Contact-force monitoring increases accuracy of right ventricular voltage mapping avoiding “false scar” detection in patients with no evidence of structural heart disease

Purpose: Electroanatomical mapping (EAM) could increase cardiac magnetic resonance imaging (CMR) sensitivity in detecting ventricular scar. Possible bias may be scar over-estimation due to inadequate tissue contact. Aim of the study is to evaluate contact-force monitoring influence during EAM, in patients with idiopathic right ventricular arrhythmias. Methods: 20 pts (13 M; 43 ± 12 y) with idiopathic right ventricular outflow tract (RVOT) arrhythmias and no structural abnormalities were submitted to Smarttouch catheter Carto3 EAM. Native maps included points collected without considering contact-force. EAM scar was defined as area ≥1 cm2 including at least 3 adjacent points with signal amplitude (bipolar <0.5 mV, unipolar 3,5 mV), surrounded by low-voltage border zone. EAM were re-evaluated offline, removing points collected with contact force <5 g. Finally, contact force-corrected maps were compared to the native ones. Results: An EAM was created for each patient (345 ± 85 points). After removing poor contact points, a mean of 149 ± 60 points was collected. The percentage of false scar, collected during contact force blinded mapping compared to total volume, was 6.0 ± 5.2% for bipolar scar and 7.1 ± 5.9% for unipolar scar, respectively. No EAM scar was present after poor contact points removal. Right ventricular areas analysis revealed a greater number of points with contact force < 5 g acquired in free wall, where reduced mean bipolar and unipolar voltage were recorded. Conclusions: To date this is the first work conducted on structurally normal hearts in which contact-force significantly increases EAM accuracy, avoiding “false scar” related to non-adequate contact between catheter and tissue

A non-canonical RNA silencing pathway promotes mRNA degradation in basal fungi

The increasing knowledge on the functional relevance of endogenous small RNAs (esRNAs) as riboregulators has stimulated the identification and characterization of these molecules in numerous eukaryotes. In the basal fungus Mucor circinelloides, an emerging opportunistic human pathogen, esRNAs that regulate the expression of many protein coding genes have been described. These esRNAs share common machinery for their biogenesis consisting of an RNase III endonuclease Dicer, a single Argonaute protein and two RNA-dependent RNA polymerases. We show in this study that, besides participating in this canonical dicer-dependent RNA interference (RNAi) pathway, the rdrp genes are involved in a novel dicer-independent degradation process of endogenous mRNAs. The analysis of esRNAs accumulated in wild type and silencing mutants demonstrates that this new rdrp-dependent dicer-independent regulatory pathway, which does not produce sRNA molecules of discrete sizes, controls the expression of target genes promoting the specific degradation of mRNAs by a previously unknown RNase. This pathway mainly regulates conserved genes involved in metabolism and cellular processes and signaling, such as those required for heme biosynthesis, and controls responses to specific environmental signals. Searching the Mucor genome for candidate RNases to participate in this pathway, and functional analysis of the corresponding knockout mutants, identified a new protein, R3B2. This RNase III-like protein presents unique domain architecture, it is specifically found in basal fungi and, besides its relevant role in the rdrp-dependent dicer-independent pathway, it is also involved in the canonical dicer-dependent RNAi pathway, highlighting its crucial role in the biogenesis and function of regulatory esRNAs. The involvement of RdRPs in RNA degradation could represent the first evolutionary step towards the development of an RNAi mechanism and constitutes a genetic link between mRNA degradation and post-transcriptional gene silencing

AglH, a thermophilic UDP‑<i>N</i>‑acetylglucosamine‑1‑phosphate:dolichyl phosphate GlcNAc‑1‑phosphotransferase initiating protein<i> N</i>‑glycosylation pathway in <i>Sulfolobus acidocaldarius</i>, is capable of complementing the eukaryal Alg7

AglH, a predicted UDP-GlcNAc-1-phosphate:dolichyl phosphate GlcNAc-1-phosphotransferase, is initiating the protein N-glycosylation pathway in the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius. AglH successfully replaced the endogenous GlcNAc-1-phosphotransferase activity of Alg7 in a conditional lethal Saccharomyces cerevisiae strain, in which the first step of the eukaryal protein N-glycosylation process was repressed. This study is one of the few examples of cross-domain complementation demonstrating a conserved polyprenyl phosphate transferase reaction within the eukaryal and archaeal domain like it was demonstrated for Methanococcus voltae (Shams-Eldin et al. 2008). The topology prediction and the alignment of the AglH membrane protein with GlcNAc-1-phosphotransferases from the three domains of life show significant conservation of amino acids within the different proposed cytoplasmic loops. Alanine mutations of selected conserved amino acids in the putative cytoplasmic loops II (D(100)), IV (F(220)) and V (F(264)) demonstrated the importance of these amino acids for cross-domain AlgH activity in in vitro complementation assays in S. cerevisiae. Furthermore, antibiotic treatment interfering directly with the activity of dolichyl phosphate GlcNAc-1-phosphotransferases confirmed the essentiality of N-glycosylation for cell survival

