Cellular Basis of Aging in the Mammalian Heart

This review is concerned with the functional and structural changes occurring in the aging heart. These changes were investigated in an integrated fashion in Fischer 344 rats at 4, 12, 20, and 29 months after birth. Mean arterial pressure, left ventricular systolic and end-diastolic pressures, as well as stroke volume remained substantially constant up to 20 months. At 29 months, however, end-diastolic pressure was significantly increased, and dP/dt and stroke volume were depressed. Focal areas of interstitial and replacement fibrosis were markedly increased at 20 and 29 months, mostly in the subendocardial region of the ventricular wall. Also the aggregate number of mononucleated and binucleated cells in the left ventricle as a function of age was determined. The number of mononucleated cells increased up to 20 months but decreased thereafter; the binucleated cells showed a reversed pattern. The aging process of the heart involves a number of interrelated events including biochemical, electrical, mechanical and structural modifications. With aging and senescence, left ventricular failure develops in the Fischer rat model, and a similar process may occur in the human as well

Laparoscopic One-Stage vs Endoscopic Plus Laparoscopic Management of Common Bile Duct Stones – A Prospective Randomized Study

Improvements in diagnostic and operative approach to CBD stones associated with cholelithiasis allow the surgeon to treat in a single stage the disease through a laparoscopic approach, The AA report the results of a prospective randomised study comparing this approach to a a double stage endoscopic plus laparoscopic cholecistectomy in 124 patients. techniques and procedures are referred and the results are statistically analysed. the outcome of the two procedures were recorded as success or failure according to the complete clearance of the CB

Whole Lung Irradiation after High-Dose Busulfan/Melphalan in Ewing Sarcoma with Lung Metastases: An Italian Sarcoma Group and Associazione Italiana Ematologia Oncologia Pediatrica Joint Study

SIMPLE SUMMARY: The lung is the most frequent site of metastasis in Ewing sarcoma, the second most common bone cancer affecting children, adolescents and young adults. The five-year overall survival of patients with isolated lung metastasis is approximately 50% after multimodal treatments including chemotherapy, surgery and radiotherapy. This retrospective study aimed to investigate the feasibility and the predictors of survival in 68 Ewing sarcoma patients with lung metastases who received high-dose chemotherapy with busulfan and melphalan, followed by reduced dose whole-lung irradiation, as part of two prospective and consecutive treatment protocols. This combined treatment strategy is feasible and might contribute to the disease control in lung metastatic Ewing sarcoma with responsive disease. Furthermore, the results of this study provide support to explore the treatment stratification for lung metastatic Ewing sarcoma based on the histological response of the primary tumor. ABSTRACT: Purpose: To analyze toxicity and outcome predictors in Ewing sarcoma patients with lung metastases treated with busulfan and melphalan (BU-MEL) followed by whole-lung irradiation (WLI). Methods: This retrospective study included 68 lung metastatic Ewing Sarcoma patients who underwent WLI after BU-MEL with autologous stem cell transplantation, as part of two prospective and consecutive treatment protocols. WLI 12 Gy for <14 years old and 15 Gy for ≥14 years old patients were applied at least eight weeks after BU-MEL. Toxicity, overall survival (OS), event-free survival (EFS) and pulmonary relapse-free survival (PRFS) were estimated and analyzed. Results: After WLI, grade 1–2 and grade 3 clinical toxicity was reported in 16.2% and 5.9% patients, respectively. The five-year OS, EFS and PRFS with 95% confidence interval (CI) were 69.8% (57.1–79.3), 61.2% (48.4–71.7) and 70.5% (56.3–80.8), respectively. Patients with good histological necrosis of the primary tumor after neoadjuvant chemotherapy showed a significant decreased risk of pulmonary relapse or death compared to patients with poor histological necrosis. Conclusions: WLI at recommended doses and time interval after BU-MEL is feasible and might contribute to the disease control in Ewing sarcoma with lung metastases and responsive disease. Further studies are needed to explore the treatment stratification based on the histological response of the primary tumor

Representing social and political life during the pandemic. Education, body, ideology, politics and beliefs in Argentina (2020-2021)

