Publications (50)400.5 Total impact
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Article: NMR spectroscopy metabolomic profiling of exhaled breath condensate in patients with stable and unstable cystic fibrosis.
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ABSTRACT: Metabolomics could provide new insights into the pathophysiology of cystic fibrosis (CF) by identifying profiles of endogenous metabolites. To investigate whether metabolomics of exhaled breath condensate could discriminate between patients with unstable CF, stable CF and healthy subjects, and whether selected metabolites were responsible for between-group differences. Twenty-nine patients with stable CF, 24 with unstable CF and 31 healthy subjects (age 9-24 years) participated in a cross-sectional study. Metabolomics was performed with high-resolution nuclear magnetic resonance spectroscopy. Partial least squares-discriminant analysis was used as classifier. The results were validated in a second independent study. Intraclass correlation coefficients for between-day and technical repeatability were 0.93 and 0.96, respectively. Bland-Altman analysis showed good within-day repeatability. Correct classification rate of CF (n=53) vs. healthy subjects (n=31) was 96% (R2=0.84; Q2=0.79). Model validation with a testing sample set obtained from subjects not included in the primary analysis (23 CF and 25 healthy subjects) showed a sensitivity of 91% and a specificity of 96%. The classification rate of stable CF (n=29) vs. unstable CF patients (n=24) was 95% (R2=0.82; Q2=0.78). Model external validation in 14 patients with stable CF and 16 with unstable CF showed a sensitivity of 86% and a specificity of 94%. Ethanol, acetate, 2-propanol and acetone were most discriminant between patients with CF and healthy subjects, whereas acetate, ethanol, 2-propanol and methanol were the most important metabolites for discriminating between patients with stable and unstable CF. Nuclear magnetic resonance spectroscopy of exhaled breath condensate is reproducible, discriminates patients with CF from healthy subjects and patients with unstable CF from those with stable CF, and identifies the metabolites responsible for between-group differences.Thorax 11/2011; 67(3):222-8. · 6.84 Impact Factor -
Article: Effects of atorvastatin and rosuvastatin on thromboxane-dependent platelet activation and oxidative stress in hypercholesterolemia.
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ABSTRACT: We examined the time-dependent effects of atorvastatin and rosuvastatin on in vivo oxidative stress and platelet activation, to assess whether these phenomena are related to any pleiotropic effect of any statin or to their LDL-lowering effect. We also asked whether the presence of specific allele frequencies in carriers of the 3'UTR/lectin-like oxidized LDL receptor-1 (LOX-1) polymorphism may influence the effect of either statin. We included 60 hypercholesterolemic subjects, previously screened for LOX-1 3'UTR polymorphism, randomized, according to genetic profile (15 T and 15 C carriers for each arm), to atorvastatin 20mg/day or rosuvastatin 10mg/day. After 8 weeks, atorvastatin and rosuvastatin were associated with comparable, significant reductions in LDL cholesterol (40.8% and 43.6%, respectively), plasma hs-CRP (9.5% vs. 13.8%), urinary 11-dehydro-thromboxane (TX) B(2) (38.9% vs. 27.1%) and 8-iso-prostaglandin (PG) F(2α) (39.4% vs. 19.4%). The impact of rosuvastatin or atorvastatin on CRP, 8-iso-PGF(2α), and 11-dehydro-TXB(2) did not differ according to the LOX-1 haplotype. On multiple regression analyses, only CRP and LDL were independent predictors of 11-dehydro-TXB(2), and only LDL was a significant predictor of 8-iso-PGF(2α). Both atorvastatin and rosuvastatin cause comparable reductions of thromboxane-dependent platelet activation, lipid peroxidation and inflammation. The presence of 3'UTR/LOX-1 polymorphism does not affect the changes induced by either statin.Atherosclerosis 11/2010; 214(1):122-8. · 3.79 Impact Factor -
Article: Determinants of thromboxane biosynthesis in rheumatoid arthritis: Role of RAGE and oxidant stress.
