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Beta-2 Glycoprotein I (β2-GPI) is the main target of anti-phospholipid antibodies (aPL) in the autoimmune anti-phospholipid syndrome, characterized by increased risk of stroke. We here investigated the antibody independent role of β2-GPI after ischemia/reperfusion, modeled in vivo by transient middle cerebral artery occlusion (tMCAo) in male C57Bl/6J mice; in vitro by subjecting immortalized human brain microvascular endothelial cells (ihBMEC) to 16 h hypoxia and 4 h re-oxygenation. ApoH (coding for β2-GPI) was upregulated selectively in the liver at 48 h after tMCAo. At the same time β2-GPI circulating levels increased. β2-GPI was detectable in brain parenchyma and endothelium at all time points after tMCAo. Parenchymal β2-GPI recognized apoptotic neurons (positive for annexin V, C3 and TUNEL) cleared by CD68+ brain macrophages. Hypoxic ihBMEC showed increased release of IL-6, over-expression of thrombomodulin and IL-1α after re-oxygenation with β2-GPI alone. β2-GPI interacted with mannose-binding lectin in mouse plasma and ihBMEC medium, potentially involved in formation of thrombi. We show for the first time that brain ischemia triggers the hepatic production of β2-GPI. β2-GPI is present in the ischemic endothelium, enhancing vascular inflammation, and extravasates binding stressed neurons before their clearance by phagocytosis. Thus β2-GPI may be a new mediator of brain injury following ischemic stroke.

Radon (222Rn) gas is the largest source of public exposure to naturally occurring radioactivity and the identification of radon priority areas is required by the Council Directive 2013/59/Euratom. Radon is also used as a tracer to improve atmospheric transport models and to indirectly estimate greenhouse gas (GHG) fluxes using the Radon Tracer Method (RTM). This method is based on the correlation between atmospheric concentrations of radon and GHG, together with information on the radon flux data. For radiological data, all European countries have installed networks of automatic gamma dose rate monitoring stations and report the real-time information gathered to the European Radiological Data Exchange Platform (EURDEP). So far, atmospheric radon activity concentrations and radon fluxes are not yet reported in EURDEP, nor routinely measured within the European radiological networks although these observations could help to avoid false positives results. Due to above applications, there is a need of building a metrological chain to ensure high quality radon activity concentrations and radon flux measurements. Both climate and radiation protection research communities underline the need for improved traceability in low-level atmospheric radon measurements (Khanbabaee et al., 2021). The EMPIR project 19ENV01 traceRadon1 is aimed towards providing the necessary measurement infrastructure and transfer standards to fulfil this need. Results of this project are particularly important for improving independent GHG emission estimates that support national reporting under the Paris Agreement on climate change and for the Council Directive 2013/59/Euratom, thus benefitting two large scientific communities. In this paper, early results, such as new activity standard developments and an overview of commercial and research radon monitors are presented and discussed. These results will feed into the traceRadon project with respect to radionuclide metrology in air and its potential for the improvement of the RTM.

Interlaboratory exercises are a good tool to compare the response of different systems to the same quantity and to identify possible inconsistencies between them. One of the main goals of the EMPIR 19ENV01 traceRadon project is to harmonize radon flux measurements based on different systems and methodologies. In the framework of the traceRadon Project, two radon flux intercomparison campaigns were carried out in October 2021 at high and at low radon source areas. Four institutions participated in the field intercomparison exercises with their own systems. Every system was based on a specific radon monitor (diffusion or pump mode) and an accumulation chamber (with manual or automatic opening). Radon fluxes were calculated by each participant using both exponential and linear fittings of the radon activity concentration measured over time within the accumulation chambers. The results of this study show mainly: (i) the exponential approach is not advisable due to the variability of the radon flux and the leakage of the systems during long-time measurements; (ii) the linear approach should be applied to minimize the measurement period in agreement with the time response and sensitivity of the monitors; (iii) radon flux measured at high radon source areas (radium content of about 800 Bq kg-¹) risks being underestimated because of the influence of dvective effects; (iv) radon flux measured at low radon source areas (radium content of about 30 Bq kg-¹) may present large uncertainties if sensitive radon monitors with pump mode are not used. Funding: This project 19ENV01 traceRadon has received funding from the EMPIR programme co-financed by the Participating States and from the European Union’s Horizon 2020 research and innovation programme. 19ENV01 traceRadon denotes the EMPIR project reference.

