RESUMEN
OBJECTIVE: Prostate cancer is a well known cause of spinal column metastases; however, an intradural location is extremely rare. It is considered to be a type of leptomeningeal spread. Cerebral seeding has usually occurred by the time of presentation. Due to a poor prognosis, surgery is rarely indicated, and controversially discussed. PATIENT AND RESULTS: We review the known cases of spinal leptomeningeal prostate cancer spread, including our patient, who developed paraparesis over 6 weeks, 3 years after prostate cancer was diagnosed. Following surgical decompression and resection, the patient additionally received radiation therapy of the spinal meninges and antihormonal treatment. Six months after surgery, the patient is still ambulatory with a good quality of life. CONCLUSION: Spinal leptomeningeal metastases occur at a late stage of systemic disease, and the prognosis is generally poor. In literature, outcomes after surgery are reported as devastating, with mortality and morbidity rates of up to 20 and 60%. The aim of surgery is to relieve pain, preserve or even restore neurological function, and reveal histology if uncertain. This may be achieved by debulking the tumor without placing the patient at an unacceptably high risk. Surgery should be performed in selected cases of spinal leptomeningeal metastases, in patients who are still ambulatory with controlled systemic disease, and should be followed by adjuvant therapy.
Asunto(s)
Carcinoma/secundario , Neoplasias Meníngeas/secundario , Neoplasias de la Próstata/patología , Neoplasias de la Médula Espinal/secundario , Anciano , Carcinoma/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Neoplasias Meníngeas/metabolismo , Neoplasias Meníngeas/cirugía , Procedimientos Neuroquirúrgicos , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/cirugía , Neoplasias de la Médula Espinal/metabolismo , Neoplasias de la Médula Espinal/cirugíaRESUMEN
OBJECTIVE: Prostate cancer is a well known cause of spinal column metastases; however, an intradural location is extremely rare. It is considered to be a type of leptomeningeal spread. Cerebral seeding has usually occurred by the time of presentation. Due to a poor prognosis, surgery is rarely indicated, and controversially discussed. PATIENT AND RESULTS: We review the known cases of spinal leptomeningeal prostate cancer spread, including our patient, who developed paraparesis over 6 weeks, 3 years after prostate cancer was diagnosed. Following surgical decompression and resection, the patient additionally received radiation therapy of the spinal meninges and antihormonal treatment. 6 months after surgery, the patient is still ambulatory with a good quality of life. CONCLUSION: Spinal leptomeningeal metastases occur at a late stage of systemic disease, and the prognosis is generally poor. In the literature, outcomes after surgery are reported as devastating, with mortality and morbidity rates of up to 20% and 60%. The aim of surgery is to relieve pain, preserve or even restore neurological function, and reveal histology if uncertain. This may be achieved by debulking the tumor without placing the patient at an unacceptably high risk. Surgery should be performed in selected cases of spinal leptomeningeal metastases, in patients who are still ambulatory with controlled systemic disease, and should be followed by adjuvant therapy.
Asunto(s)
Carcinoma/secundario , Neoplasias Meníngeas/secundario , Neoplasias de la Próstata/patología , Neoplasias de la Médula Espinal/secundario , Aracnoides/patología , Aracnoides/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Invasividad Neoplásica/diagnóstico , Invasividad Neoplásica/fisiopatología , Procedimientos Neuroquirúrgicos , Paraparesia/diagnóstico , Paraparesia/etiología , Paraparesia/fisiopatología , Piamadre/patología , Piamadre/fisiopatología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía , Radioterapia , Médula Espinal/patología , Médula Espinal/fisiopatología , Espacio Subaracnoideo/patología , Espacio Subaracnoideo/fisiopatología , Resultado del TratamientoRESUMEN
OBJECTIVE: The risk of bleeding complications caused by thrombolysis in patients with cardiac arrest and prolonged cardiopulmonary resuscitation is unclear. We evaluate the complication rate of systemic thrombolysis in patients with out-of-hospital cardiac arrest caused by acute myocardial infarction, especially in relation to duration of cardiopulmonary resuscitation. DESIGN: The study was designed as retrospective cohort study, the risk factor being systemic thrombolysis and the end-point major haemorrhage, defined as life-threatening and/or need for transfusion. Over 10.5 years, emergency cardiac care data, therapy, major haemorrhage and outcome of 265 patients with acute myocardial infarction admitted to an emergency department after successful cardiopulmonary resuscitation were registered. RESULTS: We observed major haemorrhage in 13 of 132 patients who received thrombolysis (10%, 95% confidence interval 5-15%), five of these survived to discharge, none died because of this complication. Major haemorrhage occurred in seven of 133 patients in whom no thrombolytic treatment had been given (5%, 95% confidence interval 1-9%), two of these survived to discharge. Taking into account baseline imbalances between the groups, the risk of bleeding was slightly increased if thrombolytics were used (odds ratio 2.5, 95% confidence interval 0.9-7.4) but this was not significant (P = 0.09). There was no clear association between duration of resuscitation and bleeding complications (z for trend = 1.52, P = 0.12). Survival was not significantly better in patients receiving thrombolysis (odds ratio 1.6, 0.9-3.0, P = 0.12). CONCLUSIONS: Bleeding complications after cardiopulmonary resuscitation are frequent, particularly in patients with thrombolytic treatment, but do not appear to be related to the duration of resuscitation. In the light of possible benefits on outcome, thrombolytic treatment should not be withheld in carefully selected patients.
