Lung Ultrasound and Pulmonary Function Test in Cirrhotic Patients.

Lung ultrasound (LU) is useful in the diagnosis of pulmonary interstitial-alveolar syndrome (IAS) when B-lines are detected. Its prevalence and effect in lung function is not well studied in cirrhotic patients. The objective of this study was to detect the prevalence of interstitial-alveolar involvement with LU and correlate with pulmonary function test to distinguish the effect of ascites and B-lines in pulmonary function. This was an observational single-center study with 49 patients listed for liver transplantation submitted for LU and pulmonary function tests. Patients were divided into 4 groups: no ascites and no B-lines (n = 19), B-lines only (n = 19), ascites only (n = 6), and ascites and B-lines (n = 5). There was a worse forced vital capacity (FVC) in patients with B-lines only (76.1% ± 9.2; P = .0058) and ascites only (66.8% ± 10.2; P = .0010). 1-second forced expiratory volume (FEV1) also was lower in patients with B-lines only (78.5% ± 10.3; P = .0001), ascites only (71.3% ± 13.2; P = .0004), and B-lines and ascites (74.2% ± 7.6; P = .0035). Model for End-Stage Liver Disease score was worse in the group with ascites and B-lines (22.4 ± 10.1; P = .0229). B-Lines reduced FVC and FEV1 in our study and may be an independent factor in worsening pulmonary function in these patients.

High-normal blood pressure and impaired renal function. A prospective study in a population-based cohort.

AIM: The association between high-normal blood pressure and the impairment of renal function is highly controversial. We analysed the contribution of high-normal blood pressure on incident impaired renal function. METHODS: The study was performed in a population-based cohort of 1307 subjects free of diabetes, cardiovascular and renal disease at baseline, who attended both at baseline and after 6-year follow-up a metabolic screening. The outcome was incident impaired renal function, defined as a glomerular filtration rate <60 mL/min/1.73 m2. RESULTS: Incidence of impaired renal function was 2.5%, 4.5%, 8.7% and 10.8% in optimal, normal, high-normal blood pressure and hypertension, respectively. Adjusted relative odds ratio (OR) of impaired renal function were modelled using logistic regression analyses including multiple confounders. The adjusted OR were 1.6 (95% CI 0.5-5.0) for normal blood pressure, 3.4 (1.2-10.3) for high-normal blood pressure and 3.7 (1.3-10.7) for hypertension. Results were similar after excluding overweight or obese patients. CONCLUSION: High-normal blood pressure is an independent predictor of impaired renal function. Trials are warranted to test if therapeutic intervention on blood pressure is justified also in subjects with high-normal blood pressure to preserve renal function.

Hypoglycemia is independently associated with multidimensional impairment in elderly diabetic patients.

AIM: To identify the characteristics associated with multidimensional impairment, evaluated through the Multidimensional Prognostic Index (MPI), a validated predictive tool for mortality derived from a standardized Comprehensive Geriatric Assessment (CGA), in a cohort of elderly diabetic patients treated with oral hypoglycemic drugs. METHODS AND RESULTS: The study population consisted of 1342 diabetic patients consecutively enrolled in 57 diabetes centers distributed throughout Italy, within the Metabolic Study. Inclusion criteria were diagnosis of type 2 diabetes mellitus (DM), 65 years old or over, and treatment with oral antidiabetic medications. Data concerning DM duration, medications for DM taken during the 3-month period before inclusion in the study, number of hypoglycemic events, and complications of DM were collected. Multidimensional impairment was assessed using the MPI evaluating functional, cognitive, and nutritional status; risk of pressure sores; comorbidity; number of drugs taken; and cohabitation status. The mean age of participants was 73.3 ± 5.5 years, and the mean MPI score was 0.22 ± 0.13. Multivariate analysis showed that advanced age, female gender, hypoglycemic events, and hospitalization for glycemic decompensation were independently associated with a worse MPI score. CONCLUSION: Stratification of elderly diabetic patients using the MPI might help to identify those patients at highest risk who need better-tailored treatment.

