Made available in DSpace on 2015-04-14T13:35:32Z (GMT). No. of bitstreams: 1 438286.pdf: 4118090 bytes, checksum: 3f84072ed045d46706a18668827636e2 (MD5) Previous issue date: 2008-11-24 / Introduction: Previous studies showed a possible association between the T102C polymorphism of the serotonin 2A receptor (5-HT2A) and urinary incontinence in the elderly. Since serotonin is involved in the modulation of bladder sphincter control, such association is biologically plausible. Since the pharmacological treatment of urinary incontinence (UI) includes the use of serotonin reuptake inhibitors, complementary studies of this polymorphism are of scientific and clinical importance. Objectives: The aims of this study in older women living in a senior living community were: (1) to describe and compare the allelic and genotypic frequencies of the 102C polymorphism of the serotonin 2A receptor (5-HT2A) in incontinent and continent individuals; (2) to describe and compare the urodynamic parameters in incontinents carrying different genotypes/alleles; (3) to describe and compare the frequency of the urodynamic types of urinary incontinence (stress, urge and mixed) in incontinent individuals carrying different genotypes/alleles; and (4) to describe and compare the impact of UI on the quality of life in incontinent individuals carrying different genotypes/alleles. Methodology: A case-control study was conducted including 68 incontinent older women (submitted to urodynamic evaluation) and 162 continent older women (self-reporting). The criteria for exclusion were: use of diuretics, diabetes, non-Caucasian individuals, and severe mobility and neurological disturbances. The polymorphism was analyzed by the PCR-RFLP technique. The Ethics Committee approved the study, and all participants signed an informed consent form. Results: Incontinent older women showed a significantly greater frequency of the TT genotype (TT= 34.8%, CC= 19.3%, TC= 45.9%) compared to continent older women (TT=17%, CC=23.3%, TC=59.7%) and the general sample of the population (TT=21.5%, CC=16.6%, TC=61.9%) (p=0.001). The genetic frequencies of the three samples were in Hardy-Weinberg equilibrium. Urodynamic analysis showed a significant association between the TT genotype and greater detrusor pressure at maximal cystometric capacity, lower maximal cystometric capacity and reduced bladder compliance. The TT genotype also showed a higher prevalence of urge UI (44%) than did the other genotypes (p=0.01). Analyses of indicators of quality of life and UI demonstrated a greater negative impact in carriers of the C allele (CC+TC). Conclusion: Together, the results suggest that the T102C polymorphism of the 5-HT2A receptor gene has a physiological effect on the lower urinary tract of humans. This hypothesis needs to be confirmed by complementary studies. The effect of an imbalance in the quantity of this receptor, which occurs in the TT genotype, could be associated with a greater chance or urge UI in older women. / Introdu??o: estudos pr?vios mostraram poss?vel associa??o entre o polimorfismo T102C do receptor 2A da serotonina (5-HT2A) e incontin?ncia urin?ria em idosos. Como a serotonina est? envolvida na modula??o do controle vesical-esfincteriano, tal associa??o ? biologicamente plaus?vel. Uma vez que a terap?utica farmacol?gica da incontin?ncia urin?ria (IU) inclui o uso de inibidores da recapta??o da serotonina, estudos complementares deste polimorfismo s?o de relev?ncia cl?nico-cient?fica. Objetivos: em mulheres idosas que vivem na comunidade: (1) descrever e comparar as freq??ncias al?licas e genot?picas do polimorfismo 102C do receptor 2A da serotonina (5-HT2A) em idosas incontinentes e continentes; (2) descrever e comparar os par?metros urodin?micos nas idosas incontinentes portadoras de diferentes gen?tipos/alelos; (3) descrever e comparar a freq??ncia dos tipos de incontin?ncia urin?ria urodin?mica (de esfor?o, de incontin?ncia de urg?ncia e mista) nas idosas incontinentes portadoras de diferentes gen?tipos/alelos; (4) descrever e comparar o impacto da IU na qualidade de vida nas idosas incontinentes portadoras de diferentes gen?tipos/alelos. Metodologia: um estudo caso-controle foi conduzido, sendo 68 mulheres idosas incontinentes (submetidas ? avalia??o urodin?mica) e 162 mulheres continentes (auto-relato). Os crit?rios de exclus?o foram: uso de diur?ticos, diabetes, indiv?duos de outras etnias que n?o a caucasiana, dist?rbios de mobilidade e neurol?gicos graves. O polimorfismo foi analisado por t?cnica de biologia molecular PCR-RFLP. O Comit? de ?tica aprovou a pesquisa e todos os participantes assinaram Termo de Consentimento Livre e Esclarecido. Resultados: idosas incontinentes apresentaram freq??ncia do gen?tipo TT significativamente maior (TT= 34,8%, CC= 19,3%, TC= 45,9%) do que nas mulheres continentes (TT=17%, CC=23,3%, TC=59,7%) e na amostra geral da popula??o (TT=21,5%, CC=16,6%, TC=61,9%) (p=0,001). As freq??ncias gen?ticas das tr?s amostras estavam em equil?brio de Hardy-Weinberg. An?lise urodin?mica mostrou associa??o significativa entre o gen?tipo TT e maior press?o detrusora na capacidade cistom?trica m?xima, menor capacidade cistom?trica m?xima e complac?ncia vesical reduzida. O gen?tipo TT tamb?m apresentou maior preval?ncia de IU de urg?ncia (44%) do que os demais gen?tipos (p=0,01). O conjunto destes resultados sugeriu que o gen?tipo TT est? associado a altera??es de fatores fisiol?gicos, predisponentes a incontin?ncia urin?ria. Entretanto, an?lises de indicadores da qualidade de vida e a IU mostraram maior impacto negativo em portadoras do alelo C (CC+TC). Esta condi??o pode estar associada ? sugest?o de predisposi??o de portadoras do alelo C a dist?rbios emocionais. Conclus?o: o conjunto dos resultados sugere que o polimorfismo T102C do gene do receptor 5-HT2A tenha um poss?vel efeito fisiol?gico no trato urin?rio inferior (TUI) de seres humanos. Esta hip?tese precisa ser confirmada por estudos complementares. O efeito do desbalan?o na quantidade deste receptor, que ocorre no gen?tipo TT estaria associado ? maior chance de IU de urg?ncia na mulher idosa.

