RESUMEN
OBJECTIVES: The goal of this study was to evaluate platelet function and to preliminarily assess the clinical safety of sequential treatment with tirofiban or eptifibatide followed by abciximab in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: An increasing number of acute coronary syndrome (ACS) patients are treated early with tirofiban or eptifibatide. Some later require PCI and may benefit from switching to abciximab, for which long-term benefits have been reported. METHODS: Fifty ACS patients planned for PCI were enrolled. Twenty-five patients received tirofiban followed by abciximab. Ten patients received eptifibatide followed by abciximab. Fifteen patients received only abciximab. All patients had blood samples drawn six times during the therapeutic course. Platelet function was evaluated by ADP- and TRAP-induced aggregation, flow cytometry analysis of fibrinogen binding and the cone and plate(let) analyzer, which tests shear rate-dependent platelet activation. RESULTS: Administered after tirofiban, abciximab caused a significant further decline in platelet function, as evidenced by all methods. Administered after eptifibatide, abciximab caused a significant further reduction in platelet function, as assessed by the cone and plate(let) analyzer and fibrinogen binding methods. The platelet inhibition achieved by the combination therapy was always greater than or equal to that achieved by abciximab alone. There were no major bleeding or severe thrombocytopenia episodes. Three of the 35 combination therapy patients and one of the 15 who received abciximab alone had minor bleeding. CONCLUSIONS: This is the first in vivo study of combination intravenous platelet glycoprotein IIb/IIIa inhibitor therapy. Administration of abciximab immediately after tirofiban or eptifibatide therapy effectively inhibits platelet function and appears to be safe.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Plaquetas/efectos de los fármacos , Fragmentos Fab de Inmunoglobulinas/farmacología , Péptidos/farmacología , Agregación Plaquetaria/efectos de los fármacos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/farmacología , Tirosina/análogos & derivados , Tirosina/farmacología , Abciximab , Plaquetas/fisiología , Quimioterapia Combinada , Eptifibatida , Femenino , Humanos , Masculino , Persona de Mediana Edad , TirofibánRESUMEN
BACKGROUND: Primary hemiarthroplasty of the shoulder is used to treat complex proximal humeral fractures, although the reported functional results following this method of treatment have varied widely. The aim of this study was to prospectively assess the prosthetic survival and functional outcomes in a large series of patients treated with shoulder hemiarthroplasty for a proximal humeral fracture. By determining the factors that affected the outcome, we also aimed to produce models that could be used clinically to estimate the functional outcome at one year following surgery. METHODS: A thirteen-year observational cohort study of 163 consecutive patients treated with hemiarthroplasty for a proximal humeral fracture was performed. Twenty-five patients died or were lost to follow-up in the first year after treatment, leaving 138 patients who had assessment of shoulder function with use of the modified Constant score at one year postinjury. RESULTS: The overall rate of prosthetic survival was 96.9% at one year, 95.3% at five years, and 93.9% at ten years. The overall median modified Constant score was 64 points at one year, with a typically good score for pain relief (median, 15 points) and poorer scores, with a greater scatter of values, for function (median, 12 points), range of motion (median, 24 points), and muscle power (median, 14 points). Of the factors that were assessed immediately after the injury, only patient age, the presence of a neurological deficit, tobacco usage, and alcohol consumption were significantly predictive of the one-year Constant score (p < 0.05). Of the factors that were assessed at six weeks postinjury, those that predicted the one-year Constant score included the age of the patient, the presence of a persistent neurological deficit, the need for an early reoperation, the degree of displacement of the prosthetic head from the central axis of the glenoid seen radiographically, and the degree of displacement of the tuberosities seen radiographically. CONCLUSIONS: Primary shoulder hemiarthroplasty performed for the treatment of a proximal humeral fracture in medically fit and cooperative adults is associated with satisfactory prosthetic survival at an average of 6.3 years. Although the shoulder is usually free of pain following this procedure, the overall functional result, in terms of range of motion, function, and power, at one year varies. A good functional outcome can be anticipated for a younger individual who has no preoperative neurological deficit, no postoperative complications, and a satisfactory radiographic appearance of the shoulder at six weeks. The results are poorer in the larger group of elderly patients who undergo this procedure, especially if they have a neurological deficit, a postoperative complication requiring a reoperation, or an eccentrically located prosthesis with retracted tuberosities.
Asunto(s)
Artroplastia de Reemplazo/métodos , Fracturas del Hombro/cirugía , Articulación del Hombro/cirugía , Accidentes por Caídas , Accidentes de Tránsito , Actividades Cotidianas , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Consumo de Bebidas Alcohólicas/efectos adversos , Análisis de Varianza , Artroplastia de Reemplazo/efectos adversos , Artroplastia de Reemplazo/instrumentación , Femenino , Estudios de Seguimiento , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Falla de Prótesis , Rango del Movimiento Articular , Recuperación de la Función , Reoperación , Factores de Riesgo , Fracturas del Hombro/etiología , Fracturas del Hombro/fisiopatología , Fumar/efectos adversos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVES: To examine the epidemiology and results of treatment of fractures of the distal humeral metaphysis. DESIGN: Observational cohort study. SETTING: An orthopaedic trauma unit, which provides all the fracture care for a well-defined catchment population. PATIENTS/PARTICIPANTS: A consecutive series of 320 patients with distal humeral fractures admitted to the unit between January 1988 and June 1997. INTERVENTION: We adopted a protocol of open reduction and fixation of all displaced fractures (greater than 5 mm of displacement in any plane) in patients who were medically fit for anesthesia. Postoperative immobilization was a cylinder cast for 6 weeks. Patients with undisplaced fractures or who were medically unfit were also treated nonoperatively in cylinder casts for 6 weeks. MAIN OUTCOME MEASUREMENTS: Epidemiological examination of patient subgroups and the incidence of complications of treatment. RESULTS: The overall incidence of distal humeral fractures in adults during this time was 5.7 cases per 100,000 in the population per year with an almost equal male to female ratio. There was a bimodal age distribution, simple falls were the most common overall cause of fracture, and the majority of the fractures were extra-articular (AO/OTA type A) or complete articular fractures (AO/OTA type C). The risk of complications during treatment was generally low in most patients, and the majority healed their fractures uneventfully. Overall, 90.6% of fractures united within 12 weeks and just under half of the remaining 9.4% patients with union complications healed without requiring further operative intervention by 24 weeks. The risk of union complications was higher following high-energy injuries, open fractures, and nonoperative treatment. Although the AO/OTA classification was not predictive of union complications, the "low" transcondylar (type A2.3 and A3) and simple intercondylar fracture (type C1.3) configuration had a greater risk of union complications than the "high" subtype. The rate of infection, myositis ossificans, and other implant-related complications were higher following operative treatment of type C fractures than type A and B fractures. CONCLUSIONS: The epidemiology of a consecutive unselected series of adult distal humeral fractures is defined in this study. The majority of these fractures are best treated surgically by rigid open reduction and internal fixation, except for "low" Type A and C fractures, which have a higher risk of union complications. The role of total elbow arthroplasty to treat these more complex injuries requires further evaluation.
Asunto(s)
Curación de Fractura , Fracturas del Húmero/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Niño , Estudios de Cohortes , Femenino , Humanos , Fracturas del Húmero/clasificación , Fracturas del Húmero/terapia , Incidencia , Masculino , Persona de Mediana Edad , Escocia/epidemiología , Distribución por SexoRESUMEN
The authors consider the clinical and biological data of Acquired Idiopathic Sideroblastic Anemia (AISA). The physiopathology of the syndrome is discussed; the relationships between pathologic sideroblastosis, dyserythropoiesis and ferrokinetic modifications are pointed out. The associated abnormalities of granulocytic and megacaryocytic series linked AISA to other myelodysplasia.
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Anemia Sideroblástica , Anemia Sideroblástica/metabolismo , Anemia Sideroblástica/patología , Anemia Sideroblástica/fisiopatología , Anemia Sideroblástica/terapia , Médula Ósea/patología , Eritroblastos/patología , Eritrocitos Anormales , Eritropoyesis , Hemoglobinas/biosíntesis , Humanos , Hierro/metabolismo , Persona de Mediana EdadRESUMEN
Accumulating evidence suggests that Th1 T cells play a pivotal role in the development of autoimmune diabetes. Conversely, promoting a Th2 response inhibits disease progression. However, it has not been determined whether Th2 cells are regulatory T cells that fail at the time of diabetes development in naive non-diabetic NOD mice. Therefore, in order to evaluate cytokine secretion by spleen and islet infiltrating T cells in NOD mice at different stages of the autoimmune process, we developed an ELISPOT assay that detects IL-2, IL-4, and interferon-gamma (IFN-gamma) secretion in vitro at the single-cell level. We showed that, whatever the age considered, IFN-gamma is predominantly secreted, and that no IL-4-secreting cells are detected in the islets of male and female NOD mice. Spleen cells from 8-week-old female NOD mice, which include regulatory suppressor T cells, do not secrete IL-4, either upon presentation of islet cell antigens in vitro, or after transfer in vivo, but do secrete IFN-gamma. IFN-gamma secretion by T cells from diabetic mice results from CD4 but not CD8 T cells in transfer experiments into NOD/severe combined immunodeficient (SCID) recipients. These results suggest that (i) detection of regulatory CD4 T cells in NOD mice is not paralleled by a Th2 response; (ii) beta cell destruction does not depend on a switch from a Th2 to a Th1-type response; and (iii) CD8 T cells do not participate in induction of diabetes by secreting IFN-gamma.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Células Th2/inmunología , Animales , Linfocitos T CD4-Positivos/inmunología , Femenino , Interferón gamma/metabolismo , Interleucina-4/metabolismo , Islotes Pancreáticos/inmunología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCIDRESUMEN
Delayed hypersensitivity to methylated bovine serum albumin may be induced in Mice without adjuvant, by injecting the antigen either with sensitized T lymphocytes, or by injecting just the antigen in Mice preptreated with Cyclophosphamid.
