| 1. |
- Bradnam, K. R., et al.
(författare)
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Assemblathon 2 : Evaluating de novo methods of genome assembly in three vertebrate species
- 2013
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Ingår i: GigaScience. - : BioMed Central (BMC). - 2047-217X. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The process of generating raw genome sequence data continues to become cheaper, faster, and more accurate. However, assembly of such data into high-quality, finished genome sequences remains challenging. Many genome assembly tools are available, but they differ greatly in terms of their performance (speed, scalability, hardware requirements, acceptance of newer read technologies) and in their final output (composition of assembled sequence). More importantly, it remains largely unclear how to best assess the quality of assembled genome sequences. The Assemblathon competitions are intended to assess current state-of-the-art methods in genome assembly. Results: In Assemblathon 2, we provided a variety of sequence data to be assembled for three vertebrate species (a bird, a fish, and snake). This resulted in a total of 43 submitted assemblies from 21 participating teams. We evaluated these assemblies using a combination of optical map data, Fosmid sequences, and several statistical methods. From over 100 different metrics, we chose ten key measures by which to assess the overall quality of the assemblies. Conclusions: Many current genome assemblers produced useful assemblies, containing a significant representation of their genes and overall genome structure. However, the high degree of variability between the entries suggests that there is still much room for improvement in the field of genome assembly and that approaches which work well in assembling the genome of one species may not necessarily work well for another.
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| 2. |
- Escott-Price, Valentina, et al.
(författare)
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Gene-Wide Analysis Detects Two New Susceptibility Genes for Alzheimer's Disease
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e94661-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. Principal Findings: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4x10(-6)) and 14 (IGHV1-67 p = 7.9x10(-8)) which indexed novel susceptibility loci. Significance: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.
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| 3. |
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| 4. |
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| 5. |
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| 6. |
- Tanaka, Toshiko, et al.
(författare)
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Genome-wide meta-analysis of observational studies shows common genetic variants associated with macronutrient intake
- 2013
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 1938-3207 .- 0002-9165. ; 97:6, s. 1395-1402
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Tidskriftsartikel (refereegranskat)abstract
- Background: Macronutrient intake varies substantially between individuals, and there is evidence that this variation is partly accounted for by genetic variants. Objective: The objective of the study was to identify common genetic variants that are associated with macronutrient intake. Design: We performed 2-stage genome-wide association (GWA) meta-analysis of macronutrient intake in populations of European descent. Macronutrients were assessed by using food-frequency questionnaires and analyzed as percentages of total energy consumption from total fat, protein, and carbohydrate. From the discovery GWA (n = 38,360), 35 independent loci associated with macronutrient intake at P < 5 x 10(-6) were identified and taken forward to replication in 3 additional cohorts (n = 33,533) from the DietGen Consortium. For one locus, fat mass obesity-associated protein (FTO), cohorts with Illumina MetaboChip genotype data (n 7724) provided additional replication data. Results: A variant in the chromosome 19 locus (rs838145) was associated with higher carbohydrate (beta +/- SE: 0.25 +/- 0.04%; P = 1.68 x 10(-8)) and lower fat (beta = SE: -0.21 +/- 0.04%; P = 1.57 x 10(-9)) consumption. A candidate gene in this region, fibroblast growth factor 21 (FGF21), encodes a fibroblast growth factor involved in glucose and lipid metabolism. The variants in this locus were associated with circulating FGF21 protein concentrations (P < 0.05) but not mRNA concentrations in blood or brain. The body mass index (BMI) increasing allele of the FTO variant (rs1421085) was associated with higher protein intake (beta +/- SE: 0.10 +/- 0.02%; P = 9.96 x 10(-10)), independent of BMI (after adjustment for BMI, beta +/- SE: 0.08 +/- 0.02%; P = 3.15 x 10(-7)). Conclusion: Our results indicate that variants in genes involved in nutrient metabolism and obesity are associated with macronutrient consumption in humans. Trials related to this study were registered at clinicaltrials.gov as NCT00005131 (Atherosclerosis Risk in Communities), NCT00005133 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetic and Environmental Determinants of Triglycerides), NCT01331512 (InCHIANTI Study), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).
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| 7. |
- Kronforst, K. D., et al.
(författare)
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A Neonatal Model of Intravenous Staphylococcus epidermidis Infection in Mice < 24 h Old Enables Characterization of Early Innate Immune Responses
- 2012
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus epidermidis (SE) causes late onset sepsis and significant morbidity in catheterized preterm newborns. Animal models of SE infection are useful in characterizing disease mechanisms and are an important approach to developing improved diagnostics and therapeutics. Current murine models of neonatal bacterial infection employ intraperitoneal or subcutaneous routes at several days of age, and may, therefore, not accurately reflect distinct features of innate immune responses to bacteremia. In this study we developed, validated, and characterized a murine model of intravenous (IV) infection in neonatal mice <24 hours (h) old to describe the early innate immune response to SE. C57BL/6 mice <24 h old were injected IV with 10(6), 10(7), 10(8) colony-forming units (CFU) of SE 1457, a clinical isolate from a central catheter infection. A prospective injection scoring system was developed and validated, with only high quality injections analyzed. Newborn mice were euthanized between 2 and 48 h post-injection and spleen, liver, and blood collected to assess bacterial viability, gene expression, and cytokine production. High quality IV injections demonstrated inoculum-dependent infection of spleen, liver and blood. Within 2 h of injection, SE induced selective transcription of TLR2 and MyD88 in the liver, and increased systemic production of plasma IL-6 and TNF-alpha. Despite clearance of bacteremia and solid organ infection within 48 h, inoculum-dependent impairment in weight gain was noted. We conclude that a model of IV SE infection in neonatal mice <24 h old is feasible, demonstrating inoculum-dependent infection of solid organs and a pattern of bacteremia, rapid and selective innate immune activation, and impairment of weight gain typical of infected human neonates. This novel model can now be used to characterize immune ontogeny, evaluate infection biomarkers, and assess preventative and therapeutic modalities.