Made available in DSpace on 2015-04-14T13:35:32Z (GMT). No. of bitstreams: 1 438475.pdf: 1199552 bytes, checksum: 11115a2a9f4a42a185a775b4a566fe5b (MD5) Previous issue date: 2012-03-02 / ADULT (acro-dermato-ungueal-tooth) is a human genetic syndrome that manifests clinically by skin and embryonic appendages anomalies. This syndrome pathogenesis was first identified in 2001, but nowadays it is related to more than one mutation in p63 gene. Although described almost 20 years ago (1993) in Germany, this syndrome still have few reports and this is the first brazilian family. We report here the clinical aspects of five members of a family which clinical features corresponded to phenotypic ADULT manifestations. The clinical aspects included athelia/hypotelia, photosensitivity, dystophic nails, tooth anomalies and lacrimal duct obstruction. The adermatoglyphia, manifestation found in all affected members of this family, was not described before. The histologic examination demonstrated flattening of dermal papillae and electron microsopy showed disrupted collagen fibers. The genetic sequencing of blood ssample found a mutation in p63 gene, already known as R298Q. / A ADULT (acro-dermato-ungueal-lacrimal-tooth) ? uma s?ndrome gen?tica humana que se manifesta clinicamente por altera??es cut?neas e do desenvolvimento dos ap?ndices embrion?rios. Sua etiologia foi identificada inicialmente em 2001, mas atualmente sabe-se que est? relacionada a mais de uma muta??o no gene p63. Apesar de descrita pela primeira vez h? quase duas d?cadas (1993) na Alemanha, a s?ndrome ainda ? pouco reportada e esta ? a primeira fam?lia brasileira descrita. Neste trabalho descrevemos os aspectos cl?nicos de cinco indiv?duos de uma mesma fam?lia, os quais apresentavam manifesta??es fenot?picas compat?veis com a s?ndrome ADULT. Os achados cl?nicos incluem atelia/hipotelia, fotossensibilidade, distrofia ungueal, anormalidades dent?rias e obstru??o do ducto lacrimal. A adermatoglifia, manifesta??o cl?nica demonstrada em todos os acometidos desta fam?lia, n?o fora descrita anteriormente nos portadores da s?ndrome. A avalia??o histol?gica por microscopia ?ptica evidenciou retifica??o das papilas d?rmicas e a an?lise por microscopia eletr?nica mostrou altera??o nas fibras col?genas da derme. O sequenciamento gen?tico atrav?s de amostras de sangue perif?rico identificou uma muta??o no gene p63, previamente conhecida como R298Q.

Made available in DSpace on 2015-04-14T13:35:32Z (GMT). No. of bitstreams: 1 438586.pdf: 851444 bytes, checksum: 4403bec36e79f61219a752dde80a37db (MD5) Previous issue date: 2012-03-28 / Introduction: Spasticity is an incapacitating condition resultant from central nervous system injury such as the cerebral vascular accident, commonly known as stroke (STK). It is usually associated with hypertony and with a reduction in skeletal muscle force production. This condition may generate imbalance between antagonistic muscles at the ankle joint, which can be evaluated by torque ratios (TR). Purpose: to compare the dorsiflexor/plantarflexor (DF/PF) torque ratios between a post-stroke hemiparetic spastic group (STK) and a healthy control group (CON) and to evaluate STK group functionality. Methods: an isokinetic dynamometer was used to obtain maximal PF and DF torques at an angular velocity of 60?/s of hemiparetic spastic subjetcs (59.7 ? 13.74 years of age) and twelve healthy subjects (59.0 ? 13.64 years of age). TR were obtained through the division between the maximal DF and maximal PF torques. The STK group had their functionality evaluated through the Berg Balance Scale (BBS), the Barthel Index (BI), and the Timed Up and Go test (TUG). A Mann Whitney U test was used for the within group (spastic x non-spastic limbs) and for the between group (spastic x control) comparisons of the scale results and TR, whereas an independent T-test was used for the between groups comparison of the anthropometric variables (p ≤0.05). Results: The within STK group comparison revealed higher TR in the spastic side compared to the non-spastic contralateral side (0,81?0,25 and 0,43?0,41 respectively; p=0.01). The inter-group comparison revealed that the TR of the spastic side of the STK group was higher compared to the dominant side of the CON group (0,81?0,25 and 0,30? 0,10 respectively; p≤0.01). No differences were observed for the TR between the non-spastic side of the STK group and the dominant side of the CON group (0,43?0,41 and 0,30? 0,10 respectively; p=0.56). In addition, no changes in functionality were observed in the STK patients. Discussion: These results indicate that both limbs of the STK group show muscle imbalance, which might be explained by the smaller PF torque in both limbs, resulting on an elevated TR. The elevated TR found in the CON group is probably related to the fact that all subjects were sedentary. The STK group showed normal values for functionality, suggesting that the time post injury and the spasticity degree probably influence the results of these scales. Conclusion: Muscle imbalance is present in both lower limbs of post-STK patients, although the TR are more affected in the spastic side. / Introdu??o: a espasticidade ? uma condi??o incapacitante decorrente de les?es do sistema nervoso central como o acidente vascular cerebral (AVC), podendo estar associada com a hipertonia e diminui??o da for?a nos m?sculos. Tal condi??o pode gerar desequil?brios entre as musculaturas da articula??o do tornozelo, podendo estes serem avaliados pelas raz?es de torque. Objetivos: avaliar a funcionalidade e comparar as raz?es de torque (RT) dos flexores dorsais e plantares (FD/FP) entre indiv?duos com hemiparesia esp?stica decorrente de AVC isqu?mico e indiv?duos controle. M?todos: participaram do estudo 9 indiv?duos com hemiparesia esp?stica (59,7 ? 