Resistant hypertriglyceridemia in a patient with high plasma levels of apolipoprotein CII.
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Adult↗
Biomedical subjects
G Pagano
Publications and source records attributed to G Pagano.
Platelet glycoprotein IIIa PlA1/A2 polymorphism and its relationship with diabetic nephropathy in type 2 diabetic patients.
OBJECTIVE: The increased prevalence of cardiovascular events in type 2-diabetic patients with micro- or macroalbuminuria is not completely explained by an excess of conventional risk factors for atherosclerosis. Genetic polymorphism within the platelet glycoprotein IIIa has been implicated in the etiology of acute coronary syndromes. We tested the hypothesis that the PI(A1/A2) polymorphism could in part account for the increased cardiovascular risk of type 2-diabetic patients with micro- or macroalbuminuria compared to normoalbuminuric diabetic patients. RESEARCH DESIGN AND METHODS: We have examined the PI(A1/A2) polymorphism of the platelet glycoprotein IIIa in type 2-diabetic patients: 94 with micro-, macroalbuminuria, and 94 with normoalbuminuria, matched for age, sex and body mass index. PI(A) genotypes were performed by polymerase chain reaction and restriction enzyme digestion. RESULTS: There was no significant difference in the prevalence of PI(A2)-positive genotypes (either PI(A1/A2) or PI(A2/A2)) in the two groups of patients (chi2 = 0.19, df = 1 , p = 0.66). CONCLUSIONS: These results suggest that carriage of the platelet glycoprotein IIIa PI(A2) allele does not contribute to explain the increased cardiovascular risk associated with micro- or macroalbuminuria in type 2 diabetes.
Aged↗
Effect of Sardinian heritage on risk and age at onset of type 1 diabetes: a demographic case-control study of Sardinian migrants.
BACKGROUND: Children of Sardinian heritage are at high risk of type 1 diabetes, whereas no data are available in young adults. Age at onset of type 1 diabetes could be associated with different relative weight of genetic susceptibility and environmental determinants in the pathogenesis of the disease. We test this hypothesis in subjects with Sardinian heritage 0-29 years of age living in the city of Turin, a highly industrialized area in Northern Italy. METHODS: In all, 202 cases with onset of type 1 diabetes aged 0-29 years during 1984-1991 and 1010 controls randomly selected from residents of the city of Turin, frequency-matched by sex and year of birth to cases, were included in this study. Name and place of birth of parents were ascertained by postal inquiry and linkage with city population and census files. Social class was based on the highest educational level of parents abstracted from 1991 and 1981 census files. RESULTS: Differential effects on risk of type 1 diabetes of Sardinian heritage and social class in the age groups 0-14 and 15-29 years were found. In children with one and both Sardinian parents the odds ratios (OR) were 2.09 (95% CI : 0.85-5.15) and 3.20 (95% CI : 0.75-13.64); in young adults 0.81 (95% CI : 0.18-3.64) and 1.95 (95% CI : 0.51-7.40), respectively. In subjects with low social class the OR were 1.16 (95% CI : 0.68-1.97) in children and 0.66 (95% CI : 0.41-1.05) in young adults. CONCLUSIONS: This study shows higher risk of type 1 diabetes in subjects of Sardinian heritage; higher risk in children than in young adults and a protective effect of low social class in young adults. These findings are consistent with the hypothesis of heterogeneity of type 1 diabetes by age at onset, with prevailing genetic effect in childhood and environmental determinants in adulthood.
Adolescent↗
Glycemic control and cardiovascular diseases in Type 2 diabetes mellitus. Beyond fasting glycemia and glycosylated hemoglobin.
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Blood Glucose↗
Low adherence of General Practitioners to National Cholesterol Education Program guidelines for the management of hyperlipidaemia.