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| 8. |
- Mattsson, Niklas, 1979, et al.
(författare)
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The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
- 2011
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
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| 9. |
- Rizvi, Saiyada N. F., et al.
(författare)
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Biodistribution, radiation dosimetry and scouting of 90Y-ibritumomab tiuxetan therapy in patients with relapsed B-cell non-Hodgkin's lymphoma using 89Zr-ibritumomab tiuxetan and PET
- 2012
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 39:3, s. 512-520
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Positron emission tomography (PET) with Zr-89-britumomab tiuxetan can be used to monitor biodistribution of Y-90-ibritumomab tiuxetan as shown in mice. The aim of this study was to assess biodistribution and radiation dosimetry of 90Y-ibritumomab tiuxetan in humans on the basis of Zr-89-ibritumomab tiuxetan imaging, to evaluate whether co-injection of a therapeutic amount of Y-90-ibritumomab tiuxetan influences biodistribution of Zr-89-ibritumomabtiuxetan and whether pre-therapy scout scans with Zr-89-ibritumomab tiuxetan can be used to predict biodistribution of Y-90-ibritumomab tiuxetan and the dose-limiting organ during therapy. Methods: Seven patients with relapsed B-cell non-Hodgkin's lymphoma scheduled for autologous stem cell transplantation underwent PET scans at 1, 72 and 144 h after injection of similar to 70 MBq Zr-89-ibritumomab tiuxetan and again 2 weeks later after co-injection of 15 MBq/kg or 30 MBq/kg Y-90-britumomab tiuxetan. Volumes of interest were drawn over liver, kidneys, lungs, spleen and tumours. Ibritumomab tiuxetan organ absorbed doses were calculated using OLINDA. Red marrow dosimetry was based on blood samples. Absorbed doses to tumours were calculated using exponential fits to the measured data. Results: The highest Y-90 absorbed dose was observed in liver (3.2 +/- 1.8 mGy/MBq) and spleen (2.9 +/- 0.7 mGy/MBq) followed by kidneys and lungs. The red marrow dose was 0.52 +/- 0.04 mGy/MBq, and the effective dose was 0.87 +/- 0.14 mSv/MBq. Tumour absorbed doses ranged from 8.6 to 28.6 mGy/MBq. Correlation between predicted pre-therapy and therapy organ absorbed doses as based on Zr-89-ibritumomab tiuxetan images was high (Pearson correlation coefficient r=0.97). No significant difference between pre-therapy and therapy tumour absorbed doses was found, but correlation was lower (r=0.75). Conclusion: Biodistribution of Zr-89-ibritumomab tiuxetan is not influenced by simultaneous therapy with Y-90-ibritumomab tiuxetan, and Zr-89-ibritumomab tiuxetan scout scans can thus be used to predict biodistribution and dose-limiting organ during therapy. Absorbed doses to spleen were lower than those previously estimated using In-111-ibritumomab tiuxetan. The dose-limiting organ in patients undergoing stem cell transplantation is the liver.
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| 10. |
- Abdoullaye, Doukary, et al.
(författare)
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Permanent genetic resources added to molecular ecology resources database 1 August 2009 - 30 September 2009
- 2010
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Ingår i: Molecular Ecology Resources. - : Wiley. - 1755-098X .- 1755-0998. ; 10:1, s. 232-236
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Tidskriftsartikel (refereegranskat)abstract
- This article documents the addition of 238 microsatellite marker loci and 72 pairs of Single Nucleotide Polymorphism (SNP) sequencing primers to the Molecular Ecology Resources Database. Loci were developed for the following species: Adelges tsugae, Artemisia tridentata, Astroides calycularis, Azorella selago, Botryllus schlosseri, Botrylloides violaceus, Cardiocrinum cordatum var. glehnii, Campylopterus curvipennis, Colocasia esculenta, Cynomys ludovicianus, Cynomys leucurus, Cynomys gunnisoni, Epinephelus coioides, Eunicella singularis, Gammarus pulex, Homoeosoma nebulella, Hyla squirella, Lateolabrax japonicus, Mastomys erythroleucus, Pararge aegeria, Pardosa sierra, Phoenicopterus ruber ruber and Silene latifolia. These loci were cross-tested on the following species: Adelges abietis, Adelges cooleyi, Adelges piceae, Pineus pini, Pineus strobi, Tubastrea micrantha, three other Tubastrea species, Botrylloides fuscus, Botrylloides simodensis, Campylopterus hemileucurus, Campylopterus rufus, Campylopterus largipennis, Campylopterus villaviscensio, Phaethornis longuemareus, Florisuga mellivora, Lampornis amethystinus, Amazilia cyanocephala, Archilochus colubris, Epinephelus lanceolatus, Epinephelus fuscoguttatus, Symbiodinium temperate-A clade, Gammarus fossarum, Gammarus roeselii, Dikerogammarus villosus and Limnomysis benedeni. This article also documents the addition of 72 sequencing primer pairs and 52 allele specific primers for Neophocaena phocaenoides.