13,74 anos) e 12 indiv?duos controles (59,0 ? 13,64 anos). As escalas funcionais utilizadas foram: escala modificada de Ashworth, ?ndice de Barthel, escala de Berg e o teste Timed Up Go. Um dinam?metro isocin?tico foi utilizado para a obten??o do torque m?ximo em uma velocidade angular de 60?/s. Para a obten??o das raz?es, o torque m?ximo dos FD foi dividido pelo torque m?ximo dos FP. Foi utilizado o Teste U de Mann Withney para compara??o intra e entre grupos e Teste T independente para compara??o das medidas antropom?tricas entre os grupos (p ≤0,05). Resultados: na compara??o intra-indiv?duos, houve uma diferen?a significativa entre as m?dias das RT no grupo AVC (lado afetado 0,81?0,25 e n?o afetado 0,43?0,41) (p=0,01). Para a compara??o inter-grupos, o lado afetado 0,81?0,25 do grupo AVC foi significativamente diferente do lado dominante 0,30?0,10 dos indiv?duos controle (p≤0,01). N?o houve diferen?a significativa entre o lado n?o afetado do grupo AVC 0,43?0,41 e o lado dominante do grupo controle 0,30? 0,10 (P=0,56). N?o houve altera??es da funcionalidade dos indiv?duos do grupo AVC. Discuss?o: estes resultados indicam que tanto a perna acometida como a contralateral do grupo AVC apresentam desequil?brios musculares podendo ser explicado pelo menor torque produzido pelos FP, ocasionando uma RT aumentada. O grupo controle tamb?m apresentou RT alterada, possivelmente por serem sedent?rios. Quanto ? funcionalidade, o grupo AVC apresentou resultados de normalidade, sugerindo que o tempo de les?o e o grau de espasticidade podem influenciar nestas vari?veis. Conclus?o: os desequil?brios musculares est?o presentes em ambos os membros inferiores no grupo AVC, por?m as RT s?o mais alteradas no hemicorpo esp?stico.

Made available in DSpace on 2015-04-14T13:35:33Z (GMT). No. of bitstreams: 1 438529.pdf: 18860537 bytes, checksum: 9c31f74e1e908515a22fbc3a7838b2b1 (MD5) Previous issue date: 2012-05-29 / Gastrointestinal sarcomatoid tumors (GIST) are rare malignancies, corresponding to 1 - 3% of alli GI cancers. Nevertheless, GISts are the most common GI mesenchimal malignancies. GISTs are heterogeneous in presentation, clinical course and response to therapy. Their prognosis can be roughly estimated at diagnosis by assessing tumor size, mitotic index and the topography of the primary lesion. Despite the proved utility of these prognostic factors, their limitations are well documented, and a more refined set of biological markers are much needed. The abnormal activation of the cell survival signaling pathway provided by PI3K/Akt/PTEN proteins is a well known feature in advanced epithelial and hematological malignancies, impacting the aggressiveness of the disease as well as the resistance to different traditional therapies or biological agents. Besides their multi-effect in cell survival mechanisms, the PI3K/Akt/PTEN pathway is a powerful activator of angiogenesis via VEGF protein family transcription. The different isoforms of VEGF will in turn activate the VEGF receptor (VEGFR) at the surface of endothelial cells. Therefore, VEGFR is a reliable marker of angiogenesis in human tumors. We sought to evaluate the expression of VEGFR and Akt proteins in a series of GIST patients at diagnosis, treated in a single institution, in order to correlated the levei of expression of these proteins to clinical outcomes, such as overall survival (OS) and disease free survival (DFS). The levei of expression of these proteins was also correlated to the same outcomes in a subgroup of patients with advanced disease who received more than three months of therapy with Imatinib Mesylate (GleeveC?). Methods - 48 GIST patients were evaluated. Immunohystochemistry for VEGFR and Akt was performed by tissue microarray. Results - Akt hyperexpression was statistically correlated with a shorter DFS in the group of patients with metastatic disease (ali of them receiving GleeveC?). This correlation was not observed in early cases (defined as curable disease - stages I to III). We have not observed correlation between Akt expression and OS in any clinical stage. Lower VEGFR expression was associated to a significant better OS in ali stages (including patients receiving GleeveC?). Conversely, DFS was not affected by the levei of expression of VEGFR. CONCLUSIONS - Low VEGFR expression was related to a better prognosis in any clinicalstage of GIST, reflected in larger OS. The fact that this effect was observed in GleeveC? treated patients suggests that the betler response to the drug is much more related to the biology of the tumor than to the treatment itself. Akt showed also a promising role as a prognostic marker for disease free survival in advanced disease, indicating that GISTs with hyperexpressed Akt pathway behave more aggressively or may be less sensitive to GleeveC?. / Introdu??o: GISTs s?o raros, correspondendo de 1 a 3% de todas as neoplasias do trato gastrointestinal, entretanto, s?o as neoplasias mesenquimais mais comuns desta localiza??o. Possuem uma apresenta??o, comportamento cl?nico e resposta ? terapia heterog?neos. O progn?stico pode ser grosseiramente estimado pelo tamanho tumoral ao diagn?stico, topografia e ?ndice mit?tico. Apesar da utilidade destes fatores de progn?stico de simples obten??o, a heterogeneidade da doen?a exige que marcadores mais espec?ficos sejam aplicados para uma avalia??o individual n?o apenas progn?stica ao diagn?stico, mas tamb?m preditiva ao tratamento com novas drogas dispon?veis. A ativa??o aberrante das prote?nas da via de sinaliza??o PI3K/Akt/PTEN ? um fen?meno relativamente comum em neoplasias epiteliais e hematol?gicas, com repercuss?o