Carlo M. Barbagallo

Inhibition of Thromboxane Biosynthesis and Platelet Function by Simvastatin in Type IIa Hypercholesterolemia

Abstract Thromboxane A2 (TXA2) biosynthesis is enhanced in the majority of patients with type IIa hypercholesterolemia. Because simvastatin (a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) was previously shown to reduce platelet aggregation and TXB2 production ex vivo, we investigated TXA2 biosynthesis and platelet function in 24 patients with type IIa hypercholesterolemia randomized to receive in a double-blind fashion simvastatin (20 mg/d) or placebo for 3 months. The urinary excretion of 11-dehydro-TXB2, largely a reflection of platelet TXA2 production in vivo, was measured by a previously validated radioimmunoassay technique. Blood lipid levels and urinary 11-dehydro-TXB2 excretion were significantly ( P <.001) reduced by simvastatin. In contrast, placebo-treated patients did not show any statistically significant changes in either blood lipids or 11-dehydro-TXB2 excretion. The reduction in 11-dehydro-TXB2 associated with simvastatin was correlated with the reduction in total cholesterol ( r =.81, P <.0001), LDL cholesterol ( r =.79, P <.0001), and apolipoprotein B ( r =.76, P <.0001) levels. Platelets from patients with type IIa hypercholesterolemia required significantly ( P <.01) more collagen and ADP to aggregate and synthesized less TXB2 in response to both agonists after simvastatin therapy. Bleeding time, platelet sensitivity to Iloprost, and blood lipoprotein(a) and HDL cholesterol levels were not significantly affected by either treatment. We conclude that enhanced TXA2 biosynthesis in type IIa hypercholesterolemia is, at least in part, dependent on abnormal cholesterol levels and/or other simvastatin-sensitive mechanisms affecting platelet function.

A century of trends in adult human height

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries. DOI: http://dx.doi.org/10.7554/eLife.13410.001

Novel LMF1 Nonsense Mutation in a Patient with Severe Hypertriglyceridemia

CONTEXT Lipase maturation factor 1 (LMF1) gene is a novel candidate gene in severe hypertriglyceridemia. Lmf1 is involved in the maturation of lipoprotein lipase (LPL) and hepatic lipase in endoplasmic reticulum. To date only one patient with severe hypertriglyceridemia and related disorders was found to be homozygous for a nonsense mutation in LMF1 gene (Y439X). OBJECTIVE The objective of the study was to investigate LMF1 gene in hypertriglyceridemic patients in whom mutations in LPL, APOC2, and APOA5 genes had been excluded. RESULTS The resequencing of LMF1 gene led to the discovery of a novel homozygous nonsense mutation in one patient with severe hypertriglyceridemia and recurrent episodes of pancreatitis. The mutation causes a G>A substitution in exon 9 (c.1395G>A), leading to a premature stop codon (W464X). LPL activity and mass were reduced by 76 and 50%, respectively, compared with normolipidemic controls. The proband over the years has shown a good response to treatment. The probands son, heterozygous for the W464X, shows normal plasma triglyceride levels. CONCLUSIONS We identified the second novel pathogenic mutation in LMF1 gene in a patient with severe hypertriglyceridemia. LPL deficiency in our patient was milder than in the carrier of the Y439X previously described.

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.

Overexpression of Human Hepatic Lipase and ApoE in Transgenic Rabbits Attenuates Response to Dietary Cholesterol and Alters Lipoprotein Subclass Distributions

The effect of the expression of human hepatic lipase (HL) or human apoE on plasma lipoproteins in transgenic rabbits in response to dietary cholesterol was compared with the response of nontransgenic control rabbits. Supplementation of a chow diet with 0.3% cholesterol and 3.0% soybean oil for 10 weeks resulted in markedly increased levels of plasma cholesterol and VLDL and IDL in control rabbits as expected. Expression of either HL or apoE reduced plasma cholesterol response by 75% and 60%, respectively. The HL transgenic rabbits had substantial reductions in medium and small VLDL and IDL fractions but not in larger VLDL. LDL levels were also reduced, with a shift from larger, more buoyant to smaller, denser particles. In contrast, apoE transgenic rabbits had a marked reduction in the levels of large VLDLs, with a selective accumulation of IDLs and large buoyant LDLs. Combined expression of apoE and HL led to dramatic reductions of total cholesterol (85% versus controls) and of total VLDL+IDL+LDL (87% versus controls). HDL subclasses were remodeled by the expression of either transgene and accompanied by a decrease in HDL cholesterol compared with controls. HL expression reduced all subclasses except for HDL2b and HDL2a, and expression of apoE reduced large HDL1 and HDL2b. Extreme HDL reductions (92% versus controls) were observed in the combined HL+apoE transgenic rabbits. These results demonstrate that human HL and apoE have complementary and synergistic functions in plasma cholesterol and lipoprotein metabolism.