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ABSTRACT: Thromboxane (TX) biosynthesis by platelets and other cells in response to inflammatory triggers may provide a link between chronic inflammatory disease and atherothrombosis in rheumatoid arthritis (RA). In this study, we investigated the determinants of TX biosynthesis in RA, with particular reference to enhanced oxidative stress, receptor for advanced glycation end-products (RAGE) hyperactivity, and anti-tumor necrosis factor (TNF) treatment. Fifty-four patients with RA and 20 healthy subjects were recruited and a cross-sectional comparison of urinary 11-dehydro-TXB(2), 8-iso-PGF(2alpha), and plasma endogenous secretory RAGE (esRAGE) levels was performed between patients and controls. Urinary 11-dehydro-TXB(2) was significantly higher in RA patients than in healthy controls [425 (309-592) vs 233 (158-327) pg/mg creatinine, P<0.0001]. Furthermore, urinary 8-iso-PGF(2alpha) [323 (221-515) vs 172 (91-292) pg/mg creatinine, P<0.0001] and plasma esRAGE [155 (100-240) vs 377 (195-486) pg/ml, P=0.001] were higher and lower, respectively, in patients than in controls. A direct correlation was found between urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) only in patients not on anti-TNF therapy (r=0.420, P=0.021). Conversely, patients on anti-TNF therapy showed significantly lower urinary 8-iso-PGF(2alpha) [284 (201-373) vs 404 (241-539) pg/mg creatinine, P=0.043] but not 11-dehydro-TXB(2) than anti-TNF-treated subjects, with esRAGE as the only independent predictor of 11-dehydro-TXB(2) in this group of patients (adjusted R(2)=0.496, beta=-0.725, SEM=0.025, P=0.001). In conclusion, we provide biochemical evidence of enhanced TX biosynthesis in patients with RA, driven, at least in part, by lipid peroxidation. Treatment with anti-TNF agents may blunt isoprostane generation in the absence of significant effects on TX biosynthesis. We suggest that RAGE hyperactivity may escape TNF blockade, thus contributing to persistent TX biosynthesis in this setting.Free radical biology & medicine 09/2010; 49(5):857-64. · 5.42 Impact Factor -
Article: Diagnostic performance of an electronic nose, fractional exhaled nitric oxide, and lung function testing in asthma.
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ABSTRACT: Analysis of exhaled breath by biosensors discriminates between patients with asthma and healthy subjects. An electronic nose consists of a chemical sensor array for the detection of volatile organic compounds (VOCs) and an algorithm for pattern recognition. We compared the diagnostic performance of a prototype of an electronic nose with lung function tests and fractional exhaled nitric oxide (FENO) in patients with atopic asthma. A cross-sectional study was undertaken in 27 patients with intermittent and persistent mild asthma and in 24 healthy subjects. Two procedures for collecting exhaled breath were followed to study the differences between total and alveolar air. Seven patients with asthma and seven healthy subjects participated in a study with mass spectrometry (MS) fingerprinting as an independent technique for assessing between group discrimination. Classification was based on principal component analysis and a feed-forward neural network. The best results were obtained when the electronic nose analysis was performed on alveolar air. Diagnostic performance for electronic nose, FENO, and lung function testing was 87.5%, 79.2%, and 70.8%, respectively. The combination of electronic nose and FENO had the highest diagnostic performance for asthma (95.8%). MS fingerprints of VOCs could discriminate between patients with asthma and healthy subjects. The electronic nose has a high diagnostic performance that can be increased when combined with FENO. Large studies are now required to definitively establish the diagnostic performance of the electronic nose. Whether this integrated noninvasive approach will translate into an early diagnosis of asthma has to be clarified. Trial registration: EUDRACT https://eudralink.emea.europa.eu; Identifier: 2007-000890-51; and clinicaltrials.gov; Identifier: NCT00819676.Chest 04/2010; 137(4):790-6. · 5.25 Impact Factor -
Article: Measurement of 8-isoprostane in exhaled breath condensate.
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ABSTRACT: Oxidative stress is functionally involved in the pathophysiology of lung diseases including asthma and chronic obstructive pulmonary disease. 8-Isoprostane, which is derived from free radical-catalyzed peroxidation of arachidonic acid, is one of the most reliable biomarkers of oxidative stress. Exhaled breath condensate (EBC) is a completely noninvasive method for collecting airway secretions. We developed a specific and sensitive radioimmunoassay (RIA) that has been applied to the measurement of 8-isoprostane in EBC. This RIA for 8-isoprostane has been validated using high performance liquid chromatography. Measurement of 8-isoprostane in EBC is a useful noninvasive technique for exploring the role of oxidative stress in lung diseases. This technique might provide important insights into the understanding of the clinical pharmacology of antioxidants and might be useful for monitoring the effects of pharmacological therapy.Methods in molecular biology (Clifton, N.J.) 01/2010; 594:73-84. -
Article: The contribution of cyclooxygenase-1 and -2 to persistent thromboxane biosynthesis in aspirin-treated essential thrombocythemia: implications for antiplatelet therapy.