Prediction of mortality and macrovascular complications in type 2 diabetes: validation of the UKPDS Outcomes Model in the Casale Monferrato Survey, Italy.

AIMS/HYPOTHESIS: The United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model can be used to estimate the lifetime occurrence of major diabetes-related complications in order to calculate health economic outcomes. The aim of the study was to assess the performance of the model by comparing the predicted and observed mortality and the incidence of macrovascular complications in an Italian population-based cohort with type 2 diabetes. METHODS: We used data from the Casale Monferrato Survey, a cohort enrolled in 1988 and surveyed in 1991 (n = 1,967) to assess the prevalence of cardiovascular risk factors. In 2000, a new survey included all the members of the original cohort who were still alive (n = 860), and in addition all individuals identified with a new diagnosis of type 2 diabetes since 1993 (n = 2,389). We compared the mortality predicted by the model for the 1991 survey over the subsequent 17-year period with the observed risk. The following outcomes were analysed in the 2000 survey: myocardial infarction (MI), other ischaemic heart disease, stroke, congestive heart failure (CHF) and amputation. RESULTS: For all-cause mortality, the predictions from the model at 5 and 10 years (23% and 47%, respectively) were identical to the observed risks. At 15 years, the risk of death was slightly overestimated (an estimate of 67% vs 64% observed, 95% CI 61%, 66%). The performance of the model was best for patients with a recent history of disease (duration <6 years). Among the complications, the predicted cumulative incidences of MI and CHF were very close to those observed. CONCLUSIONS/INTERPRETATION: External validation is essential to assess the accuracy of simulation models. The UKPDS Outcomes Model satisfactorily predicted a set of actual incidences of mortality and complications in an Italian diabetes cohort up to a duration of approximately 12 years. The longer term performance of such models should be carefully evaluated.

The METABOLIC Study: multidimensional assessment of health and functional status in older patients with type 2 diabetes taking oral antidiabetic treatment.

AIM: The objective of the METABOLIC Study was to evaluate overall health status, with particular focus on assessment of functional status of older patients taking oral antidiabetic drug (OAD) treatment. METHODS: The study included 1342 type 2 diabetes patients aged ≥ 65 years treated with OADs, with or without insulin, who had been referred to outpatients clinics across Italy. Information on diabetes (duration, medications taken during the last 3 months, hypoglycaemic events and diabetic complications) was collected by questionnaire, and the patients' overall health status was assessed using a multidimensional prognostic index. RESULTS: The sample recruited (mean age: 73.3 ± 5.5 years) had a mean duration of diabetes of 11.3 ± 8.2 years. Half were taking sulphonylureas alone or together with other medications, 9.7% were taking insulin in combination with other OADs, almost 30% were using biguanides and 6.2% were taking dipeptidyl peptidase-4 (DPP-4) inhibitors. Also, 12% of patients reported hypoglycaemic events, 90% of whom were taking insulin or sulphonylureas. In addition, 81% of the participants were completely independent in their activities of daily living, while 19% were mildly, moderately or severely disabled. Age, female gender, hypoglycaemic events, neuropathy and low diastolic blood pressure were the main variables associated with disability. CONCLUSION: Disability is common in older diabetic patients and some associated factors, such as hypoglycaemia and low diastolic blood pressure, have been identified. Also identified was malnutrition as a specific factor associated with hypoglycaemic events independent of the use of insulin and sulphonylureas.

Diabetes-specific variables associated with quality of life changes in young diabetic people: the type 1 diabetes Registry of Turin (Italy).

