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Biomedical subjects

F Violi

Publications and source records attributed to F Violi.

At least 91 records · Page 5Linked to original sources
PubMed1997

Oxygen free radicals and platelet activation.

This article reviews our current understanding of the role of oxygen free radicals in platelet activation. Several studies have indicated that platelets, in analogy to other circulating blood cells, are able to produce oxygen free radicals, which are likely to play an important role in the mechanism of platelet activation and aggregation. Platelet activation has been obtained with very low, physiologically relevant concentrations of radicals generated chemically, by leukocytes, and by hemoglobin derived from membrane leakage of erythrocytes. Knowledge of the role of reactive species in platelet physiology is relevant because platelets are brought into close contact with other cells capable of producing free radicals, such as neutrophils, macrophages, and endothelial cells, during the formation of thrombus. The physiopatological importance of these findings is high because it is now emerging that free radicals may have a role in the mechanism of atherosclerosis and its thrombotic complications, where the causative role of platelets is well documented. This background suggests therapeutic interventions with antioxidants as antiplatelet agents to improve the pharmacological effect of classical antiplatelet drug such as aspirin.

Antioxidants↗
PubMed1997

Enhanced thromboxane biosynthesis in patients with chronic obstructive pulmonary disease. The Chronic Obstructive Bronchitis and Haemostasis Study Group.

Thrombotic complications of pulmonary circulation occur in patients with chronic obstructive pulmonary disease (COPD). In the present study, we sought to evaluate in vivo platelet activation through the measurement of 11/dehydro-thromboxane (Tx) B2 TxA2 major metabolite in the urine, in 29 patients with COPD, compared with 29 sex- and age-matched healthy subjects. The urinary excretion of 11-dehydro-TxB2 was significantly higher in patients with COPD than in control subjects: median (range), 753 (277-4,409) and 275 (129-612) pg/mg creatinine, respectively; p < 0.0001). Moreover, 11-dehydro-TxB2 excretion was inversely related with arterial oxygen tension (rho = -0.46; p = 0.0145). In five of the 29 patients a short-term therapeutic course with oxygen supplementation induced a significant decrease of urinary 11-dehydro-TxB2 excretion: median range, 941 (452-2,640) to 445 (166-1,560) pg/mg creatinine. Moreover, selective inhibition of platelet cyclooxygenase activity by low-dose aspirin was associated with more than 90% inhibition of thromboxane metabolite excretion, demonstrating its being of platelet origin. Plasma levels of prothrombin fragment F1 + 2 were higher in patients than in control subjects (2.6 +/- 1.5 versus 0.9 +/- 0.4 nM, p = 0.0001). No relation between 11-dehydro-TxB2 excretion and plasma F1 + 2 levels was found. We conclude that platelet TxA2 biosynthesis is enhanced in patients with COPD and may be influenced by arterial oxygen tension changes.

Aged↗
PubMed1997

Ongoing prothrombotic state in the portal circulation of cirrhotic patients.

Portal thrombosis may complicate the clinical course of cirrhosis, but the pathophysiologic mechanism is unclear. Aim of the study was to evaluate the behavior of clotting system and endotoxemia in portal vein and in peripheral circulation of 11 cirrhotic patients undergoing transjugular port-systemic shunt (TIPS). Portal blood showed higher values of F1 + 2 [Median (range): 2.5 (1.1-5.3) vs. 1.1 (0.6-2.1) nM, p < 0.01], D-dimer [765 (184-1713) vs. 192 (64-813) ng/ml, p < 0.01] and endotoxemia [31 (16-47.2) vs. 13.7 (7.5-23.5) pg/ml, p < 0.01] than peripheral circulation. In the portal vein, all but one sample had F1 + 2 > 1.2 nM (upper limit of control values), all but one had D-dimer > 216 mg/dl (mean + 2 SD of controls) and 100% had values of endotoxemia > 9.6 pg/ml (upper limit of control values). Fibrinogen was lower in the portal circulation compared to peripheral circulation but the difference was not significant [85 (58-195) vs. 134 (75-244) mg/dl, p > 0.05]. Endotoxemia was directly correlated with F1 + 2 (Rho = 0.92 p < 0.006) and D-dimer (Rho = 0.93, p < 0.005). This study shows that an ongoing prothrombotic state is present in the portal circulation of cirrhotic patients and may play a pivotal role in the thrombotic episodes occurring in this clinical setting.