tanto na agressividade da neoplasia como na sua resist?ncia adquirida a tratamentos anti-neopl?sicos. Al?m da sinaliza??o para mecanismos de sobreviv?ncia, a via PI3K/Akt/PTEN est? envolvida na ativa??o de angiog?nese por meio da transcri??o de VEGF e secundariamente do seu receptor endotelial, VEGFR. O objetivo deste trabalho foi avaliar a express?o das prote?nas VEGFR, Akt e PTEN em pacientes com GIST ao diagn?stico, na tentativa de correlacionar a mesma com desfechos cl?nicos. Paralelamente acompanhamos o efeito do n?vel de express?o destas prote?nas em um subgrupo de pacientes com doen?a avan?ada que recebeu a medica??o Mesilato de Imatinib (GliveC?). M?todo: Avalia??o imunoistoqu?mica com m?todo TMA de 48 esp?cimes de GISTs utilizando os anticorpos monoclonais para Akt e VEGFR. A hiperexpress?o de Akt foi verificada em 33,3% e VEGFR em 75% das amostras. Na an?lise do grupo geral de pacientes, a hiper-express?o de Akt correlacionou-se com uma SLP (sobrevida livre de progress?o) estatisticamente encurtada (p>O.05) exclusivamente para casos com doen?a metast?tica. Esta correla??o n?o foi observada em casos com doen?a n?o inicial (est?gios I a III). No entanto, mesmo em doen?a avan?ada, a hiper-express?o de Akt n?o teve impacto na sobrevida global. Como o grupo de pacientes com doen?a avan?ada foi o grupo que recebeu GliveC?, a correla??o com SLP e hiper-express?o de Akt se manteve. A aus?ncia de express?o de VEGFR se associou com melhor sobrevida global (SG) em todos os est?gios (incluindo os pacientes que receberam GliveC?), mas n?o com sobrevida livre de doen?a (SLD). Este dado sugere que os pacientes com baixa express?o de VEGFR poderiam ter uma doen?a de biologia mais indolente, mesmo que a taxa de recorr?ncia seja id?ntica ao grupo com VEGFR hiper-expresso. Conclus?es: os resultados deste estudo sugerem que a baixa express?o de VEGFR ? um fator de progn?stico favor?vel em pacientes com doen?a em qualquer est?gio. A hiperexpress?o de Akt associa-se a uma menor SLP apenas em casos avan?ados, sugerindo que a ativa??o desta via poderia ser um mecanismo adquirido em etapas finais da doen?a que conferem resist?ncia ao GliveC?.

Made available in DSpace on 2015-04-14T13:35:33Z (GMT). No. of bitstreams: 1 439097.pdf: 7980733 bytes, checksum: af8f6a7fa6a599651957ad5f12054783 (MD5) Previous issue date: 2012-05-16 / Tuberculosis continues to be one of the deadliest diseases in the world. The emergence of drug-resistant strains of Mycobacterium tuberculosis, the unbearable side effects of the available drugs and the frequent patient non-compliance in completing the therapy have increased the need for development of new effective agents. We have previously demonstrated a potent in vitro inhibitory activity for two pentacyano(isoniazid)ferrate(II) compounds, namely IQG-607 and IQG-639 against the M. tuberculosis enoyl-ACP reductase enzyme. Importantly, IQG-607 and IQG-639 were active against cultures of M. tuberculosis H37Rv and two isoniazid-resistant clinical isolates in vitro. In the present study, the activity of these compounds was evaluated by using an in vivo murine model of tuberculosis. Swiss mice were infected with M. tuberculosis H37Rv strain, and IQG-607 and IQG-639 (250 mg/kg) were administered during 28 or 56 days. As well, a dose-response study was performed with IQG-607 (at 5, 10, 25, 50, 100, 200 and 250 mg/kg). The activity of test compounds was compared with that of the positive control drug isoniazid at 25 mg/kg. After 28 or 56 days of treatment, either IQG-607 or isoniazid significantly reduced M. tuberculosis-induced splenomegaly, and also significantly diminished the colony-forming units in both spleens and lungs. IQG-607 or isoniazid ameliorated the lung macroscopic aspect, reducing the lung lesions to a similar extent. However, IQG-639 was not capable of significantly modifying any evaluated parameter. IQG-607 did not display a classical dose-dependent profile in our murine model of tuberculosis, and 10 mg/kg was the lowest dose able to show significant activity, which was similar to the inhibition observed for higher doses. In addition, experiments using early and late controls of infection revealed a bactericidal activity for IQG-607 in our model. The promising activity of IQG-607 in M. tuberculosis-infected mice suggests that this compound might represent a good candidate for clinical development as a new antimycobacterial agent. / A tuberculose ? uma das principais causas de morte no mundo. O surgimento e dissemina??o de cepas de Mycobacterium tuberculosis resistentes a f?rmacos, os efeitos indesej?veis dos f?rmacos atualmente dispon?veis e a falta de ades?o dos pacientes ao tratamento t?m aumentado a necessidade do desenvolvimento de novos agentes anti-tuberculose. Estudos pr?vios revelaram uma potente atividade inibit?ria in vitro de dois compostos pentaciano(isoniazida)ferrato(II), denominados IQG-607 e IQG- 639, frente a enzima enoil-ACP redutase de M. tuberculosis. Ainda, o IQG- 607 e o IQG-639 foram ativos quando testados em culturas de M. tuberculosis H37Rv e sobre dois isolados cl?nicos resistentes ? isoniazida in vitro. Neste trabalho, a atividade destes dois compostos foi avaliada in vivo, utilizando um modelo murino de infec??o por M. tuberculosis. Camundongos su??os foram infectados com a cepa de M. tuberculosis H37Rv e o IQG-607 ou o IQG-639 (250 mg/kg) foram administrados aos animais durante 28 ou 56 dias. Adicionalmente, um estudo de dose-resposta foi realizado com o composto IQG-607, empregando as doses de 5, 10, 25, 50, 100, 200 e 250 mg/kg. As atividades dos compostos-teste foram comparadas ? atividade da isoniazida (25 mg/kg), o controle positivo do tratamento. Ap?s 28 ou 56 dias de tratamento, tanto o IQG-607 quanto a isoniazida reduziram significativamente a esplenomegalia induzida pela infec??o e, tamb?m, diminu?ram as unidades formadoras de col?nia, tanto nos pulm?es quanto nos ba?os dos animais tratados. O IQG-607 e a isoniazida melhoraram o aspecto macrosc?pico dos pulm?es, reduzindo as les?es pulmonares de maneira semelhante. Por sua vez, o IQG-639 n?o foi capaz de modificar significativamente nenhum par?metro avaliado neste estudo. O IQG-607 n?o apresentou um perfil cl?ssico de dose depend?ncia, sendo observada atividade inibit?ria significativa similar, entre as doses de 10 mg/kg e 250 mg/kg. Al?m disto, um experimento utilizando um controle pr?