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Biomedical subjects

M C Alessi

Publications and source records attributed to M C Alessi.

At least 37 records · Page 2Linked to original sources
PubMed2001

Antibodies to phosphatidylethanolamine as the only antiphospholipid antibodies found in patients with unexplained thromboses.

The objective of this study was to assess the interest of antiphosphatidylethanolamine antibodies (aPE) in unexplained thrombosis (UT) defined as thrombotic episode without any of the main autoimmune and hereditary thrombophilic defects. Results from 98 UT were compared to those of (I) 142 patients with thrombophilia: 67 antiphospholipid syndrome (APS) and 75 hereditary hemostatic defects (HHD); (II) 110 patients without thrombosis: 60 with systemic lupus erythematosus (SLE) and 50 with infectious diseases (ID). As compared to controls (100 blood donors), aPE prevalence was significantly higher in both autoimmune contexts (APS: 43%; SLE: 40%, p<0.0001) and among non-autoimmune pathologies, only in UT (18%, p = 0.001) conversely to HHD (8%) or ID (10%). aPE prevalence in UT was not statistically different from that found in Primary APS (32%, p = 0.076) but lower than in Secondary APS (65%, p <0.005). In UT, aPE were mainly of IgM isotype like in Primary APS and they were found alone whereas in SLE they were always associated with classical antiphospholipid antibodies. No significant association was found between any isotype of aPE and a site of thrombosis in UT as well as in APS. In conclusion, this study demonstrates an increase of the prevalence of aPE in patients with unexplained thrombosis. Thus, aPE investigation appears to be of interest in UT and their persistent presence could define a biological variant of APS.

Adult↗
PubMed2001

Adipose tissue expression of gelatinases in mouse models of obesity.

Following the observation by Brown et al. (Am J Physiol 1997; 272: C937-49) that primary rat adipocytes in culture secrete gelatinase A (MMP-2), we have evaluated gelatinase expression in adipose tissue with the use of mouse models of obesity. Wild-type mice were kept on a standard fat diet (SFD) or on a high fat diet (42% fat, HFD) and- genetically obese db/db mice were kept on SFD; gonadal and subcutaneous fat pads were removed and analysed ex vivo. These studies revealed that: 1) the HFD induced adipocyte hypertrophy; 2) after 32 weeks, significantly higher levels of 70 kDa (p <0.05) and 65 kDa proMMP-2 (p <0.01) were observed in extracts of gonadal fat pads of mice on HFD; 3) the contribution of active MMP-2 to the total level was comparable in SFD and HFD groups (20 to 30%); and 4) gelatinase B (MMP-9) was not consistently detected. These findings were confirmed by gelatin zymography and by mRNA determination using competitive RT-PCR. The presence of MMP-2 in the adipose tissue was confirmed immunologically and its localization in adipocytes revealed by immunogold electron microscopy. The potential functional role of MMP-2 in adipose tissue remains to be determined.

Adipose Tissue↗
PubMed2000

Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity.

