Production of tissue factor pathway inhibitor in cardiomyocytes and its upregulation by interleukin-1.

Tissue factor pathway inhibitor (TFPI) is a protease inhibitor that regulates tissue factor (TF)--initiated coagulation. We report here that cardiomyocytes express TFPI and the expression could be increased by Interleukin-1(IL-1beta). The TFPI expression in cardiomyocytes was confirmed by Northern blotting with rat cardiomyocytes and also by immunostaining with anti-TFPI antibody on human heart specimens from patients either with sarcoidosis, myocarditis or myocardial infarction. The regulation of TFPI expression in cardiomyocytes differs from that in endothelial cells because TFPI expression is not induced in human endothelial cells by IL-1beta.

High plasma serotonin levels in primary pulmonary hypertension. Effect of long-term epoprostenol (prostacyclin) therapy.

Elevated plasma serotonin is associated with primary pulmonary hypertension (PPH). To test whether this elevation could be related to platelet activation, the 2 pools of blood serotonin (platelets and plasma) and plasma 5-hydroxyindoleacetic acid (5-HIAA) as well as markers of platelet activation (alpha(IIb)beta(3), CD36, P-selectin, and CD63 membrane epitopes) were measured in 16 patients with severe PPH (group 1) before and at days 10 and 40 of treatment with a continuous infusion of epoprostenol (prostacyclin). The same biological parameters were also measured in 19 healthy subjects (group 2) and in 10 patients after cardiovascular surgery with extracorporeal circulation (group 3), a condition known to profoundly activate the platelets. Twelve PPH patients showed hemodynamic and clinical improvement, 3 remained stable, and 1 had the treatment stopped because of clinical aggravation. At day 0, mean plasma serotonin (5-hydroxytryptamine [5-HT]) concentration was much higher in PPH patients than in normal subjects (34.4+/-21.2 versus 9.1+/-6.0 nmol/L, respectively; P:<0.001) and positively correlated with total pulmonary resistance. The mean platelet 5-HT content was not significantly different in PPH compared with normal individuals. Mean plasma 5-HIAA concentrations were much higher in PPH than in normal patients (162+/-57 versus 61+/-7 nmol/L, respectively; P<0.001). These parameters did not significantly change during epoprostenol treatment. There was no correlation between the changes in plasma 5-HT during treatment and clinical or hemodynamic improvement. In PPH patients, the mean platelet volume significantly decreased (ANOVA, P<0.01) during treatment. Positive correlations were evidenced between the size of platelets and the number of alpha(IIb)beta(3) and CD36 epitopes. When compared with control platelets, the number of alpha(IIb)beta(3) epitopes detected on PPH platelets at day 0 tended to be higher, but this difference did not reach a statistical significance (41 300+/-7140 for PPH patients versus 36 010+/-3930 for control subjects, P=0.069). The number of CD36 epitopes, in the range of controls at day 0 (11 590+/-5080 for PPH patients versus 11 900+/-1790 for control subjects), decreased during treatment (ANOVA, P=0.038) and became significantly low at day 40 (8660+/-3520, P<0.001). The number of CD63 epitopes was not elevated, and P-selectin was never detected at any time point on PPH platelets. This glycoprotein profile indicates that the platelets of PPH patients were not highly activated but had an accelerated turnover and returned to normal under epoprostenol treatment without change of the elevated plasma serotonin, characteristic of PPH. In conclusion, neither platelet activation nor a significant alteration of the 5-HT endothelial metabolism explains the high level of plasma 5-HT in PPH patients. The 5-HT plasma concentration is not a predictive marker of the severity of PPH, and its evolution is independent of the clinical and hemodynamic status. Treatment by a potent antiaggregating agent, epoprostenol, does not affect the increase of plasma 5-HT, despite a therapeutic benefit.

Bacterial contamination of hospital physicians' stethoscopes.

Because stethoscopes might be potential vectors of nosocomial infections, this study, conducted in a 450-bed general hospital, was devised to evaluate the bacterial contamination of stethoscopes; bacterial survival on stethoscope membranes; the kinetics of the bacterial load on stethoscope membranes during clinical use; and the efficacy of 70% alcohol or liquid soap for membrane disinfection. Among the 355 stethoscopes tested, 234 carried > or =2 different bacterial species; 31 carried potentially pathogenic bacteria. Although some bacteria deposited onto membranes could survive 6 to 18 hours, none survived after disinfection.

Up-regulation of adhesion and MHC molecules on splenic monocyte/macrophages in adult haemophagocytic syndrome.

Haemophagocytic syndrome (HPS) has been associated with the abnormal activation of mono/macrophages and increased cytokine production. However, neither the phenotype of haemophagocytic monomacrophages nor the cellular origin of cytokine production have been described. We studied splenic monomacrophages and lymphocytes from five patients with HPS (two HIV- and three HIV+) and from controls without HPS (three normal HIV and two pathological HIV+). Using flow-cytometry, we observed a marked increase in the expression of MHC class I and II, M-CSF-receptor and adhesion molecules LFA-1, LFA-3, ICAM-1 (P<0.05) on HPS+ splenic monomacrophages compared to HPS-, which was independent of their HIV status. A high percentage of CD8+ lymphocytes from 4/5 HPS+ patients produced TNF alpha and IFNgamma, but no IL-6 upon in-vitro activation. In a fifth patient CD4+ but not CD8+ lymphocytes produced these cytokines. Although other cytokines might be involved in the pathophysiology of HPS as suggested by the high expression of M-CSF-receptor, these results suggest that TNF alpha and IFNgamma secretion by T cells might play a role in the up-regulation of adhesion and MHC molecules on monomacrophages from HPS.

Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy.

The T-cell antigen receptor (TCR) repertoire was studied longitudinally by analyzing the varying lengths of the beta chain CDR3 hypervariable region during the course of HIV-1 infection and following combination antiretroviral therapy. Drastic restrictions in CD8+ T-cell repertoire usage were found at all stages of natural progression and persisted during the first six months of treatment. In contrast, significant CD4+ T-cell repertoire perturbations were not found in early stages of infection but correlated with progression to AIDS. Out of ten patients presenting with pretreatment perturbations, normalization of the CD4+ repertoire was observed in eight good responders, but not in two cases of unsuccessful therapy. These results indicate that, besides CD4+ cell count rise, an efficient control of HIV replication may allow qualitative modifications of the CD4+ repertoire balance.

Vitamin K metabolism in a patient resistant to vitamin K antagonists.

We investigated various pharmacokinetic and pharmacodynamic parameters in a 63-year-old man, resistant to warfarin, fluindione, acenocoumarol and phenprocoumon. Daily doses of up to 30 mg of the long-acting phenprocoumon yielded a drug concentration of 85 mg/l (usual range 1-5 mg/l) but the international normalized ratio remained around 1. The plasma half-life of phenprocoumon was approximately 350 h (normal 120-150 h). Thus, the resistance was not due to malabsorption or to an accelerated metabolism of the drug. The level of vitamin K1 (1,202 ng/l) was insufficient to induce resistance. Decarboxyprothrombin concentrations were low, demonstrating that the gamma-carboxylation of the precursors of the vitamin K-dependent coagulation factors was not effectively reduced. The concentration of vitamin K epoxide, normally increased under oral anticoagulation, correlated to the vitamin K concentration (r2 = 0.77) but the quotient epoxide/vitamin K remained 4-fold lower than that of 22 warfarin-sensitive patients, suggesting an absence of blockade of the vitamin K reductase by phenprocoumon. This resistance to all the molecular forms of the vitamin K antagonists is most likely due to a reduced affinity of the drugs to a mutant vitamin K reductase.

[Lipoprotein anomalies in HIV infections]. / Anomalies lipoprotéiniques au cours de l'infection par le VIH.

Alterations in lipid parameters occur during many acute infections. Different studies suggest that variations in lipid parameters can be used as markers of the progression of human immunodeficiency virus (HIV) infection. Hypocholesterolemia is observed in asymptomatic HIV+ subjects, then hypertriglyceridemia appears in patients with AIDS. Several hypotheses have been raised concerning the potential causes and consequences of these modifications. Cytokine effects on different enzymes of lipid metabolism, studied in vitro and in vivo, are thought to be partially responsible for the dyslipidemia. Hypertriglyceridemia could participate in cachexia and dementia could be facilitated by the changes in cholesterol metabolism. The use of the lipid parameters is proposed in HIV positive subjects, especially during anti-viral treatment.

[New antithrombotic agents]. / Les nouveaux antithrombotiques.

The wide range of compounds currently being developed is the result of the continuing need for validated new antithrombotic agents. The prevention and treatment of venous thrombosis is predominated by anticoagulants: low molecular weight heparins, and potentially new antithrombin agents including hirudin. The effectiveness of new antiplatelet agents, and particularly c7E3 and integrelin, confirms the hypothesis concerning the role played by platelets in thrombogenesis in coronary arteries. But, due to the proaggregating effect of thrombin, anticoagulants could also have an important role in preventing arterial clots, either when given alone or in combination. Finally, the development of antithrombin and anti-platelet-glycoprotein IIb IIIa given orally is one of the major objectives of current research. Until the ideal antithrombotic agent is discovered, multiple-drug regimens combining anticoagulants and/or antiplatelet agents could be proposed in patients with a very high risk of thrombosis. Such regimens must taken into account the increased risk of bleeding and be adapted on the basis of careful laboratory surveillance.

[Hypersensitivity and resistance to antivitamins K]. / Hypersensibilité et résistance aux antivitamines K.

During the initial phase or during treatment with oral anticoagulants, hypersensitivity or resistance may be observed, requiring significant changes in prescribed dosage. A thorough knowledge of the mode of action of vitamin K and its antagonists is useful to improve understanding of unexpected response to oral anticoagulant therapy. These abnormal responses may be due to poor compliance to treatment by the patient, insufficient or excessive vitamin K intake, interference with other drugs or abnormalities of the hepatic enzymes which are the target of oral anticoagulant drugs. The search for a cause is justified by the risks associated with these abnormal responses. It must be rigorously undertaken with an accurate interrogation, use of an anticoagulation monitoring leaflet and, if necessary, measurement of plasma concentrations and pharmacokinetics of the anticoagulant drug.