Asunto(s)
Reanimación Cardiopulmonar/efectos adversos , Paro Cardíaco/terapia , Hemorragia/inducido químicamente , Infarto del Miocardio/tratamiento farmacológico , Terapia Trombolítica/métodos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
Venous thromboembolism represents a significant cause of morbidity worldwide. The factors that underly thrombophilia are manifold. The concept of Virchow defines the well known triad of stasis, humoral factors, and pathologies of the vascular wall. In the current article, an additional factor, the "accumulation of repair cells" is discussed. This novel concept highlights the mast cell that accumulates around thrombosed vessels and provides a number of important repair molecules including heparin, profibrinolytic tPA, and fibrinogenolytic beta-tryptase. Thus, mast cell recruitment and activation may result in local thrombolysis and prevention of coagulation. In line with this concept, mast cell-deficient mice are more susceptible to lethal thrombogenic stimuli compared to normal mice. The factors (cytokines) that trigger mast cell accumulation and release of repair molecules have also been identified - the most important one appears to be stem cell factor (SCF). All in all. our novel concept suggests that the patho-physiology of thrombosis may involve a "physiologic" cell that provides the same repair molecules that are used for treatment of thrombotic disorders by the physician. Whether an altered availability of components of this cellular repair system can predispose for thrombophilia remains to be determined.
Asunto(s)
Fibrinólisis , Mastocitos/fisiología , Trombosis/fisiopatología , Animales , Heparina/metabolismo , Humanos , Ratones , Ratones Mutantes , Modelos Biológicos , Proteínas Proto-Oncogénicas c-kit/fisiología , Serina Endopeptidasas/metabolismo , Factor de Células Madre/fisiología , Trombosis/etiología , Activador de Tejido Plasminógeno/metabolismo , TriptasasRESUMEN
OBJECTIVE: Spontaneous subarachnoid haemorrhage as a cause of out-of-hospital cardiac arrest is poorly evaluated. We analyse disease-specific and emergency care data in order to improve the recognition of subarachnoid haemorrhage as a cause of cardiac arrest. DESIGN: We searched a registry of cardiac arrest patients admitted after primarily successful resuscitation to an emergency department retrospectively and analysed the records of subarachnoid haemorrhage patients for predictive features. RESULTS: Over 8.5 years, spontaneous subarachnoidal haemorrhage was identified as the immediate cause in 27 (4%) of 765 out-of-hospital cardiac arrests. Of these 27 patients, 24 (89%) presented with at least three or more of the following common features: female gender (63%), age under 40 years (44%), lack of co-morbidity (70%), headache prior to cardiac arrest (39%), asystole or pulseless electric activity as the initial cardiac rhythm (93%), and no recovery of brain stem reflexes (89%). In six patients (22%), an intraventricular drain was placed, one of them (4%) survived to hospital discharge with a favourable outcome. CONCLUSIONS: Subarachnoid haemorrhage complicated by cardiac arrest is almost always fatal even when a spontaneous circulation can be restored initially. This is due to the severity of brain damage. Subarachnoid haemorrhage may present in young patients without any previous medical history with cardiac arrest masking the diagnosis initially.
