Baseline metabolic disturbances and the twenty-five years risk of incident cancer in a Mediterranean population.

BACKGROUND AND AIMS: Obesity is predictive of metabolic syndrome (metS), type 2 diabetes, cardiovascular (CV) disease and cancer. The aim of the study is to assess the risk of incident cancer connected to obesity and metS in a Mediterranean population characterized by a high prevalence of obesity. METHODS AND RESULTS: As many as 1133 subjects were enrolled in two phases and followed for 25 years (859 subjects) or 11 years (274 subjects) and incident cancer was registered in the follow-up period. Anthropometric measures and biochemical parameters were filed at baseline and evaluated as predictors of incident cancer by measuring hazards ratios (HR) using multivariate Cox parametric hazards models. Best predictive threshold for metabolic parameters and metS criteria were recalculated by ROC analysis. Fasting Blood Glucose >5.19 mmol/L [HR = 1.58 (1.0-2.4)] and the TG/HDL ratio (log10) (Males > 0.225, Females > 0.272) [HR = 2.44 (1.3-4.4)] resulted independent predictors of survival free of cancer with a clear additive effect together with age classes [45-65 years, HR = 2.47 (1.3-4.4), 65-75 years HR = 3.80 (2.0-7.1)] and male gender [HR = 2.07 (2.3-3.1)]. CONCLUSIONS: Metabolic disturbances are predictive of cancer in a 25 years follow-up of a Mediterranean population following a traditional Mediterranean diet. The high prevalence of obesity and metS and the observed underlying condition of insulin resistance expose this population to an increased risk of cardiovascular disease and cancer despite the healthy nutritional habits.

Hyperuricemia and Risk of Cardiovascular Outcomes: The Experience of the URRAH (Uric Acid Right for Heart Health) Project.

The latest European Guidelines of Arterial Hypertension have officially introduced uric acid evaluation among the cardiovascular risk factors that should be evaluated in order to stratify patient's risk. In fact, it has been extensively evaluated and demonstrated to be an independent predictor not only of all-cause and cardiovascular mortality, but also of myocardial infraction, stroke and heart failure. Despite the large number of studies on this topic, an important open question that still need to be answered is the identification of a cardiovascular uric acid cut-off value. The actual hyperuricemia cut-off (> 6 mg/dL in women and 7 mg/dL in men) is principally based on the saturation point of uric acid but previous evidence suggests that the negative impact of cardiovascular system could occur also at lower levels. In this context, the Working Group on uric acid and CV risk of the Italian Society of Hypertension has designed the Uric acid Right for heArt Health project. The primary objective of this project is to define the level of uricemia above which the independent risk of CV disease may increase in a significantly manner. In this review we will summarize the first results obtained and describe the further planned analysis.

Hypertension and diabetes mellitus are associated with cardiovascular events in the elderly without cardiovascular disease. Results of a 15-year follow-up in a Mediterranean population.

BACKGROUND AND AIMS: Epidemiological prospective data on cardiovascular (CV) events in elderly subjects from Mediterranean populations are lacking. We aimed to investigate 15-year incidence of CV events and to evaluate the association with CV risk factors in an elderly Mediterranean population. METHODS AND RESULTS: The population of a small Sicilian village were enrolled, visited and a blood sample was drawn at baseline. CV events were recorded in the 15 years of follow-up. From 1351 subjects (75% of the resident population); 315 were in the age range 65-85 years; 266 subjects free from CV disease were analysed. Seventy-seven CV events were recorded in 73 out of 266 subjects, with a 19.7% rate (in 10 years). Hypertension (HTN) (hazards ratio=2.1) and diabetes mellitus (DM) (hazards ratio=1.8) were independently associated with CV events. Subjects with both DM and HTN showed a lower survival free of CV events compared to those with DM or HTN. CONCLUSIONS: In a 15-year follow-up of an elderly Mediterranean population free from CV disease, diabetes mellitus and hypertension were related to CV events. The control of risk factors in the elderly needs to be reinforced to achieve better results in terms of CV prevention.

