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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.

The large worldwide variation in type 1 dia- betes 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 car- ried out, using semi-quantitative food frequency question- naires, 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 devel- opment, although these findings need to be confirmed in wider prospective follow-up studies.

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.

Background: Some dietary factors have been associated with the risk of type 1 diabetes in childhood. Objective: We investigated relations between dietary energy from major food groups and incidence of childhood type 1 diabetes by using an ecologic study design. Design: We conducted univariate and multivariate regression analysis with incidence rates of type 1 diabetes in the late 1980s and early 1990s among children aged < 15 y in 40 countries as the dependent variable and average per capita daily intake of major food items and other socioeconomic, demographic, and geographic risk factors as the independent variables. Results: In the univariate regression model, per capita total energy intake was nonsignificantly associated with type 1 diabetes incidence (r = 0.31, NS), whereas energy from animal sources was associated (r = 0.61, P < 0.01) and energy from vegetal sources was inversely associated (r = -0.35, P < 0.05) with diabetes incidence. Among dietary items of animal origin, meat (r = 0.55, P < 0.001) and dairy products (r = 0.80, P < 0.0001) were predictors of elevated incidence rates, whereas among dietary items of vegetal origin, cereals (r = -0.64, P < 0.001) were inverse predictors. In the multivariate analysis, the inverse relation of diabetes incidence with energy from vegetables and the direct correlation with energy from animal sources explained the positive associations of type 1 diabetes incidence with geographic and socioeconomic covariates. Conclusion: The incidence of type 1 diabetes varied worldwide according to dietary patterns. In-depth exploration of dietary risk factors during pregnancy and early neonatal life is warranted to confirm whether and to what extent diet cooperates with genetic susceptibility in the early onset of type I diabetes.

In Mediterranean countries, the incidence (per 100,000 per year) of Type 1 diabetes in children aged under 15 years shows wide variation from country to country, ranging from 2.45 in Macedonia to 34.4 in Sardinia. By interacting with environmental factors such as diet, toxins or viral infections, the HLA plus non-HLA genes of susceptibility or resistance to Type 1 diabetes so far identified are the strongest determinants of the disease as far as incidence, age at onset and sex ratio are concerned. The distribution of these genes in the Mediterranean region is still not completely known. Sardinians are the most suitable population for studying such phenomena for three main reasons: their genetic features have been repeatedly analysed in depth; their incidence rate of Type 1 diabetes is by far the highest in the Mediterranean area; and considerable colonies of Sardinian emigrants settled in neighbouring low-incidence Italian regions. Studies on Spaniards and Jews have also contributed to a better understanding of the respective roles of genetic and environmental factors. From a body of research on the Mediterranean populations, it can be concluded that great genetic heterogeneity accounts for the wide variation in incidence of Type 1 diabetes, while rather ubiquitious environmental factors trigger the disease in genetically predisposed individuals.

OBJECTIVE To examine the seasonal pattern for the clinical onset of IDDM in Finland and Sardinia, two areas where the incidence of IDDM is the highest in the world, and to determine the effect of climate and temperature on the clinical onset of IDDM. RESEARCH DESIGN AND METHODS Analysis of seasonality for the diagnosis of IDDM was based on 1,405 cases in Finland and 425 cases in Sardinia diagnosed at ≤14 years of age from 1989 to 1992. The average annual incidence of IDDM was 36.4/100,000 in Finland and 34.4/100,000 in Sardinia. Seasonal patterns were estimated presenting the data as short Fourier series up to three harmonics together with a possible linear trend. Likelihood ratio tests and Akaike's information criterion were used to determine the number of harmonics necessary to model the seasonal pattern. Seasonal patterns in both countries were compared between sexes and between the three 5-year age-groups, each controlling for the other's effect. RESULTS In both countries, a significant seasonal pattern during a calendar year was found for the sexes combined and for two age-groups (0–9 and 10–14 years). In Sardinia, two distinct cycles were found in the younger age-group, with a decreased incidence during May through August and an increased incidence during the autumn months. Two cycles were apparent in the older age-group, with the nadir occurring during June through September. In Finland, one cycle was found in the younger age-group, with a decreased incidence in June. In the older age-group, there were two distinct cycles, with a decreased incidence in June and in the September through December period. CONCLUSIONS Differences between Finland and Sardinia in the seasonal pattern for the incidence of newly diagnosed IDDM cannot be explained by differences in climate, temperature, a longer warm period in Sardinia, or other climatic phenomena. The results do not provide evidence in favor of a specific viral etiology of IDDM. It may be suggested that there are triggering events at certain times, but they are likely to be unspecinc. Nevertheless, why the incidence of IDDM in these two populations is equally high despite differences in climate, environment, and genetic background remains an unsolved question.

Cardiovascular diseases (CVD) are the leading cause of premature death and disability in the developed world. Broad consensus exists on CVD preventability through reduction of their risk factors at both the individual and population level. The latter kind of intervention implies involvement of policy-making institutions, owing to the manifold implications (agriculture, industry, environment) of such programmes. They have to be developed through three phases in succession: observational studies; intervention trials; public health action programmes. The implementation of the latter can only result from merging of biomedicine and politics and must rest on sound scientific-ethical bases. Other important issues are cost effectiveness, resort to mass media, transfer to other communities, funding and institutionalization. As a practical example of development and implementation of a public health programme, the experience of the ATS-Sardegna Campaign is briefly described.

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 α-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.

After binding to its receptor and activating the β-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 β cells, inasmuch as it improves both primary and secondary endpoints through selective inhibition of fatty acyl oxidation.

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.

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.

