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Community-acquired pneumonia (CAP) is complicated by cardiovascular events as myocardial infarction and stroke but the underlying mechanism is still unclear. We hypothesized that endothelial dysfunction may be implicated and that endotoxemia may have a role.Fifty patients with CAP and 50 controls were enrolled. At admission and at discharge, flow-mediated dilation (FMD), serum levels of endotoxins and oxidative stress, as assessed by serum levels of nitrite/nitrate (NOx) and isoprostanes, were studied.At admission, a significant difference between patients with CAP and controls was observed for FMD (2.1±0.3 vs 4.0±0.3%, p0.001), serum endotoxins (157.8±7.6 vs 33.1±4.8pg/ml), serum isoprostanes (341±14 vs 286±10 pM, p=0.009) and NOx (24.3±1.1 vs 29.7±2.2μM). Simple linear correlation analysis showed that serum endotoxins significantly correlated with Pneumonia Severity Index score (Rs=0.386, p=0.006). Compared to baseline, at discharge CAP patients showed a significant increase of FMD and NOx (from 2.1±0.3 to 4.6±0.4%, p0.001 and from 24.3±1.1 to 31.1±1.5μM, p0.001, respectively) and a significant decrease of serum endotoxins and isoprostanes (from 157.8±7.6 to 55.5±2.3pg/ml, p0.001, and from 341±14 to 312±14 pM, p0.001, respectively). Conversely, no changes for FMD, NOx, serum endotoxins and isoprostanes were observed in controls between baseline and discharge. Changes of FMD significantly correlated with changes of serum endotoxins (Rs=-0.315; p=0.001).The study provides the first evidence that CAP is characterized by impaired FMD with a mechanism potentially involving endotoxin production and oxidative stress.

SummaryBackground Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is considered a pathogenetic mechanism determining fibrosis and disease progression in non-alcoholic steatohepatitis (NASH). Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans. Aim To analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH. Methods In a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (>85% cocoa) or 40 g/day of milk chocolate (

Nonalcoholic fatty liver disease (NAFLD) has a high prevalence in the general population. Brachial artery flow-mediated dilation (FMD) is a surrogated marker of early atherosclerosis. Few data investigating the relation between FMD, NAFLD, and cardiovascular (CV) risk are available. We recruited 367 consecutive outpatients with cardiometabolic risk factors who underwent ultrasound scanning for liver steatosis and FMD. Mean age was 54.2 ± 12.2 years, and 37% were women. NAFLD was present in 281 patients (77%). Median FMD was 5.1%. FMD was significantly reduced in patients with NAFLD (p0.001), diabetes (p = 0.001), history of coronary heart disease (p = 0.034), and metabolic syndrome (p = 0.050) and in those taking antihypertensive drugs (p = 0.022). Women disclosed greater FMD than males (p = 0.033). Moreover, FMD inversely correlated with age (Spearman rank correlation test [Rs], -0.171; p = 0.001), waist circumference (Rs, -0.127; p = 0.016), fasting blood glucose (Rs, -0.204; p0.001), and gamma-glutamyl transpeptidase (Rs, -0.064; p = 0.234). At multivariate regression analysis, fasting blood glucose (β, -0.148; p = 0.008), age (β, -0.158; p = 0.005), and the presence of NAFLD (β, -0.132; p = 0.016) inversely correlated with FMD, whereas female gender predicted a better FMD (β, 0.125; p = 0.022). FMD and Framingham Risk Score (FRS) were inversely correlated (Rs, -0.183; p0.001). After dividing patients into low (FRS10; FMD, 5.5% [3.1% to 8.9%]), intermediate (FRS 10 to 20; FMD, 4.9% [2.7% to 7.5%]), and high (FRS20; FMD, 3.3% [1.7% to 4.5%]) risk, FMD significantly decreased across risk classes of FRS (p = 0.003). At multivariate regression analysis, both FRS (β, -0.129; p = 0.016) and NAFLD (β, -0.218; p0.001) were variables independently associated with FMD. In conclusion, the presence of NAFLD and FRS inversely correlated with FMD.

