Sotrovimab: una opción terapéutica en trasplante pulmonar / Sotrovimab: a therapeutic option in lung transplant patients

Antecedentes: Los trasplantados pulmonares son un grupo con mayor riesgo de desarrollar enfermedad por coronavirus 2019 (COVID-19) grave. El sotrovimab demostró reducir el riesgo de progresión de enfermedad y ha sido utilizado en pacientes con trasplante de órgano sólido, pero no ha sido estudiado en trasplantados pulmonares. Objetivo: Describir la evolución de la COVID-19 en trasplantados pulmonares tratados con sotrovimab. Material y métodos: Estudio observacional retrospectivo que incluyó trasplantados pulmonares que recibieron sotrovimab para la COVID-19 entre 2021 y 2022. Resultados: Se estudiaron 33 pacientes, 19 varones, con edad media de 61 años, 24 de ellos trasplantados bipulmonares, siendo las causas más frecuentes la enfermedad pulmonar intersticial difusa y la enfermedad pulmonar obstructiva crónica. El 90% requirieron ingreso. La mayoría necesitó algún tipo de soporte respiratorio, pudiéndose manejar el 39% con bajo flujo. El 42% presentaron sobreinfecciones, el 12% tromboembolia pulmonar y el 58% insuficiencia renal aguda. Seis pacientes fallecieron. Conclusiones: Este estudio presenta resultados similares a otros realizados en pacientes con trasplante de otro órgano sólido que recibieron sotrovimab respecto a tasas de hospitalización, mortalidad y seguridad. Se describe una menor mortalidad respecto a estudios previos de trasplantados pulmonares con infección por coronavirus 2 del síndrome respiratorio agudo grave previo al uso de sotrovimab. Este estudio sugiere que el sotrovimab es una opción terapéutica válida para la COVID-19 en trasplantados pulmonares. (AU)

Background: Lung transplant recipients are a group at higher risk of developing severe coronavirus disease 2019 (COVID-19). Sotrovimab has demonstrated a reduction in the risk of disease progression and has been used in solid organ transplant patients, but it has not been studied in lung transplant recipients. Objective: To describe the course of COVID-19 in lung transplant recipients treated with sotrovimab. Material and methods: Retrospective observational study included lung transplant recipients who received sotrovimab for COVID-19 between 2021 and 2022. Results: Thirty-three patients were studied, 19 males, with an average age of 61 years, and 24 of them had received bilateral lung transplants, with the most common causes being diffuse interstitial lung disease and chronic obstructive pulmonary disease; 90% required hospitalization. The majority needed some form of respiratory support, with 39% manageable with low-flow oxygen. Superinfections were observed in 42% of cases, pulmonary embolism in 12%, and acute renal failure in 58%. Six patients died. Conclusions: This study presents results similar to those conducted in patients with transplants of other solid organs who received sotrovimab in terms of hospitalization rates, mortality, and safety. A lower mortality rate is described compared to previous studies of lung transplant recipients with severe acute respiratory syndrome coronavirus 2 infection before the use of sotrovimab. This study suggests that sotrovimab is a valid therapeutic option for COVID-19 in lung transplant recipients. (AU)

Bronchopulmonary penetration of isavuconazole in lung transplant recipients.

Isavuconazole's (ISA) pharmacokinetics was studied among lung transplant recipients to evaluate its bronchopulmonary penetration. This study included 13 patients and showed mean serum concentrations of 3.30 (standard deviation [SD] 0.45), 5.12 (SD 1.36), and 6.31 (SD 0.95) at 2 h, 4 h, and 24 h respectively. Mean concentrations in the epithelial lining fluid were 0.969 (SD 0.895), 2.141 (SD 1.265), and 2.812 (SD 0.693) at the same time points. ISA is a drug with a tolerable safety profile that achieves adequate concentrations in the lung.

Streptococcus mitis as a New Emerging Pathogen in Pediatric Age: Case Report and Systematic Review.

