Pharmacological treatment of a Sardinian patient affected by Autosomal Recessive Hypercholesterolemia (ARH).

BACKGROUND AND AIM: Previous studies have shown that patients with autosomal recessive hypercholesterolemia (ARH) resulting from mutations in LDLRAP1 gene have a less severe cardiovascular involvement than familial hypercholesterolemia homozygotes, lower levels of low-density lipoprotein cholesterol (LDL-C), and higher levels of high-density lipoprotein cholesterol (HDL-C). In addition, ARH patients seem to be more responsive to the lipid-lowering drugs. The aim was to test the effect of a combined drug treatment in an ARH patient in the absence of plasmapheresis. METHODS AND RESULTS: Here we report the lipid-lowering effect of rosuvastatin (60 mg/day) associated with ezetimibe (10 mg/day) in a single ARH patient. The sequencing of LDLRAP1 gene showed that the patient was homozygous for the c.432insA mutation. During a 6-month treatment, we observed an 80% reduction of LDL-C and a significant increase of HDL-C and ApoA-I. Some sequence variations in PCSK9 and NPC1L1 genes found in this patient may have contributed to the success of drug treatment. CONCLUSIONS: Our findings, although limited to a single case, suggest that in many ARH patients the LDL-C goal may be reached with the more potent statins associated with ezetimibe in the absence of extracorporeal procedures.

High meat consumption is associated with type 1 diabetes mellitus in a Sardinian case-control study.

The large worldwide variation in type 1 diabetes incidence and increasing incidence over time points toward important environmental risk factors. Among them, nutrition plays an important role. The objective was to investigate the relationship between type 1 diabetes and nutritional factors in pregnancy and early in life. We carried out, using semi-quantitative food frequency questionnaires, a retrospective case-control study in 298 children of 0-15 years old, 145 of which were affected by type 1 diabetes. The diet of all children and of their mothers during pregnancy and lactation was assessed. In children, a statistically significant dose-response association between type 1 diabetes and the amount of meat consumption was found while no other nutritional factors were associated with the disease. High meat consumption seems to be an important early in life cofactor for type 1 diabetes development, although these findings need to be confirmed in wider prospective follow-up studies.

Insulin resistance: pathophysiology and rationale for treatment.

After binding to its receptor and activating the ß-subunit, insulin is faced with two divergent pathways: one is phosphatidylinositol 3-kinase (PI 3-K) dependent, while another is dependent upon activation of mitogen-activated protein kinase (MAP-K). The former is absolutely necessary for mediating most metabolic and antiapoptotic effects; the latter is linked to nonmetabolic, proliferative and mitogenic effects. In obese patients, especially with type 2 diabetes mellitus (DM2), only the PI 3-K, but not the MAP-K, is resistant to insulin stimulation: hence insulin resistance is better defined as metabolic insulin resistance. The resulting 'compensatory hyperinsulinemia' is an unsuccessful attempt to overcome the inhibition of the metabolic pathway at the price of unopposed stimulation of the MAP-K pathway, and the administration of exogenous insulin might worsen the metabolic dysfunction. As the preferential activation of the MAP-K pathway in insulin-resistant patients has atherogenic and mitogenic properties, this leads to atherosclerosis and cancer. Metformin may carry out direct protective action on human ß cells, inasmuch as it improves both primary and secondary endpoints through selective inhibition of fatty acyl oxidation.

Colchicine reduces procollagen III and increases pseudocholinesterase in chronic liver disease.

AIM: To test whether colchicine would be an effective antifibrotic agent for treatment of chronic liver diseases in patients who could not be treated with alpha-interferon. METHODS: Seventy-four patients (46 males, 28 females) aged 40-66 years (mean 53 +/- 13 years) participated in the study. The patients were affected by chronic liver diseases with cirrhosis which was proven histologically (n = 58); by chronic active hepatitis C (n = 4), chronic active hepatitis B (n = 2), and chronic persistent hepatitis C (n = 6). In the four patients lacking histology, cirrhosis was diagnosed from anamnesis, serum laboratory tests, esophageal varices and ascites. Patients were assigned to colchicine (1 mg/d) or standard treatment as control in a randomized, double-blind trial, and followed for 4.4 years with clinical and laboratory evaluation. RESULTS: Survival at the end of the study was 94.6% in the colchicine group and 78.4% in the control group (P = 0.001). Serum N-terminal peptide of type III procollagen levels fell from 34.0 to 18.3 ng/mL (P = 0.0001), and pseudocholinesterase levels rose from 4.900 to 5.610 mU/mL (P = 0.0001) in the colchicine group, while no significant change was seen in controls. Best results were obtained in patients with chronic hepatitis C and in alcoholic cirrhotics. CONCLUSION: Colchicine is an effective and safe antifibrotic drug for long-term treatment of chronic liver disease in which fibrosis progresses towards cirrhosis.