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ABSTRACT: We tested whether cyclooxygenase 2 (COX-2) expression and unacetylated COX-1 in newly formed platelets might contribute to persistent thromboxane (TX) biosynthesis in aspirin-treated essential thrombocythemia (ET). Forty-one patients on chronic aspirin (100 mg/day) and 24 healthy subjects were studied. Platelet COX-2 expression was significantly increased in patients and correlated with thiazole orange-positive platelets (r = 0.71, P < .001). The rate of TXA(2) biosynthesis in vivo, as reflected by urinary 11-dehydro-TXB(2) (TXM) excretion, and the maximal biosynthetic capacity of platelets, as reflected by serum TXB(2), were higher in patients compared with aspirin-treated healthy volunteers. Serum TXB(2) was significantly reduced by the selective COX-2 inhibitor NS-398 added in vitro. Patients were randomized to adding the selective COX-2 inhibitor, etoricoxib, or continuing aspirin for 7 days. Etoricoxib significantly reduced by approximately 25% TXM excretion and serum TXB(2). Fourteen of the 41 patients were studied again 21 (+/- 7) months after the first visit. Serum TXB(2) was consistently reduced by approximately 30% by adding NS398 in vitro, while it was completely suppressed with 50 microM aspirin. Accelerated platelet regeneration in most aspirin-treated ET patients may explain aspirin-persistent TXA(2) biosynthesis through enhanced COX-2 activity and faster renewal of unacetylated COX-1. These findings may help in reassessing the optimal antiplatelet strategy in ET.Blood 11/2009; 115(5):1054-61. · 9.90 Impact Factor -
Article: Soluble CD40L in Mediterranean Spotted Fever: relation to oxidative stress and platelet activation.
Thrombosis Research 08/2009; 125(4):362-4. · 2.44 Impact Factor -
Article: Acute effects of air pollution on pulmonary function, airway inflammation, and oxidative stress in asthmatic children.
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ABSTRACT: Air pollution is associated with respiratory symptoms, lung function decrements, and hospitalizations. However, there is little information about the influence of air pollution on lung injury. In this study we investigated acute effects of air pollution on pulmonary function and airway oxidative stress and inflammation in asthmatic children. We studied 182 children with asthma, 9-14 years of age, for 4 weeks. Daily ambient concentrations of sulfur dioxide, nitrogen dioxide, ozone, and particulate matter < or = 2.5 microm in aerodynamic diameter (PM(2.5)) were monitored from two stations. Once a week we measured spirometry and fractional exhaled nitric oxide (FeNO), and determined thiobarbituric acid reactive substances (TBARS) and 8-isoprostane--two oxidative stress markers--and interleukin-6 (IL-6) in breath condensate. We tested associations using mixed-effects regression models, adjusting for confounding variables. Interquartile-range increases in 3-day average SO2 (5.4 ppb), NO2 (6.8 ppb), and PM(2.5) (5.4 microg/m3) were associated with decreases in forced expiratory flow between 25% and 75% of forced vital capacity, with changes being -3.1% [95% confidence interval (CI), -5.8 to -0.3], -2.8% (95% CI, -4.8 to -0.8), and -3.0% (95% CI, -4.7 to -1.2), respectively. SO2, NO2, and PM(2.5) were associated with increases in TBARS, with changes being 36.2% (95% CI, 15.7 to 57.2), 21.8% (95% CI, 8.2 to 36.0), and 24.8% (95% CI, 10.8 to 39.4), respectively. Risk estimates appear to be larger in children not taking corticosteroids than in children taking corticosteroids. O3 (5.3 ppb) was not associated with health end points. FeNO, 8-isoprostane, and IL-6 were not associated with air pollutants. Air pollution may increase airway oxidative stress and decrease small airway function of asthmatic children. Inhaled corticosteroids may reduce oxidative stress and improve airway function.Environmental Health Perspectives 05/2009; 117(4):668-74. · 7.04 Impact Factor -
Article: Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin "resistance".
