RESUMO
BACKGROUND & AIMS: HIV/HCV co-infected patients with hepatocellular carcinoma (HCC) have poorer survival than HCV mono-infected patients. We aimed to evaluate the prognostic factors for survival. METHODS: From 2006 to 2013, 55 incident HCCs among HIV+/HCV+ patients, from three ANRS cohorts, were compared with 181 HCCs in HIV-/HCV+ patients from the ANRS Cirvir cohort. RESULTS: HIV+/HCV+ patients were younger (50 years [IQR: 47-53] vs 62 [54-70], P < 0.001), male (89% vs 63%, P < 0.001) than HIV-/HCV+ patients. At HCC diagnosis, both groups had a majority of non-responders to anti-HCV-therapy, and HIV+/HCV+ patients had more frequently known a previous cirrhosis decompensation (31% vs 14%, P = 0.005). At diagnostic imaging, there were more infiltrative forms of HCC in HIV+/HCV+ group (24% vs 14%, P < 0.001), associated with tumour portal thrombosis in 29%. During a median follow-up period of 11.96 [5.51-27] months since HCC diagnosis, a majority of palliative treatments were decided in HIV+/HCV+ patients (51% vs 19%, P < 0.001). The 1 and 2-year crude survival rates were 61% versus 78% and 47% versus 63%, P = 0.003 respectively. In a Cox model multivariate analysis adjusted for the cohort, age and sex, the most important prognostic factor for survival was the infiltrative form of the tumour (aRR: 8.10 [4.17-15.75], P < 0.001). CONCLUSIONS: The radiological aggressiveness of the tumour is the best prognostic factor associated with poorer survival of HCC in HIV+/HCV+ patients. High α-foetoprotein level and decompensated cirrhosis are other ones. This justifies a particular attention to the detection and the management of small nodules in this high-risk population.
Assuntos
Antivirais/uso terapêutico , Carcinoma Hepatocelular/mortalidade , Infecções por HIV/tratamento farmacológico , Hepatite C/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Idoso , Carcinoma Hepatocelular/terapia , Coinfecção/tratamento farmacológico , Coinfecção/virologia , Feminino , França , Infecções por HIV/complicações , Hepatite C/complicações , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
OBJECTIVE: Expression of human apolipoprotein (h-apo) A-IV in apoE-deficient (apoE(0)) mice (h-apoA-IV/E(0)) reduces susceptibility to atherosclerosis. Chronic infection mimicked by exposure to lipopolysaccharide (LPS) increases the size of atherosclerosis lesions in apoE(0) mice. Thus, we used h-apoA-IV/E(0) mice to determine whether h-apoA-IV plays a protective role after LPS administration. METHODS AND RESULTS: We injected apoE(0), h-apoA-IV/E(0), and C57Bl/6 (wild-type) mice intraperitoneally with either LPS or phosphate-buffered saline (PBS) every week for 10 weeks. Atherosclerotic lesions were significantly smaller in h-apoA-IV/E(0) mice treated with LPS than in their apoE(0) counterparts. The titers of IgG2a and IgG2b autoantibodies to oxidized low-density lipoprotein (LDL) were higher in the LPS-group of h-apoA-IV/E(0) mice than in apoE(0) mice, suggesting that the Th1 response is stronger in the presence of h-apoA-IV. Lymphocytes from the blood, liver, spleen, and thymus of h-apoA-IV/E(0) mice treated with LPS produced less IL-4, INF-gamma, and TNF-alpha proinflammatory cytokines than their apoE(0) counterparts. Furthermore, we demonstrated that recombinant h-apoA-IV blocks the LPS-induced stimulation of monocytes. CONCLUSIONS: The expression of h-apoA-IV in apoE(0) mice reduces the susceptibility to atherogenesis and decreases the secretion of proinflammatory cytokines after LPS administration.