Effects of synvinolin on platelet aggregation and thromboxane B2 synthesis in type IIa hypercholesterolemic patients.

An increased susceptibility of platelets to aggregation induced by various agents and a higher production of active arachidonate metabolism have been described in type IIa hypercholesterolemia. This study was designed to evaluate whether changes in platelet function could be observed in hypercholesterolemic patients after synvinolin therapy. Administration of synvinolin to 12 type IIa hypercholesterolemic patients for 24 weeks had a lipid lowering effect and resulted in a marked reduction of platelet aggregation and thromboxane formation induced by collagen and arachidonate. Maximum response was achieved at 4-8 weeks and lipid lowering effects at 2 weeks. This finding indicates that platelet changes cannot be explained by a direct effect of synvinolin on platelets, and the antiplatelet response may therefore depend on platelet membrane lipid composition changes, particularly in the platelet cholesterol content of platelet membranes, following substantial reductions of total plasma cholesterol and LDL-cholesterol.

Leukocyte count, diabetes mellitus and age are strong predictors of stroke in a rural population in southern Italy: an 8-year follow-up.

Stroke incidence rates in the Mediterranean area are higher compared to northern European countries. In this study, we present the 8-year prospective data from a small rural Sicilian town. This population, consisting of 1351 subjects (622 males and 729 females), is homogeneous for ethnic background with traditional healthy dietary habits and shows low cholesterol mean levels. We found that the risk of stroke was significantly associated with the record of at least one previous neurological symptom (PNS), such as lack of strength, loss of vision or speech or possible drop attacks, and high hematocrit in males, and to high body mass index (BMI) and waist-hip ratio (WHR), diabetes, hypertension, high leukocyte count in females. We also documented age-related differences: stroke was associated in younger subjects (age<65 years) with diabetes, high BMI, high uric acid levels and in older patients (age>/=65 years) with high WHR, hypertension, diabetes, PNS, leukocyte count and hematocrit above the 95th percentile. Multivariate analysis demonstrated an independent association between stroke and age, diabetes, leukocyte count, hypertension and PNS. In conclusion, in this rural Sicilian population, the incidence rate of stroke is 1.72 cases per 1000/year in the subjects between 40 and 75 years of age. The risk factors associated with stroke are different in younger and older subjects. Leukocyte count, as an expression of an undergoing inflammatory process, may have a relevant role at least in the elderly.

Autosomal recessive hypercholesterolemia in a Sicilian kindred harboring the 432insA mutation of the ARH gene.

We describe a Sicilian family presenting a recessive form of hypercholesterolemia harboring a mutation of the autosomal recessive hypercholesterolemia (ARH) gene. In two of the three sibs, a 26-year-old male and a 22-year-old female, a severe hypercholesterolemia was diagnosed with very high levels of plasma cholesterol (15.9 and 12.2 mmol/l, respectively); tendon xanthomatas and xanthelasms were present and in the male proband was documented a diffuse coronary atherosclerotic disease with a rapid and fatal progression. Both the parents had normal or slightly increased levels of plasma cholesterol. All causes of secondary hypercholesterolemia were ruled out as well as an involvement of the LDL receptor or apoB genes. Beta-Sitosterol plasma levels were in the normal range. Cultured fibroblasts from skin biopsy from parents and the two probands displayed a normal ability to bind and degrade 125I-LDL. Direct sequencing of ARH gene demonstrated the presence of a 432insA mutation in homozygosis in the two probands; parents were heterozygotes for the same mutation. This mutation is the first report of a mutation of the ARH gene responsible for recessive forms of hypercholesterolemia in Sicily.

Carotid atherosclerosis in renal transplant recipients: relationships with cardiovascular risk factors and plasma lipoproteins.