Critical Role of the Rb Family in Myoblast Survival and Fusion

The tumor suppressor Rb is thought to control cell proliferation, survival and differentiation. We recently showed that differentiating Rb-deficient mouse myoblasts can fuse to form short myotubes that quickly collapse through a mechanism involving autophagy, and that autophagy inhibitors or hypoxia could rescue the defect leading to long, twitching myotubes. Here we determined the contribution of pRb relatives, p107 and p130, to this process. We show that chronic or acute inactivation of Rb plus p107 or p130 increased myoblast cell death and reduced myotube formation relative to Rb loss alone. Treatment with autophagy antagonists or hypoxia extended survival of double-knockout myotubes, which appeared indistinguishable from control fibers. In contrast, triple mutations in Rb, p107 and p130, led to substantial increase in myoblast death and to elongated bi-nuclear myocytes, which seem to derive from nuclear duplication, as opposed to cell fusion. Under hypoxia, some rare, abnormally thin triple knockout myotubes survived and twitched. Thus, mutation of p107 or p130 reduces survival of Rb-deficient myoblasts during differentiation but does not preclude myoblast fusion or necessitate myotube degeneration, whereas combined inactivation of the entire Rb family produces a distinct phenotype, with drastically impaired myoblast fusion and survival

Gender Differences in Patients with Brugada Syndrome and Arrhythmic Events: Data from a Survey on Arrhythmic Events in 678 Patients.

BACKGROUND: There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs). OBJECTIVES: To compare clinical, electrocardiographic (ECG), electrophysiologic (EP) and genetic characteristics between males and females in BrS-patients with their first AE. METHODS: The multicenter Survey on AE in BrS (SABRUS) collected data on first AE in 678 BrS-patients including 619 (91.3%) males and 59 (8.7%) females aged 0.27 to 84 (mean 42.5±14.1) years at the time of AE. RESULTS: After excluding pediatric patients, females were older than males (49.5±14.4 vs. 43±12.7 years, respectively, P=0.001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, male/female ratio of AE was ≈9-fold higher compared to Caucasians. Spontaneous type 1 BrS-ECG was associated with earlier onset of AE in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS-ECG was present in males and females above age of 60 years. Females less frequently showed a spontaneous type-1 BrS-ECG (31% vs. 59%, P<0.001) or arrhythmia-inducibility at EP study (34% vs. 64%, P<0.001). An SCN5A mutation was more frequently found in females (47.6% vs. 27.8% in males, P=0.007). CONCLUSIONS: This study confirms that female BrS-patients are much rarer, display less type 1 Brugada-ECG and exhibit lower inducibility rates than males. It shows for the first time that BrS females with AE have higher SCN5A mutation rates as well as the relationship between gender vs. age at onset of AE and ethnicity

Profile of Brugada Syndrome Patients Presenting with Their First Documented Arrhythmic Event. Data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS).

BACKGROUND: Detailed information on the profile of Brugada syndrome (BrS) patients presenting their first arrhythmic event (AE) after prophylactic implantation of a cardioverter defibrillator (ICD) is limited. OBJECTIVES: 1) To compare clinical, electrocardiographic, electrophysiologic and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (CA) (group A) with those in whom the AE was documented after prophylactic ICD implantation (group B); 2) To characterize group B patients' profile using the Class II indications for ICD implantation established by HRS/EHRA/APHRS Expert Consensus Statement in 2013. METHODS: A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 BrS patients with AE (group A, n=426; group B, n=252). RESULTS: First AE occurred in group B patients 6.7 years later than in group A (46.1+ 13.3 vs. 39.4+15.1, P<0.001). Group B patients had a higher incidence of family history of sudden cardiac death (SCD) and SCN5A mutations. Of the 252 group B patients, 189 (75%) complied with the HRS/EHRA/APHRS indications whereas the remaining 63 (25%) did not. CONCLUSION: BrS patients with first AE documented after prophylactic ICD implantation exhibited their AE at a later age with a higher incidence of positive family history of SCD and SCN5A mutations compared to those presenting with an aborted CA. Only 75% of patients who suffered an AE after receiving a prophylactic ICD complied with the 2013 Class II indications, suggesting efforts are still required for improving risk stratification

Age of First Arrhythmic Event in Brugada Syndrome: Data From the SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) in 678 Patients.

