Developmental Pharmacogenetics in Pediatric Rheumatology: Utilizing a New Paradigm to Effectively Treat Patients with Juvenile Idiopathic Arthritis with Methotrexate

Although methotrexate is widely used in clinical practice there remains significant lack of understanding of its mechanisms of action and the factors that contribute to the variability in toxicity and response seen clinically. In addition to differences in drug administration, factors that affect pharmacokinetics and pharmacodynamics such as genetic variation may explain individual differences in drug biotransformation. However, the pediatric population has an additional factor to consider, namely the ontogeny of gene expression which may result in variation throughout growth and development. We review the current understanding of methotrexate biotransformation and the concept of ontogeny, with further discussion of how to implement a developmental pharmacogenomics approach in future studies

Metabolomic Profiling to Identify Molecular Biomarkers of Cellular Response to Methotrexate In Vitro

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Variation in methotrexate (MTX) efficacy represents a significant barrier to early and effective disease control in the treatment of autoimmune arthritis. We hypothesize that the utilization of metabolomic techniques will allow for an improved understanding of the biochemical basis for the pharmacological activity of MTX, and can promote the identification and evaluation of novel molecular biomarkers of MTX response. In this work, erythroblastoid cells were exposed to MTX at the physiologic concentration of 1,000 nM and analyzed using three metabolomic platforms to give a broad spectrum of cellular metabolites. MTX pharmacological activity, defined as cellular growth inhibition, was associated with an altered cellular metabolomic profile based on the analysis of 724 identified metabolites. By discriminant analysis, MTX treatment was associated with increases in ketoisovaleric acid, fructose, galactose, and 2‐deoxycytidine, and corresponding reductions in 2‐deoxyuridine, phosphatidylinositol 32:0, orotic acid, and inosine monophosphate. Inclusion of data from analysis of folate metabolism in combination with chemometric and metabolic network analysis demonstrated that MTX treatment is associated with dysregulated folate metabolism and nucleotide biosynthesis, which is in line with its known mechanism of action. However, MTX treatment was also associated with alterations in a diversity of metabolites, including intermediates of amino acid, carbohydrate, and lipid metabolism. Collectively, these findings support a robust metabolic response following exposure to physiologic concentrations of MTX. They also identify various metabolic intermediates that are associated with the pharmacological activity of MTX, and are, therefore, potential molecular biomarker candidates in future preclinical and clinical studies of MTX efficacy in autoimmune arthritis

Harry Potter como incentivo ao ensino de Inglês na escola: uma experiência do Pibid do curso de Letras/Inglês

Anais do II Seminário Seminário Estadual PIBID do Paraná: tecendo saberes / organizado por Dulcyene Maria Ribeiro e Catarina Costa Fernandes — Foz do Iguaçu: Unioeste; Unila, 2014O objetivo deste trabalho é compartilhar uma experiência desenvolvida no Projeto Pibid/Letras/Inglês, buscando incentivar a literatura como prática de ensino nas aulas de língua inglesa no Ensino Fundamental escolar. Os participantes desenvolveram e aplicaram um Caderno Literário com base nas obras literárias de J. K. Rowling e suas adaptações cinematográficas. O conteúdo do Caderno envolve desde uma introdução biográfica sobre a autora à várias atividades linguísticas, literárias e cinematográficas relacionadas à saga Harry Potter, encerrando com uma atividade esportiva com o jogo Quadribol com os alunos. Todas as atividades foram permeadas pela abordagem denominada de Literamento (PALLU, 2012) a qual integra os estudos artísticos, literários e linguísticos produzidos em língua inglesa. Os resultados desta experiência serão demonstrados como pontos de reflexão sobre formas de letramento nas escola

Crescimento e esporulação de Metarhizium flavoviride var. Flavoviride em meios de cultura e regimes de luz

