60 research outputs found
Autoantibodies against type I IFNs in patients with life-threatening COVID-19
Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men
CFPâ1 interacts with HDAC1/2 complexes in C. elegans development
CXXC finger binding protein 1 (CFPâ1) is an evolutionarily conserved protein that binds to nonâmethylated CpGârich promoters in mammals and Caenorhabditis elegans. This conserved epigenetic regulator is part of the COMPASS complex that contains the H3K4me3 methyltransferase SET1 in mammals and SETâ2 in C. elegans. Previous studies have indicated the importance of CFP1 in embryonic stem cell differentiation and cell fate specification. However, neither the function nor the mechanism of action of CFP1 is well understood at the organismal level. Here, we have used cfpâ1(tm6369) and setâ2(bn129) C. elegans mutants to investigate the function of CFPâ1 in gene induction and development. We have characterised C. elegansCOMPASS mutants cfpâ1(tm6369) and setâ2(bn129) and found that both cfpâ1 and setâ2 play an important role in the regulation of fertility and development of the organism. Furthermore, we found that both cfpâ1 and setâ2 are required for H3K4 trimethylation and play a repressive role in the expression of heat shock and saltâinducible genes. Interestingly, we found that cfpâ1 but not setâ2 genetically interacts with histone deacetylase (HDAC1/2) complexes to regulate fertility, suggesting a function of CFPâ1 outside of the COMPASS complex. Additionally, we found that cfpâ1 and setâ2 independently regulate fertility and development of the organism. Our results suggest that CFPâ1 genetically interacts with HDAC1/2 complexes to regulate fertility, independent of its function within the COMPASS complex. We propose that CFPâ1 could cooperate with the COMPASS complex and/or HDAC1/2 in a contextâdependent manner
Delineation of the insulin-responsive sequence in the rat cytosolic aspartate aminotransferase gene: binding sites for hepatocyte nuclear factor-3 and nuclear factor I.
Expression of the rat cytosolic aspartate aminotransferase gene is stimulated by glucocorticoids and repressed by insulin in the liver. The regulation by insulin and part of the glucocorticoid effect are mediated by a distal region in the promoter. A 142 bp fragment (-1844 to -1702) confers hormonal sensitivity to the heterologous thymidine kinase promoter in transient-transfection assays in H4IIEC3 hepatoma cells. Footprinting and gel-shift assays showed that several nuclear proteins bind to this region at conserved CCAAT-enhancer binding protein (C/EBP), activator protein (AP-1) and E-box sequences. Hepatocyte nuclear factor-3alpha (HNF-3)alpha and beta bind to sequences upstream of a glucocorticoid-responsive element (GRE) half-site as demonstrated by supershift experiments. Nuclear factor I (NFI)-like proteins bind downstream of the GRE half-site. These sites around the GRE motif overlap with five insulin responsive element (IRE) -like sequences (TG/ATTT). The effect of insulin was not prevented by any single mutation in the IRE-like sites. However, mutation of two IRE sites (namely IREc and d) prevented the insulin effect although only marginally affecting the glucocorticoid effect. The results suggest that the effect of insulin is due to a complex interplay of factors requiring the synergistic contribution of at least two sites and underline the contribution of HNF-3 and NFI-like proteins
Transpulmonary thermodilution detects rapid and reversible increases in lung water induced by positive end-expiratory pressure in acute respiratory distress syndrome
