Glicoproteína-P, resistência a múltiplas drogas (MDR) e relação estrutura-atividade de moduladores

Multidrug resistance, MDR is a major obstacle for cancer chemotherapy. MDR can be reversed by drugs that vary in their chemical structure and main biological activity. Many efforts have been done to overcome MDR based on studies of structure-activity relationships and in this review we summarize some aspects of MDR mediated by P-glycoprotein (P-gp), as the most experimentally and clinically tested form of drug resistance. The most significant MDR mechanisms revealed until now are shortly discussed. Physicochemical and structural properties of MDR modulators, measures of the MDR reversal, and QSAR studies are included.

Fenótipo de subfertilidade, polimorfismos cromossômicos e falhas de concepção

OBJETIVO: avaliar a prevalência de alterações citogenéticas e polimorfismos cromossômicos em casais com fenótipo de subfertilidade em uma população brasileira. MÉTODOS: foram avaliados 1.236 cariótipos de casais com fenótipo de subfertilidade de dois diferentes centros (público e privado). Esses pacientes foram classificados em dois subgrupos: um com duas ou mais perdas gestacionais, consecutivas ou não, e outro com, ao menos, uma perda gestacional ou ausência de concepção. Os cariótipos foram obtidos com bandamento convencional G e C. As anomalias citogenéticas foram agrupadas e as frequências calculadas segundo a classificação dos pacientes. Quando aplicável, os testes estatísticos de Fisher e análise de Odds Ratio foram empregados. RESULTADOS: aproximadamente 25% de todos os casos apresentaram cariótipo anormal, incluindo alterações numéricas e estruturais e também variantes polimórficas. Nos dois diferentes centros, a prevalência de variantes polimórficas diferiu, sendo de 8,9 e 3,8%, respectivamente. CONCLUSÃO: não houve diferença significativa entre a predominância de variantes polimórficas e outras alterações nos indivíduos com ou sem história de perda reprodutiva. Os resultados do presente estudo reforçam a necessidade da adequada divulgação da informação citogenética completa nos resultados de cariótipo, com atenção específica em relação às variantes polimórficas.

Phenotypic and genotypic variant of MDR-Mycobacterium tuberculosis multiple isolates in the same tuberculosis episode, Rio de Janeiro, Brazil

Assuming that the IS6110-restriction fragment length polymorphism (RFLP) changes at a constant rate of 3.2 years, this methodology was applied to demonstrate, for the first time, variant patterns of Mycobacterium tuberculosis (MTB) in multiple isolates obtained at short time intervals from sputum and blood of an HIV+ patient with multiple admissions to the Emergency Room and to the multidrug-resistant tuberculosis (MDR-TB) Reference Center of a secondary-care hospital in Rio de Janeiro, Brazil. In sputum, the IS6110-RFLP appeared in isolates with two variant patterns with 10 and 13 IS6110 copies. However, blood presented only the pattern corresponding to 10 copies, suggesting compartmentalization. With regard to the exact match of 10 of 13 bands, this may be a subpopulation with the same clonal origin and this may be related to the IS6110 transposition. A susceptibility test demonstrated an MDR profile (INH R, RIF R, SM R, and EMB R), with the sputum isolate also exhibiting EMB S (R = resistant; S = sensitive). A gene mutation confirmed resistance only to streptomycin. There was agreement between the results of the phenotypic test and the clinical response to MDR-TB treatment, suggesting serious implications with regard to treatment administration based exclusively on molecular methods, and calling attention to the fact that more effective control strategies against the emergence of MDR strains must be implemented by the TB control program to prevent transmission of MDR-MTB strains at health facilities in areas highly endemic for TB.

