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| 2. |
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| 3. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 4. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 9. |
- Mouthaan, B. E., et al.
(författare)
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Current use of imaging and electromagnetic source localization procedures in epilepsy surgery centers across Europe
- 2016
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Ingår i: Epilepsia. - : Wiley. - 0013-9580. ; 57:5, s. 770-776
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Tidskriftsartikel (refereegranskat)abstract
- Objective: In 2014 the European Union-funded E-PILEPSY project was launched to improve awareness of, and accessibility to, epilepsy surgery across Europe. We aimed to investigate the current use of neuroimaging, electromagnetic source localization, and imaging postprocessing procedures in participating centers. Methods: A survey on the clinical use of imaging, electromagnetic source localization, and postprocessing methods in epilepsy surgery candidates was distributed among the 25 centers of the consortium. A descriptive analysis was performed, and results were compared to existing guidelines and recommendations. Results: Response rate was 96%. Standard epilepsy magnetic resonance imaging (MRI) protocols are acquired at 3 Tesla by 15 centers and at 1.5 Tesla by 9 centers. Three centers perform 3T MRI only if indicated. Twenty-six different MRI sequences were reported. Six centers follow all guideline-recommended MRI sequences with the proposed slice orientation and slice thickness or voxel size. Additional sequences are used by 22 centers. MRI postprocessing methods are used in 16 centers. Interictal positron emission tomography (PET) is available in 22 centers; all using 18F-fluorodeoxyglucose (FDG). Seventeen centers perform PET postprocessing. Single-photon emission computed tomography (SPECT) is used by 19 centers, of which 15 perform postprocessing. Four centers perform neither PET nor SPECT in children. Seven centers apply magnetoencephalography (MEG) source localization, and nine apply electroencephalography (EEG) source localization. Fourteen combinations of inverse methods and volume conduction models are used. Significance: We report a large variation in the presurgical diagnostic workup among epilepsy surgery centers across Europe. This diversity underscores the need for highquality systematic reviews, evidence-based recommendations, and harmonization of available diagnostic presurgical methods.
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| 10. |
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| 11. |
- Kobulashvili, T., et al.
(författare)
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Current practices in long-term video-EEG monitoring services: A survey among partners of the E-PILEPSY pilot network of reference for refractory epilepsy and epilepsy surgery
- 2016
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Ingår i: Seizure-European Journal of Epilepsy. - : Elsevier BV. - 1059-1311. ; 38, s. 38-45
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The European Union-funded E-PILEPSY network aims to improve awareness of, and accessibility to, epilepsy surgery across Europe. In this study we assessed current clinical practices in epilepsy monitoring units (EMUs) in the participating centers. Method: A 60-item web-based survey was distributed to 25 centers (27 EMUs) of the E-PILEPSY network across 22 European countries. The questionnaire was designed to evaluate the characteristics of EMUs, including organizational aspects, admission, and observation of patients, procedures performed, safety issues, cost, and reimbursement. Results: Complete responses were received from all (100%) EMUs surveyed. Continuous observation of patients was performed in 22 (81%) EMUs during regular working hours, and in 17 EMUs (63%) outside of regular working hours. Fifteen (56%) EMUs requested a signed informed consent before admission. All EMUs performed tapering/withdrawal of antiepileptic drugs, 14 (52%) prior to admission to an EMU. Specific protocols on antiepileptic drugs (AED) tapering were available in four (15%) EMUs. Standardized Operating Procedures (SOP) for the treatment of seizure clusters and status epilepticus were available in 16 (59%). Safety measures implemented by EMUs were: alarm seizure buttons in 21 (78%), restricted patient's ambulation in 19 (70%), guard rails in 16 (59%), and specially designated bathrooms in 7 (26%). Average costs for one inpatient day in EMU ranged between 100 and 2200 Euros. Conclusion: This study shows a considerable diversity in the organization and practice patterns across European epilepsy monitoring units. The collected data may contribute to the development and implementation of evidence-based recommended practices in LTM services across Europe. (C) 2016 The Authors. Published by Elsevier Ltd. on behalf of British Epilepsy Association.