Adult↗
PubMed1997

Hyperlipidemia in dialysis patients: what treatment?

The incidence of hyperlipidemia in the dialysis population in our hospital reflects the incidence reported by other authors but we ascertained a high incidence of hypercholesterolemic patients. The importance of cardiovascular illnesses as the cause of death in patients on dialysis means taking into consideration risk factors. In our study, omega-3 fatty acids proved to be effective in about half the patients treated and did not have side effects. In a comparison of patients who underwent alternative techniques with high-flux membranes and those who underwent standard dialysis, the first group showed a virtually normal lipid profile. High-flux membranes could be a therapeutical possibility for hypertriglyceridemic patients under dialysis.

Fatty Acids, Omega-3↗
PubMed1997

Systemic clotting activation by low-grade endotoxaemia in liver cirrhosis: a potential role for endothelial procoagulant activation.

BACKGROUND: The pathophysiologic mechanism underlying the association between endotoxaemia and clotting activation in liver cirrhosis is still to be explained. AIMS: To investigate the relationship between endotoxaemia, endothelial perturbation and clotting system activation in liver cirrhosis patients. PATIENTS: The study was carried out in 30 consecutive patients (17 males, 13 females, age range 42 to 71 years) with liver cirrhosis. METHODS: Prothrombin fragment F1 + 2, endotoxaemia, von Willebrand factor and ristocetin cofactor activity were studied in all patients. Von Willebrand factor antigen release and tissue factor expression were also evaluated in cultured endothelial cells incubated with low endotoxin concentrations (125-500 pg/ml). RESULTS: Thirteen (43%) out of 30 liver cirrhosis patients showing von Willebrand factor antigen levels > 157 IU/dl (mean +/- 2SD of controls) were considered to have signs of endothelial perturbation; they had more severe liver failure (p = 0.0001), higher ristocetin cofactor activity (p = 0.0001), endotoxin (p = 0.0001) and prothrombin fragment F1 + 2 (p = 0.0001) plasma values than liver cirrhosis with normal von Willebrand factor antigen. A strong correlation (r = 0.97; p = 0.0001) was found between prothrombin fragment F1 + 2 and von Willebrand factor antigen. In in vitro experiments endotoxin induced a concentration-dependent release of von Willebrand factor antigen (p = 0.0001) and expression of tissue factor activity (p = 0.0001) and antigen (p = 0.0001) from cultured endothelial cells. CONCLUSIONS: This study suggests that the endothelial procoagulant activation induced by low-grade endotoxaemia may represent a trigger for systemic clotting activation in liver cirrhosis patients.

Adult↗
PubMed1996

Preparation and biodistribution of 99m technetium labelled oxidized LDL in man.

Radiolabelled autologous low density lipoprotein (LDL) has previously been used to study in vivo distribution and metabolism of native-LDL. Non-invasive imaging of atherosclerotic lesions using 99mTc-LDL was shown to be feasible in animal models and patients but the clinical utility remains to be assessed. Since recent reports suggest that oxidized LDL may play a major role in the pathogenesis of atherosclerosis, we developed a technique to oxidize autologous LDL and compared the biodistribution of oxidized-LDL with that of native-LDL in man. In addition, we evaluated the uptake in vivo of oxidized- and native-LDL by atherosclerotic plaques. LDL, obtained from human plasma was treated with various combinations of copper ions and H2O2 to induce oxidative modification by increasing the content of lipid peroxidation products and electrophoretic mobility. When LDL (0.3 mg/ml) was incubated with 100 microM Cu2+ and 500 microM H2O2 oxidation occurred rapidly within 1 h, and was labelled with 99mTc efficiently as native LDL. In vivo distribution studies revealed a faster plasma clearance of oxidized-LDL compared to native-LDL, and a higher uptake by the reticuloendothelial system. Tomographic scintigraphy of the neck in patients suffering from transient ischemic attacks, revealed accumulation of radiolabelled LDL preparations in the carotid artery affected by atherosclerotic lesions. We developed a technique to rapidly oxidize LDL using copper and H2O2. Biodistribution data demonstrate that oxidized-LDL is rapidly cleared from circulation, is taken up mostly by organs rich in macrophages, and can be detected at the level of carotid plaques.

Adult↗
PubMed1996

Local amplification of platelet function by 8-Epi prostaglandin F2alpha is not mediated by thromboxane receptor isoforms.

