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Biomedical subjects

Giovanni Davì

Publications and source records attributed to Giovanni Davì.

At least 19 recordsLinked to original sources
PubMed2006

Insulin resistance as a determinant of platelet activation in obese women.

OBJECTIVES: We tested the hypothesis that insulin resistance, per se, contributes to increased platelet activation in obesity, independently of underlying inflammation. BACKGROUND: Obesity, insulin resistance, and atherosclerosis are closely linked phenomena associated with low-grade inflammation. Obesity is associated with persistent platelet activation in otherwise healthy women. METHODS: We performed a cross-sectional study in 40 obese and 20 non-obese healthy women using urinary thromboxane metabolite excretion as a non-invasive index of platelet activation. An index of insulin sensitivity, S(I), and plasma adiponectin, C-reactive protein (CRP), and CD40 ligand (CD40L) levels were measured. RESULTS: Obese women had significantly (p < 0.0001) higher 11-dehydro-thromboxane B2 (11-dehydro-TXB2) excretion (median 718 vs. 211 pg/mg creatinine), CRP (1.13 vs. 0.48 mg/l), and CD40L levels (4.45 vs. 0.90 ng/ml) than controls. Obese women had lower S(I) (median 2.51 vs. 5.0 10(4) min(-1)/[microU/ml], p < 0.002) and adiponectin (6.3 vs. 10 microg/ml, p < 0.01) than control subjects. On multiple regression analysis, waist-to-hip ratio (beta = 0.27, p < 0.05) and S(I) (beta = -0.72, p < 0.04) predicted 11-dehydro-TXB2 excretion rate, independently of adiponectin, CRP, CD40L, and lipid patterns. In order to investigate the cause-effect relationship of these associations, we examined the effects of a 12-week weight loss program or a 3-week pioglitazone treatment on urinary 11-dehydro-TXB2 in 10 women with impaired S(I) and visceral obesity. Successful weight loss (0.6 kg loss/week) achieved in 5 subjects was associated with increased S(I) (+92%) and decreased CD40L (-27%), CRP (-37%), and 11-dehydro-TXB2 (-53%) (p < 0.05). Consistently, improvement of insulin sensitivity achieved with pioglitazone significantly decreased urinary 11-dehydro-TXB2 excretion (-43%, p < 0.05) without changes in body weight. CONCLUSIONS: Insulin resistance is a major determinant of platelet activation in female obesity.

Adult↗
PubMed2006

Determinants of platelet activation in Alzheimer's disease.

OBJECTIVES: To investigate the rate of platelet thromboxane (TX) biosynthesis and its determinants in Alzheimer's disease. METHODS AND RESULTS: A cross-sectional comparison of urinary 11-dehydro-TXB(2) and 8-iso-prostaglandin (PG)F(2alpha) (markers of in vivo platelet activation and lipid peroxidation, respectively), plasma Vitamin E, C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, was carried-out in 44 Alzheimer patients and 44 matched controls. To investigate the cyclooxygenase (COX)-isoform involved in TXA(2) biosynthesis, nine Alzheimer patients were treated with low-dose aspirin (100mg/d) or rofecoxib (25mg/d) for 4 days. Urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) were significantly higher in Alzheimer patients than in controls (Median: 1983.5 versus 517.5pg/mg creatinine and 938.5 versus 304.0pg/mg creatinine, p<0.0001, respectively), with a significant correlation between the two metabolites (rho=0.75, p<0.0001). An inverse correlation was observed between Vitamin E and both urinary metabolites (8-iso-PGF(2alpha): R(s)=-0.51, p=0.0004; 11-dehydro-TXB(2): R(s)=-0.44, p=0.0026) in Alzheimer patients. No difference was found in CRP, TNF-alpha and IL-6 levels between the two groups. Urinary 11-dehydro-TXB(2) was significantly reduced by aspirin, but not by rofecoxib, consistently with a COX-1-mediated TXA(2) biosynthesis. 8-iso-PGF(2alpha) excretion was not modified by either COX-inhibitor, consistently with its oxygen radical-catalyzed formation. CONCLUSIONS: Platelet activation is persistently enhanced in Alzheimer's disease. This is related, at least in part, to increased lipid peroxidation associated with inadequate levels of Vitamin E.

Aged↗
PubMed2006

Low-density lipoprotein-lowering medication and platelet function.

