| 1. |
- Pulit, SL, et al.
(författare)
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Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study.
- 2016
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Ingår i: The Lancet. Neurology. - 1474-4465. ; 15:2, s. 174-84
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Tidskriftsartikel (refereegranskat)abstract
- The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes.To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16851 cases with state-of-the-art phenotyping data and 32473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20941 cases and 364736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis.We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50×10(-8); joint OR 1·19, 1·12-1·26, p=1·30×10(-9)). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26×10(-19); joint OR 1·37, 1·30-1·45, p=2·79×10(-32)) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93×10(-7); joint OR 1·17, 1·11-1·23, p=2·29×10(-10)) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50×10(-8); joint OR 1·24, 1·15-1·33, p=4·52×10(-9)) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82×10(-8); joint OR 1·17, 1·11-1·23, p=2·92×10(-9)). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed.Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke.US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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| 2. |
- Bonkhoff, A. K., et al.
(författare)
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Outcome after acute ischemic stroke is linked to sex-specific lesion patterns
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n=503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke.
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| 3. |
- Bonkhoff, A. K., et al.
(författare)
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Sex-specific lesion pattern of functional outcomes after stroke
- 2022
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Relying on neuroimaging and clinical data of 822 acute stroke patients, Bonkhoff et al. report substantially more detrimental effects of lesions in left-hemispheric posterior circulation regions on functional outcomes in women compared to men. These findings may motivate a sex-specific clinical stroke management to improve outcomes in the longer term. Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.
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| 4. |
- Cole, J. W., et al.
(författare)
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The copy number variation and stroke (CaNVAS) risk and outcome study
- 2021
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:4 April
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose The role of copy number variation (CNV) variation in stroke susceptibility and outcome has yet to be explored. The Copy Number Variation and Stroke (CaNVAS) Risk and Outcome study addresses this knowledge gap. Methods Over 24,500 well-phenotyped IS cases, including IS subtypes, and over 43,500 controls have been identified, all with readily available genotyping on GWAS and exome arrays, with case measures of stroke outcome. To evaluate CNV-associated stroke risk and stroke outcome it is planned to: 1) perform Risk Discovery using several analytic approaches to identify CNVs that are associated with the risk of IS and its subtypes, across the age-, sex- and ethnicity-spectrums; 2) perform Risk Replication and Extension to determine whether the identified stroke-associated CNVs replicate in other ethnically diverse datasets and use biomarker data (e.g. methylation, proteomic, RNA, miRNA, etc.) to evaluate how the identified CNVs exert their effects on stroke risk, and lastly; 3) perform outcome-based Replication and Extension analyses of recent findings demonstrating an inverse relationship between CNV burden and stroke outcome at 3 months (mRS), and then determine the key CNV drivers responsible for these associations using existing biomarker data. Results The results of an initial CNV evaluation of 50 samples from each participating dataset are presented demonstrating that the existing GWAS and exome chip data are excellent for the planned CNV analyses. Further, some samples will require additional considerations for analysis, however such samples can readily be identified, as demonstrated by a sample demonstrating clonal mosaicism. Conclusion The CaNVAS study will cost-effectively leverage the numerous advantages of using existing case-control data sets, exploring the relationships between CNV and IS and its subtypes, and outcome at 3 months, in both men and women, in those of African and European-Caucasian descent, this, across the entire adult-age spectrum. Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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| 5. |
- Kalla, R., et al.
(författare)
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Analysis of systemic epigenetic alterations in inflammatory bowel disease : defining geographical, genetic, and immune-inflammatory influences on the circulating methylome
- 2023
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Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 17:2, s. 170-184
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Epigenetic alterations may provide valuable insights into gene-environment interactions play in the pathogenesis of Inflammatory Bowel Disease (IBD).METHODS: Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U) with covariates of age, sex, and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission.RESULTS: A total of 137 differentially methylated positions (DMP) were identified in IBD, including VMP1/MIR21 (p=9.11×10 -15) and RPS6KA2 (6.43×10 -13); with consistency seen across Scandinavia and UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p=1.53×10 -15). Age acceleration is seen in IBD (coefficient 0.94, p<2.2x10 -16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10 -7 vs. non-IBD r -0.14, p=0.77). Multi-omic integration of methylome, genome and transcriptome also implicate specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14-12.56, logrank p=9.70×10 -4).CONCLUSION: These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.
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| 6. |
- Andersen, M. S., et al.
(författare)
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To facilitate a fair bioeconomy transition, stronger regional-level linkages are needed
- 2022
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Ingår i: Biofuels Bioproducts & Biorefining-Biofpr. - : Wiley. - 1932-104X .- 1932-1031. ; 16:4, s. 929-941
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Tidskriftsartikel (refereegranskat)abstract
- The great hopes in Brussels that a circular bioeconomy will help bridge the growing divide between urban and rural areas and allow the hinterlands to prosper from 'green growth' are addressed in this article, which reflects on insights from three Nordic case studies of brown, green and blue biomass use at different levels of technology readiness. A closer examination of the forward, backward, fiscal and final demand linkages at regional level from increased biomass utilization, from eastern Finland and northern Sweden to Jutland and North Atlantic islands, suggests that linkages are and will remain relatively weak, predominantly dashing the expectations. As suppliers and exporters of natural resources, disadvantaged regions may all too easily get locked into a 'staples trap', where the value creation evaporates owing in part to the steep start-up costs and the associated boom-and-bust cycles, which place them in a weak position vis-a-vis the resource manufacturers and consumers. To make the prospects of development, employment and prosperity in the hinterlands materialize, measures are needed to strengthen the regional-level economic linkages. Regional-level revolving funds based on benefit-sharing instruments related to natural resources can be used to bolster economic development, as reflected in such schemes present in both China and Canada. We call for further research into whether and how such approaches can be replicated successfully by channeling revenues from biomass cultivation to regional-scale revolving funds, with mandates to strengthen long-term economic linkages and prosperity within the hinterlands. (c) 2022 The Authors. Biofuels, Bioproducts and Biorefining published by Society of Industrial Chemistry and John Wiley & Sons Ltd
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| 7. |
- Kalla, R., et al.
