RESUMO
At present, there is no ideal model for predicting the short-term outcome of patients with acute-on-chronic hepatitis B liver failure (ACHBLF). This study aimed to establish and validate a prognostic model by using the classification and regression tree (CART) analysis. A total of 1047 patients from two separate medical centres with suspected ACHBLF were screened in the study, which were recognized as derivation cohort and validation cohort, respectively. CART analysis was applied to predict the 3-month mortality of patients with ACHBLF. The accuracy of the CART model was tested using the area under the receiver operating characteristic curve, which was compared with the model for end-stage liver disease (MELD) score and a new logistic regression model. CART analysis identified four variables as prognostic factors of ACHBLF: total bilirubin, age, serum sodium and INR, and three distinct risk groups: low risk (4.2%), intermediate risk (30.2%-53.2%) and high risk (81.4%-96.9%). The new logistic regression model was constructed with four independent factors, including age, total bilirubin, serum sodium and prothrombin activity by multivariate logistic regression analysis. The performances of the CART model (0.896), similar to the logistic regression model (0.914, P=.382), exceeded that of MELD score (0.667, P<.001). The results were confirmed in the validation cohort. We have developed and validated a novel CART model superior to MELD for predicting three-month mortality of patients with ACHBLF. Thus, the CART model could facilitate medical decision-making and provide clinicians with a validated practical bedside tool for ACHBLF risk stratification.
Assuntos
Insuficiência Hepática Crônica Agudizada/mortalidade , Insuficiência Hepática Crônica Agudizada/patologia , Técnicas de Apoio para a Decisão , Hepatite B Crônica/complicações , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de SobrevidaRESUMO
BACKGROUND: Interventional treatment for overt hepatic encephalopathy (OHE), includes non-absorbable disaccharides, neomycin, rifaximin, L-ornithine-L-aspartate and branched chain amino acids (BCAA). However, the optimum regimen remains inconclusive. AIM: To compare interventions in terms of patients' adverse events and major clinical outcomes. METHODS: Literature search of PubMed, Embase, Scopus, and Cochrane Library studies published up to July 31 2014. RCTs of above interventions in OHE patients were included. Network meta-analysis combined direct and indirect evidence to estimate odds ratios (ORs) and mean difference (MD) between treatments and the probabilities of ranking for treatment based on clinical outcomes. RESULTS: Twenty eligible RCTs were included. When compared with observation, only L-ornithine-L-aspartate (OR 3.71, P < 0.001) and BCAA (OR 3.37, P < 0.001) improved clinical efficacy significantly. However, when L-ornithine-L-aspartate was compared with BCAA, non-absorbable disaccharides and neomycin, there was a trend suggesting that L-ornithine-L-aspartate may be the most effective intervention with respect to clinical improvement (OR 1.10), rifaximin (OR 1.31), non-absorbable disaccharides (OR 2.75), neomycin (OR 2.22). In addition, L-ornithine-L-aspartate (MD -20.18, 95% CI -40.12 to -0.27) provided a significant reduction in blood ammonia concentration compared with observation. Neomycin appeared to be associated with more adverse events in comparison with non-absorbable disaccharides (OR 10.15), rifaximin (OR 17.31), L-ornithine-L-aspartate (OR 3.16) or BCAA (OR 7.69). CONCLUSIONS: L-ornithine-L-aspartate treatment may show a trend in superiority for clinical efficacy among standard interventions for OHE. Rifaximin shows the greatest reduction in blood ammonia concentration, and treatment with neomycin demonstrates a higher probability in causing adverse effects among the five compared interventions.
