Publications by authors named "Stefan Jonsson"

60 Publications

Genetic insight into sick sinus syndrome.

Eur Heart J 2021 05;42(20):1959-1971

deCODE genetics/Amgen, Inc., Sturlugata 8, Reykjavik 101, Iceland.

Aims: The aim of this study was to use human genetics to investigate the pathogenesis of sick sinus syndrome (SSS) and the role of risk factors in its development.

Methods And Results: We performed a genome-wide association study of 6469 SSS cases and 1 000 187 controls from deCODE genetics, the Copenhagen Hospital Biobank, UK Biobank, and the HUNT study. Variants at six loci associated with SSS, a reported missense variant in MYH6, known atrial fibrillation (AF)/electrocardiogram variants at PITX2, ZFHX3, TTN/CCDC141, and SCN10A and a low-frequency (MAF = 1.1-1.8%) missense variant, p.Gly62Cys in KRT8 encoding the intermediate filament protein keratin 8. A full genotypic model best described the p.Gly62Cys association (P = 1.6 × 10-20), with an odds ratio (OR) of 1.44 for heterozygotes and a disproportionally large OR of 13.99 for homozygotes. All the SSS variants increased the risk of pacemaker implantation. Their association with AF varied and p.Gly62Cys was the only variant not associating with any other arrhythmia or cardiovascular disease. We tested 17 exposure phenotypes in polygenic score (PGS) and Mendelian randomization analyses. Only two associated with the risk of SSS in Mendelian randomization, AF, and lower heart rate, suggesting causality. Powerful PGS analyses provided convincing evidence against causal associations for body mass index, cholesterol, triglycerides, and type 2 diabetes (P > 0.05).

Conclusion: We report the associations of variants at six loci with SSS, including a missense variant in KRT8 that confers high risk in homozygotes and points to a mechanism specific to SSS development. Mendelian randomization supports a causal role for AF in the development of SSS.
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http://dx.doi.org/10.1093/eurheartj/ehaa1108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140484PMC
May 2021

Maedi-visna virus Vif protein uses motifs distinct from HIV-1 Vif to bind zinc and the cofactor required for A3 degradation.

J Biol Chem 2021 Jan-Jun;296:100045. Epub 2020 Nov 24.

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut, USA. Electronic address:

The mammalian apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) family of cytidine deaminases restrict viral infections by mutating viral DNA and impeding reverse transcription. To overcome this antiviral activity, most lentiviruses express a viral accessory protein called the virion infectivity factor (Vif), which recruits A3 proteins to cullin-RING E3 ubiquitin ligases such as cullin-5 (Cul5) for ubiquitylation and subsequent proteasomal degradation. Although Vif proteins from primate lentiviruses such as HIV-1 utilize the transcription factor core-binding factor subunit beta as a noncanonical cofactor to stabilize the complex, the maedi-visna virus (MVV) Vif hijacks cyclophilin A (CypA) instead. Because core-binding factor subunit beta and CypA are both highly conserved among mammals, the requirement for two different cellular cofactors suggests that these two A3-targeting Vif proteins have different biochemical and structural properties. To investigate this topic, we used a combination of in vitro biochemical assays and in vivo A3 degradation assays to study motifs required for the MVV Vif to bind zinc ion, Cul5, and the cofactor CypA. Our results demonstrate that although some common motifs between the HIV-1 Vif and MVV Vif are involved in recruiting Cul5, different determinants in the MVV Vif are required for cofactor binding and stabilization of the E3 ligase complex, such as the zinc-binding motif and N- and C-terminal regions of the protein. Results from this study advance our understanding of the mechanism of MVV Vif recruitment of cellular factors and the evolution of lentiviral Vif proteins.
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http://dx.doi.org/10.1074/jbc.RA120.015828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949081PMC
September 2021

Myocardial micro-biopsy procedure for molecular characterization with increased precision and reduced trauma.

Sci Rep 2020 05 15;10(1):8029. Epub 2020 May 15.

Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden.

Endomyocardial biopsy is a valuable tool in cardiac diagnostics but is limited by low diagnostic yield and significant complication risks. Meanwhile, recent developments in transcriptomic and proteomic technologies promise a wealth of biological data from minimal tissue samples. To take advantage of the minimal tissue amount needed for molecular analyses, we have developed a sub-millimeter endovascular biopsy device, considerably smaller than current clinical equipment, and devised a low-input RNA-sequencing protocol for analyzing small tissue samples. In in vivo evaluation in swine, 81% of biopsy attempts (n = 157) were successful. High quality RNA-sequencing data was generated from 91% of the sequenced cardiac micro-biopsy samples (n = 32). Gene expression signatures of samples taken with the novel device were comparable with a conventional device. No major complications were detected either during procedures or during 7 days' follow-up, despite acquiring a relatively large number of biopsies (median 30) in each animal. In conclusion, the novel device coupled with RNA-sequencing provides a feasible method to obtain molecular data from the myocardium. The method is less traumatic and has a higher flexibility compared to conventional methods, enabling safer and more targeted sampling from different parts of the myocardium.
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http://dx.doi.org/10.1038/s41598-020-64900-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229024PMC
May 2020

Circulating Protein Signatures and Causal Candidates for Type 2 Diabetes.

