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1.
J Neurosci ; 28(27): 6872-83, 2008 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-18596162

RESUMO

Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we studied the regulation of type III Nrg1 expression and evaluated the effect of decreased expression of the type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus, and ventral subiculum, regions involved in the regulation of sensorimotor gating and short-term memory. Adult heterozygous mutant mice with a targeted disruption for type III Nrg1 (Nrg1(tm1.1Lwr+/-)) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. Magnetic resonance imaging of type III Nrg1 heterozygous mice revealed hypofunction in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III Nrg1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between type III Nrg1 heterozygous mice and their wild-type littermates. Our findings demonstrate a role of type III Nrg1 signaling in the maintenance of corticostriatal components and in the neural circuits involved in sensorimotor gating and short-term memory.


Assuntos
Corpo Estriado/anormalidades , Hipocampo/anormalidades , Transtornos da Memória/genética , Proteínas do Tecido Nervoso/genética , Córtex Pré-Frontal/anormalidades , Transtornos de Sensação/genética , Animais , Atrofia/genética , Atrofia/metabolismo , Atrofia/fisiopatologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento/genética , Heterozigoto , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Ventrículos Laterais/anormalidades , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo/fisiologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/metabolismo , Malformações do Sistema Nervoso/fisiopatologia , Inibição Neural/genética , Vias Neurais/anormalidades , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Neuregulina-1 , Agonistas Nicotínicos/farmacologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Regiões Promotoras Genéticas/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transtornos de Sensação/metabolismo , Transtornos de Sensação/fisiopatologia
2.
J Pharmacol Toxicol Methods ; 57(1): 9-22, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17707659

RESUMO

INTRODUCTION: Prediction of the propensity of a compound to induce Torsades de Pointes continues to be a formidable challenge to the pharmaceutical industry. Development of an in vitro model for assessment of proarrhythmic potential offers the advantage of higher throughput and reduced compound quantity requirements when compared to in vivo studies. A rabbit isolated heart model (SCREENIT) has been reported to identify compounds with proarrhythmic potential based on the observance of compound-induced triangulation and instability of the monophasic action potential (MAP), ectopic beats, and reverse-use dependence of prolongation of the MAP duration. Previous reports have indicated that this model qualitatively identifies proarrhythmic compounds and suggest the use of this model to assign safety margins for human clinical use. The intent of this series of studies was to evaluate the impact of study design on the proarrhythmic concentration predicted by this model. METHODS: Nine compounds of varying proarrhythmic potential and a negative control were tested in a blinded fashion using a series of different experimental protocols: Compounds were tested at multiple concentration ranges and extended perfusion times were also evaluated. RESULTS: In general when the dataset is viewed as a whole, the model did identify proarrhythmic compounds, however the concentration at which action potential prolongation, triangulation, instability, reverse-use dependence and ectopic beats occurred often varied based on the concentration range selected. Further analysis using extended compound perfusion times demonstrated that variability may be due in part to lack of adequate equilibration of compound with the cardiac tissue. DISCUSSION: We report that the model correctly identified proarrhythmic agents in a qualitative manner, but that study design impacts the proarrhythmic concentration derived from the model.


Assuntos
Arritmias Cardíacas/induzido quimicamente , Fármacos Cardiovasculares/efeitos adversos , Potenciais de Ação/efeitos dos fármacos , Animais , Simulação por Computador , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Técnicas Eletrofisiológicas Cardíacas , Sistema de Condução Cardíaco/efeitos dos fármacos , Modelos Biológicos , Valor Preditivo dos Testes , Coelhos
3.
J Acquir Immune Defic Syndr ; 41(5): 582-9, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16652026

RESUMO

BACKGROUND AND AIMS: The significance of normal alanine aminotransferase (ALT) levels in patients with HIV/hepatitis C virus (HCV) coinfection is not well understood. METHODS: We performed a cross-sectional retrospective analysis on consecutive HIV/HCV-coinfected patients (n = 89) who underwent a liver biopsy during a 2-year period. Similar data were also collected on HCV-monoinfected patients (n = 117). RESULTS: Mean ALT levels and the percentage of patients with normal ALT (< or =40 U/L) levels were similar in HIV/HCV-coinfected (mean +/- SD, 81.7 +/- 56.1 U/L; 21%) and HCV-monoinfected patients (97.3 +/- 100.7 U/L; 18%; P = 0.19 and 0.54, respectively). Coinfected patients, however, had significantly advanced necroinflammation (P= 0.001) and fibrosis (P = 0.02) compared with monoinfected patients. The percentage of patients with advanced necroinflammation (grades 3 or 4) was lower in HCV-monoinfected patients with normal ALT levels compared with those with elevated ALT (5% vs 20%, respectively). In contrast, the percentage of coinfected patients with advanced necroinflammation was similar whether the patient had normal or elevated ALT levels (32% vs 37%, respectively). CONCLUSIONS: In coinfected patients, normal ALT levels are not an indicator of mild necroinflammation and may not portend a more benign disease course.


Assuntos
Alanina Transaminase/sangue , Infecções por HIV/complicações , Hepatite C/complicações , Adulto , Aspartato Aminotransferases/sangue , Feminino , Genótipo , Infecções por HIV/sangue , HIV-1/genética , Hepacivirus/genética , Hepatite C/sangue , Hepatite C/epidemiologia , Humanos , Inflamação/virologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Grupos Raciais , Valores de Referência , Fatores de Risco , Carga Viral
4.
J Acquir Immune Defic Syndr ; 37(1): 1125-31, 2004 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-15319671

RESUMO

Coinfection with HIV and hepatitis C virus (HCV)-specific immune responses, increases hepatic inflammation, accelerates hepatic fibrosis, and is associated with deceased treatment responses. We quantified intrahepatic lymphocyte and hepatocyte phenotypes in HCV-infected patients with (n = 38) and without (n = 41) HIV infection. A single pathologist counted positive cells in 5 portal and 5 lobular areas. Coinfected patients had 6.81 +/- 1.9 fewer CD4 cells per portal field (10.58 +/- 1.12 vs. 4.97 +/- 1.09 cells/high-power field [HPF]; P < 0.001) and 0.48 +/- 0.15 more apoptotic lymphocytes per lobular field (0.16 +/- 0.06 vs. 0.64 +/- 0.15 cell/HPF; P = 0.002) than monoinfected patients. The number of portal CD4 cells was not associated with the peripheral CD4 cell number. Portal and lobular CD8 cells did not differ between the 2 groups. Portal proliferative hepatocytes were increased in coinfected patients with HIV RNA levels of >400 copies/mL (1.13 +/- 0.32 cells/HPF; P = 0.01) compared with those with undetectable HIV RNA (0.46 +/- 0.09 cell/HPF) and monoinfected patients (0.45 +/- 0.08 cell/HPF). In conclusion, HIV coinfection is associated with fewer portal CD4 cells and increased lobular lymphocyte apoptosis that may impact on the natural history of HCV infection.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/complicações , Hepatite C/complicações , Fígado/imunologia , Divisão Celular , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Hepacivirus/imunologia , Hepatite C/imunologia , Hepatite C/virologia , Hepatócitos/fisiologia , Humanos , Imunofenotipagem , Fígado/patologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade
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