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BACKGROUND: Ageing is associated with progressive endothelial senescence and dysfunction, and cardiovascular risk. Circulating endothelial microvesicles (MVs) are pro-senescent and pro-inflammatory endothelial effectors in acute coronary syndrome. Omega-3 PUFA intake was claimed beneficial in cardiovascular prevention. PURPOSE: To investigate whether the intake of the omega-3 formulation EPA:DHA 6:1 by middle-aged and old rats reduces the shedding of pro-senescent microvesicles from cultured spleen leukocytes (SMVs) and clarify the underlying mechanisms in target coronary primary endothelial cells (ECs). METHODS: Middle-aged male Wistar rats (M, 48-week old) received 500 mg/kg/d of either EPA:DHA 6:1, EPA:DHA 1:1, or vehicle (CTL) for 7 days, old rats (72-week old) for 14 days. Spleen-derived leukocytes were prepared and cultured for 24 h and MVs collected from supernatants (SMVs). Cultured ECs were prepared from freshly isolated porcine coronary arteries. Senescence-associated ß-galactosidase activity (SA-ß-gal) was assessed by C12FDG, protein expression by Western blot analysis, oxidative stress by dihydroethidium using confocal microscopy, and procoagulant MVs by prothrombinase assay. The pro-senescent potential of SMVs from middle-aged rats (M-SMVs) was analyzed by comparison with young (Y, 12-week) and old (O) rats. RESULTS: The shedding of SMVs significantly increased with age and was inhibited by EPA:DHA 6:1 intake that also prevented ROS accumulation in spleen. Incubation of ECs with 10 nM SMVs from middle-aged and old but not those from young rats induced premature senescence after 48 h. The pro-senescent effect of M-SMVs was prevented by Losartan and associated with endothelial oxidative stress. M-SMVs induced an up-regulation of senescence markers (p16, p21, p53), pro-atherothrombotic (VCAM-1, ICAM-1, tissue factor) and pro-inflammatory markers (pNF-κB, COX-2) and proteins of the angiotensin system (ACE, AT1-R). Conversely, endothelial NO synthase was down-regulated. Intake of EPA:DHA 1:1 and 6:1 by middle-aged rats decreased SMV shedding by 14% and 24%, respectively. Only EPA:DHA 6:1 intake abolished the M-SMVs-induced endothelial senescence and reduced the pro-senescent action of O-SMVs by 45%. Protection of ECs was not observed in response to SMVs from EPA:DHA 1:1 treated rats. CONCLUSION: Ingestion of EPA:DHA 6:1 by middle-aged or old rats, respectively abolished or limited both the shedding of SMVs and their pro-senescent, pro-thrombotic and pro-inflammatory effects in ECs, most likely by triggering the local angiotensin system. EPA:DHA 6:1 may help to delay ageing-related endothelial dysfunction.
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Envejecimiento/fisiología , Micropartículas Derivadas de Células/metabolismo , Senescencia Celular/fisiología , Células Endoteliales/metabolismo , Ácidos Grasos Omega-3/administración & dosificación , Bazo/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Antihipertensivos/farmacología , Biomarcadores/metabolismo , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Vasos Coronarios/citología , Vasos Coronarios/metabolismo , Ácidos Docosahexaenoicos/administración & dosificación , Ácidos Docosahexaenoicos/química , Ácido Eicosapentaenoico/administración & dosificación , Ácido Eicosapentaenoico/química , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Ácidos Grasos Omega-3/química , Losartán/farmacología , Masculino , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo , Bazo/citología , Bazo/efectos de los fármacos , PorcinosRESUMEN
Lipodystrophies are a group of heterogeneous disorders characterized by varying degrees of body fat loss and predisposition to insulin resistance and its metabolic complications. Lipodystrophy associated metabolic abnormalities include insulin resistance, that often lead to diabetes mellitus and its complications, hypertriglyceridemia that may be severe enough to cause acute pancreatitis, and hepatic steatosis that may lead to cirrhosis. We present the case of an 18-year-old female who was hospitalized as an inaugural Diabetes Mellitus. She was diagnosed with severe hypertriglyceridemia, when she was 8 years old and was hospitalized at least three times by the Pediatric Service related to this condition. Lipodystrophy developed at the age of 11. The reason for the latest hospitalisation was hyperglycemia, hypertriglyceridemia and elevated transaminase levels. Leptin levels were very low 1.5 ug/L (ref range 4-10 ug/L in women). She was given Insulin and antihyperlipidemic therapy. However there was little improvement in laboratory results even in 2 months. A year after her hospitalisation at our clinic she started leptin therapy and her laboratory values improved. In a patient with a newly diagnosed diabetes mellitus, hypertriglyceridemia and loss of adipose tissue, lipodystrophy should be suspected.