SUMMARY Venous thromboembolism (VTE) represents a severe complication for acutely ill hospitalized medical patients. Despite several guidelines suggesting that prophylactic measures significantly reduce the risk of VTE, there is a scarce tendency to use antithrombotic drugs in these patients. We performed a meta-ana lysis of the interventional trials with antithrombotic drugs (low-molecular-weight heparin and fondaparinux) to oversee the clinical effectiveness and bleeding complications. A total of eight randomized controlled trials, including 16,524 patients, were analyzed. This meta-ana lysis suggests that in acutely ill medical patients, compared with controls, prophylaxis with antithrombotic drugs may be of clinical benefit in VTE (odds ratio [OR]: 0.512; 95% CI: 0.41–0.64; p < 0.001) and deep venous thrombosis (OR: 0.520; 95% CI: 0.41–0.67; p < 0.001); furthermore, there is no effect Practice Points

Studies conducted in the prepubertal period showed that biomarkers of oxidative stress decreased with increasing age in normocholesterolemic children (NC), and, conversely, they are persistently high in hypercholesterolemic children (HC). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the most important cellular source of reactive oxygen species. No data have been reported concerning the behavior of age-related oxidative stress generated by NOX2, the catalytic subunit of NADPH oxidase, in children. We performed a cross-sectional study comparing oxidized low-density lipoprotein (ox-LDL), as a marker of oxidative stress, and NOX2 activity, as assessed by blood levels of soluble NOX2–derived peptide (sNOX2-dp), in a population of 250 children, including 125 NC and 125 HC. HC had higher sNOX2-dp (25.8 ± 16.1 pg/ml) and ox-LDL (23.6 ± 14.4 U/l) levels as compared with NC (15.4 ± 10.1 and 11.6 ± 6.4 pg/ml, respectively; P < 0.001). Multiple linear regression analysis showed that ox-LDL and total cholesterol were the only independent predictive variables associated with sNOX2-dp. In NC, ox-LDL and sNOX2-dp significantly decreased from the first to the second quintile of age. In HC, ox-LDL and sNOX2-dp levels did not show significant differences among quintiles of age. This study suggests that NOX2 contributes to generating ox-LDL during the early phase of life in NC and to the persistent high oxidative stress in the prepubertal period of HC.

To analyze the interplay among oxidative stress, NOX2, the catalytic core of nicotinamide-adenine dinucleotide phosphate oxidase, and endothelial dysfunction in children with obesity and/or hypercholesterolemia.We performed a cross-sectional study comparing flow-mediated arterial dilation (FMD), oxidized low-density lipoprotein, and urinary excretion of isoprostanes (8-iso-PGF2α), as markers of oxidative stress, and NOX2 activity, as assessed by blood levels of soluble NOX2-dp (sNOX2-dp), in a population of 100 children, matched for age and sex, including 40 healthy subjects (HS), 20 children with hypercholesterolemia (HC), 20 obese children (OC), and 20 children with coexistence of hypercholesterolemia and obesity (HOC).HOC had higher sNOX2-dp and oxidized low-density lipoprotein levels compared with HS, HC, and OC. HC, OC, and HOC had lower FMD values compared with HS. Urinary 8-iso-PGF2α excretion was higher in HOC compared with HS. FMD was inversely correlated with sNOX2-dp levels (r = -0.483; P.001) and with the number of cardiovascular risk factors (r = -0.617; P.001). Multiple linear regression analysis showed that the number of cardiovascular risk factors was the only independent predictive variable associated with FMD (β: -0.585; P.001; R(2) = 35%) and sNOX2-dp (β: 0.587; P.001; R(2) = 34%).The study suggests that NOX2-generating oxidative stress may have a pathogenic role in the functional changes of the arterial wall occurring in HOC.

