Heart failure with reduced ejection fraction and monogenic dilated cardiomyopathy: distinct diseases? Insights from randomized controlled trials

The genetic component of heart failure with reduced ejection fraction (HFrEF) is traditionally considered as part of the non-ischaemic aetiology. Dilated cardiomyopathy (DCM) has been recognized as the most heterogeneous amongst the classical cardiomyopathy phenotypes, with >250 genes which have been causally related with the disease

Trattamento dello scompenso cardiaco con terapia genica: i risultati inattesi del trial CUPID 2

Lo scompenso cardiaco \ue8 ancora oggi un\u2019importante causa di morbilit\ue0 e mortalit\ue0 in tutto il mondo. La terapia genica dei meccanismi implicati nello scompenso cardiaco \ue8 emersa sin dagli anni \u201990 come potenziale target terapeutico incoraggiando studi preclinici su piccoli e poi pi\uf9 grandi modelli animali. Le prime esperienze in letteratura hanno documentato una ridotta espressione del reticolo sarcoplasmatico/endoplasmatico Ca2+-ATPasi2a (SERCA2a) nello scompenso cardiaco. Questi risultati hanno portato allo sviluppo di trial clinici sul trasferimento genico di SERCA2a. I primi risultati positivi in termini di fattibilit\ue0, sicurezza ed endpoint clinici hanno aperto la strada al primo grande trial randomizzato, il CUPID, su pazienti con scompenso cardiaco e frazione di eiezione ridotta in cui sono stati arruolati 250 pazienti a infusione intracoronarica di virus adeno-associati di tipo 1 (AAV1)/SERCA2a o placebo. Le grandi aspettative riposte sono state disattese e non si \ue8 osservato alcun miglioramento in termini di outcome nei pazienti trattati. In questa revisione abbiamo rivisitato i precedenti lavori che hanno portato al disegno di questo trial, analizzato le sue principali caratteristiche e risultati, fornendo infine alcune ipotesi sul motivo di un fallimento parzialmente inatteso in modo da comprendere quali possano essere le future prospettive per la terapia genica nello scompenso cardiaco

A case report of isolated cardiac light chain amyloidosis without clinically overt heart failure: an under-recognized presentation

Background: Cardiac involvement in amyloid light-chain (AL) amyloidosis usually represents a brick in the wall of a multi-system disease. The presence of cardiac deposition of free light chains (FLCs) is the main determinant of survival. Isolated cardiac AL is an uncommon scenario characterized by a challenging diagnostic and therapeutic workup. Case summary: A 57-year-old asymptomatic man was presented for an incidental finding of myocardial necrosis at the electrocardiogram (ECG) performed for newly diagnosed arterial hypertension. Alongside signs of previous myocardial infarction, transthoracic echocardiography showed a severely increased left ventricular (LV) wall thickness not consistent with ECG voltages, segmental akinaesia with normal LV systolic function with 'apical sparing' pattern. Laboratory assessment showed an unexpectedly high level of natriuretic peptide and persistently abnormal troponin in the absence of symptoms or signs of heart failure or ongoing ischaemia. Coronary angiogram confirmed the coronary artery disease. Before revascularization, a complete diagnostic workup was carried. Serum electrophoresis detected a monoclonal gammopathy that was further investigated by serum immunofixation, revealing high lambda FLCs concentration. Fat pad, bone marrow, and salivary glands biopsies resulted negative for amyloid deposition. Finally, endomyocardial biopsy was consistent with AL amyloidosis. Urgent percutaneous revascularization was performed, and the patients was timely started on chemotherapy. Discussion: The diagnosis of isolated cardiac AL amyloidosis is challenging and carries important therapeutic implications. As the short-term prognosis might be severely compromised, an accurate diagnostic flowchart has to be systematically pursued to obtain a precise diagnosis and address the optimal, tailored management

Condições ambientais em incubadora de múltiplo estágio: um estudo de caso

A produção de pintinhos de um dia é um dos segmentos mais importantes da cadeia avícola. O ambiente de incubação de frangos de corte precisa ser homogêneo e adequado de modo a não afetar a eclodibilidade e a qualidade do produto final. Avaliaram-se as condições de ambiência no interior de incubadora de estágio múltiplo durante um lote de produção em incubatório comercial. A incubadora foi dividida em seis quadrantes em cujo centro geométrico foram colocados registradores de valores de temperatura e umidade relativa. A concentração de dióxido de carbono, bem como o número de unidades formadoras de colônias (CFU) de fungos também foram amostradas nos mesmos locais; o teste não paramétrico de Kruskal-Wallis foi utilizado para análise estatística. Foram detectadas diferenças na distribuição de temperatura e umidade relativa no interior da incubadora (p ; 0,05). A incidência de fungos variou de média a boa. Pontos críticos foram detectados em todas as áreas dentro da incubadora.Production of one day-old chick production is one of the most important segments in the poultry production business. Broiler chicken incubation environment needs to be homogeneous and adequate so hatchability and final product quality are not affected. This research aimed at evaluating environmental conditions inside a multi-stage setter in a commercial hatchery house. The incubator was split into six areas and data loggers placed in the geometric center to register temperature and relative humidity data; carbon dioxide concentration and number of colony forming units (CFU) of fungi were also sampled and analyzed; Kruskal-Wallis non-parametric test was used for statistical analysis; significant differences in temperature and relative humidity distribution inside the incubator (p ; 0.05). Fungi incidence varied from average to good. Critical points were detected in all areas inside the setter