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| 12. |
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| 13. |
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| 14. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 15. |
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| 16. |
- Berre, I., et al.
(författare)
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Verification benchmarks for single-phase flow in three-dimensional fractured porous media
- 2021
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Ingår i: Advances in Water Resources. - OXFORD ENGLAND : Elsevier BV. - 0309-1708 .- 1872-9657. ; 147
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Tidskriftsartikel (refereegranskat)abstract
- Flow in fractured porous media occurs in the earth's subsurface, in biological tissues, and in man-made materials. Fractures have a dominating influence on flow processes, and the last decade has seen an extensive development of models and numerical methods that explicitly account for their presence. To support these developments, four benchmark cases for single-phase flow in three-dimensional fractured porous media are presented. The cases are specifically designed to test the methods’ capabilities in handling various complexities common to the geometrical structures of fracture networks. Based on an open call for participation, results obtained with 17 numerical methods were collected. This paper presents the underlying mathematical model, an overview of the features of the participating numerical methods, and their performance in solving the benchmark cases.
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| 18. |
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| 19. |
- Li, D. Y., et al.
(författare)
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H19 Induces Abdominal Aortic Aneurysm Development and Progression
- 2018
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 138:15, s. 1551-1568
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Tidskriftsartikel (refereegranskat)abstract
- Background: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. Methods: We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient (ApoE(-/-)) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. Results: Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1 as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1 and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1 via recruiting the transcription factor specificity protein 1 to the promoter region. Conclusions: The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.
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| 20. |
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| 21. |
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| 22. |
- de Winter, J M, et al.
(författare)
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KBTBD13 is an actin-binding protein that modulates muscle kinetics
- 2020
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Ingår i: Journal of Clinical Investigation. - : Stanford University Press. - 0021-9738 .- 1558-8238. ; 130:2, s. 754-767
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13(R408c)-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.
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| 23. |
- Fowler, A. M., et al.
(författare)
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Environmental benefits of leaving offshore infrastructure in the ocean
- 2018
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Ingår i: Frontiers in Ecology and the Environment. - : Wiley. - 1540-9295. ; 16:10, s. 571-578
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Tidskriftsartikel (refereegranskat)abstract
- The removal of thousands of structures associated with oil and gas development from the world's oceans is well underway, yet the environmental impacts of this decommissioning practice remain unknown. Similar impacts will be associated with the eventual removal of offshore wind turbines. We conducted a global survey of environmental experts to guide best decommissioning practices in the North Sea, a region with a substantial removal burden. In contrast to current regulations, 94.7% of experts (36 out of 38) agreed that a more flexible case-by-case approach to decommissioning could benefit the North Sea environment. Partial removal options were considered to deliver better environmental outcomes than complete removal for platforms, but both approaches were equally supported for wind turbines. Key considerations identified for decommissioning were biodiversity enhancement, provision of reef habitat, and protection from bottom trawling, all of which are negatively affected by complete removal. We provide recommendations to guide the revision of offshore decommissioning policy, including a temporary suspension of obligatory removal.
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| 24. |
- Hjerpe, A, et al.
(författare)
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Guidelines for cytopathologic diagnosis of epithelioid and mixed type malignant mesothelioma. Complementary statement from the International Mesothelioma Interest Group, also endorsed by the International Academy of Cytology and the Papanicolaou Society of Cytopathology
- 2015
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Ingår i: CytoJournal. - : Scientific Scholar. - 0974-5963 .- 1742-6413. ; 12, s. 26-
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Tidskriftsartikel (refereegranskat)abstract
- To provide practical guidelines for the cytopathologic diagnosis of malignant mesothelioma (MM). Cytopathologists involved in the International Mesothelioma Interest Group (IMIG) and the International Academy of Cytology (IAC), who have an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. This article is the result of discussions during and after the IMIG 2012 conference in Boston, followed by thorough discussions during the 2013 IAC meeting in Paris. Additional contributions have been obtained from cytopathologists and scientists, who could not attend these meetings, with final discussions and input during the IMIG 2014 conference in cape town. During the previous IMIG biennial meetings, thorough discussions have resulted in published guidelines for the pathologic diagnosis of MM. However, previous recommendations have stated that the diagnosis of MM should be based on histological material only.[12] Accumulating evidence now indicates that the cytological diagnosis of MM supported by ancillary techniques is as reliable as that based on histopathology, although the sensitivity with cytology may be somewhat lower.[345] Recognizing that noninvasive diagnostic modalities benefit both the patient and the health system, future recommendations should include cytology as an accepted method for the diagnosis of this malignancy.[67] The article describes the consensus of opinions of the authors on how cytology together with ancillary testing can be used to establish a reliable diagnosis of MM.
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| 30. |
- Singleton, E. H., et al.
(författare)
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The behavioral variant of Alzheimer’s disease does not show a selective loss of Von Economo and phylogenetically related neurons in the anterior cingulate cortex
- 2022
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer’s disease (bvAD) remain unclear. A selective loss of Von Economo neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD. Methods: VENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n = 9) and compared to typical AD (tAD, n = 6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n = 18) and controls (n = 13) using ANCOVAs adjusted for age and Bonferroni corrected. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss. Results: The number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0 ± 15.3, GABRQ-ir pyramidal: 260.4 ± 87.1) and tAD (VENs: 32.0 ± 18.1, p = 1.00, GABRQ-ir pyramidal: 349.8 ± 109.6, p = 0.38) and controls (VENs: 33.5 ± 20.3, p = 1.00, GABRQ-ir pyramidal: 339.4 ± 95.9, p = 0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.5 ± 82.658, p = 0.01) and no significant differences in number of VENs (bvFTD: 10.9 ± 13.8, p = 0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5. Discussion: VENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.
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| 31. |
- Söderqvist, T., et al.
(författare)
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Socio-economic Analysis of a Selected Multi-use Offshore Site in the North Sea
- 2017
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Ingår i: In: Koundouri P. (eds) The Ocean of Tomorrow. Environment & Policy, vol 56. Springer, Cham. - 9783319557700 ; , s. 43-67
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Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- A 600 MW offshore wind farm is under construction in the Netherlands Exclusive Economic Zone at a site called Gemini situated 55 km north of the Wadden Sea island of Schiermonnikoog and 85 km from the nearest Dutch port ofEemshaven. This chapter investigates the option of introducing a multi-use design for the Gemini site by adding mussel cultivation (48 kt wet weight per year) andseaweed cultivation (480 kt wet weight per year) to the wind farm. An institutional analysis indicates a political will in the Netherlands to support the development ofadding uses to offshore wind farms, but a number of implementation obstacles are also identified. Those obstacles include an absence of licences for multi-use production and legal restrictions against third-party access to wind farms. There istherefore a need for a regulatory framework for multi-use and trust-building amongactors involved in multi-use installations. A financial and economic assessment,and a cost-benefit analysis also taking into account monetized changes in CO2 emissions, indicate that adding mussel cultivation to the wind farm is likely to be both financially and socio-economically viable. Including a seaweed cultivation function is probably not financially and socio-economically viable under currenttechnical and economic conditions. Knowledge gaps and uncertainties in these assessments with respect to, for example, missing site-specific data and non-monetizedexternalities suggest further research, also including pilot cultivations of mussels and seaweed in planned single-use or multi-use installations.
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| 32. |
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| 33. |
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| 34. |
- Bartelt, Alexander, et al.
(författare)
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Thermogenic adipocytes promote HDL turnover and reverse cholesterol transport
- 2017
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Brown and beige adipocytes combust nutrients for thermogenesis and through their metabolic activity decrease pro-atherogenic remnant lipoproteins in hyperlipidemic mice. However, whether the activation of thermogenic adipocytes affects the metabolism and anti-atherogenic properties of high-density lipoproteins (HDL) is unknown. Here, we report a reduction in atherosclerosis in response to pharmacological stimulation of thermogenesis linked to increased HDL levels in APOE(star)3-Leiden. CETP mice. Both cold-induced and pharmacological thermogenic activation enhances HDL remodelling, which is associated with specific lipidomic changes in mouse and human HDL. Furthermore, thermogenic stimulation promotes HDL-cholesterol clearance and increases macrophage-to-faeces reverse cholesterol transport in mice. Mechanistically, we show that intravascular lipolysis by adipocyte lipoprotein lipase and hepatic uptake of HDL by scavenger receptor B-I are the driving forces of HDL-cholesterol disposal in liver. Our findings corroborate the notion that high metabolic activity of thermogenic adipocytes confers atheroprotective properties via increased systemic cholesterol flux through the HDL compartment.