Entomopathogenic fungi from the genus Metarhizium are largely used for the biological control of agricultural pests by conidia spreading on the field. Although conidia production is well studied in M. anisopliae, only few research studies were done in M. flavoviride. The present work was carried out alming to evaluate the Mycelial growth and sporulation of the entomopathogenic fungus Metarhizium flavoviride var. flavoviride growing at 27 ± 2°C on Potato-dextrose-agar (PDA), Czapek-agar (CZP) and a complete agar medium (CM) under three lighting regimes, (continuous illumination, light/dark cycle and an black light/dark cycle) were investigated. A completely randomized 3 × 3 (culture media × lighting regime) factorial design with four replicates was used. The best mycelial growth and sporulation occurred on the PDA and CM media under continuous illumination (PFungos entomopatogênicos do genêro Metarhizium são empregados no controle biológico de pragas agrícolas por meio da dispersão de seus conídios no campo. Embora a produção de conídios em M. anisopliae esteja bem estudada, poucas pesquisas a respeito existem na espécie M. flavoviride. O presente trabalho foi realizado para avaliar o efeito de três meios de cultura, batata-dextrose-ágar (BDA), Czapek-ágar (CZP) e meio completo (MC), e três regimes de luminosidade, claro contínuo, alternância com luz do dia/escuro e luz negra/escuro, sobre o crescimento miceliano e esporulação do fungo entomopatogênico Metarhizium flavoviride var. flavoviride. O experimento foi realizado em câmara de incubação à temperatura de 27 ± 2°C. Empregou-se um delineamento experimental inteiramente casualizado, em arranjo fatorial 3°C 3 (meios de cultura e regime de luminosidade) com quatro repetições. As melhores condições para o crescimento miceliano e esporulação foram conseguidas tanto no meio de cultura BDA como no MC quando combinados com o regime claro contínuo (

Risk score modeling of multiple gene to gene interactions using aggregated-multifactor dimensionality reduction

BACKGROUND: Multifactor Dimensionality Reduction (MDR) has been widely applied to detect gene-gene (GxG) interactions associated with complex diseases. Existing MDR methods summarize disease risk by a dichotomous predisposing model (high-risk/low-risk) from one optimal GxG interaction, which does not take the accumulated effects from multiple GxG interactions into account. RESULTS: We propose an Aggregated-Multifactor Dimensionality Reduction (A-MDR) method that exhaustively searches for and detects significant GxG interactions to generate an epistasis enriched gene network. An aggregated epistasis enriched risk score, which takes into account multiple GxG interactions simultaneously, replaces the dichotomous predisposing risk variable and provides higher resolution in the quantification of disease susceptibility. We evaluate this new A-MDR approach in a broad range of simulations. Also, we present the results of an application of the A-MDR method to a data set derived from Juvenile Idiopathic Arthritis patients treated with methotrexate (MTX) that revealed several GxG interactions in the folate pathway that were associated with treatment response. The epistasis enriched risk score that pooled information from 82 significant GxG interactions distinguished MTX responders from non-responders with 82% accuracy. CONCLUSIONS: The proposed A-MDR is innovative in the MDR framework to investigate aggregated effects among GxG interactions. New measures (pOR, pRR and pChi) are proposed to detect multiple GxG interactions

Methotrexate Polyglutamation in a Myasthenia Gravis Clinical Trial

Introduction. Methotrexate (MTX) is an immunosuppressive and anti-inflammatory drug used to treat rheumatoid arthritis (RA) and other autoimmune conditions. MTX is transported into cells, where glutamate moieties are added and is retained as methotrexate polyglutamates (MTXPGs). In the RA literature, it has been reported that the degree of polyglutamation correlates with the anti-inflammatory effect of MTX in RA. There are no prior studies evaluating the relationship between MTXPGs and myasthenia gravis (MG) outcome measures. The objective of this study was to assess the correlation between methotrexate (MTX) polyglutamates (MTXPGs) with Myasthenia Gravis (MG) outcome measures. Methods.xAn analysis was done of blood drawn from patients enrolled in the 12-month randomized, placebo-controlled study of MTX in MG study. Red blood cell MTXPGs were measured via ultraperformance liquid chromatography and tandem mass spectrometry. MTXPG was correlated to MG outcome measures using Spearman Correlation Coefficient. A two-group t-test was used to determine the difference in MTXPG based on clinical outcome responder definitions. Results. Twenty-one polyglutamate samples were analyzed of subjects on MTX while eight samples were analyzed from subjects on placebo. Pentaglutamate had the strongest correlation with the MG-ADL (0.99), while tetraglutamate had the strongest correlation with the QMG (0.54). Triglutamate had the strongest correlation with MGC (0.76). Conclusion. There were variable correlations between MTXPG1-5 and MG outcomes (rho range: 0.08 to 0.99). There are strong correlations between MTXPG and the MG-ADL, QMG, and MGC. Long chain methotrexate polyglutamates correlate better with MG outcomes