Asunto(s)
Paro Cardíaco/etiología , Hemorragia Subaracnoidea/complicaciones , Adulto , Reanimación Cardiopulmonar , Servicios Médicos de Urgencia , Femenino , Paro Cardíaco/mortalidad , Humanos , Masculino , Pronóstico , Sistema de Registros/estadística & datos numéricos , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: The IgE-mediated activation of effector cells and antigen-presenting cells through the high-affinity receptor for IgE (FcepsilonRI) represents a key pathomechanism in type I allergy and many forms of asthma. OBJECTIVE: We sought to establish an in vitro molecular model for the interaction of human FcepsilonRI, IgE, and the corresponding allergen and to identify monoclonal anti-human IgE antibodies with a therapeutic profile different from previously established anti-IgE antibodies. METHODS: Human FcepsilonRI alpha chain, a human monoclonal allergen-specific IgE antibody (chimeric Bip 1), and the corresponding allergen, the major birch pollen allergen Bet v 1, were produced as recombinant proteins and analyzed by means of circular dichroism and native overlays, respectively. Using this molecular model, as well as negative stain immunoelectron microscopic analysis, and in vitro cultivated human basophils, we characterized mouse anti-human IgE antibodies. RESULTS: We established a molecular model for the interaction of human IgE with FcepsilonRI. Using this molecular model, we identified a nonanaphylactic anti-human IgE antibody fragment (Fab12), which blocked the IgE-FcepsilonRI interaction and reacted with effector cell-bound IgE. CONCLUSION: Fab12 represents a candidate molecule for therapy of atopy and asthma because it can be used for the depletion of circulating IgE antibodies, as well as for the depletion of IgE-bearing cells.
Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Fragmentos Fc de Inmunoglobulinas/inmunología , Receptores de IgE/inmunología , Alérgenos/inmunología , Animales , Complejo Antígeno-Anticuerpo/ultraestructura , Antígenos de Plantas , Basófilos/inmunología , Liberación de Histamina , Humanos , Ratones , Proteínas de Plantas/inmunología , Unión ProteicaRESUMEN
Recent data suggest that mast cells (MCs) and their products are involved in the pathophysiology of thrombosis. In the present study, we analyzed the number, distribution, and phenotype of prostate MCs and periprostatic MCs in patients with unilateral periprostatic vein thrombosis (PVT) by immunohistochemical analysis and electron microscopy. MCs reacted with monoclonal antibodies to tryptase, chymase, and c-kit/CD117 and stained positively for tissue-type plasminogen activator (tPA) and urokinase receptor (uPAR/CD87) but did not express detectable urokinase (uPA) or plasminogen activator inhibitors (PAI-1, PAI-2). We found an increase in the mean +/- SEM number of MCs in PVT compared with control (PVT, 14.36 +/- 1.57 vs control, 5.23 +/- 0.57/mm2). The majority of MCs accumulated in the adventitia of thrombosed veins and showed a decrease in chymase expression. As MCs increase in number in PVT and express a profibrinolytic phenotype, we hypothesize that MC-derived molecules have a role in endogenous fibrinolysis.
Asunto(s)
Mastocitos/patología , Próstata/irrigación sanguínea , Próstata/patología , Trombosis de la Vena/patología , Anciano , Anciano de 80 o más Años , Austria , Recuento de Células , Humanos , Incidencia , Masculino , Mastocitos/fisiología , Persona de Mediana Edad , Fenotipo , Próstata/fisiopatología , Trombosis de la Vena/epidemiologíaRESUMEN
Mastocytosis is a term used for a group of disorders characterized by abnormal growth and accumulation of tissue mast cells (MC) in one or more organ systems. In patients with systemic mastocytosis (SM) the clinical course may be indolent or aggressive or even complicated by leukemic progression or an associated clonal hematologic non mast cell lineage disease (AHNMD). However, at first presentation (diagnosis) it may be difficult to define the category of disease and the prognosis. We report on a 48-year-old female patient with SM with urticaria pigmentosa-like skin lesions and mediator-related symptoms. She was found to have splenomegaly, a high infiltration grade (MC) in bone marrow biopsies (>30%), mild anemia, and a high serum tryptase level (>500 ng/ml). In addition, she exhibited discrete histologic signs of myeloproliferation in the 'non-affected' marrow and monoclonal blood cells established by C-KIT 2468A-->T mutation (Asp-816-Val) -analysis and HUMARA assay. Despite these findings, however, the clinical course was stable over years and no AHNMD or organ impairment developed. Because of the 'intermediate' clinical signs and absence of progression to aggressive disease, we proposed the term 'smouldering mastocytosis'.
