Sandro Muntoni

Comparison of the Seasonal Pattern in the Clinical Onset of IDDM in Finland and Sardinia

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 Akaikes 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 others 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.

Serum lipoprotein profile in the Mediterranean variant of glucose-6-phosphate dehydrogenase deficiency

Sardinian males with erythrocyte glucose-6-phosphate dehydrogenase (G-6-PD) deficiency have lower serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB), compared to normals. Since the enzyme deficiency is expressed also in nucleated cells, we studied cholesterol (C) and DNA synthesis and LDL-receptor expression in freshly isolated circulating mononuclear cells from normal and G-6-PD-deficient Sardinians. Synthesis of C (as 14C-acetate incorporation) and of DNA (as 3H-thymidine incorporation) was clearly reduced, both in basal state and after PHA stimulation, in G-6-PD-deficient cells compared to normal cells. On the other hand, no clear influence of G-6-PD deficiency on LDL-receptor expression could be demonstrated. The Mediterranean variant of G-6-PD deficiency is characterized, whatever the metabolic mechanism may be, by a serum lipoprotein pattern of reduced atherogenicity.

The pine-cone body: an intermediate structure between the cap mesenchyme and the renal vesicle in the developing nod mouse kidney revealed by an ultrastructural study.

Nephrogenesis is mainly characterized by the interaction of two distinct renal constituents, the ureteric bud and the metanephric mesenchyme. In this paper we describe by means of light and electron microscopic techniques the morphological events that take place during the early stages of cap mesenchymal formation. Samples of normal renal tissue were excised from newborn NOD mice and processed by standard light and electron microscopy techniques. In all samples examined we detected the presence of several cap mesenchymal aggregates in different stages of differentiation. They varied from small solid nodules with few ovoid cells to bigger pine-cone-like aggregates, characterized by a peculiar distribution and morphology of their cellular constituents. Our data highlight, for the first time, the presence of a specific cap mesenchymal structure, the pine-cone body and show, at ultrastructural level, how each cap aggregate epithelializes proceeding in stages from a condensed mesenchymal aggregate to the renal vesicle, through the intermediate “pine-cone body” stage.

New insights into the epidemiology of Type 1 diabetes in Mediterranean countries

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.

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.

Results of a five-year community-based programme for cardiovascular disease prevention: The ATS-Sardegna Campaign

The objective of this study was to evaluate the effects of the ATS-Sardegna Campaign on lifestyle and cardiovascular disease (CVD) risk factors in the Sardinian population. The Campaign was a community-based public health action programme funded by the Sardinian Government with a view to prevent CVD and promote healthy behaviour. It was also part of the Targeted Project FAT.MA. of the Italian National Research Council (CNR), with the main purpose of evaluating the effects of this public health initiative after a five- year intervention. The evaluation was effected with three parallel procedures: individual interviews with 1486 randomly chosen people; assessment of eating patterns through a food-frequency questionnaire; measurement of the mean levels of the major CVD risk factors in 1729 randomly chosen subjects (1044 in the calendar year 1992, and 685 in 1995, two and five years, respectively, after the beginning of the Campaign). Overall, we recorded a favourable trend in eating habits in both sexes; a significant decrease in LDL-cholesterol in males, and in systolic and diastolic blood pressure in both sexes; a non- significant decrease in prevalence of smokers among males and increase among females. The ATS-Sardegna Campaign was the first CVD prevention programme in Italy to have attained reduction in the risk profile of an entire region at the lowest ever borne cost.

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.

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.

Genetic versus environmental factors in insulin-dependent diabetes mellitus

1626 Vol 349 • May 31, 1997 residents. Thus, even assuming that children’s diet is greatly influenced by the diet of their parents, Sardinianheritage children living in Lazio would not have a different milk consumption from Lazio-heritage children, nor would children with one Sardinian parent have intermediate milk intake, as Odawara and Yamashita suggest, to account for the intermediate IDDM incidence (15·9) of these children. Moreover, among 17 regions with data for both cow’s milk consumption and IDDM incidence Sardinia was the highest outlier from the linear regression model in which R was 0·44, thus representing the most considerable exception to the association between the two variables. Finally, we want to point out that every possible influence of the microenvironment, such as persistence of original habits, was carefully explored, even on an individual basis, and could be ruled out. Yudkin proposes that non-genetic intergenerational effects, such as transplacental transmission of cytomegalovirus, could have a role in the high incidence of IDDM in Sardinia and in the Sardinian progeny in Lazio, thus accounting also for the 50% drop in incidence among children of mixed parenthood. However, he does not consider that we reported the same number of IDDM cases for children of mixed couples according to parental gender: seven with a Sardinian mother and seven with a Sardinian father. If the high incidence of IDDM among Sardinians were a consequence of transplacental transmission of a virus, Sardinian mothers should have outnumbered Sardinian fathers among mixed parents of IDDM children; and no different frequency between children of either Sardinian or mixed couples would have been found. Although we do not deny the contribution of environmental factors to the aetiology of IDDM, we reaffirm that the difference in the frequency of IDDM between two populations sharing the same environment is determined by the respective genetic susceptibilities in response to the environmental challenge.

The CINDI Health Monitor Survey. Health behaviour among the Italian adult population, 2001-2002

In accordance to the WHO-CINDI (Countrywide Integrated Non-communicable Diseases Intervention) Programme, in 2001-2002 Italy participated in the Health Monitor Survey (HMS) along with all the other CINDI member countries. The survey aimed to investigate, by the use of a standard questionnaire, the self-reported health status, life-habits, social and health conditions, use of health services and other features of the study population. Following the international CINDI protocol, the adult population (25-64 years of age) from six Italian demonstration areas were chosen: Bassiano-Lenola (LT), Brisighella (RA), Rovescala (PV), Sardinia (CA, SS), Udine (UD); Valle dell’Irno (SA). A total number of 4095 subjects, including both males and females were enrolled, with a participation rate of 53%, equal to 2202 subjects [45.7% males (M) and 54.3% females (F)]. All age groups were equally represented. From the analysis of the age-standardised rates, the following results were obtained. Self-reported “good state of health”: M 71%, F 56.9%; Hypertension: M 15.6%, F 17.5%; Diabetes: M 6.1%, F 4.2%; Back-illness: M 18%, F 22%; Gastritis: M 12.8%, F 12.6%; Headache: M 31.7%, F 54.6%; Insomnia: M 15.9%, F 28.5%; Daily smokers: M 35.7%, F 23.5%; Daily consumption of wine: M 40.2%, F 15.7%; BMI ≥ 30: M 12.3%, F 13.5%; Regular leisure physical activity: M 27.6%, F 23.1%; Hard physical activity: M 40.5%, F 24%. The results demonstrate how rural areas (Rovescala and Valle dell’Irno) experience worse health conditions. Thanks to the HMS, the population’s health needs have been focused and compared to those of other CINDI countries, in order to plan specific interventions aimed at the improvement of lifestyle and health conditions.