(författare)
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Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease
- 2021
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Ingår i: Journal of Crohn's & Colitis. - : Elsevier. - 1873-9946 .- 1876-4479. ; 15:5, s. 699-708
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Success in personalised medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay (PEA) to identify diagnostic and prognostic biomarkers in inflammatory bowel disease (IBD).METHODS: We conducted a prospective case-control study in an inception cohort of 552 patients (328 IBD, 224 non-IBD), profiling proteins recruited across 6 centres. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross validation was used to examine the performance of diagnostic and prognostic proteins.RESULTS: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls including MMP-12 (Holm adjusted p=4.1×10 -23 ) and OSM (p=3.7×10 -16). Nine of these proteins associate with cis- germline variation (59 independent SNPs). Fifteen proteins, all members of TNF independent pathways including IL-1 and OSM predicted escalation, over a median follow-up of 518 (IQR 224-756) days. Nested cross-validation of the entire data set allows characterisation of 5-protein-models (96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7, and IL8) which define a high-risk subgroup in IBD (HR 3.90, CI: 2.43-6.26), or allows distinct 2, and 3 protein models for UC and CD respectively.CONCLUSION: We have characterised a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings.
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| 8. |
- Kalla, R., et al.
(författare)
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Whole blood profiling of T-cell derived miRNA allows the development of prognostic models in inflammatory bowel disease
- 2020
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Ingår i: Journal of Crohn's & Colitis. - : Elsevier. - 1873-9946 .- 1876-4479. ; 14:12, s. 1724-1733
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: MicroRNAs (miRNAs) are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in Inflammatory Bowel Disease (IBD) pathogenesis. In our study, we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD.METHODS: In a 2-stage prospective multi-centre case control study, Next Generation sequencing was performed on a discovery cohort of immunomagnetically separated leucocytes from 32 patients (9 CD, 14 UC, 8 healthy controls) and differentially expressed signals were validated in whole blood in 294 patients (97 UC, 98 CD, 98 non-IBD) using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards.RESULTS: In stage 1, each leucocyte subset (CD4+ and CD8+ T-cells and CD14+ monocytes) was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p (p=0.01), miR-3615 (p=0.02) and miR-4792 (p=0.01). In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (HR 1.98, IQR:1.20-3.27;logrank p=1.80×10-3), in particular CD (HR 2.81; IQR: 1.11-3.53, p=6.50×10-4). Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if 2 or more criteria were met and 90% for UC if 3 or more criteria are met.INTERPRETATION: We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Vatn, S., et al.
(författare)
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Faecal microbiota signatures of IBD and their relation to diagnosis, disease phenotype, inflammation, treatment escalation and anti-TNF response in a European Multicentre Study (IBD-Character)
- 2020
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Ingår i: Scandinavian Journal of Gastroenterology. - : Taylor & Francis. - 0036-5521 .- 1502-7708. ; 55:10, s. 1146-1156
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Tidskriftsartikel (refereegranskat)abstract
- Method: We examined faecal samples, using the GA-map (TM) Dysbiosis Test, to associate gut microbiota composition with Crohn's disease (CD) and ulcerative colitis (UC) and to identify markers for future biomarker identification. We conducted a prospective case-control study (EU-ref. no. 305676) in an inception cohort of 324 individuals (64 CD, 84 UC, 116 symptomatic non-IBD controls and 44 healthy controls) across five European centres and examined 54 predetermined bacterial markers. We categorized patients according to the Montreal Classification and calculated the dysbiosis index (DI). Non-parametric tests were used to compare groups and the Bonferroni correction to adjust for multiple comparisons.Results: The fluorescent signals (FSSs) for Firmicutes and Eubacterium hallii were lower in inflammatory bowel disease (IBD) vs. symptomatic controls (p<.05). FSS for Firmicutes, Lachnospiraceae, Eubacterium hallii and Ruminococcus albus/bromii were lower, whereas the signal fo rBacteroides Fragilis was higher in UC vs. symptomatic controls (p<.05). FSS was higher for Bifidobacterium spp., Eubacterium hallii, Actinobacteria and Firmicutes among patients with ulcerative proctitis, compared to extensive colitis (p<.05). In CD, we observed no association with disease location. The DI correlated with faecal-calprotectin in both CD and in UC (p<.001). In terms of treatment escalation and anti-TNF response, differences were observed for some bacterial markers, but none of these associations were statistically significant.Conclusion: Our data reveal that the GA-map (TM) Dysbiosis Test holds the potential to characterize the faecal microbiota composition and to assess the degree of dysbiosis in new-onset IBD. On the other hand, our results cannot demonstrate any proven diagnostic or predictive value of this method to support clinical decision making.
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| 13. |
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| 14. |
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| 15. |
- Grännö, O., et al.
(författare)
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Preclinical protein signatures in blood predict Crohn's disease and Ulcerative colitis several years before the diagnosis
- 2024
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Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 18:Suppl. 1, s. I660-I661
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: We aimed to identify protein signatures predictive of a future diagnosis of inflammatory bowel disease (IBD).Methods: We conducted a case-control study, nested within large population-based cohorts with biorepositories. Samples were obtained from individuals who later in life were diagnosed with IBD (preclinical cases) and compared with age and sex-matched individuals who remained free from IBD during follow-up (controls). Using proximity extension assays (Olink, Uppsala), we measured 176 proteins. We applied regularized logistic regression to identify protein signatures of preclinical disease in serum from the discovery cohort (n=312). Their performance was validated in an external preclinical cohort (n=222). The biological relevance of identified proteins was further assessed in an inception cohort (n=144). Finally, we used an IBD twin cohort (n=327) to examine the impact of genetic and shared environmental factors on identified proteins.Results: We identified 34 proteins associated with preclinical Crohn’s disease (CD) in the discovery cohort (Pfalse discovery rate <0.10), with 9 confirmed in the validation cohort (Pfalse discovery rate <0.05). For preclinical ulcerative colitis (UC), 45 proteins were identified and 12 validated (Fig. 1A-B). In the discovery cohort, a signature of 29 proteins differentiated preclinical CD cases from controls with an AUC of 0.85 (Fig. 1G). Its performance was confirmed when applied to the preclinical validation cohort (AUC=0.84, Fig. 1H). Moreover, the signature had excellent capacity to differentiate newly diagnosed CD from healthy controls in the inception cohort (AUC = 0.99, Fig. 1I). The preclinical UC signature had a significant, but albeit lower, predictive capacity in the discovery (AUC=0.77), validation (AUC=0.67) and inception cohort (AUC=0.90, Fig. 1G-I).15 of 17 proteins associated with preclinical IBD demonstrated significantly higher intra-pair correlation coefficients in healthy monozygotic- compared to dizygotic twin pairs, indicating an influence from genetic factors on the regulation of these protein markers. The preclinical signature for CD demonstrated an AUC of 0.87 when comparing twins with preclinical CD (n=10) to matched external healthy twins. However, its predictive capacity was lower when comparing preclinical CD twins with their healthy twin siblings (AUC=0.58), i.e., when accounting for genetic and shared environmental factors. The difference in AUC estimates in the twin cohort was not significant (P=0.07).