BACKGROUND AND AIMS: Type 1 diabetes (T1DM) affects young people during the most active years of their life. Our aim was to assess quality of life (QoL) and associated variables in a large cohort of adults with childhood-onset and adult-onset T1DM. METHODS: A cohort of adult patients (18 years and older) from the T1DM Registry of Turin, Italy, was recruited. Clinical characteristics and Diabetes QoL (DQOL) questionnaire were assessed by standardized procedures. RESULTS: 310 adults completed the questionnaire. Age and diabetes duration at assessment (mean ± SD) were 32.8 ± 7.3 years and 17.3 ± 6.3 years, respectively. DQOL and its subscores were in the lower quartiles of their distributions, indicating a good level of QoL. However, scores were significantly higher in females than in males, particularly for the subscale of diabetes-related worries. In multivariate analysis, lower QoL was independently associated with female sex (ß = 1.07, 95% CI 1.03-1.11, p = 0.003), higher age at onset (ß = 1.03, 1.00-1.05, p = 0.009), lower schooling (ß = 1.05, 1.00-1.09, p = 0.02), higher fasting plasma glucose (ß = 1.03, 1.01-1.05, p = 0.008), daily SMBG >4 (ß = 1.06, 1.01-1.10, p = 0.01), severe hypoglycemia over the last year (ß = 1.06, 1.01-1.11, p = 0.02), lower numbers of diabetologic visits (ß = 1.07, 1.01-1.13, p = 0.02) and hypertension (ß = 1.06, 1.02-1.10, p = 0.005). Autonomic neuropathy was associated with diabetes impact. Female sex (ß = 4.36, 2.43-7.83) and daily SMBG >4 (ß = 3.77, 1.72-8.30) were independently associated with worst level and CSII with better level (ß = 0.22, 0.07-0.68) of diabetes-related worries. CONCLUSIONS: The impact of T1DM on QoL may depend on demographic, metabolic control-related variables, presence of complications and insulin delivery modality.

Anti-inflammatory and antioxidant effects of resveratrol in healthy smokers a randomized, double-blind, placebo-controlled, cross-over trial.

OBJECTIVE: Smokers are characterized by a low-grade systemic inflammatory state and an oxidant-antioxidant imbalance. Few human studies were conducted on the effects of resveratrol, a natural compound with anti-inflammatory and antioxidant properties, and no trial on smokers has been performed to date. We evaluated whether resveratrol has beneficial effects on markers of inflammation and oxidative stress in smokers. METHODS AND RESULTS: A randomized, double- blind, cross-over trial was performed in 50 healthy adult smokers: 25 were randomly allocated to "resveratrol-first" (30-days: 500mg resveratrol/day, 30-days wash-out, 30-days placebo) and 25 to "placebo-first" (30-days placebo, 30-days wash-out, 30-days 500mg resveratrol/day). Resveratrol significantly reduced C-reactive protein (CRP) and triglyceride concentrations, and increased Total Antioxidant Status (TAS) values. After analyzing data with general linear models to assess period and carry-over effects, the ratios of the values after resveratrol to those after placebo were respectively: 0.47 (95%CI 0.38-0.59) -CRP- and 0.71 (95%CI 0.65-0.78) -triglycerides-, while TAS increased by 74.2 µmol/L (95%CI 60.8-87.6). Uric acid, glucose, insulin, cholesterol, liver enzyme concentrations, and weight, waist circumference, and blood pressure values did not significantly change after resveratrol supplementation. CONCLUSIONS: Because resveratrol has anti-inflammatory, anti-oxidant, and hypotriglyceridemic effects, its supplementation may beneficially affect the increased cardiovascular risk of healthy smokers.

Hippocampal heat shock protein 25 expression in streptozotocin-induced diabetic mice.

Hippocampal abnormalities are believed to increase the risk of cognitive decline in diabetic patients. The underlying mechanism is unknown, but both hyperglycemia and oxidative stress have been implicated. Cellular stresses induce the expression of heat shock protein 25 (HSP25) and this results in cytoprotection. Our aim was to assess hippocampal expression of HSP25 in experimental diabetes. Mice were rendered diabetic by streptozotocin injection. Ten weeks after diabetes onset hippocampal HSP25 expression was studied by immunoblotting and immunohistochemistry (IHC). Expression of glial fibrillary acidic protein, nitrotyrosine, iNOS, HSP72, HSP90, and Cu/Zn superoxide dismutase (SOD) was assessed by either IHC or immunoblotting, Cu/Zn-SOD activity by enzymatic assay, and malondialdehyde (MDA) content by colorimetric assay. Hippocampal HSP25 was significantly increased in diabetic as compared to non-diabetic animals and localized predominantly within the pyramidal neurons layer of the CA1 area. This was paralleled by overexpression of nitrotyrosine, iNOS, SOD expression/activity, and enhanced MDA content. In experimental diabetes, HSP25 is overexpressed in the CA1 pyramidal neurons in parallel with markers of oxidative stress.