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Diabetes Mellitus Tipo 2/complicaciones , Lipodistrofia Generalizada Congénita/complicaciones , Adolescente , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Humanos , Leptina/uso terapéutico , Lipodistrofia Generalizada Congénita/tratamiento farmacológicoRESUMEN
Microparticles (MP) are plasmic membrane fragments released from cells after physiological stimulation or stress conditions like inflammation or infection. Their production is correlated to the rate of cell apoptosis. All types of cells can produce MP but they are produced mainly by platelets, endothelial cells, and leukocytes. They carry many bio-active molecules on their surface, specific to the parental cell, giving them the ability to be biomarkers and bio-effectors. MP are present in circulating blood, tissues and many biological fluids. Circulating MP levels can change during the course of many diseases. They have been the subject of many studies in the fields of cardiovascular disease and oncology. In the lungs, they are present in circulating blood and in the airways. They seem to have a role in pulmonary homeostasis in physiological situations and also in the expression of several disease processes. In this review of the literature, we were interested in the quantitative and qualitative variations in MP and their impact in airway diseases like chronic obstructive pulmonary disease (COPD) and asthma, pulmonary fibrosis and pulmonary hypertension.
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Biomarcadores/análisis , Micropartículas Derivadas de Células/fisiología , Trastornos Respiratorios/diagnóstico , Trastornos Respiratorios/etiología , Biomarcadores/metabolismo , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/metabolismo , Humanos , Enfermedades Respiratorias/diagnóstico , Enfermedades Respiratorias/etiología , Enfermedades Respiratorias/metabolismoRESUMEN
Liver and pancreas share key roles in glucose homeostasis. Liver regeneration is associated with systemic modifications and depends especially on pancreatic hormones. The aim of the study was to investigate the role of systemic factors released after two-thirds hepatectomy (2/3H) on early possible consequences of liver regeneration on endocrine pancreas structure and function. The pancreas and serum were harvested 1, 2, or 3 days after 2/3H or sham operation in Lewis rats. The HGF and VEGF serum concentrations and plasma microparticles levels were measured. The fate of endocrine pancreas was examined through islets histomorphometry and function in sham and 2/3H rats. ß-Cell line RIN-m5F viability was assessed after 24 h of growth in media supplemented with 10% serum from 2/3H or sham rats instead of FCS. Three days after surgery, the pancreas was heavier in 2/3H compared to sham rats (0.56 vs. 0.40% of body weight, p < 0.05) and the proportion of islets of intermediate size was lower in 2/3H rats (5 vs. 15%, p < 0.05). Compared to Sham, sera obtained 3 days after hepatectomy were more efficient to maintain the viability of RIN-m5F cells (99 vs. 67%, p < 0.01). Three days after surgery, no significant differences in serum HGF, a trend to significant increase in VEGF concentration and a significant increase in microparticles levels, were observed in 2/3H vs. sham rats (9.8 vs. 6.5 nM Phtd Ser Eq., p < 0.05). Liver regeneration is associated with early effects on islets and could influence ß-cell viability and function by systemic effect.
