RESUMO
No one doubts the significant variation in the practice of transfusion medicine. Common examples are the variability in transfusion thresholds and the use of tranexamic acid for surgery with likely high blood loss despite evidence-based standards. There is a long history of applying different strategies to address this variation, including education, clinical guidelines, audit and feedback, but the effectiveness and cost-effectiveness of these initiatives remains unclear. Advances in computerised decision support systems and the application of novel electronic capabilities offer alternative approaches to improving transfusion practice. In England, the National Institute for Health and Care Research funded a Blood and Transplant Research Unit (BTRU) programme focussing on 'A data-enabled programme of research to improve transfusion practices'. The overarching aim of the BTRU is to accelerate the development of data-driven methods to optimise the use of blood and transfusion alternatives, and to integrate them within routine practice to improve patient outcomes. One particular area of focus is implementation science to address variation in practice.
Assuntos
Transfusão de Sangue , Humanos , InglaterraRESUMO
Prognosis of patients with early inflammatory arthritis (EIA) is highly variable. The aim of this study was to compare, longitudinally and cross-sectionally, the levels of cytokine-expressing cells in peripheral blood (PB) from patients with EIA to those in established rheumatoid arthritis (RA) and healthy controls (HC). PB mononuclear cells from HC (n = 30), patients with EIA (n = 20) or RA (n = 38) were stimulated with phorbol myristate acetate (PMA)/ionomycin for 3 h, and stained for cell markers and cytokines. Serum cytokines and chemokines were measured by Luminex. Patients with EIA were reassessed at 6 and 12 months. The percentage of interleukin (IL)-17⺠interferon (IFN)-γ⻠CD4⺠T cells [T helper type 17 (Th17)] was increased in RA and EIAâ versusâ HC. Serum IL-1ß, IL-2, IL-4 IL-17 and macrophage inflammatory protein (MIP)-1α were increased in RA and EIAâ versusâ HC. IL-1Ra, IL-15 and IFN-α were increased in EIAâ versusâ HC. IL-6 and tumour necrosis factor (TNF)-α was increased in RA but not EIAâ versusâ HC. Disease activity scores in EIA patients improved over 12 months' treatment. Th17 percentage at baseline was correlated with both rheumatoid factor (RF) titre and functional deficit at 12 months. Baseline levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6 and IL-8 were correlated with Larsen score at 12 months. There were no significant changes in cytokine-expressing CD4⺠T cells over time, although the percentage of IL-6âºmonocytes increased. IL-17⺠CD4⺠T cells and serum IL-17 levels are increased in EIA. IL-6-expressing monocytes increase during the first year of disease, irrespective of disease-modifying anti-rheumatic drug (DMARD) therapy. We observed incomplete clinical responses, suggesting EIA patients need more intensive early therapy.
Assuntos
Artrite Reumatoide/imunologia , Proteínas Sanguíneas/metabolismo , Linfócitos T CD4-Positivos/imunologia , Interleucina-17/imunologia , Células Th17/imunologia , Adulto , Idoso , Antirreumáticos/administração & dosagem , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Proteínas Sanguíneas/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL3/sangue , Estudos Transversais , Citocinas/sangue , Progressão da Doença , Feminino , Seguimentos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Interleucina-17/sangue , Masculino , Pessoa de Meia-Idade , Células Th17/efeitos dos fármacos , Resultado do TratamentoRESUMO
OBJECTIVE: The aim was to study the potential role of basal endothelin-1 release from endocardial endothelium in isolated ferret papillary muscle preparations. METHODS: The following interventions were studied: (1) no treatment (time control); (2) endothelin-1 (5 nM); (3) endothelin-1 (5 nM) in the presence of the specific ETA receptor antagonist, BQ123 (10 microM); (4) BQ123 (10 microM) in endocardium-intact muscles; and (5) BQ123 (10 microM) in endocardium-denuded muscles (n = 6 in each group). RESULTS: Untreated muscles remained stable throughout the experiment. BQ123 fully inhibited the positive inotropic effect of exogenous endothelin-1. In endocardium-intact preparations (n = 6), exposure to BQ123 induced a progressively earlier onset and time course of isometric twitch relaxation [time to peak tension -12.3(SEM 1.8)%, relaxation half time -13.3(1.1)%; both p < 0.01], but had no effect on peak tension or on rate of tension development. Selective denudation of endocardial endothelium induced similar relaxant effects, but also significantly reduced peak tension. In endocardial endothelium-denuded preparations (n = 6), addition of BQ123 did not result in further contractile changes. CONCLUSIONS: Endocardial endothelium in situ on papillary muscle preparations tonically releases endothelin, resulting in a significantly delayed onset of isometric twitch relaxation. There is no evidence for basal endothelin-1 release from microvascular endothelial cells in this superfused preparation. A similar release of endothelin-1 from endocardial endothelium in the intact heart could influence myocardial contractile behaviour independently of changes in coronary perfusion. Endothelin-1 may have a physiological role in modulating myocardial relaxation.