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| 35. |
- Baud, Maxime O, et al.
(författare)
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European trends in epilepsy surgery.
- 2018
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Ingår i: Neurology. - 1526-632X. ; 91:2
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Tidskriftsartikel (refereegranskat)abstract
- Resective surgery is effective in treating drug-resistant focal epilepsy, but it remains unclear whether improved diagnostics influence postsurgical outcomes. Here, we compared practice and outcomes over 2 periods 15 years apart.Sixteen European centers retrospectively identified 2 cohorts of children and adults who underwent epilepsy surgery in the period of 1997 to 1998 (n = 562) or 2012 to 2013 (n = 736). Data collected included patient (sex, age) and disease (duration, localization and diagnosis) characteristics, type of surgery, histopathology, Engel postsurgical outcome, and complications, as well as imaging and electrophysiologic tests performed for each case. Postsurgical outcome predictors were included in a multivariate logistic regression to assess the strength of date of surgery as an independent predictor.Over time, the number of operated cases per center increased from a median of 31 to 50 per 2-year period (p = 0.02). Mean disease duration at surgery decreased by 5.2 years (p < 0.001). Overall seizure freedom (Engel class 1) increased from 66.7% to 70.9% (adjusted p = 0.04), despite an increase in complex surgeries (extratemporal and/or MRI negative). Surgeries performed during the later period were 1.34 times (adjusted odds ratio; 95% confidence interval 1.02-1.77) more likely to yield a favorable outcome (Engel class I) than earlier surgeries, and improvement was more marked in extratemporal and MRI-negative temporal epilepsy. The rate of persistent neurologic complications remained stable (4.6%-5.3%, p = 0.7).Improvements in European epilepsy surgery over time are modest but significant, including higher surgical volume, shorter disease duration, and improved postsurgical seizure outcomes. Early referral for evaluation is required to continue on this encouraging trend.
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| 36. |
- Boon, Hanneke, 1981-, et al.
(författare)
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Intravenous AICAR administration reduces hepatic glucose output and inhibits whole body lipolysis in type 2 diabetic patients
- 2008
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Ingår i: Diabetologia. - Heidelberg : Springer Berlin/Heidelberg. - 0012-186X .- 1432-0428. ; 51:10, s. 1893-1900
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The 5'-AMP-activated protein kinase (AMPK) pathway is intact in type 2 diabetic patients and is seen as a target for diabetes treatment. In this study, we aimed to assess the impact of the AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR) on both glucose and fatty acid metabolism in vivo in type 2 diabetic patients. METHODS: Stable isotope methodology and blood and muscle biopsy sampling were applied to assess blood glucose and fatty acid kinetics following continuous i.v. infusion of AICAR (0.75 mg kg(-1) min(-1)) and/or NaCl (0.9%) in ten male type 2 diabetic patients (age 64 +/- 2 years; BMI 28 +/- 1 kg/m(2)). RESULTS: Plasma glucose rate of appearance (R (a)) was reduced following AICAR administration, while plasma glucose rate of disappearance (R (d)) was similar in the AICAR and control test. Consequently, blood glucose disposal (R (d) expressed as a percentage of R (a)) was increased following AICAR infusion (p < 0.001). Accordingly, a greater decline in plasma glucose concentration was observed following AICAR infusion (p < 0.001). Plasma NEFA R (a) and R (d) were both significantly reduced in response to AICAR infusion, and were accompanied by a significant decline in plasma NEFA concentration. Although AMPK phosphorylation in skeletal muscle was not increased, we observed a significant increase in acetyl-CoA carboxylase phosphorylation (p < 0.001). CONCLUSIONS/INTERPRETATION: The i.v. administration of AICAR reduces hepatic glucose output, thereby lowering blood glucose concentrations in vivo in type 2 diabetic patients. Furthermore, AICAR administration stimulates hepatic fatty acid oxidation and/or inhibits whole body lipolysis, thereby reducing plasma NEFA concentration. © 2008 The Author(s).