Indoor and outdoor (atmospheric) radon activity concentrations need to be measured as accurate as possible for radiation protection and for climate applications. Particularly radon concentrations below 100 Bq ⋅ m−3, useful for the retrieval of radon prone areas and for atmospheric studies, still need a robust metrological chain to ensure their quality. Ones of the most common used commercial continuous radon monitors were compared here under slightly different environmental conditions. The measured data set were divided into two groups ( ⋅ m−3 and ≥ 100 Bq ⋅ m−3) to assess the monitors responses and their associated uncertainties. Nevertheless, these results should also to point out if commercial monitors are suitable for monitoring low atmospheric radon concentrations with an associated uncertainty of 10% (k=1). This work, carried out within the EMPIR 19ENV01 traceRadon project, aims to offer a starting point for the development of a future radon monitor as transfer standard to increase the metrological capabilities of atmospheric radon monitoring.

International audience; Radon gas is the largest source of public exposure to naturally occurring radioactivity. However, radon is also a useful tracer for understanding atmospheric processes, assessing the accuracy of chemical transport models, and enabling integrated emissions estimates of greenhouse gases. A sound metrological system for low level atmospheric radon observations is therefore needed for the benefit of the atmospheric, climate and radiation protection research communities. To this end, here we present a new calibration method for activity concentrations below 20 Bq m−3 and a prototype of the first portable radon monitor capable of achieving uncertainties of 5% (at k = 2) at these concentrations. Compliance checking of policy-driven regulations regarding greenhouse gas (GHG) emissions is an essential component of climate change mitigation efforts. Independent, reliable 'top down' methods that can be applied consistently for estimating local- to regional-scale GHG emissions (such as the radon tracer method (RTM)) are an essential part of this process. The RTM relies upon observed radon and GHG concentrations and measured or modeled radon fluxes. Reliable radon flux maps could also significantly aid EU member states comply with European COUNCIL DIRECTIVE 2013/59/EURATOM. This article also introduces the traceRadon project, key aims of which include outlining a standardized approach for application of the RTM, creating infrastructure with a traceability chain for radon concentration and radon flux measurements, and developing tools for the validation of radon flux models. Since radon progeny dominate the terrestrial gamma dose rate, the planned traceRadon activities are also expected to improve the sensitivity of radiation protection early warning networks because of the correlation known to exist between radon flux and ambient equivalent dose rates.