En este artículo se desarrollan algunos hallazgos y dimensiones derivadas del trabajo realizado en la primera parte del proyecto “Identidades, experiencias y discursos sociales en conflicto en torno a la pandemia y la pos-pandemia: un estudio multidimensional sobre las incertidumbres, odios, solidaridades, cuidados y expectativas desiguales en todas las regiones de Argentina” que forma parte del “Programa de Investigación de la Sociedad Argentina Contemporánea. Las ciencias sociales y humanas en la crisis COVID-19”. Específicamente, este artículo está realizado por los equipos de investigación del nodo Facultad de Humanidades y Ciencias de la Educación - Universidad Nacional de La Plata que responden a cuatro subredes temáticas: educación, cuerpo, creencias e ideologías, identidades y pasiones políticas. El objetivo es conocer diversas representaciones sociales en el contexto de la pandemia. En cuanto a la metodología, se realizaron entrevistas semi-estructuradas a personas con diferentes características sociodemográficas del país. Se concluye que tanto la temporalidad como la emocionalidad aparecen vinculadas con las representaciones situadas relevadas desde las cuatro subredes temáticas.This paper develops some findings and dimensions derived from the work carried out in the first part of the Project "Identities, experiences and social discourses in conflict around the pandemic and post-pandemic: a multidimensional study on uncertainties, hatred, solidarity, care and unequal expectations in all regions of Argentina" that is part of the "Research Program of the Contemporary Argentine Society. The social and human sciences in the COVID-19 crisis". Specifically, this article is made by the research teams of the Facultad de Humanidades y Ciencias de la Educación - Universidad Nacional de La Plata, that respond to four thematic subnets: Education, Body, Beliefs, Ideologies, identities and political passions. The objective is to know different social representations in the context of the pandemic. As regards the methodology, semi-structured interviews were made to people having different sociodemographic characteristics of the country. It may be concluded that both temporality and emotionality are related with the situated representations collected from the four thematic subnets.Fil: Bracco, Olga Natividad. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Centro de Investigaciones Socio Históricas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Capasso, Veronica Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Humanidades y Ciencias Sociales. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales; ArgentinaFil: Causa, Matias Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Humanidades y Ciencias Sociales. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales; ArgentinaFil: Di Piero, María Emilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Humanidades y Ciencias Sociales. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales; ArgentinaFil: Esquivel, Juliana. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Centro Interdisciplinario de Investigaciones de Género; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Humanidades y Ciencias Sociales. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales; ArgentinaFil: Ferrero Verzulli, Mario. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Centro de Investigaciones Socio Históricas; ArgentinaFil: Miño Chiappino, Jessica Sheila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Humanidades y Ciencias Sociales. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales; ArgentinaFil: Mora, Ana Sabrina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Humanidades y Ciencias Sociales. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales; ArgentinaFil: Porta Fernandez, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Humanidades y Ciencias Sociales. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales; ArgentinaFil: Saez, Mariana Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones en Humanidades y Ciencias Sociales. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación. Instituto de Investigaciones en Humanidades y Ciencias Sociales; Argentin

Representing social and political life during the pandemic: Education, body, ideology, politics and beliefs in Argentina (2020-2021)

En este artículo se desarrollan algunos hallazgos y dimensiones derivadas del trabajo realizado en la primera parte del proyecto “Identidades, experiencias y discursos sociales en conflicto en torno a la pandemia y la pos-pandemia: un estudio multidimensional sobre las incertidumbres, odios, solidaridades, cuidados y expectativas desiguales en todas las regiones de Argentina” que forma parte del “Programa de Investigación de la Sociedad Argentina Contemporánea. Las ciencias sociales y humanas en la crisis COVID-19”. Específicamente, este artículo está realizado por los equipos de investigación del nodo Facultad de Humanidades y Ciencias de la Educación - Universidad Nacional de La Plata que responden a cuatro subredes temáticas: educación, cuerpo, creencias e ideologías, identidades y pasiones políticas. El objetivo es conocer diversas representaciones sociales en el contexto de la pandemia. En cuanto a la metodología, se realizaron entrevistas semi-estructuradas a personas con diferentes características sociodemográficas del país. Se concluye que tanto la temporalidad como la emocionalidad aparecen vinculadas con las representaciones situadas relevadas desde las cuatro subredes temáticas.This paper develops some findings and dimensions derived from the work carried out in the first part of the Project "Identities, experiences and social discourses in conflict around the pandemic and post-pandemic: a multidimensional study on uncertainties, hatred, solidarity, care and unequal expectations in all regions of Argentina" that is part of the "Research Program of the Contemporary Argentine Society. The social and human sciences in the COVID-19 crisis". Specifically, this article is made by the research teams of the Facultad de Humanidades y Ciencias de la Educación - Universidad Nacional de La Plata, that respond to four thematic subnets: Education, Body, Beliefs, Ideologies, identities and political passions. The objective is to know different social representations in the context of the pandemic. As regards the methodology, semi-structured interviews were made to people having different sociodemographic characteristics of the country. It may be concluded that both temporality and emotionality are related with the situated representations collected from the four thematic subnets.Facultad de Periodismo y Comunicación Socia

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor