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Amaral M.M.,University of Buenos Aires | Sacerdoti F.,University of Buenos Aires | Jancic C.,CONICET | Repetto H.A.,Hospital Nacional Profesor Alejandro Posadas | And 3 more authors.
PLoS ONE | Year: 2013

The hemolytic uremic syndrome (HUS) associated with diarrhea is a complication of Shiga toxin (Stx)-producing Escherichia coli (STEC) infection. In Argentina, HUS is endemic and responsible for acute and chronic renal failure in children younger than 5 years old. The human kidney is the most affected organ due to the presence of very Stx-sensitive cells, such as microvascular endothelial cells. Recently, Subtilase cytotoxin (SubAB) was proposed as a new toxin that may contribute to HUS pathogenesis, although its action on human glomerular endothelial cells (HGEC) has not been described yet. In this study, we compared the effects of SubAB with those caused by Stx2 on primary cultures of HGEC isolated from fragments of human pediatric renal cortex. HGEC were characterized as endothelial since they expressed von Willebrand factor (VWF) and platelet/endothelial cell adhesion molecule 1 (PECAM-1). HGEC also expressed the globotriaosylceramide (Gb3) receptor for Stx2. Both, Stx2 and SubAB induced swelling and detachment of HGEC and the consequent decrease in cell viability in a time-dependent manner. Preincubation of HGEC with C-9 -a competitive inhibitor of Gb3 synthesis-protected HGEC from Stx2 but not from SubAB cytotoxic effects. Stx2 increased apoptosis in a time-dependent manner while SubAB increased apoptosis at 4 and 6 h but decreased at 24 h. The apoptosis induced by SubAB relative to Stx2 was higher at 4 and 6 h, but lower at 24 h. Furthermore, necrosis caused by Stx2 was significantly higher than that induced by SubAB at all the time points evaluated. Our data provide evidence for the first time how SubAB could cooperate with the development of endothelial damage characteristic of HUS pathogenesis. © 2013 Amaral et al.


Barrientos G.,University of Buenos Aires | Toro A.,University of Buenos Aires | Moschansky P.,Medicine University | Cohen M.,Laboratoire dHormonologie | And 6 more authors.
Placenta | Year: 2015

Introduction The development of the human haemochorial placenta requires complex regulatory mechanisms to protect invasive trophoblast cells from cytotoxic responses elicited by maternal immune cells. Leptin, the adipocyte derived hormone encoded by the Lep gene, is synthesized by placental trophoblasts and exerts pleiotropic effects on the immune system, including the promotion of inflammation and the activation of T cell responses. Methods To address its possible involvement in the modulation of maternal immune responses during pregnancy, we investigated the effect of leptin on the expression of the class Ib histocompatibility antigen HLA-G as one of the chief immunosuppressive strategies used by trophoblast cells. Results In vitro incubation of the trophoblast derived Swan 71 and JEG-3 cell lines with 25-50 ng/ml recombinant leptin significantly boosted HLA-G mRNA and protein expression, and this effect was abrogated upon pharmacological inhibition of the PI3K-Akt and MEK-Erk signaling pathways. A similar stimulatory effect of leptin was observed in term placental tissue explants, though 10-fold higher doses were required for stimulation. Further, JEG-3 cells treated with a leptin antisense oligodeoxynucleotide displayed decreased HLA-G expression levels, which were partially recovered by addition of stimulating doses of exogenous hormone. Immunofluorescence and qPCR analysis confirmed leptin biosynthesis in placental tissue, further showing that invasive extravillous trophoblast cells were a main source of this hormone during the first trimester of normal pregnancies. Discussion Taken together, our results show that leptin acts as an autocrine/paracrine signal promoting HLA-G expression in placental trophoblasts suggesting an important role in the regulation of immune evasion mechanisms at the fetal maternal interface. © 2015 Elsevier Ltd. All rights reserved.


Maymo J.L.,University of Buenos Aires | Perez Perez A.,University of Seville | Maskin B.,Hospital Nacional Profesor Alejandro Posadas | Duenas J.L.,Hospital Universitario Virgen Macarena | And 4 more authors.
PLoS ONE | Year: 2012

