RESUMO
PURPOSE: Deep neuromuscular blockade (NMB) can improve surgical conditions and possibly pain after low-risk laparoscopic surgery. We hypothesized that targeting a deep level of NMB by a continuous compared with an on-demand infusion of rocuronium could improve surgical conditions in patients undergoing thoraco-laparoscopic esophagectomy. METHODS: In this single-centre, randomized-controlled, double-blind trial, patients received either a continuous infusion of rocuronium 0.6 mg·kg-1·hr-1 (intervention) or NaCl 0.9% (control). Both surgeon and anesthesiologist were blinded to group assignment and the train-of-four measurements. Open-label rocuronium was given if requested (i.e., on-demand) by the surgeon. At the end of surgery, sugammadex was given if necessary to reverse the NMB. The primary outcome was the quality of surgical conditions during the abdominal phase of the operation as measured by the surgical rating scale (SRS). Secondary outcomes included the thoracic SRS, number of on-demand boluses, intraoperative surgical events, pain scores (up to 12 hr postoperatively), and duration of surgery. RESULTS: The median [interquartile range] abdominal SRS was not different between the intervention (4 [4-5]) and control (4 [4-5]) groups (median difference, 0; 95% confidence interval, 0 to 0; P = 0.45). The thoracic SRS was 4 [4-4] in both groups (P = 0.23). The median number of rocuronium bolus requests was higher in the control group compared with the intervention group (3 [3-6] vs 1 [0-2], respectively; P < 0.01). There were no between-group differences in intraoperative surgical events (P = 0.05), pain scores (overall P > 0.05), or duration of surgery (P = 0.95). CONCLUSIONS: Continuous rocuronium infusion did not improve surgical conditions when boluses of rocuronium were available on-demand. No major benefits in other outcomes were seen. TRIAL REGISTRATION: EUDRACT (2014-002147-18); registered 19 May, 2014 and clinicaltrials.gov (NCT02320734); registered 18 December, 2014.
Assuntos
Esofagectomia/métodos , Laparoscopia/métodos , Fármacos Neuromusculares não Despolarizantes/administração & dosagem , Rocurônio/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bloqueio Neuromuscular/métodos , Sugammadex/administração & dosagem , Toracoscopia/métodosRESUMO
BACKGROUND: In chronic liver disease, hepatic stellate cells (HSCs) are activated, highly proliferative and produce excessive amounts of extracellular matrix, leading to liver fibrosis. Elevated levels of toxic reactive oxygen species (ROS) produced during chronic liver injury have been implicated in this activation process. Therefore, activated hepatic stellate cells need to harbor highly effective anti-oxidants to protect against the toxic effects of ROS. AIM: To investigate the protective mechanisms of activated HSCs against ROS-induced toxicity. METHODS: Culture-activated rat HSCs were exposed to hydrogen peroxide. Necrosis and apoptosis were determined by Sytox Green or acridine orange staining, respectively. The hydrogen peroxide detoxifying enzymes catalase and glutathione-peroxidase (GPx) were inhibited using 3-amino-1,2,4-triazole and mercaptosuccinic acid, respectively. The anti-oxidant glutathione was depleted by L-buthionine-sulfoximine and repleted with the GSH-analogue GSH-monoethylester (GSH-MEE). RESULTS: Upon activation, HSCs increase their cellular glutathione content and GPx expression, while MnSOD (both at mRNA and protein level) and catalase (at the protein level, but not at the mRNA level) decreased. Hydrogen peroxide did not induce cell death in activated HSCs. Glutathione depletion increased the sensitivity of HSCs to hydrogen peroxide, resulting in 35% and 75% necrotic cells at 0.2 and 1mmol/L hydrogen peroxide, respectively. The sensitizing effect was abolished by GSH-MEE. Inhibition of catalase or GPx significantly increased hydrogen peroxide-induced apoptosis, which was not reversed by GSH-MEE. CONCLUSION: Activated HSCs have increased ROS-detoxifying capacity compared to quiescent HSCs. Glutathione levels increase during HSC activation and protect against ROS-induced necrosis, whereas hydrogen peroxide-detoxifying enzymes protect against apoptotic cell death.