Assuntos
Aminoácidos de Cadeia Ramificada/uso terapêutico , Dipeptídeos/uso terapêutico , Dissacarídeos/uso terapêutico , Encefalopatia Hepática/tratamento farmacológico , Neomicina/uso terapêutico , Rifamicinas/uso terapêutico , Aminoácidos de Cadeia Ramificada/efeitos adversos , Amônia/sangue , Dipeptídeos/efeitos adversos , Dissacarídeos/efeitos adversos , Fármacos Gastrointestinais/uso terapêutico , Humanos , Saúde Mental , Neomicina/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Rifamicinas/efeitos adversos , RifaximinaRESUMO
BACKGROUND: Major adjuvant therapies for biliary tract cancer (BTC) include fluorouracil, gemcitabine and chemoradiation (CRT), but the optimum regimen remains inconclusive. AIM: To compare these therapies in terms of patient survival rates after resection and toxic effects. METHODS: We searched PubMed for controlled trials comparing the above three therapies with each other or observation alone until 31 January 2014. We estimated the hazard ratios (HRs) for death and odds ratios (ORs) for toxic effects among different therapies. Subgroup analyses based on positive lymph node or resection margin were also performed. RESULTS: Twelve eligible articles were included. Gemcitabine improved 5-year survival (HR 2.12, 95% CI, confidence interval 1.23-4.02, P = 0.01), whereas fluorouracil (HR 1.61, 95% CI 0.74-3.67) and CRT (HR 1.55, 95% CI 0.82-3.32) provided a poorer survival outcome compared with gemcitabine after 1 year. Similarly, for 5-year survival rates, although differing, CRT did not provide a significant improvement in survival (HR 0.46, 95% CI 0.20-0.97) compared with gemcitabine. Fluorouracil did not appear to provide benefit over gemcitabine (HR 1.56, 95% CI 0.77-3.35). CRT was ranked highest for toxic effects including haematological (OR 5.45, 95% CI 0.01-483.85) and nonhaematological (OR 5.77, 95% CI 0.01-3807.40). CONCLUSIONS: Chemotherapy with gemcitabine is the optimum adjuvant treatment with a balanced benefit-toxicity ratio for resected biliary tract cancer. Chemoradiation was more likely to cause toxic effects.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias do Sistema Biliar/terapia , Quimiorradioterapia Adjuvante , Desoxicitidina/análogos & derivados , Fluoruracila/uso terapêutico , Neoplasias do Sistema Biliar/cirurgia , Desoxicitidina/uso terapêutico , Humanos , GencitabinaRESUMO
BACKGROUND AND PURPOSE: Fostamatinib is an inhibitor of spleen tyrosine kinase (TK). In patients, fostamatinib treatment was associated with increased BP. Some TK inhibitors cause BP elevation, by inhibiting the VEGF receptor 2 (VEGFR2). Here, we have assessed the mechanistic link between fostamatinib-induced BP elevation and inhibition of VEGF signalling. EXPERIMENTAL APPROACH: We used conscious rats with automated blood sampling and radio telemetry and anaesthetized rats to measure cardiovascular changes. Rat isolated aorta and isolated hearts, and human resistance vessels in vitro were also used. NO production by human microvascular endothelial cells was measured with the NO-dependent probe, DAF-FM and VEGFR2 phosphorylation was determined in mouse lung, ex vivo. KEY RESULTS: In conscious rats, fostamatinib dose-dependently increased BP. The time course of the BP effect correlated closely with the plasma concentrations of R406 (the active metabolite of fostamatinib). In anaesthetized rats, infusion of R406 increased BP and decreased femoral arterial conductance. Endothelial function was unaffected, as infusion of R406 did not inhibit hyperaemia- or ACh-induced vasodilatation in rats. R406 did not affect contraction of isolated blood vessels. R406 inhibited VEGF-stimulated NO production from human endothelial cells in vitro, and treatment with R406 inhibited VEGFR2 phosphorylation in vivo. R406 inhibited VEGF-induced hypotension in anaesthetized rats. CONCLUSIONS AND IMPLICATIONS: Increased vascular resistance, secondary to reduced VEGF-induced NO release from endothelium, may contribute to BP increases observed with fostamatanib. This is consistent with the elevated BP induced by other drugs inhibiting VEGF signalling, although the contribution of other mechanisms cannot be excluded.
Assuntos
Pressão Sanguínea/fisiologia , Oxazinas/farmacologia , Piridinas/farmacologia , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/biossíntese , Aminopiridinas , Animais , Pressão Sanguínea/efeitos dos fármacos , Células Cultivadas , Humanos , Insetos , Masculino , Camundongos , Camundongos Nus , Dados de Sequência Molecular , Morfolinas , Óxido Nítrico/biossíntese , Técnicas de Cultura de Órgãos , Pirimidinas , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: The ATP-gated P2X(7) receptor has been shown to play a role in several inflammatory processes, making it an attractive target for anti-inflammatory drug discovery. We have recently identified a novel set of cyclic imide compounds that inhibited P2X(7) receptor-mediated dye uptake in human macrophage THP-1 cells. In this study the actions and selectivity of one of these compounds, AZ11645373, were characterized. EXPERIMENTAL APPROACH: We measured membrane currents, calcium influx, and YOPRO-1 uptake from HEK cells expressing individual P2X receptors, and YOPRO1 uptake and interleukin-1beta release from THP-1 cells in response to ATP and the ATP analogue benzoylbenzoyl ATP (BzATP). KEY RESULTS: AZ11645373 up to 10 microM, had no agonist or antagonist actions on membrane currents due to P2X receptor activation at human P2X(1), rat P2X(2), human P2X(3), rat P2X(2/3), human P2X(4), or human P2X(5) receptors expressed in HEK cells. AZ11645373 inhibited human P2X(7) receptor responses in HEK cells in a non-surmountable manner with K (B) values ranging from 5 - 20 nM, with mean values not significantly different between assays. K (B) values were not altered by removing extracellular calcium and magnesium. ATP-evoked IL-1beta release from lipopolysaccharide-activated THP-1 cells was inhibited by AZ11645373, IC(50) = 90 nM. AZ11645373 was > 500-fold less effective at inhibiting rat P2X(7) receptor-mediated currents with less than 50% inhibition occurring at 10 microM. CONCLUSIONS AND IMPLICATIONS: AZ11645373 is a highly selective and potent antagonist at human but not rat P2X(7) receptors and will have much practical value in studies of human cells.