BACKGROUND: Renal transplant recipients have an increased incidence of cardiovascular disease, but less data exist about cerebrovascular atherosclerosis. In this study, we assessed the prevalence of carotid lesions as evaluated by B-mode ultrasonography in a group of renal transplant recipients, and we evaluated univariate and multivariate relationships between common risk factors and plasma lipoproteins and carotid lesions. METHODS: Fifty-seven renal transplant recipients and 113 age- and gender-matched controls underwent a complete clinical visit for the evaluation of risk factors present. In all subjects, a blood sample was collected for lipoprotein determination, and an ultrasound high-resolution B-mode imaging examination of the common carotid arteries was performed. RESULTS: We found that among renal transplant recipients, there was a significantly increased prevalence of subjects with plaque in comparison with controls (24.6% vs. 6.2%, P<0.001). At multiple analysis, carotid lesions were independently associated with age, hypertension, diabetes, smoking habit, and the presence of cardiovascular disease in controls and with age and hypertension in renal transplant recipients. Neither the lipid profile nor the presence of dyslipidemias was related to carotid score in renal transplant recipients, whereas a nonsignificant trend was observed in controls. Finally, in transplant patients, we did not find any association between carotid lesions and high-density lipoprotein subfractions. CONCLUSIONS: Age and hypertension are the main predictors of extracranial cerebrovascular atherosclerosis after renal transplantation. Because carotid lesions may represent a useful predictive marker of clinical events in nontransplant subjects, carotid artery evaluation by B-mode ultrasound might be routinely included in the management of renal transplant patients.

Factor VII activity is an independent predictor of cardiovascular mortality in elderly women of a Sicilian population: results of an 11-year follow-up.

The aim of the Epidemiological project "Ventimiglia di Sicilia" is to identify the cardiovascular risk factors in a Sicilian population with a low risk profile and healthy nutritional habits. The risk of cardiovascular mortality in older subjects (over 60 years of age) is presented for an 11 year follow-up. Females showed higher prevalence of diabetes mellitus, hypertension, obesity and higher levels of total, LDL and HDL cholesterol, factor VII activity and fibrinogen compared to males. Cardiovascular mortality was related to hypertension and obesity in males, to high factor VII activity, obesity and diabetes mellitus in females. In a Logistic Regression model the same variables were independently correlated to cardiovascular mortality with the exception of obesity. In conclusion, these findings suggest that in a population with a low risk profile, other factors, such as factor VII activity, may emerge as predictors of cardiovascular mortality.

Serum apolipoprotein profile of hypertriglyceridemic patients with chronic renal failure on hemodialysis: a comparison with type IV hyperlipoproteinemic patients.

Thirty-three patients with chronic renal failure (CRF) and uremic hypertriglyceridemia (HTG) on hemodialysis were compared with 33 type IV hyperlipoproteinemic patients matched for age, body mass index (BMI), and triglyceride (TG) levels. The two forms of hypertriglyceridemia showed different apolipoprotein profiles: apo AI, AII, and B levels and apo CII:CIII and TG:apo CIII ratios of CRF-HTG patients were lower and apo CIII levels were higher than the levels of type IV subjects.

Plasma levels of lipoproteins and apolipoproteins in congenital hypothyroidism: effects of L-thyroxine substitution therapy.

Thyroid status in humans is an important factor in the regulation of lipoprotein metabolism. There are several data on hypothyroidism in the adult population, but less information is available about congenital hypothyroidism. Since lipid metabolism at birth is substantially different from that of adults, it is not likely that the same abnormalities that occur in adult hypothyroidism are also present when this is diagnosed at early life. We studied 16 subjects with congenital hypothyroidism, seven at the time of diagnosis and also after normalization of thyroid hormone levels over a period of 2.0 +/- 1.0 months of substitution therapy with L-thyroxine (5.9 +/- 1.2 micrograms/kg/d) and nine already on L-thyroxine therapy for a period of 4.7 +/- 3.2 months. Thirty-nine apparently healthy subjects matched for age were selected as controls. In all subjects, total cholesterol (CHO), triglycerides (TG), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol (HDL-C), apolipoproteins (apo) A-I and B, lipoprotein(a) [Lp(a)] thyrotropin (TSH), (LDL-C), total and free thyroxine (T4), and triiodothyronine (T3) were determined. CHO, HDL-C, and apo A-I levels were significantly higher in patients at the time of diagnosis than in controls (respectively, P = .0079, .0007, and .0004), whereas TG, LDL-C, apo B, and Lp(a) levels were not significantly different. During L-thyroxine substitution therapy in these subjects, HDL-C and apo A-I levels significantly decreased (respectively, by a mean of -36.2% and -24.4%), with similar behavior in all subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

