RESUMEN
Tissue factor (TF, coagulation factor III, CD142) is not only the main physiological initiator of normal blood coagulation, but is also important in the natural history of solid malignancies in that it potentiates metastasis and angiogenesis and mediates outside-in signalling. TF is expressed constitutively by many tissues which are not in contact with blood and by other cells upon injury or activation; the latter include endothelial cells, tissue macrophages, and peripheral blood monocytes. It can exist encrypted and unavailable functionally in the plasma membrane and the appearance of functional TF may be due to synthesis and/or de-encryption. Inflammatory cells often express TF and act to induce its production or de-encryption by other cells locally and, apparently, at remote sites. Inappropriate expression of TF by endothelial cells, macrophages or monocytes is thought to be an important trigger of coagulation in various pathological conditions. Several studies have shown that measurements of monocyte TF (mTF) may provide clinically significant information, particularly in patients with malignant and inflammatory diseases.
Asunto(s)
Biomarcadores de Tumor/sangre , Monocitos/metabolismo , Neoplasias/sangre , Tromboplastina/metabolismo , Coagulación Sanguínea/fisiología , Regulación de la Expresión Génica/fisiología , Humanos , Tromboplastina/fisiologíaRESUMEN
Tissue factor (TF) is the main physiological initiator of blood coagulation and may be important in the biology of a variety of solid malignancies, particularly where angiogenesis is a critical factor. TF is frequently encrypted in the plasma membrane of cells in contact with blood, and is exposed only after stimulation by certain agonists. Cancer cells variably express TF and cancer cell lines which exhibit multidrug resistance contain more TF than parental cells. TF is increased in both tumour-associated macrophages and blood monocytes and has been implicated in abnormal coagulation activation seen in patients with inflammatory conditions and cancer. TF is also found in urine (uTF) in a lipid-associated form, probably of kidney origin. uTF levels can be assayed in a cost-effective manner and may be clinically important, particularly in patients with renal disorders and malignancy. uTF levels are not significantly affected by age, gender or cigarette smoking.
Asunto(s)
Biomarcadores de Tumor/orina , Enfermedades Renales/orina , Tromboplastina/orina , Factores de Edad , Coagulación Sanguínea , Resistencia a Antineoplásicos , Ensayo de Inmunoadsorción Enzimática , Humanos , Riñón/metabolismo , Enfermedades Renales/diagnóstico , Neoplasias Renales/diagnóstico , Neoplasias Renales/orina , Factores Sexuales , Tromboplastina/metabolismoRESUMEN
BACKGROUND: We have previously explored the clinical significance of urinary tissue factor (uTF) in patients with glomerulonephritis (GN) and malignancy. However, the functional and structural properties and putative cell of origin of uTF are poorly documented. In these studies we investigate these aspects of uTF. METHODS: Functional and structural properties of uTF were investigated using a one stage kinetic chromogenic assay, an enzyme-linked immunoabsorbent assay (ELISA) and transmission electron microscopy (TEM) on urine samples collected from healthy controls (n=69). The distribution of uTF and anionic phospholipid in the kidney were studied in sections from normal areas of nephrectomy specimens, using an immunoperoxidase technique. These were stained for tissue factor (TF) antigen and recombinant Annexin V. RESULTS: We found uTF to be present on subcellular particles as visualized by TEM. These particles contained anionic phospholipid as evidenced by binding to Annexin V fluorescein isothiocyanate (FITC). Although TF is present in urine in a functional and antigenic form no association was observed between the two. Using immunoperoxidase-based techniques, the cytoplasm of both distal and proximal tubules (but not glomerular cells) was positive for TF antigen and Annexin V. CONCLUSION: uTF is found on subcellular particles which provide lipid for its functional activity. Both uTF and its associated vesicles are found in the renal tubular cells.