The ghrelin gene products and exendin-4 promote survival of human pancreatic islet endothelial cells in hyperglycaemic conditions, through phosphoinositide 3-kinase/Akt, extracellular signal-related kinase (ERK)1/2 and cAMP/protein kinase A (PKA) signalling pathways.

AIMS/HYPOTHESIS: Pancreatic islet microendothelium exhibits unique features in interdependent relationship with beta cells. Gastrointestinal products of the ghrelin gene, acylated ghrelin (AG), unacylated ghrelin (UAG) and obestatin (Ob), and the incretin, glucagon-like peptide-1 (GLP-1), prevent apoptosis of pancreatic beta cells. We investigated whether the ghrelin gene products and the GLP-1 receptor agonist exendin-4 (Ex-4) display survival effects in human pancreatic islet microendothelial cells (MECs) exposed to chronic hyperglycaemia. METHODS: Islet MECs were cultured in high glucose concentration and treated with AG, UAG, Ob or Ex-4. Apoptosis was assessed by DNA fragmentation, Hoechst staining of the nuclei and caspase-3 activity. Western blot analyses and pharmacological inhibition of protein kinase B (Akt) and extracellular signal-related kinase (ERK)1/2 pathways, detection of intracellular cAMP levels and blockade of adenylyl cyclase (AC)/cAMP/protein kinase A (PKA) signalling were performed. Levels of NO, IL-1ß and vascular endothelial growth factor (VEGF)-A in cell culture supernatant fractions were measured. RESULTS: Islet MECs express the ghrelin receptor GHS-R1A as well as GLP-1R. Treatment with AG, UAG, Ob and Ex-4 promoted cell survival and significantly inhibited glucose-induced apoptosis, through activation of PI3K/Akt, ERK1/2 phosphorylation and intracellular cAMP increase. Moreover, peptides upregulated B cell lymphoma 2 (BCL-2) and downregulated BCL-2-associated X protein (BAX) and CD40 ligand (CD40L) production, and significantly reduced the secretion of NO, IL-1ß and VEGF-A. CONCLUSIONS/INTERPRETATION: The ghrelin gene-derived peptides and Ex-4 exert cytoprotective effects in islet MECs. The anti-apoptotic effects involve phosphoinositide 3-kinase (PI3K)/Akt, ERK1/2 and cAMP/PKA pathways. These peptides could therefore represent a potential tool to improve islet vascularisation and, indirectly, islet cell function.

Uric acid is not an independent predictor of cardiovascular mortality in type 2 diabetes: a population-based study.

OBJECTIVE: Although some studies have suggested that uric acid is a risk factor for mortality, this relationship is still uncertain in people with type 2 diabetes. METHODS: The study base was the population-based cohort of 1540 diabetic subjects (median age 68.9 years) of the Casale Monferrato Study. The role of serum uric acid on 15-years all-cause, cardiovascular and non-cardiovascular mortality was assessed by multivariate Cox proportional hazards modeling. RESULTS: Baseline levels of serum uric acid were negatively correlated with HbA1c, were higher in men and in the elderly and were independently associated with components of the metabolic syndrome. Out of 14,179 person-years, 1000 deaths (514 due to cardiovascular diseases) were observed. Compared to the lower quartile of uric acid, HRs (95% CI) in the upper quartile were 1.47 (1.22-1.76) for all-cause mortality; 1.40 (1.09-1.80) for cardiovascular mortality and 1.50 (1.15-1.96) for non-cardiovascular mortality. In multiple adjusted models, however, HRs were 1.30 (1.06-1.60) for all-cause mortality, 1.13 (0.85-1.50) for cardiovascular mortality and 1.50 (1.11-2.02) for non-cardiovascular mortality (men 1.87, 1.19-2.95; women 1.20, 0.80-1.80); the latter appeared to be due to neoplastic diseases (HR in all combined quartiles vs. lower quartile: both sexes 1.59, 1.05-2.40; men 1.54, 0.83-2.84, women 1.68, 0.95-2.92). CONCLUSIONS: In diabetic people, uric acid is associated with components of the metabolic syndrome but it may not be accounted as an independent risk factor for cardiovascular mortality. The increased all-cause mortality risk with higher levels of uric acid might be due to increased neoplastic mortality and deserves future studies.

