[The therapy of chronic destructive nonsuppurative cholangitis].
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Humans↗
Biomedical subjects
G Brunner
Publications and source records attributed to G Brunner.
A T-cell-related proteinase expressed by T-lymphoma cells activates their endogenous pro-urokinase.
In this report, we investigated the expression and activation of proteolytic enzymes by mouse T-lymphoma cell lines of differing metastatic potential. In contrast to the low metastatic Eb line, the metastatic variants ESb and ESb-MP secreted urokinase-type plasminogen activator (u-PA), which was present in the culture supernatant predominantly in the active form (ESb, 96%; ESb-MP, 80%). All three T-lymphoma variants expressed a mainly cell surface-associated proteinase, which proved to be immunologically and enzymatically related to the murine T-cell-associated serine proteinase-1 (MTSP-1). Intact lymphoma cells were able to activate the recombinant human proenzyme of u-PA (pro-u-PA) by a plasmin-independent mechanism, because plasmin contamination of the cells was not detectable. When ESb-MP cells were cultured in the presence of inhibitors of MTSP-1, such as antithrombin III, Pro-Phe-Arg-chloromethylketone, or aprotinin, the ratio of endogenously activated murine u-PA to inactive pro-u-PA in conditioned medium was significantly reduced (from 80% to 15%). The most potent inhibitor, antithrombin, did not inhibit plasmin-catalyzed pro-u-PA activation. These results suggest a novel autocrine mechanism of plasmin-independent pro-u-PA activation for metastatic T lymphomas by the production of an MTSP-1-related proteinase. The ability to initiate the proteolytic cascade of plasminogen activation in the absence of plasmin might contribute to the metastatic behavior of these cells observed in vivo.
Amino Acid Sequence↗
Generation of cell surface-bound plasmin by cell-associated urokinase-type or secreted tissue-type plasminogen activator: a key event in melanoma cell invasiveness in vitro.
Recently, we have shown that plasminogen activators (PAs) of both types, urokinase-type (uPA) as well as tissue-type (tPA), are involved in the in vitro invasiveness of human melanoma cells. The present study is focused on the generation and importance of cell surface-bound plasmin in this process. The human melanoma cell lines MelJuso and MeWo expressed plasminogen binding sites on the cell surface. Plasminogen binding was saturable and not species-specific, since human and bovine plasminogen bound to the cells with comparable efficiency. The activation of the proenzyme plasminogen bound on MelJuso cells, which expressed surface-associated uPA activity, occurred almost synchronously with binding to the cell surface. Removal of cell-associated uPA considerably reduced plasmin generation on these cells. In contrast, plasminogen activation on MeWo cells, which secreted tPA into the culture supernatant and which were devoid of surface-associated PA activity, was by far less effective. The efficiency of the activation process could be increased by addition of exogenous tPA. With both cell lines, plasmin generation on the cell surface was suppressed by inhibitory monoclonal antibodies specific for the respective PA type. Selective inhibition of cell surface-associated plasmin by preincubating the cells with an inhibitory monoclonal antibody or with aprotinin, as well as removal of plasmin from the cell surface, led to a significant decrease in cellular invasiveness of both cell lines into various biological substrates such as fibrin gel, the basement membrane extract Matrigel, or intact extracellular matrix. Both cell lines were able to penetrate an intact cell layer of the human keratinocyte line HaCaT, a process, which also proved to be dependent on cell-associated plasmin. In conclusion, these data provide evidence that plasminogen activation associated with the surface of human melanoma cells is catalyzed much more efficiently by cell-associated uPA (MelJuso) than by secreted tPA (MeWo). Cell-associated plasmin, which is protected from inactivation by serum inhibitors, represents the essential component of the proteolytic cascade of plasminogen activation during in vitro invasiveness of human melanoma cells.
Animals↗
[Plasmapheresis and detoxification].
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Adolescent↗
[Studies on radiation exposure of personnel in endoscopy].
Some endoscopic investigations and treatments require the use of x-ray equipment. There is no specific x-ray device for endoscopic procedures. Standard x-ray apparatus is used, which is designed to give optimal protection against radiation at the standard location of the radiologist. However during special endoscopic examinations nurses and doctors are located at parts of the x-ray apparatus which are not specially protected from x-rays. For this reason measurements were performed during endoscopic retrograde cholangiopancreatography (ERCP), percutaneous transhepatic cholangiography (PTC) and schlerotherapy at those positions, where nurses and doctors are standing or sitting during these procedures. The measurements show that at the position of the radiologist there is practically no radiation detectible. However the hands, legs and the face (eye lenses) of the assisting nurse receive relatively high radiation. The values amount to 30% of the allowed maximum. By relatively simple appliances like lead lining around the lower bottom part of the x-ray apparatus or a lead apron lowered from the ceiling between head and body of the patient the radiation load can be significantly lowered to 1% of the maximal allowed radiation. With such simple additional protection frequencies and duration of x-ray related endoscopic investigations can be extended without danger for the staff.