-tratamento demonstrou que o IQG-607 possui atividade bactericida no nosso modelo. A atividade satisfat?ria do IQG-607 em camundongos infectados com M. tuberculosis sugere que este composto pode ser um candidato promissor no desenvolvimento cl?nico de um novo agente antimicobacteriano.

Made available in DSpace on 2015-04-14T13:35:33Z (GMT). No. of bitstreams: 1 439149.pdf: 1490829 bytes, checksum: bd616615ee5265db0a960d6f77c8581d (MD5) Previous issue date: 2012-05-29 / Glioblastoma multiforme (GMB) is the most malignant and common type of all astrocytic tumours. Current standard treatment for GBM patients involves maximum surgical resection of the tumour, followed by radiotherapy and chemotherapy, usually containing the alkylating agent Temozolomide (TMZ). Despite this aggressive combination therapy, the survival rate of GBM patients is still low. This work consisted in investigating the cytotoxic effects of Akt-inhibition by MK-2206 with irradiation (RT) and TMZ on in vitro human malignant glioma. Seven malignant glioma cell lines were cultured and tested for clonogenic survival, invasion inhibition, tumour spheroid growth and proliferation. The Akt-inhibitor MK-2206 and TMZ were added at different time treatments and in varying doses. Cultures were irradiated with single dose and with fractionated γ-irradiation. Cellular modulation of Akt and p-Akt were assessed by Western blot analysis. MK-2206 reduced the levels of phospho- Akt key protein in the PI3Kinase-Akt pathway, decreased cell survival, and inhibited invasion, proliferation and cell growth. The combination of MK-2206 and RT lead to enhanced inhibition of cell proliferation and invasion, which is not observed with RT alone. The radioenhancing effect of MK-2206 was most striking in inhibition of spheroid volume growth by fractionated RT; the radiosensitizing effect of MK-2206 was stronger than that of TMZ. MK-2206 enhanced the in vitro effects of RT and TMZ in terms of decreased cell survival, invasion, proliferation and growth in malignant glioma. Effects could be ascribed to inhibition of PI3K-Akt pathway / O Glioblastoma multiforme (GBM) ? o tipo mais maligno e mais comum de todos tumores astroc?ticos. O tratamento atual para pacientes de GBM envolve m?xima remo??o cir?rgica, seguida de radio e quimioterapia, normalmente com o agente alquilante Temozolamida (TMZ). Apesar da agressividade da terapia combinada, o tempo de sobreviv?ncia dos pacientes ainda ? baixo. Este trabalho procurou investigar os efeitos citot?xicos do inibidor de Akt MK-2206 em combina??o com irradia??o (RT) e TMZ em um painel de c?lulas de gliomas humanos. Sete linhagens de glioma foram cultivadas e testadas em ensaio de sobreviv?ncia clonog?nica, inibi??o de invas?o, e modelos de prolifera??o e crescimento de volume em esfer?ides. O inibidor MK-2206 e TMZ foram adicionados em diferentes tempos de tratamento e diferentes doses. As culturas foram irradiadas com doses ?nicas ou em terapias fracionadas com irradia??o γ. A modula??o celular de Akt e fosfo-Akt foi checada via Western Blot. O composto MK-2206 reduziu a fosforila??o da prote?na chave Akt na via PI3K, diminuindo a sobreviv?ncia celular e inibindo invas?o, prolifera??o e crescimento celular. A combina??o de MK-2206 com RT levou a uma maior inibi??o de invas?o e prolifera??o, o que n?o ? observado somente com a RT. O efeito radiosens?vel de MK-2206 foi ainda maior na inibi??o do volume dos esfer?ides em terapia combinada com RT fracionada, sendo ainda maior do que o efeito combinado com TMZ. MK-2206 aumentou os efeitos in vitro de RT e TMZ em termos de redu??o de sobreviv?ncia celular, invas?o, prolifera??o e crescimento celular em gliomas malignos. Os efeitos podem ser atribu?dos a inibi??o da via PI3KAkt

Made available in DSpace on 2015-04-14T13:35:33Z (GMT). No. of bitstreams: 1 439242.pdf: 1575567 bytes, checksum: 619d0569503f83efdbc96d24f37eb2fb (MD5) Previous issue date: 2012-05-26 / Memories are not stored in its final form immediately after the acquisition. They undergo a long stabilization process known as consolidation. Consolidated memories can become labile again after the retrieval and susceptible to the action of amnesic agents. Thus, to persist must go through the re-stabilization process called reconsolidation. Several evidences indicate that the hippocampus plays an important role in both consolidation and reconsolidation process of different memories. In this way, we decided investigate the participation of NMDA and GABA receptors of dorsal hippocampus CA1 region on the retrieval and reconsolidation of spatial memory. We used the Morris water maze task (MWM) to demonstrate that infusion of AP5 (5 μg/μl), the selective antagonist of the NMDA receptor, into the dorsal hippocampus CA1 region of rats is able to block temporarily the retrieval of spatial memory. However, when we administered different doses and different times after the reactivation session in the absence of reinforcement is not observed any effect on spatial memory reconsolidation. While agonists of