Assuntos
Apolipoproteínas A/fisiologia , Arteriosclerose/prevenção & controle , Citocinas/metabolismo , Animais , Apolipoproteínas A/genética , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Arteriosclerose/sangue , Arteriosclerose/genética , Arteriosclerose/patologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Células Sanguíneas/metabolismo , Citocinas/biossíntese , Humanos , Infecções , Lipídeos/sangue , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/toxicidade , Lipoproteínas LDL/imunologia , Fígado/metabolismo , Fígado/patologia , Subpopulações de Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Monócitos/efeitos dos fármacos , Monócitos/fisiologia , Proteínas Recombinantes de Fusão/fisiologia , Baço/metabolismo , Baço/patologia , Timo/metabolismo , Timo/patologiaRESUMO
To assess prognostic factors for survival and describe Model for End-Stage liver disease (MELD) dynamics in human immunodeficiency virus+/hepatitis C virus+ (HIV+/HCV+) patients after an initial episode of hepatic decompensation.An HIV+/HCV+ cohort of patients experiencing an initial decompensation episode within the year preceding enrollment were followed prospectively. Clinical and biological data were collected every 3 months. Predictors for survival were identified using Kaplan-Meier curves and Cox models. A 2-slope-mixed linear model was used to estimate MELD score changes as a function of survival.Sixty seven patients were included in 32 centers between 2009 and 2012 (72% male; median age: 48 years [interquartile ratio (IQR):45-52], median follow-up: 22.4 months [range: 0.5-65.3]). Overall survival rates were 86%, 78%, and 59% at 6, 12, and 24 months, respectively. Under multivariate analysis, the MELD score at initial decompensation was predictive of survival, adjusted for age, type of decompensation, baseline CD4 counts, and further decompensation during follow-up as a time-dependent variable. The adjusted hazard ratio of death was 1.32 for a score 3 points higher (95% CI: [1.06-1.63], P = 0.012). MELD score kinetics within the 6 months after initial decompensation differed significantly between non-deceased and deceased patients, with a decreased (-0.49/month; P = 0.016), versus a flat (+0.06/month, P = 0.753) mean change in score.MELD is an effective tool to predict survival in HIV+/HCV+ patients with decompensated cirrhosis. A non-decreasing MELD score within 6 months following this initial decompensation episode may benefit from privileged access to liver transplantation in this poor prognosis population.
Assuntos
Coinfecção/epidemiologia , Doença Hepática Terminal/epidemiologia , Infecções por HIV/epidemiologia , Hepatite C Crônica/epidemiologia , Medição de Risco/métodos , Doença Hepática Terminal/etiologia , Feminino , Seguimentos , França/epidemiologia , Infecções por HIV/complicações , Hepatite C Crônica/complicações , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida/tendênciasRESUMO
Atherosclerosis has many features of a chronic inflammatory disease. To evaluate the role of lipopolysaccharide (LPS), mimicking a systemic infection, we administered the endotoxin to apolipoprotein E (apoE)-deficient mice. LPS injections increase the atherosclerotic lesion size and the titer of plasma autoantibodies directed against oxidized low-density lipoprotein. We found that Th1 and Th2 T cells help the activation of B cells in the autoimmune response. The number of interleukin-4 producing natural killer T cells is highly increased in peripheral blood, liver, spleen and thymus cells, as well as in the atherosclerotic plaque of the LPS-treated mice. Finally, an important adventitial infiltrate of activated lymphocytes, sign of an advanced atherosclerosis, is observed only in the LPS-treated mice. Our results demonstrate that LPS administration aggravates atherosclerosis in apoE-deficient mice. LPS-injected apoE-deficient mice appear to be an excellent animal model to analyze the implementation of new therapeutic approaches in the treatment of atherosclerosis by manipulating immunological effectors.
