Genetic modifiers of Duchenne muscular dystrophy and dilated cardiomyopathy

OBJECTIVE: Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset. METHODS: A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up. RESULTS: Patients were followed up to an average age of 15.9 \ub1 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027). CONCLUSIONS: We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts

Factors affecting adherence to guidelines for antithrombotic therapy in elderly patients with atrial fibrillation admitted to internal medicine wards

Current guidelines for ischemic stroke prevention in atrial fibrillation or flutter (AFF) recommend Vitamin K antagonists (VKAs) for patients at high-intermediate risk and aspirin for those at intermediate-low risk. The cost-effectiveness of these treatments was demonstrated also in elderly patients. However, there are several reports that emphasize the underuse of pharmacological prophylaxis of cardio-embolism in patients with AFF in different health care settings. AIMS: To evaluate the adherence to current guidelines on cardio-embolic prophylaxis in elderly (> 65 years old) patients admitted with an established diagnosis of AFF to the Italian internal medicine wards participating in REPOSI registry, a project on polypathologies/polytherapies stemming from the collaboration between the Italian Society of Internal Medicine and the Mario Negri Institute of Pharmacological Research; to investigate whether or not hospitalization had an impact on guidelines adherence; to test the role of possible modifiers of VKAs prescription. METHODS: We retrospectively analyzed registry data collected from January to December 2008 and assessed the prevalence of patients with AFF at admission and the prevalence of risk factors for cardio-embolism. After stratifying the patients according to their CHADS(2) score the percentage of appropriateness of antithrombotic therapy prescription was evaluated both at admission and at discharge. Univariable and multivariable logistic regression models were employed to verify whether or not socio-demographic (age >80years, living alone) and clinical features (previous or recent bleeding, cranio-facial trauma, cancer, dementia) modified the frequency and modalities of antithrombotic drugs prescription at admission and discharge. RESULTS: Among the 1332 REPOSI patients, 247 were admitted with AFF. At admission, CHADS(2) score was ≥ 2 in 68.4% of patients, at discharge in 75.9%. Among patients with AFF 26.5% at admission and 32.8% at discharge were not on any antithrombotic therapy, and 43.7% at admission and 40.9% at discharge were not taking an appropriate therapy according to the CHADS(2) score. The higher the level of cardio-embolic risk the higher was the percentage of antiplatelet- but not of VKAs-treated patients. At admission or at discharge, both at univariable and at multivariable logistic regression, only an age >80 years and a diagnosis of cancer, previous or active, had a statistically significant negative effect on VKAs prescription. Moreover, only a positive history of bleeding events (past or present) was independently associated to no VKA prescription at discharge in patients who were on VKA therapy at admission. If heparin was considered as an appropriate therapy for patients with indication for VKAs, the percentage of patients admitted or discharged on appropriate therapy became respectively 43.7% and 53.4%. CONCLUSION: Among elderly patients admitted with a diagnosis of AFF to internal medicine wards, an appropriate antithrombotic prophylaxis was taken by less than 50%, with an underuse of VKAs prescription independently of the level of cardio-embolic risk. Hospitalization did not improve the adherence to guideline

Obesità, Diabete e Rischio Cardiovascolare.

Il crescente interesse del mondo scientifico e delle organizzazioni sanitarie nei riguardi dell’obesità deriva dalla diffusione epidemica di questa condizione osservata negli ultimi decenni non solo nel mondo occidentale industrializzato, ma anche nei paesi in via di sviluppo (1). Nelle società più ricche, l'eccesso di peso è maggiore negli strati socio-economici più bassi e nelle fasce d'età più avanzate (2), e la percentuale di soggetti in sovrappeso (BMI>25) e con obesità franca (BMI>30) ha superato negli Stati Uniti d'America il 60% dei maschi adulti ed il 30 % delle donne tra i 50 ed i 60 anni (3). L'aspetto epidemiologico che colpisce e preoccupa di più è il trend secolare, per cui nel decennio 1980-1990 sono stati osservati drammatici aumenti del doppio o a volte anche del triplo della prevalenza dell’obesità . Per quel che riguarda la prevalenza dell’obesità in Italia, secondo i dati dell’Istituto Auxologico Italiano (4) che hanno utilizzato, come cut-off, valori di BMI ≥ 30, essa si attesta tra il 9 e il 10% ed è più bassa di quella di molti al¬tri paesi del mondo occidentale. A tal proposito sono però opportune alcune osservazioni, ed in particolare: • la prevalenza dell’obesità è aumentata del 25% in cinque anni; • la somma dei soggetti in sovrappeso e di quelli obesi interessa circa il 50 % della popolazione italiana. Dal momento che in pochi decenni la prevalenza dell'obesità è aumentata in misura epidemica, è impossibile pensare che essa sia attribuibile a mutamenti genetici. L’ipotesi del gene suscettibile, infatti, implica il ruolo dei fattori ambientali nella slatentizzazione della disposizione all'obesità (5) e tale epidemia contemporanea rappresenta, quindi, il risultato di un mismatch fra gli antichi geni dell'uomo e il nuovo ambiente in cui vive. Accettare tale impostazione eziopatogenetica ha valenze di rilievo che possono coinvolgere sia le strategie terapeutiche che quelle preventive