Assuntos
Endocárdio/metabolismo , Antagonistas dos Receptores de Endotelina , Endotelinas/metabolismo , Endotélio Vascular/metabolismo , Contração Miocárdica/fisiologia , Peptídeos Cíclicos/farmacologia , Animais , Endocárdio/efeitos dos fármacos , Endotelinas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Furões , Técnicas In Vitro , Masculino , Contração Miocárdica/efeitos dos fármacos , Músculos Papilares , Estimulação QuímicaRESUMO
OBJECTIVE: Nitric oxide released by a calcium dependent constitutive NO synthase in endocardial endothelial cells exerts characteristic effects on myocardial contraction. Interleukin 1 beta (IL-1) induces the expression of a different calcium independent NO synthase in several tissues. Activity of the latter enzyme has recently been identified in cardiac myocytes but its functional effects are unknown. The aim of this study was to investigate the effects of IL-1 on contraction of isolated ferret papillary muscle preparations. METHODS: Electrically stimulated preparations were studied in the presence of acebutolol (1 microM), indomethacin (10 microM), and polymyxin (10 micrograms.ml-1). After a 3 h equilibration period, IL-1 (10 ng.ml-1) was added and contractile behaviour monitored over the next 3 h. The following groups were studied: (1) no IL-1; (2) IL-1 alone; (3) IL-1 in the presence of dexamethasone (3 microM); (4) IL-1 in the presence of NG-monomethyl-L-arginine (L-NMMA, 50 microM); (5) IL-1 in the presence of L-NMMA (50 microM) and L-arginine (500 microM). Cyclic GMP content was measured by radioimmunoassay in all preparations. RESULTS: No significant contractile changes were noted in group 1. In group 2, IL-1 raised myocardial cyclic GMP and induced a progressive abbreviation of isometric twitch, starting 30 min after addition, with a small decrease in peak isometric tension but no change in rate of tension development. These effects were similar to those previously documented for endocardial endothelial NO but were not inhibited by endocardial endothelial denudation. IL-1 effects were inhibited in groups 3 and 4, and partially restored in group 5. CONCLUSIONS: IL-1 activates a dexamethasone sensitive myocardial L-arginine-NO pathway which raises myocardial cyclic GMP and induces marked twitch abbreviation. These effects could potentially lead to cardiac depression by limiting systolic ejection, and may be relevant in conditions where IL-1 levels are increased.