Elevated low-density lipoprotein (LDL) cholesterol (LDL-C) levels represent one of the most important risk factors for atherosclerosis and therefore cardiovascular morbidity and mortality. LDL-C operates at different levels and through various classic and non-classic mechanisms. In particular, increased or modified LDL enhances platelet function and increases sensitivity of platelets to several naturally occurring agonists. Agents that lower LDL-C in hypercholesterolemic patients have been shown to interfere with platelet function. Several studies, in fact, suggested that statins exert anti-thrombotic effects largely as a result of an anti-platelet activity. Among the other LDL-C-lowering agents those acting by interfering with cholesterol reabsorption from the gut (cholestyramine, colestipol) do not appear to interfere with platelet function, whereas peroxisome proliferator-activated receptor agonists (such as fibrates) can inhibit platelet function. The full potential of these drugs in vascular protection is only just being realized. Further studies are still needed to elucidate the full therapeutic benefits of these agents in plaque stabilization and thrombosis.

Anticholesteremic Agents↗
PubMed2005

Thromboxane-dependent CD40 ligand release in type 2 diabetes mellitus.

OBJECTIVES: The goals of this study were to characterize the platelet contribution to soluble CD40 ligand (sCD40L), to correlate its formation with the extent of oxidative stress and platelet activation, and to investigate the effects of improved metabolic control and low-dose aspirin on these processes. BACKGROUND: Inflammation, oxidative stress, and platelet activation are involved in the pathogenesis of type 2 diabetes (T2DM) and its complications. The CD40-CD40L interactions result in inflammatory and pro-thrombotic responses. METHODS: Urinary 8-iso-prostaglandin (PG)F2alpha and 11-dehydro-thromboxane (TX)B2, in vivo markers of oxidative stress and platelet activation, respectively, plasma CD40L, and C-reactive protein (CRP) were measured in 114 T2DM patients and 114 control patients. A randomized, parallel group, 17-day study of aspirin (30, 100, or 325 mg/day) was performed in 18 T2DM patients. A similar study was performed in six healthy volunteers (aspirin, 100 mg/day). Twenty poorly controlled T2DM patients were studied before and after improved metabolic control. RESULTS: Compared with control patients, diabetic patients showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, sCD40L, and CRP. On multiple regression analysis, 11-dehydro-TXB2 and 8-iso-PGF2alpha excretion rates predicted sCD40L levels. Soluble CD40L linearly correlated with 11-dehydro-TXB2 (rho = 0.67, p < 0.0001), and both were reduced after one week of aspirin (p < 0.0026), with slow recovery over 10 days after aspirin withdrawal. Improved metabolic control was associated with a reduction in sCD40L, 8-iso-PGF2alpha, and 11-dehydro-TXB2. CONCLUSIONS: This study provides several lines of evidence for the dependence of sCD40L release on TXA(2)-dependent platelet activation in T2DM and provides novel mechanistic insight into the amplification loops of persistent platelet activation in this setting.

Aged↗
PubMed2005

Soluble CD40L and cardiovascular risk in asymptomatic low-grade carotid stenosis.

BACKGROUND AND PURPOSE: We investigated whether soluble CD40L (sCD40L) may predict the risk of cardiovascular (CV) events in patients with asymptomatic carotid plaques. METHODS: Forty-two patients with asymptomatic low-grade carotid stenosis (ALCS) and 21 controls without any carotid stenosis were enrolled. All subjects had at least a major cardiovascular risk factor (CRF). Plasma levels of C-reactive protein (CRP), IL-6, and sCD40L were measured. Subjects were reviewed every 12 months (median follow-up, 8 years). RESULTS: ALCS patients had higher (P<0.0001) CRP, IL-6, and sCD40L than controls. Fourteen patients experienced a CV event. Cox regression analysis showed that only high sCD40L levels (P=0.003) independently predicted cardiovascular risk. CONCLUSIONS: High levels of sCD40L may predict the risk of CV events in ALCS.

C-Reactive Protein↗
PubMed2005

Isoprostane formation and inhibition in atherothrombosis.

Enhanced oxidant stress plays a pivotal role in the pathogenesis of several conditions such as atherothrombosis, cancer and neurodegeneration. The availability of reliable assays of isoprostanes in biological fluids has prompted clinical investigations into the pathophysiological role of lipid peroxidation in cardiovascular disease. Established risk factors for coronary heart disease have been associated with enhanced oxidant stress, leading to increased lipid peroxidation and non-enzymatic formation of bioactive isoprostanes. These risk factors include diabetes mellitus, hypercholesterolemia, obesity and hyperhomocysteinemia. Clinical studies support the hypothesis that enhanced lipid peroxidation may contribute, at least in part, to persistent platelet activation.

Animals↗
PubMed2005

Aging is characterized by a profound reduction in anti-inflammatory lipoxin A4 levels.

