Biomedical subjects
Publications and source records attributed to G Tobelem.
The authors report one case of renal rupture occurring during an extracorporeal shock wave lithotripsy (ESWL). The patient presented with a bilateral urolithiasis and ESWL, was performed on a large stone (3 cm x 3.5 cm) located in the lower calyx of the right kidney. Ultrasound and CT Scan were used to diagnose the renal rupture and a partial nephrectomy was performed.
Tremendous progress have been performed during the last 25 years in thrombosis. Thrombotic disease can result either from increased deposition or decreased dissolution of fibrin. Since the first observation of a familial antithrombin III deficiency, numerous inherited defects of antithrombotin III, protein C, protein S, heparin cofactor II and plasminogen have been described and were assumed to be responsible of a thrombophilic state. However a disparity in the clinical expression of heterozygous deficiency in coagulation inhibitors or molecular abnormalities of coagulation does exist. On one hand, the prevalence of such molecular diseases is not yet perfectly known and on the other hand, contributory factors (acquired environmental insults or other genetic abnormalities) could play a role in individuals already predisposed to thrombosis. The molecular genetics of deficiencies is going to help us to establish specific gene lesions and thromboembolic history relationships. The analysis of structural or regulatory mutations in the genes of the different coagulation inhibitors, of the molecules of the fibrinolytic system, and of the fibrinogen molecule will greatly increase our knowledge of the molecular basis of thrombosis. The influence of the genetic polymorphism of these molecules on the risk of thrombosis should be studied. Finally, cellular aspects of thrombosis including the role of blood cells and endothelial cells will bring lot of informations on the comprehension of thrombotic diseases.
The authors report their results with 58 patients presenting with pelvic lithiasis who were treated by extracorporeal lithotrity with the Dornier HM3 system. They describe the appropriate procedure of analgesia and emphasize the difficulties to locate the pelvic calculi, which sometimes requires resorting to urography during the treatment. Out of the 58 cases, success was total in 55 (94.83%), after one session of lithotrity in 52 of them and after two sessions in 3. In 2 of the 3 cases of failure, the calculi were monohydrated calcium oxalate stones located very high in the ischiadic incisure. Five cases of presacral lithiasis were treated in the ventral position, successfully in 3 cases and without success in 2. Thus it appears that shock wave lithotrity with the Dornier HM3 system with radiological location is highly effective for the treatment of pelvic lithiasis.
The ability of tissue plasminogen activator (tPA) to induce human umbilical vein endothelial (HUVE) cell migration was studied using an in vitro, serum-free wound assay system. At pharmacological doses, tPA stimulated HUVE cell migration dose-dependently. Treatment of cells with epsilon amino caproic acid (EACA) to detach cell-surface and extracellular matrix bound plasminogen, which could lead to plasmin generation, resulted in increased HUVEcell migration on stimulation with tPA.Plasminogen activator inhibitor-1 (PAI-1), a natural plasminogen activator inhibitor, abolished tPA-induced HUVEcell migration. These results demonstrate for the first time that tPA is capable of stimulating endothelial cell migration in wound assays and this effect is susceptible to PAI-1 inhibition.
The antiphospholipid antibody syndrome is characterized by venous and/or arterial thrombosis, repeated miscarriages and the presence of anticardiolipin antibodies and/or a circulating lupus anticoagulant. Antibodies directed against phospholipids constitute a family of immunoglobulins with different specificities. The mechanism through which lesions are induced by these antibodies has not yet been fully determined. Treatment includes immunosuppressive measures and prevention of recurrent thrombosis.
The human omentum contains a potent, not yet identified angiogenic activity. The omentum is very vascularized. Therefore, we investigated whether human omental microvascular endothelial cells (HOME cells) express the angiogenic peptide basic fibroblast growth factor (bFGF). Cytosol prepared from HOME cells stimulated DNA synthesis in bovine epithelial lens cells (BEL cells). The mitogenic activity could be neutralized by an anti-bFGF antibody. Basic FGF-like material from the HOME cell cytosol was bound onto a heparin-Sepharose column at 0.6 M and was eluted at 3 M NaCl. The 3 M NaCl eluted material reacted with the specific anti-bFGF antibody in an ELISA and stimulated DNA synthesis. It did not react with a specific anti-acidic fibroblast growth factor (aFGF) antibody. Western blotting experiments using the same bFGF antibody showed the presence of a major band of 17 Kd and a doublet of 20-22 Kd. Northern blotting of non-stimulated HOME cells using a specific 1.4 kb bFGF probe showed the presence of 5 molecular species of 6.6, 3.7, 2.2, 2.0, and 1.0 kb. No aFGF mRNA was detected with a specific previously characterized 4.04 kb probe. 12-O-tetradecanoylphorbol 13-acetate (TPA) did not influence significantly the expression of bFGF at the protein and mRNA level in HOME cells. Thus, protein kinase C activation by TPA did not appear to modulate significantly the expression of bFGF for that cell type. Contrastingly, human umbilical vein endothelial cells (HUVE cells), which expressed no bFGF and aFGF mRNA at a basal level, were induced to express bFGF but not aFGF mRNA when stimulated by TPA. These results suggest that the described angiogenic activity could be the bFGF-like mitogen contained in HOME cells and that these cells are different from endothelial cells derived from large vessels (HUVE cells) regarding the expression of bFGF.
Chloroquine modulates the activity of cultured human microvascular endothelial (HOME) cells in a complex fashion. At concentrations of 5-25 microM, CQ inhibits basic fibroblast growth factor (bFGF-) and human serum-induced mitogenic activity in these cells, in a dose-dependent manner. The kinetics of CQ's inhibitory actions on serum-induced mitogenesis in HOME cells slowly develops with only 30% of maximum inhibition reached after 24 hours. In HOME cells grown in serum-free medium, CQ raised tissue-plasminogen activator antigen levels in cell extracts. There was also a potentiation of bFGF-induced t-PA production. The kinetics of CQ's stimulatory effect on t-PA production by HOME cells, suggest that this effect precedes its inhibitory actions on mitogenesis. This effect of CQ on t-PA generation in endothelial cells was susceptible to cycloheximide inhibition. In wound assays, HOME cell migration, induced with bFGF and HS, was potentiated by CQ.
Angiogenesis requires the migration, differentiation and proliferation of endothelial cells. Tumor growth is angiogenesis-dependent and angiogenesis is directly or indirectly induced by the tumor. Induction of angiogenesis is, therefore, an important stage in carcinogenesis and in the development of metastasis. Numerous angiogenic factors have been identified, most of which are mitogenic for endothelial cells and only some of which are responsible for tube formation. Pharmacologic compounds such as heparin, heparin fragments and corticosteroids have been shown to be anti angiogenic substances. Recently two new inhibitors of angiogenesis, a cartilage-derived inhibitor and platelet factor 4 have been described.
The vascular system is lined by a monolayer of endothelial cells which proliferate very slowly under normal conditions. The formation of new capillary vessels is associated with some physiological circumstances and several pathological conditions. Angiogenesis requires migration, differentiation and proliferation of endothelial cells. The mechanism of tube formation is still poorly understood. Tumour growth is angiogenesis-dependent and angiogenesis is directly or indirectly induced by the tumour. Induction of angiogenesis is an important step in carcinogenesis and in metastatic development. Angiogenesis is induced during the transition from hyperplasia to neoplasia. Numerous angiogenic factors have been identified, most are mitogenic for endothelial cells and some are only responsible for tube formation. However, it is difficult to recognize which factor is the most important in vivo. Since angiogenesis is necessary for tumour growth, any natural or synthetic antiangiogenic compound may have an antineoplastic potential. Inhibition of tumour angiogenesis under the control of a tumour suppression gene could play an important role. Pharmacological compounds, such as heparin, heparin fragments and corticosteroids, have been shown to be antiangiogenic substances. More recently two new inhibitors of capillary endothelial cell proliferation and/or angiogenesis have been described: they are a cartilage-derived inhibitor and platelet factor 4.