Aim of our study was to assess adherence to the National Cholesterol Education Program Adult-Treatment Panel II (NCEP-ATP II) in patients cared for by General Practitioners (GPs) in an Italian community. The design of the work was cross-sectional cohort study; the base was an unselected cohort of 1,168 patients cared for by GPs and screened at our lipid clinic in 1994-1995 in the Province of Turin (Italy). Blood samples were collected after 12-hr fast to measure plasma levels of total cholesterol, triglycerides, HDL-cholesterol, glucose and thyroid-stimulating hormone (TSH). LDL-cholesterol was calculated using Friedewald's formula. In patients with body mass index (BMI) >30 kg/m2, an oral glucose tolerance test was performed. Blood pressure was measured in all patients, and a baseline ECG or a stress test was performed in those with unknown cardiovascular disease (CVD), then they were classified following the NCEP-ATP II criteria. Primary hyperlipidaemia accounted for 86.9% of the cohort with most patients requiring pharmacological treatment; in 34.4% of the patients, LDL-cholesterol values were > or = 6.46 mmol/l (250 mg/dl) and in 23.7% with established CVD, LDL-cholesterol levels were > or = 5.68 mmol/l (220 mg/dl). In only 7.3% of patients the NCEP treatment goals were achieved, with 1.3% among those in secondary prevention. We observed great discrepancies between clinical practice and international recommendations for the management of hyperlipidaemia.
Adult↗
Apolipoprotein H is increased in type 2 diabetic patients with microalbuminuria.
BACKGROUND AND AIM: Serum apolipoprotein H (Apo H) levels are increased in hyperlipidemic subjects and type 2 diabetics, but unknown in microalbuminuria, another disorder with an increased cardiovascular risk. We looked to see whether increased Apo H levels are associated with microalbuminuria in type 2 diabetes. METHODS AND RESULTS: Serum Apo H was calculated in 20 normoalbuminuric and 17 microalbuminuric type 2 diabetics matched for age, sex, body mass index (BMI), glycosylated haemoglobin, plasma lipids and duration of diabetes, and also compared with 20 non-diabetic controls matched for age, sex, BMI and plasma lipids. Mean serum Apo H was significantly higher in the microalbuminuric patients (31.12 +/- 1.58 SEM vs 25.25 +/- 1.52 and 24.72 +/- 0.99 mg/dL, p = 0.003). CONCLUSION: Serum apo H levels are increased in type 2 diabetics with microalbuminuria.
Albuminuria↗
A phase II safety and efficacy study of amprenavir in combination with zidovudine and lamivudine in HIV-infected patients with limited antiretroviral experience. Amprenavir PROAB2002 Study Team.
OBJECTIVE: To determine the safety and efficacy of amprenavir (APV) in combination with lamivudine (3TC) and zidovudine (ZDV). DESIGN: Multicenter, randomized, partially blinded trial. SETTING: Nine study sites in the United States and Europe. PATIENTS: A group of 84 HIV-infected subjects with no prior 3TC or protease inhibitor therapy experience, CD4 cell count > or = 150 x 10(6) cells/l, and plasma HIV RNA > 10000 copies/ml. INTERVENTIONS: 3TC/ZDV with one of three doses of APV (900, 1050, or 1200 mg) versus 3TC/ZDV with 1050 mg placebo. All medications were dosed twice daily. The 1050 mg placebo and the APV 1050 mg dose were administered blinded. After 12 weeks, APV 1050 mg was substituted for 1050 mg placebo in the control group and the blind was maintained. MAIN OUTCOME MEASURES: Reduction in plasma HIV RNA from baseline; proportion of subjects with plasma HIV RNA < 400 copies/ml; and an increase in CD4 cell count from baseline. RESULTS: During the initial 12-week study period, APV/3TC/ZDV-treated subjects had greater viral suppression than the group receiving two nucleosides. By 48 weeks, 89% of subjects in the group taking the highest APV dose (1200 mg) had plasma HIV RNA < 400 copies/ml while 42% of the 900 mg group and 60% of the 3TC/ZDV group (1050 mg APV added at week 12) had plasma HIV RNA < 400 copies/ml using an as-treated analysis. By 60 weeks, 86% of subjects in the APV 1200 mg group had plasma HIV RNA < 400 copies/ml in the as-treated analysis, while 25% (900 mg), 43% (1050 mg), and 20% (1200 mg) of subjects had viral load <400 copies/ml in a strict intent-to-treat analysis owing to treatment discontinuations. Median CD4 cell count increases at week 60 were highest for the three treatment groups who received APV throughout the study, by intent-to-treat and as-treated analyses. The most common adverse events considered to be possibly drug related were nausea, rash, oral paresthesia, diarrhea, and fatigue. CONCLUSIONS: Treatment with APV, dosed at 1200 mg twice daily in combination with 3TC/ZDV, resulted in sustained viral suppression. This combination represents a potent alternative initial antiretroviral regimen for protease inhibitor-naive individuals.