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| 16. |
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| 17. |
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| 18. |
- Parsons, Bryony N., et al.
(författare)
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Dietary Supplementation with Soluble Plantain Non-Starch Polysaccharides Inhibits Intestinal Invasion of Salmonella Typhimurium in the Chicken
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 9:2, s. 87658-
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Tidskriftsartikel (refereegranskat)abstract
- Soluble fibres (non-starch polysaccharides, NSP) from edible plants but particularly plantain banana (Musa spp.), have been shown in vitro and ex vivo to prevent various enteric pathogens from adhering to, or translocating across, the human intestinal epithelium, a property that we have termed contrabiotic. Here we report that dietary plantain fibre prevents invasion of the chicken intestinal mucosa by Salmonella. In vivo experiments were performed with chicks fed from hatch on a pellet diet containing soluble plantain NSP (0 to 200 mg/d) and orally infected with S. Typhimurium 4/74 at 8 d of age. Birds were sacrificed 3, 6 and 10 d post-infection. Bacteria were enumerated from liver, spleen and caecal contents. In vitro studies were performed using chicken caecal crypts and porcine intestinal epithelial cells infected with Salmonella enterica serovars following pre-treatment separately with soluble plantain NSP and acidic or neutral polysaccharide fractions of plantain NSP, each compared with saline vehicle. Bacterial adherence and invasion were assessed by gentamicin protection assay. In vivo dietary supplementation with plantain NSP 50 mg/d reduced invasion by S. Typhimurium, as reflected by viable bacterial counts from splenic tissue, by 98.9% (95% CI, 98.1-99.7; Pless than0.0001). In vitro studies confirmed that plantain NSP (5-10 mg/ml) inhibited adhesion of S. Typhimurium 4/74 to a porcine epithelial cell-line (73% mean inhibition (95% CI, 64-81); Pless than0.001) and to primary chick caecal crypts (82% mean inhibition (95% CI, 75-90); Pless than0.001). Adherence inhibition was shown to be mediated via an effect on the epithelial cells and Ussing chamber experiments with ex-vivo human ileal mucosa showed that this effect was associated with increased short circuit current but no change in electrical resistance. The inhibitory activity of plantain NSP lay mainly within the acidic/pectic (homogalacturonan-rich) component. Supplementation of chick feed with plantain NSP was well tolerated and shows promise as a simple approach for reducing invasive salmonellosis.
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| 19. |
- Qvarford, M., et al.
(författare)
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Polarisation-dependent X-ray absorption in high- and low-Tc Bi2Sr2Can-1CunO4+2n superconductors
- 1993
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Ingår i: Physica C: Superconductivity and its Applications. - : Elsevier BV. - 0921-4534. ; 214:1-2, s. 119-126
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Tidskriftsartikel (refereegranskat)abstract
- Taking advantage of the linear polarisation of synchrotron radiation, the polarisation dependence of the O K and Cu L3 X-ray absorption edges has been compared for in situ cleaved Bi2Sr2CaCu2O8 and Bi2Sr2CuO6 single crystals. The X-ray absorption spectra were measured by means of total electron yield detection. The spectra show for both crystals that the lowest unoccupied Cu 3d and O 2p orbitals are dominantly oriented parallel to the a-b plane, but also the presence of a small amount of unoccupied orbitals oriented perpendicular to the a-b plane can be deduced from both the O K and Cu L3 absorption spectra. A shift of the order of 0.5 eV between absorption into the in-plane and the out-of-plane Cu 3d orbitals was measured for the Bi2Sr2CaCu2O8 crystal, but no such shift was found for the Bi2Sr2CuO6 crystal.
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| 20. |
- Salomon, Benita, 1993-, et al.
(författare)
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Prognostic potential of mucosal proteins in Ulcerative Colitis
- 2024
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Ingår i: Journal of Crohn's & Colitis. - : Oxford University Press. - 1873-9946 .- 1876-4479. ; 18:Suppl. 1, s. I544-I545
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Better prognostic measures for ulcerative colitis (UC) could significantly advance patient care. While the prognostic capacity of circulating proteins in UC has been explored, the role of mucosal proteins remains largely unknown. We examined mucosal protein markers in patients with incident ulcerative colitis and evaluated their prognostic value.Methods: Biopsies from macroscopically inflamed colonic/rectal mucosa of adult patients in the Swedish inception cohort of IBD (SIC IBD) were obtained at diagnosis of UC. Patients were followed prospectively, and clinical data were recorded after 3 and 12 months. Disease course was categorised as indolent or aggressive at 12 months, based on a composite outcome of colectomy, hospital admission for active disease, treatment refractoriness towards ≥2 biological agents; the use of >2 courses of corticosteroids, or a cumulative dose of >2.5 g. Relative estimates of 162 protein markers were assessed in homogenised tissue supernatants, using proximity extension assay technology (Olink Proteomics, Uppsala, Inflammation and Oncology II panel). Mann-Whitney U test, with Benjamini-Hochberg correction was used to identify differentially regulated mucosal proteins in aggressive vs indolent disease course, with a 5% false discovery rate (FDR). Smoothly clipped absolute deviation regularised logistic regression models were used to identify prognostic signatures distinguishing aggressive from indolent disease course. Performance was estimated in a leave-one-out cross-validation and reported as the area under the receiver operating characteristic (ROC) curve (AUC).Results: 117 patients provided a macroscopically inflamed colonic/rectal biopsy at diagnosis of UC. Basic demographics and clinical characteristics are presented in Table 1. Relative protein levels of WFdc2 and CCL20 were significantly lower in lysates from patients developing an aggressive course vs patients developing an indolent course, while estimates of MMP1, CCL11, WISP-1, OPG, RSPO3 and VEGFR2 were higher (Figure 1A). Regularized logistic regression identified signatures restricted to 28 proteins, distinguishing aggressive from indolent UC courses, yielding an AUC of 0.68 (95% confidence interval (CI): 0.56-0.80) for left-out samples (Figure 1B). Incorporating extent of inflammation at diagnosis in the model improved the AUC to 0.71 (95% CI: 0.60-0.83).Conclusion: We identified prognostic mucosal protein signatures associated with future course of ulcerative colitis by analysing inflamed mucosal biopsies that were obtained at diagnosis. These protein markers may highlight pathways of relevance for ulcerative colitis outcomes.