Assuntos
Anti-Inflamatórios/farmacologia , Imidas/farmacologia , Antagonistas do Receptor Purinérgico P2 , Tiazóis/farmacologia , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Compostos de Anilina , Animais , Benzoxazóis , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Corantes Fluorescentes , Humanos , Interleucina-1beta/metabolismo , Ativação do Canal Iônico/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Potenciais da Membrana/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Técnicas de Patch-Clamp , Compostos de Quinolínio , Ratos , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Especificidade da Espécie , Tiazóis/química , Transfecção , XantenosRESUMO
The synthesis and pharmacological evaluation of a new series of potent P2X(7) receptor antagonists is disclosed. The compounds inhibit BzATP-mediated pore formation in THP-1 cells. The distribution of the P2X(7) receptor in inflammatory cells, most notably the macrophage, mast cell and lymphocyte, suggests that P2X(7) antagonists have a significant role to play in the treatment of inflammatory disease.
Assuntos
Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/síntese química , Antagonistas do Receptor Purinérgico P2 , Trifosfato de Adenosina/farmacologia , Linhagem Celular , Humanos , Cinética , Estrutura Molecular , Receptores Purinérgicos P2X7 , Relação Estrutura-AtividadeRESUMO
Destruction of bone tissue due to disease and inefficient bone healing after traumatic injury may be addressed by tissue engineering techniques. Growth factor, cytokine protein, and gene therapies will be developed, which, in conjunction with suitable carriers, will regenerate missing bone or help in cases of defective healing.
Assuntos
Regeneração Óssea/fisiologia , Fraturas Ósseas/fisiopatologia , Fraturas Ósseas/terapia , Engenharia Tecidual/métodos , Animais , Terapia Genética , HumanosRESUMO
In the United States, between 40 and 90 million hospital days are lost per year as a result of trauma and surgical procedures which result in the loss of functional tissue. This is estimated to cost the economy and healthcare providers in excess of US$ 500 billion, a figure that is increasing because of extending population lifespan. Tissue engineering and gene therapies are radical new treatments that are aimed at tissue regeneration ranging from dermal, osteal and occular repair to the replacement of failing tissue with entire biosynthetic organs. Over the last decade, numerous proteins have been identified that are able to direct the synthesis of new tissue. Such proteins include growth factors, cytokines and, more recently, transcription factors.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/uso terapêutico , Proteínas Imediatamente Precoces , Proteínas de Saccharomyces cerevisiae , Fatores de Transcrição/metabolismo , Fatores de Transcrição/uso terapêutico , Cicatrização/efeitos dos fármacos , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/análise , Proteínas de Ligação a DNA/genética , Proteína 1 de Resposta de Crescimento Precoce , Proteínas Fúngicas/metabolismo , Regulação da Expressão Gênica , Humanos , Proteínas Nucleares/metabolismo , Osteoartrite/tratamento farmacológico , Prognóstico , Regiões Promotoras Genéticas , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/genéticaRESUMO
Effective tissue repair results from a rapid, temporally orchestrated series of events. At the site of local tissue injury, the production of many growth factors and cytokines is, in part, stimulated by the early growth response transcription factors such as Egr-1. Egr-1 protein binds to a family of corepressor proteins called NAB which function to block or limit Egr-1 trans-activation of cognate target genes. NAB2 blocks Egr-1 activation of the tissue factor (TF) promoter, Egr-1 stimulated production of PDGF-AB, HGF, TGFbeta(1), and VEGF and the endogenous expression of PDGF-AB and TGFbeta(1). Expression of a wild-type NAB2 but not a dominant negative NAB2 mutant abrogates Egr-1 driven TF promoter activity and tubule formation in an in vitro model of angiogenesis. These findings may have importance in any tissue that is subject to scarring after acute or chronic injury.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Substâncias de Crescimento/biossíntese , Proteínas Imediatamente Precoces , Proteínas de Neoplasias , Neovascularização Fisiológica/efeitos dos fármacos , Proteínas Repressoras/farmacologia , Fatores de Transcrição/metabolismo , Células Cultivadas , Proteína 1 de Resposta de Crescimento Precoce , Expressão Gênica/efeitos dos fármacos , Humanos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Regiões Promotoras Genéticas , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Tromboplastina/genética , Cicatrização/efeitos dos fármacosRESUMO