Assuntos
Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Glutationa/metabolismo , Células Estreladas do Fígado/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Western Blotting , Catalase/genética , Catalase/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Imunofluorescência , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Masculino , Necrose , Oxidantes/farmacologia , RNA Mensageiro/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)-induced lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD. The aim of this study was to identify potential interactions between BA and FFA metabolism in NAFLD. Liver biopsies and serum samples from 113 morbidly obese patients receiving bariatric surgery, healthy individuals, and moderately obese NAFLD patients were studied. Serum FFA, BA, and M30 were increased in NASH versus simple steatosis, while adiponectin was significantly decreased. The NAFLD activity score (NAS) score correlated with BA levels and reversely with adiponectin. Adiponectin reversely correlated with CD95/Fas messenger RNA (mRNA) and hepatocellular apoptosis. The BA transporter high-affinity Na+ /taurocholate cotransporter (NTCP) and the BA synthesizing enzyme cholesterol 7 alpha-hydroxylase (CYP7A1) were significantly up-regulated in obese patients and hepatoma cells exposed to FFA. Up-regulation of NTCP and CYP7A1 indicate failure to activate small heterodimer partner (SHP) upon farnesoid X receptor (FXR) stimulation by increasing BA concentrations. In line with the NAS score, adiponectin levels were reversely correlated with BA levels. Adiponectin correlated with NTCP and affects Cyp7A1 expression both in vivo and in vitro. CONCLUSION: BA synthesis and serum BA levels correlated with disease severity in NAFLD, while adiponectin is reversely correlated. FFA exposure prevented SHP-mediated repression of NTCP and Cyp7A1 expression, which lead to increased BA synthesis and uptake. In NASH, BA accumulation induced hepatocyte cell death and late FXR activation failed to prevent hepatocyte injury due to decreased adiponectin levels. Early treatment with FXR ligands and/or adiponectin-receptor agonists might prevent NASH.
Assuntos
Adiponectina/fisiologia , Ácidos e Sais Biliares/efeitos adversos , Ácidos Graxos não Esterificados/fisiologia , Fígado Gorduroso/fisiopatologia , Fígado/lesões , Obesidade Mórbida/fisiopatologia , Receptores Citoplasmáticos e Nucleares/fisiologia , Adiponectina/sangue , Adulto , Ácidos e Sais Biliares/sangue , Ácidos e Sais Biliares/fisiologia , Colesterol 7-alfa-Hidroxilase/metabolismo , Comorbidade , Progressão da Doença , Ácidos Graxos não Esterificados/sangue , Fígado Gorduroso/sangue , Fígado Gorduroso/epidemiologia , Feminino , Humanos , Fígado/metabolismo , Fígado/fisiopatologia , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Obesidade/sangue , Obesidade/epidemiologia , Obesidade/fisiopatologia , Obesidade Mórbida/sangue , Obesidade Mórbida/epidemiologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Receptores Citoplasmáticos e Nucleares/sangue , Receptores Citoplasmáticos e Nucleares/metabolismo , Índice de Gravidade de Doença , Simportadores/metabolismo , Receptor fas/metabolismoRESUMO
BACKGROUND & AIMS: Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Krüppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARα-signaling. METHODS: Mice with either hepatocyte-specific depletion of KLF6 ('ΔHepKlf6') or global KLF6 heterozygosity (Klf6+/-) were fed a high fat diet (HFD) or chow for 8 or 16 weeks. Glucose and insulin tolerance tests were performed to assess insulin sensitivity. Overexpression and knockdown of KLF6 in cultured cells enabled the elucidation of underlying mechanisms. In liver samples from a cohort of 28 NAFLD patients, the expression of KLF6-related target genes was quantified. RESULTS: Mice with global- or hepatocyte-depletion of KLF6 have reduced body fat content and improved glucose and insulin tolerance, and are protected from HFD-induced steatosis. In hepatocytes, KLF6 deficiency reduces PPARα-regulated genes (Trb3, Pepck) with diminished PPARα protein but no change in Pparα mRNA, which is explained by the discovery that KLF6 represses miRNA 10b, which leads to induction of PPARα. In NAFLD patients with advanced disease and inflammation, the expression of miRNA 10b is significantly downregulated, while PEPCK mRNA is upregulated; KLF6 mRNA expression also correlates with TRB3 as well as PEPCK gene expression. CONCLUSIONS: KLF6 increases PPARα activity, whereas KLF6 loss leads to PPARα repression and attenuation of lipid and glucose abnormalities associated with a high fat diet. The findings establish KLF6 as a novel regulator of hepatic glucose and lipid metabolism in fatty liver.
Assuntos
Fígado Gorduroso/fisiopatologia , Fatores de Transcrição Kruppel-Like/fisiologia , PPAR alfa/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Transdução de Sinais/fisiologia , Ativação Transcricional/fisiologia , Animais , Células Cultivadas , Estudos de Coortes , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Fator 6 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/metabolismoRESUMO
UNLABELLED: The polymorphism, KLF6-IVS1-27A, in the Krüppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development of insulin resistance, central to NAFLD pathogenesis, we genotyped KLF6-IVS1-27 in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified messenger RNA (mRNA) expression of KLF6 and glucokinase (GCK), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine Klf6 knockdown model (DeltaKlf6). Klf6 overexpression studies in a mouse hepatocyte line were utilized to mechanistically link KLF6 with Gck promoter activity. KLF6-IVS1-27Gwt (i.e., less KLF6 splicing) was associated with stepwise increases in FPG and insulin and reduced hepatic insulin sensitivity. KLF6 binds to the liver-specific Gck promoter and activates a GCK promoter-reporter, identifying GCK as a KLF6 direct transcriptional target. Accordingly, in DeltaKlf6 hepatocytes Gck expression was reduced and stable transfection of Klf6 led to up-regulation of Gck. GCK and KLF6 mRNAs correlate directly in human NAFLD tissues and immunohistochemistry studies confirm falling levels of both KLF6 and GCK in fat-laden hepatocytes. In contrast to full-length KLF6, splice variant KLF6-SV1 increases in NAFLD hepatocytes and inversely correlates with glucokinase regulatory protein, which negatively regulates GCK activity. CONCLUSION: KLF6 regulation of GCK contributes to the development of hepatic insulin resistance. The KLF6-IVS1-27A polymorphism, which generates more KLF6-SV1, combats this, lowering hepatic insulin resistance and blood glucose.
Assuntos
Fígado Gorduroso/metabolismo , Fígado Gorduroso/fisiopatologia , Glucoquinase/metabolismo , Resistência à Insulina/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , Fígado/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Adulto , Animais , Biópsia , Glicemia/metabolismo , Estudos de Coortes , Modelos Animais de Doenças , Fígado Gorduroso/genética , Feminino , Genótipo , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fator 6 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Polimorfismo Genético/genética , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/metabolismoRESUMO
It is widely known that the liver is a central organ in lipogenesis, gluconeogenesis and cholesterol metabolism. However, over the last decades, a variety of pathological conditions highlighted the importance of metabolic functions within the diseased liver. As observed in Western societies, an increase in the prevalence of obesity and the metabolic syndrome promotes pathophysiological changes that cause non-alcoholic fatty liver disease (NAFLD). NAFLD increases the susceptibility of the liver to acute liver injury and may lead to cirrhosis and hepatocellular cancer. Alterations in insulin response, ß-oxidation, lipid storage and transport, autophagy and an imbalance in chemokines and nuclear receptor signaling are held accountable for these changes. Furthermore, recent studies revealed a role for lipid accumulation in inflammation and ER stress in the clinical context of liver regeneration and hepatic carcinogenesis. This review focuses on novel findings related to nuclear receptor signaling - including the vitamin D receptor and the liver receptor homolog 1 - in hepatic lipid and glucose uptake, storage and metabolism in the clinical context of NAFLD, liver regeneration, and cancer.