Caracterización del gen MDR-1 en pacientes con leucemia linfoblástica aguda

Tesis (Doctorado en Ciencias con Especialidad en Biología Molecular e Ingeniería Genética) UANL, 2005

Guider la pratique et la formation éthique des professionnels de la santé : établir les fondements du modèle de la déontologie réflexive (MDR)

Si l’approche par compétences au Canada et aux États-Unis est particulièrement valorisée pour orienter la pratique des professionnels de la santé (PDS) – et en bioéthique clinique –, les travaux permettant de mieux comprendre les fondements psychologiques, ontologiques et philosophiques de ces compétences sont peu présents dans la littérature en bioéthique. Les principaux outils actuellement disponibles se divisent généralement en quatre principales catégories : 1) les documents officiels (codes de déontologie, règlements institutionnels, etc.); 2) les principales théories éthiques (éthique de la discussion, éthique de la vertu, principisme, etc.); 3) les ouvrages de référence scientifiques; 4) les outils de prise de décision éthique. Ces documents sont des incontournables pour les bioéthiciens et les PDS, mais leur disparité, voire leur contenu parfois contradictoire, jumelée à une compréhension limitée de l’éthique, est souvent source de confusion dans les processus décisionnels et peut être la cause de comportements ne répondant pas aux standards éthiques des pratiques professionnelles. Notre recherche constitue une réflexion qui s’inscrit en amont de ces outils dont le caractère pragmatique a le désavantage de simplifier la réflexion théorique au profit de données plus concrètes. Nos travaux visent à développer les bases d’un modèle flexible et inclusif – le modèle de la déontologie réflexive (MDR) – permettant de : 1) poser les principaux repères philosophiques, sociaux et déontologiques des problématiques éthiques rencontrées en pratique; 2) saisir les principales tensions éthiques inhérentes à cette complexité; 3) mieux comprendre, dans une perspective psychologique et développementale, les exigences personnelles et professionnelles qu’impose le statut de professionnel de la santé dans le contexte actuel des soins de santé. Entreprise théorique, ce projet consiste principalement à mettre en relation dynamique un ensemble de dimensions (légale, éthique, clinique, sociale, psychologique) à l’oeuvre dans la rencontre du bioéthicien et du PDS avec la complexité des situations éthiques, en s’inspirant du concept de sensibilité éthique de la « petite éthique » de Paul Ricoeur (1990), du modèle des quatre composantes de Rest (1994) et de la théorie du soi et des modes identitaires d’Augusto Blasi (1993). Ce processus implique trois étapes successives : 1) une mise en ii perspective de la posture épistémologique particulière du bioéthicien et du PDS à la lumière de la « petite éthique » de Ricoeur; 2) une revue de la littérature interdisciplinaire sur le concept de sensibilité éthique afin d’en proposer une définition et de le mettre en perspective avec d’autres compétences éthiques; 3) le développement d’un cadre de référence en matière d’identité éthique professionnelle (professional ethics identity tendencies, PEIT), inspiré de la théorie du soi et des modes identitaires de Blasi. Ces PEIT proposent un repère normatif aux exigences liées à la construction de l'identité en contexte de pratique des PDS et suggèrent des pistes de réflexion quant à la formation et à la recherche en éthique professionnelle. Cette recherche souhaite établir des fondements théoriques pour le développement ultérieur du modèle de la déontologie réflexive (MDR).

A human pancreatic ribonuclease variant kills cancer cells by apoptosis and reduces the expression of P-glycoprotein in MDR cell lines

En aquesta tesi s'han estudiat les propietats antitumorals d'una variant de la ribonucleasa pancreàtica humana anomenada PE5 que incorpora un senyal de localització nuclear. Aquest estudi mostra que PE5 indueix l'apoptosi de les cèl·lules tractades i que aquesta mort és independent de l'activitat de p53. A més, l'efecte citotòxic no es veu afectat per un fenotip de resistència a múltiples drogues. Les dades també mostren que l'activitat citotòxica de PE5 és selectiva per a cèl·lules tumorals in vitro i que la capacitat citotòxica de les dues ribonucleases és semblant. S'ha estudiat l'efecte d'aquestes dues ribonucleases sobre el cicle cel·lular, l'activació de diferents caspases i l'expressió de proteïnes relacionades amb l'apoptosi i el cicle cel·lular. Els resultats indiquen que PE5 i l'onconasa maten les cèl·lules a través de mecanismes diferents. A més, PE5 però no l'onconasa, redueix l'acumulació de glicoproteïna-P en dues línies cel·lulars resistents a múltiples drogues.