A new case of apo C-II deficiency with a nonsense mutation in the apo C-II gene.

The apo C-II gene from a patient with apo C-II deficiency has been sequenced after amplification by the polymerase chain reaction (PCR). The sequence analysis revealed a substitution of adenosine for cytosine at position 3,002 in exon 3, leading to the introduction of a premature stop codon (TAA) at a position corresponding to aminoacid 37 of mature apo C-II. This mutation creates a new Rsa I restriction enzyme site in the apo C-II gene. Amplification of DNA from family members by PCR and digestion with Rsa I established that the patient is a true homozygote for this mutation. The same nucleotide has been substituted for the mutation apo C-IIPadova and apo C-IIBari previously described in two kindreds from Italy. From these data we speculate that base pair 3,002 in the apo C-II gene may represent a hot spot for mutation.

The C(-260)>T gene polymorphism in the promoter of the CD14 monocyte receptor gene is not associated with acute myocardial infarction.

CD surface molecules mediates cell activation and signaling. In particular, CD14 on blood monocytes mediate monocyte/macrophage activation by lipopolysaccharide. Lipopolysaccharide and its receptor, CD14, have been implicated in atherogenesis. It has been recently shown that a C(-260)T polymorphism in the promoter of the CD14 receptor may be a risk factor for coronary artery disease. Recently this association has been questioned because no increased risk was found with the T allele, even in the homozygous state. In the present study we investigated a possible association between the C(-260)T polymorphism in the CD14 promoter and acute myocardial infarction. Two hundred and thrteen patients with and acute myocardial infarction 213 healthy controls were included in the study. Genotype frequencies of the C(-260)T polymorphism in the CD14 promoter were determined by polimerase chain reaction and the amplified product was cleaved with HaeIII. The frequency of the T allele was not significantly different in patients compared with controls. In this study we were not able to detect differences of frequency of the allele T (-260) in the promoter of the CD14 receptor gene in survivors of myocardial infarction and controls.

Italian familial defective apolipoprotein B patients share a unique haplotype with other Caucasian patients.

Familial defective apolipoprotein (apo) B-100 together with familial hypercholesterolemia are the two common genetic conditions that cause hypercholesterolemia. Familial defective apolipoprotein B-100 is due to mutations around codon 3500 of the apo B gene. The most-characterized mutation is a G>A transition at nucleotide 10,708 that results in the substitution of arginine by glutamine at codon 3500 (Apo B Arg3500Gln). Two other mutations are caused by a C>T transition, one at nucleotide 10,800 (Apo B Arg3531Cys) and the other at nucleotide 10,707 (apo B Arg3500Trp). In the present study we describe three new Italian cases of familial defective apolipoprotein B-100 (Apo B Arg3500Gln), one from the Liguria region and two from Sicily, and the haplotype of the apo B gene co-segregating with the mutation. By screening two groups of probands, clinically diagnosed as having Familial Hypercholesterolemia (700 from mainland Italy and 305 from Sicily), the prevalence of familial defective apolipoprotein B-100 due to Arg3500Gln was found to be very low (0.28% and 0.65%, respectively). The Arg3531Cys mutation was not detected in any proband. In the three new families with Arg3500Gln mutation in the present study and in one previously described in Italy, the mutation was associated with a unique apo B haplotype, which is consistent with data previously reported for Caucasian patients [XbaI-, MspI+, EcoRI-, presence of the 5' signal peptide insertion (Ins) allele, and the 49-repeat allele of the 3'-VNTR].