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ABSTRACT: This study was conducted to assess the thromboxane (TX) dependence of biochemical and functional indexes used to monitor the effect of low-dose aspirin. Functional assays of the antiplatelet effects of low-dose aspirin variably reflect the TX-dependent component of platelet aggregation. Previous studies of aspirin resistance were typically based on a single determination of platelet aggregation. We assessed the TXB(2) dependence of biochemical and functional indexes, as well as their intersubject and intrasubject variability during administration of the drug and after its withdrawal in 48 healthy volunteers randomized to receive aspirin 100 mg daily for 1 to 8 weeks. Serum TXB(2) was uniformly suppressed by 99% of baseline. Urinary 11-dehydro-TXB(2), arachidonic acid-induced aggregation, and VerifyNow Aspirin (Accumetrics Inc., San Diego, California) showed stable, incomplete inhibition (65%, 80%, and 35%, respectively). Adenosine diphosphate- and collagen-induced aggregation was highly variable and poorly affected by aspirin, with an apparent time-dependent reversal. Inhibition of platelet cyclooxygenase activity was nonlinearly related to inhibition of platelet aggregation. Platelet function largely recovered by day 3 post-aspirin, independently of treatment duration. With any functional assay, occasionally "resistant" subjects were found to be "responders" on previous or subsequent determinations. Platelet cyclooxygenase activity, as reflected by serum TXB(2) levels, is uniformly and persistently suppressed by low-dose aspirin in healthy subjects. However, the effect of aspirin is variably detected by functional assays, potentially leading to misclassification of "responder" as "resistant" phenotypes owing to poor reproducibility of functional measurements. The nonlinearity of the relationship between inhibition of TX production and inhibition of platelet function has important clinical implications.Journal of the American College of Cardiology 03/2009; 53(8):667-77. · 14.16 Impact Factor -
Article: Determinants of platelet activation in hypertensives with microalbuminuria.
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ABSTRACT: Microalbuminuria is a predictor of adverse outcome in hypertension. We evaluated in vivo platelet activation, by urinary 11-dehydro-thromboxane (TX)B(2) and plasma P-selectin, in hypertensives with or without microalbuminuria, and its possible association with oxidative stress, by urinary 8-iso-prostaglandin (PG)F(2a) and endothelial dysfunction. Sixty essential hypertensive patients with (n=30) or without (n=30) microalbuminuria, and 30 controls were studied. Endothelial function was assessed by nitric oxide products, intercellular adhesion molecule (ICAM)-1 and asymmetric dimethylarginine (ADMA) levels. Urinary 11-dehydro-TXB(2) excretion was higher in microalbuminuric (median 805 pg/mg creatinine) compared to non-microalbuminuric patients or controls (414 and 291 pg/mg, respectively; p<0.0001). Plasma P-selectin was significantly higher in patients with microalbuminuria (median 136 ng/ml) as compared to those without microalbuminuria or controls (85 and 65 ng/ml; p<0.0001). Urinary 8-iso-PGF(2a) excretion was also enhanced in microalbuminuric (median 279 pg/mg creatinine) compared to non-microalbuminuric patients or controls (157 and 146 pg/mg, respectively; p<0.0001). A significant impairment in endothelial function was found in microalbuminuric patients, with decreased nitric oxide and increased ICAM-1 and ADMA levels. Multivariate regression analysis showed that urinary 8-iso-PGF(2a) excretion (beta=0.49; p<0.0001) and microalbuminuria (beta=0.36; p<0.001) were independently related to 11-dehydro-TXB(2) in hypertensives. Vitamin E supplementation (900 mg daily for 1 month) in 10 hypertensives with microalbuminuria was associated with normalization in median 11-dehydro-TXB(2) and 8-iso-PGF(2a). We conclude that lipid peroxidation is a major determinant of persistent platelet activation in hypertensive patients with microalbuminuria.Free radical biology & medicine 01/2009; · 5.42 Impact Factor -
Article: Exhaled 8-isoprostane and prostaglandin E(2) in patients with stable and unstable cystic fibrosis.