Asunto(s)
Sustitución de Aminoácidos , Mastocitosis/genética , Mutación Missense , Proteínas Proto-Oncogénicas c-kit/genética , Adulto , Anemia/etiología , Médula Ósea/patología , Recuento de Células , Células Clonales/química , Células Clonales/patología , Codón/genética , Análisis Mutacional de ADN , Progresión de la Enfermedad , Compensación de Dosificación (Genética) , Femenino , Humanos , Hipotensión/etiología , Mastocitos/patología , Mastocitosis/complicaciones , Mastocitosis/tratamiento farmacológico , Mastocitosis/patología , Células Mieloides/química , Células Mieloides/patología , Receptores Androgénicos/análisis , Serina Endopeptidasas/sangre , Choque/etiología , Síncope/etiología , Triptasas , Urticaria Pigmentosa/complicaciones , Urticaria Pigmentosa/tratamiento farmacológico , Urticaria Pigmentosa/genética , Urticaria Pigmentosa/patologíaRESUMEN
BACKGROUND AND OBJECTIVE: Legal regulations of cadaver examination and autopsy require fundamental changes. Regulations that result in up to 75% errors in the recorded cause of death on the death certificate make no sense. As an example, rare disease of bronchial malformation may cause sudden, unexpected death but is only detectable at autopsy with subsequent histological examination. PATIENTS AND METHODS: In an series of 17.204 autopsies (from 1980 to 1999) 894 cases of sudden, unexpected death were examined. In 28 cases (3.1%) only histological examination of the lungs provided the cause of natural death. RESULTS: Bronchial dysplasia may be clinically silent and leads to focal panazinar emphysema and atelectasis due to chronic airflow obstruction and an "air trapping" mechanism. Subsequent pulmonary hypertension results in a cor pulmonale, which may fail suddenly and unexpectedly. CONCLUSION: The diagnostic problems of natural death justifies the performance of an autopsy. This fact should be recognized legally. Using the example of bronchial malformation, it is shown that only an autopsy may reveal the exact cause of death.
Asunto(s)
Autopsia/legislación & jurisprudencia , Bronquios/anomalías , Causas de Muerte , Muerte Súbita/patología , Adolescente , Adulto , Bronquios/patología , Bronquiectasia/patología , Diagnóstico Diferencial , Femenino , Alemania , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Carbunco/historia , Guerra Biológica/historia , Brotes de Enfermedades/historia , Animales , Carbunco/epidemiología , Europa (Continente)/epidemiología , Historia del Siglo XV , Historia del Siglo XVI , Historia del Siglo XVII , Historia del Siglo XVIII , Historia del Siglo XIX , Historia del Siglo XX , Historia Antigua , Historia Medieval , Humanos , Estados UnidosRESUMEN
Leopold Mozart (1719-1787), father of Wolfgang Amadé, had profound medical knowledge and was a passionate medical dilettante. As long as the young Mozart lived with his father and travelled on his concert tours with him, Leopold cared for his son in medical matters. Doctors were only consulted occasionally. In the extensive correspondence of Mozart's father drugs and treatments used for Wolfgang Amadé are reported in detail. This represents a reliable description of the pharmacological therapies of the late 18th century. The mentioned drugs are, as far as possible, viewed from todays medical perspective.
Asunto(s)
Correspondencia como Asunto/historia , Personajes , Música/historia , Fitoterapia/historia , Austria , Historia del Siglo XVIII , Humanos , MasculinoRESUMEN
Rembrandt's painting 'The Anatomy Lesson' (1632) is revolutionary in its portrayal of members of the Anatomic Guild. It has an entirely new composition and vividly depicts the dynamics of the event and the interest of the participants. However, the structures of the dissected forearm have been taken from a copy and not from the original. The possibility of anatomic errors is discussed here. A short biography of Dr. Tulp is also included.