Circulating lupus-type anticoagulant is associated with an increased risk of arterial or venous thrombosis. The laboratory identification of lupus coagulant requires at least 2 different in vitro phospholipid-dependent coagulation techniques: immunological assessment based upon Elisa-type tests using pure phospholipids complements the coagulation procedure, but does not replace it. Circulating lupus anticoagulant is correlated with anti-phospholipid antibodies specific to phosphatidyl serine. Relationships between circulating lupus anticoagulant and anti-cardiolipin seem complex and are discussed. In fact, an entire family of anti-phospholipid antibodies exists, whose relationship with clinical manifestations remains to be determined. The effects of anti-phospholipid antibodies on human endothelial cells are described.
The authors report a series of twenty patients with pelvic ureteric stones treated by the Dornier lithotriptor. Sixteen men and 4 women were treated over a period of 8 months (November 1988 and June 1989). A single treatment session was sufficient to ensure destruction and elimination of the stones. This technique, which does not require anaesthesia, but at most simple neuroleptanalgesia, has a low morbidity (15%). In the series of 20 patients: the stones were completely eliminated in 16 cases, 1 case was a failure at 3 months and 3 patients were not reviewed. These results are assessed with a minimum follow-up of three months and a maximum follow-up of eight months. This simple, rapide, repeatable and effective therapeutic technique appears to constitute an alternative to operative endoscopy (flexible or rigid ureteroscopy) in the treatment of stones of the pelvic ureter.
The authors report six cases of milk of calcium syndrome. As in previously published cases, the diagnosis was established by the film taken in the standing position: the "lithiasic density" shrinks, densifies and exhibits a horizontal upper edge. Four patients were at first mistakenly diagnosed as having urinary lithiasis for which extracorporeal lithotripsy was scheduled. In one case, the lithotripsy was actually performed and the diagnosis of milk of calcium disease was established only immediately after the procedure. In another patient, lithotripsy was performed because small stones were thought to be present in the milk of calcium. In the two other cases, the diagnosis was made on the day before scheduled lithotripsy and this procedure was therefore cancelled. The purpose of the authors in reporting these cases is above all to point out the diagnostic value of a plain film of the abdomen in the standing position. Diagnosis must be made in time to avoid extracorporeal lithotripsy since, in milk of calcium syndrome, this procedure is illogical, inefficient and probably more hazardous than useful. On the basis of the six cases reported herein and of data from the literature, several characteristics of milk of calcium syndrome can be emphasized. Milk of calcium syndrome predominantly affects individuals with a positive personal or family history for renal lithiasis. It occurs in both sexes and all age groups, including childhood. Milk of calcium syndrome complicates partial or total dilatation of the urinary tract. Crystallization may be of the phosphatic or oxalic type. Concomitant urinary tract infection is common.(ABSTRACT TRUNCATED AT 250 WORDS)
Inherited thrombocytopathies and thrombocytopenias are very rare diseases but they constitute a model for exploring platelet physiology. These congenital platelet disorders concern adhesion, activation and release, aggregation. The diagnosis is based on specialized biological investigations. The treatment of hemorragic episodes involves platelet infusions.
Platelets play an important role in arterial thrombosis. Following the adhesion of platelets to an injured vascular wall, platelet activation occurs, involving calcium fluxes, phosphoinositol metabolism, protein phosphorylation, arachidonate cascade. This leads to the formation of the fibrinogen membrane receptor, the IIb/IIIa glycoprotein complex. Platelet aggregation results from the binding of fibrinogen and other adhesive proteins to the IIb/IIIa complex between several platelets. Numerous drugs can interfere with platelet function. Among these, only aspirin and ticlopidine have been shown to be effective in controlled trials. Aspirin, by inhibiting cyclo-oxygenase, blocks thromboxane A2 formation. Ticlopidine, by inhibiting fibrinogen binding to the complex, is a potent antiaggregation agent.