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ABSTRACT: We measured 8-isoprostane, a biomarker of oxidative stress, and prostaglandin (PG) E(2) in exhaled breath condensate in 36 stable and 14 unstable cystic fibrosis (CF) patients, and in 15 healthy age-matched controls. We studied the relationships of these eicosanoids with clinical, radiological, and systemic inflammatory parameters. Compared with controls [15.5 (11.5-17.0) pg/ml] exhaled 8-isoprostane was increased in stable CF patients [30.5 (25.3-36.0) pg/ml, P<0.001]. Unstable CF patients had higher exhaled 8-isoprostane levels [47.5 (44.0-50.0) pg/ml, P<0.001] than stable CF patients. Unlike PGE(2), exhaled 8-isoprostane was negatively correlated with FEV(1) (r=-0.67; P<0.0001; r=-0.63; P<0.02) and Shwachman score (r=-0.43, P=0.012; r=-0.58, P=0.031) and positively correlated with Chrispin-Norman score (r=0.51, P<0.002; r=0.56, P=0.039) in stable and unstable CF patients, respectively. No correlation was observed with C-reactive protein. Compared with controls [41.0 (29.0-50.0) pg/ml], exhaled PGE(2) was also elevated in stable [72.0 (64.3-81.8) pg/ml, P<0.001) and, to a greater extent, in unstable CF patients [83.0 (74.3-91.3) pg/ml, P<0.001). In patients with CF, exhaled 8-isoprostane and PGE(2) could be a useful marker of disease severity.Free Radical Biology and Medicine 09/2008; 45(6):913-9. · 5.42 Impact Factor -
Article: 8-Isoprostane in exhaled breath condensate and exercise-induced bronchoconstriction in asthmatic children and adolescents.
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ABSTRACT: Exercise-induced bronchoconstriction (EIB) in the asthmatic child is associated with persistent airway inflammation and poor disease control. EIB could arise partly from airway oxidative stress. Exhaled breath condensate (EBC) levels of 8-isoprostane (IsoP), which is a known marker of oxidative stress, might therefore be helpful for monitoring asthma noninvasively. We recruited 46 asthmatic children and adolescents 6 to 17 years of age (29 boys), all of whom underwent lung function testing, measurement of the fractional concentration of exhaled nitric oxide (FENO), and collection of EBCs for 8-IsoP measurement before and after exercise challenge. FENO was measured before exercise and 5 min and 20 min after exercise. Spirometry was repeated 1, 5, 10, 15, and 20 min after exercise. Baseline 8-IsoP levels (but not baseline FENO levels) correlated with the fall in FEV(1) 5 min after exercise (r = - 0.47; p = 0.002). 8-IsoP levels measured after exercise remained unchanged from baseline levels; conversely, FENO levels decreased in parallel with the decline in FEV(1) at 5 min (r = 0.44; p = 0.002). The mean baseline 8-IsoP concentrations were higher in patients with EIB (n = 12) than in those without EIB (n = 34; 44.9 pg/mL [95% confidence interval (CI), 38.3 to 51.5] vs 32.3 pg/mL [95% CI, 27.6 to 37.0], respectively; p < 0.01). No difference was found in the mean baseline FENO between groups (with EIB group: 38.7 ppb; 95% CI, 24.5 to 61.1; without EIB group: 29.1 ppb; 95% CI, 22.0 to 38.4). Increased 8-IsoP concentrations in EBC samples of asthmatic children and adolescents with EIB suggest a role for oxidative stress in bronchial hyperreactivity.Chest 09/2008; 135(1):66-73. · 5.25 Impact Factor -
Article: Effects of montelukast treatment and withdrawal on fractional exhaled nitric oxide and lung function in children with asthma.
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ABSTRACT: Leukotriene receptor antagonists (LTRAs) reduce fractional exhaled nitric oxide (Feno) concentrations in children with asthma, but the effect of LTRA withdrawal on Feno and lung function is unknown. We aimed to study the effect of treatment and withdrawal of montelukast, a LTRA, on airway inflammation as reflected by Feno and lung function in children with asthma. A double-blind, randomized, placebo controlled, parallel group study was undertaken in 14 atopic children with mild persistent asthma who were treated with oral montelukast (5 mg/d for 4 weeks) and 12 atopic children with mild persistent asthma who received matching placebo. A follow-up visit was performed 2 weeks after montelukast or placebo withdrawal. Montelukast reduced Feno concentrations by 17% (p = 0.067), an effect that was more pronounced (35%) [p = 0.0029] when children with seasonal atopy who were exposed to relevant allergens during the treatment phase were excluded from analysis (n = 3). Compared to those at the end of treatment, Feno concentrations were increased 2 weeks after montelukast withdrawal (p = 0.023) concomitant with a reduction in absolute FEV(1) values (p = 0.011), FEV(1) percentage of predicted values (p = 0.006), FEV(1)/FVC ratio (p = 0.002), and forced expiratory flow at 25% to 75% of FVC values (p = 0.021). These changes were not observed in the placebo group. LTRAs reduce Feno concentrations in children with asthma, and withdrawal can result in increased Feno values and worsening of lung function in children with asthma.Chest 01/2008; 132(6):1876-81. · 5.25 Impact Factor -
Article: Decreased plasma soluble RAGE in patients with hypercholesterolemia: effects of statins.
