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- Sprovieri, F., et al.
(författare)
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Atmospheric mercury concentrations observed at ground-based monitoring sites globally distributed in the framework of the GMOS network
- 2016
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 16:18, s. 11915-11935
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Tidskriftsartikel (refereegranskat)abstract
- Long-term monitoring of data of ambient mercury (Hg) on a global scale to assess its emission, transport, atmospheric chemistry, and deposition processes is vital to understanding the impact of Hg pollution on the environment. The Global Mercury Observation System (GMOS) project was funded by the European Commission (http://www.gmos.eu) and started in November 2010 with the overall goal to develop a coordinated global observing system to monitor Hg on a global scale, including a large network of ground-based monitoring stations, ad hoc periodic oceanographic cruises and measurement flights in the lower and upper troposphere as well as in the lower stratosphere. To date, more than 40 ground-based monitoring sites constitute the global network covering many regions where little to no observational data were available before GMOS. This work presents atmospheric Hg concentrations recorded worldwide in the framework of the GMOS project (2010-2015), analyzing Hg measurement results in terms of temporal trends, seasonality and comparability within the network. Major findings highlighted in this paper include a clear gradient of Hg concentrations between the Northern and Southern hemispheres, confirming that the gradient observed is mostly driven by local and regional sources, which can be anthropogenic, natural or a combination of both.
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- Donaldson, M., et al.
(författare)
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Optimal Pubertal Induction in Girls with Turner Syndrome Using Either Oral or Transdermal Estradiol: A Proposed Modern Strategy
- 2019
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Ingår i: Hormone Research in Paediatrics. - : S. Karger AG. - 1663-2818 .- 1663-2826. ; 91:3, s. 153-163
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most girls with Turner syndrome (TS) require pubertal induction with estrogen, followed by long term replacement. However, no adequately powered prospective studies comparing transdermal with oral 17 beta-estradiol administration exist. This reflects the difficulty of securing funding to study a rare condition with relatively low morbidity/mortality when competing against conditions such as cancer and vascular disease. Protocol Consensus: The TS Working Group of the European Society for Paediatric Endocrinology (ESPE) has agreed to both a 3-year oral and a 3-year transdermal regimen for pubertal induction. Prerequisites include suitable 17 beta-estradiol tablets and matrix patches to allow the delivery of incremental doses based on body weight. Study Proposal: An international prospective cohort study with single centre analysis is proposed in which clinicians and families are invited to choose either of the agreed regimens, usually starting at 11 years. We hypothesise that pubertal induction with transdermal estradiol will result in better outcomes for some key parameters. The primary outcome measure chosen is height gain during the induction period. Analysis: Assessment of the demographics and drop-out rates of patients choosing either oral or transdermal preparations; and appropriate analysis of outcomes including pubertal height gain, final height, liver enzyme and lipid profile, adherence/acceptability, cardiovascular health, including systolic and diastolic blood pressure and aortic root diameter and bone health. Conclusion: The proposed model of prospective data collection according to internationally agreed protocols aims to break the current impasse in obtaining evidence-based management for TS and could be applied to other rare paediatric endocrine conditions. (C) 2019 S. Karger AG, Basel
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- Kemaladewi, Dwi U, et al.
(författare)
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A mutation-independent approach for muscular dystrophy via upregulation of a modifier gene
- 2019
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 572:7767, s. 125-130
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Tidskriftsartikel (refereegranskat)abstract
- Neuromuscular disorders are often caused by heterogeneous mutations in large, structurally complex genes. Targeting compensatory modifier genes could be beneficial to improve disease phenotypes. Here we report a mutation-independent strategy to upregulate the expression of a disease-modifying gene associated with congenital muscular dystrophy type 1A (MDC1A) using the CRISPR activation system in mice. MDC1A is caused by mutations in LAMA2 that lead to nonfunctional laminin-α2, which compromises the stability of muscle fibres and the myelination of peripheral nerves. Transgenic overexpression of Lama1, which encodes a structurally similar protein called laminin-α1, ameliorates muscle wasting and paralysis in mouse models of MDC1A, demonstrating its importance as a compensatory modifier of the disease1. However, postnatal upregulation of Lama1 is hampered by its large size, which exceeds the packaging capacity of vehicles that are clinically relevant for gene therapy. We modulate expression of Lama1 in the dy2j/dy2j mouse model of MDC1A using an adeno-associated virus (AAV9) carrying a catalytically inactive Cas9 (dCas9), VP64 transactivators and single-guide RNAs that target the Lama1 promoter. When pre-symptomatic mice were treated, Lama1 was upregulated in skeletal muscles and peripheral nerves, which prevented muscle fibrosis and paralysis. However, for many disorders it is important to investigate the therapeutic window and reversibility of symptoms. In muscular dystrophies, it has been hypothesized that fibrotic changes in skeletal muscle are irreversible. However, we show that dystrophic features and disease progression were improved and reversed when the treatment was initiated in symptomatic dy2j/dy2j mice with apparent hindlimb paralysis and muscle fibrosis. Collectively, our data demonstrate the feasibility and therapeutic benefit of CRISPR-dCas9-mediated upregulation of Lama1, which may enable mutation-independent treatment for all patients with MDC1A. This approach has a broad applicability to a variety of disease-modifying genes and could serve as a therapeutic strategy for many inherited and acquired diseases.
