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Biomedical subjects

G Di Minno

Publications and source records attributed to G Di Minno.

At least 19 recordsLinked to original sources
PubMed1997

Hemostatic variables and ischemic cardiovascular disease: do we need a concerted effort for more profitable future clinical investigations?

Abnormally high levels of some hemostatic variables are often associated with the occurrence of the major ischemic complications of atherosclerosis, myocardial infarction, and stroke. Intervention studies have shown that prolonged treatment with antiplatelet drugs significantly reduces the recurrence of coronary and cerebral ischemic episodes. The association of the ischemic event with the hemostatic abnormality has often been just descriptive. Although suggestive, the link between the abnormality and the development and progression of atherosclerosis is only circumstantial. Finally, no information is available on the presence of one or more abnormal variables in subjects who did or did not experience a recurrence of thrombosis with treatment. To strengthen the clinical relevance of these hemostatic variables and to maximize the effectiveness of antithrombotic strategies, these indices should be taken into account in studies evaluating nonpharmacological and pharmacological interventions against arterial thrombosis. We believe that a task force on this subject would serve a useful purpose. The task force should develop and publicize within the cardiological community guidelines for (a) defining the size of the problem, (b) identifying the variables to measure, (c) standardizing detection and monitoring techniques, and (d) suggesting appropriate strategies of prevention and treatment.

Arteriosclerosis↗
PubMed1997

Endothelin abnormalities in patients with pulmonary embolism.

BACKGROUND: Endothelin (ET) is an endothelium-derived multifunctional peptide involved in the local regulation of the vascular tone. STUDY OBJECTIVES: To assess changes of endogenous ET production/excretion in the acute phase (36 h from the event) of pulmonary embolism (PE). PARTICIPANTS: Ten patients with acute PE, nine patients with acute lung injury (ALI), and 12 healthy volunteers (HVs). MEASUREMENTS AND RESULTS: ET was detected by radioimmunoassay in venous and arterial blood as well as in 24-h urine specimens. For each subject, arterial/venous immunoreactive ET (ir-ET) ratio was evaluated as an index of its pulmonary extraction/synthesis. Creatinine clearance was employed in each case to obtain a corrected renal ir-ET clearance. Renal ir-ET clearance was comparable in all three groups. Arterial/venous ir-ET ratio was comparable in PE and in ALI patients (1.31 +/- 0.25 vs 1.24 +/- 0.20; p = 0.7), while it was significantly higher in PE patients than in HV subjects (0.85 +/- 0.07; p = 0.0001). Accordingly, 24-h urine ir-ET excretion was higher in PE (120.50 +/- 27.36 ng/24 h) and ALI patients (135.80 +/- 21.60 ng/24 h) than in HV subjects (68.33 +/- 9.31 ng/24 h; p = 0.0001). CONCLUSIONS: Abnormalities of ET metabolism-mainly related to increased synthesis and/or defective pulmonary handling-occur in the acute phase of PE. The relevance of this finding with respect to the pathogenesis and/or management of pulmonary thromboembolism remains to be elucidated.

Acute Disease↗
PubMed1996

Drugs affecting plasma fibrinogen levels. Implications for new antithrombotic strategies.

Current evidence indicates that plasma fibrinogen is synthesized by the liver; that genetic and environmental factors regulate plasma fibrinogen levels; that interleukin-6 (IL-6) affects the synthesis of plasma fibrinogen by mechanisms involving protein kinase C, and that during the acute-phase response, monocytes generate a variety of monokines including IL-6. Certain drugs and nutrients have been reported to lower plasma fibrinogen levels. The mechanism(s) involved in this effect is poorly understood. However, since most of these substances quantitatively and/or qualitatively affect monocytes, the possibility that these drugs affect plasma fibrinogen levels via these cells should be considered. In addition to fibrinogen, IL-6 also regulates the synthesis of other acute-phase proteins. Especially when combined, major risk factors for atherosclerosis cause vascular injury that triggers inflammatory events. This raises the issue of whether high plasma fibrinogen levels are just the epiphenomenon of as yet unknown events in thrombosis and atherosclerosis. Thus, the issue to be addressed is whether high plasma fibrinogen concentrations should be lowered or should they serve to suggest strong interventions on established risk factors. As for other risk factors, fibrinogen measurements in population-based studies, in parallel with measurements of established risk factors will help define appropriate directions to be followed to gain insight into the issue and define new antithrombotic strategies.