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| 37. |
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| 38. |
- Bruce, Louise C, et al.
(författare)
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A multi-lake comparative analysis of the General Lake Model (GLM) : Stress-testing across a global observatory network
- 2018
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Ingår i: Environmental Modelling & Software. - : Elsevier BV. - 1364-8152 .- 1873-6726. ; 102, s. 274-291
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Tidskriftsartikel (refereegranskat)abstract
- The modelling community has identified challenges for the integration and assessment of lake models due to the diversity of modelling approaches and lakes. In this study, we develop and assess a one-dimensional lake model and apply it to 32 lakes from a global observatory network. The data set included lakes over broad ranges in latitude, climatic zones, size, residence time, mixing regime and trophic level. Model performance was evaluated using several error assessment metrics, and a sensitivity analysis was conducted for nine parameters that governed the surface heat exchange and mixing efficiency. There was low correlation between input data uncertainty and model performance and predictions of temperature were less sensitive to model parameters than prediction of thermocline depth and Schmidt stability. The study provides guidance to where the general model approach and associated assumptions work, and cases where adjustments to model parameterisations and/or structure are required.
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| 39. |
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| 40. |
- Chernogubova, E, et al.
(författare)
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Genetic Depletion of the Long Non-coding RNA H19 in Mice Protects from Elastase-induced Abdominal Aortic Aneurysms
- 2018
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Ingår i: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY. - : Ovid Technologies (Wolters Kluwer Health). - 1079-5642 .- 1524-4636. ; 38
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Long noncoding RNAs (lncRNAs) have been shown as crucial molecular regulators in various biological processes and diseases. Recently we demonstrated that lncRNA H19 is highly upregulated during abdominal aortic aneurysm (AAA) development and progression in murine models (Angiotensin II in ApoE-/- mice; porcine pancreatic elastase model (PPE) in C57BL/6 mice). Experimental H19 knock-down using specific antisense LNA oligonucleotides showed a significant reduction in AAA growth in both models. Aim of this current study was to utilize genetically mutated H19-depleted mice (H19-/-) vs. wildtype littermate controls, to assess their behavior upon experimental AAA induction using PPE. In addition, we studied the proliferation rates of smooth muscle cells, originating from either H19-/- or H19+/+ mice in a kinetic live-cell imaging system. H19-/- on a C57BL/6J background were exposed to PPE. The aortic diameter in H19-/- mice was compared to WT littermate controls (upon PPE-AAA induction) at baseline, and then consecutively at days 7, 14, and 28. Primary mouse aortic smooth muscle cells were isolated from wild type or H19-depleted aortas, and cultured and monitored in the IncuCyte live cell imaging system for 48 hours, in an effort to study their proliferation rate. H19-/- mice upon PPE-AAA induction displayed significantly lower diameters throughout the study compared to WT controls. Primary aortic smooth muscle cells from H19-depleted mice showed greatly increased proliferation rates (based on cell confluency detection) in our kinetic live-cell imaging system in comparison to WT control cells. In conclusion, our study in H19-depleted mice supports our previously presented efforts, that H19 is an important contributor to experimental AAA development and progression. Further mechanistic studies will have to reveal the molecular properties of this long non-coding RNA in smooth muscle cell survival and proliferation.
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| 41. |
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| 42. |
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| 43. |
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| 44. |
- Getahun, H, et al.
