RESUMO
Perineural dexamethasone has a ceiling dose of 4 mg for prolongation of analgesia duration after injection of long-acting local anaesthetic for peripheral nerve block, but evidence for doses < 4 mg is lacking. This randomised controlled triple-blind trial tested the hypothesis that increasing doses of perineural dexamethasone between 1 mg and 4 mg would prolong the duration of analgesia in a dose-dependent manner. Eighty ASA physical status 1-2 patients scheduled for shoulder arthroscopy under general anaesthesia with ultrasound-guided interscalene brachial plexus block were randomly allocated to receive saline (control), dexamethasone 1 mg, 2 mg, 3 mg and 4 mg, together with 20 ml ropivacaine 0.5%. Postoperative analgesia consisted of paracetamol, diclofenac and oxycodone on request, using a pre-defined protocol. The primary outcome was the duration of analgesia, defined as the time between the block procedure and the first analgesic request. Secondary outcomes included rest and dynamic pain scores, and analgesic consumption at 2 h, 24 h and 48 h postoperatively. An analysis of the dose-response relationship was performed using multiple comparison procedure-modelling. The median (IQR [range]) duration of analgesia was significantly prolonged in a dose-dependent manner: control 685 (590-860 [453-1272]) min; 1 mg 835 (740-1110 [450-1375]) min; 2 mg 904 (710-1130 [525-1365]) min; 3 mg 965 (875-1025 [730-1390]) min; 4 mg 1023 (838-1239 [518-1500]) min (p = 0.03). There were no significant differences between the secondary outcomes. Perineural administration of dexamethasone with doses between 1 mg and 4 mg, combined with ropivacaine for interscalene brachial plexus block, prolongs duration of analgesia in a dose-dependent manner.
Assuntos
Bloqueio do Plexo Braquial/métodos , Dexametasona/administração & dosagem , Dor Pós-Operatória/prevenção & controle , Adulto , Idoso , Analgesia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND.: The incidence of hemidiaphragmatic paresis with continuous interscalene brachial plexus block (CISB) can approach 100%. We tested the hypothesis that extrafascial placement of the catheter tip reduces the rate of hemidiaphragmatic paresis compared with intrafascial tip placement for CISB while providing effective analgesia. METHODS.: Seventy patients undergoing elective major shoulder surgery under general anaesthesia were randomized to receive an ultrasound-guided CISB plexus block for analgesia with the catheter tip placed either within (intrafascial group) or immediately outside (extrafascial group) the brachial plexus sheath midway between the levels of C5 and C6. Catheters were bolus dosed with ropivacaine 0.5% 20 ml before surgery, followed by an infusion of ropivacaine 0.2% at 4 ml h -1 for the first 2 days after surgery. The primary outcome was hemidiaphragmatic paresis measured by M-mode ultrasonography on postoperative day (POD) 1. Secondary outcomes included forced vital capacity, forced expiratory volume in 1 s, and rest pain scores. RESULTS.: The incidence of hemidiaphragmatic paresis on POD 1 was significantly reduced in the extrafascial group {intrafascial, 41% [95% confidence interval (CI) 25-59%]; extrafascial, 15% (95% CI 5-32%); P =0.01}. We were unable to detect a difference between groups in any of the functional respiratory outcomes or in rest pain scores [numerical rating scale (1-10): intrafascial, 3 (95% CI 2-3); extrafascial, 3 (95% CI: 2-4); P =0.93] on POD 1. CONCLUSIONS.: Placement of the catheter tip immediately outside of the brachial plexus sheath reduced the incidence of hemidiaphragmatic paresis on POD 1 associated with ultrasound-guided CISB while providing effective analgesia after major shoulder surgery. Our results do not support the routine placement of the catheter tip within the brachial plexus sheath for CISB. CLINICAL TRIAL REGISTRATION.: NCT02433561.
