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Biomedical subjects

M L Wiesel

Publications and source records attributed to M L Wiesel.

At least 37 records · Page 2Linked to original sources
PubMed1995

Thrombin does not alter vascular hyporeactivity in models of endotoxin-induced septic shock in rats.

1. Hypotension and vascular hyporesponsiveness to vasoconstrictors are observed during endotoxic shock, and are associated with increased production of nitric oxide in the vascular wall. Disseminated intravascular coagulation is another feature of septicaemia. We hypothesized that thrombin generated during disseminated intravascular coagulation might modulate the changes in vascular tone induced by endotoxin. 2. Incubation of rat aortic rings for 4 h with alpha-thrombin (0.003-3.0 NIH units/ml) did not change their reactivity to noradrenaline. Incubation for 4 h with lipopolysaccharide increased the EC50 for noradrenaline, whereas co-incubation of thrombin (0.5 NIH units/ml) with lipopolysaccharide did not alter this hyporeactivity to noradrenaline. 3. In vivo in rats, lipopolysaccharide caused early (1 h) and late (4-6 h) hyporeactivity to noradrenaline. In rats infused with lipopolysaccharide and heparin (1 U min-1 kg-1, 0.4 ml/h) or hirudin (2.2 mg ml-1 kg-1, 0.8 ml/h), vasopressor responses to noradrenaline were not different from those after infusion of lipopolysaccharide alone. Aortic rings taken from rats receiving both anticoagulant treatment and lipopolysaccharide had the same sensitivity to noradrenaline as those obtained from rats receiving lipopolysaccharide alone. 4. Our results suggest that, in vivo, disseminated intravascular coagulation does not modify the early and late effects of lipopolysaccharide on arterial pressure and that, in vitro, thrombin neither induces hyporeactivity to noradrenaline nor modifies lipopolysaccharide-induced hyporeactivity. We propose that thrombin generated during disseminated intravascular coagulation in rats does not play a major role in the alterations of vascular tone observed during endotoxic shock.

Animals↗
PubMed1995

Prothrombin fragment 1 + 2 and thrombin-antithrombin III complex as markers of activation of blood coagulation in inflammatory bowel diseases.

OBJECTIVES AND METHODS: The aims of the present work were to assess the presence of thrombin generation in Crohn's disease and in ulcerative colitis by using the prothrombin fragment 1 + 2 and the thrombin-antithrombin III complex assays and to study the possible relationships between these markers and disease activity. RESULTS: Prothrombin fragment 1 + 2 and thrombin-antithrombin III complex were significantly raised in patients with Crohn's disease (n = 69) and with ulcerative colitis (n = 25) as compared with healthy controls (n = 50). In Crohn's disease these two markers of thrombin generation were correlated with the Van Hees index (P < 0.05 and P < 0.001, respectively); values were significantly different from controls even in the patient group displaying the lowest disease activity (P < 0.001). No correlation was found with tumour necrosis factor alpha and C-reactive protein; nevertheless patients with C-reactive protein less than or equal to 10 mg/l had significant lower values of prothrombin fragment 1 + 2 (P < 0.03). In ulcerative colitis prothrombin fragment 1 + 2 and thrombin-antithrombin III complex were significantly increased by comparison with controls, were higher in patients with pancolitis and correlated with C-reactive protein (P < 0.002 and P < 0.009, respectively). CONCLUSION: These data show that prothrombin fragment 1 + 2 and thrombin-antithrombin III complex are increased in inflammatory bowel diseases and suggest that thrombin generation might be an early event in their pathogenesis.

Adolescent↗
PubMed1994

Large scale isolation of human blood monocytes by continuous flow centrifugation leukapheresis and counterflow centrifugation elutriation for adoptive cellular immunotherapy in cancer patients.

The increasing interest in mononuclear phagocytes for adoptive cellular immunotherapy (ACI) trials in cancer patients led us to define a procedural approach to harvest reproducibly highly purified single-cell suspensions of large numbers of functional human circulating blood monocytes (Mo). A semiclosed counterflow centrifugal elutriation (CCE) system has been developed, using a new large capacity Beckman JE 5.0 rotor with one interchangeable 40 ml or 5 ml separation chamber, to purify Mo from mononuclear cell (MNC) concentrates of healthy donors and cancer patients obtained by continuous flow centrifugation leukapheresis (CFCL). This method does not require a Ficoll density gradient centrifugation step. A total of 115 leukapheresis procedures were carried out in 35 patients and in 30 healthy donors by either Cobe 2997 or Cobe Spectra, with a similar efficiency in MNC apheresis. The average yield per leukapheresis procedure was 5.6 x 10(9) MNC of purity 90-100% (25-45% Mo, 40-65% lymphocytes). The average yields per elutriation procedure (R/O fraction) were 1.1 x 10(9) cells (purity 93% Mo) using the 5 ml separation chamber, and 1.5 x 10(9) cells (purity 91%) using the 40 ml separation chamber, with a respective recovery of 82 +/- 7% and 78 +/- 8% Mo. In vitro analysis of the viability and function of the purified Mo shows that neither morphological integrity nor physiological activity was compromised by this two-step isolation procedure, which additionally provides highly purified human Mo suspensions, in a quantity suitable for ACl of cancer patients.