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| 22. |
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| 23. |
- Wang, X.-Y., et al.
(författare)
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Ultrastructural injury to interstitial cells of Cajal and communication with mast cells in Crohn's disease
- 2007
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 19:5, s. 349-364
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Tidskriftsartikel (refereegranskat)abstract
- Crohn's disease associated dysmotility has been attributed to fibrosis and damage to enteric nerves but injury to interstitial cells of Cajal (ICC) could also be involved. We assessed ICC in specimens obtained from patients with Crohn's disease and determined the relation between ICC and the inflammatory infiltrate, particularly mast cells (MC) using quantitative immunohistochemistry and electron microscopy. Ultrastructural injury to ICC was patchy in all ICC subtypes but ICC-Auerbach's plexus (AP) showed damage more frequently, i.e. swelling of mitochondria, decreased electron density, autophagosomes and partial depletion of the cytoplasm. Light microscopy confirmed a significant decrease in c-kit immunoreactivity for ICC-AP and an increased number of MC in the muscularis externa. Electron microscopy showed MC exhibiting piecemeal degranulation and making frequent and selective membrane-to-membrane contact with all types of injured ICC which suggests chronic release of granule content to affect ICC. Extent of ICC injury was not associated with duration of the disease. In conclusion, ultrastructural injury and loss of ICC-AP is evident in Crohn's disease. Epidemiological and morphological data suggest that ICC have the capacity to regenerate in spite of the chronic insult. The muscularis hosts a marked number of MC that exhibit piecemeal degranulation associated with ICC and may facilitate ICC maintenance. © 2007 The Authors.
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| 24. |
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| 25. |
- Yang, H, et al.
(författare)
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Bidirectional supply of glutamine maintains enterocyte ATP content in the in vitro Ussing chamber model
- 2000
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Ingår i: International Journal of Colorectal Disease. - 0179-1958 .- 1432-1262. ; 15:5-6, s. 291-296
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Tidskriftsartikel (refereegranskat)abstract
- Glutamine is the principal energy source for enterocytes, but it is not known whether parenteral or enteral supplementation is most beneficial to gut integrity. The aim of this study was to evaluate the effects of glutamine in uni- or bidirectional supply on the viability of intestinal mucosa of starved rats during incubation in Ussing chambers. Segments of jejunum from rats starved for 48 h were randomly mounted in Ussing chambers with three nutrient solutions: Krebs buffer without glutamine, 6 mM glutamine added to the mucosal side, 6 mM glutamine added to the mucosal side and 0.6 mM glutamine to the serosal side. ATP content of the mucosa, electrophysiology, and Cr-51-ethyl-enediaminetetraacetate (EDTA) permeability were studied during 180 min of incubation. The addition of glutamine to both sides of the stripped mucosa improved ATP levels compared to the Krebs solution (P<0.05), and the addition of glutamine resulted in an increase in short circuit current (P<0.05). No significant differences were seen in Cr-51-EDTA permeability or epithelial electrical resistance. Glutamine supplementation to both the luminal and serosal side in the Ussing chamber was more effective than luminal glutamine only in maintaining ATP levels of intestinal mucosa. Bidirectional supplementation of glutamine might improve intestinal energy metabolism and viability in in vitro studies.
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| 26. |
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| 27. |
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| 28. |
- Andersson, Peter, et al.
(författare)
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Low symptomatic load in Crohn's disease with surgery and medicine as complementary treatments
- 1998
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa Healthcare. - 0036-5521 .- 1502-7708. ; 33:4, s. 423-429
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Tidskriftsartikel (refereegranskat)abstract
- Background: The treatment of Crohn's disease has changed owing to the recognition of its chronicity. Medical maintenance treatment and limited resections have evolved as major concepts of management, regarded as complementary, and both aim at reducing the symptoms.Methods: We investigated the symptomatic load in Crohn's disease as reflected in a cross-sectional study of the symptom index, physicians' assessment, and the patients' perception of health. A cohort of 212 patients from the primary catchment area and 125 referred patients were studied.Results: Of catchment area patients, 83% were receiving medication, and the annual rate of abdominal surgery was 5.7%. Corresponding figures for the referred patients were 82% and 10.3%. According to the symptom index, 87% of catchment area patients were in remission or had only mild symptoms; according to the physicians' assessment, 90% were. The patients' median perception of health was 90% of perfect health according to the visual analogue scale. The figures were similar for referred patients, except that referrals were considered more diseased by the physician.Conclusion: The great majority of patients with Crohn's disease are able to live in remission or experience only mild symptoms.
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| 29. |
- Berntsson, John, et al.