Assuntos
Bloqueio do Plexo Braquial/métodos , Plexo Braquial , Paralisia Respiratória/induzido quimicamente , Paralisia Respiratória/epidemiologia , Idoso , Analgesia Controlada pelo Paciente , Anestésicos Locais/administração & dosagem , Plexo Braquial/diagnóstico por imagem , Catéteres , Método Duplo-Cego , Ecocardiografia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/epidemiologia , Complicações Pós-Operatórias/induzido quimicamente , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/epidemiologia , Ropivacaina/administração & dosagem , Resultado do Tratamento , Ultrassonografia de IntervençãoRESUMO
We tested whether prophylactic droperidol and ondansetron, in combination with a moderate dose of dexamethasone, were equally effective in reducing nausea and vomiting after tonsillectomy in children and that both were superior to saline with dexamethasone. We randomly allocated 300 children to intravenous saline, droperidol 10 µg.kg-1 or ondansetron 150 µg.kg-1 , after induction of anaesthesia and the administration of intravenous dexamethasone 250 µg.kg-1 . The rates (95%CI) of nausea or vomiting within 24 postoperative hours were: 42/91 after saline, 46% (36%-57%); 43/87 after droperidol, 49% (39%-60%); reduced to 18/84 by ondansetron, 21% (13%-32%), p < 0.001. There were no differences in the rates of side-effects between groups. We conclude that ondansetron is more effective than saline in preventing nausea or vomiting after paediatric tonsillectomy when given with a moderate dose of dexamethasone, whereas droperidol was not.
Assuntos
Antieméticos/uso terapêutico , Dexametasona/uso terapêutico , Droperidol/uso terapêutico , Ondansetron/uso terapêutico , Náusea e Vômito Pós-Operatórios/prevenção & controle , Tonsilectomia , Criança , Pré-Escolar , Método Duplo-Cego , Droperidol/efeitos adversos , Feminino , Humanos , Masculino , Ondansetron/efeitos adversosRESUMO
We systematically reviewed 25 randomised controlled trials of ultrasound-guided brachial plexus blockade that recruited 1948 participants: either one approach vs another (axillary, infraclavicular or supraclavicular); or one injection vs multiple injections. There were no differences in the rates of successful blockade with approach, relative risk (95% CI): axillary vs infraclavicular, 1.0 (1.0-1.1), p = 0.97; axillary vs supraclavicular, 1.0 (1.0-1.1), p = 0.68; and infraclavicular vs supraclavicular, 1.0 (1.0-1.1), p = 0.32. There was no difference in the rate of successful blockade with the number of injections, relative risk (95% CI) 1.0 (1.0-1.0), p = 0.69, for one vs multiple injections. The rate of procedural paraesthesia was less with one injection than multiple injections, relative risk (95% CI) 0.6 (0.4-0.9), p = 0.004.
Assuntos
Anestésicos Locais/administração & dosagem , Bloqueio do Plexo Braquial/métodos , Plexo Braquial/diagnóstico por imagem , Ultrassonografia de Intervenção , Plexo Braquial/efeitos dos fármacos , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Based on single molecule manipulation experiments in a combined scanning tunneling microscope/frequency modulated atomic force microscope, we quantify the individual binding energy contributions to an organic-metal bond experimentally. The method allows the determination of contributions from, e.g., local chemical bonds, metal-molecule hybridization, and van der Waals interactions, as well as the total adsorption energy.
RESUMO
Temporal lobe seizures can induce the proliferation and abnormal migration of newly generated dentate granule cells, but little is known about the molecular mechanisms that govern these pathological events. Reelin and DISC1 (disrupted-in-schizophrenia 1) are proteins that play a regulatory role in the maturation and integration of new neurons in the developing and adult brain. In this study, we examined whether amygdala kindling results in aberrant neurogenesis and altered expression of reelin and DISC1 in the adult dentate gyrus. Using doublecortin immunohistochemistry, we found that short-term kindling (i.e., 30 electrical stimulations) significantly increased the number of immature neurons in the dentate subgranular zone (SGZ), whereas long-term kindling (i.e., 99 electrical stimulations) did not. However, doublecortin-labeled neurons in long-term kindled rats showed greater dendritic complexity than they did in short-term kindled or control rats. We also found that long-term kindling decreased the number of reelin-positive cells and decreased DISC1 expression in the dentate granule cell layer and subgranular zone. Interestingly, kindling-induced changes in reelin and DISC1 expression coincided with the appearance of ectopically located Prox1-labeled granule cells in the hilus. These effects occurred independently of alterations in granule cell layer length, dentate volume, or the number of hilar neurons. Taken together, these findings suggest a novel role for DISC1 in the pathophysiology of temporal lobe epilepsy and further suggest that changes in reelin and DISC1 expression may contribute to aberrant neurogenesis in the kindling model.
Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Regulação para Baixo/fisiologia , Proteínas da Matriz Extracelular/metabolismo , Excitação Neurológica/patologia , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/fisiologia , Serina Endopeptidases/metabolismo , Animais , Modelos Animais de Doenças , Proteína Duplacortina , Estimulação Elétrica/efeitos adversos , Epilepsia/patologia , Masculino , Naftalenos , Neurônios/metabolismo , Oxepinas , Ratos , Ratos Long-Evans , Proteína Reelina , Fatores de TempoRESUMO
Dietary trans fatty acids (TFA) (mainly 18:1 isomers) have two sources: they are formed during the natural bacterial hydrogenation of unsaturated fatty acids in ruminants or they come from the industrial hydrogenation of unsaturated vegetable oils. Total trans fatty acids account for 1.3% of total energy intake in France compared to 2-3% in USA. Recent epidemiologic studies and meta-analyses of well-designed controlled trials clearly showed that trans fatty acids are associated with an increase of cardiovascular risk. It seems that TFA from industrial sources are responsible for the deleterious effects particularly on lipoprotein metabolism. Specifically the consumption of industrial TFA has been associated with high plasma concentrations of triacylglycerols, LDL-cholesterol and small dense LDL and lower HDL-cholesterol concentrations. The very recent interventional trials allowed for a comparison of TFAs from different sources suggest that the intake of natural TFA have no or neutral effects on plasma lipids and other cardiovascular risk factors. However, the mechanisms underlying the isomer-specific effects are not well understood and warrant further investigations.
Assuntos
Doenças Cardiovasculares/metabolismo , Gorduras na Dieta/efeitos adversos , Metabolismo dos Lipídeos , Ácidos Graxos trans/efeitos adversos , Colesterol/sangue , Gorduras na Dieta/metabolismo , Humanos , Hiperlipidemias/metabolismo , Ácidos Graxos trans/metabolismoRESUMO
OBJECTIVES: Previous population-based studies in patients with ulcerative colitis [UC] revealed variable colectomy rates and colectomy-associated risk factors. Over the past two decades, a decrease in colectomy rates was observed. We assessed risk factors and colectomy rates over time in UC in the Swiss Inflammatory Bowel Disease Cohort Study [SIBDCS]. METHODS: Prospectively collected SIBDCS data, including disease history, baseline characteristics at enrolment, and course of disease, were retrospectively analysed. Cumulative and adjusted annual colectomy rates were calculated. RESULTS: Among 1245 UC patients analysed [54.6% male], 114 [9.2%] underwent colectomy. We observed 5-, 10-, 15-, and 20-year cumulative colectomy rates after diagnosis of 4.1%, 6.4%, 10.4%, and 14.4% of patients, respectively. Male sex (odds ratio [OR] 1.54; p = 0.035), pancolitis at diagnosis [OR = 2.16; p = 0.005], younger age at diagnosis [OR 0.89 per 5 years of age; p = 0.006] and presence of extraintestinal manifestations [EIM] [OR 2.30; p < 0.001] were risk factors for undergoing colectomy. We did not observe a significant protective effect of smoking on colectomy risk [OR 0.64; p = 0.106]. The majority of colectomies were performed within first 10 years of disease onset, with a rapidly decreasing colectomy rate after 15 years. In patients diagnosed after 2003, colectomy was performed much earlier during and individual's disease course. Nevertheless, we found a significantly decreasing trend in yearly colectomy rates over time after 2005. CONCLUSIONS: Crude and adjusted colectomy rates in Swiss UC patients were lower than those reported previously in the literature, and decreased over time.