Cell Separation↗
PubMed1994

Prevalence and significance of anticardiolipin antibodies in Crohn's disease.

Crohn's disease is a chronic inflammatory bowel syndrome in which thrombotic complications occur in the active phase. Phospholipid-binding antibodies such as anticardiolipin antibodies and lupus anticoagulants have been shown to be associated with thrombosis. Their presence has been assessed in a group of 50 patients with Crohn's disease among whom 44 had active disease. The overall prevalence of anticardiolipin antibodies was about 22%, while none of these patients had lupus anticoagulant. Anticardiolipin antibodies have been observed in both active and quiescent CD and their presence does not seem to be related to the site of CD lesions. The presence of phospholipid-binding antibodies could be a sign of vascular alterations that are potentially thrombogenic per se, and their predictive value with respect to the specific inflammatory syndrome of Crohn's disease is discussed.

Adolescent↗
PubMed1994

Variation in von Willebrand's Factor according to the treatment of acute myocardial infarction: physiopathological and clinical implications.

To investigate whether von Willebrand's Factor (vWF) changes as a result of the reperfusion strategy during acute myocardial infarction (AMI), vWF was measured on days 0, 1, 2, 3, 4, 5 and 15 in 34 patients with AMI. Thrombolysis was initiated in 22 patients and followed by a coronary angiogram 90 min later. In 13 patients the infarct-related artery was then patent (THR group). In nine patients the infarct-related artery was occluded and rescue percutaneous transluminal coronary angioplasty was performed (group THR+rPTCA). In 12 patients, primary PTCA was carried out (pPTCA group). Admission values of vWF were similarly high in the three groups, while changes in vWF over the following days were statistically different among the groups. No significant change was observed in THR, whereas a significant and prolonged increase was found after failed thrombolysis with PTCA (peak increase at day 5:1.54 +/- 0.04 U.ml-1). In the pPTCA group, a significant increase could only be found on day 3 (0.96 +/- 0.04 U.ml-1). Absence of a statistical rise in vWF might be a late indicator of successful thrombolysis. The prolonged increase in vWF after failed thrombolysis needing rescue PTCA probably reflects a higher resistance to thrombolysis, while the slight but significant increase in vWF following primary PTCA could be due to vascular injury.

Angioplasty, Balloon, Coronary↗
PubMed1994

[Comparative thrombotic risk of two contrast agents in coronary angiography].

The thrombogenic risk of contrast agents in coronary angiography is still a topical issue, particularly in comparisons between ionic and nonionic contrast agents. As a complement to a preliminary study, the repercussions on sensitive markers of haemostasis were investigated in vivo in 38 patients undergoing a standard cardiac catheterisation. After randomization, an ionic low osmolality contrast agent (Ioxaglate 320) was used in 19 patients and a nonionic low osmolality contrast agent (Iopromide 370) was used in another 19 patients, according to an identical protocol. The following parameters were assayed in arterial blood samples obtained before and after the examination in each patient: platelet markers: beta-thromboglobulin (beta TG) and platelet factor IV (PF4); prethrombotic markers: thrombin-antithrombin 3 complex (TAT) and prothrombin fragments 1 and 2 (F1 + 2) as well as partial exploration of fibrinolysis: tissue plasminogen activator inhibitors (PAI). Comparison of the results demonstrated platelet activation and the presence of prethrombotic markers in both groups. No significant difference was detected between the two groups of patients. Consequently, there does not appear to be any difference in activation of coagulation between modern, low osmolality, ionic or nonionic contrast agents. This may suggest an equivalent thrombogenic risk.

Blood Coagulation Tests↗
PubMed1994

[Von Willebrand factor in coronary disease].