Diabetes 2020 08 8;69(8):1843-1853. Epub 2020 May 8.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland

The increasing prevalence of type 2 diabetes poses a major challenge to societies worldwide. Blood-based factors like serum proteins are in contact with every organ in the body to mediate global homeostasis and may thus directly regulate complex processes such as aging and the development of common chronic diseases. We applied a data-driven proteomics approach, measuring serum levels of 4,137 proteins in 5,438 elderly Icelanders, and identified 536 proteins associated with prevalent and/or incident type 2 diabetes. We validated a subset of the observed associations in an independent case-control study of type 2 diabetes. These protein associations provide novel biological insights into the molecular mechanisms that are dysregulated prior to and following the onset of type 2 diabetes and can be detected in serum. A bidirectional two-sample Mendelian randomization analysis indicated that serum changes of at least 23 proteins are downstream of the disease or its genetic liability, while 15 proteins were supported as having a causal role in type 2 diabetes.
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http://dx.doi.org/10.2337/db19-1070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372075PMC
August 2020

Predicted loss and gain of function mutations in ACO1 are associated with erythropoiesis.

Commun Biol 2020 04 23;3(1):189. Epub 2020 Apr 23.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

Hemoglobin is the essential oxygen-carrying molecule in humans and is regulated by cellular iron and oxygen sensing mechanisms. To search for novel variants associated with hemoglobin concentration, we performed genome-wide association studies of hemoglobin concentration using a combined set of 684,122 individuals from Iceland and the UK. Notably, we found seven novel variants, six rare coding and one common, at the ACO1 locus associating with either decreased or increased hemoglobin concentration. Of these variants, the missense Cys506Ser and the stop-gained Lys334Ter mutations are specific to eight and ten generation pedigrees, respectively, and have the two largest effects in the study (Effect = -1.61 SD, CI = [-1.98, -1.35]; Effect = 0.63 SD, CI = [0.36, 0.91]). We also find Cys506Ser to associate with increased risk of persistent anemia (OR = 17.1, P = 2 × 10). The strong bidirectional effects seen in this study implicate ACO1, a known iron sensing molecule, as a major homeostatic regulator of hemoglobin concentration.
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http://dx.doi.org/10.1038/s42003-020-0921-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181819PMC
April 2020

Organisation of preventive child health services: Key to socio-economic equity in vaccine uptake?

Scand J Public Health 2020 Jul 17;48(5):491-494. Epub 2019 May 17.

Department of Medicine, Karolinska Institute, Sweden.

Measles has made a comeback in Western Europe, with more cases being reported each year. One factor behind this development is low vaccination coverage in socially disadvantaged segments of the population in many countries. This study investigates whether socioeconomic patterns of uptake of the measles, mumps and rubella (MMR) vaccine in the Nordic countries differ by national organisation of preventive health services for children. : MMR vaccine uptake before the age of two years was analysed in register data from Denmark, Finland, Iceland and Sweden, linked to family indicators of socio-economic status (SES) from national registers. : Denmark, a country where child vaccinations are administered by general practitioners, presented the lowest overall coverage of MMR at 83%. It also had the greatest difference between subpopulations of low and high SES at 14 percentage points. Finland, Iceland and Sweden, countries where preschool children are vaccinated in 'well-baby' clinics, had a higher overall coverage at 91-94%, with a more equal distribution between SES groups at 1-4 percentage points.
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http://dx.doi.org/10.1177/1403494819850430DOI Listing
July 2020

A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis.

Nat Genet 2019 02 14;51(2):267-276. Epub 2019 Jan 14.

deCODE genetics/Amgen Inc., Reykjavik, Iceland.

Nasal polyps (NP) are lesions on the nasal and paranasal sinus mucosa and are a risk factor for chronic rhinosinusitis (CRS). We performed genome-wide association studies on NP and CRS in Iceland and the UK (using UK Biobank data) with 4,366 NP cases, 5,608 CRS cases, and >700,000 controls. We found 10 markers associated with NP and 2 with CRS. We also tested 210 markers reported to associate with eosinophil count, yielding 17 additional NP associations. Of the 27 NP signals, 7 associate with CRS and 13 with asthma. Most notably, a missense variant in ALOX15 that causes a p.Thr560Met alteration in arachidonate 15-lipoxygenase (15-LO) confers large genome-wide significant protection against NP (P = 8.0 × 10, odds ratio = 0.32; 95% confidence interval = 0.26, 0.39) and CRS (P = 1.1 × 10, odds ratio = 0.64; 95% confidence interval = 0.55, 0.75). p.Thr560Met, carried by around 1 in 20 Europeans, was previously shown to cause near total loss of 15-LO enzymatic activity. Our findings identify 15-LO as a potential target for therapeutic intervention in NP and CRS.
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http://dx.doi.org/10.1038/s41588-018-0314-6DOI Listing
February 2019

Genome-wide association meta-analysis yields 20 loci associated with gallstone disease.

Nat Commun 2018 11 30;9(1):5101. Epub 2018 Nov 30.

deCODE Genetics/Amgen, Inc., Reykjavik, 101, Iceland.