Assuntos
Colectomia/estatística & dados numéricos , Colite Ulcerativa/cirurgia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Colectomia/tendências , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Suíça , Adulto JovemRESUMO
Infection by some types of human papillomavirus (HPV) is associated with the development of cervical cancer. Analysis of viral DNA from cervical tumours shows that the E2 gene is frequently disrupted during integration into the host cell's DNA. It has therefore been suggested that loss of E2p is an important step in malignant transformation. Expression of E2p in the fission yeast Schizosaccharomyces pombe retards the G2-M transition, by delaying activation of Cdc2p kinase. In contrast, S phase progression, and commitment to cell division in late G1 are not affected. The delay is independent of the transcriptional trans-activation function of E2p, and does not result from E2p DNA binding mimicking DNA damage. Increased expression of E2p also delays mitotic initiation in mammalian cells. S. pombe may thus provide a simple model for the analysis of E2p function.
Assuntos
Proteínas de Ligação a DNA , Inibidores do Crescimento/genética , Mitose/genética , Proteínas Oncogênicas Virais/biossíntese , Proteínas Oncogênicas Virais/genética , Papillomaviridae/genética , Schizosaccharomyces/genética , Schizosaccharomyces/virologia , ras-GRF1 , Adenosina Trifosfatases/fisiologia , Animais , Ciclo Celular/genética , Proteínas de Ciclo Celular/genética , Linhagem Celular Transformada , DNA Helicases/fisiologia , Proteínas Fúngicas/genética , Fase G1/genética , Fase G2/genética , Vetores Genéticos , Inibidores do Crescimento/biossíntese , Inibidores do Crescimento/fisiologia , Humanos , Rim/citologia , Mutação , Proteínas Oncogênicas Virais/fisiologia , Papillomaviridae/fisiologia , Ratos , Fase S/genética , Proteínas de Saccharomyces cerevisiae , Schizosaccharomyces/citologia , Transcrição GênicaRESUMO
Spin-labeled stearic acid is shown to exhibit the same beta-oxidation kinetics as normal stearic acid. ESR spectra recorded in conditions allowing beta-oxidation indicate that membrane-bound fatty acids can be directly beta-oxidized and that the rate of this reaction depends on the concentration of albumin in the medium. The regulating function of albumin and pool role of the lipidic phase of the mitochondrial membranes are discussed.
Assuntos
Mitocôndrias Musculares/metabolismo , Ácidos Esteáricos/metabolismo , Albuminas/farmacologia , Animais , Espectroscopia de Ressonância de Spin Eletrônica , Feminino , Técnicas In Vitro , Cinética , Membranas , Miocárdio/metabolismo , Oxirredução , Ligação Proteica , Ratos , Marcadores de SpinRESUMO
A fatty-acid-binding protein with a molecular weight of approximately 12 000 was purified from rat heart and the binding investigated by electron spin resonance. The stearic acid bound to the protein was found to be transferred to the mitochondrial beta-oxidative system, suggesting a role as transcytoplasmic fatty acid carrier for this protein. For the first time a physiological cytoplasmic protein was used as a carrier supplying the mitochondrial beta-oxidative system. A new mechanism of action is proposed to explain the control exerted by this type of protein in some membrane-linked enzymatic processes.
Assuntos
Proteínas de Transporte/metabolismo , Ácidos Graxos/metabolismo , Mitocôndrias Cardíacas/metabolismo , Proteínas Musculares/metabolismo , Miocárdio/metabolismo , Animais , Proteínas de Transporte/isolamento & purificação , Espectroscopia de Ressonância de Spin Eletrônica , Feminino , Proteínas Musculares/isolamento & purificação , RatosRESUMO
Cell cholesterol efflux to serum is stimulated after an oral fat load. The impact of meal fatty acid composition was explored by measure of serum promoted cholesterol efflux from Fu5AH cells after ingestion of 4 different fats: sunflower (Sf), oleic-sunflower (Ol), a mixed oil (Mx), and beef tallow (Bt). High density lipoprotein (HDL)2 and HDL3 were isolated and analyzed. Cholesterol efflux increased regularly after Ol (P<0.05 at 4 h and P<0.02 at 8 h), and 8 h after Mx (P<0.02) or Bt (P<0.05), but not after Sf. Percent HDL3 phospholipids increased after Ol (P<0.05 at 6 h and P<0.01 at 8 H) and 8 h after Mx (P<0.01). After Ol, variations in efflux and percent phospholipids in HDL3 (but not HDL2) were positively correlated (r=0.929; P=0.007 at 6 h). Using HDL3, efflux increased 6 h after Ol (P<0.05) but not after Sf, and efflux was correlated with HDL3 phospholipid concentration in medium (r=0.913; P=0.011). Thus postprandial increase in cholesterol efflux in influenced by ingested fats in relation to increased phospholipid availability on HDL3. The protective effect of monounsaturated fatty acids against atherogenesis might be partly mediated by an enhanced ability of postprandial serum to accept cell cholesterol.