8-epi-Prostaglandin (PG) F2alpha may be formed by cyclooxygenases 1 and 2 or by a free radical catalyzed process as an isoprostane. Concentrations of 8-epi-PGF2alpha in the range 1 nM to 1 microM induce a dose-dependent increase in platelet shape change, in calcium release from intracellular stores [Ca2+]iand in inositol phosphates; it also causes irreversible platelet aggregation, dependent on thromboxane generation, when incubated with subthreshold concentrations of ADP, thrombin, collagen, and arachidonic acid. Much higher concentrations of 8-epi-PGF2alpha (10-20 microM) alone induce weak, reversible aggregation. Although these effects are prevented by pharmacological thromboxane receptor antagonists, they are unlikely to be mediated by thromboxane receptors. Thus, 8-epi-PGF2alpha does not compete for binding at the stably expressed placental or endothelial isoforms of the thromboxane receptor or for binding of thromboxane ligands to human platelets. Furthermore, the response to 8-epi PGF2alpha exhibits structural specificity versus 8-epi PGF3alpha and PGF2alpha. Concentrations in the range that evoke its effects on platelets do not desensitize the aggregation response stimulated by thromboxane or PGH2 analogs. Unlike primary prostaglandins, which are rapidly metabolized to inactive products, 8-epi PGF2alpha circulates in plasma. However, the systemic concentrations found in healthy volunteers (median 48 pmol/liter) and in patients with hepatic cirrhosis (median 147 pmol/liter), a syndrome of oxidant stress in vivo, fall well below those which modulate platelet function. 8-Epi PGF2alpha may amplify the response to platelet agonists in syndromes where oxidant stress and platelet activation coincide. Despite blockade by thromboxane antagonists, 8-epi PGF2alpha does not activate either of the thromboxane receptor isoforms described in platelets. Activation of a distinct receptor would be consistent with the enzymatic formation of 8-epi PGF2alpha by cyclooxygenases. However, incidental activation of such a receptor by systemic concentrations of 8-epi PGF2alpha is unlikely to occur, even in syndromes of excessive free radical generation in vivo.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1996

High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia.

The aim of this study was to evaluate whether there is endothelial dysfunction in patients with cirrhosis and to detect the mechanism that may account for it. We measured plasma levels of von Willebrand factor (vWF), a marker of endothelial perturbation, and endotoxin, which releases vWF from endothelial cells in vitro, in 32 patients (18 men, 14 women, aged 39-70 years) with cirrhosis classified as mild (class A, n = 10), moderate (class B, n = 16), or severe (class C, n = 6) according to Child-Pugh's classification. vWF antigen (P < .0001) and endotoxemia (P < .0001) progressively increased from A to class C; but the increase of vWF antigen was not strictly related to liver failure, as shown by the lack of correlation between vWF and several indexes of liver protein synthesis. Analysis of the vWF subunit showed no sign of proteolytic fragmentation of the molecule. Multimeric analysis indicated intact vWF multimeric structure. In all patients, there was a strong correlation between vWF antigen and endotoxemia (rho = .92; P = .0001). In 20 selected patients, vWF antigen and endotoxemia were measured before and after 7 days of standard therapy (n = 10) or standard therapy plus nonabsorbable antibiotics. There was a significant decrease of vWF antigen (P < .02) concomitantly with the decrease of endotoxemia (P < .006) in patients taking nonabsorbable antibiotics. Human umbilical vein endothelial cells incubated in vitro with 125 to 500 pg/mL endotoxin released vWF antigen into the medium dose dependently. These results demonstrate that there is endothelial perturbation in cirrhosis and that endotoxemia may play a key role in its occurrence.

Adult↗
PubMed1996

Relation between risk factors and cardiovascular complications in patients with peripheral vascular disease. Results from the A.D.E.P. study.