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Hepatectomía , Células Secretoras de Insulina/patología , Regeneración Hepática , Animales , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Micropartículas Derivadas de Células/metabolismo , Medios de Cultivo Condicionados/farmacología , Factor de Crecimiento de Hepatocito/sangre , Insulina/metabolismo , Secreción de Insulina , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Regeneración Hepática/efectos de los fármacos , Masculino , Modelos Animales , Tamaño de los Órganos/efectos de los fármacos , Ratas Endogámicas Lew , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Microparticles (MPs) are small membrane vesicles that are shed from virtually all cells in response to stress. Widely described in atherothrombotic diseases, recent data suggest a role for circulating MPs in the hypercoagulable state associated with supraventricular tachyarrhythmia. During atrial fibrillation, several mechanisms, such as high ventricular heart rate, low or oscillatory shear stress, stretch, hypoxia, inflammation and oxidative stress, are potent inducers of apoptotic cell death, which leads to the shedding of procoagulant MPs within the vasculature. As key regulators of cell-cell cross-talk and important mediators of inflammatory, thrombogenic and proteolytic pathways, MPs directly or indirectly contribute to the amplification loops involved in atrial fibrillation. Because high levels of platelets and endothelial-derived MPs are identified during stroke and are associated with infarct size and clinical outcome, they are proposed to be a potent marker of ischaemic risk. During pulmonary vein isolation, the additional increases of platelet and leukocyte MP levels suggest the extent of tissue damage and reflect a transient activation of the coagulation cascade that could favour ischaemic stroke. Conversely, the observed decreases of several apoptotic markers some months after the restoration of sinus rhythm suggest that the extent of apoptotic processes is reversible and might enable restoration of haemostasis. In this review, we will summarise the current evidence supporting the roles of apoptosis and cell activation in the development of the prothrombotic state observed in atrial fibrillation, with a particular focus on procoagulant MPs.
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Apoptosis/fisiología , Fibrilación Atrial/metabolismo , Remodelación Atrial/fisiología , Micropartículas Derivadas de Células/metabolismo , Trombosis/metabolismo , Animales , Fibrilación Atrial/patología , Humanos , Estrés Oxidativo/fisiología , Resistencia al Corte/fisiología , Trombosis/patologíaRESUMEN
BACKGROUND: Microalbuminuria is often the first sign of renal dysfunction in diabetes. This study aimed to investigate the prevalence of microalbuminuria in Albanian type 2 diabetes patients and its association with other cardiovascular risk factors. METHODS: Three hundred and twenty-one patients with type 2 diabetes attending, diabetes centers in Albania were enrolled in this cross-sectional, multicenter study. The subjects, aged 40-70 years, had no known proteinuria or other kidney disease. Pregnant women and patients with acute infections were excluded. Data including waist circumference, duration of diabetes and history of hypertension were obtained by questionnaire. Blood samples were drawn after 12 h overnight fasting to measure glycosylated hemoglobin (HbA1c), serum cholesterol, triglyceride and creatinine. Microalbuminuria was assessed using dipstick kits in early morning urine samples. RESULTS: The prevalence of normoalbuminuria was 56.3%, microalbuminuria 40.8% and macroalbuminuria 2.8%. Systolic and diastolic blood pressure (p<0.01), HbA1c (p<0.01) and fasting plasma glucose (p<0.001) were significantly higher in microalbuminuric than in normoalbuminuric subjects. Independent risk factors for microalbuminuria were duration of diabetes (OR: 2.785, 95% CI: 1.156-3.759), systolic blood pressure (OR: 2.88, 95% CI: 1.85-6.85) and waist circumference (OR: 2.15, 95% CI: 1.01-5.45) in males and poor glycemic control (OR: 4.51, 95% CI: 1.45-13.98), duration of diabetes (OR: 2.568, 95% CI: 1.702-3.778) and waist circumference (OR: 4.87, 95% CI: 1.80-13.11) in females. CONCLUSIONS: The high proportion of type 2 diabetes patients with microalbuminuria raises implications for health policy in Albania. Screening programs and optimized control of modifiable risk factors are needed to reduce the risk of diabetic nephropathy.
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The loss of graft function after intraportal islet transplantation is likely multifactorial involving allogeneic rejection, recurrent autoimmunity, graft exhaustion due to a marginally implanted islet mass, immunosuppressant toxicity, and impaired ß-cell regeneration. Because early markers of the loss of ß-cell mass or function are lacking, monitoring of islet function remains a challenging issue. We have reported herein monitoring of membrane procoagulant microparticles (MPs) as markers of cell stress in the plasma of three recipients with various clinical histories. Early kinetics of C-peptide and MPs followed identical patterns during the first weeks after transplantation; a major increase probably reflected processes related to cell infusion and islet engraftment. Importantly in the case of rejection, MPs and C-peptide showed opposite patterns. A fall in C-peptide was associated with enhanced insulin needs. Our results suggested that a peak in MP levels might indicate rejection with prognotic value. Treatment of the loss of islet function by a new islet infusion or steroid therapy returned MP and C-peptide levels to their baselines with concomitant restoration of islet function. In the patient with suspected acute cellular rejection, MPs also appeared to be sensors of immunosuppressive steroid therapy.