Assuntos
Sangue/metabolismo , Colesterol/metabolismo , Gorduras Insaturadas na Dieta/farmacologia , Ingestão de Alimentos/fisiologia , Ácidos Oleicos/farmacologia , Adulto , Gorduras Insaturadas/química , Ácidos Graxos/análise , Feminino , Humanos , Lipoproteínas HDL/sangue , Ácido OleicoRESUMO
BACKGROUND: Studies that systematically assess change in ulcerative colitis (UC) extent over time in adult patients are scarce. AIM: To assess changes in disease extent over time and to evaluate clinical parameters associated with this change. METHODS: Data from the Swiss IBD cohort study were analysed. We used logistic regression modelling to identify factors associated with a change in disease extent. RESULTS: A total of 918 UC patients (45.3% females) were included. At diagnosis, UC patients presented with the following disease extent: proctitis [199 patients (21.7%)], left-sided colitis [338 patients (36.8%)] and extensive colitis/pancolitis [381 (41.5%)]. During a median disease duration of 9 [4-16] years, progression and regression was documented in 145 patients (15.8%) and 149 patients (16.2%) respectively. In addition, 624 patients (68.0%) had a stable disease extent. The following factors were identified to be associated with disease progression: treatment with systemic glucocorticoids [odds ratio (OR) 1.704, P = 0.025] and calcineurin inhibitors (OR: 2.716, P = 0.005). No specific factors were found to be associated with disease regression. CONCLUSIONS: Over a median disease duration of 9 [4-16] years, about two-thirds of UC patients maintained the initial disease extent; the remaining one-third had experienced either progression or regression of the disease extent.
Assuntos
Colite Ulcerativa/fisiopatologia , Progressão da Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores de Calcineurina/uso terapêutico , Estudos de Coortes , Colite Ulcerativa/tratamento farmacológico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Indução de Remissão , Suíça , Adulto JovemRESUMO
BACKGROUND: The impact of early treatment with immunomodulators (IM) and/or TNF antagonists on bowel damage in Crohn's disease (CD) patients is unknown. AIM: To assess whether 'early treatment' with IM and/or TNF antagonists, defined as treatment within a 2-year period from the date of CD diagnosis, was associated with development of lesser number of disease complications when compared to 'late treatment', which was defined as treatment initiation after >2 years from the time of CD diagnosis. METHODS: Data from the Swiss IBD Cohort Study were analysed. The following outcomes were assessed using Cox proportional hazard modelling: bowel strictures, perianal fistulas, internal fistulas, intestinal surgery, perianal surgery and any of the aforementioned complications. RESULTS: The 'early treatment' group of 292 CD patients was compared to the 'late treatment' group of 248 CD patients. We found that 'early treatment' with IM or TNF antagonists alone was associated with reduced risk of bowel strictures [hazard ratio (HR) 0.496, P = 0.004 for IM; HR 0.276, P = 0.018 for TNF antagonists]. Furthermore, 'early treatment' with IM was associated with reduced risk of undergoing intestinal surgery (HR 0.322, P = 0.005), and perianal surgery (HR 0.361, P = 0.042), as well as developing any complication (HR 0.567, P = 0.006). CONCLUSIONS: Treatment with immunomodulators or TNF antagonists within the first 2 years of CD diagnosis was associated with reduced risk of developing bowel strictures, when compared to initiating these drugs >2 years after diagnosis. Furthermore, early immunomodulators treatment was associated with reduced risk of intestinal surgery, perianal surgery and any complication.