Endothelial dysfunction plays a major role in the pathogenesis of atherosclerosis. Pro-inflammatory cytokines such as interleukin-1 beta and tumour necrosis factor alpha activate endothelial cells changing their resting phenotype to become pro-adhesive, pro-thrombotic and pro-atherogenic. Phage display in vivo biopanning has been used to identify peptide sequences that home to diseased regions of the vessel wall in low density lipoprotein receptor (LDLr) knockout mice. In LDLr knockout mice, peptide sequence determinants exhibiting organ specificity have been isolated. These sequences have applications for gene delivery, drug delivery and for improving contrast agents for vascular imaging.
Assuntos
Arteriosclerose/metabolismo , Sistemas de Liberação de Medicamentos , Receptores de LDL/metabolismo , Animais , Artérias/metabolismo , Arteriosclerose/patologia , Arteriosclerose/terapia , Bacteriófagos/genética , Sítios de Ligação , Ligação Competitiva , Modelos Animais de Doenças , Técnicas de Transferência de Genes , Rim/metabolismo , Camundongos , Camundongos Knockout , Especificidade de Órgãos , Biblioteca de Peptídeos , Peptídeos/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Análise de Sequência de ProteínaRESUMO
The healing of tissue involves a wide range of molecular, cellular, and physiological events that are coordinated in a temporally specific manner. The cellular transcription factor early growth response factor 1 (Egr-1) is expressed minutes after acute injury and serves to stimulate the production of a class of growth factors whose role is to promote tissue repair. We have studied the effects of Egr-1 expression at the site of dermal wounding in rodents. We find that Egr-1 promotes angiogenesis in vitro and in vivo, increases collagen production, and accelerates wound closure. These results show that Egr-1 gene therapy accelerates the normal healing process and raises the potential use of this therapeutic transcription factor for any aspect of tissue repair.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas Imediatamente Precoces , Fatores de Transcrição/genética , Cicatrização , Animais , Biolística , Colágeno/biossíntese , DNA Complementar/metabolismo , Proteína 1 de Resposta de Crescimento Precoce , Fatores de Crescimento Endotelial/biossíntese , Imunofluorescência , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Linfocinas/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Fisiológica/genética , Plasmídeos/genética , Plasmídeos/metabolismo , Fator de Crescimento Derivado de Plaquetas/metabolismo , Ratos , Ratos Sprague-Dawley , Pele/metabolismo , Fatores de Tempo , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta1 , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , beta-Galactosidase/metabolismoRESUMO
A new method for assessing the costs of gun injuries to a health system examines data on paid amounts, comprehensive medical expenses, and expenses over time. The authors extracted claims using injury diagnosis codes from billing forms and medical charts. The study demonstrates that a claims database can be used to accurately measure health care costs associated with gun injuries. The study is the first to include gun-related injuries treated in ambulatory care settings and to track actual payments over time.
Assuntos
Custos de Cuidados de Saúde/estatística & dados numéricos , Ferimentos por Arma de Fogo/economia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/economia , Criança , Pré-Escolar , Serviço Hospitalar de Emergência/economia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minnesota , Admissão do Paciente/economiaRESUMO
Approximately 500,000 children and infants go into out-of-home placement in the United States each year. Increased attention is being given to the health care of children as they enter and remain in placement. This article describes a model, which has been in operation for 5 years, that provides medical assessments of children as they enter emergency out-of-home placement. The model is a community partnership with the county social service department, the police department, and the hospital. A computerized database that contains records for each child, including medical findings, has been helpful in developing a profile of the children served and contributes to continuity of care.
