissinográficos as melhoras produzidas por um aparelho experimental e um aparelho placebo, e através de radiografias cefalométricas analisar fatores anatômicos relacionados com a severidade inicial do quadro e com as alterações do quadro da síndrome decorrentes do uso do aparelho experimental (Twin Block). Dezenove pacientes participaram deste estudo que foi prospectivo, com acompanhamento médio de 10,5 meses, cruzado, randomizado e duplo-cego. Foram feitas polissonografias iniciais e em uso dos aparelhos, após em média 6,47 (d.p.=2,01) meses do uso do Twin Block e 3,8 (d.p.=0,84) meses do uso do placebo e radiografias cefalométricas inicial e com o aparelho Twin Block em posição. Os dados pareados foram avaliados pelo teste de Wilcoxon, os não pareados pelos testes t de Student e Mann-Whitney e a comparação de proporções com o teste z, todos com 5% de significância (p<0.05). Os resultados mostraram tendências, embora não comprovadas estatisticamente, nas quais o grupo com SAOS moderada apresentou medidas de faringe menores e posição do osso hióide menos caudal quando comparados com o grupo com SAOS leve; que houve melhor resposta à terapia com o Twin-Block do que com o placebo, considerando-se o índice de apnéias mais hipopnéias por hora de sono (IAH), o índice de apnéias por hora de sono (IA), e a percentagem de sono REM; que a posição do osso hióide vertical diminuiu mais nos pacientes que melhoraram, tanto para o IAH quanto para o IA, que a maioria das medidas de faringe sofreram maior aumento nos pacientes que melhoraram em comparação com os que não melhoraram.Também foi possível estabelecer-se correlação positiva entre hipofaringe (HF) e os pacientes que melhoraram (avaliando pelo IAH), entre distância do osso hióide a terceira vértebra cervical (DHTV), faringe na altura do plano oclusal [NF(2)], largura do palato mole (PM) e os pacientes que melhoraram (avaliando pelo IA), além de entre NF (2) e os pacientes que não melhoraram (avaliando pelo IA). Conclui-se que o Twin Block mostrou-se clinicamente mais efetivo que o aparelho placebo no controle da SAOS, que algumas medições cefalométricas podem estar relacionadas com a severidade da síndrome medida inicialmente e que há variações de alterações anatômicas entre os pacientes que responderam e não responderam à terapia com aparelho intra-oral. / The treatment for the Obstructive Sleep Apnea Syndrome (OSAS) is necessary due to the co-morbidities associated with the syndrome. Factors such as cardiovascular problems, higher risk of automobile and work accidents, in addition to the decreased quality of life, makes the condition a serious problem to be treated. Among the treatments, clinicians have given special attention to the intra-oral appliances because it is simple and noninvasive. The objectives of this study were to evaluate by polysomnographyc indexes the improvements produced by both experimental and placebo units, and by cephalometric radiographs examine anatomical factors related with the initial severity of the syndrome and with the changes resulting from the use of the experimental appliance (Twin Block). Nineteen patients participated in this crossover, randomized, double-blind and prospective study, with monitoring average of 10.5 months. Polysomnographys were made in the initial use of the devices, after an average of 6.47 months (s.d. = 2.01) of Twin Block use and 3.8 months (s.d. = 0.84) of placebo use, along with cephalometric radiographs taken initially and with the Twin Block in position. Paired data were analyzed by the Wilcoxon test, non-paired by the Student t test and Mann-Whitney and compared proportions with the test z, all with 5% of significance (p <0.05). The results showed trends, though not statistically proven, that the group with moderate OSAS presented lower measures for the pharynx and higher hyoid bone position when compared to the group with mild OSAS; that the patients were more responsive to therapy with Twin-Block than with placebo, considering the index of more apnea hypopnea per hour of sleep (AHI), the index of sleep apnea per hour (AI), and the percentage of REM sleep; that the position of the vertical hyoid bone decreased more in patients who improved, both for the AHI and for the AI; that most pharyngeal measures suffered greater increase in patients who improved in comparison with those who did not get better. It could also be established a positive correlation between hypopharynx (HF) and patients who improved (by assessing AHI), distance between the hyoid bone and the third cervical vertebra (DHTV), pharynx in the occlusal plain [NF (2)], the width of the soft palate (PM) and patients that improved (by assessing AI), and between NF (2) and patients who had not improved (by assessing AI). It is concluded that the Twin Block was clinically more effective than the placebo unit in the control of OSAS, that some cephalometric measurements may be related to the severity of the syndrome measure initially and that there are variations in anatomic changes among patients who responded and not responded to therapy with intra-oral device.