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ABSTRACT: The receptor for advanced glycation endproducts (RAGE) is overexpressed at sites of vascular pathology. A soluble RAGE isoform (sRAGE) neutralizes the ligand-mediated damage by acting as a decoy. We hypothesized that in hypercholesterolemia up-regulation of the ligand-RAGE axis may bridge impairment of nitric oxide biosynthesis with oxidative stress. We measured in 60 hypercholesterolemic patients and 20 controls plasma total sRAGE levels, urinary 8-iso-prostaglandin (PG) F(2alpha) excretion, and plasma levels of asymmetric dimethylarginine (ADMA). The effects of two structurally different statins (pravastatin and atorvastatin) on these parameters were analyzed in 20 hypercholesterolemic subjects free of vascular disease. Plasma sRAGE was significantly lower, ADMA and urinary 8-iso-PGF(2alpha) were higher, in hypercholesterolemic versus normocholesterolemic patients. Patients on statin treatment with previous myocardial infarction had lower 8-iso-PGF(2alpha), higher sRAGE, and unchanged ADMA levels compared to subjects free of vascular disease. On multivariate regression analysis only 8-iso-PGF(2alpha) and ADMA predicted sRAGE levels. An 8-week treatment with either statin was associated with a significant reduction in urinary 8-iso-PGF(2alpha), whereas only atorvastatin raised sRAGE levels near to normal values, with no change in ADMA levels. sRAGE might serve as an endogenous protecting factor for accelerated atherosclerosis mediated by oxidative stress and endothelial dysfunction in hypercholesterolemia.Free Radical Biology and Medicine 12/2007; 43(9):1255-62. · 5.42 Impact Factor -
Article: Expression and activity of cyclooxygenase isoforms in skeletal muscles and myocardium of humans and rodents.
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ABSTRACT: Conflicting data have been reported on cyclooxygenase (COX)-1 and COX-2 expression and activity in striated muscles, including skeletal muscles and myocardium, in particular it is still unclear whether muscle cells are able to produce prostaglandins (PGs). We characterized the expression and enzymatic activity of COX-1 and COX-2 in the skeletal muscles and in the myocardium of mice, rats and humans. By RT-PCR, COX-1 and COX-2 mRNAs were observed in homogenates of mouse and rat hearts, and in different types of skeletal muscles from all different species. By Western blotting, COX-1 and -2 proteins were detected in skeletal muscles and hearts from rodents, as well as in skeletal muscles from humans. Immunoperoxidase stains showed that COX-1 and -2 were diffusely expressed in the myocytes of different muscles and in the myocardiocytes from all different species. In the presence of arachidonic acid, which is the COX enzymatic substrate, isolated skeletal muscle and heart samples from rodents released predominantly PGE(2). The biosynthesis of PGE(2) was reduced between 50 and 80% (P < 0.05 vs. vehicle) in the presence of either COX-1- or COX-2-selective blockers, demonstrating that both isoforms are enzymatically active. Exogenous PGE(2) added to isolated skeletal muscle preparations from rodents did not affect contraction, whereas it significantly fastened relaxation of a slow type muscle, such as soleus. In conclusion, COX-1 and COX-2 are expressed and enzymatically active in myocytes of skeletal muscles and hearts of rodents and humans. PGE(2) appears to be the main product of COX activity in striated muscles.Journal of Applied Physiology 10/2007; 103(4):1412-8. · 3.75 Impact Factor -
Article: Soluble RAGE in type 2 diabetes: association with oxidative stress.