The natural radioactive noble gas radon (222Rn) is originated from the decay of radium into the soil and then continuously exhaled to the lower atmosphere. Its diffusion and exhalation rate depend both on the physical and environmental conditions of the soil layers and on the meteorological conditions. With a half-life of 3.8 days and a very limited chemical activity, the 222Rn is nowadays being used as an atmospheric tracer for: i) the improvement of atmospheric transport models used, among others, to identify greenhouse gas (GHG) emission sources; ii) for the indirect estimation of GHG fluxes by the Radon Tracer Method (RTM). These previous applications need high sensitivity and precision at low radon concentrations range (< 100 Bq m-3).A new monitor, based on alpha spectrometry of 218Po electrostatically collected on a PIPs detector, has been designed and developed at the Institute of Energy Technologies (INTE) of the Universitat Politecnica de Catlunya (UPC) in the mark of the project ‘High efficiency monitor of atmospheric radon concentration for radiation protection and environmental applications (MARE2EA), reference: 2019-LLAV-00035, funded by the Catalan Agency for Management of University and Research Grants. The aim is building an instrument able to measure atmospheric radon concentration activities with high precision in order to be running at GHG atmospheric networks for the RTM applications.The monitor is an improved version of a previous prototype instrument (Grossi et al., 2012, 2020). The new instrument will allow a higher efficiency, robustness and portability. In addition, it will have a GUI interface to be user friendly. Finally, in order to reduce the air sample humidity within the detection volume of the instrument which affects the 218Po collection, a portable drying system has also been built to keep the instrument ongoing without maintenance during several weeks. ReferencesGrossi, C., Arnold, D., Adame, J. A., López-Coto, I., Bolívar, J. P., De La Morena, B. A., & Vargas, A. (2012). Atmospheric 222Rn concentration and source term at El Arenosillo 100 m meteorological tower in southwest Spain. Radiation Measurements, 47(2), 149–162. https://doi.org/10.1016/j.radmeas.2011.11.006Grossi, C., Chambers, S. D., Llido, O., Vogel, F. R., Kazan, V., Capuana, A., Werczynski, S., Curcoll, R., Delmotte, M., Vargas, A., Morguí, J.-A., Levin, I., & Ramonet, M. (2020). Intercomparison study of atmospheric 222Rn and 222Rn progeny monitors. Atmospheric Measurement Techniques, 13(5). https://doi.org/10.5194/amt-13-2241-2020

Background Animal models and few clinical reports suggest the involvement of the complement system in the onset of severe manifestations of coronavirus disease-2019 (COVID-19). However, complement contribution to endotheliopathy and hypercoagulability has not been elucidated yet. Objective To evaluate the association among complement activation, endothelial damage and disease severity or activity in COVID-19 patients. Methods In this single-centre cohort study, 148 patients with COVID-19 of different severity were evaluated upon hospital admission and 30 days later. Markers of complement activation (SC5b-9 and C5a) and endothelial perturbation (von Willebrand factor [vWF], tissue-type plasminogen activator [t-PA], plasminogen activator inhibitor-1 [PAI-1], soluble thrombomodulin [sTM], and soluble endothelial selectin [sE-selectin]) were measured in plasma. Results The patients had high plasma levels of SC5b-9 and C5a (p = 0.0001 for both) and vWF, t-PA and PAI-1 (p = 0.0001 for all). Their SC5b-9 levels correlated with those of vWF (r = 0.517, p = 0.0001) and paralleled disease severity (severe vs mild p = 0.0001, severe vs moderate p = 0.026 and moderate vs mild p = 0.001). The levels of sE-selectin were significantly increased only in the patients with severe disease. After 30 days, plasma SC5b-9, C5a and vWF levels had significantly decreased (p = 0.0001 for all), and 43% of the evaluated patients had normal levels. Conclusions Complement activation is boosted during the progression of COVID-19 and dampened during remission, thus indicating its role in the pathophysiology of the disease. The association between complement activation and the biomarkers of endothelial damage suggests that complement may contribute to tissue injury and could be the target of specific therapy.

A layer of phosphogypsum was placed at the bottom of two large volume boxes. This system allowed to measure the surface radon exhalation from phosphogypsum without altering the emitting material. The limits and optimal setup of the closed-circuit accumulation chamber technique were thoroughly studied. More precisely, the performance of different radon exhalation fitting methods was analyzed in the reference exhalation boxes, employing different measurement devices and three smaller operational accumulation chambers. As expected, the best approach to obtain the radon exhalation rate depends upon the effective decay constant of the measurement system and the time employed to perform the measurement. The time until the linear approximation can no longer be applied was scrutinized. Although this approximation is usually applied routinely in the literature, the effective time constant of the chamber is often not low enough for the linear fit to be applied safely, providing statistically acceptable measurements that can lead to significative underestimations of the radon exhalation rate.