An increased plasma plasminogen activator inhibitor-1 (PAI-1) level is a risk factor for myocardial infarction, particularly when associated with visceral obesity. Although the link between PAI-1 and obesity is well documented, little is known about the physiological relevance of PAI-1 production by adipose tissue. Therefore, we have compared adipose tissue development and insulin resistance plasma parameters in PAI-1-deficient mice (PAI-1(-/-)) and wild-type littermates (PAI-1(+/+)) in a model of nutritionally induced obesity. After 17 weeks of consuming a high-fat diet (HFD), PAI-1(+/+) mice showed marked obesity, with a 52% increase in body weight compared with mice that were kept on a standard fat diet (P<0.0001). This weight gain was accompanied by adipocyte hypertrophy and an increase in the number of stroma cells in the gonadal fat pad, expressed as stroma cells/adipocytes (0.67+/-0.05 versus 0.43+/-0. 02; P<0.001). In plasma, the HFD induced a marked increase in PAI-1 antigen (5.1+/-0.56 versus 2+/-0.22 ng/mL; P<0.001), fasting insulinemia (1.1+/-0.21 versus 0.21+/-0.04 ng/mL; P<0.001), and glycemia (7.4+/-0.5 versus 5+/-0.3 mmol/L; P<0.001), whereas plasma triglyceride levels were not affected. When we compared PAI-1(-/-) and PAI-1(+/+) mice on the HFD, PAI-1(-/-) mice gained weight faster than did PAI-1(+/+) mice, with a significant difference in body weight between 3 and 8 weeks of the diet (32+/-1.7 versus 26+/-1.6 g at 6 weeks; P<0.05). After 17 weeks of the HFD, its effect on weight gain and the number and size of adipocytes was similar in PAI-1(+/+) and PAI-1(-/-) mice. By contrast, the increase in the number of stroma cells presented by PAI-1(+/+) mice was not observed in PAI-1(-/-) mice. In obese PAI-1(-/-) mice, tissue-type PA activity and antigen levels in the gonadal fat pad were significantly higher than in obese PAI-1(+/+) mice (230+/-50 versus 47+/-20 arbitrary units/g, P<0.01; 40+/-13 versus 17+/-13 ng/g, P<0.05, respectively), whereas urokinase-type PA activity and antigen levels were similar in both groups. In plasma, nonobese PAI-1(-/-) mice displayed 62% higher insulin levels (P<0.05) than did PAI-1(+/+) mice. Obese PAI-1(-/-) mice displayed 68% higher triglyceride levels (P<0.01) and 21% lower glucose levels (P<0.05) than did PAI-1(+/+) mice. These data support an effect of PAI-1 on weight gain and adipose tissue cellularity in the induction of obesity in mice. Moreover, PAI-1 influences glucidolipidic metabolism. The elevated expression of PAI-1 observed in human obesity could be involved in mechanisms that control adipose tissue development.

Adipocytes↗
PubMed2000

The A -844G polymorphism in the PAI-1 gene is associated with a higher risk of venous thrombosis in factor V Leiden carriers.

Identification of combined genetic factors in factor V Leiden carriers is important for a more accurate risk assessment for venous thrombosis (VT). Among these individuals, we evaluated the role of polymorphisms of the plasminogen activator inhibitor-1 (PAI-1) gene in the thrombophilic phenotype. A total of 382 factor V Leiden carriers were included in the study. This population was divided into 3 groups. Group 1 (n=168) included individuals with a personal history of VT; group 2 (n=140) included individuals without personal VT but with a familial history of VT; and group 3 (n=74) included individuals without VT and with a fortuitous discovery of the factor V Leiden mutation. We compared the genotype distribution of 2 polymorphisms, A -844G and -675 4G/5G, located in the promoter region of the PAI-1 gene among these 3 groups of individuals. The A -844G allele frequency differed significantly among the 3 groups (P=0.048), the A allele being more frequent in patients who suffered from VT (61%) than in subjects without VT (52%, P=0.015), whereas no difference was observed between the 2 groups of asymptomatic individuals. The prevalence of genotype AA carriers was higher in patients with VT (38%) than in asymptomatic individuals (21%, P=0. 015), leading to an odds ratio of 1.74 (95% confidence interval, 1.3 to 3.8). Carrying the AA genotype conferred a risk of deep VT of 2. 08 (95% confidence interval, 1.28 to 3.40), whereas it did not seem to significantly influence the risk of pulmonary embolism. Concerning the -675 4G/5G polymorphism, no significant difference was observed among the 3 groups, the 4G allele frequency being 0.54 (in group 1), 0.49 (in group 2), and 0.45 (in group 3). These data suggest a role for the -A844G PAI-1 gene polymorphism in the thrombophilic phenotype of factor V Leiden carriers.