Adult↗
Mitomycin C-induced DNA damage in Fanconi anemia: cross-linking or redox-mediated effects?
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Animals↗
Impact of glycaemic control, hypertension and insulin treatment on general and cause-specific mortality: an Italian population-based cohort of type II (non-insulin-dependent) diabetes mellitus.
The aims of this study were to assess the impact of diabetes and associated variables (fasting plasma glucose, blood pressure, antidiabetic treatment, body mass index) on general and cause-specific mortality in an Italian population-based cohort with Type II (non-insulin-dependent) diabetes mellitus, comprising mainly elderly patients. The patients (n = 1967) who had Type II diabetes were identified in 1988 with an 80% estimated completeness of ascertainment. In 1995, a mortality follow-up (98% completeness) of the cohort was done amounting to a total of 11153 person-years. Observed and expected number of deaths were 577 and 428.7, respectively, giving a standardized mortality ratio (SMR) of 1.35 (95% CI 1.24-1.46). The most common underlying causes of death were malignant neoplasm, ischaemic heart disease and cerebrovascular diseases, which accounted for 18%, 17.8% and 17.5% of deaths, respectively. Cardiovascular disease as a whole (international classification of disease ICD-9 390-459) accounted for 260 of 577 deaths (SMR 1.21, 95% CI 1.07-1.36). In internal analysis, the most important predictors of general mortality were insulin-treatment (relative risk [RR] 1.72, 95% CI 1.19-2.49) and a fasting plasma glucose greater than 8.89 mmol/l ([RR] 1.29, 95 % CI 1.04-1.60), whereas the most important predictors of cardiovascular diseases were insulin-treatment and hypertension. In conclusion, this population-based study showed: 1) slight mortality excess of 35% in Type II diabetes being associated with 2) a 30% increased mortality in subjects with baseline fasting glucose greater than 8.89 mmol/l and 3) a 40% increased risk of death from cardiovascular diseases in hypertensive patients.
Aged↗
Study of the glycosylation of apolipoprotein H.
Apolipoprotein H is a single chain polypeptide composed of 326 amino acids highly glycosylated. Its carbohydrate content is approximately 19% of the molecular weight. We show that it is rich in sialic acid linked alpha (2-6) to galactose or N-acetylgalactosamine. Sialic acid is not alpha (2-3) linked to galactose. Galactose is beta (1-4) linked to N-acetylglucosamine and beta (1-3) linked to N-acetylgalactosamine. Carbohydrate O-linked chains (mainly sialic acid) are alpha (2-6) linked to galactose or N-acetylgalactosamine. Galactose is also organised in O-linked chains and beta (1-4) linked to N-acetylglucosamine and beta (1-3) linked to acetylgalactosamine. Concanavalin A lectin was used to isolate two groups of apolipoprotein H molecules bearing biantennary and truncated hybrids and high mannose and hybrid oligosaccharides. Apolipoprotein H fails to bind lysine-Sepharose. Our results thus show that it presents truncated hybrid or hybrid-type carbohydrate chains which bear few unmasked mannose residues as a terminal sugar. Biochemical analysis of carbohydrate structures conducted on single isoforms separated through IEF revealed that no specific carbohydrate complex is bound to a single isoform.
