Background: Obesity is a major modifiable risk factor for cardiovascular disease. Leptin, the hormone synthesized and released primarily by adipose tissue and found increased in obese individuals, ...has been implicated in the regulation of inflammation and arterial and venous thrombosis. Objective: To investigate the role of tissue factor (TF), the pivotal agonist of the clotting cascade, as a link between obesity and cardiovascular disease. Methods and results: In 15 obese patients, plasma levels of leptin and TF as well as TF expression in resting and endotoxin‐stimulated mononuclear leukocytes (MN) were increased when compared with healthy donors. In a selected sample of obese patients, loss of body weight led to decreased circulating leptin levels, accompanied by a reduction in plasma TF as well as in TF expression, both in resting and endotoxin‐stimulated MN. In subsequent in vitro experiments, leptin was incubated with MN from healthy subjects. Leptin induced TF activity and antigen in a dose‐dependent fashion, as assessed by clotting assay and ELISA, respectively. Increased migration of c‐Rel/p65 into the nucleus, as determined by EMSA, and development of TF mRNA in monocytes, as assessed by RT‐PCR, were observed. Experiments with mitogen‐activated protein kinase (MAPK) inhibitors, indicated the involvement of p38 and ERK1/2 pathways. Conclusions: The presence of TF‐expressing MN in blood from obese subjects and the in vitro induction of TF by pharmacologic concentrations of leptin in MN from healthy subjects suggest that TF expression by leptin‐stimulated monocytes may contribute to the cardiovascular risk associated with obesity.
OBJECTIVES—To investigate the role of interleukin-1β (IL-1β) gene polymorphisms as a link between inflammation, coagulation, and risk of ischemic vascular disease at young age.
METHODS AND RESULTS—A ...total of 406 patients with myocardial infarction (MI) at young age, frequency-matched for age, sex, and recruitment center, with 419 healthy population-based controls and 134 patients with ischemic stroke at young age, matched by age and sex, with 134 healthy population-based controls, were studied. Subjects carrying the TT genotype of the −511C/T IL-1β polymorphism showed a decreased risk of MI (odds ratio OR, 0.36; 95% CI, 0.20 to 0.64) and stroke (OR, 0.32; 95% CI, 0.13 to 0.81) after adjustment for conventional risk factors. In both studies, the T allele showed a codominant effect (P=0.0020 in MI; P=0.021 in stroke). Mononuclear cells from volunteers carrying the T allele showed a decreased release of IL-1β and a decreased expression of tissue factor after stimulation with lipopolysaccharide compared with CC homozygotes. The presence of a monoclonal antibody against IL-1β during cell stimulation resulted in a marked reduction of tissue factor activity expression.
CONCLUSIONS—−511C/T IL-1β gene polymorphism affects the risk of MI and ischemic stroke at young age and the response of mononuclear cells to inflammatory stimulation.
To investigate psychosocial characteristics of children and parents as predictors and moderators of the effect of a group intervention for children with chronic illness and their parents.
Data from a ...randomized controlled trial were used, including 194 children (8-18 years) who were assigned to a child-only intervention, a parent-child intervention, or a wait-list control group. Longitudinal multilevel regression analyses were used to test effects on change in parent and child reported internalizing and externalizing behavior problems.
For children with a more disengaged coping style or lower self-worth and for children who experienced a more secure parent-child relationship, the parent-child intervention was more effective than the child-only intervention in reducing behavior problems.
Children who are more "at risk" appear to gain more from participating in an intervention, especially if their parents are involved as well. However, the benefit of parents' involvement may depend on the quality of the parent-child relationship.
Abstract Background and aims Variations in mixed platelet–leukocyte conjugate formation in human whole blood could be genetically determined. We quantified platelet and leukocyte activation and ...interaction in families with or without early myocardial infarction and evaluated their heritability, genetic correlation and linkage to the 9p21.3 region. Methods and results The study population included 739 subjects (≥15 years old) from 54 large pedigrees, 23 with and 31 without familial myocardial infarction. Mixed platelet–leukocyte conjugates and markers of platelet or leukocyte activation (P-selectin, CD11b and L-selectin surface expression) were measured both before and after in vitro blood stimulation with collagen-ADP. All traits had significant genetic components (17.5–65.3% of the phenotypic variability), while shared household effects (0–39.6%) and environmental covariates (0–10.2%) tended to be smaller. Stimulated platelet-polymorphonuclear leukocyte (PMN) and platelet–monocyte conjugates showed the highest linkage to the 9p21.3 region (LOD = 0.94 and 1.33, respectively; empirical p value = 0.017 and 0.009). PMN markers resulted strongly genetically correlated between them in bivariate analysis among pairs of quantitative traits. Conclusion This study supports a genetic regulation of human mixed platelet–leukocyte conjugates.
Background: Epidemiological studies have shown that consumption of wine reduces the risk of coronary heart disease. Resveratrol and quercetin, two polyphenolic compounds found in grapes and red wine, ...have been shown to contribute to this protection by exerting several biological properties which could be associated with cardioprotection. Tissue factor (TF), the cellular receptor that initiates blood coagulation, plays a primary role both in hemostasis following tissue injury and in the pathogenesis of atherosclerosis which predisposes to thrombosis. Objectives: We investigated the role of resveratrol and quercetin on TF expression by endothelial and mononuclear cells (MN). Methods: Confluent human umbilical vein endothelial cells and MN collected from healthy donors were stimulated with bacterial lipopolysaccharide, interleukin‐1β or tumor necrosis factor‐α after incubation with increasing concentrations of resveratrol or quercetin. Results: In both cell types, TF activity induced by any agonist was significantly reduced by resveratrol or quercetin in a dose‐dependent fashion. Northern blot analysis indicated that resveratrol and quercetin strongly reduce TF mRNA in both cell types. The inhibition of TF mRNA originated from a reduction in nuclear binding activity of the transacting factor c‐Rel/p65, which was induced by the agonists and measured by electromobility shift assay. Western blot analysis revealed that the diminished c‐Rel/p65 activity was dependent upon inhibition of degradation of the c‐Rel/p65 inhibitory protein IκBα. Conclusions: These results provide a molecular basis which could help explain the protective activity of red wine against cardiovascular disease.
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