Animals↗
PubMed1996

Deletion polymorphism in the angiotensin-converting enzyme gene in patients with a history of ischemic stroke.

We evaluated the genotypes of the angiotensin-converting enzyme (ACE) gene in 101 subjects with and 109 subjects without a history of ischemic stroke. All were attending a metabolic ward. The two groups were compared for major risk factors for ischemic events. Genotypes were determined by polymerase chain reaction with oligonucleotide primers flanking the polymorphic region in intron 16 of the ACE gene. Deletion polymorphism of the ACE gene (DD genotype) was shown to be more common in subjects with a history of stroke than in those without (relative risk, 1.76; confidence intervals, 1.02 to 3.05). A positive family history for ischemic complications of atherosclerosis was also more common in subjects with documented events (relative risk, 1.99; confidence intervals, 1.10 to 3.59). DD genotype and a positive family history were strong independent discriminators of cerebral ischemia. Plasma levels of tissue-type plasminogen activator (TPA) and plasminogen activator inhibitor-1 help identify subjects with a history of cerebral ischemic episodes. When such fibrinolytic variables were included in the analysis, the DD genotype still strongly and independently discriminated subjects with a stroke history and significantly interacted with TPA levels > 10 ng/mL in such identification. We conclude that in subjects attending a metabolic ward, homozygosity for a deletion polymorphism of the ACE gene consistently discriminates subjects with a stroke history. Interaction with TPA improves such identification.

Adult↗
PubMed1996

[Absence of an association of the D allele of the ACE gene with arterial pressure in mild-moderate essential arterial hypertension].

To assess the relationship between the angiotensin converting enzyme (ACE) gene I/D polymorphism, blood pressure (BP) and family history of hypertension, 133 hypertensive subjects (mean age 50 +/- 9 years, 78 males, 55 females) were selected according to both casual supine BP > 140/90 mmHg and ambulatory BP > 134/88 mmHg. Drug treatment was discontinued 2 weeks before entering the study. Subjects with myocardial ischemia, as well as those with "white coat" hypertension, were excluded. The study population was subclassified according to age < or = 50 years. Polymerase chain reaction was used to detect the I/D polymorphism of the ACE gene, and the DD genotype was analysed twice. The frequencies of the I and D allele were 42 and 58%, and the distribution of the ID+ II and DD genotypes were 69 and 31% respectively. No significant relation was found among ACE genotypes (DD vs ID+ II) and casual systolic or diastolic BP as well as ambulatory BP, both in the whole study population and in the subpopulation < 50 years old. No difference was found also in the distribution of dippers and no dippers, as well as in the distribution of subjects with a positive family history in the whole sample and hypertensives < 50 years old.

Adult↗
PubMed1995

Cu/Zn superoxide dismutase in patients with non-familial Alzheimer's disease.

Chromosome 21 contains genes whose altered expression has long been associated with Down's syndrome and whose altered structure with some cases of Alzheimer's disease (AD). The gene for the Cu/Zn superoxide dismutase enzyme (SOD-1), a key enzyme in the metabolism of oxygen free radicals, is located on the distal portion of chromosome 21. Due to the triplication of the SOD-1 gene, patients with Down's syndrome have an almost 50% increase in their SOD activity. On the other hand, almost 25% of the patients with Down's syndrome over 40 years of age develop progressive dementia, with clinical symptoms of AD. Therefore, we decided to evaluate whether abnormalities in the production of free radicals could be detected in blood cells from AD patients, and whether they correlated with molecular variations in the Cu/Zn SOD-1 gene. Superoxide anion production was evaluated spectrophotometrically in suspensions of monocytes from 9 sporadic AD patients, and from 9 aged-matched apparently normal controls. After stimulation with increasing concentrations of n-formyl-methionyl-leucyl-phenylalanine (fMLP) or Ca ionophore A23187, monocyte free radical generation was quantitatively and qualitatively normal. Furthermore, restriction fragment length polymorphism (RFLP) analysis of leukocyte DNA digested with a variety of enzymes, gave comparable results in patients and controls. Our data support the possibility that in addition to the generation of free radicals, other directions should be explored to elucidate the mechanisms of dementia in AD.