Streptococcus mitis, a normal inhabitant of the oral cavity, is a member of Viridans Group Streptococci (VGS). Generally recognized as a causative agent of invasive diseases in immunocompromised patients, S. mitis is considered to have low pathogenic potential in immunocompetent individuals. We present a rare case of sinusitis complicated by meningitis and cerebral sino-venous thrombosis (CSVT) caused by S. mitis in a previously healthy 12-year-old boy with poor oral health status. With the aim of understanding the real pathogenic role of this microorganism, an extensive review of the literature about invasive diseases due to S. mitis in pediatric patients was performed. Our data define the critical role of this microorganism in invasive infections, especially in immunocompetent children and in the presence of apparently harmful conditions such as sinusitis and caries. Attention should be paid to the choice of therapy because of VGS's emerging antimicrobial resistance patterns.

Interrupted versus continuous suture for bronchial anastomosis in lung transplantation: does it matter?

OBJECTIVES: Bronchial anastomotic complications remain a major concern in lung transplantation. We aim to compare 2 different techniques, continuous suture (CS) versus interrupted suture (IS) by analysing airway complications requiring intervention. METHODS: Lung transplantations between January 2015 and December 2020 were included. Airway complications requiring intervention were classified following the 2018 International Society for Heart and Lung Transplantation consensus and analysed comparing 3 groups of patients according to surgical technique: group A, both anastomosis performed with CS; group B, both with interrupted; and group C, IS for 1 side and CS for the contralateral side. RESULTS: A total of 461 anastomoses were performed in 245 patients. The incidence of airway complications requiring intervention was 5.7% [95% confidence interval (CI): 2.8-8.6] per patient (14/245) and 3.7% (95% CI: 2.0-5.4) per anastomosis (17/461). Complications that required intervention were present in 5 out of 164 (3.1%) anastomosis with interrupted technique, and in 12/240 (5%) with CS. No significant differences were found between techniques (P = 0.184). No statistical differences were found among group A, B or C in terms of incidence of anastomotic complications, demographics, transplant outcomes or overall survival (log-rank P = 0.513). In a multivariable analysis, right laterality was significantly associated to complications requiring intervention (OR 3.7 [95% CI: 1.1-12.3], P = 0.030). Endoscopic treatment was successful in 12 patients (85.7%). Retransplantation was necessary in 2 patients. CONCLUSIONS: In summary, although it seems that anastomotic complications requiring intervention occur more frequently with CS, there are no statistical differences compared to IS. Endoscopic treatment offers good outcomes in most of the airway complications after lung transplantation.

Peripheral blood eosinophilia as a marker of acute cellular rejection in lung transplant recipients.

Previous studies in solid organ transplantation have shown a relationship between circulating eosinophil (EOS) counts and the presence of acute cellular rejection (ACR). However, the relationship between this potential biomarker and ACR in lung transplant (LTx) patients remains unclear. OBJECTIVE: To assess the association between EOS and the presence of acute cellular rejection in lung transplant recipients. MATERIALS AND METHODS: Retrospective study of 583 transbronchial biopsies (TBB) performed in 256 lung transplant patients between 2012 and 2018. We analyzed age, sex, underlying pathology, date of transplant, indications for TBB, presence and degree of ACR, and the simultaneous absolute and relative EOS. RESULTS: ACR were observed in 170 of 583 TBB (29.2%). EOS in patients with ACR were higher than in patients without ACR (203.6 ± 248/mm3 vs 103.1 ± 153/mm3; p < 0.001). High levels of both absolute and relative EOS were associated with the presence of ACR regardless of the underlying disease (odds ratio [OR] 1.003; 95% confidence interval [CI], 1.002-1.004; OR 1.226; 95% CI, 1.120-1.342) and time after transplant (OR 1.003; 95% CI, 1.002-1.004 and OR 1.239; 95% CI, 1.132-1.356). Moreover, both absolute and relative EOS were strongly associated with moderate and severe grades of ACR (OR 3.55; 95% CI, 3.00-4.10 and OR 3.56; 95% CI, 3.00-4.12). CONCLUSIONS: EOS are elevated in ACR, especially in moderate or severe ACR. Increased vigilance for ACR is therefore advisable in lung transplant recipients with elevated EOS.