Chromatography, Affinity↗
Human lipoprotein lipase HindIII polymorphism in young patients with myocardial infarction.
We investigated the possibility that the DNA HindIII polymorphism of human lipoprotein lipase (LPL) is associated with the severity of coronary artery disease (CAD) determined by angiography in young patients who survived a myocardial infarction (MI). Conflicting studies have explored the relationship linking CAD severity to the HindIII restriction site polymorphism at the LPL gene locus, and to our knowledge, no data are available from Italy. The patients were aged less than 45 years (mean age, 40.1 +/- 3.9 years); 83 were male and four were female. The 87 case-patients had a Q-wave or non-Q-wave infarction (67.3% and 32.7%, respectively); the MI was anterior (50.5%), lateral (41.7%), or inferior (7.8%). Analysis of coronary angiograms showed the absence of critical stenosis in 13.8% and the presence of monovessel disease in 50.6% and multivessel disease in 35.6% of the case-patients. The allelic frequency of the HindIII H(-) and H(+) allele was 0.37 and 0.63, respectively. There was a striking association between the HindIII polymorphism and the number of diseased vessels. The patients with HindIII(+/+) genotypes were significantly more likely to have double- or triple-vessel disease and less likely to have no significantly diseased vessels. In this study, we demonstrated that the homozygous form of the LPL HindIII(+) allele increases the risk of multivessel disease by a factor of 4 in an Italian group of young MI survivors. This association was independent from the smoking status and a positive family history for CAD and hypertension, which are known to predict CAD severity. The discrepancies in the results of these studies are difficult to explain. The lack of homogeneity in the study populations (age at which CAD occurred, number of enrolled patients, and geographical origin) and differences in the assessment of CAD severity may account for these conflicting results.
Adult↗
The binding of apolipoprotein H (beta2-Glycoprotein I) to lipoproteins.
Beta2-glycoprotein I has a high affinity for triglyceride-rich particles, activates lipoprotein lipase, and is also defined as an apolipoprotein H. Previous studies have shown that apolipoprotein H is a regular structural component of the major classes of lipoproteins. In view of these findings, we analyzed the interactions of apolipoprotein H with lipoproteins in the fasting plasma of eight normal, seven hypertriglyceridemic, and seven hypercholesterolemic subjects. After rate-zonal, density gradient ultracentrifugation, apolipoprotein H was little distributed among the different density fractions, and most of it was recovered in the last fraction that contained the lipoprotein-free plasma. A small percentage (4-13%) of the apolipoprotein H associated with plasma lipoproteins was detected at the density ranging from 1.090 to 1.225 g/ml. This result means that apolipoprotein H is little associated with lipoproteins.
Case-Control Studies↗
Cardiovascular risk profile of type 2 diabetic patients cared for by general practitioners or at a diabetes clinic: a population-based study.
The aims of this study were to compare the cardiovascular risk profiles of patients with type 2 diabetes mellitus cared for by general practitioners and those regularly attending a diabetes center. Out of an Italian population-based cohort of 1967 diabetic patients, 1574 (80%) were investigated. Patients exclusively cared for by general practitioners (23.8%) were older and showed lower prevalence of hypertension (79.0% vs 85.9%, P < 0.001), poor blood glucose control (HbA1c >8.0, 33.4% vs 47.9%, P < 0.001) and coronary heart disease (18.1% vs 22.3%, P = 0.003), and lower plasma fibrinogen (3.5 +/- 0.8 vs 3.7 +/- 0.9 g/L, P < 0.001). In logistic regression analysis, they had significantly lower ORs for HbA1c >8.8% (OR 0.67, 95% CI 0.45-0.99), hypertension (OR 0.53, 95% CI 0.36-0.78), fibrinogen >4.1 g/L (OR 0.50, 95% CI 0.32-0.77), smoking (OR 0.60, 95% Cl 0.36-1.00), and coronary heart disease (OR 0.65, 95% CI 0.45-0.93), after adjustment for age, sex, duration of diabetes, BMI, and antidiabetic treatment. Patients regularly cared for at a diabetes clinic had a higher cardiovascular risk profile, suggesting selective referral to the clinics of patients with more difficult management and/or severity of the disease. These findings have implications in the interpretation of morbidity and mortality clinic-based studies.