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Micropartículas Derivadas de Células/metabolismo , Trasplante de Islotes Pancreáticos/métodos , Adulto , Péptido C/química , Ensayos Clínicos como Asunto , Coagulantes/metabolismo , Femenino , Antígenos HLA/metabolismo , Humanos , Inmunosupresores/metabolismo , Insulina/metabolismo , Cinética , Masculino , Persona de Mediana Edad , Pronóstico , Esteroides/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: Antiphospholipid antibodies are associated with thrombosis and repeated pregnancy losses during the antiphospholipid syndrome. Several experimental findings indicate that purified antiphospholipid antibodies are directly responsible for inflammation-induced pregnancy losses, or for disruption of the annexin A5 shield at the trophoblastic interface. We previously showed that passive transfer of CIC15, a monoclonal antiphospholipid antibody binding to cardiolipin and annexin A5 that was isolated from a patient with primary antiphospholipid syndrome, induces fetal resorption in pregnant mice. OBJECTIVES: To investigate the mechanisms of CIC15-induced pregnancy loss. METHODS/RESULTS: We show that CIC15 induces fetal loss through a new mechanism that is probably related to procoagulant activity. The time course is different from those of previously described models, and histologic analysis shows that the placentas are devoid of any sign of inflammation but display some signs of thrombotic events. Despite these differences, the CIC15 and 'inflammatory' models share some similarities: lack of FcγRI/III dependency, and the efficacy of heparin in preventing fetal losses. However, this latter observation is here mostly attributable to anticoagulation rather than complement inhibition, because fondaparinux sodium and hirudin show similar efficiency. In vitro, CIC15 enhances cardiolipin-induced thrombin generation. Finally, using a combination of surface-sensitive methods, we show that, although it binds complexes of cardiolipin-annexin A5, CIC15 is not able to disrupt the two-dimensional ordered arrays of annexin A5. CONCLUSIONS: This human monoclonal antibody is responsible for pregnancy loss through a new mechanism involving thrombosis. This mechanism adds to the heterogeneity of the obstetric antiphospholipid syndrome.
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Aborto Espontáneo , Síndrome Antifosfolípido/complicaciones , Complicaciones Hematológicas del Embarazo/fisiopatología , Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/fisiopatología , Medicina Basada en la Evidencia , Femenino , Humanos , EmbarazoRESUMEN
BACKGROUND: In obesity, metabolic stress and inflammation in injured tissues could favour enhanced shedding of procoagulant microparticles (MPs). At sites of endothelium injury, the swift recruitment of procoagulant leukocyte-derived MPs enables the initiation of blood coagulation and thrombus growth. OBJECTIVES: In obese females, we sought to evaluate the impact of a very low-calorie diet (VLCD) on procoagulant MP levels, fibrinolytic status, inflammation and endothelium damage. METHODS: Circulating biomarkers of vascular damage, fibrinolytic status, platelet activation and inflammation were measured before, 30 and 90 days after starting a short-term VLCD. MPs were measured by flow cytometry and capture assays. Their procoagulant potential was quantified using functional prothrombinase assays and their cellular origin were determined using flow cytometry (endothelium, platelet, leukocyte, lymphocyte and erythrocyte-derived MP) or capture assays. RESULTS: A total of 24 obese females (39 ± 10 years) with a mean body mass index of 35 ± 4 kg m(-2) were prospectively enroled. Procoagulant leukocyte-derived MPs were associated with the waist circumference at baseline (r=0.534; P=0.010) and at 90 days follow-up (r=0.487; P=0.021). At 90 days, weight reduction (-9.8%) was associated with a lowering of blood pressure, improvement of metabolic parameters and a significant reduction of plasminogen activator inhibitor-1 (PAI-1) (-38%), procoagulant platelet-derived MPs (-43%), leukocyte-derived MPs (-28%) and leptin (-32%) levels. CONCLUSION: In obese females, a short-term VLCD results in an overall improvement of the haemostatic balance characterized by the reduction of PAI-levels, diminished release of platelet and leukocyte-derived MPs and a reduction in leptin levels, an adipocyte-derived cytokine.