Up to 40% of patients treated with tumor necrosis factor alpha inhibitors (TNFi) do not respond to therapy. Testing drug bioavailability and/or anti-drug antibody (ADAb) levels may justify dosage adjustment or switch to different drugs, enabling a personalized medicine approach. We report a multicenter cross-sectional study on different methods [ELISA and a cell based functional assay (reporter gene assay – RGA)] for drug/ADAb detection, and on the relationship between drug bioavailability and ADAb. 163 patients with rheumatoid arthritis (RA) treated with infliximab (IFX; n = 67), adalimumab (ADL; n = 49) or etanercept (ETA; n = 47) were tested for drug and ADAb levels. Furthermore, we report prospective data from additional 70 patients (59 RA and 11 juvenile idiopathic arthritis - JIA) tested for drug and ADAb levels at baseline (T0) and after 3 (T3) and 6 months (T6) of treatment with ADL or ETA only. IFX-treated patients were not included because of the increasing use of IFX biosimilars. Stringent inclusion criteria were used in order to avoid unwanted variables in both studies; none of the patients used TNFi before the study, and TNFi was used only in combination with methotrexate. Clinical response was defined according to EULAR response criteria. The two assays performed comparably in the comparison study. Accordingly, ELISA was selected for the prospective study because of its feasibility in the clinical setting. The cross-sectional study found ADAb in IFX and ADL treated groups only, that were associated with a decrease in pharmacological drug availability in the blood. Comparable results were found for the ADL-treated group in the prospective study which also showed a relationship between drug/ADAb levels and the loss of clinical response. Altogether our findings support drug and anti-drug Ab monitoring in the real-world clinical setting thus enabling individualized treatment and reducing disability in chronic inflammatory arthritis.

Este artículo contiene 12 páginas, 1 tabla, 5 figuras., In order to improve the understanding of the carbon cycle in the Pyrenean region, two atmospheric monitoring mountain stations were set up within the Long-Term Ecological Research node of Aigüestortes i Estany de Sant Maurici at Central Pyrenees, Spain. The atmospheric concentration of carbon dioxide (CO2) was measured over 2008–2014 and 2010–2014 at Estany Llong (ELL) site and Centre de Recerca d’Alta Muntanya (CRAM), respectively. Measurements were carried out fortnightly off-line with high precision instrumentation at ELL and every minute online with a lower precision sensor at CRAM in conjunction with meteorological variables. The two datasets were analyzed in this study, quantifying whenever possible annual growth rates (AGR), seasonal variability, and diurnal amplitudes. Results were also compared with the NOAA Marine Boundary Layer (MBL) reference product and CO2 data from other background monitoring stations. Four-harmonics adjusted CO2 data from ELL showed a high correlation with the NOAA MBL reference product for the same latitude (Spearman’s rho ρ = 0.96). In addition, AGRs of CO2 at ELL correlated well with those observed at Mace Head (MHD) station (ρ = 0.94), suggesting that ELL can be considered a background station. Winter CRAM CO2 data was not statistically different from ELL data, while in summer, it was 5.5 ppm lower on average, suggesting a higher photosynthesis uptake. The amplitude of the CO2 diurnal cycle at CRAM was found to be exponentially related to the local mean daily temperature and dependent on forthcoming wind sector (N-NW or E-SE-S-SW).An increase in CRAM CO2 concentrations was observed under N-NW winds during daytime, which could be related to traffic emissions. This study demonstrates that the use of CO2 sensors with low precision but continuously corrected and periodically calibrated can be used for the study of local and regional CO2 sources and sinks., This work has been mainly funded by own resources of the LAO-Climadat Lab at IC3 and by the Fluxpyr project (POCTEFA Program EFA 34/08 - Interreg IV-A). Data is available through virtual access provided and funded in the frame of eLTER H2020 - European Long-Term Ecosystem and Socio-Ecological Research Infrastructure (EC project GA: 654359; INFRAIA; 2015– 2019).

