Computational Investigation of Interactions between Carbon Nitride Dots and Doxorubicin.

The study of carbon dots is one of the frontiers of materials science due to their great structural and chemical complexity. These issues have slowed down the production of solid models that are able to describe the chemical and physical features of carbon dots. Recently, several studies have started to resolve this challenge by producing the first structural-based interpretation of several kinds of carbon dots, such as graphene and polymeric ones. Furthermore, carbon nitride dot models established their structures as being formed by heptazine and oxidized graphene layers. These advancements allowed us to study their interaction with key bioactive molecules, producing the first computational studies on this matter. In this work, we modelled the structures of carbon nitride dots and their interaction with an anticancer molecule (Doxorubicin) using semi-empirical methods, evaluating both geometrical and energetic parameters.

A targeted next-generation gene panel reveals a novel heterozygous nonsense variant in the TP63 gene in patients with arrhythmogenic cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is associated with arrhythmias and risk of sudden death. Mutations in genes encoding proteins of cardiac intercalated discs account for ∼60% of ACM cases, but the remaining 40% is still genetically elusive. OBJECTIVE: The purpose of this study was to identify the underlying genetic cause in probands with ACM. METHODS: DNA samples from 40 probands with ACM, negative for mutations in the 3 major ACM genes-DSP, PKP2, and DSG2, were screened by using a targeted gene panel consisting of 15 known ACM genes and 53 candidate genes. RESULTS: About half of patients were found to carry rare variant(s) predicted to be damaging; specifically, 9 (22.5%) showed ≥1 variants in genes associated with ACM and/or with other inherited heart diseases and 10 (25%) showed variants in candidate genes. Among the latter, we focused on 2 novel variants in TP63 and PPP1R13L candidate genes (c.796C>T, p.(R266*) and c.1858G>C, p.(A620P), respectively). The encoded proteins p63 and inhibitor of apoptosis stimulating p53 protein are known to be interacting partners. Inhibitor of apoptosis stimulating p53 protein is a shuttling multifunctional protein: in the nucleus it is critical for inhibiting p63 function, whereas in the cytoplasm it regulates desmosome integrity. According to the American College of Medical Genetics and Genomics guidelines, the variant in TP63 has been scored as likely pathogenic and the variant in PPP1R13L as a variant of uncertain significance. Importantly, the mutant TP63 allele leads to nonsense-mediated messenger RNA decay, causing haploinsufficiency. CONCLUSION: Our findings identify TP63 as a putative novel disease gene for ACM, while the possible involvement of PPP1R13L remains to be determined.

[Risk stratification in Brugada syndrome]. / Stratificazione del rischio nella sindrome di Brugada.

Individuals with type 1 Brugada ECG pattern may suffer from malignant ventricular arrhythmias (Brugada syndrome). Patients with Brugada syndrome and documented cardiac arrest should receive an implantable cardioverter-defibrillator. In the remaining subjects, the best management is controversial. Many data suggest that patients with syncope, particularly if they have a spontaneous type 1 ECG pattern, have a significant risk. In the remaining population of asymptomatic subjects, the risk is lower but not negligible. How to manage these latter cases is an unsolved issue. The usefulness of the electrophysiological study (EPS) in risk stratification, i.e. inducibility of sustained ventricular tachycardia/fibrillation, is controversial. Indeed, some authors strongly support the prognostic value of EPS, while others completely deny its usefulness. We recently published our experience concerning the usefulness of a combined approach that considered both clinical data and EPS results; 320 patients (258 males, mean age 43 years) with type 1 ECG were enrolled. No patient had previous cardiac arrest; 54% of patients had a spontaneous and 46% a drug-induced type 1 ECG. One third had syncope, two thirds were asymptomatic; 245 patients underwent EPS; 110 patients received an implantable defibrillator. Patients were followed up for 40 months. During follow-up, 17 patients had major arrhythmic events (MAE) (14 resuscitated ventricular fibrillations and 3 sudden deaths). Both spontaneous type 1 ECG and syncope significantly increased the risk (8.6% and 10.4% event rates vs 2.8% and 1.3%). MAE occurred in 14% of subjects with positive EPS, in no subjects with negative EPS, and in 5.3% of subjects without EPS. All MAE occurred in subjects who had ≥ 2 risk factors (syncope, family history of sudden death and positive EPS). Among these patients, those with spontaneous type 1 ECG had a 30% event rate. In subjects with drug-induced type 1 MAE were rare. In conclusion, 1) in subjects with the Brugada type 1 ECG neither a single clinical risk factor nor EPS alone are able to identify subjects at the highest risk; 2) a multiparametric approach (including syncope, family history of sudden death and positive EPS) helps to identify populations at the highest risk; 3) subjects at the highest risk are those with a spontaneous type 1 ECG and ≥ 2 risk factors; 4) the remainder is at low risk.