Background— Oxidative stress is suggested to play a role in favoring the occurrence of atrial fibrillation (AF). We analyzed whether vitamin E, a known antioxidant, or markers of oxidative stress are associated with AF recurrence in patients undergoing electric cardioversion. Methods and Results— A total of 144 patients (83 men; mean age, 71.1±5.4 years) underwent successful biphasic electric cardioversion of nonvalvular persistent AF. At baseline, urinary 8-isoprostaglandin F2α and serum soluble NOX2-derived peptide (sNOX2-dp), high-sensitivity C-reactive protein (hs-CRP), and vitamin E levels were measured in each patient. All patients underwent 3 months of clinical follow-up, including an office visit with ECG every week or in cases of symptom recurrence. During the follow-up, 94 patients maintained sinus rhythm, whereas 50 experienced AF recurrence. In unadjusted analysis, left atrial diameter and levels of urinary isoprostanes and serum sNOX2-dp and hs-CRP were significantly higher and serum vitamin E lower in patients with AF recurrence. In multivariable Cox analysis, serum vitamin E (hazard ratio, 0.734; 95% CI, 0.605–0.891; P P =0.047) remained significantly associated with AF recurrence. Urinary isoprostanes and serum sNOX2-dp levels were inversely correlated with serum vitamin E level ( r =−0.626, P r =−0.460, P Conclusions— The study shows that low serum vitamin E levels are associated with AF recurrence in patients who underwent cardioversion. Because vitamin E inversely correlated with oxidative stress, the findings reinforce the hypothesis of an interplay between oxidative stress and AF.

Summary. Background: Dark chocolate is reported to decrease platelet activation but the underlying mechanism is still undefined. Dark chocolate is rich in polyphenols that could exert an antiplatelet action via inhibition of oxidative stress. The aim of the present study was to assess if dark chocolate inhibits platelet reactive oxidant species (ROS) formation and platelet activation. Methods: Twenty healthy subjects (HS) and 20 smokers were randomly allocated to receive 40 g of dark (cocoa > 85%) or milk chocolate (cocoa

Background Cocoa seems to exert artery dilatation via oxidative stress inhibition but the mechanism is still unclear. Objectives To investigate whether in smokers, dark chocolate elicits artery dilatation via down-regulation of NOX2, the catalytic core of NADPH oxidase. Methods Flow-mediated dilatation (FMD), oxidative stress (as assessed by urinary isoprostanes excretion), nitric oxide generation (as assessed by serum levels of nitrite/nitrate (NOx)), NOX2 activity (as assessed by blood levels of soluble NOX2 derived peptide (sNOX2dp)) and serum epicatechin were studied in 20 smokers and 20 healthy subjects (HS) in a crossover, single-blind study. Patients were randomly allocated to 40 g dark chocolate (>85% cocoa) or 40 g of milk chocolate (#35% cocoa). FMD, urinary isoprostanes, NOx and sNOX2-dp were assessed at baseline and 2 h after chocolate ingestion. Results Smokers had lower FMD and NOx and higher sNOX2-dp compared to HS. After dark chocolate intake, urinary isoprostanes and sNOX2-dp significantly decreased and FMD and NOx significantly increased in smokers but not in HS. No changes of the above variables were observed after milk chocolate intake. Multiple linear regression analysis showed that in smokers the only independent predictive variable associated with a change in FMD was a change in sNOX2-dp. Serum epicatechin increased in either group only after dark chocolate intake, reaching values higher than 0.1 mM. Platelets from smokers (n¼5), but not from HS (n¼5), showed lower p47 phox translocation to platelet membrane and higher NOx when incubated with 0.1e10 mM epicatechin. Conclusion Results suggest that in smokers, cocoa enhances artery dilatation by lowering of NOX2 activation.