(författare)
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Increased vascular endothelial growth factor D is associated with atrial fibrillation and ischaemic stroke
- 2019
-
Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 105:7, s. 553-558
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Vascular endothelial growth factor D (VEGF-D) has important functions in lymphangiogenesis and angiogenesis. High plasma levels of VEGF-D have been associated with incidence of heart failure. The association of VEGF-D with atrial fibrillation (AF) and stroke is unclear and we hypothesised that VEGF-D could also be associated with incidence of AF and ischaemic stroke. Methods: VEGF-D was measured in fasting blood samples of 4689 subjects (40% men) without a history of AF from the Malmö Diet and Cancer Study, a prospective, population-based study in Sweden. Median age was 58 years (range 46-68). Cox regression analyses, adjusted for multiple risk factors, was used to assess AF and ischaemic stroke risk in relation to VEGF-D levels. Results: During a median follow-up time of 20.6 years, there were 637 cases of incident AF and 322 cases of first ischaemic stroke. After adjustment, VEGF-D was significantly associated with AF (HR 1.13(95% CI 1.04 to 1.23) per 1 SD increase) and ischaemic stroke (HR 1.14(95% CI 1.02 to 1.28) per 1 SD). The association with ischaemic stroke was explained by an increased incidence of AF-related stroke. HRs per 1 SD were 1.34 (95% CI 1.04 to 1.71) for AF-related ischaemic stroke and 1.04 (95% CI 0.90 to 1.19) for ischaemic stroke without AF. Conclusions: Increased VEGF-D concentrations were associated with AF and ischaemic stroke. The relationship with ischaemic stroke was more pronounced in subjects with a diagnosis of AF.
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| 30. |
- Björk, Gunnar, et al.
(författare)
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Central-moment description of polarization for quantum states of light
- 2012
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Ingår i: Physical Review A. Atomic, Molecular, and Optical Physics. - 1050-2947 .- 1094-1622. ; 85:5, s. 053835-
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Tidskriftsartikel (refereegranskat)abstract
- We present a moment expansion for the systematic characterization of the polarization properties of quantum states of light. Specifically, we link the method to the measurements of the Stokes operator in different directions on the Poincare sphere and provide a scheme for polarization tomography without resorting to full-state tomography. We apply these ideas to the experimental first-and second-order polarization characterization of some two-photon quantum states. In addition, we show that there are classes of states whose polarization characteristics are dominated not by their first-order moments (i.e., the Stokes vector) but by higher-order polarization moments.
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| 31. |
- Block, J., et al.
(författare)
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Evaluation of preventive maintenance task intervals using field data from a complete life cycle
- 2008
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Ingår i: IEEE Aerospace Conference Proceedings. - Piscataway, N.J : IEEE Communications Society. - 9781424414871 ; , s. 1-11
-
Konferensbidrag (refereegranskat)abstract
- In this paper the appropriateness of initial preventive maintenance task intervals and the improvement of changed intervals are evaluated. The evaluation criteria are partly derived from logic found in the RCM (Reliability-Centered Maintenance) methodology. Empirical data is related to the whole life cycle of the Swedish military aircraft system FPL 37 Viggen, from 1977 to 2006. The analysis shows that the maintenance intervals are partly appropriate and that some performed changes are improvements. These conclusions are strengthened if the phase-out of the aircraft system is considered, where the preventive maintenance strategy has been replaced with a corrective one, in order to achieve cost-effectiveness. Considering the perfect repair assumption, it seems that the overhaul tasks essentially bring the items back to a state as good as new. The performed evaluation mostly considers when the failures are recognized, i.e. during operation or during maintenance. Hence, aspects such as item accessibility, personnel skill levels, and maintenance task intervals for other items are not included in the evaluation.
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| 32. |
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| 33. |
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| 34. |
- Chassaing, Benoit, et al.
(författare)
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Crohn disease-associated adherent-invasive E. coli bacteria target mouse and human Peyers patches via long polar fimbriae
- 2011
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Ingår i: JOURNAL OF CLINICAL INVESTIGATION. - : American Society for Clinical Investigation. - 0021-9738. ; 121:3, s. 966-975
-
Tidskriftsartikel (refereegranskat)abstract
- Crohn disease (CD) is a multifactorial disease in which an abnormal immune response in the gastrointestinal (GI) tract leads to chronic inflammation. The small intestine, particularly the ileum, of patients with CD is colonized by adherent-invasive E. coil (AIEC) a pathogenic group of E. coil able to adhere to and invade intestinal epithelial cells. As the earliest inflammatory lesions are microscopic erosions of the epithelium lining the Peyers patches (PPs), we investigated the ability of AIEC bacteria to interact with PPs and the virulence factors involved. We found that AIEC bacteria could interact with mouse and human PPs via long polar fimbriae (LPF). An LPF-negative AIEC mutant was highly impaired in its ability to interact with mouse and human PPs and to translocate across monolayers of M cells, specialized epithelial cells at the surface of PPs. The prevalence of AIEC strains harboring the lpf operon was markedly higher in CD patients compared with controls. In addition, increased numbers of AIEC, but not LPF-deficient AIEC, bacteria were found interacting with PPs from Nod2(-/-) mice compared with WT mice. In conclusion, we have identified LPF as a key factor for AIEC to target PPs. This could be the missing link between AIEC colonization and the presence of early lesions in the PPs of CD patients.
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| 35. |
- Crawley, E. F., et al.
(författare)
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Curriculum design based on the CDIO model
- 2005
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Ingår i: SEFI 2005 Annual Conference. - : Middle East Technical University, Faculty of Engineering. - 9789754292367 ; , s. 184-191
-
Konferensbidrag (refereegranskat)abstract
- Implement-Operate (CDIO) engineering educational strategy has been adopted by a number of universities as a framework for reforming engineering programs. One of the key activities in CDIO adoption and implementation is designing the engineering curriculum to integrate personal, interpersonal and system-building learning outcomes into the curriculum. This paper details approaches and experiences from curriculum design efforts at MIT, KTH, and Chalmers.
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| 36. |
- Djupedal, Ingela, et al.
(författare)
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Analysis of small RNA in fission yeast; centromeric siRNAs are potentially generated through a structured RNA
- 2009
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Ingår i: EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 28:24, s. 3832-3844
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Tidskriftsartikel (refereegranskat)abstract
- The formation of heterochromatin at the centromeres in fission yeast depends on transcription of the outer repeats. These transcripts are processed into siRNAs that target homologous loci for heterochromatin formation. Here, high throughput sequencing of small RNA provides a comprehensive analysis of centromere-derived small RNAs. We found that the centromeric small RNAs are Dcr1 dependent, carry 50-monophosphates and are associated with Ago1. The majority of centromeric small RNAs originate from two remarkably well-conserved sequences that are present in all centromeres. The high degree of similarity suggests that this non-coding sequence in itself may be of importance. Consistent with this, secondary structure-probing experiments indicate that this centromeric RNA is partially double-stranded and is processed by Dicer in vitro. We further demonstrate the existence of small centromeric RNA in rdp1D cells. Our data suggest a pathway for siRNA generation that is distinct from the well-documented model involving RITS/RDRC. We propose that primary transcripts fold into hairpin-like structures that may be processed by Dcr1 into siRNAs, and that these siRNAs may initiate heterochromatin formation independent of RDRC activity. The EMBO Journal (2009) 28, 3832-3844. doi: 10.1038/emboj.2009.351; Published online 26 November 2009
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| 37. |
- Emami, Nazanin, et al.