the glycine site of NMDA receptors, D-SER (10 μg/μl), improves the consolidation and the reconsolidation of spatial memory. Furthermore, we found that infusion of the agonist of GABA, muscimol (0.1 μg/μl), temporarily prevents the memory retrieval of MWM. However, when the animals received infusion of muscimol before the reactivation session and the protein synthesis inhibitor, anisomycin (160 μg/μl), immediately after this session, spatial memory remains inhibited. Thus, we have demonstrated that inhibition of NMDA receptors prevents the retrieval but not the reconsolidation of the spatial memory and the NMDA agonist is capable of improving consolidation and reconsolidation of memory, while the GABA activation temporarily prevents retrieval and the impairment of memory is maintained through inhibition of protein synthesis. / As mem?rias n?o s?o armazenadas em sua forma definitiva. Logo ap?s a aquisi??o, elas passam por um longo processo de estabiliza??o conhecido como consolida??o. Mem?rias j? consolidadas podem se tornar novamente l?beis logo ap?s a evoca??o e suscet?veis a a??o de agentes amn?sicos. Dessa forma, para persistirem devem passar pelo processo de reestabiliza??o denominado, reconsolida??o. In?meras evid?ncias indicam que o hipocampo tem um papel importante tanto na consolida??o quanto na reconsolida??o de diferentes mem?rias. Assim, decidimos investigar a participa??o dos receptores NMDA e GABA da regi?o CA1 do hipocampo dorsal na evoca??o e reconsolida??o da mem?ria espacial. Utilizando a tarefa de labirinto aqu?tico de Morris (LAM) em ratos, demonstramos que a infus?o na regi?o CA1 do hipocampo do antagonista seletivo do receptor NMDA, AP5 (5 μg/μl) ? capaz de bloquear temporariamente a evoca??o da mem?ria espacial. Por?m quando administrado diferentes doses e diferentes tempos, ap?s a sess?o de reativa??o na aus?ncia de refor?o n?o se observa efeito algum sobre a reconsolida??o da mem?ria espacial. Enquanto que o agonista do s?tio da glicina no receptor NMDA, D-SER (10 μg/μl), melhora n?o s? a consolida??o, mas tamb?m a reconsolida??o da mem?ria espacial. Al?m disso, a infus?o do agonista do receptor GABA, muscimol (0,1 μg/μl), impede temporariamente a evoca??o da mem?ria do LAM. Por?m, quando os animais recebem a infus?o de muscimol antes da sess?o de reativa??o e do inibidor da s?ntese de prote?nas, anisomicina (160 μg/μl), imediatamente ap?s esta sess?o, a mem?ria espacial permanece inibida. Assim, demonstramos que a inibi??o dos receptores NMDA impede a evoca??o mas n?o a reconsolida??o da mem?ria espacial e seu agonista ? capaz de melhorar a consolida??o e a reconsolida??o dessa mem?ria, enquanto a ativa??o do receptor GABA impede temporariamente a evoca??o e o preju?zo na mem?ria ? mantido com a inibi??o da s?ntese de prote?nas.

Made available in DSpace on 2015-04-14T13:35:34Z (GMT). No. of bitstreams: 1 439241.pdf: 787581 bytes, checksum: 694a1c96909ef78e31343f07b4121e83 (MD5) Previous issue date: 2012-03-29 / Introduction: Few studies have evaluated the chronic kidney disease (CKD) risk factors for in black populations. This study aimed to determine the prevalence of renal disease (RD), risk factors for CKD and compare the estimated glomerular filtration rate (eGFR) by three methods in a group of black workers in the health field. Methods: We evaluated in a cross sectional observational study 313 individuals from the black staff of a university hospital, workers from different health professions. Was defined RD bearing individuals with GFR below 90ml/minute or protein/creatinine index in urine sample up to or greater than 0.3. We estimated the glomerular filtration using three equations: Crockoft-Gault, MDRD and CKD EPI. For data collection was used a structured questionnaire containing demographic data, risk factors for CKD, serum creatinine, blood pressure (BP) and GFR. Results: In the 313 participants 80.8% were female. The risk factors were present in this proportion: 26.8% with a diagnosis of hypertension (HA), 8.3% diabetes mellitus (DM), 79.9% with a family history (FH) of hypertension, 49.2% FH and DM, 6.45% FH for dyslipidemia, and 19.8% FH with CKD, BMI with or greater than 30 kg /m?. The prevalence of RD ranged between 12.5% (CKD-EPI) and 18.8% (MDRD). The higher prevalence of RD was observed at the stage of eGFR between 60 and 89 mL/minute. In individuals with RD, there was difference between the eGFR for the CG or MDRD and CKDEPI equations (P<0.001) difference among the three formulas for the total group analysis (P <0.001). Conclusion: RD was present in at least 12.2% of the studied group. The prevalence of RD was lower when using the CKD-EPI equation, compared to the CG and MDRD equations. It was demonstrated statistical significance (P <0.05) for the highest average age of patients with RD compared the diagnosis by eGFR by the three equations used with other individuals in the study. Among the associations of risk in the total group the most frequent were HA and FH with HA. Among the variables examined, only the mean of systolic BP was different and higher, when comparing individuals with risk factor for RD and those without this risk factor / Introdu??o: Poucos estudos t?m avaliado os fatores de risco da Doen?a Renal Cr?nica (DRC) em popula??es negras. Esta investiga??o teve como objetivo conhecer a preval?ncia da doen?a renal (DR), de fatores de risco para DRC e comparar a filtra??o glomerular estimada (FGE) por tr?s m?todos em um grupo de trabalhadores negros na ?rea da sa?de. M?todos: Em um estudo observacional transversal, foram avaliados 313 indiv?duos negros do quadro funcional de um hospital universit?rio, trabalhadores de diferentes profiss?es da sa?de. Definiu-se portadores de DR