Assuntos
GMP Cíclico/metabolismo , Dexametasona/metabolismo , Interleucina-1/farmacologia , Contração Miocárdica/efeitos dos fármacos , Óxido Nítrico/biossíntese , Músculos Papilares/efeitos dos fármacos , Acebutolol/farmacologia , Animais , Técnicas de Cultura , Estimulação Elétrica , Furões , Indometacina/farmacologia , Músculos Papilares/metabolismo , Músculos Papilares/fisiologiaRESUMO
The physiological role of cyclic GMP in the heart remains controversial. In the present study we investigated the interaction between a number of agents known to increase the level of cyclic GMP in the myocardium and alpha 1-adrenergic stimulation in isolated preparations of cardiac papillary muscle in the ferret. Inotropic responses to the cumulative addition of phenylephrine were measured in papillary muscles of the ferret in the absence and presence of 1 microM sodium nitroprusside, 1 microM atrial natriuretic peptide, 0.1 microM substance P (which stimulates the release of nitric oxide from endocardial endothelium) or 1 microM 8-bromo-cyclic GMP. In parallel experiments using similar preparations, alpha 1-induced hydrolysis of phosphatidylinositol was assessed by measuring changes in the levels of inositol 1,4,5-trisphosphate in response to 10 microM phenylephrine in the absence and presence of the same agents that increase the level of cyclic GMP. Phenylephrine (0.001-10 microM) induced a concentration-dependent positive inotropic effect that was significantly inhibited by each of the agents that increase cyclic GMP. Phenylephrine (10 microM) induced an approximately three-fold rise in the level of inositol trisphosphate in the myocardium, which was likewise significantly inhibited by each of the agents that increase cyclic GMP. These data show that agents that increase the level of cyclic GMP in the myocardium inhibit both the positive inotropic and phosphatidylinositol response to alpha 1-stimulation in isolated preparations of papillary muscle in the ferret.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
GMP Cíclico/farmacologia , Contração Miocárdica/efeitos dos fármacos , Músculos Papilares/metabolismo , Fenilefrina/farmacologia , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Animais , Fator Natriurético Atrial/farmacologia , Furões , Técnicas In Vitro , Inositol 1,4,5-Trifosfato/metabolismo , Nitroprussiato/farmacologia , Músculos Papilares/fisiologia , Estimulação Química , Substância P/farmacologiaRESUMO
We have used a bioassay-cascade system to investigate the inhibitory effects of human red blood cells on EDRF activity. The vascular smooth muscle relaxant effect of EDRF released from an endothelium-intact pig coronary artery by the calcium ionophore A23187 was inhibited by washed red cells. This inhibition of EDRF activity by red cells was similar to that expected from their haemoglobin content. This study provides further evidence that in vivo EDRF acts as a local autocoid.
Assuntos
Fatores Biológicos/farmacologia , Eritrócitos/fisiologia , Vasodilatadores/farmacologia , Animais , Calcimicina/farmacologia , Dinoprosta/farmacologia , Hemoglobinas/análise , Humanos , Técnicas In Vitro , Contração Miocárdica/efeitos dos fármacos , Óxido Nítrico , SuínosRESUMO
Endothelial cells are known to contain both soluble and particulate guanylate cyclase, but the functional role of cyclic guanosine monophosphate (cGMP) in endothelial cells remains unknown. We have investigated the effects of 8-bromo-cGMP on endothelium-dependent relaxations to acetylcholine, substance P, ATP, and the calcium ionophore A23187, and on endothelium-independent relaxations to sodium nitroprusside and glyceryl trinitrate (GTN). The ability of each of these agents to relax phenylephrine-preconstricted rings of rabbit aorta was tested in the absence and presence of 8-bromo-cGMP. In the presence of 8-bromo-cGMP, a greater concentration of phenylephrine had to be used to produce a similar level of tone and then endothelium-dependent relaxations to acetylcholine and substance P were inhibited, whereas endothelium-dependent relaxations to ATP and A23187 were unaffected. Endothelium-independent relaxations to sodium nitroprusside and GTN were only inhibited at the highest concentrations of nitroprusside and GTN. These results suggest that: (a) increasing GMP levels in endothelial cells inhibit agonist-induced release of endothelium-derived relaxing factor (EDRF); (b) a negative feedback mechanism may exist whereby EDRF stimulates soluble guanylate cyclase in endothelial cells to inhibit its own release; and (c) ATP does not induce EDRF release via phosphoinositol hydrolysis.