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1.
Ann Hepatol ; 14(5): 745-51, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26256905

RESUMO

INTRODUCTION: Progressive familial intrahepatic cholestasis type 3 (PFIC-3) is a severe liver disorder associated with inherited dysfunction of multidrug resistance protein 3 (MDR3/ABCB4), which functions as a phospholipid floppase, translocating phosphatidylcholine from the inner to the outer hemileaflet of the canalicular membrane of hepatocytes. MDR3 deficiency results in a disbalanced bile which may damage the luminal membrane of cells of the hepatobiliary system. We evaluated clinical, biochemical and histological improvement in a genetically proven PFIC-3 patient after long-term ursodeoxycholic acid (UDCA) administration. MATERIAL AND METHODS: A PFIC-3 patient and a relative with cholestatic liver disease were studied. Hepatic MDR3 expression was analyzed by immunohistochemistry and ABCB4 mutations were identified. The effect of the mutations on MDR3 expression and subcellular localization was studied in vitro. RESULTS: A 23-year-old man presented cholestasis with severe fibrosis and incomplete cirrhosis. Canalicular staining for MDR3 was faint. Sequence analysis of ABCB4 revealed two missense mutations that reduce drastically protein expression levels. After 9 years of treatment with UDCA disappearance of fibrosis and cirrhosis was achieved. CONCLUSION: These data indicate that fibrosis associated with MDR3 deficiency can be reversed by long-term treatment with UDCA, at least when there is residual expression of the protein.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/deficiência , Colagogos e Coleréticos/uso terapêutico , Colestase Intra-Hepática/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Colestase Intra-Hepática/diagnóstico , Colestase Intra-Hepática/genética , Análise Mutacional de DNA , Cães , Técnicas de Imagem por Elasticidade , Predisposição Genética para Doença , Células HEK293 , Humanos , Imuno-Histoquímica , Cirrose Hepática/diagnóstico , Cirrose Hepática/genética , Células Madin Darby de Rim Canino , Masculino , Mutação de Sentido Incorreto , Fenótipo , Indução de Remissão , Índice de Gravidade de Doença , Fatores de Tempo , Transfecção , Resultado do Tratamento , Adulto Jovem
2.
Arch Virol ; 159(5): 1109-17, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24306325

RESUMO

In Argentina, current procedures to ensure the safety of the blood supply for transfusion include the serologic detection of specific blood-borne infections. The aim of this study was to evaluate the prevalence and the genetic diversity of hepatitis B virus (HBV) and hepatitis D virus (HDV) in blood donor populations from two distantly located Argentine regions. Data from 56,983 blood donations from the Favaloro Foundation, in the city of Buenos Aires (Central Region), and the Central Blood Bank of Misiones Province (Northeast Region) were analyzed. Samples that were reactive for HBsAg were analyzed for HBV-DNA characterization and HDV serological and molecular analysis. The HBV prevalence was 0.12 % for HBsAg and 1.68 % for anti-HBc antibodies in Buenos Aires, and 0.73 % and 8.55 %, respectively, in Misiones. Seventy-seven HBsAg-reactive samples were analyzed by polymerase chain reaction for HBV-DNA. Subgenotypes A2, B2, C2, F1b and F4 (Buenos Aires) and F1b and D3 (Misiones) were detected. Several mutations within the major hydrophilic region of HBsAg, the reverse transcriptase, the basal core promoter, and the precore/core were detected. HDV genotype 1 was identified in Buenos Aires. This study confirms the circulation of several HBV subgenotypes, as well as known and newly identified variants, and the presence of HDV1 in this population. A thorough investigation has to be carried out to evaluate the clinical importance of some of the documented mutations as well as those detected in the HDV1 case.


Assuntos
Doadores de Sangue , Antígenos de Superfície da Hepatite B/sangue , Vírus da Hepatite B/isolamento & purificação , Vírus Delta da Hepatite/isolamento & purificação , DNA Polimerase Dirigida por RNA/metabolismo , Argentina/epidemiologia , Clonagem Molecular , DNA Viral/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Regulação Viral da Expressão Gênica/fisiologia , Hepatite B/sangue , Hepatite B/epidemiologia , Hepatite B/virologia , Antígenos de Superfície da Hepatite B/genética , Hepatite D/sangue , Hepatite D/epidemiologia , Hepatite D/virologia , Humanos , Mutação , Filogenia , Polimorfismo de Fragmento de Restrição , DNA Polimerase Dirigida por RNA/genética
3.
Bioorg Med Chem Lett ; 22(21): 6577-9, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23031592