os indiv?duos com a FGE abaixo de 90ml/minuto ou com ?ndice proteina/creatinina em amostra de urina igual ou maior que 0,3. Estimou-se a filtra??o glomerular utilizando-se tr?s equa??es: Crockoft-Gault, MDRD e CKD EPI. Para a coleta dos dados, foi estruturado um question?rio, contendo dados demogr?ficos, fatores de risco para DRC, creatinina s?rica, press?o arterial (PA) e FGE. Resultados: Dos 313 participantes 80,8% foram do sexo feminino. Os fatores de risco estiveram presentes nesta propor??o: 26,8% tinham diagnostico de hipertens?o arterial (HA), 8,3% de diabetes mellitus (DM), 79,9% de hist?ria familiar (HF) de HA, 49,2% de HF de DM, 6,45% HF de dislipidemia, 19,8% HF de DRC, IMC igual ou maior que 30Kg/m?. A preval?ncia de DR variou entre 12,5% (CKD-EPI) e 18,8% (MDRD). A maior preval?ncia de DR foi evidenciada no est?gio de FGE entre 60 e 89 mL/minuto. Nos indiv?duos com DR, houve diferen?a para a FGE entre as f?rmulas CG ou MDRD e CKD-EPI (P<0,001) havendo diferen?a entre as tr?s f?rmulas para o grupo total analisado (P<0,001). Conclus?o: DR esteve presente em no m?nimo 12,2% do grupo estudado. A preval?ncia da DR foi menor quando utilizamos a equa??o CKD-EPI, comparada ?s equa??es CG e MDRD. Foi evidenciada signific?ncia estat?stica (para P<0,05) para a maior m?dia de idade dos indiv?duos com DR, quando comparado o diagn?stico atrav?s da FGE pelas tr?s equa??es utilizadas com os demais indiv?duos em estudo. Entre as associa??es de risco no grupo total as mais freq?entes foram HAS e HF de HAS. Entre as vari?veis examinadas, apenas a m?dia de PA sist?lica foi diferente e maior, quando comparamos os indiv?duos com fator de risco para DR e aqueles sem este fator de risco.

Made available in DSpace on 2015-04-14T13:35:34Z (GMT). No. of bitstreams: 1 439491.pdf: 1474767 bytes, checksum: 10387186b0cf97cad4d66c8947bfeb70 (MD5) Previous issue date: 2012-03-28 / Objective: To evaluate the evidence on the clinical efficacy of platelet-rich plasma (PRP) for aesthetic treatment of the skin. Material and Methods: a narrative review was conducted initially on skin aging, options for cosmetic treatment of the aged skin, growth factors from platelets and the use of platelet-rich plasma to tissue regeneration in the experimental setting. This was followed by a comprehensive systematic review of medical literature to evaluate the clinical efficacy of PRP in the aesthetic treatment of the skin, which aimed to answer the research question. The included databases were MEDLINE, Embase and Cochrane CENTRAL. Human clinical trials evaluating the effect of PRP as a dermal stimulator in the aesthetic treatment of the skin were included. Literature search, articles selection and data extraction were performed by two independent reviewers. Results: Only seven out of 2132 identified articles met the inclusion criteria of the systematic review. Of these, 5 evaluated the effect of application of PRP for facial skin and acne scars treatment, skin renewal, prominent nasolabial folds or as ajduvant for facial plastic surgery. Two other studies have evaluated histological changes resulting from the application of PRP in the skin of the arms. All evaluated studies have demonstrated beneficial result related to PRP application. However the studies had major limitations such as small sample size, non-uniform outcome evaluation criteria and lack of a control group. Conclusion: Current scientific evidence identified through systematic review suggests that PRP is a promising method for the cosmetic treatment of the skin. However, larger clinical studies are needed with better outcomes evaluation criteria to define the role of PRP in clinical practice. / Objetivo: Avaliar o conjunto das evid?ncias sobre a efic?cia cl?nica do plasma rico em plaquetas (PRP) para o tratamento dermatol?gico est?tico. Material e M?todos: Na fundamenta??o da presente tese, foi realizada uma revis?o narrativa sobre envelhecimento cut?neo, op??es para o tratamento dermatol?gico est?tico das altera??es relacionadas ao envelhecimento cut?neo, fatores de crescimento teciduais encontrados nas plaquetas e uso do plasma rico em plaquetas para regenera??o tecidual no contexto experimental. Para responder ? quest?o de pesquisa, foi conduzida uma abrangente revis?o sistem?tica da literatura m?dica visando avaliar a efic?cia cl?nica do PRP para o tratamento dermatol?gico est?tico, compreendendo as bases de dados MEDLINE, Cochrane CENTRAL e Embase. Estudos cl?nicos em humanos avaliando o efeito do PRP como estimulador d?rmico no tratamento est?tico da pele foram inclu?dos. A busca da literatura, a sele??o de artigos e a extra??o de dados foram realizadas por dois revisores independentes. Resultados: Somente 7 de 2.132 artigos identificados encontraram os crit?rios de inclus?o da revis?o sistem?tica. Desses, 5 avaliaram o efeito da aplica??o do PRP na pele da face para tratamento de cicatrizes de acne, revitaliza??o da pele, sulcos nasolabiais proeminentes ou como adjuvante ? cirurgia pl?stica facial. Outros 2 estudos avaliaram altera??es histol?gicas decorrentes da aplica??o do PRP na pele dos bra?os. Todos estudos avaliados demonstraram resultados ben?ficos relacionados ? aplica??o do PRP. Entretanto os estudos apresentam limita??es relevantes, como pequeno tamanho amostral, crit?rios n?o uniformes na aferi??o dos desfechos e aus?ncia de grupo controle em sua maioria. Conclus?o: O atual conjunto de evid?ncia cient?fica identificado atrav?s de revis?o sistem?tica sugere que o PRP seja um m?todo promissor para o tratamento cosm?tico da pele. Entretanto, ainda s?o necess?rios estudos cl?nicos de maior porte e com melhores crit?rios de aferi??o de desfechos para definir o papel do PRP na pr?tica cl?nica.