[Brugada syndrome: diagnosis and risk stratification]. / Sindrome di Brugada: diagnosi e stratificazione del rischio.

Brugada syndrome is a genetic disease, leading to a functional reduction in sodium channel current. This anomaly occurs in the absence of other demonstrable cardiac anomalies. The ECG diagnostic pattern is characterized by coved ST-segment elevation in V1-V3 leads. Brugada syndrome may be complicated by malignant ventricular arrhythmias and sudden death. Risk stratification in individuals with type 1 Brugada ECG pattern for primary prevention of sudden death is an unsolved issue. Recognized risk factors for sudden death are spontaneous type 1 ECG pattern, syncope, or documented cardiac arrest. Family history of sudden death is a controversial risk factor. However, all these factors have a low positive predictive value. The prognostic significance of electrophysiological study (EPS) is debated. There is a consensus about the low predictive value of a positive EPS and a low specificity. However, while some authors deny at all its usefulness, others suggest that EPS is useful when considered together with other clinical risk factors. According to Brugada brothers our personal data suggest that (i) in subjects with type 1 Brugada ECG no single clinical risk factor nor EPS alone are able to identify subjects at the highest risk; (ii) a multiparametric approach (including syncope, family history of sudden death and positive EPS) helps to identify populations at the highest risk; (iii) subjects at the highest risk are those with a spontaneous type 1 ECG and at least two risk factors; (iv) the remaining are at low risk.

Unexplained syncope, Brugada-like ECG and minimal structural right ventricular abnormalities: which is the right diagnosis?

We describe a 65-year-old man with unexplained syncope, Brugada ECG pattern and right ventricular abnormalities. To reach a diagnosis of Brugada syndrome, a variety of diseases have to be excluded. This case report shows how difficult the differential diagnosis is, particularly with arrhythmogenic right ventricular cardiomyopathy, after documentation of minimal structural RV abnormalities; invasive examination may be required. In this case, three-dimensional electroanatomical bipolar voltage mapping revealed a scar area in the right ventricle in the absence of clear-cut kinetic abnormalities, but the sensitivity of this method and specificity in patients without confirmed arrhythmogenic right ventricular cardiomyopathy have not been defined.

Pace mapping of Koch's triangle reduces risk of atrioventricular block during ablation of atrioventricular nodal reentrant tachycardia.

INTRODUCTION: Slow pathway (SP) ablation of AV nodal reentrant tachycardia (AVNRT) can be complicated by second- to third-degree AV block. We assessed the usefulness of pace mapping of Koch's triangle in preventing this complication. METHODS AND RESULTS: Nine hundred nine consecutive patients undergoing radiofrequency ablation of AVNRT were analyzed. Group 1 (n=487) underwent conventional slow pathway ablation. Group 2 (n=422) underwent ablation guided by pace mapping of Koch's triangle, which located the anterogradely conducting fast pathway (AFP) based on the shortest St-H interval obtained by stimulating the anteroseptal, midseptal, and posteroseptal aspects of Koch's triangle. In group 2, AFP was anteroseptal in 384 (91%), midseptal in 33 (7.8%), and posteroseptal or absent in 5 (1.2%). In 32 of 33 patients with midseptal AFP, slow pathway ablation was performed strictly in the posteroseptal area. In 4 of 5 patients with posteroseptal or no AFP, retrograde fast pathway was ablated. Two patients refused ablation. Persistent second- to third-degree AV block was induced in 7 (1.4%) of 487 group 1 patients versus 0 (0%) of 422 group 2 patients (P=0.038). Ablation was successful in all patients in whom ablation was performed. CONCLUSION: Pace mapping of Koch's triangle identifies patients in whom the AFP is absent or is abnormally close to the slow pathway. In these cases, guiding ablation helps to avoid AV block.