ADEM post-Sars-CoV-2 infection in a pediatric patient with Fisher-Evans syndrome.

INTRODUCTION: Sars-CoV-2 is a single-strained RNA virus belonging to Coronaviridae's family. In pediatric age, the majority of patients is asymptomatic; however, several neurological manifestations associated with Sars-CoV-2 infection have been detected in a percentage of cases ranging from 17.3 to 36.4%. Acute disseminated encephalomyelitis (ADEM) has been recently included among the potential complications of Sars-Cov2 infection. The available data regarding pediatric patient show only one case. CASE REPORT: We present a case regarding a 6-year-old patient suffering from Fisher-Evans syndrome who was given sirolimus and thalidomide therapy. After 10 days since the first positive nasopharyngeal swab for Sars-CoV-2, in which he had no symptoms, he presented an episode of generalized tonic-clonic seizure with spontaneous resolution. The patient underwent MRI which showed the typical picture of acute disseminated encephalomyelitis. His clinical course was favorable, with a good response to cortisone therapy and a progressive improvement of the neuroradiological and electroencephalographic picture. CONCLUSIONS: According to our knowledge, this is the second case of an acute disseminated encephalomyelitis following SARS-CoV-2 infection in a pediatric patient, characterized by monosymptomatic onset, in which the immunosuppressive therapy practiced for the Fisher-Evans syndrome has probably contributed to a favorable evolution of ADEM, in contrast to other case described in the literature.

Bronchoscopist's perception of the quality of the single-use bronchoscope (Ambu aScope4™) in selected bronchoscopies: a multicenter study in 21 Spanish pulmonology services.

BACKGROUND: The disposable bronchoscope is an excellent alternative to face the problem of SARS-CoV-2 and other cross infections, but the bronchoscopist's perception of its quality has not been evaluated. METHODS: To evaluate the quality of the Ambu-aScope4 disposable bronchoscope, we carried out a cross-sectional study in 21 Spanish pulmonology services. We use a standardized questionnaire completed by the bronchoscopists at the end of each bronchoscopy. The variables were described with absolute and relative frequencies, measures of central tendency and dispersion depending on their nature. The existence of learning curves was evaluated by CUSUM analysis. RESULTS: The most frequent indications in 300 included bronchoscopies was bronchial aspiration in 69.3% and the median duration of these was 9.1 min. The route of entry was nasal in 47.2% and oral in 34.1%. The average score for ease of use, image, and aspiration quality was 80/100. All the planned techniques were performed in 94.9% and the bronchoscopist was satisfied in 96.6% of the bronchoscopies. They highlighted the portability and immediacy of the aScope4TM to start the procedure in 99.3%, the possibility of taking and storing images in 99.3%. The CUSUM analysis showed average scores > 70/100 from the first procedure and from the 9th procedure more than 80% of the scores exceeded the 80/100 score. CONCLUSIONS: The aScope4™ scored well for ease of use, imaging, and aspiration. We found a learning curve with excellent scores from the 9th procedure. Bronchoscopists highlighted its portability, immediacy of use and the possibility of taking and storing images.

Exploring metabolic reprogramming in melanoma via acquired resistance to the oxidative phosphorylation inhibitor phenformin.