O estudo teve como objetivo avaliar a razão de custo-efetividade, sob a perspectiva do Sistema Único de Saúde SUS, do tratamento da anemia de pacientes em Terapia Renal Substitutiva. Duas alternativas foram comparadas: um novo medicamento recentemente registrado no Brasil, o Ativador Contínuo de Receptor de Eritropoetina (Continuous Erythropoietin Receptor Activator), CERA, e outro, atualmente disponível no sistema de saúde brasileiro, a Eritropoetina Recombinante Humana - Epo-rHu. Métodos: Um modelo de Markov simulou o curso de uma coorte de pacientes em Terapia Renal Substitutiva tratados com CERA e Epo-rHu por quatro anos. A qualidade de vida associada ao uso dos medicamentos foi estimada de forma indireta, por meio de entrevista qualificada com os profissionais cuidadores, previamente submetida e aprovada pelo Comitê de Ética em Pesquisa local. Foi realizada análise de sensibilidade no modelo proposto através da variação dos parâmetros: dose dos medicamentos, custo das estratégias, taxa de desconto e efetividade utilizados para sua construção. Resultados: A média da qualidade de vida atribuída aos pacientes tratados foi 6,3 para a Epo-rHu, 7,8 para o CERA e 9,3 para os pacientes transplantados. O modelo demonstrou que a estratégia mais custo-efetiva é a terapêutica com a Epo-rHu, com um custo por QALY de R$ 21.052,00. O custo incremental por QALY ganho associado ao CERA foi de R$ 72.974,00. Conclusão: A utilização mensal do medicamento CERA está associada à maior qualidade de vida quando comparada a Epo-rHu. No entanto, a terapia com o novo medicamento não se mostrou mais custo-efetiva frente ao tratamento com Epo-rHu / This study sought to determine the cost-effectiveness of anemia treatment in dialysis patients for Brazilian Public Health System. Two alternatives were compared: a new drug, the Continuous Erythropoietin Receptor Activator, CERA, recently registred in Brazil, and another one, provided nowadays by the National Health System, Epo-rHu (Recombinant Human Eythropoietin). Methods: A Markov cohort of dialysis patients treated with CERA and Epo-rHu for four years was used to perform the base case analysis. The model outputs were QALYs and costs. The quality of life associated with each drug was measured by interviews applied to health care professionals. These interviews were previously submitted and approved by the local ethics committee. A sensitivity analysis was applied to the model to test it, varying the values of drugs dosage, costs, discount rate and effectiveness. Results: The average quality of life assigned by health care professionals to the patients treated with Epo-rHu, CERA and to kidney transplant receptors were respectively 6,3, 7,8 and 9,3. The model showed that Epo-rHu treatment was more cost-effective than CERA treatment. The cost-effectiveness ratio of Epo-rHu therapy was R$ 21.052,00. In addition, the cost per QALY gained of CERA therapy was R$ 72.974,00. Conclusion: Anemia treatment with CERA is associated with improvement in quality of life compared to Epo-rHu therapy. However, the new drug is not more cost-effective than the drug provided by the Brazilian Public Health System

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Os objetivos deste estudo foram avaliar o efeito do aparelho de avanço mandibular (Twin block - TB) no volume das vias aéreas superiores, por meio de tomografia computadorizada cone beam (CBCT); analisar, por meio da polissonografia, as mudanças no índice de apneia e hipopneia (IAH) e índice de apneia por hora de sono (IA), saturação de oxi-hemoglobina e eficiência do sono; e correlacionar o volume na CBCT e as polissonografias. Dezesseis pacientes portadores de apneia obstrutiva do sono, idade média de 47,06 anos, participaram deste estudo prospectivo, com acompanhamento médio de 7 meses. Foram feitas polissonografias iniciais (T1) e de acompanhamento (T2) com o TB em posição, e CBCT sem e com TB em posição. A segmentação e obtenção dos volumes das vias aéreas superiores foram realizadas e utilizados os testes t de Student pareado, de Wilcoxon e o índice de correlação de Spearman, com 5% de significância. Os resultados das polissonografias mostraram diferenças estatisticamente significativas entre T1 e T2 apenas para IAH (p<0,05). Houve aumento do volume da via aérea superior com TB quando comparado com o volume sem TB (p<0,05). Foi possível estabelecer-se correlação positiva entre volume da via aérea superior sem TB e IAH e IA em T1 (p<0,05), mas não houve correlação entre o volume da via aérea com TB e índices polissonográficos em T2. Pode-se concluir que, houve aumento de volume da via aérea superior com o TB e houve redução do IAH em T2 porém, sem correlação entre estes dados. / The aim of this study were to evaluate the effect of a mandibular advancement device (Twin Block TB) in the upper airway volume, with cone beam computed tomography (CBCT); to analyze, by polysomnographys, changes in apnea and hipopnea index per hour (AHI), apnea index per hour of sleep (AI), oxyhemoglobin saturation and sleep efficiency; and correlate changes in volume in CBCT and the results of polysomnography. Sixteen OSA patients, mean age of 47.07 years, participated in this prospective study, with follow up of 7 months. Initial polysomnography (T1) and follow up polysomnography (T2) were taken with TB in position, and CBCT with and without TB were taken. Upper airway segmentations and volumes were performed and were evaluated by the Student t test, the Wilcoxon test, and Spearman correlation, with 5% significance level. The results of the polysomnographs showed statistically significant differences between T1 and T2, only for AHI (p<0.05). There was an increased airway volume with TB in position when compared to volume without TB (p<0.05). A positive correlation between upper airway volume without TB and T1 AHI and AI was established (p<0.05), but there was no correlation between upper airway volume with TB and T2 polysomnography indexes. In conclusion, there was an increase in volume of the upper airway with the TB and reduction of AHI in T2 but without correlation with these data.