Clinical and molecular consequences of exon 78 deletion in DMD gene

We present a 13-year-old patient with persistent increase of serum Creatine Kinase (CK) and myalgia after exertion. Skeletal muscle biopsy showed marked reduction of dystrophin expression leading to genetic analysis of DMD gene by MLPA, which detected a single deletion of exon 78. To the best of our knowledge, DMD exon 78 deletion has never been described in literature and, according to prediction, it should lead to loss of reading frame in the dystrophin gene. To further assess the actual effect of exon 78 deletion, we analysed cDNA from muscle mRNA. This analysis confirmed the absence of 32 bp of exon 78. Exclusion of exon 78 changes the open reading frame of exon 79 and generate a downstream stop codon, producing a dystrophin protein of 3703 amino acids instead of 3685 amino acids. Albeit loss of reading frame usually leads to protein degradation and severe phenotype, in this case, we demonstrated that deletion of DMD exon 78 can be associated with a functional protein able to bind DGC complex and a very mild phenotype. This study adds a novel deletion in DMD gene in human and helps to define the compliance between maintaining/disrupting the reading frame and clinical form of the disease

Radio-frequency ablation as primary management of well-tolerated sustained monomorphic ventricular tachycardia in patients with structural heart disease and left ventricular ejection fraction over 30%

Aims Patients with well-tolerated sustained monomorphic ventricular tachycardia (SMVT) and left ventricular ejection fraction (LVEF) over 30% may benefit from a primary strategy of VT ablation without immediate need for a ‘back-up' implantable cardioverter-defibrillator (ICD). Methods and results One hundred and sixty-six patients with structural heart disease (SHD), LVEF over 30%, and well-tolerated SMVT (no syncope) underwent primary radiofrequency ablation without ICD implantation at eight European centres. There were 139 men (84%) with mean age 62 ± 15 years and mean LVEF of 50 ± 10%. Fifty-five percent had ischaemic heart disease, 19% non-ischaemic cardiomyopathy, and 12% arrhythmogenic right ventricular cardiomyopathy. Three hundred seventy-eight similar patients were implanted with an ICD during the same period and serve as a control group. All-cause mortality was 12% (20 patients) over a mean follow-up of 32 ± 27 months. Eight patients (40%) died from non-cardiovascular causes, 8 (40%) died from non-arrhythmic cardiovascular causes, and 4 (20%) died suddenly (SD) (2.4% of the population). All-cause mortality in the control group was 12%. Twenty-seven patients (16%) had a non-fatal recurrence at a median time of 5 months, while 20 patients (12%) required an ICD, of whom 4 died (20%). Conclusion Patients with well-tolerated SMVT, SHD, and LVEF > 30% undergoing primary VT ablation without a back-up ICD had a very low rate of arrhythmic death and recurrences were generally non-fatal. These data would support a randomized clinical trial comparing this approach with others incorporating implantation of an ICD as a primary strateg

The role of His-50 of alfa-synuclein in binding Cu(II): pH dependence, speciation, thermodinamics and structure

7siCopper interaction with alpha synuclein (aS) has been shown to accelerate aggregation and oligomerization of the protein. Three different aS copper binding domains have been proposed: (i) the N-terminal residues (1–9) that represent the minimal copper binding domain; (ii) the His-50 imidazole and (iii) the Asp and Glu residues within the acidic C-terminal domain. The copper coordination at the N-terminus has been extensively characterized and it is generally accepted that it provides the highest affinity site. The same does not hold for the role played by His-50 in copper binding. In this work Cu(II) coordination to peptide fragments encompassing residues 45–55 of aS has been exhaustively characterized, including systems containing the inherited mutations E46K and A53T, as model peptides of the His-50 site. Through potentiometric titrations all the speciation profiles have been determined and the stability constants have been used to estimate the dissociation constants of complexes corresponding to the binding modes at pH 6.5 and 7.5. Spectroscopic analyses allowed determination of (i) the copper coordination sphere, (ii) its geometry and (iii) the constraints wherefrom the 3D structural models of the copper complexes could be obtained.reservedmixedValensin, Daniela; Camponeschi, Francesca; Luczkowski, M.; Baratto, MARIA CAMILLA; Remelli, M.; Valensin, Gianni; Kozlowski, H.Valensin, Daniela; Camponeschi, Francesca; M., Luczkowski; Baratto, MARIA CAMILLA; M., Remelli; Valensin, Gianni; H., Kozlowsk

