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- 2019
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Tidskriftsartikel (refereegranskat)
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| 2. |
- Devos, David, et al.
(författare)
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Trial of Deferiprone in Parkinson’s Disease
- 2022
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 387:22, s. 2045-2055
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUNDIron content is increased in the substantia nigra of persons with Parkinson's disease and may contribute to the pathophysiology of the disorder. Early research suggests that the iron chelator deferiprone can reduce nigrostriatal iron content in persons with Parkinson's disease, but its effects on disease progression are unclear.METHODSWe conducted a multicenter, phase 2, randomized, double-blind trial involving participants with newly diagnosed Parkinson's disease who had never received levodopa. Participants were assigned (in a 1:1 ratio) to receive oral deferiprone at a dose of 15 mg per kilogram of body weight twice daily or matched placebo for 36 weeks. Dopaminergic therapy was withheld unless deemed necessary for symptom control. The primary outcome was the change in the total score on the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS; range, 0 to 260, with higher scores indicating more severe impairment) at 36 weeks. Secondary and exploratory clinical outcomes at up to 40 weeks included measures of motor and nonmotor disability. Brain iron content measured with the use of magnetic resonance imaging was also an exploratory outcome.RESULTSA total of 372 participants were enrolled; 186 were assigned to receive deferiprone and 186 to receive placebo. Progression of symptoms led to the initiation of dopaminergic therapy in 22.0% of the participants in the deferiprone group and 2.7% of those in the placebo group. The mean MDS-UPDRS total score at baseline was 34.3 in the deferiprone group and 33.2 in the placebo group and increased (worsened) by 15.6 points and 6.3 points, respectively (difference, 9.3 points; 95% confidence interval, 6.3 to 12.2; P<0.001). Nigrostriatal iron content decreased more in the deferiprone group than in the placebo group. The main serious adverse events with deferiprone were agranulocytosis in 2 participants and neutropenia in 3 participants.CONCLUSIONSIn participants with early Parkinson's disease who had never received levodopa and in whom treatment with dopaminergic medications was not planned, deferiprone was associated with worse scores in measures of parkinsonism than those with placebo over a period of 36 weeks.
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| 3. |
- Nebie, Ouada, et al.
(författare)
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Heat-treated human platelet pellet lysate modulates microglia activation, favors wound healing and promotes neuronal differentiation in vitro
- 2021
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Ingår i: Platelets. - : Taylor & Francis. - 0953-7104 .- 1369-1635. ; 32:2, s. 226-237
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Tidskriftsartikel (refereegranskat)abstract
- The neurorestorative efficacy of human platelet lysates in neurodegenerative disorders is still under investigation. Platelets prepared from standard and pathogen reduced platelet concentrates were pelletized, washed, concentrated, and subjected to freeze-thawing. The lysate was heated to 56 degrees C for 30 min and characterized. Toxicity was evaluated using SH-SY5Y neuroblastoma, BV-2 microglial, and EA-hy926 endothelial cells. Inflammatory activity was tested by examining tumor necrosis factor (TNF) and cyclooxygenase (COX)-2 expressions by BV-2 microglia with or without stimulation by lipopolysaccharides (LPS). The capacity to stimulate wound healing was evaluated by a scratch assay, and the capacity to differentiate SH-SY5Y into neurons was also examined. Platelet lysates contained a range of neurotrophins. They were not toxic to SH-SY5Y, EA-hy926, or BV-2 cells, did not induce the expression of TNF or COX-2 inflammatory markers by BV-2 microglia, and decreased inflammation after LPS stimulation. They stimulated the wound closure in the scratch assay and induced SH-SY5Y differentiation as revealed by the increased length of neurites as well as beta 3-tubulin and neurofilament staining. These data confirm the therapeutic potential of platelet lysates in the treatment of disorders of the central nervous system and support further evaluation as novel neurorestorative biotherapy in preclinical models.
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| 4. |
- Nebie, Ouada, et al.