Adolescent↗
PubMed2000

Thrombin-activatable fibrinolysis inhibitor antigen levels and cardiovascular risk factors.

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a recently described fibrinolysis inhibitor that circulates in plasma as a procarboxypeptidase and is converted into an active form during coagulation. The physiological relevance of TAFI is not known, but it might be involved in pathways regulating fibrin deposition. Our aim was to determine the interindividual variability of plasma TAFI antigen values and their associations with conventional cardiovascular risk factors. Six hundred twenty-six consecutive patients (277 men) attending a metabolic ward for primary prevention were studied. TAFI antigen presented a large range of values, with a 2- to 3-fold increase between the 10th and 90th percentiles. No difference was observed between the 2 sexes. A significant correlation was observed between age and TAFI levels in women only. After adjustment for age, TAFI antigen was positively correlated in men for the waist-to-hip circumference ratio and blood pressure, whereas no significant correlation was observed in women. Stepwise multiple linear regression analysis indicated a low contribution of the parameters studied to the variability of TAFI antigen levels; the waist-to-hip circumference ratio accounted for only 2% in men, and age accounted for only 3% in women. Results were compared with those of fibrinogen and plasminogen activator inhibitor-1; cardiovascular risk factors in men and women accounted for 16% and 9. 5%, respectively, of the fibrinogen variance and 36% and 32%, respectively, of the plasminogen activator inhibitor-1 variance. These observations did not attribute an important role to lifestyle characteristics in the control of TAFI antigen concentration in plasma. Because of the large interindividual variability of TAFI levels in plasma, genetic control may be involved.

Age Factors↗
PubMed2000

Plasminogen activator inhibitor 1, transforming growth factor-beta1, and BMI are closely associated in human adipose tissue during morbid obesity.

In adipose tissue from both obese mice and humans, plasminogen activator inhibitor 1 (PAI-1) expression has been reported to be upregulated to levels of increased plasma PAI-1. This elevated expression has been shown to be partly controlled by tumor necrosis factor (TNF)-alpha in mice. In humans, increased PAI-1 expression is associated with insulin resistance characterized by visceral fat accumulation. Therefore, the aim of this study was to investigate the expression pattern of PAI-1 and TNF-alpha (antigen and mRNA) in visceral human adipose fat in comparison with subcutaneous (SC) fat. Because transforming growth factor (TGF)-beta1 is a potent inducer of PAI-1 synthesis and has been shown to influence adipocyte metabolism, this work was extended to TGF-beta1 quantification. A total of 32 obese individuals (BMI 42 +/- 6.8 kg/m2) were investigated. Freshly collected visceral adipose tissue did not exhibit a higher content of PAI-1 or TGF-beta1 than did SC tissue. Although most of the TNF-alpha values were at the detection limit of the methods, TNF-alpha antigen was 3-fold higher and TNF-alpha mRNA was 1.2-fold higher in visceral fat. The levels of tissue TGF-beta1 antigen correlated well with those of PAI-1 antigen, regardless of the fat depot studied (SC tissue: n = 21, r = 0.72, P = 0.0006; visceral tissue: n = 20, r = 0.49, P < 0.03), and they were both significantly associated with BMI. Conversely, no relationship was observed between the levels of TNF-alpha and PAI-1 or TNF-alpha and BMI. Tissue PAI-1 levels were also significantly correlated with those of circulating PAI-1. These results describe, in severe obesity, a proportional increase in tissue PAI-1 and TGF-beta1 in visceral and SC tissues. This increased PAI-1 expression could be the result of tissue cytokine disturbances, such as elevated TGF-beta1 expression.

Adipose Tissue↗
PubMed2000

Plasma TAFI antigen variations in healthy subjects.