Intravenous thrombolysis in the emergency department for the treatment of acute ischaemic stroke

BACKGROUND AND AIMS: Thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rt-PA) improves outcome in patients with ischaemic stroke treated within 3 h of symptom onset, but its extended implementation is limited. A pilot study was designed to verify whether evaluation of patients with acute ischaemic stroke and their treatment with intravenous rt-PA in the emergency department (ED), followed by transportation to a semi-intensive stroke care unit, offers a safe and effective organisational solution to provide intravenous thrombolysis to acute stroke patients when a stroke unit (SU) is not available. METHODS: After checking for inclusion and exclusion criteria, ED doctors contacted the stroke team with a single page, located family members and urgently obtained computed tomography scan and laboratory tests. A stroke team investigator clinically assessed the patient, obtained written informed consent and supervised intravenous rt-PA in the ED. After treatment, the patient was transferred to the SU for rehabilitation and treatment of complications, under supervision of the same stroke team investigator. RESULTS: 52 patients were treated with intravenous rt-PA within 3 h of symptom onset. 20 patients (38%) improved neurologically after 24 h, the number increased to 30 (58%) after one week. At 3 months 22 patients had a favourable outcome (43%). The 3-month mortality rate was 12%. Symptomatic cerebral haemorrhage was observed in two patients (4%). CONCLUSIONS: Intravenous rt-PA administration in the ED is an effective organisational solution for acute ischaemic stroke when an SU is not established

"I have got something positive out of this situation": psychological benefits of caregiving in relatives of young people with muscular dystrophy.

This paper focuses on the psychological benefits of caregiving in key relatives of patients with muscular dystrophies (MD), a group of rare diseases characterized by progressive weakness and restriction of the patient's functional abilities. We describe whether relatives perceived caregiving to be a positive experience and test whether relatives' perceptions vary in relation to their view of the patient as a valued person, the degree of involvement in care, and the level of support provided by social network and professionals. The study sample included 502 key relatives of patients aged 4-25 years, suffering from Duchenne, Becker, or limb-girdle MD, in treatment for at least 6 months to one of the eight participating centers, living with at least one relative aged 18-80 years. Of key relatives, 88 % stated that they had gotten something positive out of the situation, 96 % considered their patients to be sensitive, and 94 % viewed their patients as talented. Positive aspects of caregiving were more recognized by key relatives who were more convinced that the patient was sensitive and who perceived that they received higher level of professional help and psychological social support. These results suggest that most key relatives consider that their caregiving experience has had a positive impact on their lives, despite the practical difficulties of caring for patients with MD. Professionals should help relatives to identify the benefits of caregiving without denying its difficulties. Clinicians themselves should develop positive attitudes towards family involvement in the care of patients with long-term diseases

Downregulation of the Longevity-Associated Protein Sirtuin 1 in Insulin Resistance and Metabolic Syndrome: Potential Biochemical Mechanisms

OBJECTIVE: Sirtuins (SIRTs) are NAD(+)-dependent deacetylases that regulate metabolism and life span. We used peripheral blood mononuclear cells (PBMCs) to determine ex vivo whether insulin resistance/metabolic syndrome influences SIRTs. We also assessed the potential mechanisms linking metabolic alterations to SIRTs in human monocytes (THP-1) in vitro. RESEARCH DESIGN AND METHODS: SIRT1-SIRT7 gene and protein expression was determined in PBMCs of 54 subjects (41 with normal glucose tolerance and 13 with metabolic syndrome). Insulin sensitivity was assessed by the minimal model analysis. Subclinical atherosclerosis was assessed by carotid intima-media thickness (IMT). In THP-1 cells exposed to high glucose or fatty acids in vitro, we explored SIRT1 expression, p53 acetylation, Jun NH(2)-terminal kinase (JNK) activation, NAD(+) levels, and nicotinamide phosphoribosyltransferase (NAMPT) expression. The effects of SIRT1 induction by resveratrol and of SIRT1 gene silencing were also assessed. RESULTS: In vivo, insulin resistance and metabolic syndrome were associated with low PBMC SIRT1 gene and protein expression. SIRT1 gene expression was negatively correlated with carotid IMT. In THP-1 cells, high glucose and palmitate reduced SIRT1 and NAMPT expression and reduced the levels of intracellular NAD(+) through oxidative stress. No effect was observed in cells exposed to linoleate or insulin. High glucose and palmitate increased p53 acetylation and JNK phosphorylation; these effects were abolished in siRNA SIRT1-treated cells. Glucose- and palmitate-mediated effects on NAMPT and SIRT1 were prevented by resveratrol in vitro. CONCLUSIONS: Insulin resistance and subclinical atherosclerosis are associated with SIRT1 downregulation in monocytes. Glucotoxicity and lypotoxicity play a relevant role in quenching SIRT1 expression