Gallstones are responsible for one of the most common diseases in the Western world and are commonly treated with cholecystectomy. We perform a meta-analysis of two genome-wide association studies of gallstone disease in Iceland and the UK, totaling 27,174 cases and 736,838 controls, uncovering 21 novel gallstone-associated variants at 20 loci. Two distinct low frequency missense variants in SLC10A2, encoding the apical sodium-dependent bile acid transporter (ASBT), associate with an increased risk of gallstone disease (Pro290Ser: OR = 1.36 [1.25-1.49], P = 2.1 × 10, MAF = 1%; Val98Ile: OR = 1.15 [1.10-1.20], P = 1.8 × 10, MAF = 4%). We demonstrate that lower bile acid transport by ASBT is accompanied by greater risk of gallstone disease and highlight the role of the intestinal compartment of the enterohepatic circulation of bile acids in gallstone disease susceptibility. Additionally, two low frequency missense variants in SERPINA1 and HNF4A and 17 common variants represent novel associations with gallstone disease.
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http://dx.doi.org/10.1038/s41467-018-07460-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269469PMC
November 2018

Meta-analysis of Icelandic and UK data sets identifies missense variants in SMO, IL11, COL11A1 and 13 more new loci associated with osteoarthritis.

Nat Genet 2018 12 29;50(12):1681-1687. Epub 2018 Oct 29.

deCODE genetics/Amgen, Inc., Reykjavik, Iceland.

Osteoarthritis has a highly negative impact on quality of life because of the associated pain and loss of joint function. Here we describe the largest meta-analysis so far of osteoarthritis of the hip and the knee in samples from Iceland and the UK Biobank (including 17,151 hip osteoarthritis patients, 23,877 knee osteoarthritis patients, and more than 562,000 controls). We found 23 independent associations at 22 loci in the additive meta-analyses, of which 16 of the loci were novel: 12 for hip and 4 for knee osteoarthritis. Two associations are between rare or low-frequency missense variants and hip osteoarthritis, affecting the genes SMO (rs143083812, frequency 0.11%, odds ratio (OR) = 2.8, P = 7.9 × 10, p.Arg173Cys) and IL11 (rs4252548, frequency 2.08%, OR = 1.30, P = 2.1 × 10, p.Arg112His). A common missense variant in the COL11A1 gene also associates with hip osteoarthritis (rs3753841, frequency 61%, P = 5.2 × 10, OR = 1.08, p.Pro1284Leu). In addition, using a recessive model, we confirm an association between hip osteoarthritis and a variant of CHADL (rs117018441, P = 1.8 × 10, OR = 5.9). Furthermore, we observe a complex relationship between height and risk of osteoarthritis.
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http://dx.doi.org/10.1038/s41588-018-0247-0DOI Listing
December 2018

Coding variants in and increase risk of atrial fibrillation.

Commun Biol 2018 12;1:68. Epub 2018 Jun 12.

HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway.

Most sequence variants identified hitherto in genome-wide association studies (GWAS) of atrial fibrillation are common, non-coding variants associated with risk through unknown mechanisms. We performed a meta-analysis of GWAS of atrial fibrillation among 29,502 cases and 767,760 controls from Iceland and the UK Biobank with follow-up in samples from Norway and the US, focusing on low-frequency coding and splice variants aiming to identify causal genes. We observe associations with one missense (OR = 1.20) and one splice-donor variant (OR = 1.50) in , the first ribosomal gene implicated in atrial fibrillation to our knowledge. Analysis of 167 RNA samples from the right atrium reveals that the splice-donor variant in results in exon skipping. We also observe an association with a missense variant in (OR = 1.38), encoding a component of the intercalated discs of cardiomyocytes. Both discoveries emphasize the close relationship between the mechanical and electrical function of the heart.
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http://dx.doi.org/10.1038/s42003-018-0068-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123807PMC
June 2018

Transcriptomic analysis of the harvested endothelial cells in a swine model of mechanical thrombectomy.

Neuroradiology 2018 Jul 14;60(7):759-768. Epub 2018 May 14.

Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm, Sweden.

Purpose: In mechanical thrombectomy (MT) for ischemic stroke, endothelial cells (ECs) from intracranial blood vessels adhere to the stent retriever device and can be harvested. However, understanding the molecular biology and the role of the endothelium in different pathological conditions remains insufficient. The purpose of the study was to characterize and analyze the molecular aspect of harvested ECs using cell culture and transcriptomic techniques in an MT swine model relevant to clinical ischemic stroke.

Methods: In swine, preformed thrombi were injected into the external carotid and subclavian arteries to occlude their branches. MT was performed according to clinical routine. The stent retriever device and thrombus were treated with cell dissociation buffer. The resulting cell suspension was analyzed by immunohistochemistry and was cultured. Cultured cells were analyzed using single-cell RNA sequencing (scRNA-seq) after fluorescence-activated cell sorting (FACS).

Results: A total number of 37 samples were obtained containing CD31-positive cells. Cell culture was successful in 90% of samples, and the cells expressed multiple typical EC protein markers. Eighty-nine percent of the sorted cells yielded high-quality transcriptomes, and single-cell transcriptomes from cultured cells showed that they expressed typical endothelial gene patterns. Gene expression analysis of ECs from an occluded artery did not show distinctive clustering into subtypes.

Conclusion: ECs harvested during MT can be cultured and analyzed using single-cell transcriptomic techniques. This analysis can be implemented in clinical practice to study the EC gene expression of comorbidities, such as hypertension, diabetes mellitus, and metabolic syndrome, in patients suffering from acute ischemic stroke.
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http://dx.doi.org/10.1007/s00234-018-2033-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995995PMC
July 2018

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations.

NPJ Genom Med 2017 8;2:24. Epub 2017 Aug 8.

Department of Neurology, Akershus University Hospital, Lørenskog, Norway.

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa ( = 1.6 × 10, 4.3 × 10) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in , another is a missense variant in that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.
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http://dx.doi.org/10.1038/s41525-017-0027-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677966PMC
August 2017

Identification of sequence variants influencing immunoglobulin levels.