(författare)
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Management of latent Mycobacterium tuberculosis infection: WHO guidelines for low tuberculosis burden countries
- 2015
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 46:6, s. 1563-1576
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Tidskriftsartikel (refereegranskat)abstract
- Latent tuberculosis infection (LTBI) is characterised by the presence of immune responses to previously acquired Mycobacterium tuberculosis infection without clinical evidence of active tuberculosis (TB). Here we report evidence-based guidelines from the World Health Organization for a public health approach to the management of LTBI in high risk individuals in countries with high or middle upper income and TB incidence of <100 per 100 000 per year. The guidelines strongly recommend systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating anti-tumour necrosis factor treatment, patients receiving dialysis, patients preparing for organ or haematological transplantation, and patients with silicosis. In prisoners, healthcare workers, immigrants from high TB burden countries, homeless persons and illicit drug users, systematic testing and treatment of LTBI is conditionally recommended, according to TB epidemiology and resource availability. Either commercial interferon-gamma release assays or Mantoux tuberculin skin testing could be used to test for LTBI. Chest radiography should be performed before LTBI treatment to rule out active TB disease. Recommended treatment regimens for LTBI include: 6 or 9 month isoniazid; 12 week rifapentine plus isoniazid; 3–4 month isoniazid plus rifampicin; or 3–4 month rifampicin alone.
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| 45. |
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| 46. |
- Harju, Mikael, et al.
(författare)
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Quantitative Structure–Activity Relationship Modeling on in Vitro Endocrine Effects and Metabolic Stability Involving 26 Selected Brominated Flame Retardants
- 2007
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Ingår i: Environmental Toxicology and Chemistry. - 1552-8618. ; 26:4, s. 816-26
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Tidskriftsartikel (refereegranskat)abstract
- In this work, quantitative structure–activity relationships (QSARs) were developed to aid human and environmental risk assessment processes for brominated flame retardants (BFRs). Brominated flame retardants, such as the high-production-volume chemicals polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A, and hexabromocyclododecane, have been identified as potential endocrine disruptors. Quantitative structure–activity relationship models were built based on the in vitro potencies of 26 selected BFRs. The in vitro assays included interactions with, for example, androgen, progesterone, estrogen, and dioxin (aryl hydrocarbon) receptor, plus competition with thyroxine for its plasma carrier protein (transthyretin), inhibition of estradiol sulfation via sulfotransferase, and finally, rate of metabolization. The QSAR modeling, a number of physicochemical parameters were calculated describing the electronic, lipophilic, and structural characteristics of the molecules. These include frontier molecular orbitals, molecular charges, polarities, log octanol/water partitioning coefficient, and two- and three-dimensional molecular properties. Experimental properties were included and measured for PBDEs, such as their individual ultraviolet spectra (200–320 nm) and retention times on three different high-performance liquid chromatography columns and one nonpolar gas chromatography column. Quantitative structure–activity relationship models based on androgen antagonism and metabolic degradation rates generally gave similar results, suggesting that lower-brominated PBDEs with bromine substitutions in ortho positions and bromine-free meta- and para positions had the highest potencies and metabolic degradation rates. Predictions made for the constituents of the technical flame retardant Bromkal 70-5DE found BDE 17 to be a potent androgen antagonist and BDE 66, which is a relevant PBDE in environmental samples, to be only a weak antagonist.
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| 47. |
- Hoeger, Peter H., et al.
(författare)
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Treatment of infantile haemangiomas: recommendations of a European expert group
- 2015
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Ingår i: European Journal of Pediatrics. - : Springer Science and Business Media LLC. - 1432-1076 .- 0340-6199. ; 174:7, s. 855-865
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Forskningsöversikt (refereegranskat)abstract
- With a prevalence of 2.6-4.5 %, infantile haemangiomas (IH) represent the most common tumour of infancy. While the majority of IH does not require therapy and regresses spontaneously, about 10 % of IH exhibit complications such as obstruction, ulceration or disfigurement. With the advent of oral propranolol, many conventional treatment options have become obsolete. This paper summarizes current recommendations for management of complicated IH. These recommendations have been written by an expert group after a consensus process including bibliographic review, several drafts of synthesis, meetings with quantitative voting system and redaction of an approved final manuscript. Conclusion: Oral propranolol is the first-line agent for the treatment of complicated IH.
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| 48. |
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| 49. |
- Kuehlewein, Laura, et al.