Therapeutic failures in cancer therapy are often associated with metabolic plasticity. The use of metabolic modulators as anti-cancer agents has been effective in correcting metabolic alterations; however, molecular events behind metabolic switch are still largely unexplored. Herein, we characterize the molecular and functional events that follow prolonged oxidative phosphorylation inhibition by phenformin in order to study how melanoma cells adapt to this specific metabolic pressure. We show that melanoma cells cultured up to 3 months with high doses of phenformin (R-cells) are less viable and migrate and invade less than parental (S-) cells. Microarray analysis of R-melanoma cells reveals a switch in the energy production strategy accompanied by the modulation of several immunological-associated genes. R-cells display low oxygen consumption rate and high basal extracellular acidification rate. When treated with vemurafenib, R-cell viability, growth and extracellular signal-regulated kinase activation decrease. Finally, phenformin withdrawal reverts R-cells phenotype. In summary, our study provides an in vitro model of on-off metabolic switch in melanoma and reveals interesting molecular signatures controlling metabolic reprogramming in this tumour.

A Case Report of Adult Pineoblastoma Occurring in a Pregnant Woman.

BACKGROUND/AIM: Pineoblastoma of the adult age is an uncommon tumor with only 200 cases reported. A standardized approach for an optimal adjuvant strategy is currently lacking. The case presented herein also deals with the issue of central nervous system tumors in pregnancy. CASE REPORT: A 21-year-old pregnant woman presented with massive hydrocephalus due to a mass in the pineal region detected with MRI. After positioning an urgent ventricular derivation, a cesarean section was performed. During a third ventriculocisternostomy, a biopsy revealed a pineoblastoma. After a maximal safe resection, postoperative craniospinal irradiation for a total dose of 36 Gy plus a sequential boost to the tumor bed to 54 Gy, and adjuvant chemotherapy with CDDP plus CCNU plus vincristine were performed. After one year, the patient is alive with no evidence of disease. CONCLUSION: The use of adjuvant radio-chemotherapy provided excellent outcomes in our case. The advanced gestational age facilitated the choice of the therapeutic strategy.

QT prolongation and variability: new ECG signs of atrial potentials dispersion before atrial fibrillation onset.

AIMS: QT interval may be considered an indirect marker of atrial repolarization. Aim of our study was to verify if QT interval variations precede the onset of atrial fibrillation (AF). METHODS: We analyzed 21 AF onsets recorded at 24-h Holter ECG. Triggering supraventricular extrabeats (TSVEB) were identified and matched to nontriggering supraventricular extrabeats (NTSVEB) with the same prematurity index. QT and QTc intervals and their variability (max-min QT interval) were measured in the 10 beats preceding TSVEB and NTSVEB. RESULTS: QTc (470.1 ±â€Š56.7 vs. 436.7 ±â€Š25.6 ms; P = 0.006), QT (36.8 ±â€Š13.1 vs. 21.1 ±â€Š10.1 ms; P = 0.001) and QTc variability (41.5 ±â€Š15.8 vs. 23.1 ±â€Š11.9; P = 0.001) significantly varied between TSVEB and NTSVEB. By stratifying AF onsets in vagal (n = 10) and adrenergic (n = 11) according to Heart Rate Variability, significant differences emerged concerning QT (35.20 ±â€Š16.48 vs. 22.70 ±â€Š10.23 ms, P = 0.006) and QTc variability (39.30 ±â€Š18.32 vs. 25.60 ±â€Š12.91 ms, P = 0.029) for vagal onsets and QTc (477.73 ±â€Š57.50 vs. 438.00 ±â€Š28.55 ms, P = 0.045), QT (38.36 ±â€Š9.79 vs. 19.73 ±â€Š10.21 ms, P = 0.005) and QTc variability (43.55 ±â€Š13.72 vs. 20.82 ±â€Š11.01 ms, P = 0.004) for adrenergic onsets. By stratifying AF onsets in type I (n = 7) or II (n = 14) according to a cycle length variation in the 30 s before the onset greater or smaller than 10% respectively, significant differences were noted concerning QTc (477.73 ±â€Š57.50 vs. 438 ±â€Š28.55 ms, P = 0.045), QT (43.55 ±â€Š13.72 vs. 20.82 ±â€Š11.01 ms, P = 0.005) and QTc variability (43.55 ±â€Š13.72 vs. 20.82 ±â€Š11.01 ms, P = 0.004) in type I and QT (35.20 ±â€Š16.48 vs. 22.70 ±â€Š10.23 ms, P = 0.006) and QTc variability (39.30 ±â€Š18.32 vs. 25.60 ±â€Š12.91 ms, P = 0.029) in type II onsets. CONCLUSION: Prolongation and QT variability represent a relevant substrate marker in the genesis of AF, independently of the trigger type.

