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- Carter, Helen, et al.
(författare)
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A planning palimpsest: neoliberal planning in a welfare state tradition
- 2015
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Ingår i: European Journal of Spatial Development. - 1650-9544. ; :58, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- In this article, we analyse the evolution and transformation of Danish spatial planning from its tentative origins in liberalist politics, through its rise as a central feature of the welfare state project, to its more recent entrepreneurial forms in a context of neoliberalisation. The article demonstrates how transformations of Danish spatial planning discourses and practices must be understood in context of previous discourses and practices sedimented as layers of meaning and materiality through time and over space. These layers do not completely overlay one another, but present a palimpsest saturated with contradictions as well as possibilities. We propose the notion of the ‘planning palimpsest’ as a helpful metaphor for drawing attention to the historical-geographical characteristics of planning discourses and practices.
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- Ghouse, Jonas, et al.
(författare)
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Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors
- 2021
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 78:7, s. 696-709
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensinconverting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. OBJECTIVES The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema. METHODS A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors #180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. RESULTS The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 x 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 x 10-9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 x 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI:-0.83 to-0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI:-0.46 to-0.05; P = 0.013) blood pressure. CONCLUSIONS In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor-related angioedema.
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- Granath, Carl, et al.
(författare)
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Characterization of Laminins in Healthy Human Aortic Valves and a Modified Decellularized Rat Scaffold
- 2020
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Ingår i: BioResearch Open Access. - : Mary Ann Liebert. - 2164-7844 .- 2164-7860. ; 9:1, s. 269-278
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Tidskriftsartikel (refereegranskat)abstract
- Aortic valve stenosis is one of the most common cardiovascular diseases in western countries and can only be treated by replacement with a prosthetic valve. Tissue engineering is an emerging and promising treatment option, but in-depth knowledge about the microstructure of native heart valves is lacking, making the development of tissue-engineered heart valves challenging. Specifically, the basement membrane (BM) of heart valves remains incompletely characterized, and decellularization protocols that preserve BM components are necessary to advance the field. This study aims to characterize laminin isoforms expressed in healthy human aortic valves and establish a small animal decellularized aortic valve scaffold for future studies of the BM in tissue engineering. Laminin isoforms were assessed by immunohistochemistry with antibodies specific for individual alpha, beta, and gamma chains. The results indicated that LN-411, LN-421, LN-511, and LN-521 are expressed in human aortic valves (n = 3), forming a continuous monolayer in the endothelial BM, whereas sparsely found in the interstitium. Similar results were seen in rat aortic valves (n = 3). Retention of laminin and other BM components, concomitantly with effective removal of cells and residual DNA, was achieved through 3 h exposure to 1% sodium dodecyl sulfate and 30 min exposure to 1% Triton X-100, followed by nuclease processing in rat aortic valves (n = 3). Our results provide crucial data on the microenvironment of valvular cells relevant for research in both tissue engineering and heart valve biology. We also describe a decellularized rat aortic valve scaffold useful for mechanistic studies on the role of the BM in heart valve regeneration.
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- Iveson, Timothy J., et al.
(författare)
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3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT) : an international, randomised, phase 3, non-inferiority trial
- 2018
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Ingår i: The Lancet Oncology. - : ELSEVIER SCIENCE INC. - 1470-2045 .- 1474-5488. ; 19:4, s. 562-578
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Tidskriftsartikel (refereegranskat)abstract
- Background: 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment.Methods: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1: 1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1.13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing.Findings: 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76.7% (95% CI 75.1-78.2) for the 3 month group and 77.1% (75.6-78.6) for the 6 month group, giving a hazard ratio of 1.006 (0.909-1.114, test for non-inferiority p=0.012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group).Interpretation: In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care.
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| 7. |
- Lövgren, Ingemar, 1972, et al.
(författare)
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Fracture properties of FRC determined through inverse analysis of wedge splitting and three-point bending tests
- 2005
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Ingår i: Journal of Advanced Concrete Technology. ; 3:3, s. 425-436
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Tidskriftsartikel (refereegranskat)abstract
- Fracture properties of five different steel fibre-reinforced concretes have been determined, using the wedge splitting test method (WST) and three-point bending tests (3PBT). Furthermore, for the WST method, two different specimen sizes have been investigated. Through inverse analyses, stress-crack opening (s-w) relationships have been determined for each mix and test method. Results from this investigation demonstrate the applicability of the WST method, show that inverse analysis can be used to determine stress-crack opening relationships, and the result demonstrate the effect of increased fibre content and the w/b-ratio. The major factor contributing to the differences in the determined stress-crack opening relationships is believed to be related to the variation in the number of fibres across the fracture plane. However, taking this into consideration, the inverse analyses indicate no systematic differences in the determined parameters between two WST specimen sizes, while the 3PBT seems to give slightly higher post-cracking stresses.