Asunto(s)
Tromboplastina/orina , Anexina A5/farmacología , Humanos , Riñón/química , Fosfolípidos/orina , Tromboplastina/química , Tromboplastina/fisiologíaRESUMEN
AIM: To investigate factors that influence urinary tissue factor (uTF) measurements: glomerular permeability and filtration, tubular function, haematuria, and urine bacterial growth. METHODS: uTF, protein creatinine index, glomerular filtration rate, retinol binding protein, N-acetyl-beta-D-glucosaminidase (NAG) and urinary haemoglobin (uHb) were measured in patients with hypertension, diabetes mellitus and nephrotic syndrome (n = 342), tubulo-interstitial disease (n = 50), and haematuria of uncertain cause (n = 50); measurements were also made in urine samples from healthy subjects for "simulated" haematuria (n = 6) and bacterial growth (n = 4) studies. RESULTS: There was a weak correlation of uTF with glomerular permeability and filtration (protein creatinine index and glomerular filtration rate) and with markers of tubular function (retinol binding protein and NAG). uTF concentrations were not affected by the presence of blood or bacteria in the urine sample. CONCLUSION: uTF concentrations are relatively stable. This is an important finding if the assay is to be used in clinical practice.
Asunto(s)
Hematuria/orina , Riñón/fisiopatología , Tromboplastina/orina , Acetilglucosaminidasa/orina , Bacteriuria/orina , Biomarcadores/orina , Tasa de Filtración Glomerular , Humanos , Túbulos Renales/fisiopatología , Proteinuria/orina , Proteínas de Unión al Retinol/orinaRESUMEN
The essential fatty acid gamma-linolenic acid (GLA) is an effective cytotoxic agent when applied topically and for prolonged periods to tumour cells. Topical application, by intravesical therapy, is firmly established in the treatment of superficial bladder cancer. However, this form of therapy is limited to a maximum duration of 2 h. At such a short drug exposure time, does GLA retain its cytotoxicity? We have examined this question by exposing the superficial bladder cancer cell lines MGH-U1 and RT112 to meglumine-GLA (MeGLA) for time intervals ranging from 30 min to 2 h, at drug concentrations ranging from 1000 to 1.95 microg/ml. The MTT viable biomass assay was used to assess cell kill. Greater than 90% inhibition was observed at a concentration of 125 microg/ml (IC > 90), at 2 h drug exposure. At shorter drug exposure times, higher drug concentrations were needed to induce the same effect. At 1 h drug exposure, the IC > 90 was recorded at 500 microg/ml. In vivo intravesical tolerance studies were conducted in rats. Rats exposed to 2.5 mg/ml MeGLA intravesically for 2 h or less remained well and bladder histology showed minimal changes. This study confirms that GLA retains its cytotoxicity at short drug exposure times and is well tolerated by normal bladder mucosa in vivo. Bladder mucosa tolerated > 10x the concentration required for the IC > 90 in vitro. MeGLA is therefore a feasible intravesical agent for superficial bladder cancer.
Asunto(s)
Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Ácido gammalinolénico/administración & dosificación , Administración Intravesical , Animales , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Ratas , Ratas Endogámicas F344 , Factores de Tiempo , Células Tumorales Cultivadas/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/patología , Ácido gammalinolénico/efectos adversos , Ácido gammalinolénico/uso terapéuticoRESUMEN
AIM: To investigate the significance of urinary tissue factor (uTF) concentrations in patients with glomerulonephritis. METHODS: Urine samples were collected from normal subjects (n = 57), patients with uncomplicated renal stones (n = 30), and patients with glomerulonephritis (n = 150). Samples were then centrifuged and the pellets solubilised in n-octyl-beta-glucopyranoside. uTF concentrations were determined using a one stage kinetic chromogenic assay. RESULTS: The uTF concentration was higher in patients with glomerulonephritis than in normal controls (p < 0.01) or in patients with renal stones (p < 0.05). uTF activity correlated with the protein creatinine index (PCI, r = 0.41, p < 0.001) and seven patients with glomerulonephritis and a PCI < or = 0.1 g/mmol had raised uTF. Glomerulonephritis patients were subdivided into two groups depending on the PCI: < 0.2 g/mmol creatinine (mild to moderate proteinuria, group I) and > or = 0.2 g/mmol creatinine (heavy proteinuria, group II). In group I, uTF concentrations were higher in patients with either immune complex (IC) glomerulonephritis (p < 0.01) or non-IC (p < 0.05) glomerulonephritis than in normal controls. In group II, the IC glomerulonephritis group had higher uTF concentrations than normal controls (p < 0.001) or patients with renal stones (p < 0.01); and non-IC glomerulonephritis patients had higher uTF than normal controls (p < 0.01). When the glomerulonephritis groups were divided into broad WHO subtypes, the significance level varied with the type of glomerulonephritis. CONCLUSIONS: uTF is increased in patients with glomerulonephritis, and its concentration may reflect the aetiopathogenesis of glomerulonephritis.