Nat Genet 2017 Aug 19;49(8):1182-1191. Epub 2017 Jun 19.

Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.

Immunoglobulins are the effector molecules of the adaptive humoral immune system. In a genome-wide association study of 19,219 individuals, we found 38 new variants and replicated 5 known variants associating with IgA, IgG or IgM levels or with composite immunoglobulin traits, accounted for by 32 loci. Variants at these loci also affect the risk of autoimmune diseases and blood malignancies and influence blood cell development. Notable associations include a rare variant at RUNX3 decreasing IgA levels by shifting isoform proportions (rs188468174[C>T]: P = 8.3 × 10, β = -0.90 s.d.), a rare in-frame deletion in FCGR2B abolishing IgG binding to the encoded receptor (p.Asn106del: P = 4.2 × 10, β = 1.03 s.d.), four IGH locus variants influencing class switching, and ten new associations with the HLA region. Our results provide new insight into the regulation of humoral immunity.
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http://dx.doi.org/10.1038/ng.3897DOI Listing
August 2017

Sequence variant at 4q25 near PITX2 associates with appendicitis.

Sci Rep 2017 06 8;7(1):3119. Epub 2017 Jun 8.

deCODE genetics/Amgen, Inc, Reykjavik, 101, Iceland.

Appendicitis is one of the most common conditions requiring acute surgery and can pose a threat to the lives of affected individuals. We performed a genome-wide association study of appendicitis in 7,276 Icelandic and 1,139 Dutch cases and large groups of controls. In a combined analysis of the Icelandic and Dutch data, we detected a single signal represented by an intergenic variant rs2129979 [G] close to the gene PITX2 associating with increased risk of appendicitis (OR = 1.15, P = 1.8 × 10). We only observe the association in patients diagnosed in adulthood. The marker is close to, but distinct from, a set of markers reported to associate with atrial fibrillation, which have been linked to PITX2. PITX2 has been implicated in determination of right-left symmetry during development. Anomalies in organ arrangement have been linked to increased prevalence of gastrointestinal and intra-abdominal complications, which may explain the effect of rs2129979 on appendicitis risk.
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http://dx.doi.org/10.1038/s41598-017-03353-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465083PMC
June 2017

Economic conditions, hypertension, and cardiovascular disease: analysis of the Icelandic economic collapse.

Health Econ Rev 2017 Dec 23;7(1):20. Epub 2017 May 23.

Faculty of Economics, University of Iceland, Oddi v/Sturlugotu, 101, Reykjavik, Iceland.

Previous research has found a positive short-term relationship between the 2008 collapse and hypertension in Icelandic males. With Iceland's economy experiencing a phase of economic recovery, an opportunity to pursue a longer-term analysis of the collapse has emerged. Using data from a nationally representative sample, fixed-effect estimations and mediation analyses were performed to explore the relationship between the Icelandic economic collapse in 2008 and the longer-term impact on hypertension and cardiovascular health. A sensitivity analysis was carried out with pooled logit models estimated as well as an alternative dependent variable. Our attrition analysis revealed that results for cardiovascular diseases were affected by attrition, but not results from estimations on the relationship between the economic crisis and hypertension. When compared to the boom year 2007, our results point to an increased probability of Icelandic women having hypertension in the year 2012, when the Icelandic economy had recovered substantially from the economic collapse in 2008. This represents a deviation from pre-crisis trends, thus suggesting a true economic-recovery impact on hypertension.
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http://dx.doi.org/10.1186/s13561-017-0157-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442036PMC
December 2017

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets.

Nat Genet 2017 Mar 6;49(3):416-425. Epub 2017 Feb 6.

Department of Internal Medicine B-Cardiology, Intensive Care, Pulmonary Medicine and Infectious Diseases, University Medicine Greifswald, Greifswald, Germany.

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.
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http://dx.doi.org/10.1038/ng.3787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326681PMC
March 2017

Preserved Collateral Blood Flow in the Endovascular M2CAO Model Allows for Clinically Relevant Profiling of Injury Progression in Acute Ischemic Stroke.

PLoS One 2017 9;12(1):e0169541. Epub 2017 Jan 9.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Interventional treatment regimens have increased the demand for accurate understanding of the progression of injury in acute ischemic stroke. However, conventional animal models severely inhibit collateral blood flow and mimic the malignant infarction profile not suitable for treatment. The aim of this study was to provide a clinically relevant profile of the emergence and course of ischemic injury in cases suitable for acute intervention, and was achieved by employing a M2 occlusion model (M2CAO) that more accurately simulates middle cerebral artery (MCA) occlusion in humans. Twenty-five Sprague-Dawley rats were subjected to Short (90 min), Intermediate (180 min) or Extended (600 min) transient M2CAO and examined longitudinally with interleaved diffusion-, T2- and arterial spin labeling perfusion-weighted magnetic resonance imaging before and after reperfusion. We identified a rapid emergence of cytotoxic edema within tissue regions undergoing infarction, progressing in several distinct phases in the form of subsequent moderation and then reversal at 230 min (p < 0.0001). We identified also the early emergence of vasogenic edema, which increased consistently before and after reperfusion (p < 0.0001). The perfusion of the penumbra correlated more strongly to the perfusion of adjacent tissue regions than did the perfusion of regions undergoing infarction (p = 0.0088). This was interpreted as an effect of preserved collateral blood flow during M2CAO. Accordingly, we observed only limited recruitment of penumbra regions to the infarction core. However, a gradual increase in infarction size was still occurring as late as 10 hours after M2CAO. Our results indicate that patients suffering MCA branch occlusion stand to benefit from interventional therapy for an extended time period after the emergence of ischemic injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0169541PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221807PMC
August 2017

A supramolecular assembly mediates lentiviral DNA integration.