The Thrombin Activatable Fibrinolysis Inhibitor (TAFI) is a recently described inhibitor of fibrinolysis. The physiological variations of plasma TAFI antigen are not well known. We studied TAFI antigen values in healthy populations with a commercially available kit from Milan Analytica (Switzerland). Broad range of TAFI antigen values (from 41% to 259%) was found in a population of 249 healthy individuals. Gender as well as pregnancy did not influence mean values of TAFI antigen. There was a positive correlation between TAFI antigen and age in female (r = 0.28; p <0.05) but not in male populations. Mean TAFI antigen value of a black African male group [mean +/- SD (range): 87 +/- 23 (39-144%)] was significantly lower than the one of age matched Caucasian men [114 +/- 34 (52-259%)] (p <0.0001). TAFI antigen values were very stable within individuals, they did not significantly vary on day time or at several months period. Thus, in contrast to large inter-individual variations, TAFI antigen levels are quite stable within individuals.

Adult↗
PubMed2000

Hypofibrinolysis and increased PAI-1 are linked to atherothrombosis via insulin resistance and obesity.

Plasminogen activator inhibitor 1 (PAI-1) is the primary physiological inhibitor of plasminogen activation in vivo. Circulating PAI-1 levels are elevated in patients with coronary heart disease and may play an important role in the development of atherothrombosis by decreasing fibrin degradation. Increased PAI-1 expression can also directly influence vessel wall remodelling. Prospective cohort studies have underlined the association between increased plasma PAI-1 levels and the risk of coronary events, but the predictive capacity of PAI-1 disappeared after adjustments for insulin resistance markers. The insulin resistance syndrome, which is characterized partly by obesity with visceral fat accumulation, is considered as a major regulator of PAI-1 expression. Recently, production of PAI-1 by adipose tissue, in particular by fat from omentum, has been evidenced, and it has been proposed that it could be responsible for the elevated plasma PAI-1 level observed in insulin resistance. The role of stroma cells, tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta as possible enhancers of PAI-1 synthesis are presently emphasized. Glucocorticoids and insulin may also be implicated. Moreover, a weak genetic control of plasma PAI-1 concentration has been described in patients with high plasma levels of PAI-1. The role of PAI-1 in the development of adipose tissue metabolism is important to consider as PAI-1 -/- mice submitted to a high-fat diet showed changes in cell composition of adipose tissue and in plasma insulin and triglyceride levels.

Adipose Tissue↗
PubMed1999

[Thrombolytics and their use].

Thrombolytic agents directly or indirectly activate plasminogen into plasmin, the true thrombolytic being plasmin. Streptokinase is a non-enzyme protein which has occupied the reference position so far. Streptokinase is immunogenic and its activity is neutralised by pre-existing antistreptococcal antibodies. Its administration provokes a systemic activation of fibrinolysis. Urokinase and anisoylated streptokinase-plasminogen complex have no clear advantages when compared with streptokinase. More fibrin specific agents (tissue plasminogen activator, prourokinase) do not improve the risk of bleeding (0.75% in brain). Haemostasis survey does not allow bleeding prediction, but contributes to its control by quantifying the systemic fibrinolytic activity of the drug and checking the anticoagulation level induced by heparin (which is often associated to thrombolysis).

Fibrinolysin↗
PubMed1999

PAI-1 produced ex vivo by human adipose tissue is relevant to PAI-1 blood level.

Human adipose tissue has been shown to produce plasminogen activator inhibitor type 1 (PAI-1). However, the importance of adipose tissue in the regulation of the PAI-1 plasma level is not known. The aim of this study was to investigate the relation between the production of PAI-1 by adipose tissue, plasma PAI-1 level, and variables related to the insulin resistance state. The link between the production of PAI-1 inducers such as tumor necrosis factor-alpha and transforming growth factor-beta and the production of PAI-1 by adipose tissue was also evaluated. Blood samples were obtained as soon as possible to the induction of anesthesia from 30 patients undergoing elective abdominoplasty. PAI-1 antigen levels measured in conditioned media after a 19-hour incubation period of adipose tissue explants were significantly correlated with plasma PAI-1 antigen levels (r=0.54, P=0.004) and with systemic lipid parameters such as triglycerides and high density lipoprotein cholesterol (r=0. 46, P=0.014; r=-0.50, P=0.01, respectively) but not with insulinemia and body mass index. PAI-1 production by adipose tissue was correlated with those of TNF-alpha (r=0.5, P=0.01) and TGF-beta (r=0. 53, P=0.007). These results emphasize the role of adipose tissue in determining plasma levels of PAI-1, with a local contribution of TNF-alpha and TGF-beta in PAI-1 production by adipose tissue.