Asunto(s)
Glomerulonefritis/orina , Tromboplastina/orina , Biomarcadores/orina , Creatinina/orina , Glomerulonefritis/complicaciones , Glomerulonefritis/patología , Humanos , Cálculos Renales/metabolismo , Proteinuria/complicacionesRESUMEN
We have studied the clinical, radiological and pathological features of three patients with recurrent massive lower gastrointestinal arterial haemorrhage. Case 1 was an example of Dieulafoy's vascular malformation within the proximal ascending colon in a 46-year-old woman. Cases 2 and 3 were men aged 81 and 83 years with arterial erosions contained within small mucosal diverticula in the hepatic flexure and descending colon, respectively. All three patients presented with recurrent acute episodes of massive lower gastrointestinal haemorrhage. Selective mesenteric angiography was performed in cases 1 and 3 to localize the bleeding point in both patients. The features were very different to those of angiodysplasia, lacking the tuft of abnormal vessels and the early venous filling phase commonly seen in the latter condition. The patients were all successfully treated by partial colectomy. The aetiology of Dieulafoy's vascular malformation remains unclear. The ruptured arteries in cases 2 and 3 shared many histological features with the Dieulafoy lesion in case 1. The lesions in cases 1 and 2 were associated with recent oral non-steroidal anti-inflammatory therapy, suggesting coincidental mucosal ulceration as a contributory factor.
Asunto(s)
Sistema Digestivo/irrigación sanguínea , Hemorragia Gastrointestinal/patología , Adulto , Anciano , Anciano de 80 o más Años , Angiografía , Arterias/patología , Colon/diagnóstico por imagen , Colon/patología , Divertículo/patología , Femenino , Hemorragia Gastrointestinal/diagnóstico por imagen , Hemorragia Gastrointestinal/cirugía , Humanos , Mucosa Intestinal/patología , MasculinoRESUMEN
AIMS: To immunophenotype and quantitate glomerular and interstitial inflammatory cells in cases of idiopathic membranous and IgA glomerulopathy; to correlate cell numbers with aspects of clinical data and renal function. METHODS: Routine indirect immunoperoxidase staining was performed on frozen section renal biopsy specimens for T and B lymphocyte related antigens, macrophages and MHC class II antigens. Double immunohistochemical staining was performed to identify CD45RO+ and CD45RA+ cells. RESULTS: In IgA glomerulopathy correlations were found relating interstitial cell numbers to creatinine concentration at biopsy (CD45RO+ and CD45RA+ cells) and follow up creatinine concentration (CD3+, CD4+, CD8+, CD45RO+, and CD45RA+ cells). Also in IgA glomerulopathy mean arterial pressure at biopsy correlated with interstitial cell numbers and most recent follow up creatinine concentration. There were no correlations between glomerular inflammatory cells and renal function in either disease. Double staining showed that although most glomerular CD45RO+ and CD45RA+ cells were macrophages, positive cells in the interstitium were lymphocytes. The interstitial CD45RO+:RA+ ratio in normal renal biopsy specimens was approximately 5:1; for IgA glomerulopathy it was 1.5 and was 1.0 in idiopathic membranous glomerulopathy. CONCLUSIONS: This study demonstrates that interstitial, and not glomerular, inflammatory cell numbers correlate with renal function in primary glomerular disease and that double staining is necessary to interpret positive immunostaining for antigens located on more than one type of inflammatory cell. Detailed investigation of the interstitial CD45RO+ and CD45RA+ cells may give an insight into the pathogenesis of glomerular disease.