(författare)
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Young's modulus and degree of conversion of different combination of light-cure dental resins
- 2009
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Ingår i: The Open Dentistry Journal. - : Bentham Science Publishers Ltd.. - 1874-2106. ; 3, s. 202-207
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate Young's modulus and degree of conversion of several combinations of bisGMA,To evaluate Young's modulus and degree of conversion of several combinations of bisGMA, UEDMA, TEGDMA light-cure dental resin.Methods: Young's modulus and DC% were studied for 21 different resin combinations of bisGMA, TEGDMA and Young's modulus and DC% were studied for 21 different resin combinations of bisGMA, TEGDMA and UEDMA. Small universal testing machine and photo-calorimetry were used for the tests. The results were evaluated using ANOVA and Duncan's multiple range tests and regular t-test. Results: Young's modulus varied between 2.37±0.2 GPa (100% TEGDMA) and 4.15±0.2 GPa (100% bisGMA). By adding Young's modulus varied between 2.37±0.2 GPa (100% TEGDMA) and 4.15±0.2 GPa (100% bisGMA). By adding TEGDMA to bisGMA or UEDMA, the Young's modulus decreased significantly (p<0.05). Degree of conversion was significantly (p<0.05) higher when the wt% of TEGDMA was high in the mixtures than for highly concentrated bis-GMA (resin mixtures with TEGDMA in comparison to mixture with bisGMA had higher degree of conversion). DC% was significantly higher (p<0.05) for binary mixtures of UEDMA and TEGDMA, and significantly lower for 100 wt% bis-GMA´(p<0.05). The DC% values were between 53.1%±0.9% (100% bisGMA) and 85.6%±1% (80% UEDMA-20% TEGDMA). The concentration of bisGMA, in the monomer mixture, affected DC% and Young's modulus oppositely. Conclusions: The differences in the values for DC% were mostly justified by the differences in the molecular structures of The differences in the values for DC% were mostly justified by the differences in the molecular structures of the different monomers. It was also revealed that higher DC% does not always result in a higher Young's modulus, because molecular and network structural parameters play major roles in the final physical properties of the mixtures.
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| 38. |
- Finnveden, Göran, et al.
(författare)
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Policy Instruments towards a sustainable waste management
- 2016
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Ingår i: Solid waste management: Policy and planning for a sustainable society. - : Apple Academic Press. - 9781771883740 - 9780429091650 ; , s. 185-246, s. 185-246
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 39. |
- Georgakis, Marios K., et al.
(författare)
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Circulating Monocyte Chemoattractant Protein-1 and Risk of Stroke : Meta-Analysis of Population-Based Studies Involving 17 180 Individuals
- 2019
-
Ingår i: Circulation Research. - 0009-7330. ; 125:8, s. 773-782
-
Tidskriftsartikel (refereegranskat)abstract
- Rationale: Proinflammatory cytokines have been identified as potential targets for lowering vascular risk. Experimental evidence and Mendelian randomization suggest a role of MCP-1 (monocyte chemoattractant protein-1) in atherosclerosis and stroke. However, data from large-scale observational studies are lacking. Objective: To determine whether circulating levels of MCP-1 are associated with risk of incident stroke in the general population. Methods and Results: We used previously unpublished data on 17 180 stroke-free individuals (mean age, 56.7±8.1 years; 48.8% men) from 6 population-based prospective cohort studies and explored associations between baseline circulating MCP-1 levels and risk of any stroke, ischemic stroke, and hemorrhagic stroke during a mean follow-up interval of 16.3 years (280 522 person-years at risk; 1435 incident stroke events). We applied Cox proportional-hazards models and pooled hazard ratios (HRs) using random-effects meta-analyses. After adjustments for age, sex, race, and vascular risk factors, higher MCP-1 levels were associated with increased risk of any stroke (HR per 1-SD increment in ln-transformed MCP-1, 1.07; 95% CI, 1.01-1.14). Focusing on stroke subtypes, we found a significant association between baseline MCP-1 levels and higher risk of ischemic stroke (HR, 1.11 [1.02-1.21]) but not hemorrhagic stroke (HR, 1.02 [0.82-1.29]). The results followed a dose-response pattern with a higher risk of ischemic stroke among individuals in the upper quartiles of MCP-1 levels as compared with the first quartile (HRs, second quartile: 1.19 [1.00-1.42]; third quartile: 1.35 [1.14-1.59]; fourth quartile: 1.38 [1.07-1.77]). There was no indication for heterogeneity across studies, and in a subsample of 4 studies (12 516 individuals), the risk estimates were stable after additional adjustments for circulating levels of IL (interleukin)-6 and high-sensitivity CRP (C-reactive protein). Conclusions: Higher circulating levels of MCP-1 are associated with increased long-term risk of stroke. Our findings along with genetic and experimental evidence suggest that MCP-1 signaling might represent a therapeutic target to lower stroke risk.Visual Overview: An online visual overview is available for this article.
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| 40. |
- Geraedts, Maartje C. P., et al.
(författare)
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Release of Satiety Hormones in Response to Specific Dietary Proteins Is Different between Human and Murine Small Intestinal Mucosa
- 2010
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Ingår i: Annals of Nutrition and Metabolism. - : S. Karger AG. - 0250-6807 .- 1421-9697. ; 56:4, s. 308-313
-
Tidskriftsartikel (refereegranskat)abstract
- Background/Aim: High protein diets are the most effective to stimulate cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1) release; however, which proteins are the most potent is not known. Here, the effects of specific dietary proteins on intestinal CCK and GLP-1 release were examined. Methods: Duodenal biopsies of 10 healthy male subjects and 10 male rats were taken and placed in an Ussing chamber system. The biopsies were exposed on the luminal side to buffer, egg protein, codfish protein, ovomucoid, pea protein, and wheat protein. After an exposure time of 2 h, samples were taken from the serosal side. Results: Pea protein and wheat protein increased CCK and GLP-1 release in human duodenal tissue, while codfish protein only increased CCK release. No elevated levels of CCK and GLP-1 were found after exposure of rat tissue to different proteins. Conclusion: Pea and wheat protein are the most potent stimulators of CCK and GLP-1 release in human duodenal tissue, and may therefore be good dietary additives in weight management. Copyright (C) 2010 S. Karger AG, Basel
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| 41. |
- Geraldi, Joana G, et al.
