| 1. |
- Ederle, Joerg, et al.
(författare)
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Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial
- 2010
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Ingår i: The Lancet. - 1474-547X. ; 375:9719, s. 985-997
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Tidskriftsartikel (refereegranskat)abstract
- Background Stents are an alternative treatment to carotid endarterectomy for symptomatic carotid stenosis, but previous trials have not established equivalent safety and efficacy. We compared the safety of carotid artery stenting with that of carotid endarterectomy. Methods The International Carotid Stenting Study (ICSS) is a multicentre, international, randomised controlled trial with blinded adjudication of outcomes. Patients with recently symptomatic carotid artery stenosis were randomly assigned in a 1:1 ratio to receive carotid artery stenting or carotid endarterectomy. Randomisation was by telephone call or fax to a central computerised service and was stratified by centre with minimisation for sex, age, contralateral occlusion, and side of the randomised artery. Patients and investigators were not masked to treatment assignment. Patients were followed up by independent clinicians not directly involved in delivering the randomised treatment. The primary outcome measure of the trial is the 3-year rate of fatal or disabling stroke in any territory, which has not been analysed yet. The main outcome measure for the interim safety analysis was the 120-day rate of stroke, death, or procedural myocardial infarction. Analysis was by intention to treat (ITT). This study is registered, number ISRCTN25337470. Findings The trial enrolled 1713 patients (stenting group, n=855; endarterectomy group, n=858). Two patients in the stenting group and one in the endarterectomy group withdrew immediately after randomisation, and were not included in the ITT analysis. Between randomisation and 120 days, there were 34 (Kaplan-Meier estimate 4.0%) events of disabling stroke or death in the stenting group compared with 27 (3.2%) events in the endarterectomy group (hazard ratio [HR] 1.28, 95% CI 0.77-2.11). The incidence of stroke, death, or procedural myocardial infarction was 8.5% in the stenting group compared with 5.2% in the endarterectomy group (72 vs 44 events; HR 1.69, 1.16-2.45, p=0.006), Risks of any stroke (65 vs 35 events; HR 1.92, 1.27-2.89) and all-cause death (19 vs seven events; HR 2.76, 1.16-6.56) were higher in the stenting group than in the endarterectomy group. Three procedural myocardial infarctions were recorded in the stenting group, all of which were fatal, compared with four, all non-fatal, in the endarterectomy group. There was one event of cranial nerve palsy in the stenting group compared with 45 in the endarterectomy group. There were also fewer haematomas of any severity in the stenting group than in the endarterectomy group (31 vs 50 events; p=0.0197). Interpretation Completion of long-term follow-up is needed to establish the efficacy of carotid artery stenting compared with endarterectomy. In the meantime, carotid endarterectomy should remain the treatment of choice for patients suitable for surgery.
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| 2. |
- Jacobs, Kevin B, et al.
(författare)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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| 3. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 4. |
- Andersson, Hanna, et al.
(författare)
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Disulfide Cyclized Tripeptide Analogues of Angiotensin IV as Potent and Selective Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)
- 2010
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Ingår i: Journal of Medicinal Chemistry. - 0022-2623. ; 53, s. 8059-8071
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Tidskriftsartikel (refereegranskat)abstract
- The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and is believed to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. Configurational analysis of three pairs of diastereomeric Ang IV analogues was performed using a combination of solution NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The compounds encompassing l-amino acids only (4, 8, and 12) showed significantly higher bioactivity compared to their lld-epimers (5, 9, and 13). The best inhibitors in the series, compounds 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 and 5.2 nM, respectively.
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| 7. |
- Meier, Markus, et al.
(författare)
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Comparing reconstructed past variations and future projections of the Baltic sea ecosystem first results from multi model ensemble simulations
- 2012
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Ingår i: Environmental Research Letters. - : IOP Publishing. - 1748-9326. ; 7:3, s. 034005-
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Tidskriftsartikel (refereegranskat)abstract
- Multi-model ensemble simulations for the marine biogeochemistry and food web of the Baltic Sea were performed for the period 1850-2098, and projected changes in the future climate were compared with the past climate environment. For the past period 1850-2006, atmospheric, hydrological and nutrient forcings were reconstructed, based on historical measurements. For the future period 1961-2098, scenario simulations were driven by regionalized global general circulation model (GCM) data and forced by various future greenhouse gas emission and air-and riverborne nutrient load scenarios (ranging from a pessimistic 'business-as-usual' to the most optimistic case). To estimate uncertainties, different models for the various parts of the Earth system were applied. Assuming the IPCC greenhouse gas emission scenarios A1B or A2, we found that water temperatures at the end of this century may be higher and salinities and oxygen concentrations may be lower than ever measured since 1850. There is also a tendency of increased eutrophication in the future, depending on the nutrient load scenario. Although cod biomass is mainly controlled by fishing mortality, climate change together with eutrophication may result in a biomass decline during the latter part of this century, even when combined with lower fishing pressure. Despite considerable shortcomings of state-of-the-art models, this study suggests that the future Baltic Sea ecosystem may unprecedentedly change compared to the past 150 yr. As stakeholders today pay only little attention to adaptation and mitigation strategies, more information is needed to raise public awareness of the possible impacts of climate change on marine ecosystems.