The bHLH transcription factor DEC1 promotes thyroid cancer aggressiveness by the interplay with NOTCH1.

Aberrant re-activation of transcription factors occurs frequently in cancer. Recently, we found the basic helix-loop-helix transcription factors DEC1 and DEC2 significantly up-regulated in a model of highly aggressive thyroid cancer, raising the hypothesis that these factors might be part of the program driving progression of these tumors. Here, we investigated for the first time the function of DEC1 and DEC2 in thyroid cancer. Using both gain- and loss-of-function approaches, we showed that DEC1 more than DEC2 sustains progression of thyroid cancer by promoting cell growth and invasiveness. We demonstrated that DEC1 controls NOTCH1 expression and that the interplay with the NOTCH pathway is relevant for DEC1 function in thyroid cancer. We confirmed this observation in vivo showing that DEC1 expression is a specific feature of tumor cells, that this transcription factor is significantly over-expressed in all major thyroid cancer histotypes and that its expression correlated with NOTCH1 in these tumors. Finally, we performed RNA-sequencing to define the DEC1-associated gene expression profile in thyroid cancer cells and we discovered that DEC1 drives the expression of many cell cycle-related genes, uncovering a potential new function for this transcription factor in cancer.

Very long-term outcome following transcatheter ablation of atrial fibrillation. Are results maintained after 10 years of follow up?

Aims: Atrial fibrillation (AF) transcatheter ablation is a safe and effective procedure. However, outcome over 10 years of follow-up has never been reported. The aim of this study is to assess outcome, describe predictors of recurrences, and report on quality of life (QoL) the decade after an AF ablation. Methods and results: Patients referred for AF ablation in a single high volume centre from June 2004 to June 2006 were enrolled and followed in a prospective fashion by yearly clinical assessment and Holter monitoring. Among 255 patients (42.7% paroxysmal AF, 77% males, after a follow-up of 125 ± 7 months), 132 (52%) were arrhythmia-free including (58, 32% after a single procedure) while 27 (10%) progressed to permanent AF. At multivariate analysis, a greater left atrium antero-posterior diameter (HR 1.05 95% CI 1.02-1.09, P = 0.02) related to arrhythmic recurrences, while no increase in blood pressure (HR 0.06 95% CI 0.02-0.20, P = 0.01), BMI (HR 0.06 95% CI 0.02-0.09, P < 0.001), and fasting glucose (HR 0.58 95% CI 0.36-0.92, P = 0.02) during follow-up were protective for arrhythmic recurrences. Overall QoL improved significantly, significantly related to the absence of recurrences, arrhythmic burden reduction and blood pressure, and BMI control (P < 0.001). Conclusion: The outcome of AF ablation over more than 10 years is characterized by a low incidence of progression towards permanent AF. Greater LA anteroposterior diameter related to arrhythmic recurrences, while blood pressure, BMI, and fasting blood glucose control emerged as predictors of sinus rhythm maintenance. Eventually, QoL improved significantly over the follow-up.

Preliminary Experience with a Novel System of Facet Fixation to Treat Patients with Lumbar Degenerative Disease. A New Perspective in Minimally Invasive Spine Surgery?