Ongoing low-grade chronic inflammation represents a pathogenetic background for age-related diseases. In this report, we tested the hypothesis that endogenous anti-inflammatory mechanisms may become less efficient with age, resulting in increased susceptibility to inflammatory disorders. Using previously validated ELISA assays, we evaluated urinary levels of the anti-inflammatory, pro-resolution, arachidonic acid (AA) metabolite, lipoxin (LX)A(4) and of the pro-inflammatory cysteinyl leukotrienes (cysLTs) in volunteers aged from 26 to over 100 years. (i) LXA(4) excretion was decreased in elderly people, resulting in a profound unbalance of the LXA(4)/cysLTs ratio, which may be considered an index of the endogenous anti-inflammatory potential. A significant inverse correlation was denoted between age and the LXA(4)/cysLTs ratio (rho = -0.41, P = 0.0026). We conclude that aging is associated with a switch in arachidonic acid metabolism that prevents formation of key 'stop signals' of the inflammatory reaction. This may contribute to promote the development of disease in elderly.

Adult↗
PubMed2004

Helicobacter pylori infection causes persistent platelet activation in vivo through enhanced lipid peroxidation.

OBJECTIVE: We aimed at investigating the relationship between Helicobacter pylori infection and in vivo lipid peroxidation and platelet activation, as reflected by urinary 8-iso-prostaglandin (PG)F(2alpha) and 11-dehydro-thromboxane (TX)B2, respectively, in otherwise healthy dyspeptic subjects. METHODS AND RESULTS: We measured urinary 8-iso-PGF2alpha and 11-dehydro-TXB2 excretion in 40 dyspeptic subjects with a positive 13C-urea breath test and 38 dyspeptic individuals with a negative test. Moreover, we investigated the effects of H pylori eradication on prostanoid metabolite excretion in 23 H pylori-positive subjects. We also measured prostanoid metabolite excretion before and after selective cyclooxygenase-2 inhibition with rofecoxib in 4 H pylori-positive subjects. Urinary 8-iso-PGF2alpha and 11-dehydro-TXB2 excretion was significantly higher in the H pylori-positive individuals than in controls. A significant direct correlation was found between the degree of positivity to the 13C-urea breath test and urinary 8-iso-PGF2alpha excretion. The latter was linearly correlated with urinary 11-dehydro-TXB2. Successful eradication of H pylori infection led to a significant reduction in both 8-iso-PGF(2alpha) and 11-dehydro-TXB2. Furthermore, their levels were unaffected after treatment with rofecoxib. CONCLUSIONS: Our study provides evidence of enhanced in vivo lipid peroxidation and platelet activation in association with H pylori infection and suggests a novel mechanism by which an infectious agent could contribute to atherothrombosis.

Adult↗
PubMed2004

Soluble CD40 ligand plasma levels in lung cancer.

PURPOSE: Tumor-induced platelet activation may cause the release of various cytokines, including CD40 ligand (CD40L). Activation of the CD40/CD40L pathway in human tumors may result in thrombin generation, which is known to be involved in angiogenesis. Thus, we investigated whether soluble (s)CD40L levels are increased in patients with lung cancer as a result of platelet and/or coagulation activation. EXPERIMENTAL DESIGN: Citrated plasma samples were obtained from 120 patients with different stages and histotypes of lung cancer and 60 age- and sex-matched control subjects. sCD40L, sP-selectin (marker of platelet activation), prothrombin fragment 1 + 2, and thrombin-antithrombin III complex levels (both markers of coagulative activation) were measured in all samples. RESULTS: Patients with lung cancer had median sCD40L levels higher than in control subjects (0.46 versus 0.13 ng/ml; P < 0.0001), although correlation with the stage of disease was not evident. Nonetheless, sCD40L levels were significantly higher in squamous cancer compared with adenocarcinoma (0.75 versus 0.27 ng/ml; P < 0.05). Moreover, median sCD40L levels were higher in stage IV compared with nonmetastatic squamous lung cancer (1.02 versus 0.61 ng/ml; P < 0.05). sCD40L levels significantly correlated with sP-selectin (P < 0.001), prothrombin fragment 1 + 2 (P < 0.001), or thrombin-antithrombin III complex (P < 0.05) in squamous lung cancer, but only sP-selectin (P = 0.011) was independently related to sCD40L. CONCLUSIONS: These findings indicate that elevated sCD40L levels can be preferentially found in patients with advanced squamous cancer and provide evidence that increased levels of this cytokine are associated to the occurrence of in vivo platelet activation.