Made available in DSpace on 2015-04-14T13:35:34Z (GMT). No. of bitstreams: 1 439669.pdf: 2432426 bytes, checksum: 926062560772ee0fef9ad537b63bff41 (MD5) Previous issue date: 2012-06-22 / Introduction: Peritoneal dialysis ultrafiltration failure is a functional abnormality associated with increased risk of death and technique failure. Daily ultrafiltration volume early on therapy may predict patient and technique survival. Objective: to determine the relationship between to presence of risk factors, daily ultrafiltration volume, patient and technique survival. Patients and Method: Data were extracted from the observational, multicenter, BRAZPD cohort study. From a population of 2419 suitable patients, 977 incident patients were selected. At the three-month therapy interval, demographic, clinical and technical variables were appraised and daily ultrafiltration volume was analyzed by quartiles (1st: &#8804; 700 ml; 2nd: > 700 ml up to &#8804; 1100 ml; 3rd: > 1100 ml up to < 1600 ml; 4th: &#8805; 1600 ml), as were its changes at the sixth and twelfth follow-up months. Two outcomes were considered : death and technique failure, which were analyzed till the 30th therapy month. Comparison between groups, correlations, patient and technique uni and multivariate survival analyses, using Kaplan-Meier technique and Cox regression analysis, were performed. Results: Age (HR=1.038; 95% CI: 1.027-1.049; P<0.01), diabetes (HR=1.416; 95% CI: 1.043-1.922; P=0.03) and number of co-morbidities (HR=2.687; 95% CI: 1.336-5.407; P<0,01) were directly associated with increased patient mortality. The 4th ultrafiltration quartile related with higher patient and technique survival (P=0.02 and P=0.10, respectively); peritonitis had a strong negative effect upon therapy maintenance (HR=3.459; 95% CI: 2.218-5.394; P<0.01). Conclusion: young, non-diabetic patients had increased chance for survival. High ultrafiltration volumes promoted patient and technique survival. Peritonitis significantly reduced the likelihood of technical success. / Introdu??o: A falha de ultrafiltra??o na di?lise peritoneal ? uma anormalidade funcional associada a risco aumentado para morte e para falha t?cnica. O volume di?rio de ultrafiltra??o, aos tr?s meses de terapia, pode ser fator de risco e preditor precoce para sobrevida de paciente e t?cnica. Objetivo: determinar a rela??o entre a presen?a de fatores de risco, volume di?rio ultrafiltrado e sobrevida de paciente e terapia. Pacientes e M?todo: estudo de coorte baseado em dados do estudo BRAZPD, multic?ntrico, observacional. Foram inclu?dos 977 pacientes incidentes, dentre 2419 eleg?veis. Aos tr?s meses de terapia analisaram-se vari?veis demogr?ficas, cl?nicas e t?cnicas. O volume di?rio de ultrafiltra??o foi analisado por quartis, (1? quartil: &#8804; 700 ml; 2? quartil: > 700 ml e &#8804; 1100 ml; 3? quartil: > 1100 ml e < 1600 ml; 4? quartil: &#8805; 1600 ml, assim como sua varia??o aos seis e doze meses de seguimento. Dois desfechos foram contemplados: morte e falha t?cnica, analisados at? 30 meses de terapia. Compara??es entre grupos, correla??es bem como an?lise univariada de sobrevida - de paciente e t?cnica - foi feita pela t?cnica de Kaplan-Meier e multivariada por regress?o de Cox. Resultados: idade (HR=1,038; IC 95%: 1,027-1,049; P<0,001), Diabetes Mellitus (HR=1,416; IC 95%: 1,043-1,922; P<0,026) e n?mero de comorbidades (HR=2,687; IC 95% -1,336-5,407; P<0,01) foram diretamente associados com mortalidade aumentada do paciente. O quarto quartil de ultrafiltra??o associou-se a maior sobrevida do paciente e da t?cnica (P=0,02 e P=0,10, respectivamente); a ocorr?ncia de peritonite teve impacto negativo para manuten??o da terapia (HR=3,459; IC 95%: 2,218-5,394; P<0,01). Conclus?o: pacientes jovens, sem diabetes tiveram maior chance de sobrevida. Ter alto volume de ultrafiltra??o foi favor?vel ? sobrevida de pacientes e da t?cnica. A ocorr?ncia de peritonite reduziu significativamente a chance de sucesso da t?cnica.