Vitamin C inhibits platelet expression of CD40 ligand

Upon stimulation with agonists, platelets express CD40 ligand (CD40L), a transmembrane protein implicated in the initiation and progression of atherosclerotic disease. We have recently discovered that oxidative stress plays a major role in platelet CD40L expression. In this study, we sought to determine whether vitamin C, a known antioxidant, is able to influence platelet CD40L expression. In vitro experiments were done by stimulating platelets with collagen in the presence or absence of vitamin C (50-100 mu M) or vehicle as control. An in vivo study was done in 10 healthy subjects who were randomized to intravenous infusion of placebo or 1 g vitamin C for 45 min in a crossover design. At the end of infusion platelet CD40L and O2- were measured. The in vitro study demonstrated that vitamin C dose dependently inhibited platelet CD40L expression without affecting agonist-induced platelet aggregation. In subjects treated with placebo no changes of platelet CD40L and O2- were observed; conversely, vitamin C infusion caused a significant and parallel decrease of platelet O2- (-70%, P < 0.001) and CD40L (-68%, P < 0.001). Platelet aggregation was not modified by either treatment. This study suggests that water-soluble antioxidants, which scavenge superoxide radicals, may reduce platelet CD40L expression. (c) 2005 Elsevier Inc. All rights reserved

Von willebrand and factor VIII portosystemic circulation gradient in cirrhosi. Implications for portal vein thrombosis

OBJECTIVES: Portal vein thrombosis seems to be dependent on local hypercoagulation and venous stasis; data regarding endothelial damage are lacking. METHODS: von Willebrad factor, a marker of endothelial damage/perturbation, factor VIII, and lipopolysaccharides (LPS) were studied in the portal and systemic circulation of 20 cirrhotic patients undergoing transjugular intrahepatic portosystemic procedure. RESULTS: von Willebrad factor, factor VIII, and LPS were higher in the portal compared with systemic circulation, with a significant correlation between LPS and the other 2 variables. DISCUSSION: Endothelial damage and hypercoagulation coexist in the portal tree of patients with cirrhosis, and both could contribute to portal vein thrombosis. LPS may be a potential trigger of endothelial damage

Analysis of a coupled fluid-structure interaction model of the left atrium and mitral valve

We present a coupled left atrium ‐ mitral valve model based on computed tomography scans with fibre‐reinforced hyperelastic materials. Fluid‐structure interaction is realised by using an immersed boundary‐finite element framework. Effects of pathological conditions, e.g. mitral valve regurgitation and atrial fibrillation, and geometric and structural variations, namely uniform vs non‐uniform atrial wall thickness and rule‐based vs atlas‐based fibre architectures, on the system are investigated. We show that in the case of atrial fibrillation, pulmonary venous flow reversal at late diastole disappears and the filling waves at the left atrial appendage orifice during systole have reduced magnitude. In the case of mitral regurgitation, a higher atrial pressure and disturbed flows are seen, especially during systole, when a large regurgitant jet can be found with the suppressed pulmonary venous flow. We also show that both the rule‐based and atlas‐based fibre defining methods lead to similar flow fields and atrial wall deformations. However, the changes in wall thickness from non‐uniform to uniform tend to underestimate the atrial deformation. Using a uniform but thickened wall also lowers the overall strain level. The flow velocity within the left atrial appendage, which is important in terms of appendage thrombosis, increases with the thickness of the left atrial wall. Energy analysis shows that the kinetic and dissipation energies of the flow within the left atrium are altered differently by atrial fibrillation and mitral valve regurgitation, providing a useful indication of the atrial performance in pathological situations

Assessment of HCC response to Yttrium-90 radioembolization with gadoxetate disodium MRI: correlation with histopathology.

Transarterial &lt;sup&gt;90&lt;/sup&gt; Y radioembolization (TARE) is increasingly being used for hepatocellular carcinoma (HCC) treatment. However, tumor response assessment after TARE may be challenging. We aimed to assess the diagnostic performance of gadoxetate disodium MRI for predicting complete pathologic necrosis (CPN) of HCC treated with TARE, using histopathology as the reference standard. This retrospective study included 48 patients (M/F: 36/12, mean age: 62 years) with HCC treated by TARE followed by surgery with gadoxetate disodium MRI within 90 days of surgery. Two radiologists evaluated tumor response using RECIST1.1, mRECIST, EASL, and LI-RADS-TR criteria and evaluated the percentage of necrosis on subtraction during late arterial, portal venous, and hepatobiliary phases (AP/PVP/HBP). Statistical analysis included inter-reader agreement, correlation between radiologic and pathologic percentage of necrosis, and prediction of CPN using logistic regression and ROC analyses. Histopathology demonstrated 71 HCCs (2.8 ± 1.7 cm, range: 0.5-7.5 cm) including 42 with CPN, 22 with partial necrosis, and 7 without necrosis. EASL and percentage of tumor necrosis on subtraction at the AP/PVP were independent predictors of CPN (p = 0.02-0.03). Percentage of necrosis, mRECIST, EASL, and LI-RADS-TR had fair to good performance for diagnosing CPN (AUCs: 0.78 - 0.83), with a significant difference between subtraction and LI-RADS-TR for reader 2, and in specificity between subtraction and other criteria for both readers (p-range: 0.01-0.04). Radiologic percentage of necrosis was significantly correlated to histopathologic degree of tumor necrosis (r = 0.66 - 0.8, p &lt; 0.001). Percentage of tumor necrosis on subtraction and EASL criteria were significant independent predictors of CPN in HCC treated with TARE. Image subtraction should be considered for assessing HCC response to TARE when using MRI. • Percentage of tumor necrosis on image subtraction and EASL criteria are significant independent predictors of complete pathologic necrosis in hepatocellular carcinoma treated with &lt;sup&gt;90&lt;/sup&gt; Y radioembolization. • Subtraction, mRECIST, EASL, and LI-RADS-TR have fair to good performance for diagnosing complete pathologic necrosis in hepatocellular carcinoma treated with &lt;sup&gt;90&lt;/sup&gt; Y radioembolization