Cholangiography↗
Capillary isotachophoretic determination of cysteinyl leukotrienes.
The cysteinyl leukotrienes (LTs) C4, D4 and E4 are among the most potent lipid mediators of anaphylaxis and inflammation. A capillary isotachophoretic method is described for the determination of these cysteinyl LTs. The method is based on anionic separation and detection using UV (254 nm) and conductivity detectors. The total analysis time is of the order of 30 min. The limit of detection of the method was determined to be 0.5 nmol of LTE4. Despite of similar chemical structures, all three cysteinyl LTs can be determined simultaneously.
Amino Acid Sequence↗
Coordinate secretion and functional synergism of T cell-associated serine proteinase-1 (MTSP-1) and endoglycosidase(s) of activated T cells.
Cell lysates and exocytosed soluble mediator(s) (ESM) released from CD8+ T cell lines (TCL) by receptor-triggered secretory exocytosis were tested for degradation of proteoglycans associated with in vitro produced subendothelial extracellular matrix (ECM). ESM was found to release low-molecular weight (kav 0.5-0.6) fragments from the sulfated proteoglycans in ECM. In the presence of heparin, an inhibitor for endoglycosidase activity, only high-molecular-weight products (kav 0.2) were formed. Preincubation of ESM with HD-prolylphenylalanyl-arginyl-chloromethylketone (PFR-CK) an inhibitor for the T cell-associated serine proteinase-1 (MTSP-1) totally prevented release of high- and low-molecular weight proteoglycan fragments. Furthermore, it was shown that purified MTSP-1 is able to release from ECM high-molecular weight proteoglycans and that this process is inhibitable by PFR-CK but not by heparin. Further treatment of these soluble high-molecular weight sulfated proteoglycans with ESM from TCL 1.D9 led to appearance of low-molecular weight split products (kav 0.5-0.6). This conversion was inhibitable by heparin but not by PFR-CK. These findings indicate that activated T cells contain two enzymatic activities, i.e. MTSP-1 and at least one endoglycosidase, which after receptor-triggered secretion can synergize in the degradation of sulfated proteoglycans in subendothelial ECM.
Animals↗
Urokinase-type and tissue-type plasminogen activators are essential for in vitro invasion of human melanoma cells.
This study evaluates the contribution of two types of plasminogen activators (PAs; tissue-type PA (tPA) versus urokinase-type PA (uPA) toward the invasiveness of human melanoma cells in a novel in vitro assay. We identified two human melanoma cell lines, MelJuso and MeWo, expressing uPA or tPA as shown at mRNA, protein, and enzyme activity level. MelJuso cells produced uPA as well as plasminogen activator inhibitor-1 (PAI-1). The latter was, however, not sufficient to neutralize the cell-associated or secreted uPA activity. MeWo cells secreted tPA, but the enzyme was not found to be cell-associated. PAI-1 production by these cells was not detectable. Plasminogen activation and fibrinolytic capacity of both cell lines were reduced by anticatalytic monoclonal antibodies specific for the respective type of PA or by aprotinin. In a novel in vitro invasion assay, antibodies to PA as well as aprotinin decreased the invasiveness of both cell lines into a fibrin gel, Matrigel, or intact extracellular matrix. Our results confirm the importance of uPA-catalyzed plasminogen activation in tumor cell invasiveness. Furthermore, we provide evidence that tPA, beyond its key role in thrombolysis, can also be involved in in vitro invasion of human melanoma cells.
Collagen↗
Circadian pattern of large neutral amino acids, glucose, insulin, and food intake in anorexia nervosa and bulimia nervosa.