[Diet and psychological therapy in a group of severely obese patients]. / Terapia dietetica e psicologica in un gruppo di grandi obesi.

The authors evaluated the usefulness of the psychological therapy in addition to usual diet treatment. Fifty subjects with severe obesity, have been randomly assigned to two different treatment groups: a) diet; b) diet plus psychotherapy. At the end of the study only the patients treated with diet plus psychotherapy showed any highly significant body weight reduction and a better diet adherence.

Apo-lipoprotein profile in subjects with extracranial carotid atherosclerosis.

Relationships between plasma lipoproteins and cerebrovascular atherosclerosis are not completely clear. In a group of asymptomatic nondiabetic normolipidemic subjects, plasma lipid and apolipoprotein profiles have been related to extracranial carotid atherosclerotic lesions, as assessed by B-mode ultrasonography and independent relations between lipid and clinical parameters and carotid atherosclerosis have been evaluated. We have found that subjects with atherosclerotic lesions (both intimal thickening or plaque) had TG levels and CHO/HDL-C and LDL-C/HDL-C ratios significantly higher and HDL-C and apo A-I levels significantly lower in comparison with subjects with normal arteries. When patients were divided according to the lesions of carotid arteries subjects with atherosclerotic plaque presented HDL-C and apo A-I levels significantly reduced and TG and apo B levels and CHO/HDL-C and LDL-C/HDL-C ratios significantly increased in comparison with subjects with normal arteries, and HDL-C levels reduced and CHO/HDL-C and LDL-C/HDL-C ratios increased in comparison with subjects with intimal thickening. Patients with intimal thickening and normal subjects differed for HDL-C and TG levels and CHO/HDL-C and LDL-C/HDL-C ratios. At multivariate analysis HDL-C levels (negatively), age, hypertension and cigarette smoking (positively) resulted independently associated with cerebrovascular atherosclerosis. Our data seem to show that, although several lipid and apoprotein abnormalities are able to initiate the atherosclerotic process in extracranial carotid district, probably the presence of low HDL-cholesterol levels is an important condition to determine the further worsening of the lesions.

Thyroid function and release of thyroid-stimulating hormone and prolactin from the pituitary in human obesity.

Thyroid function, basal serum thyroid-stimulating hormone (TSH) and prolactin concentrations, and the effects of 200 micrograms TSH-releasing hormone (TRH) given intravenously on TSH (delta TSH) and prolactin (delta prolactin) were investigated in 25 euthyroid obese subjects and 20 lean controls. No significant differences in serum thyroid hormone concentrations, glucose metabolism parameters, or basal TSH and prolactin concentrations were detected between groups, but a significant (P less than 0.01) increase in delta TSH and a significant (P less than 0.01) decrease in delta prolactin were observed in obese subjects. No significant differences in basal TSH and prolactin were observed in obese men and women compared with corresponding lean controls, but delta prolactin decreased significantly (P less than 0.01) in obese men and women compared with lean controls and TSH increased significantly (P less than 0.01) in obese men and women. No correlation was found between delta TSH or delta prolactin and body mass index. The study suggests that hyper-responsiveness of TSH and hyporesponsiveness of prolactin to TRH in obese subjects can be related to changes in the central serotoninergic system.

Lipoprotein(A) levels and apoprotein(a) phenotypes in a Sicilian population.