Pleiotropic effects of leptin have been identified in reproduction and pregnancy, particularly in the placenta, where it works as an autocrine hormone. In this work, we demonstrated that human chorionic gonadotropin (hCG) added to JEG-3 cell line or to placental explants induces endogenous leptin expression. We also found that hCG increased cAMP intracellular levels in BeWo cells in a dose-dependent manner, stimulated cAMP response element (CRE) activity and the cotransfection with an expression plasmid of a dominant negative mutant of CREB caused a significant inhibition of hCG stimulation of leptin promoter activity. These results demonstrate that hCG indeed activates cAMP/PKA pathway, and that this pathway is involved in leptin expression. Nevertheless, we found leptin induction by hCG is dependent on cAMP levels. Treatment with (Bu)2cAMP in combination with low and non stimulatory hCG concentrations led to an increase in leptin expression, whereas stimulatory concentrations showed the opposite effect. We found that specific PKA inhibition by H89 caused a significant increase of hCG leptin induction, suggesting that probably high cAMP levels might inhibit hCG effect. It was found that hCG enhancement of leptin mRNA expression involved the MAPK pathway. In this work, we demonstrated that hCG leptin induction through the MAPK signaling pathway is inhibited by PKA. We observed that ERK1/2 phosphorylation increased when hCG treatment was combined with H89. In view of these results, the involvement of the alternative cAMP/Epac signaling pathway was studied. We observed that a cAMP analogue that specifically activates Epac (CPT-OMe) stimulated leptin expression by hCG. In addition, the overexpression of Epac and Rap1 proteins increased leptin promoter activity and enhanced hCG. In conclusion, we provide evidence suggesting that hCG induction of leptin gene expression in placenta is mediated not only by activation of the MAPK signaling pathway but also by the alternative cAMP/Epac signaling pathway. © 2012 Maymó et al.


Monsalvo A.C.,Fundacion INFANT | Batalle J.P.,Fundacion INFANT | Lopez M.F.,Fundacion INFANT | Krause J.C.,Vanderbilt University | And 25 more authors.
Nature Medicine | Year: 2011

Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition-a marker of complement activation mediated by immune complexes-was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics. © 2011 Nature America, Inc. All rights reserved.


PubMed | Carol Davila University of Medicine and Pharmacy, Hospital Nacional Profesor Alejandro Posadas, Stanford University, National and Kapodistrian University of Athens and 19 more.
Type: Journal Article | Journal: Annals of gastroenterology : quarterly publication of the Hellenic Society of Gastroenterology | Year: 2017

We have established a multicenter international consortium to better understand the natural history of acute pancreatitis (AP) worldwide and to develop a platform for future randomized clinical trials.The AP patient registry to examine novel therapies in clinical experience (APPRENTICE) was formed in July 2014. Detailed web-based questionnaires were then developed to prospectively capture information on demographics, etiology, pancreatitis history, comorbidities, risk factors, severity biomarkers, severity indices, health-care utilization, management strategies, and outcomes of AP patients.Between November 2015 and September 2016, a total of 20 sites (8 in the United States, 5 in Europe, 3 in South America, 2 in Mexico and 2 in India) prospectively enrolled 509 AP patients. All data were entered into the REDCap (Research Electronic Data Capture) database by participating centers and systematically reviewed by the coordinating site (University of Pittsburgh). The approaches and methodology are described in detail, along with an interim report on the demographic results.APPRENTICE, an international collaboration of tertiary AP centers throughout the world, has demonstrated the feasibility of building a large, prospective, multicenter patient registry to study AP. Analysis of the collected data may provide a greater understanding of AP and APPRENTICE will serve as a future platform for randomized clinical trials.


PubMed | Hospital Nacional Profesor Alejandro Posadas and Hospital Mariano Y Luciano Of La Vega
Type: Journal Article | Journal: Archivos argentinos de pediatria | Year: 2017

Carbon monoxide is known as the silent murderer because it is a colorless and odorless gas. According to these characteristics, toxicity goes unnoticed which makes the diagnosis difficult. In most cases, the cold periods and group poisoning make suspect its presence because inappropriate heat both in home or public environments. Our goal is to inform about a mass carbon monoxide poisoning in a childrens parties room using a combustion source installed, not for the purpose of heating, but as a supply of light (generator), emphasizing that it can occur in any time of the year.


Rios F.G.,Hospital Nacional Profesor Alejandro Posadas | Risso-Vazquez A.,Sanatorio Otamendi Miroli | Alvarez J.,Hospital Universitario Austral | Vinzio M.,Sanatorio Trinidad San Isidro | And 3 more authors.
International Journal of Gynecology and Obstetrics | Year: 2012

Objective: To identify the reasons for admitting pregnant women to intensive care units (ICUs) in Buenos Aires, Argentina. Methods: The admission diagnoses of pregnant women hospitalized over 2 years at 4 ICUs were retrospectively studied. Results: During the studied period, 242 (3.9%) of the 6271 ICU patients were pregnant women, for an incidence of 8.1 per 1000 deliveries. The main reasons for admitting them at ICUs were hypertensive disorders, followed by postpartum hemorrhage and sepsis. More than a third (39.7%) was in a first pregnancy. The main nonobstetric reason for admission was pneumonia. The median pregnancy duration on admission was 36 weeks (range, 33-38 weeks) but it was less than 34 weeks for 66 (27.2%) of the women, 12.4% on whom required ventilation. Mortality was highest among those admitted for nonobstetric reasons (13.3% vs 0.5%; P < 0.05). The median stay for obstetric or nonobstetric conditions was 2 versus 5 days (range, 2-3 days vs 2-8 days) (P < 0.001). Conclusion: Postpartum hemorrhage and hypertensive disorders were the most common reasons for admitting pregnant women to an ICU, followed by sepsis. Nonobstetric causes of admission were associated with higher morbidity and mortality rates. © 2012 International Federation of Gynecology and Obstetrics.


