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Guarnieri V.,IRCCS Casa Sollievo della Sofferenza Hospital | Valentina D'Elia A.,Medical Genetics Institute | Baorda F.,IRCCS Casa Sollievo della Sofferenza Hospital | Pazienza V.,IRCCS Casa Sollievo della Sofferenza Hospital | And 13 more authors.
Molecular Genetics and Metabolism | Year: 2012

Background: Autosomal dominant hypocalcemia (ADH) is an endocrine disorder caused by activating mutations of the calcium-sensing receptor (CASR) gene which plays a major role in maintaining calcium homeostasis. Biochemical features of ADH are hypocalcemia and hypercalciuria with inappropriately low levels of parathyroid hormone (PTH). We report on two four-generation families affected by ADH. Aim: To identify mutations of CASR gene in subjects affected by familial idiopathic hypoparathyroidism. To perform functional assays of identified CASR variants by transient transfection on HEK293 cells. Results: We identified two CASR variants (Q681R and P221L): the Q681R variant was novel while the P221L had been previously published. Functional assays on the Q681R variant showed that it did not alter the whole expression nor the correct plasmamembrane localization, but enhanced the signaling function, increasing the sensitivity of the receptor as compared to the WT. Conclusions: We report two activating CASR mutations in two families affected by ADH and the functional assays performed on the novel variant Q681R. Our work enlarged the spectrum of mutations of the CASR and contributed to a better elucidation of the protein function. © 2012 Elsevier Inc.

Bacci S.,Clinical Unit of Endocrinology | Prudente S.,IRCCS Casa Sollievo della Sofferenza Mendel Laboratory | Copetti M.,Unit of Biostatistics | Spoto B.,CNR Institute of Biomedicine and Molecular Immunology Alberto Monroy | And 24 more authors.
Atherosclerosis | Year: 2013

Objective: Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. Design and setting: 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). Results: 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p = 0.006). 3. A significant association was also observed with ISI (p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p = 0.009). Conclusions: Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies. © 2012 Elsevier Ireland Ltd.

Carecchio M.,University College London | Carecchio M.,University of Piemonte Orientale | Magliozzi M.,CSS Mendel Laboratory | Copetti M.,Biostatistics Unit | And 12 more authors.
Movement Disorders | Year: 2013

Mutations or exon deletions of the epsilon-sarcoglycan (SGCE) gene cause myoclonus-dystonia (M-D), but a subset of M-D patients are mutation-negative and the sensitivity and specificity of current genetic testing criteria are unknown. We screened 46 newly enrolled M-D patients for SGCE mutations and deletions; moreover, 24 subjects previously testing negative for SGCE mutations underwent gene dosage analysis. In our combined cohorts, we calculated sensitivity, specificity, positive and negative predictive values, and area under the curve of 2 published sets of M-D diagnostic criteria. A stepwise logistic regression was used to assess which patients' characteristics best discriminated mutation carriers and to calculate a new mutation predictive score ("new score"), which we validated in previously published cohorts. Nine of 46 (19.5%) patients of the new cohort carried SCGE mutations, including 5 novel point mutations and 1 whole-gene deletion; in the old cohort, 1 patient with a complex phenotype carried a 5.9-Mb deletion encompassing SGCE. Current diagnostic criteria had a poor ability to discriminate SGCE-positive from SGCE-negative patients in our cohort; conversely, age of onset, especially if associated with psychiatric features (as included in the new score), showed the best discriminatory power to individuate SGCE mutation carriers, both in our cohort and in the validation cohort. Our results suggest that young age at onset of motor symptoms, especially in association with psychiatric disturbance, are strongly predictive for SGCE positivity. We suggest performing gene dosage analysis by multiple ligation-dependent probe amplification (MLPA) to individuate large SGCE deletions that can be responsible for complex phenotypes. © 2013 Movement Disorder Society.

Rossi M.C.,Center for Outcomes Research and Clinical Epidemiology | Rossi M.C.,Laboratory of Clinical Epidemiology of Diabetes and Chronic Diseases | Lucisano G.,Center for Outcomes Research and Clinical Epidemiology | Lucisano G.,Laboratory of Clinical Epidemiology of Diabetes and Chronic Diseases | And 11 more authors.
Patient Education and Counseling | Year: 2015