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| 11. |
- Babiuc, M. C., et al.
(författare)
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Testing the well-posedness of characteristic evolution of scalar waves
- 2014
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Ingår i: Classical and quantum gravity. - : IOP Publishing. - 0264-9381 .- 1361-6382. ; 31:2, s. 025022-
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Tidskriftsartikel (refereegranskat)abstract
- Recent results have revealed a critical way in which lower order terms affect the well-posedness of the characteristic initial value problem for the scalar wave equation. The proper choice of such terms can make the Cauchy problem for scalar waves well posed even on a background spacetime with closed lightlike curves. These results provide new guidance for developing stable characteristic evolution algorithms. In this regard, we present here the finite difference version of these recent results and implement them in a stable evolution code. We describe test results which validate the code and exhibit some of the interesting features due to the lower order terms.
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| 12. |
- Danad, Ibrahim, et al.
(författare)
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Carotid artery intima-media thickness, but not coronary artery calcium, predicts coronary vascular resistance in patients evaluated for coronary artery disease
- 2012
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Ingår i: European Heart Journal: Cardiovascular Imaging. - : Oxford University Press (OUP). - 2047-2404 .- 2047-2412. ; 13:4, s. 317-323
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Tidskriftsartikel (refereegranskat)abstract
- Aims There is growing evidence that coronary artery disease (CAD) affects not only the conduit epicardial coronary arteries, but also the microvascular coronary bed. Moreover, coronary microvascular dysfunction (CMVD) often precedes the stage of clinically overt epicardial CAD. Coronary artery calcium (CAC) and carotid intima-media thickness (C-IMT) measured with computed tomography (CT) and ultrasound, respectively, are among the available techniques to non-invasively assess atherosclerotic burden. An increased CAC score and C-IMT have also been associated with CMVD. It is therefore of interest to explore and compare the potential of CAC against C-IMT to predict minimal coronary vascular resistance (CVR). Methods and results We evaluated 120 patients (mean age 56 +/- 9 years, 58 men) without a documented history of CAD in whom and results obstructive CAD was excluded. All patients underwent C-IMT measurements, CAC scoring, and vasodilator stress O-15-water positron emission tomography (PET)/CT, during which the coronary flow reserve (CFR) and minimal CVR were analysed. Minimal CVR increased significantly with increasing tertiles of C-IMT (22 +/- 6, 27 +/- 11, and 28 +/- 9 mmHg mL(-1) min(-1) g(-1), P < 0.01), whereas the CFR was comparable across all C-IMT groups (P = 0.50). Minimal CVR increased significantly with an increase in CAC score (23 +/- 9, 27 +/- 8, 32 +/- 10, and 32 +/- 7 mmHg mL(-1) min(-1) g(-1). P < 0.01), whereas the CFR did not show a significant decrease with higher CAC scores (P = 0.18). Multivariable regression analysis revealed that C-IMT (P = 0.03), but not CAC, was independently associated with minimal CVR. Conclusion C-IMT, but not CAC score, independently predicts minimal CVR in patients with multiple cardiovascular risk factors and suspected of CAD.
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| 13. |
- Danad, Ibrahim, et al.
(författare)
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Coronary risk factors and myocardial blood flow in patients evaluated for coronary artery disease : a quantitative [15O]H2O PET/CT study
- 2012
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 39:1, s. 102-112
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThere has been increasing interest in quantitative myocardial blood flow (MBF) imaging over the last years and it is expected to become a routinely used technique in clinical practice. Positron emission tomography (PET) using [15O]H2O is the established gold standard for quantification of MBF in vivo. A fundamental issue when performing quantitative MBF imaging is to define the limits of MBF in a clinically suitable population. The aims of the present study were to determine the limits of MBF and to determine the relationship among coronary artery disease (CAD) risk factors, gender and MBF in a predominantly symptomatic patient cohort without significant CAD.MethodsA total of 128 patients (mean age 54 ± 10 years, 50 men) with a low to intermediate pretest likelihood of CAD were referred for noninvasive evaluation of CAD using a hybrid PET/computed tomography (PET/CT) scanner. MBF was quantified with [15O]H2O at rest and during adenosine-induced hyperaemia. Obstructive CAD was excluded in these patients by means of invasive or CT-based coronary angiography.ResultsGlobal average baseline MBF values were 0.91 ± 0.34 and 1.09 ± 0.30 ml·min−1·g−1 (range 0.54–2.35 and 0.59–2.75 ml·min−1·g−1) in men and women, respectively (p < 0.01). However, no gender-dependent difference in baseline MBF was seen following correction for rate–pressure product (0.98 ± 0.45 and 1.09 ± 0.30 ml·min−1·g−1 in men and women, respectively; p = 0.08). Global average hyperaemic MBF values were 3.44 ± 1.20 ml·min−1·g−1 in the whole study population, and 2.90 ± 0.85 and 3.78 ± 1.27 ml·min−1·g−1 (range 1.52–5.22 and 1.72–8.15 ml·min−1·g−1) in men and women, respectively (p < 0.001). Multivariate analysis identified male gender, age and body mass index as having an independently negative impact on hyperaemic MBF.ConclusionGender, age and body mass index substantially influence reference values and should be corrected for when interpreting hyperaemic MBF values.