Pezzano S.C.,University of Buenos Aires | Torres C.,University of Buenos Aires | Fainboim H.A.,Hospital F J Muniz | Bouzas M.B.,Hospital F J Muniz | And 6 more authors.
Clinical Microbiology and Infection | Year: 2011

Hepatitis B virus (HBV) is classified into eight major genotypes, A-H, which are geographically distributed worldwide. The aim of this work was to describe the clinical characteristics associated with the HBV genotypes circulating in Buenos Aires city. The study included 139 patients infected with HBV, whose clinical courses were classified as acute symptomatic self-limiting hepatitis, inactive carrier state and chronic active hepatitis (HBV e-antigen (HBeAg)-positive and HBeAg-negative). The HBV genotypes were determined in 128 patients by PCR-restriction fragment length polymorphism and phylogenetic analysis. Biochemical, virological, clinical and histological features were analysed. A differential distribution of genotypes between acute symptomatic and chronic infections was found. Among the acute cases, genotype F was predominant (65.2%, 30/46) and genotype D was rare (4.3%, 2/46), whereas among the chronic infections, a homogeneous distribution of genotypes A (26.8%, 22/82), D (31.7%, 26/82) and F (36.6%, 30/82), with an unusual presence of genotypes B (1.2%, 1/82) and C (3.7%, 3/82), was observed. Regarding the liver histology of chronically infected patients, genotype F tended to display higher histological activity indexes. Mutations related to HBV surface antigen immunoreactivity, antiviral resistance and HBeAg-negative status were studied. This work constitutes, to our knowledge, the first description of the clinical characteristics related to HBV genotypes in Argentina, where the distribution of genotypes in patients with acute infection has not been reported previously. Finally, it was established that genotype F is the prevalent genotype among the acute symptomatic infections in Buenos Aires city, and that it shows a tendency to cause an adverse disease outcome among the chronic cases. © 2010 The Authors. Journal Compilation © 2010 European Society of Clinical Microbiology and Infectious Diseases.


Ruffillo G.,Hospital Nacional Profesor Alejandro Posadas | Fassio E.,Hospital Nacional Profesor Alejandro Posadas | Alvarez E.,Hospital Nacional Profesor Alejandro Posadas | Landeira G.,Hospital Nacional Profesor Alejandro Posadas | And 3 more authors.
Journal of Hepatology | Year: 2011

Background & Aims: Liver biopsy (LB) is the only means to evaluate fibrosis in NAFLD. Two scoring systems, NAFLD fibrosis score and BARD score, were proposed to separate cases with and without severe fibrosis (SF). Our aim was to compare the utility of both scores in patients with biopsy-proven NAFLD. Methods: 138 consecutive patients of our series were included (67 male, median age 49 years). A NAFLD fibrosis score lower than -1.455 would exclude SF. A score greater than 0.676 would predict SF. An intermediate score is defined as indeterminate. The BARD score ranges from 0 to 4. Scores 0-1 are considered to have a high negative predictive value (NPV) for SF. The results of the scores were compared with LB staging. NPV, positive predictive value (PPV) and area under the ROC curve (AUROC) were calculated for both systems. Results: A total of 37 patients had SF. NAFLD fibrosis score was indeterminate in 42 cases. Among the 91 patients with low score, 74 did not have SF but 17 patients had SF. All of 5 patients with a high score had SF. Sensitivity was 22.7%; specificity, 100%; NPV, 81.3%; and PPV, 100%. The BARD score was low in 96 patients and high in 42. Among the 96 patients with a low score, 78 did not have SF but 18 did. Among 42 patients with a high score, 19 had SF. Sensitivity was 51.4%; specificity, 77.2%; NPV, 81.3%; and PPV, 45.2%. AUROC were 0.68 (95% CI, 0.57-0.78) and 0.67 (95% CI, 0.56-0.77) for NAFLD fibrosis and BARD scores, respectively. Conclusions: Both systems were useful in identifying patients without SF (NPV 81.3%) but the BARD score is easier to estimate and does not have indeterminate results. © 2010 European Association for the Study of the Liver.

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