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Factores de Coagulación Sanguínea/metabolismo , Plaquetas/metabolismo , Restricción Calórica , Leptina/sangre , Leptina/metabolismo , Leucocitos/metabolismo , Obesidad/sangre , Inhibidor 1 de Activador Plasminogénico/metabolismo , Adolescente , Adulto , Anciano , Biomarcadores/sangre , Endotelio Vascular/metabolismo , Eritrocitos/metabolismo , Femenino , Hemostasis , Humanos , Persona de Mediana Edad , Obesidad/dietoterapia , Obesidad/metabolismo , Estudios Prospectivos , Tromboplastina/metabolismo , Trombosis/metabolismo , Pérdida de Peso , Adulto JovenAsunto(s)
Plaquetas/patología , Micropartículas Derivadas de Células/patología , Microscopía de Fuerza Atómica , Nanopartículas , Neoplasias/sangre , Animales , Plaquetas/inmunología , Micropartículas Derivadas de Células/inmunología , Citometría de Flujo , Humanos , Neoplasias/inmunología , Glicoproteína IIb de Membrana Plaquetaria/sangre , Reproducibilidad de los Resultados , Manejo de Especímenes , Propiedades de SuperficieRESUMEN
Thrombosis remains one of the leading causes of mortality and morbidity in developed countries. Relevant markers of the primary thrombotic risk however remain of limited accessibility, and clinicians are left with markers of essentially etiological nature. Fortunately, new entities, testifying to cellular activation or damage within the vascular compartment, have been recently described and are in the validation process. Microparticles (MP) are plasma membrane fragments released by stimulated or apoptotic cells. In the vascular compartment, they constitute a disseminated storage pool of bioactive effectors involved in inflammation, thrombosis, vascular tone, angiogenesis. Their biological characteristics are predetermined by the cytosolic and membraneous components hijacked from the activated cells. Their procoagulant properties are based on, (i) the accessibility of phosphatidylserine, a procoagulant aminophospholipid exposed after stimulation and necessary for the assembly of the blood clotting enzyme complexes, and (ii) the possible presence of tissue factor, the major initiator of the coagulation cascade. The incidence of MP in haemostatic processes has been demonstrated in physiology and pathology. They are now considered true pathogenic markers of the thrombotic risk.
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Membrana Celular/química , Trombosis/sangre , Animales , Biomarcadores , Vasos Sanguíneos/química , Vasos Sanguíneos/ultraestructura , Humanos , Riesgo , Trombosis/epidemiologíaRESUMEN
BACKGROUND: Cardiovascular and metabolic risk factors represent potential targets for intervention. A good metabolic control, associated with control of blood pressure and cholesterol levels is proven to reduce the risk of cardiovascular disease among individuals with diabetes mellitus. OBJECTIVES: To examine 2004-2005 medical records of adults with previously diagnosed diabetes and to evaluate the fulfillment of diabetes guidelines treatment, for the metabolic control and management of cardiovascular risk factors. RESEARCH, DESIGN AND METHODS: We reviewed the data from the National Register of Diabetes (Tirana district), updated during this period. As guidelines we used the ADA 2006 Recommendations for metabolic control, HTA, lipid profile and aspirin therapy. RESULTS: We examined 7259 medical records. Only 14.58% of the patients had an HbA1c <7%. Central obesity was present in 39% of our patients. Overall, only 31.9% of our patients achieved the target for blood pressure (SBP<130 mmHg and DBP<80 mmHg). Two-third of our patients had total cholesterol >200 mg/dl. In total, only 5.5% of our patients attained recommended goals of cardiovascular risk factors for HbA1c, blood pressure and lipid profile. CONCLUSIONS: The follow-up of diabetic patients during the transient period in Albania is marked by a deterioration of diabetes metabolic control and poor management of cardiovascular risk factors. Further public health efforts are needed for better control of these risk factors among adults with diagnosed diabetes.
