Improving stroke risk prediction and individualised treatment in carotid atherosclerosis

Background: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. Currently, this risk estimation is based on measurements of stenosis and neurological symptoms, which determines the therapy of either medical treatment with or without carotid endarterectomy. The efficacy of this therapy is low and higher accuracy of diagnosis and therapy is warranted. Imaging of carotid plaque morphology using software for visualisation of plaque components may improve assessment of plaque phenotype and stroke risk. These studies aimed firstly to investigate if, and if yes, how, the carotid plaque morphology with image analysis of CTA associated with on-going biology in the corresponding specimen. Secondly, if risk stratification in clinical risk scores can be linked to the aforementioned associations. Finally, if the on-going biological processes can be specifically predicted out of the CTA imaging analysis. Methods: Plaque features were analysed in pre-operative CTA with dedicated software. In study I and II, the plaques were stratified according to quantified high and low of each feature, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry was performed to evaluate the findings in plaques. In study III, patient phenotype, according to clinical stroke risk scores of CAR and ABCD2 stratified the cohorts of high vs low scores which were subsequently profiled with microarrays, followed by bioinformatic analyses and correlation analyses of plaque morphology in CTA. In study IV, the microarray transcriptomes were individually coupled to morphological data from the CTA analysis, developing models with machine intelligence to predict the gene expression from a CTA image. The models were then tested in unseen patients. Results: In study I, stabilising markers and processes related to SMCs and ECM organisation were associated with highly calcified plaques, while inflammatory and lipid related processes were repressed. PRG4, a novel marker for atherosclerosis, was identified as the most up-regulated gene in highly calcified plaques. Study II showed that carotid lesions with large lipid rich necrotic core, intraplaque haemorrhage or plaque burden were characterized by molecular signatures coupled with inflammation and extracellular matrix degradation, typically linked with instability. Symptomatology associated with large lipid rich necrotic core and plaque burden. Cross-validated prediction model for symptoms, showed that plaque morphology by CTA alone was superior to stenosis degree. Study III revealed that a high clinical risk score in CAR and ABCD2, reflect a plaque phenotype linked to immune response and coagulation, where the novel ABCB5, was one of the most up-regulated genes. The high risk scores correlated with the plaque components matrix and calcification but no positive association with stenosis degree. Study IV resulted in 414 robustly predicted transcripts from the CTA image analysis, of which pathway analysis showed biological processes associated with typical pathophysiology of atherosclerosis and plaque instability. The model testing demonstrated a good correlation between predicted and observed transcript expression levels and pathway analysis revealed a unique dominant mechanism for each individual. Conclusions: Biological processes in carotid plaques associated to vulnerability, can be linked to plaque morphology analysed with CTA image analysis. Patient phenotype classified with clinical risk scores associates to plaque phenotype and morphology in CTA. The biological processes in the atherosclerotic plaque can be predicted with plaque morphology CTA analysis in this small pilot study, providing a possibility to precision medicine after validation in larger scale studie

Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization

Background and aims: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. We recently found enrichment of genes associated with calcification in carotid plaques from asymptomatic patients. Here, we hypothesized that calcification represents a stabilising feature of plaques and investigated how macro-calcification, as estimated by computed tomography (CT), correlates with gene expression profiles in lesions. Methods: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high- and lowcalcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients. Results: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells. Conclusions: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.The European Union’s Horizon 2020/Marie Sklodowska-Curie grant agreement No 722609 (INTRICARE);Swedish Heart and Lung FoundationSwedish Research Council (K2009-65X-2233-01-3, K2013- 65X-06816-30-4, 349-2007-8703)Uppdrag Besegra Stroke (P581/ 2011-123)Stockholm County Council (ALF2011-0260, ALF-2011- 0279)Swedish Society for Medical ResearchTore Nilsson’s FoundationMagnus Bergvall’s FoundationKarolinska Institutet FoundationEuropean Commission (722609)Publishe

Two ice-core delta O-18 records from Svalbard illustrating climate and sea-ice variability over the last 400 years

Ice cores from the relatively low-lying ice caps in Svalbard have not been widely exploited in climatic studies owing to uncertainties about the effect of meltwater percolation. However, results from two new Svalbard ice cores, at Lomonosovfonna and Austfonna, have shown that with careful site selection, high-resolution sampling and multiple chemical analyses it is possible to recover ice cores from which part of the annual signals are preserved, despite the considerable meltwater percolation. The new Svalbard ice cores are positioned in different parts of Svalbard and cover the past 800 years. In this paper we focus on the last 400 years. The delta(18)O signals from the cores are qualitatively similar over most of the twentieth century, suggesting that they record the same atmospheric signal. Prior to AD 1920, the Austfonna ice core exhibits more negative delta(18)O values than Lomonosovfonna, although there are intermittent decadal-scale periods throughout the record with similar values. We suggest that the differences reflect the effect of the inversion layer during the winter. The pattern in the delta(18)O records is similar to the Longyearbyen air-temperature record, but on an annual level the correlation is low. The Austforma record correlates well with the temperature record from the more distant and southwesterly located Jan Mayen. A comparison of the ice-core and sea-ice records from this period suggests that sea-ice extent and Austforma delta(18)O are related over the past 400 years. This may reflect the position of the storm tracks and their direct influence on the relatively low-altitude Austfonna. Lomonosovfonna may be less sensitive to such changes and primarily record free atmospheric changes instead of variations in sea-ice extent, the latter is probably a result of its higher elevation