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- Benisek, Martin, et al.
(författare)
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Dioxins and dioxin-like compounds in composts and digestates from European countries as determined by the in vitro bioassay and chemical analysis
- 2015
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Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 122, s. 168-175
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Tidskriftsartikel (refereegranskat)abstract
- Aerobic composting and anaerobic digestion plays an important role in reduction of organic waste by transforming the waste into humus, which is an excellent soil conditioner. However, applications of chemical-contaminated composts on soils may have unwanted consequences such as accumulation of persistent compounds and their transfer into food chains. The present study investigated burden of composts and digestates collected in 16 European countries (88 samples) by the compounds causing dioxin-like effects as determined by use of an in vitro transactivation assay to quantify total concentrations of aryl hydrocarbon receptor-(AhR) mediated potency. Measured concentrations of 2,3,7,8-Tetrachlorodibeno-p-dioxin (2,3,7,8-TCDD) equivalents (TEQ(bio)) were compared to concentrations of polycyclic aromatic hydrocarbons (PAHs) and selected chlorinated compounds, including polychlorinated dibenzo-p-dioxins/furans (PCDD/Fs), co-planar polychlorinated biphenyls (PCBs), indicator PCB congeners and organochlorine pesticides (OCPs). Median concentrations of TEQ(bio), (dioxin-like compounds) determined by the in vitro assay in crude extracts of various types of composts ranged from 0.05 to 1.2 with a maximum 8.22 mu g (TEQ(bio)) kg(-1) dry mass. Potencies were mostly associated with less persistent compounds such as PAHs because treatment with sulfuric acid removed bioactivity from most samples. The pan-European investigation of contamination by organic contaminants showed generally good quality of the composts, the majority of which were in compliance with conservative limits applied in some countries. Results demonstrate performance and added value of rapid, inexpensive, effect-based monitoring, and points out the need to derive corresponding effect-based trigger values for the risk assessment of complex contaminated matrices such as composts.
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- Gawlik, Kinga I., et al.
(författare)
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Laminin α1 reduces muscular dystrophy in dy2Jmice
- 2018
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Ingår i: Matrix Biology. - : Elsevier BV. - 0945-053X. ; 70, s. 36-49
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Tidskriftsartikel (refereegranskat)abstract
- Muscular dystrophies, including laminin α2 chain-deficient muscular dystrophy (LAMA2-CMD), are associated with immense personal, social and economic burdens. Thus, effective treatments are urgently needed. LAMA2-CMD is either a severe, early-onset condition with complete laminin α2 chain-deficiency or a milder, late-onset form with partial laminin α2 chain-deficiency. Mouse models dy 3K /dy 3K and dy 2J /dy 2J , respectively, recapitulate these two forms of LAMA2-CMD very well. We have previously demonstrated that laminin α1 chain significantly reduces muscular dystrophy in laminin α2 chain-deficient dy 3K /dy 3K mice. Among all the different pre-clinical approaches that have been evaluated in mice, laminin α1 chain-mediated therapy has been shown to be one of the most effective lines of attack. However, it has remained unclear if laminin α1 chain-mediated treatment is also applicable for partial laminin α2 chain-deficiency. Hence, we have generated dy 2J /dy 2J mice (that express a substantial amount of an N-terminal truncated laminin α2 chain) overexpressing laminin α1 chain in the neuromuscular system. The laminin α1 chain transgene ameliorated the dystrophic phenotype, restored muscle strength and reduced peripheral neuropathy. Thus, these findings provide additional support for the development of laminin α1 chain-based therapy for LAMA2-CMD.
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