Mycobacteria Target DC-SIGN to Suppress Dendritic Cell Function

Mycobacterium tuberculosis represents a world-wide health risk and immunosuppression is a particular problem in M. tuberculosis infections. Although macrophages are primarily infected, dendritic cells (DCs) are important in inducing cellular immune responses against M. tuberculosis. We hypothesized that DCs represent a target for M. tuberculosis and that the observed immuno-suppression results from modulation of DC functions. We demonstrate that the DC-specific C-type lectin DC-SIGN is an important receptor on DCs that captures and internalizes intact Mycobacterium bovis bacillus Calmette-Guérin (BCG) through the mycobacterial cell wall component ManLAM. Antibodies against DC-SIGN block M. bovis BCG infection of DCs. ManLAM is also secreted by M. tuberculosis–infected macrophages and has been implicated as a virulence factor. Strikingly, ManLAM binding to DC-SIGN prevents mycobacteria- or LPS-induced DC maturation. Both mycobacteria and LPS induce DC maturation through Toll-like receptor (TLR) signaling, suggesting that DC-SIGN, upon binding of ManLAM, interferes with TLR-mediated signals. Blocking antibodies against DC-SIGN reverse the ManLAM-mediated immunosuppressive effects. Our results suggest that M. tuberculosis targets DC-SIGN both to infect DCs and to down-regulate DC-mediated immune responses. Moreover, we demonstrate that DC-SIGN has a broader pathogen recognition profile than previously shown, suggesting that DC-SIGN may represent a molecular target for clinical intervention in infections other than HIV-1

Dermatosis terra firma-forme

Se presenta un caso de dermatosis terra firma-forme (DTFF), patología benigna de etiología desconocida, que toma su nombre de la coloración pardusca que remeda tierra o suciedad

European Project on Osteoarthritis (EPOSA): methodological challenges in harmonization of existing data from five European population-based cohorts on aging

BackgroundThe European Project on OSteoArthritis (EPOSA), here presented for the first time, is a collaborative study involving five European cohort studies on aging. This project focuses on the personal and societal burden and its determinants of osteoarthritis (OA). The aim of the current report is to describe the purpose of the project, the post harmonization of the cross-national data and methodological challenges related to the harmonization process MethodsThe study includes data from cohort studies in five European countries (Germany, Italy, the Netherlands, Spain and the United Kingdom) on older community-dwelling persons aged ? 59 years. The study design and main characteristics of the five cohort studies are described. Post harmonization algorithms are developed by finding a "common denominator" to merge the datasets and weights are calculated to adjust for differences in age and sex distribution across the datasets. ResultsA harmonized database was developed, consisting of merged data from all participating countries. In total, 10107 persons are included in the harmonized dataset with a mean age of 72.8 years (SD 6.1). The female/male ratio is 53.3/46.7%. Some variables were difficult to harmonize due to differences in wording and categories, differences in classifications and absence of data in some countries. The post harmonization algorithms are described in detail in harmonization guidelines attached to this paper. ConclusionsThere was little evidence of agreement on the use of several core data collection instruments, in particular on the measurement of OA. The heterogeneity of OA definitions hampers comparing prevalence rates of OA, but other research questions can be investigated using high quality harmonized data. By publishing the harmonization guidelines, insight is given into (the interpretation of) all post harmonized data of the EPOSA study. <br/

The clinical relevance of oliguria in the critically ill patient : Analysis of a large observational database

Funding Information: Marc Leone reports receiving consulting fees from Amomed and Aguettant; lecture fees from MSD, Pfizer, Octapharma, 3 M, Aspen, Orion; travel support from LFB; and grant support from PHRC IR and his institution. JLV is the Editor-in-Chief of Critical Care. The other authors declare that they have no relevant financial interests. Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Urine output is widely used as one of the criteria for the diagnosis and staging of acute renal failure, but few studies have specifically assessed the role of oliguria as a marker of acute renal failure or outcomes in general intensive care unit (ICU) patients. Using a large multinational database, we therefore evaluated the occurrence of oliguria (defined as a urine output 16 years) patients in the ICON audit who had a urine output measurement on the day of admission were included. To investigate the association between oliguria and mortality, we used a multilevel analysis. Results: Of the 8292 patients included, 2050 (24.7%) were oliguric during the first 24 h of admission. Patients with oliguria on admission who had at least one additional 24-h urine output recorded during their ICU stay (n = 1349) were divided into three groups: transient - oliguria resolved within 48 h after the admission day (n = 390 [28.9%]), prolonged - oliguria resolved > 48 h after the admission day (n = 141 [10.5%]), and permanent - oliguria persisting for the whole ICU stay or again present at the end of the ICU stay (n = 818 [60.6%]). ICU and hospital mortality rates were higher in patients with oliguria than in those without, except for patients with transient oliguria who had significantly lower mortality rates than non-oliguric patients. In multilevel analysis, the need for RRT was associated with a significantly higher risk of death (OR = 1.51 [95% CI 1.19-1.91], p = 0.001), but the presence of oliguria on admission was not (OR = 1.14 [95% CI 0.97-1.34], p = 0.103). Conclusions: Oliguria is common in ICU patients and may have a relatively benign nature if only transient. The duration of oliguria and need for RRT are associated with worse outcome.publishersversionPeer reviewe