Is left ventricular hypertrophy a low-level inflammatory state? A population-based cohort study.

BACKGROUND AND AIMS: Cross-sectional studies have shown that chronic sub-clinical inflammation is associated with left ventricular hypertrophy (LVH), but results are conflicting. We investigated the association between baseline LVH and high-sensitivity C-reactive protein (CRP) values, both cross-sectionally and after a six-year-follow-up, in a population-based cohort (n = 1564) and a subgroup from this cohort (n = 515), without obesity, diabetes, metabolic syndrome or any drugs. METHODS AND RESULTS: ECG tracings at baseline were interpreted according to the Cornell voltage-duration product criteria: 166/1564 subjects (10.6%) showed LVH. Patients with baseline LVH showed increased BMI, waist circumference, blood pressure, and a worse metabolic pattern. Their CRP values both at baseline and at follow-up were almost two-fold higher than in patients without LVH. Similar results were found in the healthier sub-sample. In a multiple regression model, CRP at follow-up was directly associated with baseline LVH (expressed as Cornell voltage-duration product) in the whole cohort (ß = 0.0003; 95%CI 0.0002-0.0006; p < 0.001) and in the sub-sample (ß = 0.0003; 0.0002-0.0004; p < 0.001), after adjusting for age, sex, BMI, waist circumference, smoking, exercise levels, blood pressure and baseline CRP values. CONCLUSION: Baseline LVH, which is associated with systemic inflammation, predicts increased CRP values at follow-up, independently of cardiovascular and metabolic risk factors, both in a population-based cohort and a healthier sub-sample. The inflammatory consequences of LVH might be an intriguing subject for further researches.

Direct costs in diabetic and non diabetic people: the population-based Turin study, Italy.

BACKGROUND AND AIMS: We compared direct costs of diabetic and non diabetic people covered by the Italian National Health System, focusing on the influence of age, sex, type of diabetes and treatment. METHODS AND RESULTS: Diabetic people living in Turin were identified through the Regional Diabetes Registry and the files of hospital discharges and prescriptions. Data sources were linked to the administrative databases to assess health care services used by diabetic (n = 33,792) and non diabetic people(n = 863,123). Data were analyzed with the two-part model; the estimated direct costs per person/year were €3660.8 in diabetic people and €895.6 in non diabetic people, giving a cost ratio of 4.1. Diabetes accounted for 11.4% of total health care expenditure. The costs were attributed to hospitalizations (57.2%), drugs (25.6%), to outpatient care (11.9%), consumable goods (4.4%) and emergency care (0.9%). Estimated costs increased from € 2670.8 in diabetic people aged <45 years to € 3724.1 in those aged >74 years, the latter representing two third of the diabetic cohort; corresponding figures in non diabetic people were € 371.6 and € 2155.9. In all expenditure categories cost ratios of diabetic vs non diabetic people were higher in people aged <45 years, in type 1 diabetes and in insulin-treated type 2 diabetes. CONCLUSION: Direct costs are 4-fold higher in diabetic than in non diabetic people, mainly due to care of the elderly and inpatient care. In developed countries, demographic changes will have a profound impact on costs for diabetes in next years.