Percepções sobre o plantão psicológico em uma Delegacia de Defesa da Mulher

O plantão psicológico realizado em Delegacia de Defesa da Mulher (DDM) é uma ferramenta no combate à violência contra a mulher. Entretanto as plantonistas estão inseridas em um ambiente de muita carga emocional. Objetivou-se analisar as percepções das plantonistas e agentes de uma DDM sobre a violência de gênero e seus impactos psíquicos no cotidiano pessoal e de trabalho dessas mulheres. Entrevistaram-se 23 mulheres com idade entre 19 e 56 anos (M=28, 26; DP=10, 15), e o material coletado foi analisado pelo software Iramuteq. Foram avaliados 1.304 segmentos de texto, gerando uma retenção de 98,27% do total, os quais conceberam seis classes, dentre as quais a de maior expressividade foi a classe 1 “impacto da violência”, com 21,55% dos segmentos de texto. Desgastes físicos e emocionais são desencadeados pelos atendimentos, porém as plantonistas e agentes da DDM não recebem apoio emocional para realizar suas funções, tendo assim que desenvolver estratégias de enfrentamento pessoal

Optimization of Anaerobic Co-Digestion of Pasteurized Slaughterhouse By-Products Incorporating Residues from Bioethanol Industry to Balance C/N Ratios

Anaerobic digestion of pig slaughterhouse waste (SW) and corn sieving waste (CSW), and anaerobic co-digestion of CSW/SW were studied at lab scale employing several carbon to nitrogen ratio (C/N) and total solids (TS) content. Mixtures with highest biogas yield and suitable process stability values were scaled up to pilot scale. Results showed that SW and CSW co-digestion improved biogas yield over that obtained from mono-digestion of both substrates. Thus, CSW could be a proper substrate to balance C/N and improve biogas yield. Also, all studies reveal that the best biogas yield for each C/N mixture was achieved for the lowest TS content. Moreover, SW/CSW mixture with C/N 15 and 5% TS achieved the highest biogas yield and the best process stability. Pilot scale assay demonstrates that biogas yield, methane yield and Organic Matter Removal (OMR) for C/N 15 mixture were 41%, 25%, and 24% higher than those using C/N 20, respectively. Methane content was similar for both C/N 15 and C/N 20 at pilot scale. However, other gasses composition (H 2 , CO 2 ) presented variations.Fil: Galvan, Maria Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Transferencia de Villa María. Universidad Nacional de Villa María. Centro de Investigaciones y Transferencia de Villa María; ArgentinaFil: Degano, Salvador. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Transferencia de Villa María. Universidad Nacional de Villa María. Centro de Investigaciones y Transferencia de Villa María; ArgentinaFil: Cagnolo, Mara Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Transferencia de Villa María. Universidad Nacional de Villa María. Centro de Investigaciones y Transferencia de Villa María; ArgentinaFil: Becker, Analía. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Centro de Investigaciones y Transferencia de Villa María. Universidad Nacional de Villa María. Centro de Investigaciones y Transferencia de Villa María; ArgentinaFil: Hilbert, Jorge Antonio. Instituto Nacional de Tecnología Agropecuaria. Centro Nacional de Investigaciones Agropecuarias Castelar; ArgentinaFil: Fuentes Mora, Mauren. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Fisicoquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; ArgentinaFil: Acevedo, Diego Fernando. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Departamento de Fisicoquímica; Argentina. Universidad Nacional de Río Cuarto. Facultad de Ciencias Exactas Fisicoquímicas y Naturales. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados. - Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Tecnologías Energéticas y Materiales Avanzados; Argentin

Sinus of valsalva aneurysm in Blau's syndrome

Blau syndrome is a rare granulomatous disorder inherited in an autosomal dominant manner characterized by the early appearance of granulomatous arthritis, skin rash and anterior uveitis. There are very few data on the cardiovascular manifestations of Blau syndrome. Here we report the first case of sinus of valsava aneurysm in Blau syndrome. In isolated unruptured aneurysms of a sinus of Valsalva without compromise of the aortic valve and/or the coronary ostia, repair may be accomplished by simple placation of the aneurysm or excision of the aneurysm(s) and patch closure of the defect(s) between the aortic annulus and the sinu-vascular ridge. Because of the particular conditions in our case, the repair was performed with replacement of the aortic valve and root using a composite graft employing a modified Bentall's technique