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients

Background: Mortality due to COVID-19 is high, especially in patients requiring mechanical ventilation. The purpose of the study is to investigate associations between mortality and variables measured during the first three days of mechanical ventilation in patients with COVID-19 intubated at ICU admission. Methods: Multicenter, observational, cohort study includes consecutive patients with COVID-19 admitted to 44 Spanish ICUs between February 25 and July 31, 2020, who required intubation at ICU admission and mechanical ventilation for more than three days. We collected demographic and clinical data prior to admission; information about clinical evolution at days 1 and 3 of mechanical ventilation; and outcomes. Results: Of the 2,095 patients with COVID-19 admitted to the ICU, 1,118 (53.3%) were intubated at day 1 and remained under mechanical ventilation at day three. From days 1 to 3, PaO2/FiO2 increased from 115.6 [80.0-171.2] to 180.0 [135.4-227.9] mmHg and the ventilatory ratio from 1.73 [1.33-2.25] to 1.96 [1.61-2.40]. In-hospital mortality was 38.7%. A higher increase between ICU admission and day 3 in the ventilatory ratio (OR 1.04 [CI 1.01-1.07], p = 0.030) and creatinine levels (OR 1.05 [CI 1.01-1.09], p = 0.005) and a lower increase in platelet counts (OR 0.96 [CI 0.93-1.00], p = 0.037) were independently associated with a higher risk of death. No association between mortality and the PaO2/FiO2 variation was observed (OR 0.99 [CI 0.95 to 1.02], p = 0.47). Conclusions: Higher ventilatory ratio and its increase at day 3 is associated with mortality in patients with COVID-19 receiving mechanical ventilation at ICU admission. No association was found in the PaO2/FiO2 variation

Comparación de distintas estrategias para la predicción de muerte a corto plazo en el paciente anciano infectado

Objective. The aim of this study was to determine the utility of a post hoc lactate added to SIRS and qSOFA score to predict 30-day mortality in older non-severely dependent patients attended for infection in the Emergency Department (ED). Methods. We performed an analytical, observational, prospective cohort study including patients of 75 years of age or older, without severe functional dependence, attended for an infectious disease in 69 Spanish ED for 2-day three seasonal periods. Demographic, clinical and analytical data were collected. The primary outcome was 30-day mortality after the index event. Results. We included 739 patients with a mean age of 84.9 (SD 6.0) years; 375 (50.7%) were women. Ninety-one (12.3%) died within 30 days. The AUC was 0.637 (IC 95% 0.587-0.688; p= 2 and 0.698 (IC 95% 0.635- 0.761; p= 2. Comparing receiver operating characteristic (ROC) there was a better accuracy of qSOFA vs SIRS (p=0.041). Both scales improve the prognosis accuracy with lactate inclusion. The AUC was 0.705 (IC95% 0.652-0.758; p<0.001) for SIRS plus lactate and 0.755 (IC95% 0.696-0.814; p<0.001) for qSOFA plus lactate, showing a trend to statistical significance for the second strategy (p=0.0727). Charlson index not added prognosis accuracy to SIRS (p=0.2269) or qSOFA (p=0.2573). Conclusions. Lactate added to SIRS and qSOFA score improve the accuracy of SIRS and qSOFA to predict short-term mortality in older non-severely dependent patients attended for infection. There is not effect in adding Charlson index

Absence of the hemochromatosis gene Cys282Tyr mutation in three ethnic groups from Algeria (Mzab), Ethiopia, and Senegal

A Celtic origin for hemochromatosis, a common genetic iron metabolism disorder, has been postulated for a long time. To check whether the two mutations recently identified in the HLA-class I candidate gene for this disease were found only in Caucasians, we examined their frequencies in individuals originating from Algeria, Ethiopia, and Senegal. The presumably disease-causing mutation, responsible for the Cys282Tyr substitution, was not found in any member of these ethnic groups, although it was shown to be highly prevalent in populations of European ancestry. This geographic distribution supports the previously suggested Celtic origin for the disease. In contrast, the mutation responsible for the His63Asp substitution is not restricted to European populations. Although absent in the Senegalese, it was found on about 9% of the chromosomes of the Central Ethiopians and Algerians (Mzab) genotyped for this study. This second mutation, which probably represents a common variant unrelated to hemochromatosis, thus appears to have occurred earlier than that responsible for the Cys282Tyr substitution. More detailed population studies are needed to provide information on the age of these two mutations and eventually show how the hemochromatosis-causing mutation chronologically spread throughout Europe

Genistein inhibits PDGF-stimulated proteoglycan synthesis in vascular smooth muscle without blocking PDGFβ receptor phosphorylation

The signaling pathways that regulate the synthesis and structure of proteoglycans secreted by vascular smooth muscle cells are potential therapeutic targets for preventing lipid deposition in the early stage of atherosclerosis. PDGF stimulates both core protein expression and elongation of glycosaminoglycan (GAG) chains on proteoglycans. In this study we investigated the effects of the tyrosine kinase inhibitor genistein on PDGF mediated receptor phosphorylation and proteoglycan synthesis in human vascular smooth muscle cells. We demonstrate that genistein does not block phosphorylation of the activation site of the PDGF receptor at Tyr857 and two other downstream sites Tyr 751 and Tyr1021. Genistein blocked PDGF-mediated proteoglycan core protein synthesis however it had no effect on GAG chain elongation. These results differ markedly to two other tyrosine kinase inhibitors, imatinib and Ki11502, that block PDGF receptor phosphorylation and PDGF mediated GAG elongation. We conclude that the action of genistein on core protein synthesis does not involve the PDGF receptor and that PDGF mediates GAG elongation via the PDGF receptor