Epidemic multidrug-resistant (MDR-AmpC) Salmonella enterica serovar Newport strains contain three phage regions and a MDR resistance plasmid

Multidrug-resistant (MDR-AmpC) Salmonella enterica serovar Newport has caused serious disease in animals and humans in North America, whereas in the UK S. enterica serovar Newport is not associated with severe disease and usually sensitive to antibiotics; MDR S. Newport (not AmpC) strains have only been isolated from poultry. We found that UK poultry strains belonged to MLST type ST166 and were distinct from cattle isolates for being able to utilize D-tagotose and when compared by pulsed-field gel electrophoresis (PFGE), comparative genomic hybridization (CGH) and diversity arrays technology (DArT). Cattle strains belonged to the ST45 complex differing from ST166 at all seven loci. PFGE showed that 19 out of 27 cattle isolates were more than 85% similar to each other and some UK and US strains were indistinguishable. Both CGH and DArT identified genes (including phage-related ones) that were uniquely present in the US isolates and two such genes identified by DArT showed sequence similarities with the pertussis-like (artAB) toxin. This work demonstrates that MDR-AmpC S. Newport from the USA are genetically closely related to pan-susceptible strains from the UK, but contained three extra phage regions and a MDR plasmid.

Correlação entre os parâmetros do cortisol salivar e o fenótipo de fragilidade em idosos institucionalizados

Introduction: The Frailty Syndrome is characterized by the decrease of energy reserve and the reduced resistance to stressors. Studies indicate that the neuroendocrine markers can be related to the appearance of this syndrome. The main endocrine answer to stress is the increase of cortisol levels. Objective: To analyze the correlation between the frailty syndrome the salivary cortisol in elderly residing in nursing homes. Method: A traversal study was accomplished, in João Pessoa city, PB, with a sample composed by 69 institutionalized elderly. The collected data refer to the frailty phenotype (weight loss, exhaustion, slowness, weakness, and lower level of physical activity) and to salivary cortisol parameters (first measure - 6-7h; second measure - 11-12h; third measure - 16-17h). In the statistical analysis the Pearson s correlation test was used, Chi square Test and Anova and Simple Linear Regression analyses. Results: The sample was composed by 37.7% of men and 62.3% of women, with age average of 77.52 (±7.82). There was a percentile of 45.8% frail elderly. The frail elderly obtained higher cortisol values in the third measure (p=0.04) and the frailty load was significantly associated to the first measure (r=0.25, p=0.04). The simple linear regression analysis presented a determination rate (R2=0.05) between frailty load and first cortisol measure. Conclusion: The largest cortisol values in the morning and before sleeping among the frail elderly supply indications that can have a relationship of cortisol increase levels and the frailty presence in elderly from nursing homes.

