| 1. |
- Sarwar, Nadeem, et al.
(author)
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Interleukin-6 receptor pathways in coronary heart disease : a collaborative meta-analysis of 82 studies
- 2012
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In: The Lancet. - New York, NY, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 379:9822, s. 1205-1213
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Journal article (peer-reviewed)abstract
- Background: Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling. Methods: In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125 222 participants. We also compared the frequency of Asp358Ala in 51 441 patients with coronary heart disease and in 136 226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6. Findings: The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele >= 0.04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34.3% (95% CI 30.4-38.2) and of interleukin 6 by 14.6% (10.7-18.4), and mean concentration of C-reactive protein was reduced by 7.5% (5.9-9.1) and of fibrinogen by 1.0% (0.7-1.3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3.4% (1.8-5.0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes. Interpretation: Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.
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| 2. |
- Botling, Johan, et al.
(author)
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Biomarker Discovery in Non-Small Cell Lung Cancer : Integrating Gene Expression Profiling, Meta-analysis, and Tissue Microarray Validation
- 2013
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:1, s. 194-204
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Journal article (peer-reviewed)abstract
- Purpose: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.Experimental Design: Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).Results: The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate < 1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.Conclusions: Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics. Clin Cancer Res; 19(1); 194-204. (c) 2012 AACR.
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| 3. |
- Vimaleswaran, Karani S, et al.
(author)
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Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
- 2014
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In: The lancet. Diabetes & endocrinology. - 2213-8595 .- 2213-8587. ; 2:9, s. 719-29
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Journal article (peer-reviewed)abstract
- Background Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings In phenotypic analyses (up to n=49363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, −0·12 mm Hg, 95% CI −0·20 to −0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97–0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, −0·02 mm Hg, −0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of −0·10 mm Hg in systolic blood pressure (−0·21 to −0·0001; p=0·0498) and a change of −0·08 mm Hg in diastolic blood pressure (−0·15 to −0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96–0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of −0·29 mm Hg in diastolic blood pressure (−0·52 to −0·07; p=0·01), a change of −0·37 mm Hg in systolic blood pressure (−0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87–0·97; p=0·002). Interpretation Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
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| 4. |
- Adams, Kelly L., et al.
(author)
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Steady-State Electrochemical Determination of Lipidic Nanotube Diameter Utilizing an Artificial Cell Model
- 2010
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In: Analytical Chemistry. - : American Chemical Society (ACS). - 1520-6882 .- 0003-2700. ; 82:3, s. 1020-1026
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Journal article (peer-reviewed)abstract
- By exploiting the capabilities of steady-state electrochemical measurements, we have measured the inner diameter of a lipid nanotube using Fick’s first law of diffusion in conjunction with an imposed linear concentration gradient of electroactive molecules over the length of the nanotube. Fick’s law has been used in this way to provide a direct relationship between the nanotube diameter and the measurable experimental parameters Δi (change in current) and nanotube length. Catechol was used to determine the Δi attributed to its flux out of the nanotube. Comparing the nanotube diameter as a function of nanotube length revealed that membrane elastic energy was playing an important role in determining the size of the nanotube and was different when the tube was connected to either end of two vesicles or to a vesicle on one end and a pipet tip on the other. We assume that repulsive interaction between neck regions can be used to explain the trends observed. This theoretical approach based on elastic energy considerations provides a qualitative description consistent with experimental data.
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| 5. |
- Björkman, Lena, 1965, et al.
(author)
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The proinflammatory activity of recombinant serum amyloid A is not shared by the endogenous protein in the circulation.
- 2010
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In: Arthritis and rheumatism. - : Wiley. - 1529-0131 .- 0004-3591. ; 62:6, s. 1660-5
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Elevated serum levels of the acute-phase protein serum amyloid A (SAA) are a marker for active rheumatoid arthritis (RA), and SAA can also be found in the tissues of patients with active RA. Based on a number of studies with recombinant SAA (rSAA), the protein has been suggested to be a potent proinflammatory mediator that activates human neutrophils, but whether endogenous SAA shares these proinflammatory activities has not been directly addressed. The present study was undertaken to investigate whether SAA in the plasma of patients with RA possesses proinflammatory properties and activates neutrophils in a manner similar to that of the recombinant protein. METHODS: Neutrophil activation was monitored by flow cytometry, based on L-selectin shedding from cell surfaces. Whole blood samples from healthy subjects and from RA patients with highly elevated SAA levels were studied before and after stimulation with rSAA as well as purified endogenous SAA. RESULTS: Recombinant SAA potently induced cleavage of L-selectin from neutrophils and in whole blood samples. Despite highly elevated SAA levels, L-selectin was not down-regulated on RA patient neutrophils as compared with neutrophils from healthy controls. Spiking SAA-rich whole blood samples from RA patients with rSAA, however, resulted in L-selectin shedding. In addition, SAA purified from human plasma was completely devoid of neutrophil- or macrophage-activating capacity. CONCLUSION: The present findings show that rSAA is proinflammatory but that this activity is not shared by endogenous SAA, either when present in the circulation of RA patients or when purified from plasma during an acute-phase response.
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| 6. |
- Glentis, G. -O, et al.
