RESUMO
Hepatitis C virus (HCV) is a major cause of hepatic disease and of liver transplantation worldwide. Mannan-binding lectin (MBL), encoded by the MBL2 gene, can have an important role as an opsonin and complement activating molecule in HCV persistence and liver injury. We assessed the MBL2 polymorphism in 102 Euro-Brazilian patients with moderate and severe chronic hepatitis C, paired for gender and age with 102 HCV seronegative healthy individuals. Six common single nucleotide polymorphisms in the MBL2 gene, three in the promoter (H/L, X/Y and P/Q) and three in exon 1 (A, the wild-type, and B, C or D also known as O) were evaluated using real-time polymerase chain reaction with fluorescent hybridization probes. The concentration of MBL in plasma was measured by enzyme-linked immunosorbent assay. The frequency of the YA/YO genotype was significantly higher in the HCV patients compared with the controls (P = 0.022). On the other hand, the genotypes associated with low levels of MBL (XA/XA, XA/YO and YO/YO) were decreased significantly in the patients with severe fibrosis (stage F4), when compared with the patients with moderate fibrosis (stage F2) (P = 0.04) and to the control group (P = 0.011). Furthermore, MBL2 genotypes containing X or O mutations were found to be associated with non-responsiveness to pginterferon and ribavirin treatment (P = 0.023). MBL2 polymorphisms may therefore be associated not only with the development of chronic hepatitis C, but also with its clinical evolution and response to treatment.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/genética , Interferon-alfa/uso terapêutico , Cirrose Hepática/virologia , Lectina de Ligação a Manose/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/genética , Masculino , Lectina de Ligação a Manose/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
A successful gene therapy clinical trial that also encountered serious adverse effects has sparked extensive study and debate about the future directions for retrovirus-mediated interventions. Treatment of X-linked severe combined immunodeficiency with an oncoretrovirus harboring a normal copy of the gc gene was applied in two clinical trials, essentially curing 13 of 16 infants, restoring a normal immune system without the need for additional immune-related therapies. Approximately 3 years after their gene therapy, tragically, 3 of these children, all from the same trial, developed leukemia as a result of this experimental treatment. The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene. In this review, we will explore the causes of this unwanted event and some of the possibilities for reducing the risk of its reoccurrence.
Assuntos
Humanos , Terapia Genética , Leucemia/etiologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Transformação Celular Neoplásica , Ensaios Clínicos como Assunto , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos/genética , Fatores de Risco , Transdução Genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologiaRESUMO
A successful gene therapy clinical trial that also encountered serious adverse effects has sparked extensive study and debate about the future directions for retrovirus-mediated interventions. Treatment of X-linked severe combined immunodeficiency with an oncoretrovirus harboring a normal copy of the gammac gene was applied in two clinical trials, essentially curing 13 of 16 infants, restoring a normal immune system without the need for additional immune-related therapies. Approximately 3 years after their gene therapy, tragically, 3 of these children, all from the same trial, developed leukemia as a result of this experimental treatment. The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene. In this review, we will explore the causes of this unwanted event and some of the possibilities for reducing the risk of its reoccurrence.
Assuntos
Terapia Genética , Leucemia/etiologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia , Transformação Celular Neoplásica , Ensaios Clínicos como Assunto , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Vetores Genéticos/genética , Humanos , Fatores de Risco , Transdução Genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologiaRESUMO
The effect of the reduction of intra-abdominal pressure on the lower esophageal sphincter pressure (LESP) and the 24-hour pH monitoring were studied in 16 patients with ascites before and after paracentesis. LESP did not change (P > 0.05) with the reduction of intra-abdominal pressure (before paracentesis: 17.48 mmHg and postparacentesis: 18.67 mmHg). The results were divided into two groups according to the achieved reduction in intra-abdominal pressure group A were those in who the reduction was greater than 70% and B consisted of those a reduction of less than 70%. LESP did not change even when results for each group were considered separately (P > 0.05): group A (before: 15.60 mmHg; after: 18.09 mmHg); group B (before: 23.09 mmHg; after: 20.40 mmHg). However the 24-h pH monitoring showed pathological reflux in patients with ascites that was reduced with the paracentesis (P < 0.05; total number of reflux episodes before paracentesis was 520.26, and after, 136.26). All pH-monitoring parameters were statistically different (P < 0.05) before and after the reduction of intra-abdominal pressure for group A but not for group B. LESP does not change significantly (P > 0.05) when the intra-abdominal pressure is significantly reduced (P < 0.05). Patients with ascites showed gastroesophageal reflux. Intra-abdominal pressure reduction greater than 70% lead to a significant reduction in gastroesophageal reflux.
Assuntos
Abdome/fisiologia , Ascite/fisiopatologia , Junção Esofagogástrica/fisiologia , Refluxo Gastroesofágico/prevenção & controle , Estudos de Casos e Controles , Humanos , Concentração de Íons de Hidrogênio , Hepatopatias/fisiopatologia , Monitorização Fisiológica , Paracentese , Pressão , Estudos ProspectivosRESUMO
The clinical significance of isolated anti-HBc is still a challenge. To elucidate the real importance of this finding in our blood donors, an investigation algorithm was tested. One hundred and twelve isolated anti-HBc seropositive blood donors underwent clinical evaluation and retesting of HBV markers. Those who presented repeatedly reactive isolated anti-HBc, received a single dose of hepatitis B recombinant vaccine to verify anti-HBs early response. A HBV-DNA determination by PCR was done for those who did not test positive to anti-HBs after vaccine. The level of anti-HBc was recorded as a ratio of the sample-to-cut-off values (S:C ratio) in 57 candidates at donation. Comparing true and false-positive anti-HBc results, the different S:C ratios of them were statistically significant and when less than 2, implying in a false-positive result probability over 80%. A high percent of false-positive results (16.07%) was verified after anti-HBc retesting. HBV immunity was characterized in 49.11%, either by anti-HBs detection in retesting (15.18%), or after a single dose HBV vaccination (33.93%). HBV-DNA was negative in all tested donors. In conclusion, this algorithm was useful to clarify the meaning of isolated anti-HBc in most of our blood donors.