Assuntos
Cuidados no Lar de Adoção/organização & administração , Profissionais de Enfermagem , Atenção Primária à Saúde/organização & administração , Serviço Social/organização & administração , Adolescente , Criança , Pré-Escolar , Serviços de Saúde Comunitária/organização & administração , Continuidade da Assistência ao Paciente/organização & administração , Serviços Médicos de Emergência/organização & administração , Feminino , Humanos , Lactente , Masculino , Minnesota , Modelos Organizacionais , Avaliação de Programas e Projetos de SaúdeRESUMO
The early growth response factor-1 (Egr-1) gene encodes a zinc finger transcription factor which is critical for cell proliferation and differentiation. The human Egr-1 promoter comprises regulatory elements including two Sp1 sites, an AP1 site, two cAMP response elements and an Egr-1 binding site. In addition to these transcription factor binding sites, the promoter harbours five serum response elements (SREs) and associated binding sites for the Ets transcription factor family, previously identified from partial sequence data (Sakamoto et al, Oncogene 6; 867-871, 1991). We now report the full sequence of the human Egr-1 promoter and confirm the presence of a fifth serum response element. This element is functionally active in a minimal promoter vector in response to the MAP kinase kinase MEK1.
Assuntos
Proteínas de Ligação a DNA/genética , Proteínas Imediatamente Precoces , Regiões Promotoras Genéticas , Fatores de Transcrição/genética , Sequência de Bases , Sítios de Ligação , DNA/química , DNA/genética , Proteína 1 de Resposta de Crescimento Precoce , Humanos , Dados de Sequência Molecular , Sequências Reguladoras de Ácido Nucleico , Elementos de Resposta , Análise de Sequência de DNA , Homologia de Sequência do Ácido NucleicoRESUMO
In atherosclerosis, endothelial cells at sites of stenosis experience elevated levels of shear stress. We have constructed a series of shear stress-inducible transcription units (SITUs) expressing the luciferase reporter gene and determined their activation by fluid shear stress in transfected endothelial cells. Chimeric promoters were constructed that comprised basal transcription factor-binding sites coupled to a shear stress response element (SSRE). We have used consensus binding sites for transcription factors NF-kappaB, Ap1, Sp1, Oct1, and Egr-1/Sp1 in either the presence or absence of the previously defined "GAGACC" SSRE. The response of the promoters to shear stress was determined after transfection into human umbilical vein endothelial cells (HUVECs). After transient transfection into HUVECs, fluid shear stress activated the promoters by between two- and eightfold. The most responsive SITUs comprised an overlapping Sp1/Egr-1-binding site linked to a TATA box with (SP5) or without (SP7) the GAGACC SSRE. Instillation of SP5 DNA in vivo into the left carotid artery of rabbit and subsequent generation of a stenosis using a mechanical wire occluder caused a 10-fold upregulation of luciferase reporter gene expression at the site of vessel occlusion. These vectors show promise for therapeutic gene expression at sites of occlusive vascular disease.
Assuntos
Doenças Cardiovasculares/terapia , Endotélio Vascular/metabolismo , Terapia Genética , Regiões Promotoras Genéticas , Animais , Sequência de Bases , Células Cultivadas , Primers do DNA , Humanos , Coelhos , Transcrição Gênica , TransfecçãoRESUMO
Hemodynamic forces such as fluid shear stress have been shown to modulate the activity of an expanding family of genes involved in vessel wall homeostasis and the pathogenesis of vascular disease. We have investigated the effect of shear stress on tissue factor (TF) gene expression in human endothelial cells (ECs) and in a rat arterial model of occlusion. As measured by reverse transcriptase polymerase chain reaction, exposure of ECs to 1.5 N/m2 shear stress resulted in a time-dependent induction of endogenous TF transcripts of over 5-fold. Transient transfection of TF promoter mutants into cultured ECs suggests the involvement of the transcription factor Egr-1 in mediating the response of the TF promoter to shear stress. To address the importance of flow induction of Egr-1 in vivo, we have established a flow-restricted rat arterial model and determined the level of expressed Egr-1 and TF at the site of restricted flow using immunohistochemistry. We report an increase in the level of Egr-1 and TF protein in ECs expressed at the site of restricted flow. Elevated expression of Egr-1 and TF is restricted to a highly localized area, as evidenced by the fact that no significant increase in level can be detected at arterial sites distal to the site of occlusion. These findings suggest a direct role for Egr-1 in flow-mediated induction of TF and further substantiate the importance of shear stress as a modulator of vascular endothelial gene function in vivo.