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Enfermedades Cardiovasculares/etiología , Complicaciones de la Diabetes , Diabetes Mellitus/fisiopatología , Adhesión a Directriz , Hipertensión/complicaciones , Obesidad/complicaciones , Adulto , Anciano , Albania/epidemiología , Glucemia/metabolismo , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/metabolismo , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Humanos , Hipercolesterolemia/complicaciones , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/epidemiología , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Lipoproteínas LDL/sangre , Masculino , Registros Médicos , Síndrome Metabólico , Persona de Mediana Edad , Obesidad/epidemiología , Factores de RiesgoRESUMEN
Sepsis and trauma lead to a sustained activation of monocytes and endothelium. In the vascular compartment, stimulated cells release microparticles. Circulating MP provide an additional procoagulant phospholipid surface enabling the assembly of the clotting enzymes complexes and thrombin generation. Their procoagulant properties rely on the exposition of phosphatidylserine, made accessible after cell stimulation and on the possible presence of tissue factor, the main cellular initiator of blood coagulation. Microparticles constitute the main reservoir of blood-borne tissue factor activity. At sites of endothelium injury, enhanced release or recruitment of procoagulant MP through P-selectin-PSGL-1 pathway could concentrate TF activity above a threshold allowing blood coagulation to be triggered. Converging evidences from experimental or clinical data highlight a role for MP harboring tissue factor in the initiation of disseminated intravascular coagulopathy. In these settings, the pharmacological modulation of MP levels or biological functions through activated protein C or factor VIIa allows challenging issues.
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Endotelio Vascular/ultraestructura , Inflamación/fisiopatología , Monocitos/ultraestructura , Sepsis/sangre , Trombosis/fisiopatología , Apoptosis , Endotelio Vascular/patología , Endotelio Vascular/fisiopatología , Humanos , Inflamación/sangre , Modelos Cardiovasculares , Trombosis/sangre , Heridas y Lesiones/sangreRESUMEN
Circulating procoagulant microparticles (MP) are pathogenic markers of enhanced coagulability associated to a variety of disorders and released from stimulated vascular cells. When derived from endothelial cells, MP were found characteristic of thrombotic propensity in primary antiphospholipid syndrome (APS). The prothrombotic status of a patient with antiphospholipid antibodies (APL), a past history of mesenteric vein thrombosis and presenting myocardial infarction and extensive intracardiac thrombosis was examined by measurement of circulating procoagulant MP. MP of platelet and endothelial origins were highly elevated with respect to values detectable in patients with myocardial infarction and no history of APS (6- and 3-fold elevation, respectively) or in healthy volunteers (13- and 25-fold elevation, respectively). In this particular patient, with moderate APL titer, a drastic release of procoagulant MP could have contributed to thrombus growth and the development of extensive intracardiac thrombosis.
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During percutaneous coronary angioplasty, platelet inhibition by clopidogrel and aspirin has drastically decreased the risk of thrombotic occlusion of the stented vessels. However, despite the widespread use of these drugs, the incidence of acute or subacute stent thrombosis remains elevated, concerning 1 to 2% of the treated patients. Considerable differences in the responsiveness to clopidogrel could be observed, suggesting a possible underlying biological resistance. "Clopidogrel resistance" has recently been associated to an increased risk of thrombotic events following coronary angioplasty. Variations in enteric absorption, biotransformation in the liver by the CYP3A4, changes in the ADP receptor P2Y12, abnomalies of intraplatelet signal transduction, extent of platelet activation, class angina, diabetes mellitus may account for the considerable interindividual response variability widely reported. In this view, laboratory tests evaluating "clopidogrel resistance" might be useful tools for the identification and follow-up of patients at higher thrombotic risk. Indeed, in these patients, further platelet inhibition can be achieved by higher doses of clopidogrel.