The rs553668 polymorphism of the ADRA2A gene predicts the worsening of fasting glucose values in a cohort of subjects without diabetes. A population-based study.

AIMS: Single-nucleotide polymorphisms in the human ADRA2A gene have been associated with increased risk of Type 2 diabetes. The associations between the rs553668 polymorphism and fasting glucose concentrations both cross-sectionally and longitudinally after 6-year follow-up were evaluated in an adult Caucasian population-based cohort. METHODS: From a cohort of 1658 individuals, after excluding patients with diabetes, those who died and those whose blood samples were not available for genotyping, data of 1345 individuals were analysed. RESULTS: Subjects homozygous for the A allele showed significantly increased baseline fasting glucose values and a significant worsening of fasting glucose (ß = 0.48; 95% CI 0.10-0.86) and insulin secretion (ß =-20.75; -32.67 to -8.82 for homeostasis model assessment for ß-cell function) at follow-up by using generalized estimating equations. Incidence of impaired fasting glucose and diabetes was almost twofold higher in subjects homozygous for the A allele (respectively: incident impaired fasting glucose 7.6-8.2, 16.1%, incident diabetes 1.7-2.3, 3.2% in GG, AG, AA carriers). CONCLUSIONS: Our results suggested that the rs553668 polymorphism is associated with glucose worsening in subjects without diabetes at baseline.

Contributors to the obesity and hyperglycemia epidemics. A prospective study in a population-based cohort.

OBJECTIVE: Relatively unexplored contributors to the obesity and diabetes epidemics may include sleep restriction, increased house temperature (HT), television watching (TW), consumption of restaurant meals (RMs), use of air conditioning (AC) and use of antidepressant/antipsychotic drugs (ADs). DESIGN AND SUBJECTS: In a population-based cohort (n=1597), we investigated the possible association among these conditions, and obesity or hyperglycemia incidence at 6-year follow-up. Subjects with obesity (n=315) or hyperglycemia (n=618) at baseline were excluded, respectively, 1282 and 979 individuals were therefore analyzed. RESULTS: At follow-up, 103/1282 became obese; these subjects showed significantly higher body mass index, waist circumference, saturated fat intake, RM frequency, TW hours, HT, AC and AD use, and lower fiber intake, metabolic equivalent of activity in h per week (METS) and sleep hours at baseline. In a multiple logistic regression model, METS (odds ratio=0.94; 95% confidence interval (CI) 0.91-0.98), RMs (odds ratio=1.47 per meal per week; 1.21-1.79), being in the third tertile of HT (odds ratio=2.06; 1.02-4.16) and hours of sleep (odds ratio=0.70 per h; 0.57-0.86) were associated with incident obesity. Subjects who developed hyperglycemia (n=174/979; 17.8%) had higher saturated fat intake, RM frequency, TW hours, HT, AC and AD use at baseline and lower METS and fiber intake. In a multiple logistic regression model, fiber intake (odds ratio=0.97 for each g per day; 0.95-0.99), RM (1.49 per meal per week; 1.26-1.75) and being in the third tertile of HT (odds ratio=1.95; 1.17-3.26) were independently associated with incident hyperglycemia. CONCLUSIONS: Lifestyle contributors to the obesity and hyperglycemia epidemics may be regular consumption of RM, sleep restriction and higher HT, suggesting potential adjunctive non-pharmacological preventive strategies for the obesity and hyperglycemia epidemics.

NR2A subunit of the N-methyl D-aspartate receptors are required for potentiation at the mossy fiber to granule cell synapse and vestibulo-cerebellar motor learning.