The variability of the atmospheric concentration of the 7Be and 210Pb radionuclides is strongly linked to the origin of air masses, the strength of their sources and the processes of wet and dry deposition. It has been shown how these processes and their variability are strongly affected by climate change. Thus, a deeper knowledge of the relationship between the atmospheric radionuclides variability measured close to the ground and these atmospheric processes could help in the analysis of climate scenarios. In the present study, we analyze the atmospheric variability of a 14-year time series of 7Be and 210Pb in a Mediterranean coastal city using a synergy of different indicators and tools such as: the local meteorological conditions, global and regional climate indexes and a lagrangian atmospheric transport model. We particularly focus on the relationships between the main pathways of air masses and sun spots occurrence, the variability of the local relative humidity and temperature conditions, and the main modes of regional climate variability, such as the North Atlantic Oscillation (NAO) and the Western Mediterranean Oscillation (WeMO). The variability of the observed atmospheric concentrations of both 7Be and 210Pb radionuclides was found to be mainly positively associated to the local climate conditions of temperature and to the pathways of air masses arriving at the station. Measured radionuclide concentrations significantly increase when air masses travel at low tropospheric levels from central Europe and the western part of the Iberian Peninsula, while low concentrations are associated with westerly air masses. We found a significant negative correlation between the WeMO index and the atmospheric variability of both radionuclides and no significant association was observed for the NAO index.

The aim of this multicenter study was to assess the present risk of fetal complications and the inherent risk factors in pregnant women with lupus nephritis. Seventy-one pregnancies in 61women (59 Caucasians and 2 Asians) with lupus nephritis were prospectively followed between October 2006 and December 2013. All patients received a counselling visit within 3 months before the beginning of pregnancy and were followed by a multidisciplinary team. At baseline mild active nephritis was present in 15 cases (21.1%). Six pregnancies (8.4%) resulted in fetal loss. Arterial hypertension at baseline (P = 0.003), positivity for lupus anticoagulant (P = 0.001), anticardiolipin IgG antibodies (P = 0.007), antibeta2 IgG (P = 0.018) and the triple positivity for antiphospholipid antibodies (P = 0.004) predicted fetal loss. Twenty pregnancies (28.2%) ended pre-term and 12 newborns (16.4%) were small for gestational age. Among the characteristics at baseline, high SLE disease activity index (SLEDAI) score (P = 0.027), proteinuria (P = 0.045), history of renal flares (P = 0.004), arterial hypertension (P = 0.009) and active lupus nephritis (P = 0.000) increased the probability of preterm delivery. Odds for preterm delivery increased by 60% for each quarterly unit increase in SLEDAI and by 15% for each quarterly increase in proteinuria by 1 g per day. The probability of having a small for gestational age baby was reduced by 85% in women who received hydroxychloroquine therapy (P = 0.023). In this study, the rate of fetal loss was low and mainly associated with the presence of antiphospholipid antibodies. Preterm delivery remains a frequent complication of pregnancies in lupus. SLE and lupus nephritis activity are the main risk factors for premature birth. Arterial hypertension predicted both fetal loss and preterm delivery. Based on our results the key for a successful pregnancy in lupus nephritis is a multidisciplinary approach with close medical, obstetric and neonatal monitoring. This entails: a) a preconception evaluation to establish and inform women about pregnancy risks; b) planning pregnancy during inactive lupus nephritis, maintained inactive with the lowest possible dosage of allowed drugs; c) adequate treatment of known risk factors (arterial hypertension, antiphospholipid and antibodies); d) close monitoring during and after pregnancy to rapidly identify and treat SLE flares and obstetric complications.