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Resistencia a Medicamentos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Ticlopidina/análogos & derivados , Angioplastia de Balón , Clopidogrel , Relación Dosis-Respuesta a Droga , Humanos , Polimorfismo Genético , Receptores Purinérgicos P2/genética , Trombosis/prevención & control , Ticlopidina/uso terapéuticoRESUMEN
BACKGROUND: In multicellular organisms, apoptosis and subsequent microparticle shedding play a key role in homeostasis. Having long been considered as << cellular dust >>, microparticles released in biological fluids upon cell activation or apoptosis appear as multifunctional bioeffectors involved in the modulation of key functions including immunity, inflammation, hemostasis and thrombosis, angiogenesis. MP constitute reliable markers of vascular damage, accessible to biological detection whilst the cells they originate from remain sequestered in tissues or are promptly submitted to phagocytosis. RECENT FINDINGS: MP modulate biological functions of target cells through the transfer of cytoplasmic content, lipids and membrane receptors. The pharmacological modulation of circulating levels of microparticles could be of particular interest in thrombotic or inflammatory diseases, cancer or hemophilia. CONCLUSION: MP can now be viewed not only as a hallmark of cell damage but also as a true biological tool.
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Apoptosis/fisiología , Biomarcadores , Inflamación/fisiopatología , Tromboplastina/fisiología , Trombosis/fisiopatología , Adulto , Comunicación Celular/fisiología , Membrana Celular/fisiología , Citoesqueleto/fisiología , Femenino , Hemostasis , Homeostasis , Humanos , Inmunidad/fisiología , Masculino , Microcuerpos/fisiología , Tamaño de la Partícula , Fagocitosis , Fenotipo , Embarazo , Selectinas/fisiologíaRESUMEN
Microparticles are membrane fragments liberated by activated or apoptopic cells. Thought for a long time to be cellular debris with no specific biologic function, in the vascular compartment they are a circulating reservoir of cellular effectors involved in thrombosis, inflammation, vascular remodelling and angiogenesis. High concentrations of circulating procoagulating microparticles found in many cardiovascular diseases indicate the importance of platelet, endothelial and monocytic activation and could contribute to the persistence of atherothrombotic disease. Pharmacological modulation of circulating microparticle concentrations could become a major therapeutic target in the future.
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Coagulación Sanguínea , Enfermedades Cardiovasculares/sangre , Fracciones Subcelulares/metabolismo , Plaquetas/metabolismo , Enfermedades Cardiovasculares/prevención & control , Endotelio Vascular/metabolismo , Regulación de la Expresión Génica , Humanos , Inflamación/metabolismo , Leucocitos/metabolismo , Selectina-P/metabolismo , Trombosis/sangreRESUMEN
OBJECTIVE: The aim of this prospective case-control study was to assess the long-term effectiveness of interdisciplinary cognitive-behavioural-nutritional therapy, combined with daily physical exercise and relaxation sessions, on weight and psychosocial issues during a 6-week in-hospital stay. SETTING: Five years (60 +/- 1 months) later, the patients were readmitted for a one-day medical evaluation including a physical examination and laboratory work-up, and the completion of a detailed questionnaire focusing on dietary and psychosocial factors that may affect weight loss/regain. SUBJECTS: The follow-up population consisted of 55 morbidly obese subjects aged 49.5 +/- 2 years (45 females and 10 males; BMI: 40 +/- 0.7 kg/m2). During their initial 6-week in-hospital stay, they lost an average of 7.6 +/- 0.4 kg. RESULTS: Five years later, 25.5% of the patients had lost a further 11.9 +/- 1.8 kg, 20% maintained their initial weight loss (0.6 +/- 0.4 kg), and 54.5% regained weight (10.4 +/- 1 kg). The weight changes significant correlated with the degree of psychosocial difficulties (p < 0.001), eating behaviour problems (p < 0.001), dietary fat intake (p < 0.005) and total energy intake (p < 0.05). Fasting plasma insulin and blood glucose concentrations were significantly higher in the patients who regained weight after five years, and significantly lower in those who had lost more weight. CONCLUSION: As a whole, these results show the efficacy of an interdisciplinary approach to the long-term treatment of morbidly obese patients. It is likely that an outpatient psychological follow-up would have improved this therapeutic success.