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| 9. |
- Olesen, Kim, et al.
(författare)
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Diversity of respiratory parameters and metabolic adaptation to low oxygen tension in mesenchymal stromal cells
- 2022
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Ingår i: Metabolism Open. - : Elsevier. - 2589-9368. ; 13:March
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveCell metabolism has been shown to play an active role in regulation of stemness and fate decision. In order to identify favorable culture conditions for mesenchymal stromal cells (MSCs) prior to transplantation, this study aimed to characterize the metabolic function of MSCs from different developmental stages in response to different oxygen tension during expansion.Materials and methodsWe cultured human fetal cardiac MSCs and human adult bone-marrow MSCs for a week under hypoxia (3% O2) and normoxia (20% O2). We performed mitochondrial characterization and assessed oxygen consumption- and extracellular acidification-rates (OCR and ECAR) in addition to oxygen-sensitive respiration and mitochondrial complex activities, using both the Seahorse and Oroboros systems.ResultsAdult and fetal MSCs displayed similar basal respiration and mitochondrial amount, however fetal MSCs had lower spare respiratory capacity and apparent coupling efficiency. Fetal MSCs expanded in either hypoxia or normoxia demonstrated similar acidification rates, while adult MSCs downregulated their aerobic glycolysis in normoxia. Acute decrease in oxygen tension caused a higher respiratory inhibition in adult compared to fetal MSCs. In both sources of MSCs, minor changes in complex activities in normoxic and hypoxic cultures were found.ConclusionsIn contrast to adult MSCs, fetal MSCs displayed similar respiration and aerobic glycolysis at different O2 culture concentrations during expansion. Adult MSCs adjusted their respiration to glycolytic activities, depending on the culture conditions thus displaying a more mature metabolic function. These findings are relevant for establishing optimal in vitro culturing conditions, with the aim to maximize engraftment and therapeutic outcome.
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| 10. |
- Olesen, Kim
(författare)
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Extracellular factors for preservation and delivery of stromal cells
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Modulating the immune response after a myocardial infarction seems like an appropriate strategy for reducing myocardial fibrosis. Mesenchymal Stromal Cells are immunomodulatory and have thus gained interest, but have so far not achieved the desired clinical outcomes. This is believed to due to the loss of their immunomodulatory and proliferative capacity during expansion and poor cell survival and retention upon delivery to the myocardium. The use of extracellular factors such as extracellular matrices, paracrine factors, nutrients as well as manipulation gas composition during culture might be used to overcome some of these shortcomings, which is further explored in this thesis.We demonstrated in Study I, that encapsulation of human cells by thermos-responsive microcapsules, which upon exposure to physiological temperature partially decompose and enable release of the cells. The hydrogel combination of agarose, gelatin and fibrinogen provided both thermos-responsive features and attachment points for the cells, preventing cell death. However, additional components can be used to support the encapsulated cells while retaining the thermo-responsiveness. In order to discover such components, we developed an in vitro model to study the cell- and extracellular matrix dynamics making use of the organ’s extracellular matrix and define anatomical regions that are capable of retaining the desired phenotype of the cell. To generate such a syngeneic model, naïve stromal cells were isolated from fetal rat hearts, and cultured on decellularized extracellular matrix sections of adult rat hearts. We found that when culturing cells with pericyte-like characteristics on the matrices, the surface marker expressions of CD146 and PDGFR-β were depending on the matrix composition, and especially of laminin alpha 4. Cells expressing CD146 were mainly located to the atrioventricular junction and to the perivascular niche, while PDGFR-β expression was more widespread. Since CD146 is also a potency marker for Mesenchymal Stromal Cells, these results indicate a matrix dependent niche for naïve stromal cells. These findings were next verified by immunohistochemistry of the native rat heart, where CD146 populations were mainly found in the atrioventricular and perivascular niche.In Study III, we explored the preferred metabolism of adult and fetal MSCs. It is known that proliferating stem-, progenitor cells utilize glycolysis, even in presence of oxygen. Therefore, we wanted to explore the metabolic profiles of human fetal (naïve) and MSCs during culture in either hypoxia 3% (close to physiological oxygen tension) or normoxia 20%. Adult MSCs grown in hypoxia retained oxidative phosphorylation and increased glycolytic activity, adapting a progenitor metabolic profile while in normoxia the adult MSCs down-regulated glycolysis and adapted an adult, or differentiated cell metabolic profile. Fetal MSCs demonstrated preserved oxidative phosphorylation and glycolytic activity regardless of oxygen tension, thus exhibiting a stem-, progenitor metabolic profile.The findings from these studies might help in designing future culture protocols and delivery systems for cell therapies.
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