(författare)
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Innovation in project management: Voices of researchers
- 2008
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Ingår i: International Journal of Project Management. - : Elsevier BV. - 0263-7863 .- 1873-4634. ; 26:5, s. 586-589
-
Tidskriftsartikel (refereegranskat)abstract
- This paper reports and reflects on the discussions about the nature of the discipline of project management that took place during the 8th conference of the International Research Network of Organizing by Projects (IRNOP VIII), held in Brighton in September 2007. The discussions started with the provocative motion “This house believes that we no longer need the discipline of project management”. The arguments are organised in the following areas: the use of the traditional body of knowledge by practitioners and by academics; the use of project management as a knowledge field by practitioners and by academics. The discussions indicate that project management research is in a fruitful moment of revolution of paradigms. We wish that the new paradigm accepts the plurality of research in projects and we need discussions supporting and also refusing the ‘motion’, and by this means, proposing answers, rather than the answer, to the future of ‘the project management discipline’.
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| 42. |
- Hannula, R, et al.
(författare)
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Hepatitis C outreach project and cross-sectional epidemiology in high-risk populations in Trondheim, Norway
- 2021
-
Ingår i: Therapeutic advances in infectious disease. - : SAGE Publications. - 2049-9361 .- 2049-937X. ; 8, s. 20499361211053929-
-
Tidskriftsartikel (refereegranskat)abstract
- Hepatitis C is highly prevalent among people who use drugs (PWUD), and the hepatitis C virus (HCV) epidemic is less characterised in Norway. The aims of the study were to assess the prevalence and treatment willingness in high-risk populations by reaching out to frequently visited sites for high-risk populations. Methods: Individuals from high-risk populations were included from September 2015 to March 2017. Two dedicated study nurses frequently visited the local opioid substitution clinic, outpatient clinics, PWUD day centres, local prison, and refugee centre in Trondheim, Norway. Demographic data, risk behaviour, and clinical symptoms were obtained by study questionnaire. Subjects with anti-HCV+ rapid test were subsequently tested for HCV RNA and genotyped. Viraemic patients were offered referral for HCV treatment evaluation. Results: A total of 381 participants were included in the study: 52 immigrants, 62 prisoners, and 267 PWUD. The anti-HCV prevalence rates were 0% ( n = 0) in immigrants, 40% ( n = 25) in prisoners, and 61% ( n = 164) in PWUD, with 24% ( n = 15) of prisoners and 42% ( n = 108) of PWUD being viraemic. Of those qualifying for treatment ( n = 31), 30 wished to be evaluated. Conclusion: This study showed high HCV prevalence in prisoners and PWUD and that infected high-risk patients were interested in treatment evaluation.
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| 43. |
- Hellstrand, Kristoffer, 1956, et al.
(författare)
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Age-Related Efficacy of Immunotherapy with Histamine Dihydrochloride and Interleukin-2 for Relapse Prevention in Acute Myeloid Leukemia
- 2011
-
Ingår i: Annals of Hematology. - : Springer Science and Business Media LLC. - 0939-5555 .- 1432-0584. ; 90:Suppl. 1
-
Tidskriftsartikel (refereegranskat)abstract
- Recurrence of leukemia after the completion of induction and consolidation chemotherapy is a significant clinical concern in acute myeloid leukemia (AML). Apart from allogeneic bone marrow transplantation there is no consensus about effective relapse-protective therapy beyond the consolidation phase, and the standard of care for the majority of patients in complete remission (CR) hence is no treatment. Here we present updated results from a phase 3 trial (n=320) evaluating the prevention of relapse in AML patients receiving immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2). This trial was previously reported to meet the primary endpoint of improved leukemia-free survival (LFS) in the primary population of all randomized patients. Our results imply that treatment with HDC/IL-2 prevents relapse in patients 40–70 years old in first CR (p=0.008, leukemia-free survival (LFS), n=190, log rank test) with a more than 80% relative increase in the likelihood of LFS at 3 years. HDC/IL-2 was not significantly efficacious in young patients (<40 years old). Further studies are underway to define the impact of HDC/IL-2 on immune function and the putative efficacy of therapy in genetic subgroups of AML.
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| 44. |
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| 45. |
- Klimov, A. B., et al.
(författare)
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Assessing the Polarization of a Quantum Field from Stokes Fluctuations
- 2010
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 105:15, s. 153602-
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Tidskriftsartikel (refereegranskat)abstract
- We propose an operational degree of polarization in terms of the variance of the Stokes vector minimized over all the directions of the Poincare sphere. We examine the properties of this second-order definition and carry out its experimental determination. Quantum states with the same standard (first-order) degree of polarization are correctly discriminated by this new measure. We argue that a comprehensive quantum characterization of polarization properties requires a whole hierarchy of higher-order degrees.
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| 46. |
- Lewis, K., et al.