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Platelet-derived growth factor (PDGF) is known to inhibit collagen-induced platelet aggregation. Collagen-induced binding of 125I-PDGF to human washed platelets was therefore investigated. It was found 1) to be time-dependent, reaching a plateau at 20 degrees C after 30 min, 2) collagen concentration-dependent, 3) specifically inhibited by unlabeled PDGF, and 4) saturable. Scatchard plot analysis showed a single class of sites with 3000 +/- 450 molecules bound/cell and an apparent KD of 1.2 +/- 0.2 10(-8) M. The effects of PDGF on collagen-induced phosphoinositide breakdown and protein phosphorylation were also investigated. At 50 ng/ml PDGF, a concentration which completely inhibited collagen-induced aggregation, the breakdown of [32P]phosphatidylinositol 4,5-biphosphate (PIP2) and [32P]phosphatidylinositol 4-phosphate (PIP) was observed, but the subsequent replenishment of [32P]PIP2 was inhibited. The same PDGF concentration totally inhibited collagen-induced phosphatidic acid formation. PDGF also completely prevented phosphorylation of P43 and P20, as a result of protein kinase C activation consecutive to phosphoinositide metabolism. These results suggest that (i) a specific PDGF receptor can be induced by collagen, and (ii) PDGF can effect the early events of collagen-induced platelet activation by inhibiting PIP2 resynthesis and P43 and P20 phosphorylation. It is concluded that PDGF might be involved in a negative feed-back control of platelet activation.
Binding of 125I-thrombin to endothelial cells derived from human umbilical vein was studied in tissue culture. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and autoradiography revealed covalent binding of thrombin in a 72-kDa complex. This binding is specific and requires the catalytically active site of the enzyme. Formation of the complex could be detected as early as 3 min after addition of thrombin or with a thrombin concentration as low as 0.5 nM. This irreversible binding exhibits thrombin dose-dependence and reaches maximum levels at a concentration of 50 nM (10 fmol/10(5) cells). Some characteristics of the 72-kDa complex were compared to those of the complexes formed between thrombin and protease nexin originating from fibroblasts or platelets: (i) its electrophoretic mobility on SDS-PAGE is identical to that of the thrombin-platelet protease nexin complex, (ii) heparin prevents the appearance of the complex on the cell surface, (iii) plasmin in a 100-fold molar excess prevents the covalent linkage of thrombin, suggesting that the protease specificity of the endothelial component involved in the complex might not be restricted to thrombin. Yet no release, nor any secretion of the endothelial protein, could be detected. These results indicate that active thrombin binds covalently to a specific endothelial protein that is in several respects similar to fibroblast or platelet protease nexin and provides a thrombin binding site distinct from thrombomodulin and glycosaminoglycans.
The binding, internalization, and degradation of basic fibroblast growth factor (bFGF) in human omental microvascular endothelial cells (HOME cells) were investigated. Binding studies of bFGF in human endothelial cells have not yet been reported. Basic FGF bound to HOME cells (KD of 42.0 +/- 3.8 pM and 70,526 +/- 6121 binding sites/cell for the high-affinity sites, KD of 0.933 +/- 0.27 nM and 630,252 +/- 172,459 sites/cell for low-affinity binding sites). The number of low-affinity binding sites was found to be variable. Washing the cells with 2 M phosphate-buffered saline removed completely 125I-bFGF bound to low-affinity binding sites but decreased also the high-affinity binding. The majority of the surface-bound 125I-bFGF was removed by washing the cells with acetic acid buffer at pH 3. At 37 degrees C, 30% of the cell-associated 125I-bFGF became resistant to the acidic wash after 90 min, suggesting that this fraction of bound 125I-bFGF was internalized. At this temperature, degradation of the internalized ligand was followed after 1 h by the appearance of three major bands of 15,000, 10,000, and 8,000 Da and was inhibited by chloroquine. These results demonstrated two classes of binding sites for bFGF in HOME cells; the number of high-affinity binding sites being larger than the number reported for bovine capillary endothelial cells. The intracellular processing of bFGF in HOME cells seems to be different from that of heparin binding growth factor-1 in murine lung capillary endothelial cells and of eye-derived growth factor-1 in Chinese hamster fibroblasts.