Consorzio Mario Negri Sud

Santa Maria Imbaro, Italy

Consorzio Mario Negri Sud

Santa Maria Imbaro, Italy
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Weller S.G.,Mayo Medical School | Capitani M.,Unit of Genomic Approaches to Membrane Traffic | Cao H.,Mayo Medical School | Micaroni M.,Consorzio Mario Negri Sud | And 4 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

The size and integrity of the Golgi apparatus is maintained via a tightly controlled regulation of membrane traffic using a variety of different signaling and cytoskeletal proteins. We have recently observed that activation of c-Src has profound effects on Golgi structure, leadingto dramatically vesiculatedcisternae in a variety of cell types. As the large GTPase dynamin (Dyn2) has been implicated in Golgi vesiculation during secretion, we tested whether inhibiting Dyn2 activity by expression of a Dyn2K44A mutant or siRNA knockdown could attenuate active Src-induced Golgi fragmentation. Indeed, these perturbations attenuated fragmentation, and expression of a Dyn2Y(231/597)F mutant protein that cannot be phosphorylated by Src kinase had a similar effect . Finally, we find that Dyn2 is markedly phosphorylated during the transit of VSV-G protein through the TGNwhereas expression of the Dyn2Y(231/597) F mutant significantly reduces exit of the nascent protein from this compartment. These findings demonstrate that activation of Dyn2 by Src kinase regulates Golgi integrity and vesiculation during the secretory process.

Roncaglioni M.C.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs | Avanzini F.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs | Barlera S.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs | Marzona I.,Instituto Of Ricovero E Cura A Carattere Scientifico Irccs | And 7 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: Trials have shown a beneficial effect of n-3 polyunsaturated fatty acids in patients with a previous myocardial infarction or heart failure. We evaluated the potential benefit of such therapy in patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infarction. METHODS: In this double-blind, placebo-controlled clinical trial, we enrolled a cohort of patients who were followed by a network of 860 general practitioners in Italy. Eligible patients were men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. Patients were randomly assigned to n-3 fatty acids (1 g daily) or placebo (olive oil). The initially specified primary end point was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes. RESULTS: Of the 12,513 patients enrolled, 6244 were randomly assigned to n-3 fatty acids and 6269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6239 (11.7%) had received n-3 fatty acids and 745 of 6266 (11.9%) had received placebo (adjusted hazard ratio with n-3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P=0.58). The same null results were observed for all the secondary end points. CONCLUSIONS: In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity. Copyright © 2013 Massachusetts Medical Society.

Caironi P.,University of Milan | Tognoni G.,Consorzio Mario Negri Sud | Masson S.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Fumagalli R.,University of Milan Bicocca | And 11 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established. METHODS: In this multicenter, open-label trial, we randomly assigned 1818 patients with severe sepsis, in 100 intensive care units (ICUs), to receive either 20% albumin and crystalloid solution or crystalloid solution alone. In the albumin group, the target serum albumin concentration was 30 g per liter or more until discharge from the ICU or 28 days after randomization. The primary outcome was death from any cause at 28 days. Secondary outcomes were death from any cause at 90 days, the number of patients with organ dysfunction and the degree of dysfunction, and length of stay in the ICU and the hospital. RESULTS: During the first 7 days, patients in the albumin group, as compared with those in the crystalloid group, had a higher mean arterial pressure (P = 0.03) and lower net fluid balance (P<0.001). The total daily amount of administered fluid did not differ significantly between the two groups (P = 0.10). At 28 days, 285 of 895 patients (31.8%) in the albumin group and 288 of 900 (32.0%) in the crystalloid group had died (relative risk in the albumin group, 1.00; 95% confidence interval [CI], 0.87 to 1.14; P = 0.94). At 90 days, 365 of 888 patients (41.1%) in the albumin group and 389 of 893 (43.6%) in the crystalloid group had died (relative risk, 0.94; 95% CI, 0.85 to 1.05; P = 0.29). No significant differences in other secondary outcomes were observed between the two groups. CONCLUSIONS: In patients with severe sepsis, albumin replacement in addition to crystalloids, as compared with crystalloids alone, did not improve the rate of survival at 28 and 90 days. (Funded by the Italian Medicines Agency; ALBIOS number, NCT00707122.) Copyright © 2014 Massachusetts Medical Society. All rights reserved.