Risk factors for cardiovascular disease in Sardinia from 1978 to 2001: a comparative study with Italian mainland.

BACKGROUND: This study is a survey of cardiovascular risk factors in Sardinia in the years 1999-2001 and allows us to update previously observed trends of such factors and to compare them with those in the Italian mainland. METHODS: Random samples of free living population of the Mediterranean island of Sardinia, Italy, were collected. Overall, 6818 subjects, 50% of each sex, and aged 20-80+ years constituted the sample. Personal and family data were collected using a semiquantitative questionnaire of frequencies. Blood biochemical variables related to risk for atherosclerosis were measured. In particular, serum total cholesterol, HDL-cholesterol, triglycerides, Apo A-1, Apo B, Lp(a), uric acid, blood glucose and plasma homocysteine were analyzed in each subject enrolled. RESULTS: In the age classes 20-59 years, during a 30 year period, prevalence of smoking among males continued to decrease from 58 to 24% (p for trend <0.001), and, for the first time, prevalence of smoking among females decreased as well: from 31% in 1995 to 20% in 2001 (p for trend <0.001). In contrast, a steady increase in TC (mg/dl) (189, 206, 215, 216, p for trend <0.05 in males and 184 197, 212, 217, p for trend <0.05 in females), and LDL-C (136, 143, 138, 144, p for tend <0.05 in males and 127, 139, 136, 135, p for trend <0.05 in females) was observed. HDL-C showed a steady increase (p for trend <0.01 in males and females). Lp(a) values were high in both sexes, a finding linked to the ethnic influence on them. Systolic and diastolic blood pressure values (mm Hg) increased with age. In the present survey (population aged 20-80+ years, current smokers were 17.5% among males and 13.8% among females. Total and HDL-cholesterol were higher than in other parts of Italy (209 vs 205 in males, and 211 vs 204 in females), while systolic and diastolic blood pressure were lower. CONCLUSION: Overall, total- and LDL-cholesterol showed an increasing trend, while blood pressure and smoking habits had a decreasing tendency. The increase in blood cholesterol follows the trend in other areas of the world, mainly due to changing dietary habits. Therefore, a campaign of eating information and education (population strategy) could favourably modify cardiovascular risk, as occurred in Sardinia during the past decade with the Regional ATS-Sardegna Campaign.

Incidence of diabetes mellitus among children of Italian migrants substantiates the role of genetic factors in the pathogenesis of type 1 diabetes.

UNLABELLED: To investigate the role of genetic and environmental factors in the pathogenesis of type 1 diabetes mellitus (T1D), we carried out a study in Germany aimed at comparing the prevalence and incidence of T1D among children of migrant Italians from high-risk (Sardinia) and low-risk (continental Italy) regions versus German children. Children from Italy were identified by the "Baden-Wuerttemberg (BW) Diabetes Incidence Registry", which registered 4017 newly diagnosed T1D patients, aged 0-14 years, between 1987 and 2003. Data relating to T1D children from Sardinia were elicited from more than 2000 questionnaires. Our findings were: (1) T1D is more frequent among German children than among children of Italian migrants [incidence rate (IR) 14.8/100,000/year, 95% confidence interval (CI) 14.4-15.4 vs. IR 10.8/100,000/year, 95% CI 8.2-13.6); (2) the incidence of T1D among Italian children residing in Germany is similar to that of Italian children in the home country (IR 10.8/100,000/year, 95% CI 8.2-13.6 vs. 8.4/100,000/year, 95% CI 7.9-8.9); (3) the prevalence of T1D among Sardinian children is higher than that among German children (0.11%, 95% CI 0.11-0.12) independent of the place where the Sardinian children are living (Sardinian children in Germany 2.3%, 95% CI 0.5-6.5 vs. Sardinian children in Sardinia 0.30%, 95% CI 0.27-0.32). CONCLUSION: Children from high- and low-risk areas of Italy have incidence rates of T1D that are closer to those of their native regions than to those of German children, indicating that genetic factors play a predominant role in the pathogenesis of T1D.

Effects of chronic hyperinsulinemia in insulin-resistant patients.

Selective insulin resistance influences pathogenesis and treatment of type 2 diabetes and metabolic syndrome. Downregulation of the antiatherogenic pathway and maintained activity of the proatherogenic and cancerogenic pathways lead to atherosclerosis and cancer. Exogenous insulin added to "compensatory" hyperinsulinemia might worsen the primary end points, resulting in potential increase in cardiovascular and cancer events in spite of improvement of surrogate metabolic end points. Conversely, metformin can improve primary and surrogate end points.

Gene-nutrient interactions in G6PD-deficient subjects--implications for cardiovascular disease susceptibility.