RESUMO

The ability of cells to acquire resistance to multiple pharmaceuticals, namely multidrug resistance (MDR), is often mediated by the over-expression of efflux transporters of the ATP-binding cassette (ABC) superfamily; for example P-glycoprotein (P-gp or MDR1), breast cancer resistance protein (BCRP or ABCG2), and multidrug resistance-associated protein MRP1. ABCs pump drug molecules out of cells against a concentration gradient, reducing their intracellular concentration. The ability of polymeric amphiphiles to inhibit ABCs as well as the cellular pathways involved in the inhibition has been extensively investigated. This work investigated for the first time the effect of branched poly(ethylene oxide)-poly(propylene oxide) block copolymers (poloxamines) on the levels of mRNA encoding for MDR1, BCRP and MRP1, in a human hepatoma cell line (Huh7). Copolymers with a broad range of molecular weights and hydrophilic-lipophilic balances were assayed. Results confirmed the down-regulation of mdr1 and abcg2 genes. Conversely, the mrp1 gene was not affected. These findings further support the versatility of these temperature- and pH-responsive copolymers to overcome drug resistance in cancer and infectious diseases.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Regulação para Baixo/efeitos dos fármacos , Proteínas de Neoplasias/genética , Tensoativos/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Aminas/química , Aminas/farmacologia , Linhagem Celular Tumoral , Humanos , Ácido Oxâmico/química , Ácido Oxâmico/farmacologia , Reação em Cadeia da Polimerase
4.
J Clin Virol ; 54(3): 223-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22608280

RESUMO

BACKGROUND: Guidelines suggest that all HBsAg-positive patients should be tested for anti-HDV IgG antibodies and to confirm active hepatitis D virus (HDV) infection by detection of HDV RNA by reverse transcriptase (RT) polymerase chain reaction (PCR). OBJECTIVES: The aim of this study was to determine the serological prevalence and molecular features of HDV within an Amerindian community from Argentina exhibiting positivity for HBsAg and/or anti-HBc total Ig. STUDY DESIGN: Forty-six plasma samples were tested for the detection of total anti-HDV antibodies by ELISA. Concomitantly, a partial RNA region coding for the delta antigen (HDAg) was amplified by RT-nested PCR (RT-nPCR). In silica translation of DNA sequences into the amino acid (aa) sequence of HDAg-S (aa110-195) and HDAg-L (aa110-214) was performed. RESULTS: Out of 46 HDV non-reactive samples by ELISA, 3 were HDV RNA positive by RT-nPCR. These samples were anti-HBc-only positive, 2 of them identified as cases of occult hepatitis B infection (OBI). The 3 cases were HBeAg-negative and showed normal ALT/AST levels. All sequences were ascribed to HDV genotype 1, but exhibited nucleotide differences in HDAg-L coding region, among which, mutations at codons 197 and 201 - reportedly known to promote in vitro an unsuitable interaction with HBsAg - were observed. CONCLUSIONS: These results provide evidence of covert HDV infection even among OBI, highlighting the need to reevaluate the currently applied guidelines for HDV diagnostic algorithms, as well as to explore if the observed mutations promote any effect on HDV pathogenesis.


Assuntos
Hepatite B/complicações , Vírus Delta da Hepatite/genética , Antígenos da Hepatite delta/sangue , Antígenos da Hepatite delta/genética , Adolescente , Adulto , Idoso , Argentina , Doenças Assintomáticas , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Anticorpos Anti-Hepatite/sangue , Humanos , Imunoglobulina G/sangue , Indígenas Sul-Americanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , RNA Viral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA , Estudos Soroepidemiológicos , Adulto Jovem
5.
Antiviral Res ; 87(1): 74-7, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20403388

RESUMO

Hepatitis B virus (HBV) variants may either emerge in patients with chronic hepatitis B (CHB) as a result of positive selection pressure exerted by their own immune response, or during therapy with nucleos(t)ide analogues (NAs). Naturally occurring HBV variants with primary antiviral resistance are rarely observed. The aim of this study was to retrospectively analyze the (eventual) circulation of HBV variants with natural resistance to NAs currently used as therapy for CHB in Argentina. This study reports 13 cases of CHB-infected patients with natural antiviral resistance to at least one NA. Five of them were also carriers of S-variants that might escape the humoral immune system recognition with potential resistance to adefovir. In addition to the already reported A2 HBV subgenotype association to NAs natural resistance, E and F genotypes association to such resistance is described for the first time. These findings suggest that sequence analysis of the HBV reverse transcriptase might be an essential tool before starting antiviral therapy, in order to choose the proper NAs for optimizing the therapeutic management of chronically infected patients. Moreover, the circulation and transmission of S-mutants with resistance to such antiviral drugs should be of public health concern as they may represent an additional risk for the community.


Assuntos
Adenina/análogos & derivados , Antivirais/farmacologia , Farmacorresistência Viral , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/virologia , Mutação de Sentido Incorreto , Organofosfonatos/farmacologia , Adenina/farmacologia , Adolescente , Adulto , Argentina , Criança , Pré-Escolar , Feminino , Genótipo , Vírus da Hepatite B/classificação , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
6.
Ing. sanit. ambient ; (68): 60-5, may.-jun. 2003. ilus
Artigo em Espanhol | BINACIS | ID: biblio-1163033
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