RESUMO
Myotonic dystrophy type 1 (DM1) is a multisystem genetic disorder caused by a triplet nucleotide repeat expansion in the 3' untranslated region of the Dystrophia Myotonica-Protein Kinase (DMPK) gene. DMPK gene transcripts containing CUG expanded repeats accumulate in nuclear foci and ultimately cause altered splicing/gene expression of numerous secondary genes. The study of primary cell cultures derived from patients with DM1 has allowed the identification and further characterization of molecular mechanisms underlying the pathology in the natural context of the disease. In this study we show for the first time impaired nuclear structure in fibroblasts of DM1 patients. DM1-derived fibroblasts exhibited altered localization of the nuclear envelope (NE) proteins emerin and lamins A/C and B1 with concomitant increased size and altered shape of nuclei. Abnormal NE organization is more common in DM1 fibroblasts containing abundant nuclear foci, implying expression of the expanded RNA as determinant of nuclear defects. That transient expression of the DMPK 3' UTR containing 960 CTG but not with the 3' UTR lacking CTG repeats is sufficient to generate NE disruption in normal fibroblasts confirms the direct impact of mutant RNA on NE architecture. We also evidence nucleoli distortion in DM1 fibroblasts by immunostaining of the nucleolar protein fibrillarin, implying a broader effect of the mutant RNA on nuclear structure. In summary, these findings reveal that NE disruption, a hallmark of laminopathy disorders, is a novel characteristic of DM1.
Assuntos
Núcleo Celular/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Distrofia Miotônica/genética , Distrofia Miotônica/patologia , Nucléolo Celular/patologia , Células Cultivadas , Humanos , Expansão das Repetições de TrinucleotídeosRESUMO
Enteric-coated tablets containing mycophenolate sodium have been developed to reduce gastric toxicity. The objective of this study was to compare 2 enteric-coated formulations containing 360 mg of mycophenolate sodium: the innovator product, Myfortic, and an agent that recently became available in Mexico, Femulan. For both formulations, mycophenolate sodium content was within the 90% to 110% range of the label claimed dose, and no impurities were present as determined at high-performance liquid chromatography. Mycophenolate sodium release was assayed by applying the US Pharmacopeia apparatus 2 dissolution test at 2 different pH values (1.2 and 6.8) to mimic conditions in the stomach and the small intestine, respectively. At pH 1.2, mycophenolate sodium release was less than 2%, with respect to the label claimed dose, for both formulations. At pH 6.8, mean (range) mycophenolate sodium release with Myfortic was 104.9% (104.0%-105.6%), and with femulan was 62.3% (51.3%-67.7%); the difference between formulations achieved statistical significance (P = .04). Moreover, intratablet variability with the generic formulation was unacceptable. Variation between the highest and lowest drug release was 32.0% for Femulan, and 1.02% for Myfortic. Thus, it is likely that Femulan results in insufficient and irreproducible absorption of mycophenolate sodium in the small intestine, leading to inadequate immunosuppressive efficacy. It is concluded that Femulan and myfortic are not equivalent formulations. Furthermore, Femulan is not a suitable formulation for clinical use in organ transplantation because it does not meet pharmaceutical quality standards.
Assuntos
Imunossupressores/química , Ácido Micofenólico/química , Ácido Micofenólico/farmacocinética , Comprimidos com Revestimento Entérico , Estabilidade de Medicamentos , Medicamentos Genéricos/química , Concentração de Íons de Hidrogênio , México , Ácido Micofenólico/uso terapêutico , Sódio , Solubilidade , SoluçõesRESUMO
Dystrophin and dystrophin-associated proteins (DAPs) form a complex around the sarcolemma, which gives stability to the sarcolemma and leads signal transduction. Recently, the nuclear presence of dystrophin Dp71 and DAPs has been revealed in different non-muscle cell types, opening the possibility that these proteins could also be present in the nucleus of muscle cells. In this study, we analyzed by Immunofluorescence assays and Immunoblotting analysis of cell fractions the subcellular localization of Dp71 and DAPs in the C(2)C(12) muscle cell line. We demonstrated the presence of Dp71, alpha-sarcoglycan, alpha-dystrobrevin, beta-dystroglycan and alpha-syntrophin not only in plasma membrane but also in the nucleus of muscle cells. In addition, we found by Immunoprecipitation assays that these proteins form a nuclear complex. Interestingly, myogenesis modulates the presence and/or relative abundance of DAPs in the plasma membrane and nucleus as well as the composition of the nuclear complex. Finally, we demonstrated the presence of Dp71, alpha-sarcoglycan, beta-dystroglycan, alpha-dystrobrevin and alpha-syntrophin in the C(2)C(12) nuclear envelope fraction. Interestingly, alpha-sarcoglycan and beta-dystroglycan proteins showed enrichment in the nuclear envelope, compared with the nuclear fraction, suggesting that they could function as inner nuclear membrane proteins underlying the secondary association of Dp71 and the remaining DAPs to the nuclear envelope. Nuclear envelope localization of Dp71 and DAPs might be involved in the nuclear envelope-associated functions, such as nuclear structure and modulation of nuclear processes.
Assuntos
Núcleo Celular/metabolismo , Proteínas Associadas à Distrofina/análise , Distrofina/análise , Células Musculares/metabolismo , Desenvolvimento Muscular/fisiologia , Membrana Nuclear/metabolismo , Animais , Membrana Celular/metabolismo , Células Cultivadas , Distrofina/genética , Distrofina/metabolismo , Complexo de Proteínas Associadas Distrofina/análise , Complexo de Proteínas Associadas Distrofina/metabolismo , Proteínas Associadas à Distrofina/genética , Proteínas Associadas à Distrofina/metabolismo , Imunofluorescência , Camundongos , RNA Mensageiro/metabolismoRESUMO
Mexico has a large and rapidly growing labor force. This paper projects the Mexican national labor force from 1980 to 2005, with varying assumptions of vital rates, economic activity, and international migration. Projections are also made for the urban and rural components of the Mexican population, assuming inter-component migration flows. Results indicate that the Mexican labor force will grow over the projection period at an average annual rate of 907,000 to 1,183,000 workers; will age slightly; and will have a much higher proportion female. Implications are discussed in terms of Mexican-U.S. migration, possible agreements on free trade, and global trends in workforce.
Assuntos
Emprego/estatística & dados numéricos , Adulto , Fatores Etários , Emigração e Imigração/estatística & dados numéricos , Feminino , Fertilidade , Previsões , Humanos , Masculino , México , Pessoa de Meia-Idade , Dinâmica Populacional , Fatores Sexuais , Fatores Socioeconômicos , Mulheres Trabalhadoras/estatística & dados numéricosRESUMO
Se presenta el caso de un adolescente con hipertension arterial grave, en quien clinicamente y por metodos de gabinete se considero que la hipertension era de origen renovascular. La arteriografia renal mostro compresion de la arteria renal derecha por un tumor parapielico. El estudio histologico del mismo revelo que se trataba de un feocromocitoma extraadrenal. El paciente se curo de la hipertension arterial despues de la nefrectomia y extirpacion del tumor