Subclinical functional and structural renal abnormalities predict new onset type 2 diabetes in patients with primary hypertension

Recent studies suggest a close relationship between renal dysfunction and new onset diabetes (NOD). The aim of the study was to investigate the association between subclinical functional and structural renal abnormalities and NOD in primary hypertension (PH). This observational prospective study (9.1\ub12.2 years follow-up) includes 231 consecutive untreated non-diabetic patients with PH and without overt nephropathy. The primary end point was NOD. Albuminuria (albumin to creatinine ratio, ACR), glomerular filtration rate (eGFR), and renal structure and hemodynamics (ultrasound scan and Doppler) were evaluated at baseline. During 2106 person-years of follow-up, 10 patients developed diabetes (incidence rate 4.7/1000 person-years). Patients with NOD showed a higher body mass index, serum uric acid, serum creatinine and ACR, and lower eGFR and renal volume (RV) to resistive index (RI) ratio (RV/RI) at baseline, as compared with the 221 controls that did not develop diabetes. When all renal variables were taken into consideration, RV/RI was the only variable significantly related to diabetes (hazard ratio 1.04, P=0.0342). Patients in the lowest tertile of RV/RI were more likely to develop diabetes (10.4 vs 2.6 vs 0%, P=0.0044). For each s.d. decrease of RV/RI, the risk of NOD increased by 68% (P=0.0012). Subclinical functional and structural renal abnormalities are independent predictors of diabetes in P

Evaluation of the in vitro activity of ceftaroline and its potential against a collection of hospital-acquired methicillin-resistant S.aureus and hospital-acquired methicillin-susceptible S.aureus isolates recovered from various clinical samples

Aim of the study was the evaluation of the in vitro activity of ceftaroline and its potential against a collection of Hospital-Acquired Methicillin-Resistant Staphylococcus aureus (HA-MRSA) and Hospital-Acquired Methicillin-Susceptible S. aureus (HA-MSSA) isolates. S. aureus isolates from outpatients were also examined. A total of 30 MSSA and 50 MRSA strains were studied.The isolates were collected during a four-year period (2006-2010) from the Pavia area (North-West of Italy). MICs and MBCs were performed in duplicate by broth dilution method (EUCAST 2012). Susceptibility category assessments for ceftaroline was made using EUCAST 2013 breakpoints. MICs of the antibiotics included in MicroScan Pos Breakpoint Combo Type 32 Panels (Siemens) were also evaluated. Genotyping was performed by PFGE. Ceftaroline MIC values for MSSA strains ranged from 0.06 mg/L to 0.5 mg/L and from 0.125 mg/L to 2 mg/L for MRSA strains, of which 4/50 exhibited a MIC value of 2 mg/L. The MIC value of these 4 isolates was confirmed by macromethod. Two out of four, clonally related, belonged to hVISA category. Furthermore, MIC50 and MIC90 were evaluated: MSSA MIC50 value was 0.125 mg/L, while MIC90 was 0.25 mg/L; MIC50 and MIC90 values of the MRSA were 0.5 mg/L and 1 mg/L, respectively. Finally, the bactericidal activity of this molecule was investigated by MBC method. Ceftaroline MIC and MBC values coincided in 96.25% of cases, only in 3 cases the MBC value was one dilution higher than MIC value. Ceftaroline demonstrated bactericidal activity against a large number of S. aureus, included MRSA and hVISA