BACKGROUND/AIMS: The enzyme glucose-6-phosphate dehydrogenase (G6PD) is the principal source of reducing equivalents, necessary for regenerating reduced glutathione through NADPH in order to protect cells from oxidative damage, and whichin erythrocytes produces hemolysis. When fava beans are ingested by G6PD-deficient subjects (gene-nutrient interaction), or some oxidant drugs are assumed (gene-drug interactions), a life-threatening hemolysis can occur. However, the same defect results in lower cardiovascular disease (CVD) risk. METHODS: Physiopathological, clinical and mortality studies of CVD risk in relation with G6PD deficiency have been surveyed. RESULTS: CVD risk in men was lowered in the G6PD-deficient state, and was associated with reduced levels of plasma low-density lipoprotein cholesterol (LDL-C) compared to the normal condition (p < 0.05). Both cholesterol and DNA synthesis in circulating mononuclear cells from G6PD-deficient men were likewise reduced (p = 0.05). CONCLUSIONS: Since NADPH is a necessary cofactor for the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA R), G6PD deficiency appears to be a naturally occurring model of HMG-CoA R restraint, whose consequences are similar to those produced on the same enzyme by statins. G6PD deficiency therefore results in protection against CVD, despite an increased susceptibility to oxidative stress.

Nitrate in community water supplies and risk of childhood type 1 diabetes in Sardinia, Italy.

We tested the hypothesis of an association between childhood type 1 diabetes (T1D) risk and nitrate concentration in drinking water in Sardinia, Italy, using Poisson regression analysis. Childhood T1D risk showed an inverse trend with increasing quartile of nitrate level in the total population and among men. A nitrate concentration in drinking water below 10 mg/l is unlikely to account for the spatial variation in childhood T1D incidence.

Epidemiological association between some dietary habits and the increasing incidence of type 1 diabetes worldwide.

BACKGROUND/AIMS: The variation in incidence of type 1 diabetes (T1D) worldwide is genetically based. However, its increasing incidence is environmentally determined. Our aim was to describe the role of nutritional habits and of gene-nutrient interactions in the rising incidence of TID. METHODS: We did an ecological study in the 37 world areas were a 3% yearly increase of T1D incidence had been reported, and we calculated through the FAO's Food Balance Sheets the per caput daily supply of milk, meat and cereals from 1961 to 2000 and its correlation with the TID incidence. RESULTS: The supply of milk and cereals remained almost unchanged, whereas that of meat increased by over 31%. The absolute mean TID increase (number of cases per 100,000 per year) was + 0.32. A significant positive correlation with supply of milk was present from 1961 to 2000, while that with meat and cereals became significant in 1983 and 2000. CONCLUSION: Our ecological analysis indicates that nutritional factors, and in particular meat consumption, play a role in the incidence of T1D and its increase worldwide. Further experimental and case-control studies are warranted in order to assess the gene-nutrient interactions.

Riskard 2005. New tools for prediction of cardiovascular disease risk derived from Italian population studies.

BACKGROUND AND AIM: The need to update tools for the estimate of cardiovascular risk prompted the "Gruppo di Ricerca per la Stima del Rischio Cardiovascolare in Italia" to produce a new chart and new software called Riskard 2005. METHODS AND RESULTS: Data from 9 population studies in 8 Italian regions, for a grand total of 17,153 subjects (12,045 men and 5,108 women) aged 35-74 and for a total exposure of about 194,000 person/years were available. A chart for the estimate of cardiovascular risk (major coronary, cerebrovascular and peripheral artery disease events) in 10 years was produced for men and women aged 45-74 free from cardiovascular diseases. Risk factors employed in the estimate were sex, age (6 classes), systolic blood pressure (4 classes), serum cholesterol (5 classes), diabetes, and cigarette smoking (4 classes). Estimates were produced for absolute risk and for relative risk, the latter against levels expected in the general population that produced the risk functions. Software was produced for the separate estimate of major coronary, cerebrovascular and cardiovascular events (the latter made by coronary, cerebrovascular and peripheral artery disease of atherosclerotic origin) for follow-up at 5, 10 or 15 years, in men a women aged 35-74 years at entry and free from cardiovascular diseases. Risk factors employed here were sex, age, body mass index, mean physiological blood pressure, HDL cholesterol, non-HDL cholesterol, cigarette smoking, diabetes and heart rate. The output is based on several indicators: absolute risk, relative risk (as defined above), ideal risk (for a very favourable risk profile), biological age of risk, comparisons among the above indicators, the percent contribution of risk factors to the excess of estimated risk above the level of the ideal risk, and the description of trends in risk estimate in relation to repeated measurements. CONCLUSIONS: These tools represent progress compared to similar tools produced some years ago by the same Research Group.