Adenocarcinoma↗
PubMed2004

Recombinant activated factor VII therapy in acquired hemophilia of the elderly.

Acquired hemophilia is a life-threatening condition associated with a high mortality, occurring mainly in elderly patients. We report on a 92-year-old male, administered two courses of 90 microg kg(-1) of recombinant activated factor VII (rFVIIa) due to failure of human factor VIII (FVIII) therapy, without side effects nor evidence of thrombotic complications. Despite the bleeding being completely under control, the patient died on day 11 of acute respiratory failure due to pneumonia. This case confirms previous reports on the complexity and severity of this disorder, showing that rFVIIa is an effective and safe agent for achieving hemostasis even in elderly patients with a FVIII inhibitor.

Aged↗
PubMed2004

Inflammation, insulin resistance, and obesity.

Obesity, in particular visceral obesity, has strong associations with cardiovascular disease and is related to many factors that are constituents of the metabolic syndrome. Increasing evidence suggests that features of the metabolic syndrome, including visceral obesity, are associated with a low-grade inflammatory state. Indeed, visceral fat is a source of several molecules, such as leptin, adiponectin, tumor necrosis factor-alpha, and interleukin 6, that are collectively called adipokines. All of them may induce a proinflammatory state and oxidative damage, leading to initiation and progression of atherosclerosis. Reduced-energy diets might represent an effective and healthful approach for long-term weight loss in patients with metabolic syndrome by reducing the underlying inflammatory condition.

Arteriosclerosis↗
PubMed2004

Determinants of F2-isoprostane biosynthesis and inhibition in man.

Several cardiovascular risk factors are characterized by the coexistence of low-grade inflammation, enhanced oxidative stress and lipid peroxidation. It has been hypothesized that F2-isoprostanes, a product of in vivo lipid peroxidation, may transduce the effects of metabolic and hemodynamic abnormalities into increased cardiovascular risk. Thus, the formation of these compounds, including urinary 8-iso-Prostaglandin (PG) F2alpha, has been investigated in clinical settings putatively associated with oxidant stress. Enhanced lipid peroxidation together with increased in vivo platelet activation have been found in association with the major cardiovascular risk factors. Thus, F2-isoprostanes may transduce the effects of oxidant stress associated with complex metabolic disorders into specialized forms of cellular activation. In particular, the low-grade inflammatory state characterizing metabolic disorders such as obesity, hypercholesterolemia, type 2 diabetes mellitus, and homozygous homocystinuria may be the primary trigger of thromboxane-dependent platelet activation mediated, at least in part, through enhanced lipid peroxidation. Moreover, oxidative stress may promote endothelial dysfunction through increased production of reactive oxygen species that inactivate nitric oxide. Accumulation and activation of leukocytes plays a key role in atherosclerosis and its complications. Interestingly, neutrophil adhesion induced by minimally modified low-density lipoproteins is mainly mediated by F2-isoprostanes. Although epidemiological studies suggest an inverse relationship between antioxidant vitamin intake and cardiovascular disease, several clinical trials have obtained conflicting results on the effects of vitamin E supplementation on the risk of cardiovascular events. On the other hand, the use of F2-isoprostane formation as a biochemical end-point for dose-finding studies of vitamin E supplementation has helped clarifying the unique features of its pharmacodynamic effects on lipid peroxidation. This information could be extremely valuable in the selection of the appropriate patient subgroups that may benefit from antioxidant interventions.

Antioxidants↗
PubMed2004

Oxidant stress and platelet activation in hypercholesterolemia.

Hypercholesterolemia is the dominant risk factor associated with atherothrombotic disorders in the western world. Consequently, much attention has been devoted to defining its role in the pathogenesis of atherosclerosis. It is currently recognized that hypercholesterolemia induces phenotypic changes in the microcirculation that are consistent with oxidative and nitrosative stresses. Superoxide is generated via several cellular systems and, once formed, participates in a number of reactions, yielding various free radicals, such as hydrogen peroxide, peroxynitrite, or oxidized low-density lipoproteins. Once oxidant stress is invoked, characteristic pathophysiologic features ensue, such as platelet activation and lipid peroxidation, which are both involved in the initiation and progression of the atherosclerotic lesions. Thus, therapeutic strategies that act to maintain the normal balance in the oxidant status of the vascular bed may prove effective in reducing the deleterious consequences of hypercholesterolemia.

Antioxidants↗
PubMed2004

[New insights in the pathogenesis of prothrombotic state associated with hypercholesterolemia].