PURPOSE: We report our experience with a novel surgical device for the treatment of lumbar degenerative microinstability. Facet Wedge (DePuy Synthes, Raynham, Massachusetts, United States) is a novel technique of intra-articular lumbar facet fixation that provides a minimally invasive alternative to standard posterior fixation. MATERIALS AND METHODS: From November 2014 to July 2015, 38 patients underwent single-level Facet Wedge implantation. The main surgical indications included herniated disk (18 patients), spinal canal and foraminal stenosis (14 patients), and Meyerding grade I degenerative spondylolisthesis (6 patients). All the patients showed radiologic signs of microinstability: hyperintensity in both facet joints (facet fluid signal) in T2-weighted magnetic resonance imaging and a black disk as a sign of degenerative disease. No slippage was evident at dynamic radiograph. After a period of conservative treatment (minimum of 6 months), surgery was performed. All patients' follow-up lasted over at least 12 months. RESULTS: The low back visual analog scale score decreased significantly after surgery (from an average of 8.2 to 3.1 at final follow-up). Postoperatively, the Oswestry Disability Index showed a significant reduction (14.7 on average). No slippage or signs of adjacent segment degeneration was detected in neuroimaging follow-up. CONCLUSION: Facet Wedge allows facet fixation in lumbar degenerative microinstability. To the best of our knowledge, this is the first clinical series reported in the literature on this novel device.

Synthesis and antiangiogenic activity study of new hop chalcone Xanthohumol analogues.

Angiogenesis induction is a hallmark of cancer. Antiangiogenic properties of Xanthohumol (XN), a naturally occurring prenylated chalcone from hops, have been widely reported. Here we describe the synthesis and study the antiangiogenic activity in vitro of a series of XN derivatives, where different substituents on the B-ring of the chalcone scaffold were inserted. The new XN derivatives inhibited human umbilical-vein endothelial cell (HUVEC) proliferation, adhesion, migration, invasion and their ability to form capillary-like structures in vitro at 10 µM concentration. The preliminary results indicate that the phenolic OH group in R, present in natural XN, is not necessary for having antiangiogenic activity. In fact, the most effective compound from this series, 13, was characterized by a para-methoxy group in R and a fluorine atom in R2 on B-ring. This study paves the way for future development of synthetic analogues of XN to be used as cancer angiopreventive and chemopreventive agents.

Risk factors, survival, and impact of prophylaxis length in cytomegalovirus-seropositive lung transplant recipients: A prospective, observational, multicenter study.

BACKGROUND: The optimal length of cytomegalovirus (CMV) prophylaxis in lung transplantation according to CMV serostatus is not well established. METHODS: We have performed a prospective, observational, multicenter study to determine the incidence of CMV infection and disease in 92 CMV-seropositive lung transplant recipients (LTR), their related outcomes and risk factors, and the impact of prophylaxis length. RESULTS: At 18 months post transplantation, 37 patients (40%) developed CMV infection (23 [25%]) or disease (14 [15.2%]). Overall mortality was higher in patients with CMV disease (64.3% vs 10.2%; P<.001), but only one patient died from CMV disease. In the multivariate analysis, CMV disease was an independent death risk factor (odds ratio [OR] 18.214, 95% confidence interval [CI] 4.120-80.527; P<.001). CMV disease incidence was higher in patients with 90-day prophylaxis than in those with 180-day prophylaxis (31.3% vs 11.8%; P=.049). Prophylaxis length was an independent risk factor for CMV disease (OR 4.974, 95% CI 1.231-20.094; P=.024). Sixteen patients withdrew from prophylaxis because of adverse events. CONCLUSION: CMV infection and disease in CMV-seropositive LTR remain frequent despite current prophylaxis. CMV disease increases mortality, whereas 180-day prophylaxis reduces the incidence of CMV disease.

Does antiarrhythmic drugs premedication improve electrical cardioversion success in persistent atrial fibrillation?

AIMS: Aim of this study is to evaluate the impact of antiarrhythmic drugs (AADs) administration for at least one month before ECV on the acute and long term success rate of the procedure. METHODS: 1313 consecutive persistent AF patients were enrolled in 3 different centers (Turin, Asti and Avellino): 692 patients received AADs before and after ECV (group A), 621 patients were treated only after the procedure, at discharge (group B). Primary end point was the restoration and maintenance of sinus rhythm acutely and at a long-term follow up. RESULTS: Acute ECV success was higher in group A compared with group B (99% vs. 88%, p=0.0001) and a fewer number of shock attempts were administered (1.15±0.42 vs. 1.27±0.53 p<0.0001). Moreover group A maintained SR more often than group B at one month (99% vs. 89%, log-rank p<0.0001), at one year (55% vs. 48% log-rank p=0.01) and at the end of follow up (mean 2.7±2.1years, 45% vs. 29%, log-rank p<0.0001). At multivariate analysis AADs premedication was the strongest independent predictor of acute and long-term ECV success (respectively p<0.0001 OR 10.71 CI 5.10-22.50 and p=0.004, OR 1.50 CI 1.14-1.97). At sensitivity analysis no differences were found between ADDs in terms of acute success improvement (p=0.605), number of shock attempts (p=0.853) and long term SR maintenance (log-rank p=0.480). CONCLUSIONS: AADs administration for at least 4weeks before the ECV in persistent AF increases significantly the acute success rate and this result was maintained over a long-term follow-up.

Autonomic Tone Activity Before the Onset of Atrial Fibrillation.

INTRODUCTION: The autonomic nervous system has been proven to play a major role in the onset of atrial fibrillation (AF), along with a predisposing substrate and a specific trigger event usually consisting of a premature supraventricular ectopic beat (SVEB). By means of heart rate variability (HRV) analysis, we investigated the activity of the autonomic nervous system before SVEBs nontriggering and triggering AF. METHODS AND RESULTS: We evaluated 28 patients with at least 1 episode of sustained AF (>30 seconds) recorded during 24-hour Holter monitorings. We performed HRV analysis during the hour preceding 35 AF onsets and compared these results with the HRV values before nontriggering SVEBs with similar prematurity. According to the low frequency (LF)/high frequency (HF) ratio in the 5 minutes before the onset, AF episodes were classified as either vagal (LF/HF ratio <1.5) or adrenergic (LF/HF ratio ≥1.5).Vagal episodes (16) showed a decrease in LF (from 50.81 ± 1.67 to 32.73 ± 3.54) and an increase in HF (from 36.00 ± 2.30 to 54.7 ± 3.69) throughout the hour preceding the onset. Adrenergic episodes (19) had opposite changes in LF (from 55.4 ± 4.95 to 67.51 ± 5.24) and HF (from 33.78 ± 5.82 to 27.96 ± 3.51) during the same period. No similar trends were observed before the selected nontriggering SVEBs. CONCLUSION: Only SVEBs occurring during a phase of hyperactivity of one of the 2 branches of the autonomic nervous system are able to trigger episodes of AF.

Hop derived flavonoid xanthohumol inhibits endothelial cell functions via AMPK activation.

Angiogenesis, a process characterized by the formation of new blood vessels from pre-existing ones, is a crucial step in tumor growth and dissemination. Recently, increased attention has been addressed to the ability of flavonoids to prevent cancer by suppressing angiogenesis, strategy that we named "angioprevention". Several natural compounds exert their anti-tumor properties by activating 5' adenosine monophosphate-activated protein kinase (AMPK), a key regulator of metabolism in cancer cells. Drugs with angiopreventive activities, in particular metformin, regulate AMPK in endothelial cells. Here we investigated the involvement of AMPK in the anti-angiogenic effects of xanthohumol (XN), the major prenylated flavonoid of the hop plant, and mechanisms of action. The anti-angiogenic activity of XN was more potent than epigallocatechin-3-gallate (EGCG). Treatment of endothelial cells with XN led to increased AMPK phosphorylation and activity. Functional studies using biochemical approaches confirmed that AMPK mediates XN anti-angiogenic activity. AMPK activation by XN was mediated by CAMMKß, but not LKB1. Analysis of the downstream mechanisms showed that XN-induced AMPK activation reduced nitric oxide (NO) levels in endothelial cells by decreasing eNOS phosphorylation. Finally, AKT pathway was inactivated by XN as part of its anti-angiogenic activity, but independently from AMPK, suggesting that these two signaling pathways proceed autonomously. Our study dissects the molecular mechanism by which XN exerts its potent anti-angiogenic activity, pointing out AMPK as a crucial signal transducer.