The value of studying factors of haemostasis and thrombosis in patients with coronary artery disease is established. The endothelial lesion and evolution of the thrombus play key roles in acute coronary syndromes and coronary angioplasty. The von Willebrand factor (VWF) is known for its participation in primary haemostasis. Deficits of this factor lead to a haemorrhagic syndrome, von Willebrand's disease. This glycoprotein is mainly synthesised by the endothelial cells. Its polymeric composition allows identification of two types of multimeres. The high molecular weight, active multimeres are liberated from the endothelium after stimulation by thrombin. Low molecular weight multimeres are less active and are secreted continuously. The VWF promotes platelet adhesion and facilitates platelet aggregation. Experimental pig models with VWF deficiency show that this factor is essential for the constitution of an occlusive thrombus. Several physiopathological mechanisms interact to increase VWF concentrations during thrombosis: the endothelial lesion, adrenergic stimulation, acute phase reaction. Increased VWF concentrations have been reported in many clinical situations. The results are most demonstrative in coronary artery disease. The VWF is abnormally high from the time of hospital admission in patients with acute myocardial infarction and continues to increase up to the 5th day before falling, without returning to normal values, at the 15th day. It is a sensitive though not specific late diagnostic marker of myocardial infarction. Increased VWF concentrations are not proportional to the severity of coronary atherosclerosis. They are, however, related to the infarct size, to the inflammatory reaction and to the prothrombotic phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗
PubMed1992

Hemostatic changes in human adoptive immunotherapy with activated blood monocytes or derived macrophages.

Human blood monocytes (Mo) and monocyte-derived macrophages (M psi) possess cytotoxic effects against tumor cell lines when appropriately stimulated by various biological response modifiers, e.g., gamma interferon (gamma IFN) and muramyltripeptide (MTP). Activated Mo/M psi represent a new tool for the treatment of human malignancies, termed "adoptive cellular immunotherapy". Activated Mo/M psi express tissue factor procoagulant activity (PCA), which is a physiological trigger of blood coagulation. PCA was evaluated in vitro using a modification of the one-stage recalcification clotting time, and hemostatic changes were studied in vivo in cancer patients. Nine patients with peritoneal carcinomatosis were injected intraperitoneally with activated Mo and 11 patients with non-small cell lung carcinomas were infused intravenously with activated M psi. Hemostatic changes were followed using activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen level, antithrombin III (ATIII) and protein C (PC) activities. Fibrinolytic activity was estimated by euglobulin lysis time and assays for plasminogen and fibrin/fibrinogen degradation products (FDP). These assays were performed before and after each autologous infusion and on days 2 and 3. Activated Mo and M psi expressed potent PCA (85.5 +/- 7.5 U/ml for MTP activated Mo and 50 +/- 5.3 U/ml for gamma IFN activated M psi suspensions). In both groups of patients, APTT, PT, and TT underwent no significant variations. There was no significant consumption of ATIII or PC, and fibrinolysis was not activated during the study period. In the group injected intraperitoneally with MTP-activated Mo, fibrinogen showed a significant and progressive increase in relation to the development of an inflammatory reaction, reaching a maximum average value of 6.1 g/l at the end of the therapy with a concomitant increase in FDP levels. This increase was not observed after intravenous therapy with gamma IFN-activated M psi. No patient suffered from hemorrhagic or thrombotic events. In our experience, repeated injections of activated Mo or M psi expressing potent tissue factor PCA did not induce significant in vivo activation of the coagulation system in cancer patients.

Aged↗
PubMed1992

Electrophoretic studies on molecular defects of von Willebrand factor and platelet glycoprotein IIb-IIIa with antibodies produced in egg yolk from laying hens.

Immunoglobulins isolated from egg yolk (IgYs) are a convenient source of polyclonal antibodies. Their purification is simple and the yields important (50 mg immunoglobulins/egg). Nevertheless their biochemical characteristics are different from those of rabbit antibodies generally used for the study of molecular defects of plasmatic and platelet proteins. Provided standardization is achieved, IgYs can be used for immunoelectrophoresis, immunoprecipitation or immunoblotting assays. We describe here the electrophoretic and immunoblotting conditions employed to explore human plasmatic and platelet von Willebrand factor (vWF) and human platelet GP IIb-IIIa using IgYs. These two proteins are involved in primary hemostasis and their absence or abnormality is responsible for hereditary bleeding disorders. The methods were applied to the characterization of patients with vWF or GP IIb-IIIa defects and compared to classical mammalian IgG immunoelectrophoretic techniques. Results were further confirmed by flow cytometric analysis.

Animals↗
PubMed1992

Hairy cell leukemia and factor VIII inhibitor: a case report.

Acquired factor VIII inhibitors are usually described in hemophilia A, although some cases have been documented in chronic inflammatory diseases and malignant tumors. We report here the first case of a factor VIII inhibitor appearing in the course of hairy cell leukemia. Interferon therapy over a 5 month period led to complete remission of leukemia with parallel disappearance of the acquired factor VIII inhibitor.

Factor VIII↗
PubMed1992

[Variations of plasma Willebrand factor and fibrinogen in coronary pathology].