Aged↗
PubMed1995

Raised plasma fibrinogen concentrations in subjects attending a metabolic ward--relation to family history and vascular risk factors.

We have evaluated plasma fibrinogen levels in 171 subjects attending a metabolic ward. As in the general population, a significant difference in plasma fibrinogen concentrations (p < 0.05) was found between subjects with diabetes mellitus or hypertension and those without. However, fibrinogen was also abnormally high (p < 0.05) when evaluated according to the presence of a family history of ischemic complications of atherosclerosis (p < 0.05). In this setting, fibrinogen correlated with diabetes mellitus or hypertension as well as with familial risk, and the latter interacted with hypertension (p < 0.05) in accounting for plasma fibrinogen. The relationships between certain fibrinogen genotypes and familial risk have then been evaluated. Analysis of a locus (1.3 kb, HAE III digestion) of the promoter region of the B beta fibrinogen gene, identified a polymorphic cutting site. The allele with the alternative restriction site (H1) was associated with mean fibrinogen levels which were 0.1-0.3 g/l lower than those associated with the other allele (H2). This difference was not statistically significant. No obvious association was found between the familial risk and the presence of the H2 allele. We conclude that in a group of subjects from a metabolic ward, a positive family history for ischemic complications of atherosclerosis is consistently associated with high plasma fibrinogen levels. Interaction with hypertension significantly strengthens the association.

Adult↗
PubMed1994

Abnormally high circulation levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with a history of ischemic stroke.

We evaluated 106 subjects with and 109 subjects without a history of ischemic stroke. All were attending a metabolic ward. The two groups were compared for major risk factors for ischemic events. A positive family history for ischemic complications of atherosclerosis was more common in subjects with a history of stroke than in those without; moreover, plasma levels of plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (TPA) were higher in patients with documented previous events. A strong positive significant correlation was found between TPA and PAI-1 levels, and an interaction between age and TPA was observed when the sample was stratified according to ages being above or below 70 years. When the patient population was analyzed according to the number of ischemic events, it was found that 62 of the 106 subjects with a history of stroke had experienced more than one ischemic event. Under these conditions, the levels of TPA and PAI-1 still correlated with the occurrence of previous ischemic episodes. As in the whole patient sample, TPA was the strongest discriminator. We conclude that in subjects attending a metabolic ward, TPA and PAI-1 levels consistently help identify subjects with a history of cerebral ischemic episodes and that TPA is the strongest discriminator.

Adult↗
PubMed1993

Plasma predictors of ischemic complications of atherosclerosis: open issues.

In western countries, acute myocardial infarction is the commonest cause of morbidity and mortality [19]. An occlusive coronary thrombus on an ulcerated atherosclerotic plaque in the coronary arteries is the etiological event in more than 90% of patients with Q-wave myocardial infarction [38]. The underlying abnormality in non-Q-wave myocardial infarction is often a ruptured atherosclerotic plaque, which acts as a nidus for the deposition and activation of platelets. In this case, thrombosis occurs, but may not be totally occlusive, or an early spontaneous recanalization may occur. On the other hand, some clinical trials showed that a prolonged treatment with antiplatelet drugs significantly reduces the recurrence of coronary ischemia. Thus, atherosclerosis is a necessary condition for myocardial infarction, but it is not sufficient in that it usually needs the occurrence of thrombosis. However, only 25-30% of these thrombotic events are prevented by the administration of antiplatelets drugs. In recent years, epidemiological studies identified some hemostatic parameters whose abnormalities may help predict the risk of ischemic events: fibrinogen [14], plasminogen activator inhibitor-1 (PAI-1) [3], lipoprotein(a) [46], anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) [10], leukocyte count [34], blood viscosity [34]. Some of these, such as fibronogen and PAI-1 are acute-phase proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Anticardiolipin↗
PubMed1993

Functionally abnormal monocytes in hypercholesterolemia.