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ABSTRACT: Advanced glycation end products (AGEs) contribute to diabetic vascular complications by engaging the AGE receptor (RAGE). A soluble RAGE form (sRAGE) acts as a decoy domain receptor, thus decreasing AGE cellular binding. A cross-sectional comparison of sRAGE, asymmetric dimethylarginine (ADMA) plasma levels (index of endothelial dysfunction), and urinary 8-iso-prostaglandin (PG)F(2alpha) (marker of oxidative stress) was performed between 86 diabetic patients and 43 controls. Plasma sRAGE levels were significantly lower and ADMA levels were significantly higher in diabetic patients as compared to controls (P<0.0001). HbA1c and urinary 8-iso-PGF(2alpha) were correlated inversely with sRAGE and directly with ADMA. On multivariate analysis HbA1c was independently related to sRAGE levels in diabetic patients. Twenty-four of 86 patients with newly diagnosed diabetes and 12 patients in poor metabolic control were reevaluated after treatment with a hypoglycemic agent or insulin, respectively. Improvement in metabolic control by oral agents or insulin resulted in a significant increase in sRAGE and decrease in ADMA levels (P<0.0001). Thus, poor glycemic control reduces sRAGE levels, in association with enhanced oxidative stress and endothelial dysfunction in diabetes. These abnormalities are susceptible to modulation by improvement in metabolic control.Free Radical Biology and Medicine 09/2007; 43(4):511-8. · 5.42 Impact Factor -
Article: Endothelial dysfunction in patients with spontaneous venous thromboembolism.
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ABSTRACT: A high incidence of atherosclerotic lesions and cardiovascular events has been reported in patients with spontaneous venous thromboembolism. Endothelial dysfunction is an early marker of atherosclerosis and has predictive value for ischemic events. We have evaluated endothelial function in patients with a history of spontaneous venous thromboembolism. Patients with a history of symptomatic, objectively confirmed, spontaneous venous thromboembolism were included in a case-control study. Exclusion criteria were any known risk factors for cardiovascular diseases, other conditions associated with endothelial dysfunction, estro-progestinic therapy or pregnancy. Controls were age- (+/-5 years) and sex-matched subjects with the same exclusion criteria but without previous venous thromboembolism. Endothelial function was evaluated by the non-invasive measurement of flow-mediated vasodilation of the brachial artery and of plasma markers of endothelium activation; platelet activation parameters were also measured. Twenty-eight cases (8 females; mean age 59+/-15 years) and 28 controls (8 females; mean age 58+/-15) were studied. Flow-mediated vasodilation was 3.5+/-0.6% in cases (95% CIs: 2.2 to 4.8) and 5.7+/-0.6% (4.2 to 6.8) in controls (p=0.015). Brachial artery blood flow and hyperemic blood flow did not differ between the two groups. Plasma von Willebrand factor and soluble P-selectin levels were significantly higher in patients with venous thromboembolism, while plasma soluble CD40 ligand and urinary 11-dehydro-TxB2 levels were similar in cases and controls. Patients with spontaneous venous thromboembolism have endothelial dysfunction, unlike age- and sex- matched controls. This finding suggests that spontaneous venous thromboembolism may be a condition associated with an enhanced risk of atherosclerosis.Haematologica 07/2007; 92(6):812-8. · 6.42 Impact Factor -
Article: Determinants of platelet activation in Alzheimer's disease.
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ABSTRACT: To investigate the rate of platelet thromboxane (TX) biosynthesis and its determinants in Alzheimer's disease. 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. 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.Neurobiology of aging 03/2007; 28(3):336-42. · 5.94 Impact Factor -
Article: Eicosanoid Biosynthesis and Metabolism in Myeloproliferative Disordersa
Annals of the New York Academy of Sciences 12/2006; 744(1):229 - 236. · 3.15 Impact Factor -
Article: Insulin resistance as a determinant of platelet activation in obese women.
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ABSTRACT: We tested the hypothesis that insulin resistance, per se, contributes to increased platelet activation in obesity, independently of underlying inflammation. 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. 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. 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. Insulin resistance is a major determinant of platelet activation in female obesity.Journal of the American College of Cardiology 12/2006; 48(12):2531-8. · 14.16 Impact Factor
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Institutions
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2010
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Università degli Studi di Siena
Siena, Tuscany, Italy
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2002–2010
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Università degli Studi G. d'Annunzio Chieti e Pescara
Chieti, Abruzzo, Italy -
Accademia di Agricoltura di Torino
Torino, Piedmont, Italy
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2008
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Ospedale Pediatrico Bambino Gesù
Roma, Latium, Italy
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2006–2008
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Sapienza University of Rome
Roma, Latium, Italy -
Sacred Heart University
Fairfield, CT, USA
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2004
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Istituto Dermopatico dell'Immacolata
Roma, Latium, Italy
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2003
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University-Hospital of Padova
Padova, Veneto, Italy
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