Asunto(s)
Terapia Cognitivo-Conductual/métodos , Estado Nutricional , Obesidad/terapia , Grupo de Atención al Paciente , Índice de Masa Corporal , Estudios de Casos y Controles , Ejercicio Físico , Femenino , Estudios de Seguimiento , Hospitalización , Humanos , Tiempo de Internación , Masculino , Persona de Mediana Edad , Obesidad/rehabilitación , Estudios Prospectivos , Terapia por RelajaciónRESUMEN
Circulating procoagulant microparticles (MP) were measured as markers of vascular damage and prothrombotic risk in patients undergoing ST-segment myocardial infarction (STEMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) and additional GPIIb-IIIa antagonists. Cells possibly more responsive to GPIIb-IIIa (alpha(IIb)beta(3)) antagonists were evidenced through MP phenotypes by comparison with healthy volunteers (HV) and STEMI patients treated by PTCA without GPIIb-IIIa antagonist (CP). In 50 STEMI patients, blood samples were collected at day 1 and day 6. Circulating procoagulant MP were captured on annexin V and quantified by prothrombinase assay as nanomolar phosphatidylserine equivalents (nm PhtdSer). Platelet activation by thrombin was confirmed through independent measurement of soluble GPV (sGPV). With respect to HV, procoagulant MP levels were high in patients with STEMI or unstable angina, platelet-derived MP and elevated sGPV testifying to significant platelet activation. A substantial release of endothelial-derived MP was evidenced simultaneously. In abciximab-treated patients, procoagulant MP, mainly of platelet origin, decreased precociously at day 1 (4.2 +/- 0.6 vs. CP 15.5 +/- 2.1 nm PhtdSer; P = 0.001) together with sGPV (36 +/- 3 vs. CP 58 +/- 8 ng mL(-1); P = 0.02). Leukocyte-derived MP decreased at day 6 (0.12 +/- 0.04 vs. CP 0.56 +/- 0.12 nm PhtdSer; P = 0.01) suggesting a possible effect on underlying inflammatory status. In patients presenting cardiovascular events at 6-month follow-up, procoagulant MP levels at day 1 could be indicative of a worsened outcome. MP could constitute a relevant parameter for the follow-up of STEMI patients treated by GPIIb-IIIa antagonists.
Asunto(s)
Angioplastia Coronaria con Balón/efectos adversos , Infarto del Miocardio/sangre , Inhibidores de Agregación Plaquetaria/farmacología , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Complejo GPIb-IX de Glicoproteína Plaquetaria/análisis , Trombofilia/tratamiento farmacológico , Abciximab , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Aspirina/uso terapéutico , Biomarcadores/sangre , Femenino , Estudios de Seguimiento , Humanos , Fragmentos Fab de Inmunoglobulinas/farmacología , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Masculino , Persona de Mediana Edad , Infarto del Miocardio/terapia , Tamaño de la Partícula , Inhibidores de Agregación Plaquetaria/uso terapéutico , Complejo GPIb-IX de Glicoproteína Plaquetaria/efectos de los fármacos , Valor Predictivo de las Pruebas , Pronóstico , Solubilidad , Trombofilia/diagnóstico , Trombofilia/etiologíaRESUMEN
Endothelial apoptosis and platelet activation play a key role in atherothrombotic event. These two mechanisms resulting membrane thickening leading to procoagulant microparticle (MP) liberation into the blood stream. In the vascular compartment, MP contribute to increased thrombin formation, to platelet activation, and prolong inflammation of the arterial wall by inducing the synthesis of cytokines and adhesion of glycoproteins by the endothelial cells. In diabetic patients, increased endothelial apoptosis associated with intense platelet and monocytic activation could contribute to accelerated atherothrombosis. Endothelial, platelet and monocytic derived MP, found in high concentrations in these patients, induce a prothrombotic, proadhesive and proinflammatory tendency in the vascular comportment which could directly impact on the vascular prognosis. In diabetes, increased platelet or monocytic MP is a marker for microvascular disease. Likewise, in acute coronary syndromes of diabetic patients, high concentrations of procoagulant MP could be associated with a poor cardiovascular prognosis. In these diabetic patients, many treatments (antioxidant, antiplatelet, lipid lowering, antihypertensive) significantly reduce the levels of MP and parameters associated with inflammation. MP are one of the key factors linking inflammation, oxidative stress, apoptosis and thrombosis in accelerated atherothrombotic disease of the diabetic. In future, the measurement of MP should help evaluate the efficacy of antioxidant and antiplatelet therapy, especially in diabetic patients.