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| 14. |
- de Langen, Adrianus J, et al.
(författare)
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Monitoring response to antiangiogenic therapy in non-small cell lung cancer using imaging markers derived from PET and dynamic contrast-enhanced MRI
- 2011
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 52:1, s. 48-55
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Tidskriftsartikel (refereegranskat)abstract
- With antiangiogenic agents, tumor shrinkage may be absent, despite survival benefit. The present study assessed the predictive value of molecular imaging for the identification of survival benefit during antiangiogenic treatment with bevacizumab and erlotinib in patients with advanced non–small cell lung cancer.Methods:Patients were evaluated using an imaging protocol including CT, 18F-FDG PET, H215O PET, and dynamic contrast-enhanced MRI to derive measurements on tumor size, glucose metabolism, perfusion, and microvascular permeability. The percentage change in imaging parameters after 3 wk of treatment as compared with baseline was calculated and correlated with progression-free survival (PFS).Results:Forty-four patients were included, and 40 underwent CT and 18F-FDG PET at both time points. Complete datasets, containing all imaging modalities, were available for 14 patients. Bevacizumab and erlotinib treatment resulted in decreased metabolism, perfusion, and tumor size. A decrease in standardized uptake value or tumor perfusion of more than 20% at week 3 was associated with longer PFS (9.7 vs. 2.8 mo, P = 0.01, and 12.5 vs. 2.9 mo, P = 0.009, respectively). Whole-tumor Ktrans (the endothelial transfer constant) was not associated with PFS, but patients with an increase of more than 15% in the SD of tumor Ktrans values—that is, an increase in regions with low or high Ktrans values—after 3 wk had shorter PFS (2.3 vs. 7.0 mo, P = 0.008). A partial response, according to the response evaluation criteria in solid tumors (RECIST), at week 3 was also associated with prolonged PFS (4.6 vs. 2.9 mo, P = 0.017). However, 40% of patients with a partial response as their best RECIST response still had stable disease at week 3. In these cases tumor perfusion was already decreased and Ktrans heterogeneity showed no increase, indicating that the latter parameters seem to be more discriminative than RECIST at the 3-wk time point.Conclusion:PET and dynamic contrast-enhanced MRI were able to identify patients who benefit from bevacizumab and erlotinib treatment. Molecular imaging seems to allow earlier response evaluation than CT.
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| 15. |
- Freire-Moran, Laura, et al.
(författare)
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Critical shortage of new antibiotics in development against multidrug-resistant bacteria-Time to react is now
- 2011
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Ingår i: Drug resistance updates. - : Elsevier BV. - 1368-7646 .- 1532-2084. ; 14:2, s. 118-124
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Forskningsöversikt (refereegranskat)abstract
- Two commercial databases (Pharmaprojects and Adis Insight R&D) were queried for antibacterial agents in clinical development. Particular attention was given to antibacterial agents for systemic administration. For each agent, reviewers were requested to indicate whether its spectrum of activity covered a set of selected multidrug-resistant bacteria, and whether it had a new mechanism of action or a new target. In addition, PubMed was searched for antibacterial agents in development that appeared in review articles. Out of 90 agents that were considered to fulfil the inclusion criteria for the analysis, 66 were new active substances. Fifteen of these could be systemically administered and were assessed as acting via a new or possibly new mechanism of action or on a new or possibly new target. Out of these, 12 agents were assessed as having documented in vitro activity against antibiotic-resistant Gram-positive bacteria and only four had documented in vitro activity against antibiotic-resistant Gram-negative bacteria. Of these four, two acted on new or possibly new targets and, crucially, none acted via new mechanisms of action. There is an urgent need to address the lack of effective treatments to meet the increasing public health burden caused by multidrug-resistant bacteria, in particular against Gram-negative bacteria.
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| 16. |
- Freischmidt, Axel, et al.
(författare)
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Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers
- 2014
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137:11, s. 2938-2950
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.
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| 17. |
- Hepburn, Lucy, et al.
