Impact of treatment on myocardial lysyl oxidase expression and collagen cross-linking in patients with heart failure

The aim of this study was to investigate whether torasemide modifies collagen cross-linking in the failing human heart. We analyzed the degree of cross-linking and the expression of the enzyme lysyl oxidase, which regulates cross-linking, in the myocardium of patients with chronic heart failure at baseline and after 8 months of treatment with either torasemide or furosemide in addition to their standard heart failure therapy. Whereas lysyl oxidase protein expression was very scarce in normal hearts, it was highly expressed in failing hearts. Cross-linking was increased (P<0.001) in heart failure patients compared with normal hearts. These 2 parameters decreased (P=0.021 and P=0.034) in torasemide-treated patients and remained unchanged in furosemide-treated patients. In addition, more (P=0.009) patients showed normalization of left ventricular chamber stiffness in the torasemide subgroup than in the furosemide subgroup after treatment. Lysyl oxidase expression correlated with cross-linking (r=0.661; P<0.001), and cross-linking correlated with left ventricular chamber stiffness (r=0.452; P=0.002) in all patients. These findings show for the first time that lysyl oxidase overexpression is associated with enhanced collagen cross-linking in the failing human heart. In addition, we report that the ability of torasemide to correct both lysyl oxidase overexpression and enhanced collagen cross-linking results in normalization of left ventricular chamber stiffness in patients with heart failure. Lysyl oxidase may thus represent a target for reduction of stiff collagen and improvement of left ventricular mechanical properties in heart failure patients

Association of cardiotrophin-1 with myocardial fibrosis in hypertensive patients with heart failure

Cardiotrophin-1 has been shown to be profibrogenic in experimental models. The aim of this study was to analyze whether cardiotrophin-1 is associated with left ventricular end-diastolic stress and myocardial fibrosis in hypertensive patients with heart failure. Endomyocardial biopsies from patients (n=31) and necropsies from 7 control subjects were studied. Myocardial cardiotrophin-1 protein and mRNA and the fraction of myocardial volume occupied by collagen were increased in patients compared with controls ( P <0.001). Cardiotrophin-1 overexpression in patients was localized in cardiomyocytes. Cardiotrophin-1 protein was correlated with collagen type I and III mRNAs ( r =0.653, P <0.001; r =0.541, P <0.01) and proteins ( r =0.588, P <0.001; r =0.556, P <0.005) in all subjects and with left ventricular end-diastolic wall stress ( r =0.450; P <0.05) in patients. Plasma cardiotrophin-1 and N-terminal pro-brain natriuretic peptide and serum biomarkers of myocardial fibrosis (carboxy-terminal propeptide of procollagen type I and amino-terminal propeptide of procollagen type III) were increased ( P <0.001) in patients compared with controls. Plasma cardiotrophin-1 was correlated with N-terminal pro-brain natriuretic peptide ( r =0.386; P <0.005), carboxy- terminal propeptide of procollagen type I ( r =0.550; P <0.001), and amino-terminal propeptide of procollagen type III ( r =0.267; P <0.05) in all subjects. In vitro, cardiotrophin-1 stimulated the differentiation of human cardiac fibroblast to myofibroblasts ( P <0.05) and the expression of procollagen type I ( P <0.05) and III ( P <0.01) mRNAs. These findings show that an excess of cardiotrophin-1 is associated with increased collagen in the myocardium of hypertensive patients with heart failure. It is proposed that exaggerated cardiomyocyte production of cardiotrophin-1 in response to increased left ventricular end-diastolic stress may contribute to fibrosis through stimulation of fibroblasts in heart failure of hypertensive origi

Altered cardiac expression of peroxisome proliferator-activated receptor-isoforms in patients with hypertensive heart disease