Assuntos
Fígado Gorduroso/metabolismo , Glucose/metabolismo , Metabolismo dos Lipídeos/fisiologia , Neoplasias Hepáticas/metabolismo , Humanos , Regeneração Hepática/fisiologia , Hepatopatia Gordurosa não Alcoólica , Receptores de Calcitriol/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
UNLABELLED: Hepatic stellate cells (HSCs) survive and proliferate in the chronically injured liver. ATP-binding cassette (ABC) transporters play a crucial role in cell viability by transporting toxic metabolites or xenobiotics out of the cell. ABC transporter expression in HSCs and its relevance to cell viability and/or activation have not been reported so far. The aim of this study was to investigate the expression, regulation, and function of multidrug resistance-associated protein (Mrp)-type and multidrug resistance protein (Mdr)-type ABC transporters in activated rat HSCs. Rat HSCs were exposed to cytokines or oxidative stress. ABC transporter expression was determined by quantitative polymerase chain reaction and immunohistochemistry. HSCs were exposed to the Mdr inhibitors verapamil and PSC-833 and the Mrp inhibitor MK571. Mdr and Mrp transporter function was evaluated with flow cytometry. Apoptosis was determined by activated caspase-3 and acridine orange staining, and necrosis was determined by Sytox green nuclear staining. An in vivo model of carbon tetrachloride (CCl(4))-induced liver fibrosis was used. With respect to hepatocytes, activated HSCs expressed high levels of Mrp1 and comparable levels of Mrp3, Mrp4, Mdr1a, and Mdr1b but not the hepatocyte-specific transporters bile salt export pump, Mrp2, and Mrp6. Mrp1 protein staining correlated with desmin staining in livers from CCl(4)-treated rats. Mrp1 expression increased upon activation of HSCs. Cytokines induced Mdr1b expression only. Oxidative stress was not a major regulator of Mdr and Mrp transporter expression. Activated HSCs became necrotic when exposed to the Mrp inhibitors. CONCLUSION: Activated HSCs contain relatively high levels of Mrp1. Mrp-type transporters are required for the viability of activated HSCs. Mrp-dependent export of endogenous metabolites is important for the survival of activated HSCs in chronic liver diseases.
Assuntos
Fígado/citologia , Fígado/fisiologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Transportadores de Cassetes de Ligação de ATP/classificação , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/fisiologia , Animais , Sobrevivência Celular/fisiologia , Células Cultivadas , Hepatócitos/metabolismo , Humanos , Interferon gama/farmacologia , Interleucina-1beta/farmacologia , Fígado/efeitos dos fármacos , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Estresse Oxidativo/fisiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/farmacologia , Membro 4 da Subfamília B de Transportadores de Cassetes de Ligação de ATPRESUMO
BACKGROUND: In chronic liver injury, hepatic stellate cells (HSCs) proliferate and produce excessive amounts of connective tissue causing liver fibrosis and cirrhosis. Oxidative stress has been implicated as a driving force of HSC activation and proliferation, although contradictory results have been described. AIM: To determine the effects of oxidative stress on activated HSC proliferation, survival and signalling pathways. METHODS: Serum-starved culture-activated rat HSCs were exposed to the superoxide anion donor menadione (5-25 micromol/L) or hydrogen peroxide (0.2-5 mmol/L). Haem oxygenase-1 mRNA expression, glutathione status, cell death, phosphorylation of mitogen-activated protein (MAP) kinases and proliferation were investigated. RESULTS: Menadione induced apoptosis in a dose- and time-dependent, but caspase-independent manner. Hydrogen peroxide induced necrosis only at extremely high concentrations. Both menadione and hydrogen peroxide activated Jun N-terminal kinase (JNK) and