Asunto(s)
Glomerulonefritis por IGA/inmunología , Glomerulonefritis Membranosa/inmunología , Riñón/inmunología , Antígenos Comunes de Leucocito/análisis , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Glomerulonefritis por IGA/fisiopatología , Glomerulonefritis Membranosa/fisiopatología , Humanos , Inmunidad Celular , Técnicas para Inmunoenzimas , Inmunofenotipificación , Riñón/fisiopatología , Glomérulos Renales/inmunología , Túbulos Renales/inmunología , Masculino , Persona de Mediana EdadRESUMEN
One of the rarer causes of a pelvic mass is a myxo-papillary ependymoma. We describe the unusual presentation of a locally advanced tumour in an elderly lady.
Asunto(s)
Glioma/secundario , Neoplasias Pélvicas/secundario , Neoplasias de la Médula Espinal/patología , Anciano , Anciano de 80 o más Años , Diagnóstico Diferencial , Femenino , Proteína Ácida Fibrilar de la Glía/análisis , Glioma/química , Humanos , Neoplasias Pélvicas/químicaRESUMEN
The case of a young, heterosexual man who was investigated for proteinuria is reported. A renal biopsy specimen showed a focal and segmental membranous glomerulopathy. He was later found to be HIV positive and died from cerebral infarction associated with HIV vasculitis 16 months after his initial presentation. Unusual forms of immune complex mediated glomerulopathies should alert the pathologist to the possibility of HIV associated disease.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/complicaciones , Glomerulonefritis Membranosa/microbiología , Adulto , Glomerulonefritis Membranosa/patología , Humanos , Glomérulos Renales/ultraestructura , Masculino , Nervio Troclear/irrigación sanguínea , Vasculitis/microbiología , Vasculitis/patologíaRESUMEN
A case of B-CLL which was complicated by chronic renal failure due to leukaemic infiltration of the kidney is reported. Treatment with chlorambucil, prednisolone, and renal bed irradiation resulted in a substantial improvement in renal function which persisted until the the patient's death from marrow failure some eight years later. The temporal association between treatments and response suggested that renal bed radiotherapy had contributed to the improvement in renal function. This case is one of only two reported cases in which chronic renal failure due to CLL has been treated with radiotherapy. It is unique in that the renal response was shown histologically. Leukaemic infiltration of the kidney is common in CLL but, characteristically, is not associated with renal impairment. An improvement in renal function has been described in two patients with acute renal failure after chemotherapy.
Asunto(s)
Fallo Renal Crónico/etiología , Leucemia Linfocítica Crónica de Células B/patología , Infiltración Leucémica/complicaciones , Clorambucilo/uso terapéutico , Terapia Combinada , Humanos , Riñón/patología , Riñón/efectos de la radiación , Fallo Renal Crónico/patología , Fallo Renal Crónico/terapia , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéuticoRESUMEN
A series of nine cases of localized amyloidosis of the lower genitourinary tract are reported. The patients comprised six males and three females with an age range of 50-79 years at initial presentation. Clinically and on cystoscopy, the lesions were often diagnosed as neoplasms. Histologically, seven cases had typical features of localized amyloid deposits, while two cases had an unusual appearance with a florid histiocytic and giant cell reaction. Using an immunoperoxidase staining method the deposits were non-reactive with antibodies to serum amyloid A protein, prealbumin and beta 2 microglobulin, while equivocal immunoreactivity was seen with anti-light chain antibodies.