Traditionally studies aimed at elucidating the molecular mechanisms underlying cerebellar motor learning have been focused on plasticity at the parallel fiber to Purkinje cell synapse. In recent years, however, the concept is emerging that formation and storage of memories are both distributed over multiple types of synapses at different sites. Here, we examined the potential role of potentiation at the mossy fiber to granule cell synapse, which occurs upstream to plasticity in Purkinje cells. We show that null-mutants of N-methyl d-aspartate-NR2A receptors (NMDA-NR2A(-/-) mice) have impaired induction of postsynaptic long-term potentiation (LTP) at the mossy fiber terminals and a reduced ability to raise the granule cell synaptic excitation, while the basic excitatory output of the mossy fibers is unaffected. In addition, we demonstrate that these NR2A(-/-) mutants as well as mutants in which the C terminal in the NR2A subunit is selectively truncated (NR2A(ΔC/ΔC) mice) have deficits in phase reversal adaptation of their vestibulo-ocular reflex (VOR), while their basic eye movement performance is similar to that of wild type littermates. These results indicate that NMDA-NR2A mediated potentiation at the mossy fiber to granule cell synapse is not required for basic motor performance, and they raise the possibility that it may contribute to some forms of vestibulo-cerebellar memory formation.

The incidence of type 1 diabetes is increasing in both children and young adults in Northern Italy: 1984-2004 temporal trends.

AIMS/HYPOTHESIS: A shift towards younger age at onset of diabetes in susceptible people has been suggested as a possible explanation for the increasing temporal trend in incidence of type 1 diabetes. We aimed to test this hypothesis by assessing trends in incidence rates in the period 1984-2004 in children and young adults in Northern Italy. METHODS: The study bases were: (1) children resident in the Province of Turin in the period 1984-2004 and in the remaining areas of the Piedmont Region in the period 1990-2004; and (2) young adults (15-29 years) resident in the Province of Turin in the period 1984-2003. Temporal trends in rates were analysed using Poisson regression models. RESULTS: A total of 1,773 incident cases were identified. Overall incidence rates/100,000 person-years in the age groups 0-14 and 15-29 years were 11.3 (95% CI 10.7-12.0) and 7.1 (95% CI 6.6-7.7), respectively, with sex differences among young adults only (incidence rate ratio [IRR] in males vs females 1.41 [95% CI 1.20-1.64]). Average annual increases in incidence rates were similar in children and young adults at 3.3% (95% CI 2.5-4.1). Compared with the period 1984-89, in 2000-2004 a 60% higher risk was found in both age 0-14 years (IRR 1.60, 95% CI 1.31-1.95) and 15-29 years (IRR 1.57, 95% CI 1.26-1.96) groups. The Poisson modelling showed no interaction between calendar period and age at onset. CONCLUSIONS/INTERPRETATION: Incidence of type 1 diabetes in Northern Italy is increasing over time in both children and young adults, not supporting the hypothesis of a shift towards younger age as the main explanation for the increasing temporal trend in children.

ANTI-HSP60 and ANTI-HSP70 antibody levels and micro/ macrovascular complications in type 1 diabetes: the EURODIAB Study.

OBJECTIVES: The heat shock proteins 60 and 70 (HSP60, HSP70) play an important role in cytoprotection. Under stress conditions they are released into the circulation and elicit an immune response. Anti-HSP60 and anti-HSP70 antibody levels have been associated with cardiovascular disease. Type 1 diabetes is associated with a greatly increased risk of micro- and macrovascular complications. Therefore, we investigated whether anti-HSP60 and anti-HSP70 antibody levels were associated with micro- and macrovascular complications in type 1 diabetic patients. DESIGN: A cross-sectional nested case-control study from the EURODIAB Study of 531 type 1 diabetic patients was performed. SUBJECTS: Cases (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were all those with no evidence of any complication. We measured anti-HSP60 and anti-HSP70 antibody levels and investigated their cross-sectional associations with diabetic complications. RESULTS: Anti-HSP70 antibody levels were significantly greater in control than in case subjects, whereas anti-HSP60 antibody levels were similar in the two groups. In logistic regression analysis, anti-HSP70 levels in the upper quartiles were associated with a 47% reduced odds ratio of micro/macrovascular complications, independently of conventional risk factors, markers of inflammation and endothelial dysfunction [odds ratio (OR) = 0.53, 95% confidence intervals (CI): 0.28-1.02]. CONCLUSIONS: In this large cohort of type 1 diabetic subjects, we found an independent and inverse association between serum anti-HSP70 antibody levels and diabetic micro/macrovascular complications. This suggests that anti-HSP70 antibody levels may be a novel marker of protection from chronic diabetic complications.