Assuntos
Doença de Crohn/tratamento farmacológico , Doença de Crohn/epidemiologia , Doença de Crohn/cirurgia , Procedimentos Cirúrgicos do Sistema Digestório/estatística & dados numéricos , Intervenção Médica Precoce , Fatores Imunológicos/administração & dosagem , Intestinos/efeitos dos fármacos , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Adjuvantes Imunológicos/uso terapêutico , Adulto , Idoso , Certolizumab Pegol/administração & dosagem , Certolizumab Pegol/efeitos adversos , Estudos de Coortes , Doença de Crohn/patologia , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Infliximab/administração & dosagem , Infliximab/efeitos adversos , Intestinos/patologia , Intestinos/cirurgia , Masculino , Pessoa de Meia-Idade , Suíça/epidemiologia , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The leukemia-associated cell surface antigen p 24 is found on normal platelets as well as on Bernard Soulier syndrome and thrombasthenia type I platelets. ALB6 IgG (a monoclonal antibody against p 24) induces the aggregation of platelets from normal donors but not from thrombasthenia. In contrast, ALB6 Fab inhibits platelet aggregation induced by collagen, ADP, thrombin, ionophore A 23187 and ALB6 IgG. The results suggest that ALB6 interferes with a mechanism common to all aggregation pathways; the possible mechanisms are discussed.
Assuntos
Anticorpos Monoclonais , Anticorpos Antineoplásicos , Leucemia Linfoide/imunologia , Agregação Plaquetária , Sítios de Ligação de Anticorpos , Fibrinogênio/metabolismo , Humanos , Imunoquímica , Fragmentos Fab das Imunoglobulinas , Imunoglobulina G , Técnicas In VitroRESUMO
Human lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the metabolism of cholesterol and is postulated to participate in the physiological process called reverse cholesterol transport. We have used transgenic mice (Tgm) expressing either both human apolipoprotein AI (apo AI) and human LCAT genes or only the human apo AI gene (HuAILCAT or HuAI Tgm, respectively) to assess the consequences of LCAT overexpression on serum lipid and lipoprotein profiles and on the ability of each serum to promote bidirectional flux of cholesterol between serum and Fu5AH hepatoma cells. Mean serum LCAT activity of HuAILCAT Tgm was 2-fold increased compared to the HuAI group (48+/-9 vs. 24+/-5 nmol/ml per h, P<0.01 for HuAILCAT and HuAI Tgm, respectively) and the cholesterol esterification rates were not significantly different between the two groups of animals (66+/-11 vs. 74+/-18 nmol/ml per h for HuAILCAT and HuAI Tgm, respectively). HuAILCAT Tgm exhibited higher total cholesterol serum values (2.3-fold) due to an increase in both HDL-cholesterol (1. 9-fold) and non-HDL-cholesterol (3-fold). The HDL particles from HuAILCAT Tgm were relatively phospholipid depleted and cholesterol enriched compared to HuAI mice. When cells were incubated for six hours with the mouse serum, the fractional efflux of radiolabeled cholesterol was slightly increased with the HuAILCAT Tgm (1.2-fold) but the increase in intracellular cholesterol content was also 2-fold higher than with the HuAI Tgm. Fu5AH can be viewed as a model for the evaluation of bidirectional flux of cholesterol in SR-BI-rich cells. In this model LCAT overexpression in mice, by increasing both HDL and non-HDL-cholesterol, mostly enhances the uptake of cholesterol by the cells, which would be of benefit for the last step of reverse cholesterol transport in hepatocytes.