Asunto(s)
Hipersensibilidad Tardía/inmunología , Inmunidad Celular , Albúmina Sérica Bovina/inmunología , Linfocitos T/inmunología , Adyuvantes Inmunológicos , Animales , Ciclofosfamida/farmacología , Inmunidad Celular/efectos de los fármacos , Inmunización Pasiva , RatonesRESUMEN
The injection of Cy before immunization provokes an intensification of delayed-type hypersensitivity (DTH) to methylated bovine serum albumin (M-BSA) and a diminution of about 90% of the cell number in various lymphoid tissues. The relationship between these observations, the time of administration, the dose of injected Cy and the intensity of DTH reactions, allows us to formulate hypotheses concerning the physiological modulation of DTH.
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Ciclofosfamida/farmacología , Hipersensibilidad Tardía/inmunología , Animales , Células de la Médula Ósea , Ciclofosfamida/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Metilación , Ratones , Albúmina Sérica Bovina/análogos & derivados , Albúmina Sérica Bovina/inmunología , Timo/citología , Factores de TiempoRESUMEN
The nonobese diabetic (NOD) mouse has been developed as a model for insulin-dependent diabetes. One gene required for the development of diabetes is associated with the major histocompatibility complex. This gene possibly could be linked to class II genes, which show a unique pattern in NOD mice. To evaluate the role of the I-A class II antigen expressed in NOD mice, we studied the effect of anti-I-A monoclonal antibodies on disease onset in vivo. Long-term treatment with anti-class II IgG2a antibodies specific for NOD I-A antigen prevented the spontaneous development of diabetes, as opposed to control antibodies shown not to react with NOD I-A antigen. Anti-class II antibodies apparently elicited active immune suppression, requiring a fully immunocompetent host, rather than passive blockade of class II antigen. Treatment with anti-class II antibody effectively prevented the adoptive transfer of diabetes produced by splenocytes from diabetic NOD mice into newborn mice but failed to prevent adoptive transfer into irradiated adult NOD recipients. Direct evidence for the induction of suppressor cells was obtained from the passive transfer of spleen cells from anti-class II antibody-treated NOD donors. The injection of anti-class II antibody-treated spleen cells collected from NOD donors prevented the development of diabetes, which normally follows transfer of diabetogenic spleen cells into irradiated 8-week-old male NOD recipients. Depletion experiments indicate that CD4+ cells are responsible for anti-class II-induced protection transferred by spleen cells.
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Anticuerpos Monoclonales/uso terapéutico , Diabetes Mellitus Experimental/prevención & control , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunización Pasiva , Animales , Diabetes Mellitus Experimental/genética , Inmunoglobulina G/inmunología , Masculino , Ratones , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Bazo/citología , Linfocitos T/inmunologíaRESUMEN
The NOD mouse, which shows many features of human IDDM, is extensively used to evaluate the role of T lymphocytes in the pathogenesis of autoimmune diabetes. The development of diabetes in this model appears to be controlled by a finely tuned immunoregulatory balance between autoaggressive T cells and regulatory immune phenomena, the disruption of which may result in destruction of insulin-secreting cells. The absolute requirement of sublethal irradiation to permit transfer of the disease to non-diabetic adult syngeneic mice provides indirect evidence for the presence of regulatory T cells in non-diabetic NOD mice. We have previously reported that the reconstitution of irradiated recipients by CD4+ T cells from nondiabetic female NOD mice blocks the transfer of diabetes by spleen cells from diabetic donors. We now report evidence that anti-CD4 monoclonal antibodies can substitute for irradiation in rendering adult NOD male mice susceptible to diabetes transfer by diabetogenic spleen cells. Efficient diabetes transfer can be achieved in non-irradiated adult NOD recipients provided they are thymectomized and CD4+ T-cell depleted prior to the transfer. The role of thymectomy is to limit T cell regeneration after anti-T cell monoclonal antibody challenge. Our data confirm that regulatory CD4+ T-cells, which efficiently counterbalance diabetogenic cells, are present in adult NOD male animals.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Diabetes Mellitus Tipo 1/patología , Citometría de Flujo , Inmunoterapia Adoptiva , Depleción Linfocítica , Masculino , Ratones , Ratones Endogámicos NOD , Bazo/inmunología , Linfocitos T Reguladores/inmunología , Timo/citologíaRESUMEN