Purpose: It has been suggested that, by recruiting lung regions and enlarging the distribution volume of the cold indicator, increasing the positive end-expiratory pressure (PEEP) may lead to an artefactual overestimation of extravascular lung water (EVLW) by transpulmonary thermodilution (TPTD). Methods: In 60 ARDS patients, we measured EVLW (PiCCO2 device) at a PEEP level set to reach a plateau pressure of 30 cmH2O (HighPEEPstart) and 15 and 45 min after decreasing PEEP to 5 cmH2O (LowPEEP15âČ and LowPEEP45âČ, respectively). Then, we increased PEEP back to the baseline level (HighPEEPend). Between HighPEEPstart and LowPEEP15âČ, we estimated the degree of lung derecruitment either by measuring changes in the compliance of the respiratory system (Crs) in the whole population, or by measuring the lung derecruited volume in 30 patients. We defined patients with a large derecruitment from the other ones as patients in whom the Crs changes and the measured derecruited volume were larger than the median of these variables observed in the whole population. Results: Reducing PEEP from HighPEEPstart (14 ± 2 cmH2O) to LowPEEP15âČ significantly decreased EVLW from 20 ± 4 to 18 ± 4 mL/kg, central venous pressure (CVP) from 15 ± 4 to 12 ± 4 mmHg, the arterial oxygen tension over inspired oxygen fraction (PaO2/FiO2) ratio from 184 ± 76 to 150 ± 69 mmHg and lung volume by 144 [68â420] mL. The EVLW decrease was similar in âlarge derecruitersâ and the other patients. When PEEP was re-increased to HighPEEPend, CVP, PaO2/FiO2 and EVLW significantly re-increased. At linear mixed effect model, EVLW changes were significantly determined only by changes in PEEP and CVP (p < 0.001 and p = 0.03, respectively, n = 60). When the same analysis was performed by estimating recruitment according to lung volume changes (n = 30), CVP remained significantly associated to the changes in EVLW (p < 0.001). Conclusions: In ARDS patients, changing the PEEP level induced parallel, small and reversible changes in EVLW. These changes were not due to an artefact of the TPTD technique and were likely due to the PEEP-induced changes in CVP, which is the backward pressure of the lung lymphatic drainage. Trial registration ID RCB: 2015-A01654-45. Registered 23 October 2015
PrĂ©sentation multi-kystique dâun adĂ©nocarcinome lĂ©pidique mucineux
International audienc
Determination of about thirty elements in aluminium and its alloys by means of neutron activation analysis
Bioreactance reliably detects preload responsiveness by the end-expiratory occlusion test when averaging and refresh times are shortened
Background: The end-expiratory occlusion (EEXPO) test detects preload responsiveness, but it is 15 s long and induces small changes in cardiac index (CI). It is doubtful whether the Starling bioreactance device, which averages CI over 24 s and refreshes the displayed value every 4 s (Starling-24.4), can detect the EEXPO-induced changes in CI (ÎCI). Our primary goal was to test whether this Starling device version detects preload responsiveness through EEXPO. We also tested whether shortening the averaging and refresh times to 8 s and one second, respectively, (Starling-8.1) improves the accuracy of the device in detecting preload responsiveness using EEXPO. Methods: In 42 mechanically ventilated patients, during a 15-s EEXPO, we measured âCI through calibrated pulse contour analysis (CIpulse, PiCCO2 device) and using the Starling device. For the latter, we considered both CIStarling-24.4 from the commercial version and CIStarling-8.1 derived from the raw data. For relative âCIStarling-24.4 and âCIStarling-8.1 during EEXPO, we calculated the area under the receiver operating characteristic curve (AUROC) to detect preload responsiveness, defined as an increase in CIpulse â„ 10% during passive leg raising (PLR). For both methods, the correlation coefficient vs. âCIpulse was calculated. Results: Twenty-six patients were preload responders and sixteen non preload-responders. The AUROC for âCIStarling-24.4 was significantly lower compared to âCIStarling-8.1 (0.680 ± 0.086 vs. 0.899 ± 0.049, respectively; p = 0.027). A significant correlation was observed between âCIStarling-8.1 and âCIpulse (r = 0.42; p = 0.009), but not between âCIStarling-24.4 and âCIpulse. During PLR, both âCIStarling-24.4 and âCIStarling-8.1 reliably detected preload responsiveness. Conclusions: Shortening the averaging and refresh times of the bioreactance signal to 8 s and one second, respectively, increases the reliability of the Starling device in detection of EEXPO-induced âCI. Trial registration: No. IDRCB:2018-A02825-50. Registered 13 December 2018
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