BACKGROUND: Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE. METHODS AND RESULTS: A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter-defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27-84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±15.0 years; P<0.001). In adult patients (≥16 years), women experienced AE 6.5 years later than men (P=0.003). Whites and Asians exhibited their AE at the same median age (43 years). CONCLUSIONS: SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE

Fever-related arrhythmic events in the multicenter Survey on Arrhythmic Events in Brugada Syndrome

BACKGROUND: The literature on fever related arrhythmic events (AE) in Brugada syndrome (BrS) is currently limited to few case reports and small series. OBJECTIVE: The current study aims to describe the characteristics of fever-related AE in a large cohort of BrS patients. METHODS: SABRUS is a multicenter study on 678 BrS patients with first AE documented at time of aborted cardiac arrest (ACA) (n=426) or after prophylactic ICD implantation (n=252). RESULTS: In 35(6%) of the 588 patients with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%) and proband (70%). Age at time of AE was 29±24 (range 0.3-76) years. Most patients (80%) presented with ACA and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope and spontaneous type 1 Brugada-ECG were noted in 17%, 40% and 66% of patients, respectively. VF was induced at EPS in 9/19(47%) patients. An SCN5A mutation was found in 14/28(50%) patients. The highest proportion of fever-related AE was observed in the pediatric population (age <16), with disproportionally higher event rate in the very young (0-5 years old) (65%). Males were involved in all age groups and females only in the pediatric and elderly groups. Fever-related AE affected 17 Caucasians aged<24 years, but no Asians aged <24 years. CONCLUSIONS: The risk of fever-related AE in BrS markedly varies according to age group, gender and ethnicity. Taking these factors into account could help the clinical management of BrS patients with fever

Making Free Trade Fair

Philosophers have done very little work on what makes trade fair. Perhaps the most extensive discussion is Malgorzata Kurjanska and Mathias Risse’s article, “Fairness in Trade II: export subsidies and the fair trade movement.”2 In their article, Kurjanska and Risse consider the case for trade subsidies and the Fair Trade movement. They suggest that it is not permissible for developed countries to give their producers subsidies because doing so does not strike an appropriate balance between meeting the needs of the global poor and protecting domestic workers (Kurjanska and Risse, 2008: 34). Kurjanska and Risse also argue that the case for Fair Trade hinges, primarily, on whether or not it is part of the best development strategy for poor countries. They do not think Fair Trade is part of the best development strategy and, so, they believe purchasing Fair Trade certified goods is only acceptable because doing so does not constitute a large share of the market in traded goods. This chapter argues that the case against subsidies and Fair Trade Kurjanska and Risse present is much weaker than they make out. To the contrary, it argues that giving some subsidies and purchasing some Fair Trade certified goods may even be necessary to make trade fair. Section 11.2 starts by saying a few words about the normative framework Kurjanska and Risse adopt

Fish, Fish-Derived n-3 Fatty Acids, and Risk of Incident Atrial Fibrillation in the Atherosclerosis Risk in Communities (ARIC) Study

Results of observational and experimental studies investigating the association between intake of long-chain n-3 polyunsaturated fatty acids (PUFAs) and risk of atrial fibrillation (AF) have been inconsistent.We studied the association of fish and the fish-derived n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with the risk of incident AF in individuals aged 45-64 from the Atherosclerosis Risk in Communities (ARIC) cohort (n = 14,222, 27% African Americans). Intake of fish and of DHA and EPA were measured via food frequency questionnaire. Plasma levels of DHA and EPA were measured in phospholipids in a subset of participants (n = 3,757). Incident AF was identified through the end of 2008 using ECGs, hospital discharge codes and death certificates. Cox proportional hazards regression was used to estimate hazard ratios of AF by quartiles of n-3 PUFAs or by fish intake.During the average follow-up of 17.6 years, 1,604 AF events were identified. In multivariable analyses, total fish intake and dietary DHA and EPA were not associated with AF risk. Higher intake of oily fish and canned tuna was associated with a nonsignificant lower risk of AF (p for trend = 0.09). Phospholipid levels of DHA+EPA were not related to incident AF. However, DHA and EPA showed differential associations with AF risk when analyzed separately, with lower risk of AF in those with higher levels of DHA but no association between EPA levels and AF risk.In this racially diverse sample, dietary intake of fish and fish-derived n-3 fatty acids, as well as plasma biomarkers of fish intake, were not associated with AF risk