OBJECTIVE - To determine the functional health status and treatment satisfaction in patients with type 2 diabetes from the Evaluation of Lantus Effect ON Optimization of use of single dose Rapid insulin (ELEONOR) study that investigated whether a telecare program helps optimization of basal insulin glargine with one bolus injection of insulin glulisine. RESEARCH DESIGN AND METHODS - Functional health status and treatment satisfaction were investigated using the 36-Item Short-Form (SF-36) Health Survey, the World Health OrganizationWell-Being Questionnaire (WBQ), and the Diabetes Treatment Satisfaction Questionnaire. RESULTS - Of 291 randomized patients, 238 completed the study (telecare: 114; self-monitoring blood glucose: 124). Significant improvements were detected in most SF-36 domains, in WBQ depression and anxiety scores, and in treatment satisfaction, without differences between study groups. CONCLUSIONS - An insulin regimen that substantially improves metabolic control, while minimizing the risk of hypoglycemia, can positively affect physical and psychologic well-being and treatment satisfaction irrespective of the educational support system used. © 2011 by the American Diabetes Association.

Palmer S.C.,University of Otago | Nistor I.,Grigore T. Popa University of Medicine and Pharmacy | Craig J.C.,University of Sydney | Pellegrini F.,Consorzio Mario Negri Sud | And 5 more authors.
PLoS Medicine | Year: 2013

Background:Calcimimetic agents lower serum parathyroid hormone levels in people with chronic kidney disease (CKD), but treatment effects on patient-relevant outcomes are uncertain. We conducted a systematic review and meta-analysis to summarize the benefits and harms of calcimimetic therapy in adults with CKD and used cumulative meta-analysis to identify how evidence for calcimimetic treatment has developed in this clinical setting.Methods and Findings:Cochrane and Embase databases (through February 7, 2013) were electronically searched to identify randomized trials evaluating effects of calcimimetic therapy on mortality and adverse events in adults with CKD. Two independent reviewers identified trials, extracted data, and assessed risk of bias.Eighteen trials comprising 7,446 participants compared cinacalcet plus conventional therapy with placebo or no treatment plus conventional therapy in adults with CKD. In moderate- to high-quality evidence (based on Grading of Recommendations Assessment, Development, and Evaluation criteria) in adults with CKD stage 5D (dialysis), cinacalcet had little or no effect on all-cause mortality (relative risk, 0.97 [95% confidence interval, 0.89-1.05]), had imprecise effect on cardiovascular mortality (0.67 [0.16-2.87]), and prevented parathyroidectomy (0.49 [0.40-0.59]) and hypercalcemia (0.23 [0.05-0.97]), but increased hypocalcemia (6.98 [5.10-9.53]), nausea (2.02 [1.45-2.81]), and vomiting (1.97 [1.73-2.24]). Data for clinical outcomes were sparse in adults with CKD stages 3-5. On average, treating 1,000 people with CKD stage 5D for 1 y had no effect on survival and prevented about three patients from experiencing parathyroidectomy, whilst 60 experienced hypocalcemia and 150 experienced nausea. Analyses were limited by insufficient data in CKD stages 3-5 and kidney transplant recipients.Conclusions:Cinacalcet reduces the need for parathyroidectomy in patients with CKD stage 5D, but does not appear to improve all-cause or cardiovascular mortality. Additional trials in CKD stage 5D are unlikely to change our confidence in the treatment effects of cinacalcet in this population.Please see later in the article for the Editors' Summary. © 2013 Palmer et al.