p38. Hydrogen peroxide also activated extracellular signal-regulated protein. Menadione, but not hydrogen peroxide, reduced cellular glutathione levels. Inhibition of JNK or supplementation of glutathione reduced menadione-induced apoptosis. Non-toxic concentrations of menadione or hydrogen peroxide inhibited platelet-derived growth factor- or/and serum-induced proliferation. CONCLUSION: Reactive oxygen species (ROS) inhibit HSC proliferation and promote HSC cell death in vitro. Different ROS induce different modes of cell death. Superoxide anion-induced HSC apoptosis is dependent on JNK activation and glutathione status.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Células Estreladas do Fígado/efeitos dos fármacos , Estresse Oxidativo , Transdução de Sinais/efeitos dos fármacos , Superóxidos/toxicidade , Laranja de Acridina , Animais , Western Blotting , Primers do DNA/genética , Células Estreladas do Fígado/citologia , Peróxido de Hidrogênio/toxicidade , MAP Quinase Quinase 4/metabolismo , Compostos Orgânicos , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas , Vitamina K 3/toxicidade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Most chronic liver diseases are accompanied by oxidative stress, which may induce apoptosis in hepatocytes and liver injury. Oxidative stress induces heme oxygenase-1 (HO-1) expression. This stress-responsive cytoprotective protein is responsible for heme degradation into carbon monoxide (CO), free iron, and biliverdin. CO is an important intracellular messenger; however, the exact mechanisms responsible for its cytoprotective effect are not yet elucidated. Thus, we investigated whether HO-1 and CO protect primary hepatocytes against oxidative-stress-induced apoptosis. In vivo, bile duct ligation was used as model of chronic liver disease. In vitro, primary hepatocytes were exposed to the superoxide anion donor menadione in a normal and in a CO-- containing atmosphere. Apoptosis was determined by measuring caspase-9, -6, -3 activity and poly(ADP-ribose) polymerase cleavage, and necrosis was determined by Sytox green staining. The results showed that (1) HO-1 is induced in chronic cholestatic liver disease, (2) superoxide anions time- and dose-dependently induce HO-1 activity, (3) HO-1 overexpression inhibits superoxide-anions-induced apoptosis, and (4) CO blocks superoxide-anions-induced JNK phosphorylation and caspase-9, -6, -3 activation and abolishes apoptosis but does not increase necrosis. We conclude that HO-1 and CO protect primary hepatocytes against superoxide-anions-induced apoptosis partially via inhibition of JNK activity. CO could represent an important candidate for the treatment of liver diseases.
Assuntos
Apoptose , Monóxido de Carbono/química , Regulação Enzimológica da Expressão Gênica , Heme Oxigenase-1/metabolismo , Hepatócitos/citologia , MAP Quinase Quinase 4/metabolismo , Estresse Oxidativo , Animais , Caspases/metabolismo , Hepatócitos/metabolismo , Hepatopatias/patologia , Modelos Biológicos , Necrose , Isoformas de Proteínas , Ratos , Superóxidos/metabolismoRESUMO
Targeted therapies have drastically changed the management of metastatic melanoma and have shown encouraging results on tumour progression but are also known for their high rates of adverse reactions. In general, targeted therapies are contraindicated during pregnancy due to concerns about teratogenesis. For the BRAF V600 inhibitor vemurafenib, the available literature about the effects on human pregnancy is limited to a single case report. In patients with metastatic melanoma that wish to continue their pregnancy, targeted therapies like vemurafenib offer the only possibility of improving maternal outcome. In this article, we report on a pregnant woman with metastatic melanoma who was treated with vemurafenib during pregnancy and experienced a fatal adverse reaction.