BACKGROUND. Endothelial dysfunction and intima-media thickness are precocious manifestations of hypercholesterolemia, but the mechanism is unclear. OBJECTIVE. The aim of the study was to analyze the interplay among endothelial dysfunction, intima-media thickness, and oxidative stress in children with hypercholesterolemia. METHODS. We performed a cross-sectional study comparing flow-mediated dilation, intima-media thickness, lipid profile, urinary isoprostanes as markers of oxidative stress, and platelet expression of gp91phox, the catalytic unit of nicotinamide-adenine dinucleotide phosphate oxidase, in a population of 50 children with hypercholesterolemia (mean age ± SD: 10.0 ± 3.7 years) and 50 children without hypercholesterolemia (mean age: 9.2 ± 3.5 years). Four children with hereditary deficiency of gp91phox were studied also. RESULTS. Children with hypercholesterolemia had reduced flow-mediated dilation (mean ± SD: 6.2 ± 2.4 vs 9.2 ± 2.5%) and enhanced intima-media thickness (0.45 ± 0.07 vs 0.40 ± 0.06 mm), urinary isoprostanes (86.9 ± 51.6 vs 45.9 ± 25.6 pg/mg creatinine), and gp91phox platelet expression (4.4 ± 3.8 vs 2.0 ± 1.7 mean fluorescence) compared with control subjects. At bivariate analysis, flow-mediated dilation was correlated with low-density lipoprotein cholesterol, intima-media thickness, urinary isoprostanes, and platelet gp91phox. Stepwise multiple linear regression analysis showed that, in children with hypercholesterolemia, flow-mediated dilation and intima-media thickness were significantly associated with low-density lipoprotein cholesterol and urinary isoprostanes; also, gp91phox platelet expression was an independent predictor of urinary isoprostanes. Children with gp91phox hereditary deficiency showed downregulation of platelet gp91phox and reduced urinary excretion of isoprostanes. CONCLUSIONS. The study suggests that gp91phox-mediated oxidative stress may have a pathogenic role in the anatomic and functional changes of the arterial wall occurring in children with premature atherosclerosis.

Background NOX ‐2, the catalytic subunit of NADPH oxidase, has a key role in the formation of reactive oxidant species and is implicated in impairing flow‐mediated dilation ( FMD ). Dark chocolate exerts artery dilatation via down‐regulating NOX 2‐mediated oxidative stress. The aim of this study was to investigate whether dark chocolate improves walking autonomy in peripheral artery disease ( PAD ) patients via an oxidative stress‐mediated mechanism. Methods and Results FMD , serum levels of isoprostanes, nitrite/nitrate (NOx) and sNOX 2‐dp, a marker of blood NOX 2 activity, maximal walking distance ( MWD ) and maximal walking time ( MWT ) were studied in 20 PAD patients (14 males and 6 females, mean age: 69±9 years) randomly allocated to 40 g of dark chocolate (>85% cocoa) or 40 g of milk chocolate (≤35% cocoa) in a single blind, cross‐over design. The above variables were assessed at baseline and 2 hours after chocolate ingestion. Dark chocolate intake significantly increased MWD (+11%; P MWT (+15%; P P P =0.01) and sNOX 2‐dp (−37%; P MWD was independently associated with Δ of MWT ( P P =0.018). In vitro study demonstrated that HUVEC incubated with a mixture of polyphenols significantly increased nitric oxide ( P P VCAM 1 ( P Conclusion In PAD patients dark but not milk chocolate acutely improves walking autonomy with a mechanism possibly related to an oxidative stress‐mediated mechanism involving NOX 2 regulation. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01947712.

Endothelial dysfunction and intima-media thickness (IMT) are precocious manifestations of hypercholesterolemia but the mechanism is unclear. The aim of the study was to analyse the interplay among endothelial dysfunction, IMT and oxidative stress in hypercholesterolemic children (HC). We performed a cross-sectional study comparing flow mediated dilation (FMD), IMT, lipid profile, urinary isoprostanes as markers of oxidative stress, and platelet expression of gp91phox, the catalytic unit of NADPH oxidase, in a population of 50 HC (mean age 10.0±3.7 years) and 50 normocholesterolemic children (NC) (mean age 9.2±3.5 years). Four children with hereditary deficiency of gp91phox were also studied. HC had reduced FMD (6.2±2.4 vs. 9.2±2.5%; p