(författare)
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A Spaetzle-like role for nerve growth factor beta in vertebrate immunity to Staphylococcus aureus
- 2014
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 346:6209, s. 641-646
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Tidskriftsartikel (refereegranskat)abstract
- Many key components of innate immunity to infection are shared between Drosophila and humans. However, the fly Toll ligand Spaetzle is not thought to have a vertebrate equivalent. We have found that the structurally related cystine-knot protein, nerve growth factor β (NGFβ), plays an unexpected Spaetzle-like role in immunity to Staphylococcus aureus infection in chordates. Deleterious mutations of either human NGFβ or its high-affinity receptor tropomyosin-related kinase receptor A (TRKA) were associated with severe S. aureus infections. NGFβ was released by macrophages in response to S. aureus exoproteins through activation of the NOD-like receptors NLRP3 and NLRP4 and enhanced phagocytosis and superoxide-dependent killing, stimulated proinflammatory cytokine production, and promoted calcium-dependent neutrophil recruitment. TrkA knockdown in zebrafish increased susceptibility to S. aureus infection, confirming an evolutionarily conserved role for NGFβ-TRKA signaling in pathogen-specific host immunity.
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| 18. |
- Heskamp, Sandra, et al.
(författare)
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Imaging of Human Epidermal Growth Factor Receptor Type 2 Expression with (18)F-Labeled Affibody Molecule Z(HER2:2395) in a Mouse Model for Ovarian Cancer
- 2012
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 53:1, s. 146-153
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Tidskriftsartikel (refereegranskat)abstract
- Affibody molecules are small (7 kDa) proteins with subnanomolar targeting affinity. Previous SPECT studies in xenografts have shown that the Affibody molecule (111)In-DOTA-Z(HER2:2395) can discriminate between high and low human epidermal growth factor receptor type 2 (HER2)-expressing tumors, indicating that radiolabeled Affibody molecules have potential for patient selection for HER2-targeted therapy. Compared with SPECT, PET with positron-emitting radionuclides, such as (18)F, may improve imaging of HER2 expression because of higher sensitivity and improved quantification of PET. The aim of the present study was to determine whether the (18)F-labeled NOTA-conjugated Affibody molecule Z(HER2:2395) is a suitable agent for imaging of HER2 expression. The tumor-targeting properties of (18)F-labeled Z(HER2:2395) were compared with (111)In- and (68)Ga-labeled Z(HER2:2395) in mice with HER2-expressing SK-OV-3 xenografts. Methods: Z(HER2:2395) was conjugated with NOTA and radiolabeled with (18)F, (68)Ga, and (111)In. Radiolabeling with (18)F was based on the complexation of Al(18)F by NOTA. The 50% inhibitory concentration values for NOTA-Z(HER2:2395) labeled with (19)F, (69)Ga, and (115)In were determined in a competitive cell-binding assay using SK-OV-3 cells. Mice bearing subcutaneous SK-OV-3 xenografts were injected intravenously with radiolabeled NOTA-Z(HER2:2395). One and 4 h after injection, PET/CT or SPECT/CT images were acquired, and the biodistribution was determined by ex vivo measurement. Results: The 50% inhibitory concentration values for (19)F-, (69)Ga-, and (115)In-NOTA-Z(HER2:2395) were 5.0, 6.3, and 5.3 nM, respectively. One hour after injection, tumor uptake was 4.4 +/- 0.8 percentage injected dose per gram (% ID/g), 5.6 +/- 1.6 % ID/g, and 7.1 +/- 1.4 % ID/g for (18)F-, (68)Ga-, and (111)In-NOTA-Z(HER2:2395), respectively, and the respective tumor-to-blood ratios were 7.4 +/- 1.8, 8.0 +/- 1.3, and 4.8 +/- 1.3. Tumor uptake was specific, because uptake could be blocked efficiently by coinjection of an excess of unlabeled Z(HER2:2395). PET/CT and SPECT/CT images clearly visualized HER2-expressing SK-OV-3 xenografts. Conclusion: This study showed that (18)F-NOTA-Z(HER2:2395) is a promising new imaging agent for HER2 expression in tumors. Affibody molecules were successfully labeled with (18)F within 30 min, based on the complexation of Al(18)F by NOTA. Further research is needed to determine whether this technique can be used for patient selection for HER2-targeted therapy.
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| 19. |
- Hough, Josh, et al.
(författare)
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Evolutionarily Stable Sex Ratios And Mutation Load
- 2013
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Ingår i: Evolution. - : Wiley. - 0014-3820 .- 1558-5646. ; 67:7, s. 1915-1925
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Tidskriftsartikel (refereegranskat)abstract
- Frequency-dependent selection should drive dioecious populations toward a 1:1 sex ratio, but biased sex ratios are widespread, especially among plants with sex chromosomes. Here, we develop population genetic models to investigate the relationships between evolutionarily stable sex ratios, haploid selection, and deleterious mutation load. We confirm that when haploid selection acts only on the relative fitness of X- and Y-bearing pollen and the sex ratio is controlled by the maternal genotype, seed sex ratios evolve toward 1:1. When we also consider haploid selection acting on deleterious mutations, however, we find that biased sex ratios can be stably maintained, reflecting a balance between the advantages of purging deleterious mutations via haploid selection, and the disadvantages of haploid selection on the sex ratio. Our results provide a plausible evolutionary explanation for biased sex ratios in dioecious plants, given the extensive gene expression that occurs across plant genomes at the haploid stage.
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| 20. |
- Luyssaert, S, et al.