(author)
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Efficient spectral analysis in the missing data case using sparse ML methods
- 2014
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In: European Signal Processing Conference. - 2219-5491.
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Conference paper (peer-reviewed)abstract
- Given their wide applicability, several sparse high-resolution spectral estimation techniques and their implementation have been examined in the recent literature. In this work, we further the topic by examining a computationally efficient implementation of the recent SMLA algorithms in the missing data case. The work is an extension of our implementation for the uniformly sampled case, and offers a notable computational gain as compared to the alternative implementations in the missing data case.
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| 7. |
- Jin, Chunsheng, et al.
(author)
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Human Synovial Lubricin Expresses Sialyl Lewis x Determinant and Has L-selectin Ligand Activity
- 2012
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 287:43, s. 35922-35933
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Journal article (peer-reviewed)abstract
- Lubricin (or proteoglycan 4 (PRG4)) is an abundant mucin-like glycoprotein in synovial fluid (SF) and a major component responsible for joint lubrication. In this study, it was shown that O-linked core 2 oligosaccharides (Gal beta 1-3(GlcNAc beta 1-6)GalNAc alpha 1-Thr/Ser) on lubricin isolated from rheumatoid arthritis SF contained both sulfate and fucose residues, and SF lubricin was capable of binding to recombinant L-selectin in a glycosylation-dependent manner. Using resting human polymorphonuclear granulocytes (PMN) from peripheral blood, confocal microscopy showed that lubricin coated circulating PMN and that it partly co-localized with L-selectin expressed by these cells. In agreement with this, activation-induced shedding of L-selectin also mediated decreased lubricin binding to PMN. It was also found that PMN recruited to inflamed synovial area and fluid in rheumatoid arthritis patients kept a coat of lubricin. These observations suggest that lubricin is able to bind to PMN via an L-selectin-dependent and -independent manner and may play a role in PMN-mediated inflammation.
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| 8. |
- Karlsson, Johan, et al.
(author)
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Laplace model for multi-axial responses in fatigue analysis of a cultivator frame
- 2014
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In: Proceedings of the 3rd International Commercial Vehicle Technology Symposium (CVT 2014). ; , s. 141-150, s. 141-150
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Conference paper (peer-reviewed)abstract
- This paper reviews means for fatigue damage rates estimation using Laplace distributed multiaxial loads. The model is suitable for description of stresses containing transients of random amplitudes and locations. Explicit formulas for computing the expected value of rainflow damage index as a function of excess kurtosis are given for correlated loads. A Laplace model is used to describe variability of forces and bending moments measured at some location on a cultivator frame. An example of actual cultivator data is used to illustrate the model and demonstrate the accuracy of damage index prediction.
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| 9. |
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| 10. |
- Nåbo, Arne, et al.
(author)
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Förares tankar om framtida automatiserad bilkörning : en fokusgruppstudie
- 2013
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Reports (other academic/artistic)abstract
- Det man ofta avser med automatiserad körning är möjligheten att låta föraren överlåta en del- eller hela köruppgiften till fordonet själv. Det kan även handla om att fordonet själv ska kunna ta över kontrollen i en situation som föraren inte klarar av. Metoden diskussion i fokusgrupp har använts för att få en bred och omfångsrik beskrivning av hur förare kan resonera kring automatiserad körning. Fyra diskussioner genomfördes med totalt 28 deltagare. Deltagarna ombads att tänka i framtida (5-20 år) möjligheter. Frågeställningar som gavs var: Vad ser man framför sig? Finns det skäl att införa automatiserad körning? Vilka funktioner vill man ha? Finns det för- och nackdelar? Hur skulle man kunna tänka kring tillit/säkerhetsfrågor om man har en bil som kör av sig själv? Den första delen av diskussionen var mer generellt fokuserad på synpunkter på automatiserad körning. Sedan fick deltagarna se filmklipp som exemplifierade olika grader av automatiserad körning, och diskussionen handlade om reflektioner på dessa. Sist fick deltagarna fylla i en enkät för att fånga varje individs tankar och åsikter. Flera olika infallsvinklar belystes och ämnen i fokus var kopplat till vem automatiserad körning är till för och vem som har råd. En hel del av diskussionen handlade om säkerhet med lite olika infallsvinklar, till exempel om det medför en ökad hastighet, tekniska problem och om datasäkerhet. En oro var att framtidens förare tappar kunskap och att utbildning blir viktigt. När det gällde framtidens fordon var det inte helt självklart att det man ser framför sig är en bil som den ser ut idag. Frågor kring ansvar, lagar och förordningar diskuterades också. En lång lista med innovativa lösningar blev även utfallet från gruppernas diskussioner. När det gällde de helautomatiserade systemen så var deltagarna mer positivt inställda till system där föraren övervakar det som sker, än system där föraren kan ägna sig åt annat. Deltagarna var i allmänhet mer positivt inställda till system som finns idag, än till mer avancerade, framtida system. Generellt kunde det noteras att vissa förare ville ha automatik för de tråkiga långa körpassen (dvs. av komfortskäl), medan andra ville ha automatik för att klara av svåra körsituationer (dvs. av säkerhetsskäl). Båda dessa behov behöver sannolikt tillgodoses i framtiden.
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