Asunto(s)
Anatomía Artística/historia , Personajes , Medicina en las Artes , Pinturas/historia , Historia del Siglo XVII , Humanos , Países BajosRESUMEN
BACKGROUND: Pulmonary embolism (PE) is a possible noncardiac cause of cardiac arrest. Mortality is very high, and often diagnosis is established only by autopsy. METHODS: In a retrospective study, we analyzed clinical presentation, diagnosis, therapy, and outcome of patients with cardiac arrest after PE admitted to the emergency department of an urban tertiary care hospital. RESULTS: Within 8 years, PE was found as the cause in 60 (4.8%) of 1246 cardiac arrest victims. The initial rhythm diagnosis was pulseless electrical activity in 38 (63%), asystole in 19 (32%), and ventricular fibrillation in 3 (5%) of the patients. Pronounced metabolic acidosis (median pH, 6.95, and lactate level, 16 mmol/L) was found in most patients. In 18 patients (30%), the diagnosis of PE was established only postmortem. In 42 (70%) it was diagnosed clinically, in 24 of them the diagnosis of PE was confirmed by echocardiography. In 21 patients, 100 mg of recombinant tissue-type plasminogen activator was administered as thrombolytic treatment, and 2 (10%) of these patients survived to hospital discharge. Comparison of patients of the thrombolysis group (n = 21) with those of the nonthrombolysis group (n = 21) showed a significantly higher rate of return of spontaneous circulation (81% vs 43%) in the thrombolysis group (P=.03). CONCLUSIONS: Mortality related to cardiac arrest caused by PE is high. Echocardiography is supportive in determining PE as the cause of cardiac arrest. In view of the poor prognosis, thrombolysis should be attempted to achieve return of spontaneous circulation and probably better outcome.
Asunto(s)
Paro Cardíaco/etiología , Embolia Pulmonar/complicaciones , Anciano , Austria , Causas de Muerte , Ecocardiografía , Servicio de Urgencia en Hospital , Femenino , Paro Cardíaco/diagnóstico , Paro Cardíaco/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/mortalidad , Resucitación , Estudios Retrospectivos , Tasa de Supervivencia , Terapia TrombolíticaRESUMEN
BACKGROUND: Cricothyrotomy is the ultimate option for a patient with a life-threatening airway problem. METHODS: The authors compared the first-time performance of surgical (group 1) versus Seldinger technique (group 2) cricothyrotomy in cadavers. Intensive care unit physicians (n = 20) performed each procedure on two adult human cadavers. Methods were compared with regard to ease of use and anatomy of the neck of the cadaver. Times to location of the cricothyroid membrane, to tracheal puncture, and to the first ventilation were recorded. Each participant was allowed only one attempt per procedure. A pathologist dissected the neck of each patient and assessed correctness of position of the tube and any injury inflicted. Subjective assessment of technique and cadaver on a visual analog scale from 1 (easiest) to 5 (worst) was conducted by the performer. RESULTS: Age, height, and weight of the cadavers were not different. Subjective assessment of both methods (2.2 in group 1 vs. 2.4 in group 2) and anatomy of the cadavers (2.2 in group 1 vs. 2.4 in group 2) showed no statistically significant difference between both groups. Tracheal placement of the tube was achieved in 70% (n = 14) in group 1 versus 60% (n = 12) in group 2 (P value not significant). Five attempts in group 2 had to be aborted because of kinking of the guide wire. Time intervals (mean +/- SD) were from start to location of the cricothyroid membrane 7 +/- 9 s (group 1) versus 8 +/- 7s (group 2), to tracheal puncture 46 +/- 37s (group 1) versus 30 +/- 28s (group 2), and to first ventilation 102 +/- 42s (group 1) versus 100 +/- 46s (group 2) (P value not significant). CONCLUSIONS: The two methods showed equally poor performance.