Arrhythmogenic right ventricular cardiomyopathy: ECG progression over time and correlation with long-term follow-up.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease primarily affecting the right ventricle and potentially causing sudden death in young people. Our aims are to analyse the progression over time of electrocardiographic (ECG) findings and to investigate their prognostic impact. METHODS: Sixty-eight patients (69% men; age 31 ±â€Š19 years) with ARVC diagnosis were followed up for a mean of 17 ±â€Š8 years. Follow-up included baseline ECG, 24-h Holter ECG, signal-averaged ECG, stress test, echocardiography, cardiac magnetic resonance and electrophysiologic study. RESULTS: During follow-up 12 (18%) patients died: three of sudden cardiac death (SCD), four of end-stage heart failure and five of noncardiac causes. Aborted SCD occurred in 7 (10%) patients, syncope in 31 (46%), sustained ventricular tachycardia in 43 (63%), heart failure in 18 (26%), atrial fibrillation in 16 (24%) and 3 (4%) patients underwent heart transplant. Twenty-four (35%) patients had implantable cardiac defibrillator (15 and 5 of them received both appropriate and inappropriate interventions, respectively and 7 experienced device-related complications). Of the ECG parameters registered at the enrolment, left anterior fascicular block (P = 0.001), QRS duration in lead 1 (P < 0.001), Epsilon wave (P < 0.001), T wave inversion in V4-V5-V6 (P = 0.012, P = 0.001 and P = 0.006) and low QRS voltages (P = 0.001) progressed over time. At multivariate analysis Epsilon wave (odds ratio 20.9, confidence interval 95% 1.8-239.8, P = 0.015) was the only predictor of the composite endpoint of SCD, heart failure-related death or heart transplant. CONCLUSION: Apart from playing a pivotal role in ARVC diagnosis, a simple ECG feature such as Epsilon wave is a marker of poor prognosis.

Prolonged QT interval in ST-elevation myocardial infarction: predictors and prognostic value in medium-term follow-up.

AIMS: The prognostic role of corrected QT interval in ST-elevation myocardial infarction is still unknown. This study aims to identify the prognostic value of corrected QT interval prolongation (≥480 ms) in acute coronary syndrome. METHODS: One hundred and eighty-five consecutive patients with ST-elevation myocardial infarction were prospectively enrolled and electrocardiographic monitoring of corrected QT interval was performed during the hospitalization. RESULTS: Over a mean period of 17.6 ±â€Š11 months, 16 (8.6%) patients died because of cardiovascular diseases, 6 (3.2%) patients experienced aborted sudden cardiac death, 3 (1.6%) cerebral ischemic strokes, 11 (6%) recurrent myocardial ischemia and 6 (3.2%) acute heart failure. At univariate analysis a corrected QT interval peak of at least 480 ms relates to cardiovascular death (P < 0.001), aborted sudden cardiac death (P = 0.037), cerebral ischemic stroke (P = 0.016) and recurrences of myocardial infarction (P = 0.032). Multivariate analysis confirms its role an independent predictor of cardiovascular death [odds ratio 6.38, 95% confidence interval (CI) 1.77-22.92, P = 0.004], together with an ejection fraction of 35% or less (odds ratio 4.20, 95% CI 1.24-14.16, P = 0.021). The presence of either corrected QT of at least 480 ms or ejection fraction of 35% or less increases the sensitivity and the accuracy to correctly predict cardiovascular death without a significant reduction in specificity (sensitivity 88%, specificity 69%, accuracy 88%, area under curve 0.83, 95% CI 0.72-0.94, P < 0.01). CONCLUSION: A corrected QT interval peak of at least 480 ms in the acute phase of ST-elevation myocardial infarction is an independent predictor of cardiovascular death. Its association with reduced ejection fraction (≤35%) increases risk stratification accuracy.