Science 2017 01;355(6320):93-95

Chromatin Structure and Mobile DNA, The Francis Crick Institute, London, NW1 1AT, UK.

Retroviral integrase (IN) functions within the intasome nucleoprotein complex to catalyze insertion of viral DNA into cellular chromatin. Using cryo-electron microscopy, we now visualize the functional maedi-visna lentivirus intasome at 4.9 angstrom resolution. The intasome comprises a homo-hexadecamer of IN with a tetramer-of-tetramers architecture featuring eight structurally distinct types of IN protomers supporting two catalytically competent subunits. The conserved intasomal core, previously observed in simpler retroviral systems, is formed between two IN tetramers, with a pair of C-terminal domains from flanking tetramers completing the synaptic interface. Our results explain how HIV-1 IN, which self-associates into higher-order multimers, can form a functional intasome, reconcile the bulk of early HIV-1 IN biochemical and structural data, and provide a lentiviral platform for design of HIV-1 IN inhibitors.
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http://dx.doi.org/10.1126/science.aah7002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321526PMC
January 2017

[The prevalence of sexual abuse and sexual assault against icelandic adolescents].

Laeknabladid 2016 Jun;102(6):289-95

Introduction: Sexual abuse and sexual assaults against children and adolescents is one of the most significant threats to their health. The aim of the current study was to investigate its prevalence and effects on Icelandic teenagers in the 10th grade.

Material And Methods: The study is based on data collected for the Icelandic part of the HBSC-project (Health and behaviour of school- aged children). Standardized questionnaires were sent to all students in 10th grade in Iceland of which 3,618 participated. The students experience of sexual abuse or assaults was assessed by asking them how often they had been against their will a) touched in a sexual way, b) made to touch someone else in a sexual way, c) the subject of an attempted rape or d) subjected to rape.

Results: The results showed that 14.6% (527) participants had experienced sexual abuse or assault. Of these, 4.5% (162) had one such experience but 10.1% had either suffered certain type of abuse or assault more than once, or had experienced more than one kind. About 1% of participants (35) said that they had suffered many times from many forms of abuse and assaults. The prevalence of poor mental well-being and risk behaviour was much higher amongst those that had experienced sexual abuse or assault.

Conclusion: Although the results show that the prevalence of sexual abuse and assault against Icelandic adolescents is similar to other Western countries, we find it to be higher than a previous study a decade ago.

Key Words: Sexual abuse, sexual assault, adolescents. Correspondence: Arsaell Mar Arnarsson, [email protected]
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http://dx.doi.org/10.17992/lbl.2016.06.87DOI Listing
June 2016

Access to the brain parenchyma using endovascular techniques and a micro-working channel.

J Neurosurg 2017 Feb 25;126(2):511-517. Epub 2016 Mar 25.

Department of Clinical Neuroscience, Karolinska Institutet.

OBJECTIVE Several older studies report a low risk for parenchymal access to the CNS by surgical techniques. In more recent studies, including those with post-puncture CT scans, there are indications that the risk of bleeding might approach 8%. New therapies, such as those that use viral vectors, modified mRNA, or cell transplantation, will probably warrant more parenchymal access to the CNS. Other minimally invasive routes might then be tempting to explore. This study was designed in 2 parts to address the possibility of using the endovascular route. The first aim was to test the ability to create a parenchymal micro-working channel to the CNS in macaque monkeys through the vessel wall. Second, the biocompatibility of a device-associated, detached, distal securing plug that was made of nitinol was investigated in swine for 1 year. METHODS Trans-vessel wall intervention in the middle cerebral artery and associated cerebral parenchyma was performed in 4 rhesus macaque monkeys using a full clinical angiography suite. A contrast agent and methylene blue were injected to test the working channel and then detached at the distal end to act as a securing plug through the vessel wall. One-year follow-ups were also performed using angiography and histological analysis in 10 swine with 24 implants that were distributed in the external carotid artery tree. RESULTS The cerebral interventions were performed without acute bleeding. Both the contrast agent and methylene blue were infused into the brain parenchyma and subarachnoidal space via the endovascular micro-working channel (7 injections in 4 animals). In the 1-year follow-up period, the implant that was left in the external carotid vessel wall in the swine was covered by the endothelium, which was followed by dislodgement just outside the blood vessel with thin capsule formation. No stenosis in the artery was detected on 1-year angiography. The animals showed normal behavior and blood sample results during the follow-up period. This is the first histological demonstration of nitinol biocompatibility when the implant is positioned through an arterial wall and indicates that the trans-vessel wall technique is not comparable with stent placement and its ability to induce intimal hyperplasia and restenosis. CONCLUSIONS This study demonstrates that the trans-vessel wall technique is applicable to brain intervention in macaque monkeys, providing a micro-working channel for delivery or sampling. The long-term follow-up study of the detached device in swine showed no clinical or biochemical complications and a normal angiography appearance.
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http://dx.doi.org/10.3171/2016.1.JNS152543DOI Listing
February 2017

Two mutations in the vif gene of maedi-visna virus have different phenotypes, indicating more than one function of Vif.