Natural History of Dilated Cardiomyopathy in Children

The long-term progression of idiopathic dilated cardiomyopathy (DCM) in pediatric patients compared with adult patients has not been previously characterized. In this study, we compared outcome and long-term progression of pediatric and adult DCM populations

Arrhythmic risk stratification in non-ischaemic dilated cardiomyopathy

Dilated cardiomyopathy is a primary disease of the heart muscle, which affects relatively young patients with a low comorbidity profile. It is characterized by structural and/or functional abnormalities leading to systolic dysfunction of the left ventricle or of both ventricles, often associated with dilatation, in the absence of an ischaemic, valvular, or pressure overload cause sufficient to explain the phenotype. Although the prognosis of the disease has greatly improved over the last few decades, prognostic stratification remains a fundamental objective, especially about the prediction of potentially life-threatening arrhythmic events. An accurate diagnostic work-up and an appropriate aetiopathogenetic characterization affect the patients' outcome and represent the essential basis of an adequate prognostic stratification. It is necessary to adopt a multiparametric approach, especially when the aim is the prediction of arrhythmic risk; it includes an integration of medical history and physical examination with cardiac imaging and genetic testing, in order to obtain a personalized diagnosis and therapeutic strategies. Furthermore, the evaluation should be repeated at every clinical check-up, considering the dynamic trend of the pathology and the arrhythmic risk changes over time. This article aims to illustrate how, starting from an exhaustive aetiological and clinical-instrumental characterization, including all diagnostic methods available at present time, it is possible to obtain a tailored diagnostic evaluation and stratification of the arrhythmic risk as accurate as possible

Condições ambientais em incubadora de múltiplo estágio: um estudo de caso

Production of one day-old chick production is one of the most important segments in the poultry production business. Broiler chicken incubation environment needs to be homogeneous and adequate so hatchability and final product quality are not affected. This research aimed at evaluating environmental conditions inside a multi-stage setter in a commercial hatchery house. The incubator was split into six areas and data loggers placed in the geometric center to register temperature and relative humidity data; carbon dioxide concentration and number of colony forming units (CFU) of fungi were also sampled and analyzed; Kruskal-Wallis non-parametric test was used for statistical analysis; significant differences in temperature and relative humidity distribution inside the incubator (p 0.05). Fungi incidence varied from average to good. Critical points were detected in all areas inside the setter.A produção de pintinhos de um dia é um dos segmentos mais importantes da cadeia avícola. O ambiente de incubação de frangos de corte precisa ser homogêneo e adequado de modo a não afetar a eclodibilidade e a qualidade do produto final. Avaliaram-se as condições de ambiência no interior de incubadora de estágio múltiplo durante um lote de produção em incubatório comercial. A incubadora foi dividida em seis quadrantes em cujo centro geométrico foram colocados registradores de valores de temperatura e umidade relativa. A concentração de dióxido de carbono, bem como o número de unidades formadoras de colônias (CFU) de fungos também foram amostradas nos mesmos locais; o teste não paramétrico de Kruskal-Wallis foi utilizado para análise estatística. Foram detectadas diferenças na distribuição de temperatura e umidade relativa no interior da incubadora (p 0,05). A incidência de fungos variou de média a boa. Pontos críticos foram detectados em todas as áreas dentro da incubadora.145149Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq

Prognostic Prediction of Genotype vs Phenotype in Genetic Cardiomyopathies

Background: Diverse genetic backgrounds often lead to phenotypic heterogeneity in cardiomyopathies (CMPs). Previous genotype-phenotype studies have primarily focused on the analysis of a single phenotype, and the diagnostic and prognostic features of the CMP genotype across different phenotypic expressions remain poorly understood. Objectives: We sought to define differences in outcome prediction when stratifying patients based on phenotype at presentation compared with genotype in a large cohort of patients with CMPs and positive genetic testing. Methods: Dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy, left-dominant arrhythmogenic cardiomyopathy, and biventricular arrhythmogenic cardiomyopathy were examined in this study. A total of 281 patients (80% DCM) with pathogenic or likely pathogenic variants were included. The primary and secondary outcomes were: 1) all-cause mortality (D)/heart transplant (HT); 2) sudden cardiac death/major ventricular arrhythmias (SCD/MVA); and 3) heart failure-related death (DHF)/HT/left ventricular assist device implantation (LVAD). Results: Survival analysis revealed that SCD/MVA events occurred more frequently in patients without a DCM phenotype and in carriers of DSP, PKP2, LMNA, and FLNC variants. However, after adjustment for age and sex, genotype-based classification, but not phenotype-based classification, was predictive of SCD/MVA. LMNA showed the worst trends in terms of D/HT and DHF/HT/LVAD. Conclusions: Genotypes were associated with significant phenotypic heterogeneity in genetic cardiomyopathies. Nevertheless, in our study, genotypic-based classification showed higher precision in predicting the outcome of patients with CMP than phenotype-based classification. These findings add to our current understanding of inherited CMPs and contribute to the risk stratification of patients with positive genetic testing