OBJECTIVE: To investigate whether cardiac expression of the nuclear peroxisome proliferator-activated receptor alpha (PPARalpha) is altered in patients with hypertensive heart disease (HHD). METHODS: We studied endomyocardial septal biopsies from 24 patients with essential hypertension divided into three groups: 6 without left ventricular hypertrophy (LVH) (HT group), 10 with LVH (LVH group), and 8 with LVH and heart failure (HF) (HF group). The expression of two PPARalpha isoforms (the native active and the truncated inhibitory) was analyzed by Western blot and reverse transcription polymerase chain reaction (RT-PCR), and two PPARalpha target genes were evaluated by RT-PCR. Histomorphological features were evaluated in a second myocardial sample from LVH and HF groups. RESULTS: Whereas the expression of native PPARalpha protein was lower (p<0.05) in LVH and HF groups than in the HT group, truncated PPARalpha protein was overexpressed (p<0.001) in the HF group as compared with LVH and HT groups. The mRNA expression of native and truncated PPARalpha was similar in the three groups of hypertensives. In addition, a progressive decrease (p for trend<0.05) in the two PPARalpha target genes mRNA expression was observed among HT, LVH and HF groups. The amount of truncated PPARalpha protein correlates directly with cardiomyocytes apoptosis and inversely with cardiomyocytes density in patients with HHD. In addition, the expression of truncated PPARalpha protein was directly correlated with left ventricular volumes, and inversely with ejection fraction in all hypertensives. CONCLUSIONS: These findings suggest that post-transcriptional regulation of PPARalpha isoforms is altered in patients with HHD, namely in those developing HF. An excess of the truncated inhibitory isoform may be involved in hypertensive left ventricular failure and remodeling

Contribution of polymorphisms in IFNG and TNF to complications of the allogeneic hematopoietic stem cell transplantation with sibling donors

Las complicaciones del trasplante alogénico de células progenitoras hematopoyéticas (TACPH) relacionado incluyen tiempos variables de engraftment,enfermedad injerto contra huésped (EICH), infeccionesbacterianas y reactivación de citomegalovirus(CMV), entre otras. La existencia de polimorfismosen genes no HLA que codifican citoquinas proinflamatoriastales como el factor de necrosis tumoralalfa (TNF) e interferón gamma (IFNG) condicionaría la aparición de estas complicaciones. Se evaluóel impacto de la variante +1349 CAn del gen INFG y del polimorfismo -308 G/A de TNF en el engraftment y en la EICH en 148 receptores de TACPHrealizados en los centros participantes. Con respecto al engraftment tardío (≥15 días), el análisis multivariado confirmó el poder predictivo desfavorable del genotipo CAno12/no12 (baja producción) de IFNG(OR 3,9; p=0,003), médula ósea (MO) como fuente de células progenitoras (OR 4,6; p=0,013) y bacteriemia (OR 3,0; p=0,033). En relación a EICHa 3-4,las variables independientes fueron el genotipo de baja producción de IFNG (OR 0,1; p=0,008), bacteriemia (OR 3,3; p=0,048) y presencia de CMV(OR3,3; p=0,046). Y con respecto a EICHc, el riesgo fue influenciado por el genotipo -308 GG (producción baja) de TNF (OR 3,3; p=0,038), SP como fuente (OR 5,0; p=0,028), acondicionamiento mieloablativo (OR 3,3; p=0,014) y antecedente de EICHa 2-4 (OR 2,6; p=0,029). Aunque es necesario confirmar estos hallazgos, el genotipo de baja producción de IFNG se asoció con engraftment tardío y menor EICHa, mientras que los genotipos de baja producción de TNF se relacionaron con mayor incidencia de EICHc. Las variantes polimórficas estudiadas contribuirían al desarrollo de complicaciones en pacientes con TACPH relacionado.Complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) include variable engraftment times, acute (aGVHD) and chronic (cGVHD) graft-versus-host diseases, bacterial infections and reactivation of cytomegalovirus (CMV), among others. The existence of polymorphisms in non-HLA genes that encode pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF) and interferon gamma (IFNG) would condition the appearance of these complications. The impact of polymorphic variants +1349 CAn of INFG gene and -308 G/A of TNF was evaluated on the engraftment and GVHD in 148 allo-HSCT recipients with sibling donors. In the multivariate analysis, the genotype CAno12/no12 (low production) of INFG (OR 3.9, p=0.003), bone marrow (BM) as source of progenitor cells (OR 4.6, p=0.013) and bacteremia (OR 3.0, p=0.033) maintained their predictive power with respect to late engraftment (≥15 days). Genotype of low IFNG production (OR 0.1, p=0.008), bacteremia (OR 3.3, p=0.048) and presence of CMV (OR 3.3, p=0.046) showed a significant association with aGVHD 3-4. And with respect to cGVHD, the genotype -308 GG (low production) of TNF (OR 3.3, p=0.038), PB as source (OR 5.0, p=0.028), myeloablative conditioning (OR 3.3, p=0.014) and previous aGVHD 2-4 (OR 2.6, p=0.029). Although it is necessary to confirm these findings, the genotype of lower IFNG production was associated with a later engraftment and less severe aGVHD and genotypes of lower TNF production was related to a higher incidence of cGVHD contributing to the development of complications in allo-HSCT.Fil: Palau Nagore, Maria Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Berro, Mariano. Universidad Austral; ArgentinaFil: Bestach, Yesica Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Rivas, M.M.. Universidad Austral; ArgentinaFil: Foncuberta, C.. Instituto Alexander Fleming; ArgentinaFil: Vitriu, A.. Instituto Alexander Fleming; ArgentinaFil: Remaggi, G.. Fundaleu; ArgentinaFil: Martínez Rolón, J.. Fundaleu; ArgentinaFil: Jaimovich, Sebastian Gaston. Fundación Favaloro; ArgentinaFil: Requejo, A.. Fundación Favaloro; ArgentinaFil: Padros, K.. Primer Centro Argentino de Inmunogenética; ArgentinaFil: Rodríguez, M.B.. Primer Centro Argentino de Inmunogenética; ArgentinaFil: Kusminsky, G.. Universidad Austral; ArgentinaFil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Belli, Carolina Bárbara. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