RESUMO
BACKGROUND: Deep muscle relaxation has been shown to facilitate operating conditions during laparoscopic surgery. Minimally invasive esophageal surgery is a high-risk procedure in which the use of deep neuromuscular block (NMB) may improve conditions in the thoracic phase as well. Neuromuscular antagonists can be given on demand or by continuous infusion (deep NMB). However, the positioning of the patient often hampers train-of-four (TOF) monitoring. A continuous infusion thus may result in a deep NMB at the end of surgery. The use of neostigmine not only is insufficient for reversing deep NMB but also may be contraindicated for this procedure because of its cholinergic effects. Sugammadex is an effective alternative but is rather expensive. This study aims to evaluate the use of deep versus on-demand NMB on operating, anaesthesiologic conditions, and costs in patients undergoing a two- or three-phase thoracolaparoscopic esophageal resection. METHODS/DESIGN: We will conduct a single-center randomized controlled double-blinded intervention study. Sixty-six patients undergoing a thoracolaparoscopic esophageal resection will be included. Patients will receive either continuous infusion of rocuronium 0.6 mg/kg per hour (group 1) or continuous infusion of NaCl 0.9 % 0.06 ml/kg per hour (group 2). In both groups, on-demand boluses of rocuronium can be given (open-label design). The primary aim of this study is to compare the surgical rating scale (SRS) during the abdominal phase. Main secondary aims are to evaluate SRS during the thoracic phase, to evaluate anesthesiologic conditions, and to compare costs (in euros) associated with use of rocuronium, sugammadex, and duration of surgery. DISCUSSION: This study is the first to evaluate the benefits of deep neuromuscular relaxation on surgical and anaesthesiologic conditions during thoracolaparoscopic esophageal surgery. This surgical procedure is unique because it consists of both an abdominal phase and a thoracic phase taking place in different order depending on the subtype of surgery (a two- or three-stage transthoracic esophagectomy). In addition, possible benefits associated with deep NMB, such as decrease in operating time, will be weighed against costs. TRIAL REGISTRATION: European Clinical Trials Database (EudraCT) number: 2014-002147-18 (obtained 19 May 2014) ClinicalTrials.gov: NCT02320734 (obtained 18 Dec. 2014).
Assuntos
Androstanóis/administração & dosagem , Esofagectomia/métodos , Laparoscopia , Relaxamento Muscular/efeitos dos fármacos , Bloqueadores Neuromusculares/administração & dosagem , Toracoscopia , Androstanóis/efeitos adversos , Androstanóis/economia , Protocolos Clínicos , Análise Custo-Benefício , Método Duplo-Cego , Esquema de Medicação , Custos de Medicamentos , Esofagectomia/efeitos adversos , Esofagectomia/economia , Humanos , Infusões Parenterais , Laparoscopia/efeitos adversos , Laparoscopia/economia , Monitorização Intraoperatória/métodos , Países Baixos , Bloqueadores Neuromusculares/efeitos adversos , Bloqueadores Neuromusculares/economia , Projetos de Pesquisa , Rocurônio , Toracoscopia/efeitos adversos , Toracoscopia/economia , Fatores de Tempo , Resultado do TratamentoRESUMO
Genomics and proteomics have become increasingly important in biomedical science in the past decade, as they provide an opportunity for hypothesis-free experiments that can yield major insights not previously foreseen when scientific and clinical questions are based only on hypothesis-driven approaches. Use of these tools, therefore, opens new avenues for uncovering physiological and pathological pathways. Liver fibrosis is a complex disease provoked by a range of chronic injuries to the liver, among which are viral hepatitis, (non-) alcoholic steatohepatitis and autoimmune disorders. Some chronic liver patients will never develop fibrosis or cirrhosis, whereas others rapidly progress towards cirrhosis in a few years. This variety can be caused by disease-related factors (for example, viral genotype) or host-factors (genetic/epigenetic). It is vital to establish accurate tools to identify those patients at highest risk for disease severity or progression in order to determine who are in need of immediate therapies. Moreover, there is an urgent imperative to identify non-invasive markers that can accurately distinguish mild and intermediate stages of fibrosis. Ideally, biomarkers can be used to predict disease progression and treatment response, but these studies will take many years due to the requirement for lengthy follow-up periods to assess outcomes. Current genomic and proteomic research provides many candidate biomarkers, but independent validation of these biomarkers is lacking, and reproducibility is still a key concern. Thus, great opportunities and challenges lie ahead in the field of genomics and proteomics, which, if successful, could transform the diagnosis and treatment of chronic fibrosing liver diseases.