Yersinia enterocolitica Serum Resistance Proteins YadA and Ail Bind the Complement Regulator C4b-Binding Protein

Many pathogens are equipped with factors providing resistance against the bactericidal action of complement. Yersinia enterocolitica, a Gram-negative enteric pathogen with invasive properties, efficiently resists the deleterious action of human complement. The major Y. enterocolitica serum resistance determinants include outer membrane proteins YadA and Ail. Lipopolysaccharide (LPS) O-antigen (O-ag) and outer core (OC) do not contribute directly to complement resistance. The aim of this study was to analyze a possible mechanism whereby Y. enterocolitica could inhibit the antibody-mediated classical pathway of complement activation. We show that Y. enterocolitica serotypes O:3, O:8, and O:9 bind C4b-binding protein (C4bp), an inhibitor of both the classical and lectin pathways of complement. To identify the C4bp receptors on Y. enterocolitica serotype O:3 surface, a set of mutants expressing YadA, Ail, O-ag, and OC in different combinations was tested for the ability to bind C4bp. The studies showed that both YadA and Ail acted as C4bp receptors. Ail-mediated C4bp binding, however, was blocked by the O-ag and OC, and could be observed only with mutants lacking these LPS structures. C4bp bound to Y. enterocolitica was functionally active and participated in the factor I-mediated degradation of C4b. These findings show that Y. enterocolitica uses two proteins, YadA and Ail, to bind C4bp. Binding of C4bp could help Y. enterocolitica to evade complement-mediated clearance in the human host

Observation of long ionizing tracks with the ICARUS T600 first half-module

F. Arneodo, B. Bade"ek, A. Badertscher, B. Baiboussinov, M. Baldo Ceolin, G. Battistoni, B. Bekman, P. Benetti, E. Bernardini, M. Bischofberger, A. Borio di Tigliole, R. Brunetti, A. Bueno, E. Calligarich, M. Campanelli, C. Carpanese, D. Cavalli, F. Cavanna, P. Cennini, S. Centro, A. Cesana, C. Chen, D. Chen, D.B. Chen, Y. Chen, D. Cline, Z. Dai, C. De Vecchi, A. Dabrowska, R. Dolfini*, M. Felcini, A. Ferrari, F. Ferri, Y. Ge, A. Gigli Berzolari, I. Gil-Botella, K. Graczyk, L. Grandi, K. He, J. Holeczek, X. Huang, C. Juszczak, D. Kie"czewska, J. Kisiel, T. Koz"owski, H. Kuna-Ciska", M. Laffranchi, J. Łagoda, Z. Li, F. Lu, J. Ma, M. Markiewicz, A. Martinez de la Ossa, C. Matthey, F. Mauri, D. Mazza, G. Meng, M. Messina, C. Montanari, S. Muraro, S. Navas-Concha, M. Nicoletto, G. Nurzia, S. Otwinowski, Q. Ouyang, O. Palamara, D. Pascoli, L. Periale, G. Piano Mortari, A. Piazzoli, P. Picchi, F. Pietropaolo, W. P ! o"ch"opek, T. Rancati, A. Rappoldi, G.L. Raselli, J. Rico, E. Rondio, M. Rossella, A. Rubbia, C. Rubbia, P. Sala, D. Scannicchio, E. Segreto, F. Sergiampietri, J. Sobczyk, J. Stepaniak, M. Szeptycka, M. Szleper, M. Szarska, M. Terrani, S. Ventura, C. Vignoli, H. Wang, M. W ! ojcik, J. Woo, G. Xu, Z. Xu, A. Zalewska, J. Zalipska, C. Zhang, Q. Zhang, S. Zhen, W. Zipper a INFN Laboratori Nazionali del Gran Sasso, s.s. 17bis Km 18+910, Assergi (L'Aquila), Italy b Institute of Experimental Physics, Warsaw University, Warszawa, Poland c Institute for Particle Physics, ETH H . onggerberg, Z . urich, Switzerland Dipartimento di Fisica e INFN, Universit " a di Padova, via Marzolo 8, Padova, Italy Dipartimento di Fisica e INFN, Universit " a di Milano, via Celoria 16, Milano, Italy f Institute of Physics, University of Silesia, Katowice, Poland Dipartimento di Fisica e INFN, Universit " a di Pavia, via Bassi 6, Pavia, Italy Dpto de F!isica Te ! orica y del Cosmos & C.A.F.P.E., Universidad de Granada, Avda. Severo Ochoa s/n, Granada, Spain Dipartimento di Fisica e INFN, Universit " a dell'Aquila, via Vetoio, L'Aquila, Italy CERN, CH-1211 Geneva 23, Switzerland Politecnico di Milano (CESNEF), Universit " a di Milano, via Ponzio 34/3, Milano, Ital