(författare)
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The European land and inland water CO2, CO, CH4 and N2O balance between 2001 and 2005
- 2012
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Ingår i: Biogeosciences. - : European Geosciences Union (EGU) / Copernicus Publications. - 1726-4170 .- 1726-4189. ; 9:8, s. 3357-3380
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Tidskriftsartikel (refereegranskat)abstract
- Globally, terrestrial ecosystems have absorbed about 30% of anthropogenic greenhouse gas emissions over the period 2000-2007 and inter-hemispheric gradients indicate that a significant fraction of terrestrial carbon sequestration must be north of the Equator. We present a compilation of the CO2, CO, CH4 and N2O balances of Europe following a dual constraint approach in which (1) a land-based balance derived mainly from ecosystem carbon inventories and (2) a land-based balance derived from flux measurements are compared to (3) the atmospheric data-based balance derived from inversions constrained by measurements of atmospheric GHG (greenhouse gas) concentrations. Good agreement between the GHG balances based on fluxes (1294 +/- 545 Tg C in CO2-eq yr(-1)), inventories (1299 +/- 200 Tg C in CO2-eq yr(-1)) and inversions (1210 +/- 405 Tg C in CO2-eq yr(-1)) increases our confidence that the processes underlying the European GHG budget are well understood and reasonably sampled. However, the uncertainty remains large and largely lacks formal estimates. Given that European net land to atmosphere exchanges are determined by a few dominant fluxes, the uncertainty of these key components needs to be formally estimated before efforts could be made to reduce the overall uncertainty. The net land-to-atmosphere flux is a net source for CO2, CO, CH4 and N2O, because the anthropogenic emissions by far exceed the biogenic sink strength. The dual-constraint approach confirmed that the European biogenic sink removes as much as 205 +/- 72 Tg C yr(-1) from fossil fuel burning from the atmosphere. However, This C is being sequestered in both terrestrial and inland aquatic ecosystems. If the C-cost for ecosystem management is taken into account, the net uptake of ecosystems is estimated to decrease by 45% but still indicates substantial C-sequestration. However, when the balance is extended from CO2 towards the main GHGs, C-uptake by terrestrial and aquatic ecosystems is offset by emissions of non-CO2 GHGs. As such, the European ecosystems are unlikely to contribute to mitigating the effects of climate change.
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| 21. |
- Mueller, D., et al.
(författare)
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Comparison of optical and microphysical properties of pure Saharan mineral dust observed with AERONET Sun photometer, Raman lidar, and in situ instruments during SAMUM 2006
- 2012
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 117, s. D07211-
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Tidskriftsartikel (refereegranskat)abstract
- The Saharan Mineral Dust Experiment (SAMUM) 2006, Morocco, aimed at the characterization of optical, physical, and radiative properties of Saharan dust. AERONET Sun photometer, several lidars (Raman and high-spectral-resolution instruments), and airborne and ground-based in situ instruments provided us with a comprehensive set of data on particle-shape dependent and particle-shape independent dust properties. We compare 4 measurement days in detail, and we carry out a statistical analysis for some of the inferred data products for the complete measurement period. Particle size distributions and complex refractive indices inferred from the Sun photometer observations and measured in situ aboard a research aircraft show systematic differences. We find differences in the wavelength-dependence of single-scattering albedo, compared to light-scattering computations that use data from SOAP (spectral optical absorption photometer). AERONET data products of particle size distribution, complex refractive index, and axis ratios were used to compute particle extinction-to-backscatter (lidar) ratios and linear particle depolarization ratios. We find differences for these parameters to lidar measurements of lidar ratio and particle depolarization ratio. Differences particularly exist at 355 nm, which may be the result of differences of the wavelength-dependent complex refractive index that is inferred by the methods employed in this field campaign. We discuss various error sources that may lead to the observed differences.
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| 22. |
- Pfander, Claudia, et al.
(författare)
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A scalable pipeline for highly effective genetic modification of a malaria parasite
- 2011
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Ingår i: Nature Methods. - : Springer Science and Business Media LLC. - 1548-7091 .- 1548-7105. ; 8:12, s. 1078-1082
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Tidskriftsartikel (refereegranskat)abstract
- In malaria parasites, the systematic experimental validation of drug and vaccine targets by reverse genetics is constrained by the inefficiency of homologous recombination and by the difficulty of manipulating adenine and thymine (A+T)-rich DNA of most Plasmodium species in Escherichia coli. We overcame these roadblocks by creating a high-integrity library of Plasmodium berghei genomic DNA (>77% A+T content) in a bacteriophage N15-based vector that can be modified efficiently using the lambda Red method of recombineering. We built a pipeline for generating P. berghei genetic modification vectors at genome scale in serial liquid cultures on 96-well plates. Vectors have long homology arms, which increase recombination frequency up to tenfold over conventional designs. The feasibility of efficient genetic modification at scale will stimulate collaborative, genome-wide knockout and tagging programs for P. berghei.
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| 23. |
- Robertsson, Otto, et al.
(författare)
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Challenges in prosthesis classification.