(författare)
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Clinical phenotype and course of PDE6A-associated retinitis pigmentosa disease, characterized in preparation for a gene supplementation trial
- 2020
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Ingår i: JAMA Ophthalmology. - : American Medical Association (AMA). - 2168-6165. ; 138:12, s. 1241-1250
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Treatment trials require sound knowledge on the natural course of disease. OBJECTIVE To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with retinitis pigmentosa (RP) associated with biallelic sequence variations in the PDE6A gene in preparation for a gene supplementation trial. DESIGN, SETTING, AND PARTICIPANTS This prospective, longitudinal, observational cohort study was conducted from January 2001 to December 2019 in a single center (Centre for Ophthalmology of the University of Tübingen, Germany) with patients recruited multinationally from 12 collaborating European tertiary referral centers. Patients with retinitis pigmentosa, sequence variants in PDE6A, and the ability to provide informed consent were included. EXPOSURES Comprehensive ophthalmological examinations; validation of compound heterozygosity and biallelism by familial segregation analysis, allelic cloning, or assessment of next-generation sequencing-read data, where possible. MAIN OUTCOMES AND MEASURES Genetic findings and clinical features describing the entire cohort and comparing patients harboring the 2 most common disease-causing variants in a homozygous state (c.304C>A;p.(R102S) and c.998 + 1G>A;p.?). RESULTS Fifty-seven patients (32 female patients [56%]; mean [SD], 40 [14] years) from 44 families were included. All patients completed the study. Thirty patients were homozygous for disease-causing alleles. Twenty-seven patients were heterozygous for 2 different PDE6A variants each. The most frequently observed alleles were c.304C>A;p.(R102S), c.998 + 1G>A;p.?, and c.2053G>A;p.(V685M). The mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50). The median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11 019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees). Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%). Sixty-nine of 108 eyes (62.9%) showed additional findings on optical coherence tomography imaging (eg, cystoid macular edema or macular atrophy). The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S). CONCLUSIONS AND RELEVANCE Seventeen of the PDE6A variants found in these patients appeared to be novel. Regarding the clinical findings, disease was highly symmetrical between the right and left eyes and visual impairment was mild or moderate in 90% of patients, providing a window of opportunity for gene therapy.
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| 50. |
- Kurzejamska, E, et al.
(författare)
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C/EBPβ expression is an independent predictor of overall survival in breast cancer patients by MHCII/CD4-dependent mechanism of metastasis formation.
- 2014
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Ingår i: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 281, s. 441-442
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Tidskriftsartikel (refereegranskat)abstract
- CCAAT-enhancer binding protein β (C/EBPβ) is a transcription factor that has a critical role in mammary gland development and breast cancer progression. Loss of C/EBPβ increases metastatic dissemination of mouse mammary tumor cells. However, the mechanism by which C/EBPβ expression affects metastasis formation remains unknown. This study aims at determining the relationship between C/EBPβ and survival of breast cancer patients, and elucidating C/EBPβ's link with metastasis formation. C/EBPβ expression was evaluated in 137 cases of human breast cancer, and the correlation with overall survival was estimated by Kaplan-Meier analysis. Additionally, the mouse 4T1 tumor model was used for in vivo studies. Decreased C/EBPβ expression was found to be associated with shorter overall survival of breast cancer patients. In the murine 4T1 model, loss of C/EBPβ affects tumor growth, morphology and promotes metastatic spread to the lungs. Immunohistochemical analyses showed that C/EBPβ inhibition leads to increased major histocompatibility complex II (MHCII) expression, followed by the accumulation of CD45-, CD3- and CD4-positive (CD4+) lymphocytes in the tumors. Inflammation involvement in C/EBPβ-mediated metastasis formation was confirmed by DNA microarray and by experiments on CD4+ cell-deprived nude mice. Additionally, anti-CD3 and anti-CD4 treatments of C/EBPβ-silenced tumor-bearing mice resulted in reverting the C/EBPβ effect on tumor growth and metastasis. Altogether, C/EBPβ is a predictor of overall survival in breast cancer patients, and affects tumor growth, morphology and lung metastasis formation in murine 4T1 model. The mechanism of metastasis formation involves immunologic response depending on C/EBPβ-mediated activation of MHCII and accumulation of CD4+ lymphocytes in the tumor.
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