Insulin, glucose, and large neutral amino acids (LNAA) were studied in 10 patients with anorexia nervosa, 13 patients with bulimia nervosa, and 15 healthy controls. Blood samples were collected at hourly intervals during the day and at two-hour intervals during the night over a 24-hour period. Ad libitum caloric and relative carbohydrate intake was significantly reduced in the anorectic and bulimic patients. Elevated concentrations of beta-hydroxybutyric acid (BHBA) were seen in the bulimic group, and low triiodothyronine (T3) concentrations in the anorectic group. Mean plasma glucose and insulin concentrations were significantly lowered in both groups. The tryptophan (Trp) to LNAA ratio was reduced in anorectic, but not in bulimic patients. These findings suggest that Trp influx into the brain is reduced in anorectic patients, possibly impairing central serotonergic function.
Amino Acids↗
Phospholipase C release of basic fibroblast growth factor from human bone marrow cultures as a biologically active complex with a phosphatidylinositol-anchored heparan sulfate proteoglycan.
Basic fibroblast growth factor (bFGF) is a potent mitogen for human bone marrow stromal cells and stimulates haematopoiesis in vitro. We report here that primary human bone marrow cultures contain bFGF and express heparin-like bFGF binding sites on the cell surface and in the extracellular matrix (ECM). bFGF bound predominantly to a 200-kD cell surface heparan sulfate proteoglycan (HSPG), which was also found in conditioned medium. bFGF was released from bone marrow cultures by incubation with phosphatidylinositol-specific phospholipase C (PI-PLC) and, less efficiently, by plasmin. Solubilized bFGF was found as a complex with the 200-kD HSPG. The complex was biologically active as shown by its ability to stimulate plasminogen activator production in bovine aortic endothelial cells. bFGF-HSPG complexes of bovine endothelial cells, however, were not released by PI-PLC. While only trace amounts of the bFGF-binding 200-kD HSPG were released spontaneously from bone marrow cultures, incubation with PI-PLC solubilized almost all of the 200-kD HSPG. The HSPG could be metabolically labeled with ethanolamine or palmitate, which was partially removed by treatment with PI-PLC. These findings indicate linkage of the HSPG to the cell surface via a phosphatidylinositol anchor. Plasmin released the 200-kD HSPG less efficiently than PI-PLC. We conclude that HSPGs of human bone marrow serve as a reservoir for bFGF, from which it can be released in a biologically active form via a dual mechanism; one involving a putative endogenous phospholipase, the other involving the proteolytic cascade of plasminogen activation.
Adult↗
The contribution of diffusion to the termination of penicillin-induced convulsive activity in the awake rat.
1. Experiments were performed to investigate the contribution of diffusion to the termination of PCN induced convulsive (epileptiform) activity in the awake rat. The basic question was whether convulsive activity terminates at the same critical concentration Ct of PCN independently of the concentration Co of PCN injected into the superficial layer of the foreleg field of the right motor cortex. Different concentrations Co were used, the lowest being 16 IU PCN/0.5 microliters saline, the largest 1000 IU PCN/0.5 microliters saline. The convulsive activity was recorded by means of the electroencephalogram (EEG). 2. Mathematical calculations concerning the diffusion of the substances were performed by using the diffusion equation with a PCN diffusion coefficient D = 3.52 x 10(-4) mm2/s and the tortuosity factor lambda = 1.62. 3. The lowest dose of PCN used was considered as a threshold dose for acute induction of convulsive activity because only 4 out of 9 rats treated with 16 IU PCN developed epileptiform activity. For the range of doses between 16 and 32 IU, the median frequency of convulsive potentials was dose-dependent, and increased from 7.9 to 13.8 pot./min, respectively. For higher doses covering the range between 63 and 1000 IU, there was only an insignificant increase from 19.2 to 22.7 pot./min, respectively. 4. The median period of convulsive activity increased significantly (p less than 0.05 or less than 0.01) and monotonically from 19.5 min in rats treated with 16 IU PCN to 267 min after treatment with 1000 IU PCN. 5. At the end of the convulsive activity, the median critical concentration Ct within the artificial focus ranged from 1.75 to 1.31 IU/0.5 microliters saline in rats treated with 16 to 125 IU PCN, while after induction of convulsive activity with doses of 250, 500 or 1000 IU PCN, Ct gradually increased to 2.01, 2.83, and 3.75 IU/0.5 microliters, respectively. This means that the brain became less sensitive for PCN the longer the epileptiform activity lasted. 6. It is concluded that during long-lasting convulsive activity, the brain takes advantage of its plastic properties by eliciting counteracting mechanisms. These self-protective factors may utilize neuronal networks which needs some time to become effective in the control of the cortical activity.
Administration, Topical↗
[The concept of "silent" heart failure].