The relationship between risk factors and the onset of cardiovascular events was analyzed in patients suffering from peripheral obstructive arterial disease. One thousand and eleven patients were recruited in 120 Italian centers and participated in a clinical trial on picotamide (A.D.E.P. study), whose results have been previously reported. Patients were followed-up for 18 months and cardiovascular events were recorded. Hypertension (35%), smoking (34%), and diabetes (19%) were the most common risk factors at baseline. During the follow-up period, 246 patients (11.7%) had a cardiovascular event, mainly affecting cerebral, cardiac or peripheral circulation. Thirty-five of these events (14.2%) were fatal. A logistic regression analysis showed in general that hypertension (odds ratio 1.48), an ankle arm pressure ratio lower than 0.8 (odds ratio 1.42), smoking (odds ratio 1.43), previous vascular surgery (odds ratio 1.35), high white blood cell (WBC) count (odds ratio 1.15 for a difference of 2.0 x 10(9) WBC/1) and plasma fibrinogen (odds ratio 1.16 for a difference of 1.05 g/l) were significantly associated with a higher incidence of cardiovascular events. In particular, deaths of any origin were more frequent in patients with an ankle/arm pressure ratio below 0.8. High plasma fibrinogen increased the risk of cerebrovascular events, hypertension or coronary heart events and, to a less evident extent, peripheral vascular complications and cerebrovascular events. A history of vascular surgery increased the risk of peripheral vascular complications. Both smoking and a high WBC count showed to be borderline significant risk factors for coronary heart events and the former also for peripheral vascular complications. In male patients (84%), ankle/arm pressure ratio lower than 0.8, high fibrinogen and hypertension were the most important factors for cardiovascular events. This study helps to identify some categories at higher risk of cardiovascular events among patients with peripheral obstructive arterial disease; this finding is useful to plan future trials to decrease the frequency of such complications.

Adult↗
PubMed1996

Bleeding time does not predict gastrointestinal bleeding in patients with cirrhosis. The CALC Group. Coagulation Abnormalities in Liver Cirrhosis.

BACKGROUND/AIMS: Bleeding time, a laboratory test which explores primary hemostasis, may be prolonged in cirrhosis, but whether abnormal bleeding time identifies patients with cirrhosis who are at risk of bleeding has never been investigated. The aim of this study was to analyze the relationship between bleeding time and the risk of gastrointestinal bleeding. METHODS: Eighty consecutive patients with liver cirrhosis (47 males, 33 females; age, 60 +/- 9 years; range 31 to 83 years) and esophageal varices were enrolled in the study. RESULTS: In the whole series of patients bleeding time was 11 +/- 6 min; it increased as the degree of liver deficiency increased, from low to severe (p = 0.007). During 14 +/- 9 (median (range): 12 (1-34) months of follow-up, 28 (35%) patients experienced gastrointestinal bleeding. They had a longer bleeding time, higher incidence of previous bleeding, more severe liver failure and larger variceal size than patients who did not bleed. However, multivariate analysis (Cox's model) showed that only previous bleeding, liver failure and variceal size were independently associated with bleeding. Similar data were obtained in patients with moderate-severe liver insufficiency (B and C degree according to Child-Pugh's classification). In patients who had never bled (n = 54), the severity of liver failure and variceal size were independent predictors of bleeding. CONCLUSIONS: This study shows that bleeding time is not a predictor of gastrointestinal bleeding in patients with cirrhosis.

Adult↗
PubMed1996

Protection of low density lipoprotein oxidation at chemical and cellular level by the antioxidant drug dipyridamole.

1. The oxidative modification of low density lipoprotein (LDL) is thought to be an important factor in the initiation and development of atherosclerosis. Natural and synthetic antioxidants have been shown to protect LDL from oxidation and to inhibit atherosclerosis development in animals. Synthetic antioxidants are currently being tested, by they are not necessarily safe for human use. 2. We have previously reported that dipyridamole, currently used in clinical practice, is a potent scavenger of free radicals. Thus, we tested whether dipyridamole could affect LDL oxidation at chemical and cellular level. 3. Chemically induced LDL oxidation was made by Cu(II), Cu(II) plus hydrogen peroxide or peroxyl radicals generated by thermolysis of 2,2'-azo-bis(2-amidino propane). Dipyridamole, (1-10 microM), inhibited LDL oxidation as monitored by diene formation, evolution of hydroperoxides and thiobarbituric acid reactive substances, apoprotein modification and by the fluorescence of cis-parinaric acid. 4. The physiological relevance of the antioxidant activity was validated by experiments at the cellular level where dipyridamole inhibited endothelial cell-mediated LDL oxidation, their degradation by monocytes, and cytotoxicity. 5. In comparison with ascorbic acid, alpha-tocopherol and probucol, dipyridamole was the more efficient antioxidant with the following order of activity: dipyridamole > probucol > ascorbic acid > alpha-tocopherol. The present study shows that dipyridamole inhibits oxidation of LDL at pharmacologically relevant concentrations. The inhibition of LDL oxidation is unequivocally confirmed by use of three different methods of chemical oxidation, by several methods of oxidation monitoring, and the pharmacological relevance is demonstrated by the superiority of dipyridamole over the naturally occurring antioxidants, ascorbic acid and alpha-tocopherol and the synthetic antioxidant probucol.