Role of portal venous platelet activation in patients with decompensated cirrhosis and TIPS

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On-Treatment Platelet Reactivity is a Predictor of Adverse Events in Peripheral Artery Disease Patients Undergoing Percutaneous Angioplasty

Objectives: Few data are available on the association between a different entity of platelet inhibition on antiplatelet treatment and clinical outcomes in patients with peripheral artery disease (PAD). The aim of this study was to evaluate the degree of on-treatment platelet reactivity, and its association with ischaemic and haemorrhagic adverse events at follow up in PAD patients undergoing percutaneous transluminal angioplasty (PTA). Methods: In this observational, prospective, single centre study, 177 consecutive patients with PAD undergoing PTA were enrolled, and treated with dual antiplatelet therapy with aspirin and a P2Y12 inhibitor. Platelet function was assessed on blood samples obtained within 24 h from PTA by light transmission aggregometry (LTA) using arachidonic acid (AA) and adenosine diphosphate (ADP) as agonists of platelet aggregation. High on-treatment platelet reactivity (HPR) was defined by LTA ≥ 20% if induced by AA, and LTA ≥ 70% if induced by ADP. Follow up was performed to record outcomes (death, major amputation, target vessel re-intervention, acute myocardial infarction and/or myocardial revascularisation, stroke/TIA, and bleeding). Results: HPR by AA and HPR by ADP were found in 45% and 32% of patients, respectively. During follow up (median duration 23 months) 23 deaths (13%) were recorded; 27 patients (17.5%) underwent target limb revascularisation (TLR), two (1.3%) amputation, and six (3.9%) myocardial revascularisation. Twenty-four patients (15.6%) experienced minor bleeding. On multivariable analysis, HPR by AA and HPR by ADP were independent predictors of death [HR 3.8 (1.2–11.7), p =.023 and HR 4.8 (1.6–14.5), p =.006, respectively]. The median value of LTA by ADP was significantly lower in patients with bleeding complications than in those without [26.5% (22–39.2) vs. 62% (44.5–74), p &lt;.001). LTA by ADP ≤ 41% was independently associated with bleeding HR 14.6 (2.6–24.0), p =.001] on multivariable analysis. Conclusions: In this study a high prevalence of on-clopidogrel and aspirin high platelet reactivity was found, which was significantly associated with the risk of death. Conversely, a low on-clopidogrel platelet reactivity was associated with a higher risk of bleeding. These results document that the entity of platelet inhibition is associated with both thrombotic and bleeding complications in PAD patients

Oxidative Stress and Gut-Derived Lipopolysaccharides in Neurodegenerative Disease: Role of NOX2

Background. Neurodegenerative diseases (ND) as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis represent a growing cause of disability in the developed countries. The underlying physiopathology is still unclear. Several lines of evidence suggest a role for oxidative stress and NADPH oxidase 2 (NOX2) in the neuropathological pathways that lead to ND. Furthermore, recent studies hypothesized a role for gut microbiota in the neuroinflammation; in particular, lipopolysaccharide (LPS) derived from Gram-negative bacteria in the gut is believed to play a role in causing ND by increase of oxidative stress and inflammation. The aim of this study was to assess NOX2 activity as well as serum 8-iso-prostaglandin F2α (8-iso-PGF2α), serum H2O2, and LPS in patients with ND compared to controls. Methods. One hundred and twenty-eight consecutive subjects, including 64 ND patients and 64 controls (CT) matched for age and gender, were recruited. A cross-sectional study was performed to compare serum activity of soluble NOX2-dp (sNOX2-dp), blood levels of isoprostanes, serum H2O2, and LPS in these two groups. Serum zonulin was used to assess gut permeability. Results. Compared with CT, ND patients had higher values of sNOX2-dp, 8-iso-PGF2α, H2O2, and LPS. Simple linear regression analysis showed that sNOX2-dp was significantly correlated with serum LPS (Rs=0.441; p&lt;0.001), zonulin (Rs=0.411; p&lt;0.001), serum H2O2 (Rs=0.329; p&lt;0.001), and 8-iso-PGF2α (Rs=0.244; p=0.006). LPS significantly correlated with serum zonulin (Rs=0.818; p&lt;0.001) and 8-iso-PGF2α (Rs=0.280; p=0.001). A multiple linear regression analysis was performed to define the independent predictors of sNOX2-dp. LPS (SE, 0.165; standardized coefficient β, 0.459; p&lt;0.001) and 8-iso-PGF2α (SE, 0.018; standardized coefficient β, 0.220; p=0.005) emerged as the only independent predictive variables associated with sNOX2-dp (R2=57%). Conclusion. This study provides the first report attesting that patients with ND have high NOX2 activation that could be potentially implicated in the process of neuroinflammation