Two ice-core d18O records from Svalbard illustrating climate and sea-ice variability over the last 400 years

Ice cores from the relatively low-lying ice caps in Svalbard have not been widely exploited in climatic studies owing to uncertainties about the effect of meltwater percolation. However, results from two new Svalbard ice cores, at Lomonosovfonna and Austfonna, have shown that with careful site selection, high-resolution sampling and multiple chemical analyses it is possible to recover ice cores from which part of the annual signals are preserved, despite the considerable meltwater percolation. The new Svalbard ice cores are positioned in different parts of Svalbard and cover the past 800 years. In this paper we focus on the last 400 years. The delta(18)O signals from the cores are qualitatively similar over most of the twentieth century, suggesting that they record the same atmospheric signal. Prior to AD 1920, the Austfonna ice core exhibits more negative delta(18)O values than Lomonosovfonna, although there are intermittent decadal-scale periods throughout the record with similar values. We suggest that the differences reflect the effect of the inversion layer during the winter. The pattern in the delta(18)O records is similar to the Longyearbyen air-temperature record, but on an annual level the correlation is low. The Austforma record correlates well with the temperature record from the more distant and southwesterly located Jan Mayen. A comparison of the ice-core and sea-ice records from this period suggests that sea-ice extent and Austforma delta(18)O are related over the past 400 years. This may reflect the position of the storm tracks and their direct influence on the relatively low-altitude Austfonna. Lomonosovfonna may be less sensitive to such changes and primarily record free atmospheric changes instead of variations in sea-ice extent, the latter is probably a result of its higher elevation

Snow Chemistry Across Antarctica

An updated compilation of published and new data of major-ion (Ca, Cl, K, Mg, Na, NO3, SO4) and methylsulfonate (MS) concentrations in snow from 520 Antarctic sites is provided by the national ITASE (International Trans-Antarctic Scientific Expedition) programmes of Australia, Brazil, China, Germany, Italy, Japan, Korea, New Zealand, Norway, the United Kingdom, the United States and the national Antarctic programme of Finland. The comparison shows that snow chemistry concentrations vary by up to four orders of magnitude across Antarctica and exhibit distinct geographical patterns. The Antarctic-wide comparison of glaciochemical records provides a unique opportunity to improve our understanding of the fundamental factors that ultimately control the chemistry of snow or ice samples. This paper aims to initiate data compilation and administration in order to provide a framework for facilitation of Antarctic-wide snow chemistry discussions across all ITASE nations and other contributing groups. The data are made available through the ITASE web page (http:// www2.umaine.edu/itase/content/syngroups/snowchem.html) and will be updated with new data as they are provided. In addition, recommendations for future research efforts are summarized

Effekten av bolagsskattereformen 2013 : en undersökning av företags effektiva skatter

Bolagsskattesystemets utformning är viktig eftersom den påverkar samhällsekonomin i ett antal olika avseenden. När bolagsskatt diskuteras måste två begrepp särskiljas. Faktisk skattesats återges i lagtext och effektiv skattesats är den skatt företag betalar. Sveriges bolagsskattesystem har genomgått en rad reformer. I denna rapport undersöks hur bolagsskattereformen 2013 påverkat svenska företags effektiva skattesats och om reformens utformning haft branschvisa effekter. Tidigare studier baserade på Devereux och Griffiths (2003) beräkningsmetod för effektiva skatter har genomförts. Dessa beräkningar och dock utförda med fiktiva siffror på ett modellföretag. För att genomföra undersökningen har vi samlat in årsredovisningsdata från 5000 moderbolag i Sverige. Undersökningens resultat visade att den genomsnittliga effektiva (median) skattesatsen sjönk från 25,5 (26,7) till 18,5 (22,4) efter skattereformen. Företag och branscher beskattas olika. De med låg beskattning kan göra omfattande skattemässiga justeringar medan företag med hög beskattning inte har motsvarande möjlighet. Resultaten visar att Devereux och Griffiths (2003) metod med beräkningar för ett modellföretag ger en mycket onyanserad bild av effekterna av en skattereform.