Hypercholesterolemia and overt atherosclerotic disorders have been associated with a low-grade inflammation that involves not only the intrinsic cells of the artery wall, but also circulating cells. Platelets as well as monocytes participate importantly in this disease process through the release of a wide variety of biologically active substances. Recent findings on the inflammatory actions of platelets have opened new perspectives in the comprehension of the pathogenetic mechanism(s) of atherosclerosis. Stimulated platelets, in fact, actively synthesize proinflammatory cytokines which have been all involved in the inflammatory process associated to hypercholesterolemia and plaque development. In this context, increasing evidence suggests that interrelated inhibition of inflammation and thrombosis induced by statins could largely contribute to clinical benefits from lipid-lowering therapy.

Arteriosclerosis↗
PubMed2003

Enhanced lipid peroxidation and platelet activation in the early phase of type 1 diabetes mellitus: role of interleukin-6 and disease duration.

BACKGROUND: To investigate early events possibly related to the development of diabetic angiopathy, we examined whether 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) formation, a marker of in vivo oxidant stress, is altered in different stages of type 1 diabetes (T1DM) and whether it correlates with the rate of thromboxane (TX) A2 biosynthesis, a marker of in vivo platelet activation. We also investigated the relationship between inflammatory markers and F2-isoprostane formation in this setting. METHODS AND RESULTS: A cross-sectional study was performed in 23 insulin-treated patients aged <18 years with new-onset T1DM ( 1 year, group B). Urinary 8-iso-PGF2alpha and 11-dehydro-TXB2 were measured in all patients and in age- and gender-matched controls. Circulating interleukin-6 (IL-6), tumor necrosis factor-alpha, and C-reactive protein were also determined as markers of the inflammatory response. Fifteen of the 23 children in group A were reexamined after 12 months. Compared with either controls or group B, diabetic children in group A showed significantly higher levels of 8-iso-PGF2alpha, 11-dehydro-TXB2, IL-6, tumor necrosis factor-alpha, and C-reactive protein. Statistically significant correlations between IL-6 and both 8-iso-PGF2alpha (r=0.63, P<0.001) and 11-dehydro-TXB2 (r=0.51, P<0.01) were observed. The 15 patients reexamined after 1 year showed a significant reduction in lipid peroxidation and platelet activation (P<0.02 and P<0.001, respectively), consistent with reduced levels of IL-6 and tumor necrosis factor-alpha. CONCLUSIONS: These results demonstrate that enhanced lipid peroxidation and platelet activation represent early events in T1DM that are possibly related to an acute inflammatory response. These noninvasive indexes may help in further examining T1DM pathophysiology and monitoring pharmacological interventions to interfere with disease development and progression.

Adolescent↗
PubMed2003

Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus.

OBJECTIVES: The aim of our study was to assess whether acute, short-term hyperglycemia affects platelet reactivity in patients with Type II diabetes mellitus (T2DM). BACKGROUND: Hyperglycemic spikes are thought to precipitate ischemic events in T2DM. Previous studies have shown in vivo platelet activation in diabetes; however, no studies have assessed whether acute in vivo hyperglycemia induces further activation of platelets. METHODS: In a cross-over, randomized, double-blind study, 12 patients with T2DM underwent 4 h of either acute hyperglycemia (13.9 mmol/l, 250 mg/dl) or euglycemia (5.5 mmol/l, 100 mg/dl). Shear stress-induced platelet activation, P-selectin and lysosomal integral membrane protein (LIMP) expression on platelets in the bleeding-time blood, urinary 11-dehydro-thromboxane B(2) (TxB(2)) excretion, von Willebrand factor:antigen (vWF:Ag), and von Willebrand factor:activity (vWF:activity) were measured before and after hyperglycemia or euglycemia. RESULTS: Shear stress-induced platelet activation, P-selectin and LIMP expression on platelets in the bleeding-time blood, and urinary 11-dehydro-TxB(2) excretion increased significantly after hyperglycemic clamping, whereas no changes were observed after euglycemic clamping. Plasma vWF:Ag and vWF:activity increased strikingly in parallel fashion after hyperglycemic clamping, whereas no changes were observed after euglycemic clamping. CONCLUSIONS: Our data demonstrate that acute, short-term hyperglycemia induces an increased activation of platelets exposed to high shear stress conditions in vitro (filtration method) or in vivo (bleeding time). In vivo platelet activation is reflected by an increased urinary excretion of 11-dehydro-TxB(2). The increased levels of vWF in the circulation correlate with the increase in platelet activation markers and may indicate some degree of causation. Acute, short-term hyperglycemia in T2DM may precipitate vascular occlusions by facilitating platelet activation.

Acute Disease↗