Virology 2016 Jan 17;488:37-42. Epub 2015 Nov 17.

Institute for Experimental Pathology, Keldur, University of Iceland, Reykjavik, Iceland. Electronic address:

Like most other lentiviruses, maedi-visna virus (MVV) requires Vif for replication in natural target cells and in vivo. Here, we show that Vif-deficient MVV accumulates G-A mutations in the sequence context characteristic of ovine APOBEC3, consistent with a role of MVV Vif in neutralizing APOBEC3. We studied two point mutations in the vif gene of MVV. One was a tryptophan to arginine mutation that affects the interaction with APOBEC3 and caused G-A hypermutation. The other mutation was a proline to serine mutation that together with a mutation in the capsid protein caused attenuated replication in fetal ovine synovial (FOS) cells but not in sheep choroid plexus (SCP) cells. There was no hypermutation associated with this mutation. These results suggest that MVV Vif exerts more than one function and that there may be interaction between Vif and the capsid. The results also suggest the involvement of an unknown host factor in MVV Vif function.
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http://dx.doi.org/10.1016/j.virol.2015.10.035DOI Listing
January 2016

Lineage-Specific Viral Hijacking of Non-canonical E3 Ubiquitin Ligase Cofactors in the Evolution of Vif Anti-APOBEC3 Activity.

Cell Rep 2015 May 14;11(8):1236-50. Epub 2015 May 14.

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biosciences, QB3, University of California, San Francisco, San Francisco, CA 94158, USA; J. David Gladstone Institutes, San Francisco, CA 94158, USA. Electronic address:

HIV-1 encodes the accessory protein Vif, which hijacks a host Cullin-RING ubiquitin ligase (CRL) complex as well as the non-canonical cofactor CBFβ, to antagonize APOBEC3 antiviral proteins. Non-canonical cofactor recruitment to CRL complexes by viral factors, to date, has only been attributed to HIV-1 Vif. To further study this phenomenon, we employed a comparative approach combining proteomic, biochemical, structural, and virological techniques to investigate Vif complexes across the lentivirus genus, including primate (HIV-1 and simian immunodeficiency virus macaque [SIVmac]) and non-primate (FIV, BIV, and MVV) viruses. We find that CBFβ is completely dispensable for the activity of non-primate lentiviral Vif proteins. Furthermore, we find that BIV Vif requires no cofactor and that MVV Vif requires a novel cofactor, cyclophilin A (CYPA), for stable CRL complex formation and anti-APOBEC3 activity. We propose modular conservation of Vif complexes allows for potential exaptation of functions through the acquisition of non-CRL-associated host cofactors while preserving anti-APOBEC3 activity.
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http://dx.doi.org/10.1016/j.celrep.2015.04.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613747PMC
May 2015

Liver parenchyma access and lesion marker via the endovascular route.

J Surg Res 2015 May 30;195(2):488-94. Epub 2015 Jan 30.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden. Electronic address:

Background: Neoadjuvant chemotherapeutic regimens for metastatic colorectal cancer are now so effective that they can cause "vanishing" lesions. With new advances such as local ablation, intra-arterial treatments in bolus with pumps or with beads, and isolation of hepatic perfusion, the need for a working channel to the liver may be warranted, ideally reducing the risk of spreading neoplastic cells.

Materials And Methods: The endovascular trans-vessel wall Extroducer device makes it possible to gain direct access to the liver parenchyma. The distal tip is then detached, to act as both a marker and a securing plug in the vessel defect. We used ex vivo and in vivo tests to evaluate the device as a working channel for local administration of substances to the parenchyma and as a marker for detection with both transabdominal and intraoperative ultrasonography.

Results: We could deploy the Extroducer device without any hemorrhagic or thromboembolic complications in vivo, and we were able to detect all markers ex vivo and in vivo using both transabdominal and intraoperative ultrasonography. Furthermore, we found that it is possible to administer substances to the liver parenchyma using the catheter.

Conclusions: The trans-vessel wall technique can be used to establish a working channel to the liver parenchyma for administration of any substance, such as chemotherapeutic agents or cells. The detached device can also be used as a marker for ultrasound-guided partial liver resection in "vanishing lesions." The technique should have a low risk of seeding of neoplastic cells. This study in large animals forms a strong basis for translation to clinical studies.
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http://dx.doi.org/10.1016/j.jss.2015.01.048DOI Listing
May 2015

Web-based versus traditional paper questionnaires: a mixed-mode survey with a Nordic perspective.

J Med Internet Res 2013 Aug 26;15(8):e173. Epub 2013 Aug 26.

Department of Public Health, Section for General Practice, Aarhus University, Aarhus C, Denmark.

Background: Survey response rates have been declining over the past decade. The more widespread use of the Internet and Web-based technologies among potential health survey participants suggests that Web-based questionnaires may be an alternative to paper questionnaires in future epidemiological studies.

Objective: To compare response rates in a population of parents by using 4 different modes of data collection for a questionnaire survey of which 1 involved a nonmonetary incentive.