- 2011
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Ingår i: Journal of Bone and Joint Surgery. American Volume. - 1535-1386. ; 93 Suppl 3, s. 72-75
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Tidskriftsartikel (refereegranskat)abstract
- Accurate prosthesis classification is critical for total joint arthroplasty surveillance and assessment of comparative effectiveness. Historically, prosthesis classification was based solely on the names of the prosthesis manufacturers. As a result, prosthesis designs changed without corresponding name changes, and other prostheses' names changed over time without substantial design modifications. As the number of prostheses used in total joint arthroplasty on the market increased, catalog and lot numbers associated with prosthesis descriptions were introduced by manufacturers. Currently, these catalog and lot numbers are not standardized, and there is no consensus on categorization of these numbers into brands or subbrands. Classification of the attributes of a prosthesis also varies, limiting comparisons of prostheses across studies and reports. The development of a universal prosthesis classification system would standardize prosthesis classification and enhance total joint arthroplasty research collaboration worldwide. This is a current area of focus for the International Consortium of Orthopaedic Registries (ICOR).
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| 24. |
- Schmidt, G. A., et al.
(författare)
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Climate forcing reconstructions for use in PMIP simulations of the last millennium (v1.0)
- 2011
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 4:1, s. 33-45
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Tidskriftsartikel (refereegranskat)abstract
- Simulations of climate over the Last Millennium (850-1850 CE) have been incorporated into the third phase of the Paleoclimate Modelling Intercomparison Project (PMIP3). The drivers of climate over this period are chiefly orbital, solar, volcanic, changes in land use/land cover and some variation in greenhouse gas levels. While some of these effects can be easily defined, the reconstructions of solar, volcanic and land use-related forcing are more uncertain. We describe here the approach taken in defining the scenarios used in PMIP3, document the forcing reconstructions and discuss likely implications.
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| 25. |
- Schmidt, G. A., et al.
(författare)
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Climate forcing reconstructions for use in PMIP simulations of the last millennium (v1.0)
- 2010
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X. ; 3:3, s. 1549-1586
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Tidskriftsartikel (refereegranskat)abstract
- Simulations of climate over the Last Millennium (850-1850 CE) have been incorporated into the third phase of the Paleoclimate Modelling Intercomparison Project (PMIP3). The drivers of climate over this period are chiefly orbital, solar, volcanic, changes in land use/land cover and some variation in greenhouse gas levels. While some of these effects can be easily defined, the reconstructions of solar, volcanic and land use-related forcing are more uncertain. We describe here the approach taken in defining the scenarios used in PMIP3, document the forcing reconstructions and discuss likely implications.
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| 26. |
- Schmidt, G. A., et al.
(författare)
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Climate forcing reconstructions for use in PMIP simulations of the Last Millennium (v1.1)
- 2012
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Ingår i: Geoscientific Model Development. - : Copernicus GmbH. - 1991-959X .- 1991-9603. ; 5:1, s. 185-191
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Tidskriftsartikel (refereegranskat)abstract
- We update the forcings for the PMIP3 experiments for the Last Millennium to include new assessments of historical land use changes and discuss new suggestions for calibrating solar activity proxies to total solar irradiance.
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| 27. |
- Sinha, Abhinav, et al.
(författare)
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A cascade of DNA-binding proteins for sexual commitment and development in Plasmodium
- 2014
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Ingår i: Nature. - : Macmillan Publishers Ltd.. - 0028-0836 .- 1476-4687. ; 507:7491, s. 253-257
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Tidskriftsartikel (refereegranskat)abstract
- Commitment to and completion of sexual development are essential for malaria parasites (protists of the genus Plasmodium) to be transmitted through mosquitoes. The molecular mechanism(s) responsible for commitment have been hitherto unknown. Here we show that PbAP2-G, a conserved member of the apicomplexan AP2 (ApiAP2) family of DNA-binding proteins, is essential for the commitment of asexually replicating forms to sexual development in Plasmodium berghei, a malaria parasite of rodents. PbAP2-G was identified from mutations in its encoding gene, PBANKA_143750, which account for the loss of sexual development frequently observed in parasites transmitted artificially by blood passage. Systematic gene deletion of conserved ApiAP2 genes in Plasmodium confirmed the role of PbAP2-G and revealed a second ApiAP2 member (PBANKA_103430, here termed PbAP2-G2) that significantly modulates but does not abolish gametocytogenesis, indicating that a cascade of ApiAP2 proteins are involved in commitment to the production and maturation of gametocytes. The data suggest a mechanism of commitment to gametocytogenesis in Plasmodium consistent with a positive feedback loop involving PbAP2-G that could be exploited to prevent the transmission of this pernicious parasite.
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| 28. |
- Stackelberg, Otto, et al.