Asunto(s)
Servicios Médicos de Urgencia , Laringe/cirugía , Músculos Respiratorios/cirugía , Sistema Respiratorio/cirugía , Procedimientos Quirúrgicos Operativos , Cartílago Tiroides/cirugía , Anciano , Cadáver , Femenino , Humanos , Unidades de Cuidados Intensivos , Laringe/anatomía & histología , Masculino , Persona de Mediana Edad , Cuello/anatomía & histología , Músculos Respiratorios/anatomía & histología , Cartílago Tiroides/anatomía & histología , Tráquea/anatomía & histología , Tráquea/cirugíaRESUMEN
Johann Wolfgang von Goethe (1749-1832) underwent a heart attack on March 20th 1832 after suffering from a febrile infection of the airways. Two days later he died under the signs of heart failure. A detailed report is given from his physician Dr. Carl Vogel. Extracts of this document are presented and commented. The last words of Goethe remain unclear.
Asunto(s)
Personajes , Insuficiencia Cardíaca/historia , Infarto del Miocardio/historia , Infecciones del Sistema Respiratorio/historia , Alemania , Historia del Siglo XVIII , Historia del Siglo XIX , Humanos , Masculino , Registros MédicosRESUMEN
The prevalence of pulmonary thromboembolism at autopsy was assessed in a retrospective study of a cohort of 185 patients undergoing maintenance hemodialysis treatment who died in the last decade. The overall frequency of thromboembolism was 12.43% in the dialysis population, which statistically was significantly less than in a control group of 8,051 nondialysis patients (21.77%; P = 0.0023). Moreover, pulmonary thromboembolism was less frequently fatal or contributing to death in the dialysis group than in the control group (P = 0.039). The prevalence of pulmonary thromboembolism in the dialysis group remained statistically unchanged over the 10-year period and was independent of a steady increase in the percentage of patients receiving recombinant erythropoietin therapy and the average hematocrit values. The occurrence of preterminal pulmonary thromboembolism was associated with a shorter period since onset of hemodialysis treatment and with infection as cause of death (P = 0. 031; P = 0.029, respectively). No statistically significant influence of the type of basic renal disease, type of dialysis anticoagulation, or dialysis access could be found. Our data suggest that, at least in the preterminal stage, the introduction of recombinant erythropoietin within the last decade had no substantial influence on the prevalence of pulmonary thromboembolism.
Asunto(s)
Eritropoyetina/uso terapéutico , Embolia Pulmonar/epidemiología , Embolia Pulmonar/prevención & control , Diálisis Renal , Anciano , Causas de Muerte , Estudios de Cohortes , Femenino , Humanos , Masculino , Prevalencia , Proteínas Recombinantes , Estudios RetrospectivosRESUMEN
A number of recent data suggest that mast cells (MC) and their products are involved in the pathophysiology of thrombosis. In the current study, we have evaluated the number, distribution, and phenotype of MC in patients with deep vein thrombosis of the lower limb (DVT) (n = 15). Contralateral nonthrombosed limb veins served as control (CO). MC were examined by Giemsa staining and by immunohistochemistry using antibodies against tryptase, chymase, tissue-type plasminogen activator (tPA), urokinase (uPA), urokinase receptor (uPAR), and plasminogen activator inhibitors (PAI-1, PAI-2). We found an increase in the number of tryptase-positive MC in DVT compared with CO (DVT: 9.1+/-1.0 v CO: 4.7+/-0.6 MC/mm2, P < .05). Most of these MC appeared to accumulate in the adventitia of the thrombosed veins, in vicinity of the vasa vasorum. In both DVT and CO, MC reacted with monoclonal antibodies to c-kit, tryptase, and chymase. MC also stained positive for tPA and urokinase receptor, but did not express detectable PAI-1 or PAI-2. As compared with CO, a decreased proportion of MC in DVT was found to stain positive for chymase and tPA. Together, our results show that MC increase in number in DVT and express a profibrinolytic phenotype. We hypothesize that MC and MC-derived profibrinolytic molecules play a role in the pathophysiology of DVT.