Renal and cardiac abnormalities in primary hypertension

Objective The relationship between mild reduction in renal function and cardiac structure and function have not yet been fully elucidated. We investigated cardiac and renal abnormalities in 400 untreated, nondiabetic patients (65% men, mean age 47 years) with primary hypertension and normal serum creatinine. Methods Renal abnormalities were defined as creatinine clearance less than 75 ml/min per 1.73m2 (Cockcroft\u2013Gault formula) and/or the presence of microalbuminuria (albumin-to-creatinine ratio). Left ventricular structure and function were assessed by echocardiography. Results The prevalence of microalbuminuria and reduced creatinine clearance was 13 and 31%, respectively. Patients with renal abnormalities shared greater left ventricular mass index, higher prevalence of left ventricular hypertrophy, and unfavorable geometric patterns. Microalbuminuria was also associated with inappropriate left ventricular mass and depressed midwall fractional shortening, whereas reduced creatinine clearance was associated with lower stroke volume and higher central pulse pressure/stroke volume ratio and total peripheral resistance. Stepwise regression analysis showed that both albuminuria and creatinine clearance were independently related to left ventricular mass. Logistic regression analysis of the reciprocal interaction of microalbuminuria and reduced creatinine clearance on the occurrence of subclinical cardiac damage showed that reduced creatinine clearance entailed a greater risk of left ventricular hypertrophy in patients with normal albuminuria alone, whereas the presence of microalbuminuria was associated with a greater risk of left ventricular hypertrophy independently of creatinine clearance. Conclusions These findings provide further proof of the role of cardiorenal interaction in the development of hypertension-related cardiovascular disease, and may have clinical implications. J Hypertens 27:1064\u20131073 Q 200

Sub-clinical organ damage in hypertension and obesity

BACKGROUND: The development of sub-clinical organ damage precedes and predicts the occurrence of cardiovascular (CV) events in hypertensive as well as in obese patients. AIM AND METHODS: We investigated the prevalence and clinical correlates of organ damage (OD), namely carotid atherosclerosis (US scan) and urine albumin to creatinine ratio (three non-consecutive first morning samples) in a group of 164 obese patients and in an age- and gender-matched group of non-obese hypertensive patients. RESULTS: There was a significantly greater prevalence and severity of OD in obese patients as compared to non-obese hypertensive patients. In particular obese patients more frequently had microalbuminuria (16 vs 7%, \u3c7(2) 5.8, P=0.0157) and carotid abnormalities (53 vs 10%, \u3c7(2) 69.5, P<0.0001) as well as higher urinary albumin excretion rate (-0.05 \ub1 0.52 vs -0.28 \ub1 0.43log ACR, P<0.0001) and carotid intima-media thickness (0.955 \ub1 0.224 vs 0.681 \ub1 0.171, <0.0001). Notably, the coexistence of hypertension and obesity did not entail a greater prevalence and severity of OD. Moreover, after adjusting for potentially confounding factors including blood pressure levels, diagnosis of diabetes, and lipid profile, morbidly obese patients showed a 5-fold, and 22-fold higher risk of having microalbuminuria, and carotid atherosclerosis, respectively. CONCLUSIONS: Sub-clinical OD is highly prevalent in obese patients, even in the absence of high blood pressure. Hypertension and obesity seem to exert an independent, possibly non-additive role on the occurrence of organ damage

HATEMETER: Hate speech tool for monitoring, analysing and tackling Anti-Muslim hatred online. eCrime

This report presents the results of project “Hatemeter - Hate speech tool for monitoring, analysing and tackling anti-Muslim hatred online” (hereinafter also referred to as “Hatemeter”, project reference: 764583). The project has been coordinated by the University of Trento (Italy) and especially by eCrime, the research group on ICT, law and criminology of the Department ‘Fac¬ulty of Law’, with the cooperation of the Department of Sociology and Social Research, in partnership with Fondazione Bruno Kessler (Italy), University Toulouse 1 Capitole (France), Teesside University (United King¬dom), Amnesty International – Sezione Italiana (Italy), StophHate UK (United Kingdom), and Collectif Contre l’Islamophobie en France (France). The project was funded by the European Commission - Directorate-Gen¬eral Justice and Consumers under the Rights, Equality and Citizenship Programme (2014-2020) and lasted 24 months: from February 2018 to January 2020