The aim of this study was to evaluate the influence of lipoprotein(a) levels and apoprotein(a) isoform size in determining the low cardiovascular risk of a rural, inland Sicilian population. Plasma levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, lipoprotein(a) and apoprotein B and AI were measured in a sample of 278 subjects (141 males, 137 females) representative of a population of 1351 subjects (622 males, 729 females). The apoprotein(a) isoforms were also identified. Results indicated that the levels of the common lipo-apoliproprotein parameters were lower than those of other populations, while lipoprotein(a) plasmatic levels and apoprotein(a) isoform distribution were similar to those of other Caucasian populations. The distribution of lipoprotein(a) levels was skewed to the right, with a higher prevalence of low levels, the apoprotein(a) isoforms most strongly represented in our sample were of intermediate size (25-27 kringles IV). Univariate analysis showed that lipoprotein(a) levels were correlated to apoprotein(a) isoform size (R = -0.48, p < 0.001) and to the age of the subjects (R = +0.13, p < 0.01). In a multiple regression analysis, lipoprotein(a) levels were correlated to the apoprotein(a) isoform size of the homozygous isoforms or smaller heterozygous isoforms, while larger heterozygous forms were not correlated. In conclusion, our study showed that in our population, lipoprotein(a) levels and apoprotein(a) isoforms are similar to those of other Caucasian populations. Other factors, such as the physical activity of a rural population or the Mediterranean diet, must be considered in order to explain the lower cardiovascular risk of this population.

[Characteristics of a statine of the most recent generation]. / Caratteristiche di una statina di ultima generazione.

LDL cholesterol levels are directly related to increased risk of cardiovascular disease. Several classes of drugs are available for the reduction of high cholesterol levels, but the highest efficacy has been demonstrated by HMG-CoA reductase inhibitors (statins). Cerivastatin is a third generation, synthetic statin, characterized by the highest pharmacological and therapeutic potency among currently marketed statins, and whose lipid-lowering efficacy has been demonstrated in a number of large, multicenter trials. Along with improvements in triglycerides and HDL cholesterol, cerivastatin at the dosage of 0.4 mg/day achieved a mean 36% reduction in LDL cholesterol. Analysis of clinical trials indicates that the molecule has age and gender-related effects, with a greater cholesterol reduction in women than in men and in elderly than younger patients. Cerivastatin has a dual hepatic metabolism pathway, via the CYP3A4 and CYP2C8 isoenzymes of cytochrome P450; therefore no potentially significant drug interactions with other CYP3A4 inhibitors, for instance erythromycin and itraconazole, have been reported. Cerivastatin tolerability profile at dosages investigated is similar to that of placebo.

[Plasma lipids and apoproteins. The effect of cigarette smoking]. / Lipidi ed apoproteine plasmatiche. Influenza del fumo di sigaretta.

Cigarette smoking produces lipo-apoprotein modifications, which makes it more atherogenic. In this study we have evaluated lipids and apoproteins in 178 normolipidemic, healthy subjects, in relation to their smoking habits. In smokers we have found lower levels of HDL-cholesterol and apo A-I and higher levels of triglyceride and apo B. Number of cigarette smoked in a day directly correlated with triglycerides and apo B (r = 0.321 and 0.313 respectively) and inversely with HDL-cholesterol (r = -0.274). These alterations seem to be due to an inhibition that smoking could cause on lipolytic processes. Further studies need to establish influences that smoking-related alterations have in the atherosclerotic lesions of smokers.

[Short-term metabolic compensation improves the lipo-apoprotein profile in type II diabetics in secondary insufficiency]. / Il compenso metabolico a breve termine migliora il profilo lipo-apoproteico nei diabetici di tipo II in insufficienza secondaria.

In the present study the effect of short-term metabolic control on plasma lipids and apoproteins in a group of subjects with type II diabetes mellitus in insulin treatment for secondary failure to oral agent therapy (sulphonylureas) was examined. For this reason 40 diabetic patients and 40 normal controls were studied. The lipoapoproteic pattern at the admission in the study and after a steady metabolic control, achieved by conventional insulin therapy and estimated by seric fructosamine, was evaluated. Diabetic patients, when compared with normal controls, showed a more atherogenic lipo-apoproteic profile and after achieving metabolic control, showed a reduction of triglyceride and apo B levels and a significant increase of the apo AI levels. The achievement of a good metabolic control, even after a short time, was associated with an improvement of the lipo-apoproteic profile, altered in diabetes mellitus in secondary failure.