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Adolescent↗
[Diagnosis and therapy of fulminant liver failure].
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Combined Modality Therapy↗
[Tuberculosis following organ transplantation].
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Antitubercular Agents↗
The protective effect of cyclosporine against cirrhotic alteration of the liver.
We have successfully applied the immunosuppressive drug cyclosporine in patients with primary biliary cirrhosis and in some patients with chronic active hepatitis. After several years of treatment, we have found a histologic remission tendency in cirrhotic alteration of some patients. This observation indicates that cyclosporine could have protective effects against fibrosis or cirrhotic alteration. To clarify this, we treated Sprague-Dawley rats in which the cirrhotic alteration of the liver was induced by injection of 0.5 ml/kg body weight carbon tetrachloride intramuscularly twice a week with cyclosporine (orally); the control animals were given saline solution instead of cyclosporine. After 6 weeks, we examined the liver histologically to determine the grade of fibrosis and cirrhosis and the grade of fatty degeneration; in group 2 we gave 1 mg/kg body weight cyclosporine daily, and in group 3 it was given every second day. We found excellent protective effects of cyclosporine against cirrhotic alteration in both groups compared with the control group. In group 3 only 25% of the animals showed grade 3 fibrosis and cirrhosis; however, the rate in the control animals (group 4) was 64.3%. In the daily application of cyclosporine (group 2) we found reduced effects of the drug compared with group 3. In group 1 we ordered 10 mg/kg body weight cyclosporine, which causes severe hepatotoxicity. In group 5, animals with hepatic damage from carbon tetrachloride were treated from the third week with cyclosporine. The effect of cyclosporine was not as beneficial compared with the groups in which we ordered cyclosporine from the first week. These results suggest excellent anticirrhotic effects of cyclosporine. This drug should be ordered as early as possible in the treatment of chronic hepatic damage and in an adequate minimal dosage.
Alanine Transaminase↗
[Obstructive jaundice in proximal pancreatitis after sclerosing of a bleeding duodenal ulcer].
Two weeks after successful endoscopic sclerotherapy of a bleeding duodenal ulcer a fifty-year old male patient developed a benign enlargement of the head of the pancreas and obstructive jaundice. He underwent exploratory laparotomy with choledocho-jejunostomy because there was no evidence of malignant disease. The enlargement of the head of the pancreas and obstructive jaundice are considered to be symptoms of a pancreatitis as a complication of the endoscopic sclerotherapy.
Choledochostomy↗
Activation of pro-urokinase by the human T cell-associated serine proteinase HuTSP-1.
The human T cell-associated serine proteinase-1 (HuTSP-1) is expressed by activated T lymphocytes and is exocytosed upon their interaction with target cells. Here, we report that HuTSP-1 is able to convert single-chain human pro-urokinase into the active two-chain enzyme. Time-dependent activation by HuTSP-1 of recombinant human pro-urokinase as well as natural pro-urokinase derived from human melanoma cells was demonstrated in a chromogenic assay specific for active urokinase type plasminogen activator and in immunoblotting experiments revealing the conversion of single-chain into two-chain urokinase. Control experiments excluded plasmin as the activating agent. These data suggest a novel pathway for plasmin generation during T cell-mediated processes such as immune responses and extravasation of immune cells.
Enzyme Activation↗
Intravenous therapy with high doses of ranitidine and omeprazole in critically ill patients with bleeding peptic ulcerations of the upper intestinal tract: an open randomized controlled trial.
Thirty-nine critically ill patients with actively bleeding peptic ulcerations--Forrest Ib--in the stomach or duodenum were randomly allocated to intravenous therapy with 400 mg ranitidine per day or 80 mg omeprazole per day (120 mg on the 1st day) for 5 days. Successful therapy was proven by control endoscopy on day 6 if less than 2.5 liters of blood had to be transfused from the start of therapy to maintain a hemoglobin value of 10g/l or above. Treatment failure meant that more than 2.5 liters of blood were necessary to maintain a hemoglobin level above 10 g/l. Of 20 patients in the ranitidine group bleeding stopped in only 3 patients (15%). Of 17 patients who continued bleeding under ranitidine therapy the bleeding could be controlled in 13 patients after changing to omeprazole treatment. Of 19 patients in the omeprazole group bleeding stopped in 16 patients (84%). These results demonstrate that the significantly more effective reduction of acidity by omeprazole is promising for the therapy of bleeding peptic ulcerations and may reduce the need for invasive therapy or operation.
Duodenal Ulcer↗