Antioxidants↗
PubMed1995

Association between low-grade disseminated intravascular coagulation and endotoxemia in patients with liver cirrhosis.

BACKGROUND & AIMS: Hyperfibrinolysis may complicate the clinical course of liver cirrhosis. The aim of this study was to evaluate if, in cirrhosis, hyperfibrinolysis is primary or secondary to intravascular clotting activation and if endotoxemia is associated with activation of clotting and/or the fibrinolytic system. METHODS: Clotting, fibrinolytic indexes, and endotoxemia were studied in 41 cirrhotic patients and 20 healthy subjects. RESULTS: Twenty-seven cirrhotic patients (66%) had high plasma levels of prothrombin fragment F1 + 2, a marker of thrombin generation. Nineteen patients had elevated values of D-dimer, a marker of fibrinolysis in vivo. All patients with high values of D-dimer also had high values of prothrombin fragment F1 + 2. Endotoxemia was elevated in patients with severe liver failure and significantly correlated to prothrombin fragment F1 + 2. Thirty patients were treated for 7 days either with standard therapy (n = 15) or with standard therapy plus nonabsorbable antibiotics (n = 15). Although standard therapy did not significantly change laboratory indexes, a significant reduction of endotoxemia, prothrombin fragment F1 + 2, and D-dimer was found in those patients who received the combined treatment. CONCLUSIONS: This study shows that, in cirrhotic patients, hyperfibrinolysis is not a primary phenomenon but occurs as a consequence of clotting activation and that endotoxemia might play a pathophysiological role.

Adult↗
PubMed1995

A potent chain-breaking antioxidant activity of the cardiovascular drug dipyridamole.

The antioxidant properties of the antithrombotic drug dipyridamole have been studied using lipid oxidation assays based on the generation of peroxy radicals by azo compounds. Dipyridamole was observed to prevent both peroxidation of arachidonic acid micelles in aqueous solution and peroxidation of methyl linoleate in organic solvents; in contrast to vitamin E, dipyridamole was found to scavenge both hydrophilic and hydrophobic radicals. The rate constant for the reaction of dipyridamole with methyl linoleate peroxyl radicals at 37 degrees C was calculated as 2 x 10(6) M-1s-1, in comparison to 1 x 10(6) M-1s-1 of vitamin E under the same conditions. The antioxidant efficiency of the drug was confirmed in experiments with radiolysis-induced oxidation and through measurements of malondialdehyde production and diene formation. As a result of radical scavenging, a relatively stable dipyridamole radical was formed that could be detected by electron spin resonance spectroscopy. The particular antioxidant properties of dipyridamole may explain the vasodilating and antiplatelet effects of this cardiovascular drug.

Antioxidants↗
PubMed1995

Prognostic value of clotting and fibrinolytic systems in a follow-up of 165 liver cirrhotic patients. CALC Group.

One hundred sixty-five patients with cirrhosis diagnosed by needle liver biopsy were followed for 2 years to evaluate the relation between clotting factors and survival. Patients with spontaneous bacterial peritonitis, hepatic carcinoma, and cholestatic liver diseases were excluded. Patients were classified as A (n = 34), B (n = 75), or C (n = 56) according to Child-Pugh criteria. During the follow-up 45 patients died of liver failure or gastrointestinal hemorrhage. Nonsurvivor patients had significantly higher values of bilirubin and D-dimer, a marker of fibrinolysis in vivo, lower values of albumin, prothrombin activity, fibrinogen, prekallikrein, factor VII, and a more prolonged activated partial thromboplastin time than survivors. All these variables and Child-Pugh classification were significantly associated with survival in a univariate analysis. Multivariate analysis (Cox's model) showed that only prekallikrein and factor VII were independently predictors of survival. Ninety-three percent of patients with prekallikrein values < 32% died within 32 months of follow-up, whereas factor VII < 34% identified 93% of patients who died within 10 months of follow-up. This study suggests that factor VII is an early predictor of survival and may be a useful test to better identify cirrhotic patients who should be candidates for liver transplantation.

Aged↗