The non-obese diabetic (NOD) mouse spontaneously develops a T cell-mediated autoimmune disease, sharing many features with human insulin-dependent diabetes mellitus (IDDM), leading to insulin-secreting beta cell destruction. The role of CD4+ T cells has been evidenced at two levels. First, CD4+ T cells from diabetic animals are required to transfer diabetes to non-diabetic recipients in conjunction with CD8+ effector T cells. Second, suppressive CD4+ T cells have been characterized in non-diabetic NOD mice. T cells with different functions can thus share the CD4+ phenotype. Since CD4+ T cells can be divided into at least two subgroups on the basis of CD45 isoform expression, we evaluated the distribution of CD4+ T cells expressing the CD45RA isoform on NOD mouse thymocytes and peripheral T cells. The percentage of CD45RA+ cells was dramatically increased among the most mature CD3bright thymocytes and among CD4+ T cells in lymph nodes of the NOD mouse as compared with control strains. This increase was related to the development of insulitis. Interestingly, the CD45RA isoform was expressed on most CD4+ T cells invading the islets. In vivo treatment with an anti-CD45RA mAb prevented the development of insulitis and spontaneous diabetes in female animals but not the transfer of diabetes by T cells collected from diabetic NOD donors. These results indicate that anti-CD45RA mAb is only effective if given before the full commitment of effector T cells to the destruction of islet beta cells. Thus CD4+CD45RA+ T cells play a key role in early activation steps of anti-islet immunity.
Asunto(s)
Enfermedades Autoinmunes/etiología , Diabetes Mellitus Tipo 1/etiología , Subgrupos de Linfocitos T/inmunología , Animales , Anticuerpos Monoclonales/farmacología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/prevención & control , Antígenos CD4 , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Femenino , Inmunización Pasiva , Islotes Pancreáticos/inmunología , Islotes Pancreáticos/patología , Antígenos Comunes de Leucocito , Masculino , Ratones , Ratones Endogámicos NOD , Proteína Tirosina Fosfatasa no Receptora Tipo 1 , Timo/citología , Timo/inmunologíaRESUMEN
The nonobese diabetic (NOD) mouse is a relevant model for studying human insulin-dependent diabetes mellitus (IDDM). The selective destruction of insulin-secreting cells in this model is subsequent to an autoimmune reaction directed towards the beta cells inside the islets of Langerhans of the pancreas. Given the key role played by T cells in the development of IDDM, we investigated a model of IDDM prevention in NOD mice by administration of a monoclonal antibody to the alpha/beta dimer of the T cell receptor for antigen. Our data provide evidence that aiming at the T cell receptor protects against both spontaneous and cyclophosphamide-induced diabetes in the NOD mouse. Interestingly, potential clinical application is suggested by the efficient and durable reversal of recent onset diabetes in mice treated with anti-alpha/beta monoclonal antibody within 1 week following the clinical discovery of IDDM.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedades Autoinmunes/terapia , Diabetes Mellitus Tipo 1/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Animales , Enfermedades Autoinmunes/prevención & control , Diabetes Mellitus Tipo 1/prevención & control , Rechazo de Injerto , Masculino , Ratones , Ratones Endogámicos DBA , Receptores de Antígenos de Linfocitos T alfa-beta , Trasplante de Piel , Linfocitos T/fisiologíaRESUMEN
The nonobese diabetic (NOD) mouse is a widely used model for genetic studies of insulin-dependent diabetes mellitus due to the similarities between the murine and human diseases. To aid in the localization and identification of diabetes-related susceptibility genes, we have constructed an interspecific backcross between NOD and Mus spretus (SEG/Pas) mice. Although no diabetic animals were observed in the first backcross generation of (SEG/Pas x NOD) x NOD (BC1), the incidence of insulitis (lymphocyte infiltration of the islets of Langerhans) exceeded 20% after injections of cyclophosphamide, a treatment that provokes an acute form of diabetes in NOD mice. Insulitis, a prediabetic condition, is a useful phenotype in studies of diabetes susceptibility. In the second backcross (BC2) generation, 8% of the animals became diabetic and 76% were found to have insulitis. Genetic mapping studies in the BC2 families confirmed the importance of the major histocompatibility complex region on the severity of insulitis and suggested that additional susceptibility loci were linked to markers on mouse chromosomes 3, 6, and 15. Mus spretus crosses have been an important tool in recent advances in murine genetics, and our results extend their usefulness to the study of a multifactorial disease.