Asunto(s)
Amiloidosis/patología , Enfermedades Urogenitales Femeninas/patología , Enfermedades Urogenitales Masculinas , Anciano , Amiloidosis/inmunología , Femenino , Enfermedades Urogenitales Femeninas/inmunología , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Enfermedades Ureterales/inmunología , Enfermedades Ureterales/patología , Enfermedades Uretrales/inmunología , Enfermedades Uretrales/patología , Enfermedades de la Vejiga Urinaria/inmunología , Enfermedades de la Vejiga Urinaria/patologíaRESUMEN
The effect of cyclosporin A (CyA) was studied on the morphology and protein excretion of a rabbit chronic serum sickness nephritis using cationized bovine serum albumin (cBSA). One group of rabbits was given intravenous (i.v.) immunizing doses of cBSA and Escherichia coli endotoxin. One week later, these animals began a 6-week i.v. injection schedule of cBSA only. A second group followed the same injection protocol, but was given intramuscular (i.m.) CyA for 3 days prior to the immunizing dose of cBSA/endotoxin and throughout the subsequent cBSA schedule. A third group was given i.m. CyA only. Regular blood samples for CyA levels were taken from animals given the drug. Two 24-h urine samples were obtained from all animals in the study. Analysis of the blood samples showed that immunosuppressive levels of CyA were achieved after two i.m. doses of CyA. These levels were maintained during the course of the schedule. Morphologically, all rabbits completing the cBSA only injection schedule showed evidence of an immune-mediated glomerulopathy with variably severe membranous and endocapillary proliferative change. Less than half the rabbits in the cBSA/CyA group showed any evidence of membranous change. The glomeruli of animals given CyA only were normal. No morphological evidence of CyA toxicity was seen in any animal given the drug. The proteinuria profiles, however, suggested that as well as reducing protein excretion in rabbits given cBSA, CyA may interact with the immunizing dose of cBSA to produce an early, reversible, nephrotoxic effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Ciclosporina/uso terapéutico , Glomerulonefritis Membranosa/tratamiento farmacológico , Animales , Cationes , Modelos Animales de Enfermedad , Endotoxinas/administración & dosificación , Escherichia coli , Glomerulonefritis Membranosa/patología , Terapia de Inmunosupresión , Glomérulos Renales/patología , Masculino , Conejos , Albúmina Sérica BovinaRESUMEN
Chronic immune complex glomerulonephritis was induced in a group of New Zealand white rabbits by daily intravenous injections of cationized bovine serum albumin (cBSA). The animals were serially killed and renal tissue was embedded in the hydrophilic resin Lowicryl K4M for immunoelectron microscopy. The results demonstrate the progressive deposition of rabbit IgG in the glomerular basement membrane in this model, with aggregation of immunoglobulins occurring only in the subepithelial space. Proteinuria developed concurrently with this event. Glomerular visceral epithelial cell (GVEC) endocytosis of immune material was observed at various stages of the disease process, suggesting that GVECs may be part of a clearance mechanism acting within the glomerulus.
Asunto(s)
Glomerulonefritis Membranosa/patología , Glomérulos Renales/ultraestructura , Animales , Complejo Antígeno-Anticuerpo/análisis , Membrana Basal/patología , Membrana Basal/ultraestructura , Cationes , Enfermedad Crónica , Modelos Animales de Enfermedad , Endocitosis/inmunología , Glomerulonefritis Membranosa/inmunología , Inmunoglobulina G/inmunología , Glomérulos Renales/patología , Masculino , Microscopía Inmunoelectrónica , Conejos , Albúmina Sérica BovinaRESUMEN
Glomerulopathy and nephrotic syndrome were induced in rats by intravenous puromycin aminonucleoside. Ten days after the injection of puromycin, the animals have developed heavy proteinuria. During this phase, glomerular epithelial cell endocytosis was studied by injecting a conjugate of horseradish peroxidase and poly-L-lysine. This conjugate has been shown to be endocytosed by glomerular epithelial cells. The rats were serially sacrificed from 1 min to 24 h after this injection. Peroxidase was localised cytochemically and observed at light and electron microscopy. The early events of endocytosis in glomerulopathy (namely the binding to the plasma membrane, the membrane invagination and the formation of the early vesicles) were qualitatively similar to those in the normal. The later events (the fusion of the vesicles and their movement within the cells) were inhibited. The results show that puromycin aminonucleoside damages epithelial cell endocytotic activity and affects the later processing of the conjugate within the cells.