Aged↗
Apolipoprotein H is not affected by in vitro glycosylation.
Increased nonenzymatic glycosylation of all major classes of apolipoproteins has been demonstrated in diabetes. In this work we deal with the in vitro nonenzymatic glycosylation of apolipoprotein H, whose role in lipid metabolism is still poorly understood and whose levels increase in diabetes. Apolipoprotein H was isolated from human plasma and purified through a combination of affinity chromatography and continuous elution electrophoresis. The in vitro glycosylation was performed by incubating purified apolipoprotein H with high concentration of glucose. Our results indicate that the in vitro nonenzymatic glycosylation has no effect on the physical properties of apolipoprotein H, despite the fact that this apolipoprotein contains a high number of lysine residues. Since the in vitro concentration of glucose was far higher than the levels normally found in diabetic subjects, it is unlikely for apolipoprotein H to become glycosylated in diabetes.
Blotting, Western↗
Acute methylprednisolone administration induces a transient alteration of glucose tolerance and pyruvate dehydrogenase in humans.
BACKGROUND: Glucocorticoid administration induces alteration of glucose tolerance, and impairment of glucose oxidation may contribute to glucocorticoid-induced derangement of glucose metabolism. We investigated glucose tolerance following methylprednisolone administration in humans. In the same model, we evaluated pyruvate dehydrogenase (PDH), the rate limiting enzyme of glucose oxidation, in peripheral blood mononuclear cells. MATERIALS AND METHODS: Methylprednisolone (2 x 40 mg, iv, one dose every 12 h) was administered to six healthy volunteers. Glucose tolerance was evaluated through an oral glucose tolerance test (oGTT, 75 g glucose) at least a week before and after drug administration (2 and 24 h post-drug). To assess modifications of lipid metabolism circulating free fatty acids (FFA) and glycerol were measured, during fasting and oGTT. The active form of PDH (PDHa) was evaluated in peripheral blood mononuclear cells, both as ex vivo activity and as in vitro response to insulin (30 pmol l-1). RESULTS: Methylprednisolone induced an alteration of glucose tolerance 2 h after its administration. Such alteration was completely reversed at 24 h. Alteration of glucose tolerance was accompanied by decreased ex vivo PDHa activity. PDH responsiveness to insulin in vitro was also impaired. Circulating FFA were unmodified, but decreased glycerol levels suggested a slight inhibition of lipolysis. CONCLUSIONS: Acute methylprednisolone administration in humans induced a transient decrease of glucose tolerance 2 h after drug administration, accompanied by hyperinsulinaemia, inhibition of ex vivo PDH activity and its response to insulin in vitro. These alterations were completely abolished at 24 h, suggesting that methylprednisolone can be safely administered acutely. Furthermore, methylprednisolone induced only minor modifications of circulating FFA and glycerol, indicating minimal impact on lipid metabolism.
Adult↗
Clinical, immunological, and genetic heterogeneity of diabetes in an Italian population-based cohort of lean newly diagnosed patients aged 30-54 years. Piedmont Study Group for Diabetes Epidemiology.