Effects on Lipoprotein Subclasses of Combined Expression of Human Hepatic Lipase and Human apoB in Transgenic Rabbits

Objective—The effects of combined expression of human hepatic lipase (HL) and human apolipoprotein B (apoB) on low-density lipoprotein (LDL) subclasses were examined in rabbits, a species naturally deficient in HL activity. Methods and Results—In apoB-transgenic rabbit plasma, >80% of the protein was found in the 1.006- to 1.050-g/mL fraction. Gradient gel electrophoresis (GGE) of this fraction revealed two distinct species, designated large and small LDL. A denser fraction (d=1.050 to 1.063 g/mL) contained small LDL as well as another discrete LDL subspecies, designated very small LDL. Expression of HL resulted in reductions in protein concentrations in the 1.006- to 1.050-g/mL density-gradient subfractions containing large (6.5±4.1 versus 32.6±12.0 mg/dL, P <0.005) and small LDL (59.6±17.4 versus 204.3±50.3 mg/dL, P <0.002). A concomitant small but not significant increase in protein concentration in the denser LDL fraction (48.0±28.2 versus 44.6±18.2 mg/dL) was due primarily to an increase in very small LDL (25.9±3.1 versus 9.6±5.4% of total LDL GGE densitometric area, P <0.002). Conclusion—These findings support a direct role for HL in regulating total plasma LDL concentrations as well as in the production of smaller, denser LDL from larger, more buoyant precursors.

Liver is not the unique site of synthesis of β2-glycoprotein I (apolipoprotein H) : evidence for an intestinal localization

Apolipoprotein H is a protein of about 50 kilodaltons, structurally related to the regulators of the complement activation family. Its physiological function is poorly understood but it has been implicated in lipid metabolism and coagulative pathways. The major site of synthesis is thought to be the liver. Several reports indicate that apolipoprotein H is the antigen of the antiphospholipid antibodies and also behaves as an acute-phase reactant. Moreover, 40% of plasma apolipoprotein H is associated with very low-density lipoprotein, high-density lipoprotein, and postprandial chylomicrons. In this study we investigated other sites of synthesis by reverse transcription/polymerase chain reaction and we found apolipoprotein H mRNA expression in intestinal cell lines and tissues. Immunohistochemistry was performed on various fresh and paraffin-embedded tissues and apolipoprotein H was immunolocalized in the cytoplasm of hepatocytes and epithelial cells from colon and jejunum. This study indicates that apolipoprotein H is expressed at both mRNA and protein levels in enterocytes.

Nutritional characteristics of a rural Southern Italy population: the Ventimiglia di Sicilia Project.

Objective: Knowledge of alimentary habits among populations permits a better definition of appropriate public health interventions. We designed the epidemiological project “Ventimiglia di Sicilia” to characterize the risk profile in a rural village with low total cholesterol levels and low early cardiovascular mortality but with a large prevalence of overweight and obesity, which previously have been significantly associated with total mortality. Methods: 488 individuals of age 20 to 69 years were included in the dietary survey conducted by a seven-day food record. Results: Alimentary habits were characterized by high consumption of total and complex carbohydrates (respectively 52.5 ± 7.6% and 46.6 ± 8.2% of daily energy) and by a low cholesterol intake (92.5 ± 35.0 mg/1000 kcal/day). Fat intake was 34.7 ± 7.7% of daily energy due to a higher consumption of monounsaturated fats in respect to saturated fats (respectively 20.5 ± 5.1% and 10.2 ± 2.9% of daily energy). In particular, in this population there was a large consumption of bread, pasta, fresh vegetables, olive oil and fruits. We also observed an excess of total calories (about 2900 kcal/day in men and 2100 kcal/day in women) not balanced by a high degree of physical activity levels. Furthermore we found a significant higher total and saturated fat consumption in the youngest individuals and in people with higher educational levels. Conclusions: Dietary habits of Ventimiglia di Sicilia still follow the nutritional characteristics typical of the Mediterranean diet. The high total calorie intake indicates a quantitative more than qualitative problem, which may account the large prevalence of overweight and obesity and may represent a public health issue that needs to be corrected in such a rural population.

Plasma Lipid, Apolipoprotein and Lp(a) Levels in Elderly Normolipidemic Women: Relationships with Coronary Heart Disease and Longevity

The relation between plasma lipids and coronary heart disease (CHD) in the elderly is still debated, as well as the proposed role of lipoproteins as markers of longevity. In this study both normolipidemic elderly and middle-aged women with CHD showed higher triglycerides and apolipoprotein B levels and lower high-density lipoprotein (HDL)-cholesterol and apolipoprotein A-I levels in comparison with age-matched subjects without CHD. In the middle-aged group, hypertension and HDL-cholesterol levels and, in the elderly group, only HDL-cholesterol levels were independently associated with CHD. No significant difference was found between a group of healthy centenarians and elderly and middle-aged subjects without CHD. These data suggest that plasma lipids are also related to CHD in the elderly and that, even if at present we are not able to consider them as predictors of longevity, some lipoprotein features may contribute to select subgroups of subjects in which other factors play a further role in life expectancy.

No association between Glu298Asp endothelial nitric oxide synthase polymorphism and Italian sporadic Alzheimer's disease.

A great amount of evidence suggests that neuroinflammation may be a major pathogenetic mechanism in the pathophysiology of sporadic Alzheimers Disease (sAD). Recently, polymorphisms in the endothelial nitric oxide synthase (NOS3) gene have been associated to late onset Alzheimers Disease in a British population. However, other groups failed to replicate this finding in Asiatic and Caucasian populations. We conducted a case-control study including a clinically well-defined group of 149 sAD patients and 149 age and sex matched controls to test the association between NOS3 Glu298Asp polymorphism and sAD in an ethnically homogenous Italian population. All subjects were genotyped at NOS3 and apolipoprotein E. No significant difference was found in either allele or genotype frequencies between cases and controls, even after stratification for Apolipoprotein E4 carrier status. The NOS3 Glu298Asp polymorphism does not appear to influence the risk of developing sAD in an Italian population.