β2 glycoprotein I (β2GPI)-dependent anti-phospholipid antibodies (aPL) induce thrombosis and affect pregnancy. The CMV-derived synthetic peptide TIFI mimics the PL-binding site of β2GPI and inhibits β2GPI cell-binding in vitro and aPL-mediated thrombosis in vivo. Here we investigated the effect of TIFI on aPL-induced fetal loss in mice. TIFI inhibitory effect on in vitro aPL binding to human trophoblasts was evaluated by indirect immunofluorescence and ELISA. TIFI effect on aPL-induced fetal loss was investigated in pregnant C57BL/6 mice treated with aPL or normal IgG (NHS). Placenta/fetus weight and histology and RNA expression were analyzed. TIFI, but not the control peptide VITT, displayed a dose-dependent inhibition of aPL binding to trophoblasts in vitro. Injection of low doses of aPL at day 0 of pregnancy caused growth retardation and increased fetal loss rate, both significantly reduced by TIFI but not VITT. Consistent with observations in humans, histological analysis showed no evidence of inflammation in this model, as confirmed by the absence of an inflammatory signature in gene expression analysis, which in turn revealed a TIFI-dependent modulation of molecules involved in differentiation and development processes. These findings support the non-inflammatory pathogenic role of aPL and suggest innovative therapeutic approaches to aPL-dependent fetal loss.

In vitro studies have documented β2 glycoprotein I (β2GPI) binding to endothelial cells (ECs) and trophoblast using antiphospholipid antibodies. The in vivo binding of β2GPI to these cells and the conditions that favor their interaction have not been investigated. We analyzed the in vivo distribution of cyanine 5.5-labeled β2GPI in mice and evaluated the effect of pregnancy and circulating antibodies on its tissue localization. The signal was detected in the liver by whole body scan and ex vivo analysis. The β2GPI failed to bind to the vascular endothelium and reacted only with the ECs of uterine vessels. In pregnant mice the protein was localized on ECs and trophoblast at the embryo implantation sites. Immunized mice showed a similar β2GPI biodistribution to naive mice but the immunized pregnant animals exhibited a significant increase in fetal loss associated with C3 and C9 deposition at the implantation sites. Treatment of mice with LPS after β2GPI-Cy5.5 injection promoted protein localization on gut and brain ECs associated with IgG, C1q, and C9 deposition in immunized mice. These findings indicate that β2GPI binding to EC requires priming with pro-inflammatory factors which is not needed for uterine and placental localization probably dependent on hormonal changes.

Background Antiphospholipid antibodies (aPL) can be detected in asymptomatic carriers and infectious patients. The aim was to investigate whether a novel line immunoassay (LIA) differentiates between antiphospholipid syndrome (APS) and asymptomatic aPL+ carriers or patients with infectious diseases (infectious diseases controls (IDC)). Methods Sixty-one patients with APS (56 primary, 22/56 with obstetric events only, and 5 secondary), 146 controls including 24 aPL+ asymptomatic carriers and 73 IDC were tested on a novel hydrophobic solid phase coated with cardiolipin (CL), phosphatic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, beta2-glycoprotein I (β2GPI), prothrombin, and annexin V. Samples were also tested by anti-CL and anti-β2GPI ELISAs and for lupus anticoagulant activity. Human monoclonal antibodies (humoAbs) against human β2GPI or PL alone were tested on the same LIA substrates in the absence or presence of human serum, purified human β2GPI or after CL-micelle absorption. Results Comparison of LIA with the aPL-classification assays revealed good agreement for IgG/IgM aß2GPI and aCL. Anti-CL and anti-ß2GPI IgG/IgM reactivity assessed by LIA was significantly higher in patients with APS versus healthy controls and IDCs, as detected by ELISA. IgG binding to CL and ß2GPI in the LIA was significantly lower in aPL+ carriers and Venereal Disease Research Laboratory test (VDRL) + samples than in patients with APS. HumoAb against domain 1 recognized β2GPI bound to the LIA-matrix and in anionic phospholipid (PL) complexes. Absorption with CL micelles abolished the reactivity of a PL-specific humoAb but did not affect the binding of anti-β2GPI humoAbs. Conclusions The LIA and ELISA have good agreement in detecting aPL in APS, but the LIA differentiates patients with APS from infectious patients and asymptomatic carriers, likely through the exposure of domain 1. Electronic supplementary material The online version of this article (doi:10.1186/s13075-016-1018-x) contains supplementary material, which is available to authorized users.