| 1. |
- Bastard, Paul, et al.
(författare)
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Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.
- 2021
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Ingår i: The Journal of experimental medicine. - 1540-9538. ; 218:7
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Tidskriftsartikel (refereegranskat)abstract
- Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-β and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.
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| 2. |
- Chtarto, Abdelwahed, et al.
(författare)
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A regulatable AAV vector mediating GDNF biological effects at clinically-approved sub-antimicrobial doxycycline doses
- 2016
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Ingår i: Molecular Therapy - Methods and Clinical Development. - : Elsevier BV. - 2329-0501. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical and clinical data stress the importance of pharmacologically-controlling glial cell line-derived neurotrophic factor (GDNF) intracerebral administration to treat PD. The main challenge is finding a combination of a genetic switch and a drug which, when administered at a clinically-approved dose, reaches the brain in sufficient amounts to induce a therapeutic effect. We describe a highly-sensitive doxycycline-inducible adeno-associated virus (AAV) vector. This vector allowed for the first time a longitudinal analysis of inducible transgene expression in the brain using bioluminescence imaging. To evaluate the dose range of GDNF biological activity, the inducible AAV vector (8.0 × 10(9) viral genomes) was injected in the rat striatum at four delivery sites and increasing doxycycline doses administered orally. ERK/Akt signaling activation as well as tyrosine hydroxylase downregulation, a consequence of long-term GDNF treatment, were induced at plasmatic doxycycline concentrations of 140 and 320 ng/ml respectively, which are known not to increase antibiotic-resistant microorganisms in patients. In these conditions, GDNF covered the majority of the striatum. No behavioral abnormalities or weight loss were observed. Motor asymmetry resulting from unilateral GDNF treatment only appeared with a 2.5-fold higher vector and a 13-fold higher inducer doses. Our data suggest that using the herein-described inducible AAV vector, biological effects of GDNF can be obtained in response to sub-antimicrobial doxycycline doses.
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| 3. |
- Rosenbaum, Ralph K., et al.
(författare)
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The Glasgow consensus on the delineation between pesticide emission inventory and impact assessment for LCA
- 2015
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Ingår i: The International Journal of Life Cycle Assessment. - : Springer Science and Business Media LLC. - 0948-3349 .- 1614-7502. ; 20:6, s. 765-776
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Pesticides are applied to agricultural fields to optimise crop yield and their global use is substantial. Their consideration in life cycle assessment (LCA) is affected by important inconsistencies between the emission inventory and impact assessment phases of LCA. A clear definition of the delineation between the product system model (life cycle inventory—LCI, technosphere) and the natural environment (life cycle impact assessment—LCIA, ecosphere) is missing and could be established via consensus building.Methods: A workshop held in 2013 in Glasgow, UK, had the goal of establishing consensus and creating clear guidelines in the following topics: (1) boundary between emission inventory and impact characterisation model, (2) spatial dimensions and the time periods assumed for the application of substances to open agricultural fields or in greenhouses and (3) emissions to the natural environment and their potential impacts. More than 30 specialists in agrifood LCI, LCIA, risk assessment and ecotoxicology, representing industry, government and academia from 15 countries and four continents, met to discuss and reach consensus. The resulting guidelines target LCA practitioners, data (base) and characterisation method developers, and decision makers.Results and discussion: The focus was on defining a clear interface between LCI and LCIA, capable of supporting any goal and scope requirements while avoiding double counting or exclusion of important emission flows/impacts. Consensus was reached accordingly on distinct sets of recommendations for LCI and LCIA, respectively, recommending, for example, that buffer zones should be considered as part of the crop production system and the change in yield be considered. While the spatial dimensions of the field were not fixed, the temporal boundary between dynamic LCI fate modelling and steady-state LCIA fate modelling needs to be defined.Conclusions and recommendations: For pesticide application, the inventory should report pesticide identification, crop, mass applied per active ingredient, application method or formulation type, presence of buffer zones, location/country, application time before harvest and crop growth stage during application, adherence with Good Agricultural Practice, and whether the field is considered part of the technosphere or the ecosphere. Additionally, emission fractions to environmental media on-field and off-field should be reported. For LCIA, the directly concerned impact categories and a list of relevant fate and exposure processes were identified. Next steps were identified: (1) establishing default emission fractions to environmental media for integration into LCI databases and (2) interaction among impact model developers to extend current methods with new elements/processes mentioned in the recommendations.
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