OBJECTIVE: In lean diabetic patients, the presentation of the disease does not allow one to easily distinguish between type 1 and type 2. Aims of this study were to describe clinical, immunological, and genetic features of lean newly diagnosed diabetic patients. RESEARCH DESIGN AND METHODS: A population-based cohort of 130 lean (BMI < 25 kg/m2) newly diagnosed patients, aged 30-54 years, was identified among residents of the province of Turin. Islet cell antibodies (ICAs), anti-GAD, fasting and glucagon-stimulated C-peptide values, and HLA DQA1-DQB1 susceptibility genotypes were assessed within 2 months of the diagnosis. RESULTS: A total of 45 (34.6%) and 29 (22.3%) patients were, respectively, ICA+ and anti-GAD+, with 15 (11.5%) having both antibodies. In 59 patients, ICAs and/or anti-GAD antibodies were detected, giving a high prevalence of autoimmunity (45.4%, 95% Cl 36.8-54.0); relative to patients without markers (n = 71), they were younger (40.8 +/- 7.5 vs. 45.0 +/- 6.5 years, P < 0.001) and showed lower values of fasting C-peptide (0.56 +/- 0.33 vs. 0.79 +/- 0.41 nmol/l, P < 0.001) and stimulated C-peptide (1.03 +/- 0.56 vs. 1.42 +/- 0.69 nmol/l, P < 0.001). The lowest stimulated C-peptide values were found in patients with both ICA and anti-GAD antibodies. Frequencies of adult-onset type 1 and type 2 diabetes were, respectively, 49.2 and 50.8%. Clinical and genetic features were not useful in the classification of patients. CONCLUSIONS: Almost 50% of lean young and middle-aged patients were ICA+ and/or anti-GAD+, suggesting a high prevalence of a slowly evolving form of type 1 diabetes. The evaluation at diagnosis of both beta-cell secretory capacity and markers of autoimmunity is recommended to provide a pathogenetic classification of the disease.
Adult↗
Concordance between American Diabetes Association and World Health Organization criteria in a northwestern Italian population.
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Blood Glucose↗
Role of lipid, apolipoprotein levels and apolipoprotein E genotype in young Italian patients with myocardial infarction.
BACKGROUND AND AIM: Studies of young patients with acute myocardial infarction (AMI) have demonstrated that conventional risk factors are usually responsible for their premature atherosclerosis. No account has yet been published of the risk profile of young Italians surviving an AMI. In this study, the conventional risk factors, lipids and apolipoproteins, and apolipoprotein E (APOE) allele distribution were evaluated in 98 consecutive AMI survivors (94 males, 4 females) aged 40.1 +/- 3.9 for at least three months after their acute event. These survivors were matched for age, sex, body mass index and presence of diabetes mellitus with 98 controls selected from subjects admitted to the same hospital for other reasons. METHODS AND RESULTS: Lipid profiles and APOE polymorphism were determined in both groups. Coronary angiography during hospitalization showed the absence of critical stenosis in 6.6% of the survivors, mono-vessel disease in 57.7%, and multi-vessel disease in 35.5%. The survivors had a higher frequency of smoking, hypertension, family history for coronary artery disease (CAD) and dyslipidemia, and a much greater frequency of 3 or more risk factors than the controls: Odd ratios (OR) 7.4, 95% confidence interval (CI) 2.5-18.6, p = 0.0000. Significant differences were found between the groups for triglycerides (p = 0.000002), total cholesterol (p = 0.003), LDL-cholesterol (p = 0.012), HDL-cholesterol (p = 0.0002), apolipoprotein AI (p = 0.00001), and Apolipoprotein B (p = 0.000001). No differences were observed in APOE allele distribution (APOE*4 0.11 vs 0.08, APOE*3 0.86 vs 0.89, APOE*2 0.03 vs 0.03), nor in lipid profile when both higher risk genotype (E3/4, E4/4, E2/4) and lower risk genotype groups (E2/2, E2/3, E3/3) were analysed. OR were calculated as measures of the association of the E4-positive genotypes with AMI. They indicated a non-significant increase in risk of AMI when the survivors were compared with the controls (OR 1.78, 95% CI 0.84-3.70, p = 0.13). CONCLUSIONS: This study provides further evidence that conventional coronary risk factors are usually present in young AMI patients. The APOE*4 allele was associated with a 1.8 non-significant increase in the risk of AMI in our group with premature CAD. Comparison with controls showed that the presence of three or more risk factors sharply increased the probability of premature CAD and that hyper-triglyceridemia is an independent risk factor. The data on APOE polymorphism are less certain and a larger study is needed.
Adult↗