Asunto(s)
Mastocitos/citología , Venas/inmunología , Trombosis de la Vena/inmunología , Anciano , Anciano de 80 o más Años , Antígenos CD/metabolismo , Quimasas , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Mastocitos/enzimología , Mastocitos/metabolismo , Persona de Mediana Edad , Fenotipo , Activadores Plasminogénicos/metabolismo , Inactivadores Plasminogénicos/metabolismo , Proteínas Proto-Oncogénicas c-kit/metabolismo , Serina Endopeptidasas/metabolismoRESUMEN
Recent data suggest that mast cells (MC) and their products (heparin, proteases) are involved in the regulation of coagulation and fibrino(geno)lysis. The key enzyme of fibrinolysis, plasmin, derives from its inactive progenitor, plasminogen, through catalytic action of plasminogen activators (PAs). In most cell systems, however, PAs are neutralized by plasminogen activator inhibitors (PAIs). We report that human tissue MC as well as the MC line HMC-1 constitutively produce, express, and release tissue-type plasminogen activator (tPA) without producing inhibitory PAIs. As assessed by Northern blotting, highly enriched lung MC (>98% pure) as well as HMC-1 expressed tPA mRNA, but did not express mRNA for PAI-1, PAI-2, or PAI-3. The tPA protein was detectable in MC-conditioned medium by Western blotting and immunoassay, and the MC agonist stem cell factor (c-Kit ligand) was found to promote the release of tPA from MC. In addition, MC-conditioned medium induced fibrin-independent plasmin generation as well as clot lysis in vitro. These observations raise the possibility that MC play an important role in endogenous fibrinolysis.
Asunto(s)
Fibrinólisis , Mastocitos/enzimología , Activador de Tejido Plasminógeno/biosíntesis , Línea Celular , Células Cultivadas , Endotelio Vascular/química , Endotelio Vascular/citología , Endotelio Vascular/enzimología , Humanos , Inmunohistoquímica , Pulmón/química , Pulmón/citología , Pulmón/enzimología , Mastocitos/química , Mastocitos/metabolismo , Músculo Liso Vascular/química , Músculo Liso Vascular/citología , Músculo Liso Vascular/enzimología , Inhibidor 1 de Activador Plasminogénico/análisis , Inhibidor 1 de Activador Plasminogénico/biosíntesis , Inhibidor 1 de Activador Plasminogénico/genética , ARN Mensajero/biosíntesis , Activador de Tejido Plasminógeno/análisis , Activador de Tejido Plasminógeno/genética , Activador de Tejido Plasminógeno/fisiología , Venas UmbilicalesRESUMEN
OBJECTIVE: Stem cell factor (SCF), the ligand for the SCF receptor (c-kit) expressed on precursors and mature mast cells (MC), is a major agonist for human MC (e.g., SCF induces MC development, chemotaxis, activation, proliferation of MC precursors, mediates MC adhesion, and changes MC releasability). We investigated expression of SCF and c-kit in synovial membrane with particular reference to the mechanism of local MC hyperplasia and inflammation in arthritis. METHODS: We conducted single and double labeling immunohistochemistry (ABC, APAAP, indirect immunofluorescence techniques) with antibodies to SCF, c-kit, MC tryptase, Ki-67 antigen (marker for proliferating cells), and CD68 (monocyte/macrophage marker). Synovial specimens analyzed were from 31 patients: traumatic arthritis (TrA, n=9), osteoarthritis (OA, n=12), and rheumatoid arthritis (RA, n=10). Control experiments were performed on human lung, skin, and buccal mucosa tissues, on the HMC-1 mast cell line, and isolated lung MC. Morphometry was performed by computerized image analysis. RESULTS: Synovial c-kit expression was found to be restricted to MC, whereas SCF is detected in synovial lining cells, stromal fibroblasts, monocyte/macrophages, endothelial cells, and in vascular basement membranes. SCF staining was localized to MC as well, but it was not possible to specify whether this represents SCF produced by or bound (via c-kit) to MC. In inflamed synovial membranes/areas, SCF was found to be redistributed into the extracellular matrix. Redistribution of SCF was accompanied by degranulation and/or accumulation of c-kit+ MC, the hyperplasia of which correlated positively with histologic inflammation/inflammatory cell densities, but did not appear to involve MC proliferation in situ. These findings appeared to be common for all the conditions (TrA, OA, RA) studied. CONCLUSION: In addition to the demonstration/characterization of SCF and c-kit protein expression in human synovium, results of this study suggest the hypothesis that, in arthritis, local mobilization of SCF may play a role in the development of synovial MC hyperplasia without inducing in situ proliferation of MC, and that the synovial SCF/MC c-kit system may contribute to the local nonspecific inflammatory response/arthritic flares in TrA, OA, and RA.