(författare)
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Alcohol Consumption, Specific Alcoholic Beverages, and Abdominal Aortic Aneurysm
- 2014
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 130:8, s. 646-
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Tidskriftsartikel (refereegranskat)abstract
- Background-Studies investigating the role of alcohol consumption in the development of abdominal aortic aneurysm (AAA) are scarce. We aimed to examine associations between total alcohol consumption and specific alcoholic beverages and the hazard of AAA. Methods and Results-The study population was made up of 44 715 men from the Cohort of Swedish Men and 35 569 women from the Swedish Mammography Cohort who were 46 to 84 years of age at baseline in 1998. Cox proportional hazards models were used to estimate hazard ratios with 95% confidence intervals for the associations between alcohol consumption, assessed through a food frequency questionnaire, and AAA, identified by means of linkage to the Swedish Inpatient Register and the Swedish Vascular Registry (Swedvasc). Over the 14-year follow-up until December 2011 (1 019 954 person-years), AAAs occurred in 1020 men and 194 women. Compared with the consumption of 1 glass of alcohol per week (12 g of ethanol), the hazard ratio of AAA among men who consumed 10 glasses per week was 0.80 (95% confidence interval, 0.68-0.94). The corresponding hazard ratio among women who consumed 5 glasses per week was 0.57 (95% confidence interval, 0.40-0.82). Among participants free from cardiovascular disease, total alcohol consumption did not seem to be associated with hazard of the disease. The most commonly consumed alcoholic beverages, beer among men and wine among women, were inversely associated, whereas no association was observed for liquor. Conclusions-Moderate alcohol consumption, specifically wine and beer, was associated with a lower hazard of abdominal aortic aneurysm. The associations between higher doses of alcohol and risk of the disease remain unknown.
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| 29. |
- Stackelberg, Otto, et al.
(författare)
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Fruit and Vegetable Consumption With Risk of Abdominal Aortic Aneurysm
- 2013
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 128:8, s. 795-802
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Tidskriftsartikel (refereegranskat)abstract
- Background Dietary factors affecting the risk of developing abdominal aortic aneurysm (AAA) are scarcely investigated. The aim of this study was to investigate the associations of fruit and vegetable consumption with the risk to develop AAA. Methods and Results The prospective Cohort of Swedish Men and the Swedish Mammography Cohort, consisting of 44317 men and 36 09 women, 46 to 84 years of age at the start of the 13-year follow-up (1998-2010), were used. Fruit and vegetable consumption was assessed at baseline with a 96-item food-frequency questionnaire. By linkage to the Swedish Inpatient Register and the Swedish Vascular Registry (Swedvasc), 1086 primary cases of AAA (222 ruptured) were identified. Cox proportional hazards models were used to estimate hazard ratios with 95% confidence intervals (CIs). Those in the highest quartile of fruit consumption (>2.0 servings/d), in comparison with those in the lowest quartile (<0.7 servings/d), had a 25% (95% CI, 9%-38%) lower risk of AAA, and a 43% (95% CI, 11%-64%) lower risk of ruptured AAA, specifically. Consumption of 2 fruits per day was associated with 31% (95% CI, 11%-47%) lower risk of nonruptured AAA, and 39% (95% CI, 1%-63%) lower risk of ruptured AAA, in comparison with no consumption of fruit. No association was observed between vegetable consumption and AAA risk. Conclusions We observed an inverse association between consumption of fruit, but not vegetables, and the risk of AAA, with a more pronounced association with ruptured AAA.
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| 30. |
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| 31. |
- Tan, B. K., et al.
(författare)
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A superconducting millimetre switch with multiple nano-bridges
- 2014
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Ingår i: 25th International Sympsoium on Space Terahertz Technology, ISSTT 2014; Moscow; Russian Federation; 27 April 2014 through 30 April 2014. ; , s. 164-169
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Konferensbidrag (refereegranskat)abstract
- In this paper, we describe the design of a planar superconducting on/off switch comprising a high normal resistance nano-bridge deposited across a slotline transmission line. We present preliminary experimental results measured at 220 GHz range, and we discuss in detail the various parameters that affect the performance of the planar on/off switch, including the optimum thickness required for the nano-bridge to achieve high dynamic range and low transmission loss. The analysis is done by combining the accurate superconducting surface impedance description with rigorous electromagnetic simulations, and comparing the simulated results with the measured performance of a previously fabricated on/off switch fed by a backto- back unilateral finline taper. Finally, we propose an improved method to further increase the dynamic range of the switch, by introducing a multi-bridge design to tune out the residual inductance of the nano-bridges.
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| 32. |
- Tidblad, Johan, et al.
(författare)
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Effects of air pollution on materials and cultural heritage : ICP materials celebrates 25 years of research
- 2012
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Ingår i: International Journal of Corrosion. - : Hindawi Limited. - 1687-9325 .- 1687-9333. ; 2012
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Forskningsöversikt (refereegranskat)abstract
- An overview is given of all results from the International Co-operative Programme on Effects on Materials including Historic and Cultural Monuments (ICP Materials), which was launched in 1985. Since then, about twenty different materials have been exposed repeatedly in a network of test sites consisting of more than twenty sites with an extensive environmental characterisation and more than sixty official reports have been issued. Recent results on trends in corrosion, soiling, and pollution show that corrosion of carbon steel, zinc, and limestone is today substantially lower than 25 years ago, but while corrosion of carbon steel has decreased until today, corrosion of zinc and limestone has remained more or less constant since the turn of the century. Unique data are given on measured HNO3 concentrations from 2002-2003, 2005-2006, and 2008-2009, and the relative average decrease was about the same from 2002-2003 to 2005-2006 as it was from 2005-2006 to 2008-2009.
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