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.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.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 trend0.001), and, for the first time, prevalence of smoking among females decreased as well: from 31% in 1995 to 20% in 2001 (p for trend0.001). In contrast, a steady increase in TC (mg/dl) (189, 206, 215, 216, p for trend0.05 in males and 184 197, 212, 217, p for trend0.05 in females), and LDL-C (136, 143, 138, 144, p for tend0.05 in males and 127, 139, 136, 135, p for trend0.05 in females) was observed. HDL-C showed a steady increase (p for trend0.01 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.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.

Previous studies suggest a reduction in cardiovascular risk among subjects expressing the glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49) deficient phenotype. We aimed to test this hypothesis in male subjects expressing the G6PD-deficient phenotype vs wild type G6PD. In a case-control study we examined consecutive patients admitted for acute myocardial infarction or unstable angina, and controls admitted for diagnoses other than coronary heart disease (CHD). The G6PD phenotype was determined by measuring the enzyme activity in erythrocytes, as the absorbance rate change due to NADPH reduction. The CHD risk associated with the G6PD phenotype was assessed with unconditional logistic regression. G6PD-deficient subjects were less frequently represented among cases (11.8%) than among controls (18.6%, p=0.002). The genetic condition of G6PD deficiency conveyed a significant reduction in CHD risk (OR=0.6; 95% CI 0.4 to 0.9). We confirm the hypothesis that subjects with the G6PD-deficient phenotype are less prone to CHD. We suggest that such a protective effect may be ascribable to a reduced 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA R) activity, a statin-like effect, as well as to a downregulation in NADPH oxidase activity with a consequent reduction in oxygen-free radical production.

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.

Summary Background The relative importance of genetic and environmental factors in causing insulin-dependent diabetes mellitus (IDDM) is unknown. We studied this question by assessing the incidence of the disease in children, born in a region with a low incidence of IDDM (Lazio), but whose parents came from a region with high incidence (Sardinia). Methods We identified all IDDM cases that occurred between 1989 and 1994. We used as the denominator the number of children aged 0–14 born in Lazio of Sardinian parents to calculate incidence. We compared this rate with the incidences of IDDM in the populations of Lazio and Sardinia. Findings The age-adjusted incidence of IDDM in Sardinian-heritage children born and living in Lazio was 33·8 per 100 000 per year (95% CI 7·0–99·0) for those with two Sardinian parents, and 15·9 (8·7–26·6) for those with only one parent from Sardinia. The former incidence was not different from that recorded in Sardinia (34·4, 31·3–37·9), but was fourfold that of Lazio-heritage children (7·9, 7·1–8·8). Interpretation Our results show that two different ethnic groups living in the same region have a fourfold difference in incidence of IDDM. Children of Sardinian-heritage born in Lazio have the same incidence as the population of origin, which is genetically prone to the disease. Moreover, children with one Sardinian parent had a rate half that of Sardinians and double that of the indigenous population. We conclude that in a given population genetic susceptibility determines the frequency of IDDM in response to the environmental challenge.

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.

OBJECTIVE To verify whether the high incidence of insulin-dependent diabetes mellitus (IDDM) in Sardinia is an epidemic outbreak or a steady phenomenon. RESEARCH DESIGN AND METHODS All newly diagnosed cases of IDDM with onset in patients 0–29 years of age between 1 January 1989 and 31 December 1992 among residents in Sardinia were obtained from the Sardinian IDDM Incidence Registry. The local IDDM patient association (Associazione Diabete Infantile Giovanile) served as the secondary and independent source. RESULTS The completeness of ascertainment was 91%. The age-standardized mean annual incidence of IDDM (per 100,000) was 34.4 in the 0- to 14-year-old age-group and 26.2 in the entire 0- to 29-year-old range, respectively. Men-to-women ratios were 1.38 and 1.55, respectively. Seasonal variation in incidence was observed, with a peak in fall and winter and a nadir in summer. CONCLUSIONS Sardinia has a very high and steady IDDM incidence rate, which is up to fivefold that of other Italian regions and Mediterranean countries and approaches the Finnish top rate in the world. Interaction between the genetic peculiarity of Sardinians and still unidentified powerful environmental agents is likely to account for the phenomenon.

We investigated the relationship between fasting plasma glucose (FPG) and mean red cell volume (MCV) in 103 diabetic patients. Patients were selected among those admitted to our Diabetic Clinic according to the following criteria: absence of anemia, polycytemia, liver disease and use of drugs other than antidiabetic agents. All patients had peripheral blood profile performed on admission on a fasting venous sample for MCV and FPG. A highly significant correlation (r = 0.336; p less than 0.0005) was found between MCV and FPG in individual patients and when analyzed as a whole group. Patients were then divided into two subgroups according to FPG, using the value of 200 mg/dl as an arbitrary limit. The correlation between MCV and FPG remained significant, though weak (r = 0.243; 0.10 greater than p greater than 0.05) only in the subgroup with FPG greater than 200 mg/dl (n = 36). Therefore our data suggest a relationship between FPG and MCV in diabetic patients with FPG exceeding 200 mg/dl. The nature of this relation is only a matter of speculation.

In 102 insulin-dependent diabetic patients without retinopathy and with visual acuity 20/20, the Farnsworth-Munsell 100-Hue test was performed, and glycosylated hemoglobin (GlHb) levels were determined. In 70% of the patients, a dyschromatopsia in the yellow-blue axis (tritanopia) was found. No correlation existed between duration of diabetes and tritanopia. On the other hand, the degree of this visual defect was positively correlated with GlHb levels. Thus, dyschromatopsia might be associated with poor metabolic control. It is suggested that dyschromatopsia is a consequence of hypoxia at the neuroepithelial level. The high levels of GlHb could be a contributory cause of hypoxia by reduction of both oxygen release capacity and erythrocyte deformability.