Methods: A random sample of 3148 parents of Danish children aged 2-17 years were invited to participate in the Danish part of the NordChild 2011 survey on their children's health and welfare. NordChild was conducted in 1984 and 1996 in collaboration with Finland, Iceland, Norway, and Sweden using mailed paper questionnaires only. In 2011, all countries used conventional paper versions only except Denmark where the parents were randomized into 4 groups: (1) 789 received a paper questionnaire only (paper), (2) 786 received the paper questionnaire and a log-in code to the Web-based questionnaire (paper/Web), (3) 787 received a log-in code to the Web-based questionnaire (Web), and (4) 786 received log-in details to the Web-based questionnaire and were given an incentive consisting of a chance to win a tablet computer (Web/tablet). In connection with the first reminder, the nonresponders in the paper, paper/Web, and Web groups were also present with the opportunity to win a tablet computer as a means of motivation. Descriptive analysis was performed using chi-square tests. Odds ratios were used to estimate differences in response rates between the 4 modes.

Results: In 2011, 1704 of 3148 (54.13%) respondents answered the Danish questionnaire. The highest response rate was with the paper mode (n=443, 56.2%). The other groups had similar response rates: paper/Web (n=422, 53.7%), Web (n=420, 53.4%), and Web/tablet (n=419, 53.3%) modes. Compared to the paper mode, the odds for response rate in the paper/Web decreased by 9% (OR 0.91, 95% CI 0.74-1.10) and by 11% (OR 0.89, 95% CI 0.73-1.09) in the Web and Web/tablet modes. The total number of responders for NordChild declined from 10,291 of 15,339 (67.09%) in 1984 and 10,667 of 15,254 (69.93%) in 1996 to 7805 of 15,945 (48.95%) in 2011 with similar declines in all 5 Nordic countries.

Conclusions: Web-based questionnaires could replace traditional paper questionnaires with minor effects on response rates and lower costs. The increasing effect on the response rate on participants replying for a nonmonetary incentive could only be estimated within the 2 Web-based questionnaire modes before the first reminder. Alternative platforms to reach higher participation rates in population surveys should reflect the development of electronic devices and the ways in which the population primarily accesses the Internet.
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http://dx.doi.org/10.2196/jmir.2595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757995PMC
August 2013

Host restriction of lentiviruses and viral countermeasures: APOBEC3 and Vif.

Viruses 2013 Jul 30;5(8):1934-47. Epub 2013 Jul 30.

Institute for Experimental Pathology, University of Iceland, Keldur, 112 Reykjavik, Iceland.

It is becoming increasingly clear that organisms have developed a variety of mechanisms to fight against viral infection. The viruses have developed means of counteracting these defences in various ways. The APOBEC3 proteins are a mammalian-specific family of nucleic acid cytidine deaminases that block retroviral infection. These inhibitors are counteracted by the Vif proteins encoded by most lentiviruses. In this paper, we will review the interaction of the lentiviral Vif proteins with the APOBEC3 proteins, with an emphasis on sheep APOBEC3 and maedi-visna virus (MVV) Vif.
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http://dx.doi.org/10.3390/v5081934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761234PMC
July 2013

Increased stress among women following an economic collapse--a prospective cohort study.

Am J Epidemiol 2013 May 13;177(9):979-88. Epub 2013 Feb 13.

There is a scarcity of data on mental health effects of the global economic recession. In this study, we investigated potential change in self-reported levels of psychological stress in the Icelandic population as a result of the major national economic collapse that occurred in 2008. We used a national cohort of 3,755 persons who responded to a survey administered in 2007 and 2009, including demographic questions and a stress measure (the 4-item Perceived Stress Scale). We used repeated-measures analysis of variance and logistic regression models to assess change in mean stress levels and risk of high stress levels (>90th percentile) in 2009 as compared with 2007. Age-adjusted mean stress levels increased between 2007 and 2009 (P = 0.004), though the increase was observed only for women (P = 0.003), not for men (P = 0.34). Similarly, the odds ratios for experiencing high stress levels were increased only among women (odds ratio (OR) = 1.37), especially among women who were unemployed (OR = 3.38), students (OR = 2.01), had middle levels of education (OR = 1.65), or were in the middle income bracket (OR = 1.59). The findings indicate that psychological stress may have increased following the economic collapse in Iceland, particularly among females in economically vulnerable groups.
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http://dx.doi.org/10.1093/aje/kws347DOI Listing
May 2013

Does neighbourhood social capital aid in levelling the social gradient in the health and well-being of children and adolescents? A literature review.

BMC Public Health 2013 Jan 23;13:65. Epub 2013 Jan 23.

Department of Public Health, Ghent University, De Pintelaan 185 blok A, 9000, Ghent, Belgium.

Background: Although most countries in the European Union are richer and healthier than ever, health inequalities remain an important public health challenge. Health-related problems and premature death have disproportionately been reported in disadvantaged neighbourhoods. Neighbourhood social capital is believed to influence the association between neighbourhood deprivation and health in children and adolescents, making it a potentially interesting concept for policymakers.

Methods: This study aims to review the role of social capital in health inequalities and the social gradient in health and well-being of children and adolescents. A systematic review of published quantitative literature was conducted, focussing on (1) the mediating role of neighbourhood social capital in the relationship between socio-economic status (SES) and health-related outcomes in children and adolescents and (2) the interaction between neighbourhood social capital and socio-economic characteristics in relation to health-related outcomes in children and adolescents. Three electronic databases were searched. Studies executed between 1 January 1990 and 1 September 2011 in Western countries (USA, New Zealand, Australia and Europe) that included a health-related outcome in children or adolescents and a variable that measured neighbourhood social capital were included.