Assuntos
Apolipoproteína A-I/genética , Colesterol/metabolismo , Lipoproteínas HDL/sangue , Fígado/enzimologia , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Animais , Transporte Biológico , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Recém-Nascido , Lipoproteínas HDL/fisiologia , Fígado/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Sensibilidade e Especificidade , Estatísticas não ParamétricasRESUMO
The high triglyceride/low HDL-cholesterol trait is a common finding in the general population. The aim of the present study was to analyze and interpret the relationships between triglycerides (TG), HDL-related parameters and serum cholesterol efflux potential in an asymptomatic population including both normo- and hyperlipidemic individuals. In a large sample (n = 1143) of this population, there was a negative correlation between TG and HDL-cholesterol (HDL-C) (r = -0.49, P<0.0001) whereas the negative correlation between TG and HDL-phospholipid (HDL-PL) (r = -0.29, P<0.0001) was weaker, leading to a strong positive correlation between TG and HDL-PL/C ratio (r = 0.58, P<0.0001). Thus, increased TG concentrations were associated with an enrichment of HDL with PL. Since we have demonstrated previously that HDL-PL is the major determinant for cholesterol efflux potential from Fu5AH rat hepatoma cells, we determined the effect of the variations in HDL lipid composition on the cholesterol efflux capacity in a subsample of 198 subjects. Compared with normolipidemic subjects (NLP) (TG< or = 1.7 mmol/l; LDL-C< or = 4.1 mmol/l, n=58), hypertriglyceridemic subjects (HTG) (TG>1.7 mmol/l, n=63) exhibited lower HDL-C levels (1.08+/-0.21 vs. 1.25+/-0.32, P=0.0003) whereas they showed similar HDL-PL concentrations (1.25+/-0.21 vs. 1.25+/-2.7) and, thus, higher HDL-PL/C ratio (1.17+/-0.15 vs. 1.02+/-0.14, P=0.0001). The relative efflux capacity of serum measured in the Fu5AH system (5% serum, 4 h incubation at 37 degrees C) was on average identical in the HTG and NLP groups. Thus, this study provides evidence that despite decreased HDL concentrations, as determined routinely by the HDL-C assay, some HTG subjects maintained serum cholesterol efflux capacity thanks to the enrichment of HDL with PL.
Assuntos
Carcinoma Hepatocelular/metabolismo , Lipoproteínas HDL/sangue , Neoplasias Hepáticas/metabolismo , Fosfolipídeos/sangue , Triglicerídeos/sangue , Adulto , Animais , Sangue/metabolismo , Carcinoma Hepatocelular/patologia , Membrana Celular/metabolismo , Colesterol/metabolismo , Humanos , Hipercolesterolemia/sangue , Hiperlipidemias/sangue , Hipertrigliceridemia/sangue , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Ratos , Valores de Referência , Células Tumorais CultivadasRESUMO
Specific extracellular matrix molecules and growth factors (GFs) with angiogenic properties could be combined with biomaterials to enhance angiogenesis and subsequently tissue ingrowth through the wall of the porous structure. In this study, composite fibrin matrices containing hyaluronic acid (HA), fibronectin (FN) and/or fibroblast growth factor-1 (FGF-1), FGF-2 and an endothelial cell growth supplement (ECGS) were adsorbed onto Dacron meshes which were then implanted subcutaneously in mice. The release from the implants and the tissue distribution of implanted GFs were determined in vivo using radiolabelled FGF-2. Angiogenesis was quantified by counting the number of capillaries present in each Dacron histological serial section. Radiolabelled GF was rapidly released from matrices and was absent from them by day 28. A very low percentage of the implanted radiolabelled GFs was found in the kidneys and livers of the animals. The number of microvessels formed within fibrin-impregnated samples was increased in the presence of HA and ECGS at 14 d and of FN and ECGS or FGF-2 at 28 d. FGF-1 had no direct effect on angiogenesis in our model. These results indicate that enhancement of vascularization within prosthesis mesh may be achieved by using fibrin as a support for angiogenic molecules such as HA, FN and FGFs.