(författare)
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The neuroprotective activity of heat-treated human platelet lysate biomaterials manufactured from outdated pathogen-reduced (amotosalen/UVA) platelet concentrates
- 2019
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Ingår i: Journal of Biomedical Science. - : BMC. - 1021-7770 .- 1423-0127. ; 26
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Tidskriftsartikel (refereegranskat)abstract
- Background: Effective neurorestorative therapies of neurodegenerative diseases must be developed. There is increasing interest in using human platelet lysates, rich in neurotrophic factors, as novel disease-modifying strategy of neurodegeneration. To ensure virus safety, pathogen reduction treatments should be incorporated in the preparation process of the platelet concentrates used as source material. We therefore investigated whether platelet concentrates (PC) pathogen-inactivated using a licensed photo-inactivation treatment combining photosensitive psoralen (amotosalen) and UVA irradiation (Intercept) can serve as source material to prepare platelet lysates with preserved neuroprotective activity in Parkinson's disease models.Methods: Intercept treated-PCs were centrifuged, when reaching expiry day (7 days after collection), to remove plasma and platelet additive solution. The platelet pellet was re-suspended and concentrated in phosphate buffer saline, subjected to 3 freeze-thaw cycles (-80 degrees C/37 degrees C) then centrifuged to remove cell debris. The supernatant was recovered and further purified, or not, by heat-treatment as in our previous investigations. The content in proteins and neurotrophic factors was determined and the toxicity and neuroprotective activity of the platelet lysates towards LUHMES cells or primary cortical/hippocampal neurons were assessed using ELISA, flow cytometry, cell viability and cytotoxicity assays and proteins analysis by Western blot.Results: Platelet lysates contained the expected level of total proteins (ca. 7-14 mg/mL) and neurotrophic factors. Virally inactivated and heat-treated platelet lysates did not exert detectable toxic effects on neither Lund human mesencephalic dopaminergic LUHMES cell line nor primary neurons. When used at doses of 5 and 0.5%, they enhanced the expression of tyrosine hydroxylase and neuron-specific enolase in LUHMES cells and did not significantly impact synaptic protein expression in primary neurons, respectively. Furthermore, virally-inactivated platelet lysates tested were found to exert very strong neuroprotection effects on both LUHMES and primary neurons exposed to erastin, an inducer of ferroptosis cell death.Conclusion: Outdated Intercept pathogen-reduced platelet concentrates can be used to prepare safe and highly neuroprotective human heat-treated platelet pellet lysates. These data open reassuring perspectives in the possibility to develop an effective biotherapy using virally-inactivated platelet lysates rich in functional neurotrophins for neuroregenerative medicine, and for further bio-industrial development. However, the data should be confirmed in animal models.
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| 5. |
- Pavon-Jordan, Diego, et al.
(författare)
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Climate-driven changes in winter abundance of a migratory waterbird in relation to EU protected areas
- 2015
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Ingår i: Diversity and Distributions. - : Wiley. - 1366-9516. ; 21:5, s. 571-582
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Tidskriftsartikel (refereegranskat)abstract
- AimSpecies are responding to climate change by changing their distributions, creating debate about the effectiveness of existing networks of protected areas. As a contribution to this debate, we assess whether regional winter abundances and distribution of the Smew Mergellus albellus, a migratory waterbird species listed on Annex I (EU Birds Directive) that overwinters exclusively in European wetlands, changed during 1990-2011, the role of global warming in driving distributional changes and the effectiveness of the network of Special Protection Areas (SPAs, EU Birds Directive) in the context of climate change. LocationEurope. MethodsWe used site-specific counts (6,883 sites) from 16 countries covering the entire flyway to estimate annual abundance indices and trends at country, region (north-eastern, central and south-western) and flyway scales, inside and outside SPAs. We fitted autoregressive models to assess the effect of winter temperature on the annual abundance indices whilst accounting for autocorrelation. ResultsThe Smew wintering distribution shifted north-eastwards in Europe in accordance with the predictions of global warming, with increasing numbers in the north-eastern region and declines in the central region. Trends in wintering numbers were more positive in SPAs on the north-eastern and south-western part of the flyway. However, a large proportion of the wintering population remains unprotected in north-eastern areas outside of the existing SPA network. Main conclusionsSPAs accommodated climate-driven abundance changes in the north-eastern region of the wintering distribution by supporting increasing numbers of Smew in traditional and newly colonized areas. However, we highlight gaps in the current network, suggesting that urgent policy responses are needed. Given rapid changes in species distributions, we urge regular national and international assessments of the adequacy of the EU Natura 2000 network to ensure coherence in site-safeguard networks for this and other species.
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| 6. |
- Pavón-Jordán, Diego, et al.
(författare)
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Habitat- and species-mediated short- and long-term distributional changes in waterbird abundance linked to variation in European winter weather
- 2019
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Ingår i: Diversity and Distributions. - : Wiley. - 1366-9516. ; 25:2, s. 225-239
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Many species are showing distribution shifts in response to environmental change. We explored (a) the effects of inter-annual variation in winter weather conditions on non-breeding distributional abundance of waterbirds exploiting different habitats (deep-water, shallow water, farmland) and (b) the long-term shift in the population centroid of these species and investigate its link to changes in weather conditions. Location: Europe. Methods: We fitted generalized additive mixed Models to a large-scale, 24-year dataset (1990–2013) describing the winter distributional abundance of 25 waterbird species. We calculated the annual and long-term (3-year periods) population centroid of each species and used the winter North Atlantic Oscillation (NAO) index to explain the inter-annual and long-term shifts in their location. Results: (a) Year-to-year southwestwards shifts in the population centroids of deep- and shallow-water species were linked to negative NAO values. Shallow-water species shifted northeastwards associated with positive NAO values and the distance shifted increased with increasing NAO. Deep-water species shifted northeastwards up to zero NAO indices, but showed no further increase at higher NAO values. (b) Deep-water species showed long-term northeastwards shifts in distributional abundance throughout the 1990s and the 2000s. Shallow-water species, on the other hand, shifted northeastwards during the 1990s and early 2000s, but southwestwards thereafter. There were no significant links between the NAO and year-to-year movements or long-term shifts in farmland species’ population centroid. Main Conclusions: We provide evidence for a link between both year-to-year and long-term changes in waterbird winter distributional abundances at large geographical scales to short- and long-term changes in winter weather conditions. We also show that species using shallow water, deep-water and farmland habitats responded differently, especially at high NAO values. As well as important ecological implications, these findings contribute to the development of future conservation measures for these species under current and future climate change.
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