Adipose Tissue↗
PubMed1999

Glucocorticoids and insulin promote plasminogen activator inhibitor 1 production by human adipose tissue.

Plasminogen activator inhibitor 1 (PAI-1) is likely to play a role in vascular disease, primarily in subjects with android obesity. It has been demonstrated that PAI-1 is overexpressed in adipose tissue from obese subjects and that visceral adipose tissue produced more PAI-1 than subcutaneous fat. In the present study, the effect of insulin and glucocorticoids, which are key mediators of adipose tissue metabolism, was examined in relation to PAI-1 synthesis by human adipose tissue explants (HAT), collagenase isolated human adipocytes (IHA), cultured human stromal cells (cSC), and differentiated adipocytes from the murine clonal cell line 3T3-F442A. A significant increase in PAI-1 antigen release (1.5-fold) from HAT was detectable after 16 h of treatment with insulin concentrations of at least 10(-8) mol/l. This was associated with a PAI-1 mRNA increase. Concomitant addition of insulin (10(-8) mol/l) to forskolin (5 x 10(-5) mol/l) reversed the decrease in PAI-1 antigen caused by forskolin alone. No effect on PAI-1 antigen was observed when insulin was incubated with IHA or cSC. 3T3 F442A cells were sensitive to insulin with a four- and twofold increase in PAI-1 antigen and mRNA levels, respectively, after 16 h of stimulation with 10(-8) mol/l. Dexamethasone (DXM) significantly enhanced PAI-1 antigen and mRNA expression by HAT (1.5- and 2.5-fold increase, respectively) at concentrations of at least 10(-8) mol/l. A higher stimulation was observed with IHA (sevenfold increase) and with the differentiated 3T3 F442 cell line. Cortisol was found to be less potent than DXM. No effect was observed when glucocorticoids were incubated with cSC. Coincubation of HAT with insulin (10(-7) mol/l) and DXM (10(-7) mol/l) led to an additive effect on PAI-1 synthesis. These results support the hypothesis that PAI-1 expression in human adipose tissue is controlled by insulin and glucocorticoids and may help to explain the increase in plasma PAI-1 levels observed in patients with android obesity.

3T3 Cells↗
PubMed1999

Relationship of plasminogen activator inhibitor-1 levels following thrombolytic therapy with rt-PA as compared to streptokinase and patency of infarct related coronary artery.

BACKGROUND: Type 1 plasminogen activator inhibitor (PAI-1) is considered to be risk factor for acute myocardial infarction (AMI). A rebound of circulating PAI-1 has been reported after rt-PA administration. We investigated the relationships between PAI-1 levels before and after thrombolytic therapy with streptokinase (SK) as compared to rt-PA and the patency of infarct-related arteries. METHODS AND RESULTS: Fifty five consecutive patients with acute MI were randomized to streptokinase or rt-PA. The plasma PAI-1 levels were studied before and serially within 24 h after thrombolytic administration. Vessel patency was assessed by an angiogram at 5+/-1days. The PAI-1 levels increased significantly with both rt-PA and SK as shown by the levels obtained from a control group of 10 patients treated with coronary angioplasty alone. However, the area under the PAI-1 curve was significantly higher with SK than with rt-PA (p<0.01) and the plasma PAI-1 levels peaked later with SK than with rt-PA (18 h versus 3 h respectively). Conversely to PAI-1 levels on admission, the PAI-1 levels after thrombolysis were related to vessel patency. Plasma PAI-1 levels 6 and 18 h after SK therapy and the area under the PAI-1 curve were significantly higher in patients with occluded arteries (p<0.002, p<0.04 and p<0.05 respectively). The same tendency was observed in the t-PA group without reaching significance. CONCLUSIONS: This study showed that the PAI-1 level increase is more pronounced after SK treatment than after t-PA treatment. There is a relationship between increased PAI-1 levels after thrombolytic therapy and poor patency. Therapeutic approaches aimed at quenching PAI-1 activity after thrombolysis might be of interest to improve the efficacy of thrombolytic therapy for acute myocardial infarction.