Results: Eight studies met the inclusion criteria for the review. The findings are mixed. Only two of five studies confirmed that neighbourhood social capital mediates the association between neighbourhood deprivation and health and well-being in adolescents. Furthermore, two studies found a significant interaction between neighbourhood socio-economic factors and neighbourhood social capital, which indicates that neighbourhood social capital is especially beneficial for children who reside in deprived neighbourhoods. However, two other studies did not find a significant interaction between SES and neighbourhood social capital. Due to the broad range of studied health-related outcomes, the different operationalisations of neighbourhood social capital and the conceptual overlap between measures of SES and social capital in some studies, the factors that explain these differences in findings remain unclear.

Conclusions: Although the findings of this study should be interpreted with caution, the results suggest that neighbourhood social capital might play a role in the health gradient among children and adolescents. However, only two of the included studies were conducted in Europe. Furthermore, some studies focussed on specific populations and minority groups. To formulate relevant European policy recommendations, further European-focussed research on this issue is needed.
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http://dx.doi.org/10.1186/1471-2458-13-65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574053PMC
January 2013

Alcohol consumption in movies and adolescent binge drinking in 6 European countries.

Pediatrics 2012 Apr 5;129(4):709-20. Epub 2012 Mar 5.

Institute for Therapy and Health Research, Kiel, Germany.

Objective: The goal of this study was to investigate whether the association between exposure to images of alcohol use in movies and binge drinking among adolescents is independent of cultural context.

Methods: A cross-sectional survey study in 6 European countries (Germany, Iceland, Italy, Netherlands, Poland, and Scotland) was conducted. A total of 16 551 pupils from 114 public schools with a mean (± SD) age of 13.4 (± 1.18) years participated. By using previously validated methods, exposure to alcohol use in movies was estimated from the 250 top-grossing movies of each country (years 2004-2009). Lifetime binge drinking was the main outcome measure.

Results: Overall, 27% of the sample had consumed >5 drinks on at least 1 occasion in their life. After controlling for age, gender, family affluence, school performance, television screen time, sensation seeking and rebelliousness, and frequency of drinking of peers, parents, and siblings, the adjusted β-coefficient for lifetime binge drinking in the entire sample was 0.12 (95% confidence interval: 0.10-0.14; P < .001). The crude relationship between movie alcohol use exposure and lifetime binge drinking was significant in all countries; after covariate adjustment, the relationship was still significant in 5 of 6 countries. A sensitivity analysis revealed that the association is content specific, as there was no significant association between lifetime binge drinking and exposure to smoking in movies.

Conclusions: The link between alcohol use in movies and adolescent binge drinking was robust and seems relatively unaffected by cultural contexts.
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http://dx.doi.org/10.1542/peds.2011-2809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3313641PMC
April 2012

High youth access to movies that contain smoking in Europe compared with the USA.

Tob Control 2013 Jul 18;22(4):241-4. Epub 2011 Dec 18.

Institute for Therapy and Health Research (IFT-Nord), Harmsstrasse 2, Kiel, Germany.

Background: Based on evidence that exposure to smoking in movies is associated with adolescent smoking, the WHO has called on countries to assign a rating that restricts youth access to such movies.

Objective: To evaluate youth access to movies that portray smoking in European countries and compare with that in the USA.

Methods: The authors identified the most commercially successful movies screened in six European countries (Germany, Iceland, Italy, the Netherlands, Poland and UK) and the USA between 2004 and 2009. The authors coded the 464 movies that were screened in both Europe and the USA according to whether or not they portrayed smoking.

Results: 87% of the movies were 'youth' rated in Europe (ratings board classification as suitable for those younger than 16 years) compared to only 67% in the USA (suitable for those younger than 17 years). Smoking was portrayed in 319 (69%) movies. 85% of the movies that portrayed smoking were 'youth' rated in Europe compared with only 59% in the USA (p<0.001).

Conclusions: Tobacco imagery is still common in popular films shown in European countries and the USA. None of the seven countries examined followed the WHO recommendations on restricting youth access to movies that portray smoking. Compared to the USA, European youths have access to substantially more movies in general, and this gives them access to more movies that portray smoking in particular.
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http://dx.doi.org/10.1136/tobaccocontrol-2011-050050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3779888PMC
July 2013

Propagating and detecting an infectious molecular clone of maedi-visna virus that expresses green fluorescent protein.

J Vis Exp 2011 Oct 9(56). Epub 2011 Oct 9.

Institute for Experimental Pathology, University of Iceland.

Maedi-visna virus (MVV) is a lentivirus of sheep, causing slowly progressive interstitial pneumonia and encephalitis. The primary target cells of MVV in vivo are considered to be of the monocyte lineage. Certain strains of MVV can replicate in other cell types, however. The green fluorescent protein is a commonly used marker for studying lentiviruses in living cells. We have nserted the egfp gene into the gene for dUTPase of MVV. The dUTPase gene is well conserved in most lentivirus strains of sheep and goats and has been shown to be important in replication of CAEV. However, dUTPase has been shown to be dispensable for replication of the molecular clone of MVV used in this study both in vitro and in vivo. MVV replication is strictly confined to cells of sheep or goat origin. We use a primary cell line from the choroid plexus of sheep (SCP cells) for transfection and propagation of the virus. The fluorescent MVV is fully infectious and EGFP expression is stable over at least 6 passages. There is good correlation between measurements of TCID₅₀ and EGFP. This virus should therefore be useful for rapid detection of infected cells in studies of cell tropism and pathogenicity in vitro and in vivo.
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http://dx.doi.org/10.3791/3483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227179PMC
October 2011
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