(författare)
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Decreased epithelial barrier function evoked by exposure to metabolic stress and nonpathogenic E. coli is enhanced by TNF-a
- 2008
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Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology. - : American Physiological Society. - 0193-1857 .- 1522-1547. ; 294:3
-
Tidskriftsartikel (refereegranskat)abstract
- A defect in mitochondrial activity contributes to many diseases. We have shown that monolayers of the human colonic T84 epithelial cell line exposed to dinitrophenol (DNP, uncouples oxidative phosphorylation) and nonpathogenic Escherichia coli (E. coli) (strain HB101) display decreased barrier function. Here the impact of DNP on macrophage activity and the effect of TNF-a, DNP, and E. coli on epithelial permeability were assessed. DNP treatment of the human THP-1 macrophage cell line resulted in reduced ATP synthesis, and, although hyporesponsive to LPS, the metabolically stressed macrophages produced IL-1ß, IL-6, and TNF-a. Given the role of TNF-a in inflammatory bowel disease (IBD) and the association between increased permeability and IBD, recombinant TNF-a (10 ng/ml) was added to the DNP (0.1 mM) + E. coli (106 colony-forming units), and this resulted in a significantly greater loss of T84 epithelial barrier function than that elicited by DNP + E. coli. This increased epithelial permeability was not due to epithelial death, and the enhanced E. coli translocation was reduced by pharmacological inhibitors of NF-?ß signaling (pyrrolidine dithiocarbamate, NF-?ß essential modifier-binding peptide, BAY 11-7082, and the proteosome inhibitor, MG132). In contrast, the drop in transepithelial electrical resistance was unaffected by the inhibitors of NF-?ß. Thus, as an integrative model system, our findings support the induction of a positive feedback loop that can severely impair epithelial barrier function and, as such, could contribute to existing inflammation or trigger relapses in IBD. Thus metabolically stressed epithelia display increased permeability in the presence of viable nonpathogenic E. coli that is exaggerated by TNF-a released by activated immune cells, such as macrophages, that retain this ability even if they themselves are experiencing a degree of metabolic stress. Copyright © 2008 the American Physiological Society.
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| 47. |
- Lopes, Fernando, et al.
(författare)
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ER-stress mobilization of death-associated protein kinase-1-dependent xenophagy counteracts mitochondria stress-induced epithelial barrier dysfunction
- 2018
-
Ingår i: Journal of Biological Chemistry. - : AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC. - 0021-9258 .- 1083-351X. ; 293:9, s. 3073-3087
-
Tidskriftsartikel (refereegranskat)abstract
- The gut microbiome contributes to inflammatory bowel disease (IBD), in which bacteria can be present within the epithelium. Epithelial barrier function is decreased in IBD, and dysfunctional epithelial mitochondria and endoplasmic reticulum (ER) stress have been individually associated with IBD. We therefore hypothesized that the combination of ER and mitochondrial stresses significantly disrupt epithelial barrier function. Here, we treated human colonic biopsies, epithelial colonoids, and epithelial cells with an uncoupler of oxidative phosphorylation, dinitrophenol (DNP), with or without the ER stressor tunicamycin and assessed epithelial barrier function by monitoring internalization and translocation of commensal bacteria. We also examined barrier function and colitis in mice exposed to dextran sodium sulfate (DSS) or DNP and co-treated with DAPK6, an inhibitor of death-associated protein kinase 1 (DAPK1). Contrary to our hypothesis, induction of ER stress (i.e. the unfolded protein response) protected against decreased barrier function caused by the disruption of mitochondrial function. ER stress did not prevent DNP-driven uptake of bacteria; rather, specific mobilization of the ATF6 arm of ER stress and recruitment of DAP K1 resulted in enhanced autophagic killing (xenophagy) of bacteria. Of note, epithelia with a Crohns disease susceptibility mutation in the autophagy gene ATG16L.1 exhibited less xenophagy. Systemic delivery of the DAPK1 inhibitor DAPK6 increased bacterial translocation in DSS- or DNP-treated mice. We conclude that promoting ER stress ATF6 DAPK1 signaling in transporting enterocytes counters the transcellular passage of bacteria evoked by dysfunctional mitochondria, thereby reducing the potential for metabolic stress to reactivate or perpetuate inflammation.
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| 48. |
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| 49. |
- Mossberg, J., et al.
(författare)
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Crossing the biorefinery valley of death? Actor roles and networks in overcoming barriers to a sustainability transition
- 2018
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Ingår i: Environmental Innovation and Societal Transitions. - : Elsevier BV. - 2210-4224. ; 27, s. 83-101
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Tidskriftsartikel (refereegranskat)abstract
- Pilot and demonstration plants (PDPs) play important roles in technological development; representing bridges between basic knowledge generation and technological breakthroughs and industrial application and commercial adoption. Moreover, they also help pursue socio-technical goals, not least by creating arenas where key actors’ agency can be linked to the broader systemic context. This paper addresses the importance of the actor networks around PDP. The aim is to propose a role-based typology that can be used as an illustrative tool to facilitate a more generic analysis of PDP actor networks and their dynamics. For this purpose the paper pursues a primarily inductive approach to investigate the barriers experienced by the actors in their joint efforts to further transform the PDPs and gain a broader legitimacy for the new technologies after the initial technology verification and demonstration phases. To aid the analysis, the actor networks surrounding four Swedish biorefinery PDPs are investigated empirically.
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| 50. |
- Nilsson, Lars J, et al.
(författare)
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Counting beans or moving mountains - the predicament of energy efficiency policy
- 2011
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Ingår i: Energy efficiency first. - Stockholm : European Council for an Energy Efficient Economy (ECEEE). - 9789163344558
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Konferensbidrag (refereegranskat)abstract
- Many studies identify energy efficiency as the most important and least costly option for reducing CO2-emissions while at the same time contributing to other policy objectives. The main challenge seems to be how to design, implement and evaluate policy to ensure that these opportunities are captured and policy perceived as legitimate. There is often a gap between rhetoric or broadly stated objectives in policy development and the narrow focus on verifying additional savings in evaluation. Ancillary benefits and costs are often overlooked and the primary criteria for impact evaluations are whether policies deliver additional and cost-effective savings. In practice, however, such impact evaluations are fraught with fundamental methodological difficulties and uncertainty. Double counting, spill-over, free rider and rebound effects are real and recognised factors that complicate evaluation. This has been experienced in the development of a harmonised calculation model as stipulated by the Energy Services Directive where a fair amount of attention has been given to such factors. In the mean time the more challenging, yet non-binding, 20 percent target of the EU Energy Efficiency Action Plan is stressing a need for new policy implementation. The question then becomes: how can the legitimate demands for policy to deliver additional savings be realistically addressed in practice and balanced against broad and long-term objectives? To answer this question, we provide an overview and assessment of the issues, opportunities, and correction factors for energy efficiency policy design and evaluation. We challenge the preoccupation with verifying countable savings and argue that it can be counterproductive. What counts are policy frameworks that can unleash and accelerate energy efficiency across all sectors in order to reach levels that are commensurate with broader energy and climate policy goals.
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