Assuntos
Arteriosclerose/imunologia , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Lipopolissacarídeos , Células Th1/imunologia , Células Th2/imunologia , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Autoanticorpos/sangue , Linfócitos B/imunologia , Doença Crônica , Citocinas/biossíntese , Progressão da Doença , Citometria de Fluxo , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-4/biossíntese , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Lipídeos/sangue , Lipoproteínas LDL/imunologia , Fígado/patologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Baço/patologia , Timo/patologiaRESUMO
Various studies have correlated apolipoprotein (apo) A-I, the major component high-density lipoprotein, with protection against development of cardiovascular disease. Although apoA-I expression has been previously detected in the liver and intestine, we have discovered that the human apoA-I gene is also expressed in the heart. Using transgenic (Tg) mice generated with the human apoA-I/C-III/A-IV gene cluster and Tg mice produced with just the 2.2 kb human apoA-I gene, we have detected significant levels of apoA-I expression in the heart. Furthermore, the detection of apoA-I expression in the hearts of human apoA-I Tg mice indicates that the minimal regulatory elements necessary for cardiac expression of the gene are located near its coding sequence. To determine if the apoA-I gene is also expressed in the human heart, similar analyses were performed, where apoA-I expression was found in both adult and fetal hearts. Furthermore in-depth investigation of the various regions of human and Tg mouse hearts revealed that the apoA-I mRNA was present in the ventricles and atria, but not in the aorta. In situ hybridization of Tg mouse hearts revealed that apoA-I expression was restricted to the cardiac myocyte cells. Finally, heart explants and cardiac primary culture experiments with Tg mice showed secretion of particles containing the human apoA-I protein, and metabolic labeling experiments have also detected a 28 kDa human apoA-I protein secreted from the heart. From these novel findings, new insights into the role and function of apoA-I can be extrapolated.
Assuntos
Apolipoproteína A-I/genética , Coração/metabolismo , Miocárdio/metabolismo , Animais , Apolipoproteína A-I/metabolismo , Sequência de Bases , Primers do DNA , Regulação Enzimológica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reação em Cadeia da Polimerase , RNA Mensageiro/genéticaRESUMO
Ampullary organs of Acipenser naccarii sturgeons were examined by optical and electronic microscopy (transmission electron microscopy and scanning electron microscopy) from hatching until 1 month later when the juvenile phase is completely established. It was observed that, when A. naccarii begins to feed actively, the ultrastructural characteristics of ampullary organs already correspond to those of adult animals. These organs may, therefore, be functional and, together with taste buds, facilitate food search after exhaustion of yolk sac food reserves. Mature ampullary organs of A. naccarii are formed by an ampulla that communicates with the exterior by means of a short channel. These ampullae correspond to the sensory portion of these receptors and are formed by two cell types: receptor cells and support cells. Receptor cells present a kinocilium on their free surface and establish ribbon synapses with axon nerve endings that arise from the underlying conjunctive tissue. Support cells enclose receptor cells, bear stereocilia and occasional cilia, and are of a secretory nature. The mucus associated with ampullary organs mainly comprises neutral mucopolysaccharides, whereas mucopolysaccharides are usually acid in other fish groups.
Assuntos
Peixes/anatomia & histologia , Órgãos dos Sentidos/ultraestrutura , Células Receptoras Sensoriais/ultraestrutura , Animais , Cílios/ultraestrutura , Peixes/embriologia , Peixes/crescimento & desenvolvimento , Glicosaminoglicanos/análise , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Muco/química , Organogênese , Órgãos dos Sentidos/química , Órgãos dos Sentidos/embriologia , Órgãos dos Sentidos/crescimento & desenvolvimento , Células Receptoras Sensoriais/embriologia , Células Receptoras Sensoriais/crescimento & desenvolvimentoRESUMO
Fructose intake has increased steadily during the past two decades. The objective of this study was to determine the effect of fructose intake on lipid metabolism in apolipoprotein (apo) AI-CIII-AIV transgenic (Tg) mice that have severe hypertriglyceridemia and moderate hypercholesterolemia. Tg and control mice were fed for 9 mo a commercial nonpurified diet and had free access to water or 250 g/L fructose solution. In Tg mice, fructose intake increased triglycerides and cholesterol but did not induce insulin resistance. There were no differences in human hepatic apo AI and apo CIII mRNA levels in fructose-fed mice compared with untreated mice, but apo AIV mRNA was greater, indicating a differential expression of the apo AI and apo AIV genes in response to dietary perturbations. Interestingly, the plasma concentration of the three human apolipoproteins was enhanced in fructose-fed Tg mice compared with untreated Tg mice. Our data suggest that long-term fructose consumption had strong adverse effects in this hyperlipidemic mouse model.