Assuntos
Algoritmos , Doadores de Sangue , Anticorpos Anti-Hepatite B/sangue , Antígenos do Núcleo do Vírus da Hepatite B/imunologia , Adulto , Análise de Variância , Reações Falso-Positivas , Feminino , Vacinas contra Hepatite B/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
It has been estimated that 3% of the world population is infected with the hepatitis C virus. Those who are blood product recipients or have been illicit drug users are at risk. Dental and medical procedures as well as tattooing and acupuncture are also risk factors. Chronic infection occurs in up to 85% of infected cases but they may remain without symptoms during years or even decades, and clinical presentation varies. Determination of anti-HCV in sera is a fairly sensitive tool for the diagnosis, and confirmation requires the identification of HCV-RNA. Staging of the liver disease as well as definition of its present activity can be graded by liver biopsy. The aim of treatment is to stop the progression of the hepatic disease by inhibiting viral replication. Due to the low therapeutic efficacy combined with important side-effects, the administration of interferon and ribavirin have specific indications and contraindications. Predictive factors of therapeutic response, particularly viral load and genotypes of HCV, are useful in the evaluation of patients.
Assuntos
Hepatite C , Antivirais/uso terapêutico , Previsões , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Interferons/uso terapêutico , Ribavirina/uso terapêuticoRESUMO
It has been estimated that 3% of the world population is infected with the hepatitis C virus. Those who are blood product recipients or have been illicit drug users are at risk. Dental and medical procedures as well as tattooing and acupuncture are also risk factors. Chronic infection occurs in up to 85% of infected cases but they may remain without symptoms during years or even decades, and clinical presentation varies. Determination of anti-HCV in sera is a fairly sensitive tool for the diagnosis, and confirmation requires the identification of HCV-RNA. Staging of the liver disease as well as definition of its present activity can be graded by liver biopsy. The aim of treatment is to stop the progression of the hepatic disease by inhibiting viral replication. Due to the low therapeutic efficacy combined with important side-effects, the administration of interferon and ribavirin have specific indications and contraindications. Predictive factors of therapeutic response, particularly viral load and genotypes of HCV, are useful in the evaluation of patients.
Estima-se que cerca de 3% da população mundial esteja infectada pelo vírus da hepatite C. Todos os que receberam transfusão de sangue ou seus componentes e os usuários de drogas podem estar infectados. Procedimentos odontológicos, médicos, tatuagem ou acupuntura também constituem fatores de risco. A infecção se cronifica em até 85% dos indivíduos, com evolução assintomática durante anos ou décadas e apresentação clínica variada. Para o diagnóstico, a determinação do anti-VHC revela-se muito sensível e a confirmação se faz pela determinação do RNA-VHC no sangue; o estadiamento da doença e a avaliação da atividade inflamatória pela biópsia hepática. O tratamento objetiva deter a progressão da doença hepática através da inibição da replicação viral. Devido à baixa eficácia terapêutica aliada a importantes efeitos colaterais do interferon e da ribavirina, esses medicamentos encontram indicações e contra-indicações específicas. Vários fatores preditivos de resposta ao tratamento, principalmente a carga viral e o genótipo do VHC, mostram-se úteis na avaliação dos pacientes.
Assuntos
Humanos , Hepatite C , Antivirais/uso terapêutico , Previsões , Hepatite C/diagnóstico , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Interferons/uso terapêutico , Ribavirina/uso terapêuticoRESUMO
The use of gene therapy continues to be a promising, yet elusive, alternative for the treatment of cancer. The origins of cancer must be well understood so that the therapeutic gene can be chosen with the highest chance of successful tumor regression. The gene delivery system must be tailored for optimum transfer of the therapeutic gene to the target tissue. In order to accomplish this, we study models of G1 cell-cycle control in both normal and transformed cells in order to understand the reasons for uncontrolled cellular proliferation. We then use this information to choose the gene to be delivered to the cells. We have chosen to study p16, p21, p53 and pRb gene transfer using the pCL-retrovirus. Described here are some general concepts and specific results of our work that indicate continued hope for the development of genetically based cancer treatments.
Assuntos
Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos/genética , Glioblastoma/genética , Glioblastoma/terapia , Retroviridae/genética , Animais , Ciclo Celular/genética , Ciclo Celular/fisiologia , Transformação Celular Neoplásica/genética , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Genes Supressores de Tumor , Humanos , Camundongos , RatosRESUMO
The use of gene therapy continues to be a promising, yet elusive, alternative for the treatment of cancer. The origins of cancer must be well understood so that the therapeutic gene can be chosen with the highest chance of successful tumor regression. The gene delivery system must be tailored for optimum transfer of the therapeutic gene to the target tissue. In order to accomplish this, we study models of G1 cell-cycle control in both normal and transformed cells in order to understand the reasons for uncontrolled cellular proliferation. We then use this information to choose the gene to be delivered to the cells. We have chosen to study p16, p21, p53 and pRb gene transfer using the pCL-retrovirus. Described here are some general concepts and specific results of our work that indicate continued hope for the development of genetically based cancer treatments