Assuntos
Sistemas de Liberação de Medicamentos , Neovascularização Fisiológica/efeitos dos fármacos , Polietilenotereftalatos/metabolismo , Animais , Materiais Biocompatíveis , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Fibrina/metabolismo , Fibrina/farmacologia , Fator 1 de Crescimento de Fibroblastos/metabolismo , Fator 1 de Crescimento de Fibroblastos/farmacologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fibronectinas/metabolismo , Fibronectinas/farmacologia , Ácido Hialurônico/metabolismo , Ácido Hialurônico/farmacologia , Inflamação/induzido quimicamente , Marcação por Isótopo , Camundongos , Polietilenotereftalatos/efeitos adversos , Polietilenotereftalatos/química , Próteses e Implantes , Pele/metabolismoRESUMO
Hyperglycaemia in diabetic patients results in non-enzymatic glycation of plasma proteins, including lipoproteins such as high-density lipoproteins (HDL). We studied the effects of in vitro HDL glycation on the activity of lecithin-cholesterol acyl transferase (LCAT), a key enzyme in HDL plasma metabolism. LCAT was prepared from non-diabetic subjects and HDL by sequential density ultracentrifugation (in the density range of 1.063-1.21 g/ml) from both diabetic and non-diabetic patients. HDL from non-diabetic patients were glycated in vitro by incubating lipoproteins with 100 mmol/l glucose for various times at 37 degrees C with sodium cyanoborohydride as reducing agent. Glycation of HDL protein was quantified by measuring the percentage of derived amino acid residues using the TNBS assay. Kinetic parameters of LCAT were first determined using native HDL from non-diabetic patients and in vitro glycated HDL. With native HDL, Km and Vmax were 51.1 +/- 4.2 mumol/l (n = 8) and 12.9 +/- 2.4 nmol/ml/h (n = 8), respectively. Enzyme reactivity, calculated as the Vmax/Km ratio, was 0.25 +/- 0.04 h-1 (n = 8). In the case of moderate glycation (derived residues < 30%; n = 19) a significant increase in both Km (18.2 +/- 3.4%; mean +/- S.D.) and Vmax (9.3 +/- 2.4%) was observed. In contrast, with a high level of glycation (derived residues > 30%; n = 8), both parameters fell (Km, 25 +/- 6.3%; Vmax, 34.1 +/- 3.3%). In addition, whatever the level of glycation, enzyme reactivity was lower in the presence of in vitro glycated HDL. This decrease in LCAT reactivity was not due to a peroxidative process nor to an alteration of the protein and lipid composition of in vitro glycated HDL. It could, however, be explained by glycation of lysine residues in apolipoprotein A-I, which is the most potent activator of LCAT. In a second series of experiments, native diabetic HDL preparations were used as LCAT substrate. No alteration in Km values was observed, but there was a significant decrease in both Vmax (28%) and enzyme reactivity (32%). This difference in Km and Vmax alterations between native diabetic HDL and in vitro glycated HDL with low levels of glycation might be explained by the impact of physiological modifications, other than glycation, which could differently affect the chemicophysical properties of HDL in diabetic patients.(ABSTRACT TRUNCATED AT 400 WORDS)
Assuntos
Lipoproteínas HDL/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferase/metabolismo , Diabetes Mellitus/sangue , Diabetes Mellitus/enzimologia , Humanos , Cinética , Fosfatidilcolina-Esterol O-Aciltransferase/isolamento & purificação , Proteínas/metabolismoRESUMO
There has been much debate regarding the potential influence of stress on epilepsy. Many studies have reported that stress can affect seizure susceptibility through eliciting either proconvulsant or anticonvulsant effects within the nervous system. In this study, we investigated the potential anticonvulsant effect of a 10-min swim stress on convulsions induced by a single systemic injection of lithium chloride followed 4 h later with pilocarpine. Rats pretreated with lithium chloride and exposed to a 10-min swim stressor prior to pilocarpine injection displayed a significant delay to seizure onset compared to unstressed rats or rats exposed to swim stress 10 min after lithium chloride, 2 h after lithium chloride, or immediately after pilocarpine injection. We then determined whether administration of a glucocorticoid antagonist (mifepristone; 10 or 50 mg/kg), an alpha(2)-adrenergic antagonist (yohimbine; 2 or 5 mg/kg), or a nonspecific opioid blocker (naloxone; 0.2 or 1 mg/kg) could prevent the anticonvulsant effect of swim stress. Only the high dose of yohimbine was capable of inhibiting the anticonvulsant effect of swim stress on lithium-pilocarpine seizures. Our findings highlight the importance of an endogenous noradrenergic-dependent anticonvulsant system in mediating the effects of swim stress on seizures. Further studies exploring the benefits of treatments with noradrenergic acting drugs in epilepsy is well warranted.