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| 8. |
- Spégel, Peter, et al.
(författare)
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Time-resolved metabolomics analysis of beta-cells implicates the pentose phosphate pathway in the control of insulin release
- 2013
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Ingår i: Biochemical Journal. - 0264-6021. ; 450, s. 595-605
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Tidskriftsartikel (refereegranskat)abstract
- Insulin secretion is coupled with changes in beta-cell metabolism. To define this process, 195 putative metabolites, mitochondrial respiration, NADP(+), NADPH and insulin secretion were measured within 15 mm of stimulation of clonal INS-1 832/13 beta-cells with glucose. Rapid responses in the major metabolic pathways of glucose occurred, involving several previously suggested metabolic coupling factors. The complexity of metabolite changes observed disagreed with the concept of one single metabolite controlling insulin secretion. The complex alterations in metabolite levels suggest that a coupling signal should reflect large parts of the beta-cell metabolic response. This was fulfilled by the NADPH/NADP(+) ratio, which was elevated (8-fold; P < 0.01) at 6 min after glucose stimulation. The NADPH/NADP+ ratio paralleled an increase in ribose 5-phosphate (>2.5-fold; P < 0.001). Inhibition of the pentose phosphate pathway by trans-dehydroepiandrosterone (DHEA) suppressed ribose 5-phosphate levels and production of reduced glutathione, as well as insulin secretion in INS-1 832/13 beta-cells and rat islets without affecting ATP production. Metabolite profiling of rat islets confirmed the glucose-induced rise in ribose 5-phosphate, which was prevented by DHEA. These findings implicate the pentose phosphate pathway, and support a role for NADPH and glutathione, in beta-cell stimulus-secretion coupling.
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| 9. |
- Andersson, Anders G., et al.
(författare)
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A numerical study of the location and function of the entrance of a fishway in a regulated river
- 2010
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Ingår i: 8th International Symposium on ECOHYDRAULICS. ; , s. 277-284
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Konferensbidrag (refereegranskat)abstract
- Simulation driven design with Computational Fluid Dynamics has been used to evaluate the flow downstream a hydropower plant with regards to upstream migrating fish. Field measurements with an Acoustic Doppler Current Profiler were performed and the measurements were used to validate the simulations. The measurements indicate a more unstable flow than the simulations and the tailrace jet from the turbines is stronger in the simulations. The simulations are however considered to capture the important features of the flow in a way that makes them viable for attraction water simulations. A fishway entrance was included in the simulations and the subsequent attraction water was evaluated for two positions and two angles of the entrance at different turbine discharges. Results show that both positions are viable and that a position where the flow from the fishway does not have to compete with the flow from the power plant will generate superior attraction water. Simulations were also performed further downstream where the flow from the turbines meets the old river bed which is the current fish passage for upstream migrating fish. A modification of the old river bed was made in the model as one scenario to generate better attraction water. This considerably increases the attraction water although it cannot compete with the flow from the tailrace tunnel.
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| 10. |
- Andersson, Anders G., et al.
(författare)
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A study of the location of the entrance of a fishway in a regulated river with CFD and ADCP
- 2012
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Ingår i: Modelling and Simulation in Engineering. - : Hindawi Limited. - 1687-5591 .- 1687-5605. ; 2012
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Tidskriftsartikel (refereegranskat)abstract
- Simulation-driven design with computational fluid dynamics has been used to evaluate the flow downstream of a hydropower plant with regards to upstream migrating fish. Field measurements with an Acoustic Doppler Current Profiler were performed, and the measurements were used to validate the simulations. The measurements indicate a more unstable flow than the simulations, and the tailrace jet from the turbines is stronger in the simulations. A fishway entrance was included in the simulations, and the subsequent attraction water was evaluated for two positions and two angles of the entrance at different turbine discharges. Results show that both positions are viable and that a position where the flow from the fishway does not have to compete with the flow from the power plant will generate superior attraction water. Simulations were also performed for further downstream where the flow from the turbines meets the old river bed which is the current fish passage for upstream migrating fish. A modification of the old river bed was made in the model as one scenario to generate better attraction water. This considerably increases the attraction water although it cannot compete with the flow from the tailrace tunnel.
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