What predicts the occurrence of the metabolic syndrome in a population-based cohort of adult healthy subjects?

BACKGROUND: Metabolic syndrome (MS), the concurrence of hyperglycaemia, dyslipidaemia, hypertension and visceral obesity, increases cardiovascular risk and mortality. Predictors of MS were previously evaluated in patients without the full syndrome, but with some of its traits. This might confound the resulting associations. METHODS: The relationship between baseline variables and MS development was evaluated in healthy middle-aged subjects without any MS component at baseline, over a 4.5-year follow-up. RESULTS: From a population-based cohort of 1658 subjects, 241 individuals showed no MS components and 201 (83.4%) of them participated in a follow-up screening. At baseline, patients who developed the MS (n = 28/201; 13.9%) showed significantly higher Homeostasis Model Assessment-Insulin Resistance score (HOMA-IR) and C-reactive protein (CRP) values, and lower exercise level than subjects who did not. In a multiple logistic regression analysis, after multiple adjustments, the only baseline variable significantly (p < 0.01) associated with the MS was CRP (OR = 4.05; 95% CI 2.23-7.38; p < 0.001). Results did not change after adjusting for weight gain. The area under the receiver-operating curve was 0.83 for CRP after multiple adjustments. The optimal cut-off point of baseline CRP values was 2.1 mg/L, with 86% (95% CI 81-90) sensitivity and 75% (69-81) specificity in predicting the MS. Baseline CRP resulted associated with after-study glucose values in a multiple regression model (beta = 0.14; 0.08-0.20; p < 0.001). CONCLUSIONS: Higher baseline CRP values confer a significant increased risk of developing the MS in healthy subjects, independently of weight gain.

Plasma visfatin concentrations after a lifestyle intervention were directly associated with inflammatory markers.

BACKGROUND AND AIMS: The biological activity and regulation of the novel adipokine visfatin are still largely unknown. Our aim was to evaluate if visfatin plasma concentrations may be influenced by a lifestyle intervention. METHODS AND RESULTS: Out of 335 dysmetabolic patients from a population-based cohort, randomized to receive a lifestyle intervention program (intervention group) or family physician usual care (controls), 20 patients per group were randomly selected for plasma visfatin determination. The before-after variation (Delta) in visfatin concentration at 1-year from randomization, and the correlations between (Delta)visfatin and intervention-induced changes in waist circumference, fasting glucose, markers of inflammation, and oxidative stress were evaluated. The intervention group showed a significant improvement in waist circumference, and many metabolic/inflammatory variables, while the controls worsened. Visfatin concentrations slightly decreased in the former and significantly increased in the controls ((Delta)visfatin=-2.4 vs 66.0 ng/ml, p<0.001). In robust regression models, the following variables resulted associated with (Delta)visfatin: (Delta)waist circumference, (Delta)fasting glucose, (Delta)hs-CRP (high-sensitivity C-reactive protein) and (Delta)TNFalpha (tumor necrosis factor-alpha). Significant effects on (Delta)visfatin of (Delta)TNFalpha (beta=16.8; 6.1-25.6; p=0.003) and, modified by group, of (Delta)hs-CRP (beta=29.8; 95% CI 15.4-44.2; p<0.001 and beta=4.2; 2.9-5.5; p<0.001 in the control and intervention group, respectively) were detected. By controlling for (Delta)waist, the effects of (Delta)TNFalpha and of (Delta)hs-CRP on (Delta)visfatin by group did not change, while (Delta)waist was no longer associated. The association between (Delta)visfatin and (Delta)glucose was no longer significant, after adjusting for (Delta)hs-CRP. CONCLUSION: Visfatin values increased with waist circumference and were associated with variations of inflammatory markers, suggesting participation in inflammatory mechanisms.