Objective: We evaluated empowerment in T2DM and identified its correlates. Methods: A sample of individuals self-administered the Diabetes Empowerment Scale-Short Form (DES-SF) and other 9 validated instruments (person-centered outcomes). Correlates of DES-SF were identified through univariate and multivariate analyses. For person-centered outcomes, ORs express the likelihood of being in upper quartile of DES-SF (Q4) by 5 units of the scale. Results: Overall, 2390 individuals were involved. Individuals in Q4 were younger, more often males, had higher levels of school education, lower HbA1c levels and prevalence of complications as compared to individuals in the other quartiles. The likelihood of being in Q4 was directly associated with higher selfreported self-monitoring of blood glucose (SDSCA6-SMBG) (OR. =. 1.09; 95% CI: 1.03-1.15), higher satisfaction with diabetes treatment (GSDT) (OR. =. 1.15; 95% CI: 1.07-1.25), perceived quality of chronic illness care and patient support (PACIC-SF) (OR. =. 1.23; 95% CI: 1.16-1.31), and better person-centered communication (HCC-SF) (OR. =. 1.10; 95% CI: 1.01-1.19) and inversely associated with diabetes-related distress (PAID-5) (OR. =. 0.95; 95% CI: 0.92-0.98). Adjusted DES-SF mean scores ranged between centers from 69.8 to 93.6 (intra-class correlation. =. 0.10; p<. 0.0001). Conclusions: Empowerment was associated with better glycemic control, psychosocial functioning and perceived access to person-centered chronic illness care. Practice of diabetes center plays a specific role. Practice implications: DES-SF represents a process and outcome indicator in the practice of diabetes centers. © 2015 Elsevier Ireland Ltd.

Mazzoccoli G.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Copetti M.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Dagostino M.P.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | Grilli M.,Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza | And 4 more authors.
Atherosclerosis | Year: 2012

Objective: Epicardial fat (EpiF) reflects abdominal visceral adiposity and visceral fat plays an important role in the development of an unfavorable metabolic and atherosclerosis risk profile. An increased cardiovascular risk has been evidenced in patients with deep venous thrombosis (DVT). Advancing age is characterized by alterations of body fat mass and function In this study we studied the association between EpiF, DVT, age, obesity and other atherosclerosis risk factors. Methods and results: 77 patients were recruited: 44 men and 33 women, 38 without DVT (65.9 ± 16.3 years, range 26-92 years) and 39 with DVT (65.4 ± 17.2 years, range 28-90 years). The study design was balanced for established atherosclerosis risk factors (gender, obesity, smoking habits, dyslipidemia, diabetes mellitus, arterial hypertension), for previous cardiovascular events, for use of statins and platelet anti-aggregating agents. Multivariate regression model and RECPAM regression tree were used to study the association between EpiF thickness and the other potential risk factors. Patients with DVT showed a thicker EpiF with respect to those without DVT (12 ± 2 mm vs. 9 ± 2 mm respectively, p < 0.001). Multivariate linear regression model showed that DVT, obesity and age were positively associated with EpiF thickness after adjusting for the established atherosclerosis risk factors. Furthermore, the RECPAM analysis was performed to evaluate interactions between DVT, age and obesity: four main distinct and homogeneous subgroups of patients in terms of EpiF thickness were identified. The most important variable in partitioning patients was represented, as expected, by DVT (p < 0.001) followed by age (p = 0.004), while obesity did not contribute to the model as well as the other atherosclerosis risk factors. Patients with DVT and older than 41 years of age had higher EpiF thickness in respect of patients with DVT and younger than 41 years of age. In patients without DVT the estimated cut-off age was 50 years, and older patients had thicker EpiF in respect of patients younger than 50 years of age. Conclusion: DVT should be considered as strongly associated with EpiF thickness. Advancing age (with or without spontaneous DVT) is significantly associated with an increased EpiF thickness. The measurement of EpiF thickness, a valuable marker of cardio-metabolic risk, may represent a useful and reliable method to evaluate cardiovascular risk in patients with idiopathic deep phlebothrombosis. © 2012 Elsevier Ireland Ltd.

Paroni G.,Geriatric Unit | Seripa D.,Geriatric Unit | Panza F.,Geriatric Unit | Addante F.,Geriatric Unit | And 6 more authors.
Age | Year: 2012