In order to determine a marker of prethrombotic states, reliable and easy to measure, we studied 200 patients under 60 years of age admitted to hospital for a precordial chest pain. Four groups were established: transmural myocardial infarction, acute infarction without Q wave, unstable angina and atypical chest pain. Fibrinogen, von Willebrand factor, cholesterol, and triglyceride levels were measured as well as the white cell and platelet counts. There was a statistically significant correlation between transmural myocardial infarction and increased levels of fibrinogen, von Willebrand factor and white blood cells. Von Willebrand factor was already increased in the acute phase of transmural infarction, reached a maximum on the fifth day and then decreased slowly during the following ten days. This study suggests that plasma von Willebrand factor could be a reliable marker of transmural myocardial infarction in the acute phase or during the two weeks following the thrombotic event.

Angina Pectoris↗
PubMed1991

[Influence of protein S deficiency on the arterial thrombosis risk].

Protein S is the cofactor of activated protein C which, together with the antithrombin system, is a major regulator of coagulation. Congenital protein S deficiency is an important risk factor for venous thrombosis. In this study of 105 patients with protein S deficiency, 64 had one of several thromboembolic accidents, including 14 arterial thrombotic accidents involving the central nervous system or the myocardium. These accidents occurred in young subjects (mean age: 25 +/- 13 years) only one-third of whom had another risk factor. This high frequency of arterial thrombosis associated with protein S deficiency calls for a prospective study in young subject with cerebral vascular accident or myocardial infarction.

Adolescent↗
PubMed1991

DNA amplification of HIV genome in hemophiliacs and in newborns from seropositive mothers.

We evaluated the validity of DNA enzymatic amplification (PCR) in a population at risk for HIV-1 infection, consisting of hemophiliacs and children born to seropositive mothers. All but one of the seropositive hemophiliacs and controls were found positive with the three sets of primers. All the seronegative patients and controls were found negative in PCR. No correlation with the anti-nef serology was found, one seropositive being anti-nef negative and three seronegative anti-nef positive. The results obtained with PCR are in good agreement with classical serology, and this would suggest that the possible period of latency may not be as long as suspected. No seroconversion has been described in hemophiliacs since solvent-detergent inactivated blood products have been in use, and seronegative hemophiliacs no longer constitute a population at risk. Studies on seronegative sexual partners of seropositive patients would be of great interest. For newborns from seropositive mothers, PCR is the only possible technique in early age before seronegativation of the healthy children. Further studies will be required to determine the fiability and sensitivity of the test.

Base Sequence↗
PubMed1991

Phase I trial of intravenous infusion of ex-vivo-activated autologous blood-derived macrophages in patients with non-small-cell lung cancer: toxicity and immunomodulatory effects.

The purpose of this phase I study was to evaluate the toxicity and biological activity of autologous blood-derived macrophages activated ex-vivo with recombinant human interferon gamma (rhuIFN gamma) [monokine-activated killer (MAK) cells] and administered intravenously to 11 lung cancer patients once a week for 6 consecutive weeks. Peripheral blood monocytes were collected by leukapheresis and then purified by counterflow elutriation. The MAK cells were generated by culturing the purified monocytes in Teflon bags for 7 days and adding rhuIFN gamma to the cultured cells for the last 18 h. These MAK cells expressed differentiation-associated surface antigen MAX1, and were cytotoxic in vitro against tumour cell line U937. The MAK cells were infused at dose levels from 1 x 10(7) to 5 x 10(8) on an intrapatient dose-escalating schedule. No severe adverse side-effects occurred. Toxicity was mild to moderate [primarly fever (75%) and chills (32%)], non-dose-dependent, and non-cumulative. No consistent change in haemostatic function, or liver or renal function was observed. Dose-limiting toxicity was not reached at 5 x 10(8) cells (optimal dose reproduced for each patient). The maximum tolerated dose was not determined. The immunomodulatory activity of i.v. infused MAK cells was demonstrated both in vivo by significant increases in granulocyte count and neopterin level in the patients' peripheral blood post-infusion and in vitro by secretory products (IL-1. TNF alpha, neopterin, and thromboplastin-like substance) in the culture supernatants. The in vivo traffic patterns of autologous MAK cells labelled ex-vivo with 111In oxine were studied in 7 patients. Gamma imaging showed an immediate but transient lung uptake (less than 24 h), and a progressive uptake of radioactivity in the liver and spleen was seen from 6 h to 72 h post-infusion. Our results indicate that the preparation of high numbers of autologous, blood-derived MAK cells is a feasible procedure, and their transfusion is safe for patients. This immunotherapeutic approach seems to be encouraging from the point of view of establishing an adjuvant therapeutic modality in cancer patients with minimal residual disease.

Aged↗