We investigated some functions of monocytes from 20 type IIa hypercholesterolemic (HC) and five homozygous familial hypercholesterolemic (FH) patients. Monocytes from the HC patients contained as much cholesterol and formed as much thromboxane B2 in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP) or calcium ionophore A23187 as those from normal individuals. In contrast, the generation of prostaglandin E2 and 6-ketoprostaglandin F1 alpha in response to these agonists was 1.5-3 times normal, and that of leukotriene B4 was 40-60% of the normal value (p < 0.05 for all). Studies in which the combination of fMLP or A23187 with sodium arachidonate were employed suggested that these abnormalities were independent of the availability of the endogenous substrate for the lipoxygenase or cyclooxygenase enzymes. Quantitatively and qualitatively comparable abnormalities were found in monocytes from the five FH patients, and these were little affected when the patients' plasma cholesterol levels were almost normalized by low density lipoprotein apheresis. In keeping with the abnormalities in the eicosanoid metabolism, monocytes from HC patients exhibited a defective ability (p < 0.05) to generate O2-, the extent of which was correlated with the impaired formation of leukotriene B4. On the other hand, adhesion studies indicated that patients' cells exhibited an abnormally high ability to adhere to glass (p < 0.01). These data indicate the presence of functionally abnormal monocytes in hypercholesterolemia and suggest a direction to be followed to understand the importance of such cells in the premature atherosclerosis that occurs in these patients.

Adolescent↗
PubMed1993

Abnormally high thromboxane biosynthesis in homozygous homocystinuria. Evidence for platelet involvement and probucol-sensitive mechanism.

Homocystinuria due to homozygous cystathionine beta-synthase deficiency is an inborn error of metabolism characterized by a high incidence of thrombosis and premature atherosclerosis. We evaluated TXA2 biosynthesis in vivo and several in vitro tests of platelet function in 11 homocystinuric patients and 12 healthy controls. In vitro, patients' platelet aggregation was within control values as were TXB2 formation, fibrinogen binding, and ATP secretion in response to thrombin. In contrast, the urinary excretion of 11-dehydro-TXB2, a major enzymatic derivative of TXA2, was > 2 SD of controls in all patients (1,724 +/- 828 pg/mg creatinine, mean +/- SD, in patients vs. 345 +/- 136 in controls, P < 0.001). The administration to four patients of low-dose aspirin (50 mg/d for 1 wk) reduced metabolite excretion by > 80%. The recovery of 11-dehydro-TXB2 excretion over the 10 d that followed aspirin cessation occurred with a pattern consistent with the entry into the circulation of platelets with intact cyclooxygenase activity. Prolonged partial reduction in the abnormally high excretion of both 11-dehydro-TXB2 and 2,3-dinor-TXB2, was also observed in seven patients who ingested 500 mg daily for 3 wk of the antioxidant drug probucol. These results provide evidence for enhanced thromboxane biosynthesis in homocystinuria and for its partial dependence on probucol-sensitive mechanisms. Furthermore, the elevated TXA2 formation in homocystinuria is likely to reflect, at least in part, in vivo platelet activation.

Adolescent↗
PubMed1992

Fibrinogen and mechanisms of thrombosis. A difficult link.

Epidemiological observations indicate that high plasma fibrinogen levels are strongly correlated to the frequency of two major thrombotic complications of atherosclerosis: stroke and myocardial infarction. Thrombosis is increasingly recognized as a central mechanism in stroke and myocardial infarction, and fibrinogen is involved in events thought to play a major role in thrombosis. Therefore, elucidation of the relationship between fibrinogen and thrombosis may strengthen the predictive value of this protein and define new interventions against stroke and myocardial infarction. In addition, advances in the understanding of the atherogenic potential of several risk factors of coronary heart disease took advantage of information emerging from the measurement of the factor in population-based studies. Thus, it is conceivable that measuring plasma fibrinogen to predict stroke and myocardial infarction is a major direction to be followed to gain insight into the thrombogenic potential on this protein and inspire new strategies against thrombotic complications of atherosclerosis.

Blood Viscosity↗