Klotho (KL) gene has been involved in severe alterations of physiological biochemical parameters leading to premature aging-like phenotypes and strikingly shortening lifespan. KL participates to the regulation of a number of intracellular biochemical pathways, including lipid profile and glucose metabolism. Aim of this study was to investigate the possible association between KL locus and biological parameters commonly accepted as indicators of the clinical status in hospitalized older patients. We genotyped the single-nucleotide polymorphisms (SNPs) rs9536314, rs1207568, and rs564481 at the KL locus in 594 hospitalized older patients (65-99 years), consecutively attending a geriatric ward, and tested the association of these KL variants with biological quantitative traits using analyses of covariance and genetic risk score models. Significant associations of rs9536314 with serum levels of hemoglobin, albumin, and high-density lipoprotein cholesterol (HDL-C) as well as significant associations of rs564481 with serum levels of hemoglobin, fasting insulin, and fasting glucose were observed. Gender-segregated analyses confirmed these associations, and suggested that the associations of KL genotypes with HDL-C, fasting glucose and fasting insulin levels may be driven by the female gender, while the association with serum levels of hemoglobin may be driven by the male gender. The association of KL genotypes with creatinine levels was found only in females, while the association with insulin-like growth factor-1 (IGF-1) and lymphocytes count (LC) was found only in males. The genetic risk score (GRS) models further confirmed significant associations among KL SNPs and hemoglobin, total cholesterol, and HDL-C. Gender-segregated analyses with the GRS-tagged approach confirmed the associations with HDL-C, fasting glucose, and fasting insulin levels in females, and with hemoglobin and LC in males. Our findings suggested that KL locus may influence quantitative traits such as serum levels of lipid, fasting glucose, albumin and hemoglobin in hospitalized older patients, with some gender differences suggested for creatinine, IGF-1 levels, and LC, thus being one of the genetic factors possibly contributing to age-related diseases and longevity. © The Author(s) 2011.

Rizza S.,University of Rome Tor Vergata | Copetti M.,Unit of Biostatistics | Cardellini M.,University of Rome Tor Vergata | Porzio O.,University of Rome Tor Vergata | And 11 more authors.
Atherosclerosis | Year: 2012

Objective: Undiagnosed diabetes (DM2), especially in individuals that have experienced a major atherosclerotic vascular event, could increase the risk of a second major cardiovascular (CV) event. The aim of this study was to evaluate the impact of type 2 diabetes (DM2), diagnosed after a major cardiovascular event, on subsequent CV disease in high risk individuals. Methods: 411 subjects without known DM2 and with a history of a prior major CV event were followed for a second major CV event (fatal and nonfatal MI, fatal and nonfatal stroke or any arterial revascularization procedure). At baseline, each individual underwent a physical, biochemical examination, an OGTT and dosed A1c. In addition, patients were classified as having monovascular or polyvascular disease. The average follow-up duration was 31 months. Results: The incidence of second CV events was 10.70 per 100 person-years (114 events/1066 person-years). The diagnosis of occult DM2 was not associated with major CV events, either using A1c values ≥6.5%, fasting glucose ≥126 mg/dL or 2 h post-load glucose ≥200 mg/dL. Polyvascular disease was the only significant predictor of a second major CV event (HR 2.60, 95% CI 1.72-3.95) after adjustment for age, BMI, smoking status, systolic blood pressure, high-density and low-density lipoprotein cholesterol and high sensitivity C-reactive protein. Conclusion: DM2 that was newly diagnosed after established vascular atherosclerotic disease did not increase the risk of new major CV events. In our population only the polyvascular disease was able to identify the subjects at high risk for a second major cardiovascular event. © 2012 Elsevier Ireland Ltd.

Ravani P.,University of Calgary | Palmer S.C.,University of Otago | Oliver M.J.,University of Toronto | Quinn R.R.,University of Calgary | And 15 more authors.
Journal of the American Society of Nephrology | Year: 2013

Clinical practice guidelines recommend an arteriovenous fistula as the preferred vascular access for hemodialysis, but quantitative associations between vascular access type and various clinical outcomes remain controversial. We performed a systematic review of cohort studies to evaluate the associations between type of vascular access (arteriovenous fistula, arteriovenous graft, and central venous catheter) and risk for death, infection, and major cardiovascular events. We searched MEDLINE, EMBASE, and article reference lists and extracted data describing study design, participants, vascular access type, clinical outcomes, and risk for bias. We identified 3965 citations, of which 67 (62 cohort studies comprising 586,337 participants) met our inclusion criteria. In a randomeffects meta-analysis, compared with persons with fistulas, those individuals using catheters had higher risks for all-cause mortality (risk ratio=1.53, 95% CI=1.41-1.67), fatal infections (2.12, 1.79-2.52), and cardiovascular events (1.38, 1.24-1.54). Similarly, compared with persons with grafts, those individuals using catheters had higher risks for mortality (1.38, 1.25-1.52), fatal infections (1.49, 1.15-1.93), and cardiovascular events (1.26, 1.11-1.43). Compared with persons with fistulas, those individuals with grafts had increased all-cause mortality (1.18, 1.09-1.27) and fatal infection (1.36, 1.17-1.58), but we did not detect a difference in the risk for cardiovascular events (1.07, 0.95-1.21). The risk for bias, especially selection bias, was high. In conclusion, persons using catheters for hemodialysis seem to have the highest risks for death, infections, and cardiovascular events compared with other vascular access types, and patients with usable fistulas have the lowest risk. Copyright © 2013 by the American Society of Nephrology.

Pilotto A.,S Antonio Hospital | Gallina P.,Health Services Directorate | Fontana A.,Unit of Biostatistics | Sancarlo D.,Gerontology and Geriatrics Research Laboratory | And 9 more authors.
Journal of the American Medical Directors Association | Year: 2013

Objectives: To develop and validate a Multidimensional Prognostic Index (MPI) for mortality based on information collected by the Multidimensional Assessment Schedule (SVaMA), the recommended standard tool for multidimensional assessment of community-dwelling older subjects in seven Italian regions. Design: Prospective cohort study. Participants: Community-dwelling subjects older than 65 years who underwent an SVaMA evaluation from 2004 to 2010 in Padova Health District, Veneto, Italy. Measurements: The MPI-SVaMA was calculated as a weighted (weights were derived from multivariate Cox regressions) linear combination of the following nine domains: age, sex, main diagnosis, and six scores, ie, the Short Portable Mental Status Questionnaire, the Barthel index (contains two domains: activities of daily living and mobility), the Exton-Smith scale, the Nursing Care Needs, and the Social Network Support by a structured interview. Subjects were followed for a median of 2 years; those who had not died were followed for at least 1 year. The MPI-SVaMA score ranged from 0 to 1 and 3 grades of severity of the MPI-SVaMA were calculated on the basis of estimated cutoffs. Discriminatory power and calibration were further assessed. Results: A total of 12,020 subjects (mean age 81.84 ± 7.97 years) were included. Two random cohorts were selected: (1) a development cohort, ie, 7876 subjects (mean age 81.79 ± 8.05, %females: 63.1) and (2) a validation cohort, ie, 4144 subjects (mean age: 81.95 ± 7.83, %females: 63.7).The discriminatory power for mortality of MPI-SVaMA was 0.828 (95% CI 0.817-0.838) and 0.832 (95% CI 0.818-0.845) at 1 month and 0.791 (95% CI 0.784-0.798) and 0.792 (95% CI 0.783-0.802) at 1 year in development and validation cohorts, respectively. MPI-SVaMA results were well calibrated showing lower than 10% differences between predicted and observed mortality, both in development and validation cohorts. Conclusions: The MPI-SVaMA is an accurate and well-calibrated prognostic tool for mortality in community-dwelling older subjects, and can be used in clinical decision making. © 2013 American Medical Directors Association, Inc.

PubMed | ASL TO, Metabolism and Diabetes Unit, The Second University of Naples, Laboratory of Clinical Epidemiology of Diabetes and Chronic Diseases and Metabolism And Diabetes Unit Hospital St Martin
Type: Journal Article | Journal: Acta diabetologica | Year: 2015

Hypoglycemia is common in type 1 diabetes mellitus (T1DM). We aimed to update the incidence of severe and symptomatic hypoglycemia and investigate several correlated factors.In this multicenter, observational retrospective study, the data of 206 T1DM patients from a sample of 2,229 consecutive patients seen at 18 diabetes clinics were analyzed. Sociodemographic and clinical characteristics, severe hypoglycemia in the past 12 months, and symptomatic hypoglycemia in the past 4 weeks were recorded with a self-report questionnaire and a clinical form during a routine visit. Poisson multivariate models were applied.A minority of patients accounted for the majority of both severe and symptomatic episodes. The incidence rate (IR) of severe hypoglycemia was 0.49 (0.40-0.60) events/person-years. The incidence rate ratio (IRR) was higher in patients with previous severe hypoglycemia (3.71; 2.28-6.04), neuropathy (4.16; 2.14-8.05), long duration (>20 years, 2.96; 1.60-5.45), and on polypharmacy (1.24; 1.13-1.36), but it was lower when a complication was present. The IR of symptomatic hypoglycemia was 53.3 events/person-years, with an IRR significantly higher among women or patients with better education, or shorter duration or on pumps. The IRR was lower in patients with higher BMI or neuropathy or aged more than 50 years.Fewer than 20 % of T1DM patients are free from hypoglycemia, with one in six having experienced at least one severe episode in the last year. The distribution is uneven, with a tendency of episodes to cluster in some patients. Severe and symptomatic episodes have different correlates and reflect different conditions.

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