Biomarkers↗
PubMed1998

Visceral fat as a main determinant of plasminogen activator inhibitor 1 level in women.

OBJECTIVE: To substantiate in a premenopausal population of women, the link between visceral adipose tissue and circulating plasminogen activator inhibitor 1 (PAI-1) levels. DESIGN: Study of correlations between anthropometric parameters and PAI-1 and evaluation of the changes induced by weight loss. SUBJECTS: Forty-two healthy pre-menopausal women (aged 18-51 y, with a wide range of body mass index (BMI, 21-48.8 kg/m2). Thirteen women were evaluated after weight loss (6.6+/-3.3 kg). MEASUREMENTS: BMI, waist and hip circumferences. Total, subcutaneous and visceral adipose tissue areas at the L3-L4 level by computed tomography. Insulin, cholesterol, triglyceride, HDL cholesterol, PAI-1 activity, PAI-1 antigen and tissue plasminogen activator (tPA) antigen. RESULTS: PAI-1 activity, PAI antigen and tPA antigen were positively correlated with visceral adipose tissue, but not with subcutaneous adipose tissue. This correlation was independent of insulin or triglyceride levels. The amount of visceral adipose tissue explained 28% of the PAI-1 activity variance. Weight loss confirmed this link, PAI-1 diminution being correlated only with visceral adipose tissue loss and not with total fat, insulin or triglyceride decrease. CONCLUSION: This study suggests, like in vitro studies, that visceral fat may be an important contributor to the circulating PAI-1.

Adipose Tissue↗
PubMed1998

Metabolic determinants are much more important than genetic polymorphisms in determining the PAI-1 activity and antigen plasma concentrations: a family study with part of the Stanislas Cohort.

Increased plasma plasminogen activator inhibitor-1 (PAI-1) concentration has been identified as a risk factor for coronary heart disease. We investigated the relative contribution of both metabolic factors involved in the insulin resistance (IR) syndrome and polymorphisms of the PAI-1 gene to plasma levels of PAI-1 in 228 healthy nuclear white families from the Stanislas Cohort. Variables related to IR included body mass index, waist-to-hip ratio, fasting insulin, triglyceride, and HDL cholesterol. Five PAI-1 gene polymorphisms were studied, including a newly described G+12078A substitution in the 3' region. A sex difference was observed, with fathers exhibiting higher IR state and PAI-1 levels and stronger correlations between PAI-1 and IR variables than mothers. Such a difference was not observed in offspring. Family correlations were of similar magnitude for fibrinolytic parameters and IR variables. The PAI-1 genotypes A-844G, -675 4G/5G, and G+12078A polymorphisms, which were in strong linkage disequilibrium, were associated with plasma PAI-1 levels. In multivariate analysis, IR explained a major part of PAI-1 variability (49% in fathers, 29% in mothers), whereas polymorphisms had only a minor contribution, explaining 3% of variability in women and having no significant effect in men. We conclude that plasma levels of PAI-1 are, in a healthy population, primarily determined by the IR syndrome, this relationship being stronger in males. The contribution of the PAI-1 gene seems larger in females. These results deserve special attention for understanding the relationships observed between fibrinolytic parameters and the risk of developing a cardiovascular ischemic event.

Adolescent↗