Fenótipo neuropsicológico de adolescentes com síndrome de Down

This research aimed to contribute to the characterization of a neuropsychological phenotype of adolescents with Down Syndrome (DS). A multicases study of six adolescents (three males and three females, aged 13 to 14 years) diagnosed with DS and treated at two institutions in the city of Natal (Brazil), was conducted. Participants were assessed using the methodological approach developed by Luria, which is composed by four complementary stages. The first one aimed to investigate the qualitative impact of DS in school life and social development of the adolescents; dimensions of behavior and social-affective aspects of the members of the study were investigated. In the second stage participants performed a battery of neuropsychological tests in order to identify strengths and weaknesses in their cognitive functioning. The third stage was incorporated into the second in order to analyze the quality of the activity of the participants along the quantitative evaluation, highlighting strategies used, errors produced among other indicators. Lastly, the fourth stage refers to the intervention with the participants. Although this is not a specific objective of the study, it is argued that the outcome of this research will subsidize the practice of different professionals working with this clinical group. The results of the first stage emphasized the presence of difficulties in social relationships and in school life of observed adolescents. In turn, the second and third stages pointed out to the presence of difficulties in tasks involving logical and abstract thinking, as well as difficulties in expressive language. In relation to visual memory, we observed a better performance in activities of lower complexity, ie, with less interference of executive functioning, particularly in terms of the functions of planning and initiative. Finally, it was found motor and mental retardation, affecting significantly the performance related to different cognitive areas. The results highlighted here can be considered as subsidies for future interventions, suggesting the need for developping projects that take into account different aspects constituents of the human subject, involving not only the individual with developmental changes, as well as their families, teachers, schools and society in general

Avaliação do polimorfismo de grupos sanguíneos e fenótipo de hemoglobinas em um grupo de universitários de São José do Rio Preto, SP

The studies of the phenotypes of the blood groups are important for blood transfusions, for obstetrics, neonatology and law medicine, apart from its application in anthropology where it can be used as genetic markers in population studies. Works with hemoglobin polymor-phisms as a genetic marker of populations has been increased over the last few years, particularly for different population groups of Brazil. In the investigation the hemoglobin polymorphisms of 200 university students from São José do Rio Preto, Brazil were studied to establish a possible relation between the different phenotypes. Statistical analysis of the phenotypes showed that the differences observed were not significant, without a relationship among the polymorphisms of blood groups and hemoglobins.

Estudo do fenótipo osteoblástico em células-tronco mesenquimais de ratos normotensos e espontaneamente hipertensos na presença ou não de doença periodontal

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Fenótipo Lewis negativo: potencial fator de risco para infecção por cepa RH de Toxoplasma gondii em gestantes

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Caracterização do fenótipo comportamental e de linguagem na síndrome de Williams-Beuren

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Análise da supressão do fenótipo de sensibilidade a temperatura do mutante tif51A Q22H/L93F em Saccharomyces cerevisiae

O fator de início da tradução de eucariotos eIF5A é uma proteína essencial para a viabilidade celular, altamente conservada em arqueas e em eucariotos e apresenta uma modificação pós-traducional única em que um resíduo específico de lisina é modificado para o aminoácido hipusina. O processo de hipusinação é essencial para a função de eIF5A e consequentemente para a viabilidade celular. eIF5A foi descrita inicialmente como um fator de início da tradução, pois estimula a síntese de metionil-puromicina in vitro, porém, dados recentes de nosso e de outros grupos mostraram um papel para eIF5A na etapa de elongação da tradução. eIF5A é um homólogo estrutural do fator de elongação da tradução P (EF-P) de bactérias. EF-P também estimula a síntese de metionil-puromicina, sendo essencial para viabilidade celular em bactérias, além disso EF-P também apresenta uma modificação pós-traducional semelhante à hipusinação. Recentemente, em nosso laboratório, foi isolado o RNA transportador de alanina (tRNAAla) como supressor do fenótipo de sensibilidade a temperatura do mutante tif51AQ22H/L93F de eIF5A, sugerindo uma possível correlação funcional entre estes fatores. Tendo em vista a homologia estrutural entre eIF5A e EF-P e a possível homologia funcional entre estes fatores, pretende-se entender a relação de eIF5A com o tRNA de alanina e com isso contribuir para a caracterização do papel específico desta proteína na elongação da tradução. Portanto, foram clonados diferentes genes que codificam para diversos tRNA´s (glicina, leucina, prolina, metionina e fenilalanina) para averiguar se a supressão observada para o tRNA de alanina também pode ser vista com estes outros tRNA’s ou se é específica. Considerando-se que eIF5A foi descrita a mais de trinta anos sem que sua função específica fosse caracterizada, este estudo pode contribuir... (Resumo completo, clicar acesso eletrônico abaixo)