RICORS2040 : The need for collaborative research in chronic kidney disease

Chronic kidney disease (CKD) is a silent and poorly known killer. The current concept of CKD is relatively young and uptake by the public, physicians and health authorities is not widespread. Physicians still confuse CKD with chronic kidney insufficiency or failure. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. Thus health authorities may consider CKD a non-issue: very few persons eventually need KRT and, for those in whom kidneys fail, the problem is 'solved' by dialysis or kidney transplantation. However, KRT is the tip of the iceberg in the burden of CKD. The main burden of CKD is accelerated ageing and premature death. The cut-off points for kidney function and kidney damage indexes that define CKD also mark an increased risk for all-cause premature death. CKD is the most prevalent risk factor for lethal coronavirus disease 2019 (COVID-19) and the factor that most increases the risk of death in COVID-19, after old age. Men and women undergoing KRT still have an annual mortality that is 10- to 100-fold higher than similar-age peers, and life expectancy is shortened by ~40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth greatest global cause of death by 2040 and the second greatest cause of death in Spain before the end of the century, a time when one in four Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded Centres for Biomedical Research (CIBER) network structure in Spain. Realizing the underestimation of the CKD burden of disease by health authorities, the Decade of the Kidney initiative for 2020-2030 was launched by the American Association of Kidney Patients and the European Kidney Health Alliance. Leading Spanish kidney researchers grouped in the kidney collaborative research network Red de Investigación Renal have now applied for the Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) call for collaborative research in Spain with the support of the Spanish Society of Nephrology, Federación Nacional de Asociaciones para la Lucha Contra las Enfermedades del Riñón and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true

Acute rhabdomyolysis and delayed pericardial effusion in an Italian patient with Ebola virus disease : a case report

Background: During the 2013-2016 West Africa Ebola virus disease (EVD) epidemic, some EVD patients, mostly health care workers, were evacuated to Europe and the USA. Case presentation: In May 2015, a 37-year old male nurse contracted Ebola virus disease in Sierra Leone. After Ebola virus detection in plasma, he was medically-evacuated to Italy. At admission, rhabdomyolysis was clinically and laboratory-diagnosed and was treated with aggressive hydration, oral favipiravir and intravenous investigational monoclonal antibodies against Ebola virus. The recovery clinical phase was complicated by a febrile thrombocytopenic syndrome with pericardial effusion treated with corticosteroids for 10days and indomethacin for 2months. No evidence of recurrence is reported. Conclusions: A febrile thrombocytopenic syndrome with pericardial effusion during the recovery phase of EVD appears to be uncommon. Clinical improvement with corticosteroid treatment suggests that an immune-mediated mechanism contributed to the pericardial effusion

Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network

Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time, and attempts to address it require a clear understanding of how ecological communities respond to environmental change across time and space. While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes, vast areas of the tropics remain understudied. In the American tropics, Amazonia stands out as the world's most diverse rainforest and the primary source of Neotropical biodiversity, but it remains among the least known forests in America and is often underrepresented in biodiversity databases. To worsen this situation, human-induced modifications may eliminate pieces of the Amazon's biodiversity puzzle before we can use them to understand how ecological communities are responding. To increase generalization and applicability of biodiversity knowledge, it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple organism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region's vulnerability to environmental change. 15%–18% of the most neglected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lost