Palmer S.C.,University of Otago | Craig J.C.,University of Sydney | Navaneethan S.D.,Cleveland Clinic | Tonelli M.,University of Alberta | And 2 more authors.
Annals of Internal Medicine | Year: 2012

Background: Statins have uncertain benefits in persons with chronic kidney disease (CKD) because individual trials may have insufficient power to determine whether treatment effects differ with severity of CKD. Purpose: To summarize the benefits and harms of statin therapy for adults with CKD and examine whether effects of statins vary by stage of kidney disease. Data Sources: Cochrane and EMBASE databases (inception to Feb- ruary 2012). Study Selection: Randomized trials comparing the effects of statins with placebo, no treatment, or another statin on mortality and cardiovascular outcomes. Data Extraction: Two independent reviewers extracted data and assessed risk of bias. Data Synthesis: Eighty trials comprising 51 099 participants com- pared statin with placebo or no treatment. Treatment effects varied with stage of CKD. Moderate- to high-quality evidence indicated that statins reduced all-cause mortality (relative risk [RR], 0.81 [95% CI, 0.74 to 0.88]), cardiovascular mortality (RR, 0.78 [CI, 0.68 to 0.89]), and cardiovascular events (RR, 0.76 [CI, 0.73 to 0.80]) in persons not receiving dialysis. Moderate- to high-quality evidence indicated that statins had little or no effect on all-cause mortality (RR, 0.96 [CI, 0.88 to 1.04]), cardiovascular mortality (RR, 0.94 [CI, 0.82 to 1.07]), or cardiovascular events (RR, 0.95 [CI, 0.87 to 1.03]) in persons receiving dialysis. Effects of statins in kidney transplant recipients were uncertain. Statins had little or no effect on cancer, myalgia, liver function, or withdrawal from treat- ment, although adverse events were evaluated systematically in fewer than half of the trials. Limitation: There was a reliance on post hoc subgroup data for earlier stages of CKD. Conclusion: Statins decrease mortality and cardiovascular events in persons with early stages of CKD, have little or no effect in persons receiving dialysis, and have uncertain effects in kidney transplant recipients. Primary Funding Source: None. © 2012 American College of Physicians.

De Berardis G.,Consorzio Mario Negri Sud | Lucisano G.,Consorzio Mario Negri Sud | D'Ettorre A.,Consorzio Mario Negri Sud | Pellegrini F.,Consorzio Mario Negri Sud | And 4 more authors.
JAMA - Journal of the American Medical Association | Year: 2012

Context: The benefit of aspirin for the primary prevention of cardiovascular events is relatively small for individuals with and without diabetes. This benefit could easily be offset by the risk of hemorrhage. Objective: To determine the incidence of major gastrointestinal and intracranial bleeding episodes in individuals with and without diabetes taking aspirin. Design, Setting, and Participants: A population-based cohort study, using administrative data from 4.1 million citizens in 12 local health authorities in Puglia, Italy. Individuals with new prescriptions for low-dose aspirin (≤300 mg) were identified during the index period from January 1, 2003, to December 31, 2008, and were propensity-matched on a 1-to-1 basis with individuals who did not take aspirin during this period. Main Outcome Measures: Hospitalizations for major gastrointestinal bleeding or cerebral hemorrhage occurring after the initiation of antiplatelet therapy. Results: There were 186 425 individuals being treated with low-dose aspirin and 186 425 matched controls without aspirin use. During amedian follow-up of 5.7 years, the overall incidence rate of hemorrhagic events was 5.58 (95% CI, 5.39-5.77) per 1000 person-years for aspirin users and 3.60 (95% CI, 3.48-3.72) per 1000 person-years for those without aspirin use (incidence rate ratio [IRR], 1.55; 95% CI, 1.48-1.63). The use of aspirin was associated with a greater risk of major bleeding in most of the subgroups investigated but not in individuals with diabetes (IRR, 1.09; 95% CI, 0.97-1.22). Irrespective of aspirin use, diabetes was independently associated with an increased risk of major bleeding episodes (IRR, 1.36; 95% CI, 1.28-1.44). Conclusions: In a population-based cohort, aspirin use was significantly associated with an increased risk of major gastrointestinal or cerebral bleeding episodes. Patients with diabetes had a high rate of bleeding that was not independently associated with aspirin use. ©2012 American Medical Association. All rights reserved.

Sutterlin C.,University of California at Irvine | Colanzi A.,Consorzio Mario Negri Sud | Colanzi A.,Telethon Institute of Genetics and Medicine | Colanzi A.,National Research Council Italy
Journal of Cell Biology | Year: 2010

The mammalian Golgi apparatus is characterized by a ribbon-like organization adjacent to the centrosome during interphase and extensive fragmentation and dispersal away from the centrosome during mitosis. It is not clear whether this dynamic association between the Golgi and centrosome is of functional significance. We discuss recent findings indicating that the Golgi-centrosome relationship may be important for directional protein transport and centrosome positioning, which are both required for cell polarization. We also summarize our current knowledge of the link between Golgi organization and cell cycle progression. © 2010 Sütterlin and Colanzi.

Rudel L.L.,Consorzio Mario Negri Sud
Current Atherosclerosis Reports | Year: 2010

Dietary interventions have been consistently proposed as a part of a comprehensive strategy to lower the incidence and severity of coronary heart disease (CHD), in the process providing long-term cardioprotection. Replacement of dietary saturated fatty acids (SFA) with higher intakes of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) has been reported to be inversely associated with risk of CHD. The observed lower incidence of CHD among populations consuming a Mediterranean-type diet, mainly enriched in MUFA from olive oil, has long supported the belief that MUFA are an optimal substitution for SFA. However, both epidemiologic and interventional studies suggest that although substituting MUFA-rich foods for SFA-rich foods in the diet can potentially lower total plasma cholesterol concentrations, this substitution does not lower the extent of coronary artery atherosclerosis. In addition, although recent evidence suggests that the source of MUFA (animal fat vs vegetable oils) may differentially influence the correlation between MUFA intake and CHD mortality, animal studies suggest that neither source is cardioprotective. © 2010 Springer Science+Business Media, LLC.

Strippoli G.F.M.,Consorzio Mario Negri Sud
Clinical Journal of the American Society of Nephrology | Year: 2012

Background and objectives The few existing studies of sexual dysfunction in women on hemodialysis are limited by small sample size. This large, cross-sectional study evaluated the prevalence and correlates of female sexual dysfunction in advanced kidney disease. Design, setting, participants, & methods A total of 1472 women with ESRD undergoing hemodialysis were recruited to a multinational, cross-sectional study conducted within a collaborative dialysis network in Europe and South America. Sexual dysfunction was identified by the Female Sexual Function Index. Correlates of self-reported sexual dysfunction were identified by regression analyses. Results: Of the 1472 women, 659 completed questionnaires (45%). More than half (362 of 659 [55%]) lived with a partner, and 232 of 659 (35%) reported being sexually active. Of these 659 respondents, 555 (84%) reported sexual dysfunction. Women with a partner (282 of 362 [78%]) were less likely to report sexual dysfunction than those without a partner (273 of 297 [92%]) (P<0.001). Sexual dysfunction was independently associated with age, depressive symptoms, less education, menopause, diabetes, and diuretic therapy. Nearly all women who were not wait-listed for a kidney transplant and were living without a partner (249 of 260 [96%]) reported sexual dysfunction. More than half (128 of 232 [55%]) of sexually active women reported sexual dysfunction, associated with age, depressive symptoms, menopause, low serum albumin, and diuretic therapy. Conclusions: This descriptive study suggests most women on hemodialysis experience sexual problems. Additional research on the relevance of sexual dysfunction to symptom burden and quality of life in these women is needed. © 2012 by the American Society of Nephrology.

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