| 1. |
- Folkersen, Lasse, et al.
(author)
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Mapping of 79 loci for 83 plasma protein biomarkers in cardiovascular disease
- 2017
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In: PLOS Genetics. - : PUBLIC LIBRARY SCIENCE. - 1553-7390 .- 1553-7404. ; 13:4
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Journal article (peer-reviewed)abstract
- Recent advances in highly multiplexed immunoassays have allowed systematic large-scale measurement of hundreds of plasma proteins in large cohort studies. In combination with genotyping, such studies offer the prospect to 1) identify mechanisms involved with regulation of protein expression in plasma, and 2) determine whether the plasma proteins are likely to be causally implicated in disease. We report here the results of genome-wide association (GWA) studies of 83 proteins considered relevant to cardiovascular disease (CVD), measured in 3,394 individuals with multiple CVD risk factors. We identified 79 genome-wide significant (p<5e-8) association signals, 55 of which replicated at P<0.0007 in separate validation studies (n = 2,639 individuals). Using automated text mining, manual curation, and network-based methods incorporating information on expression quantitative trait loci (eQTL), we propose plausible causal mechanisms for 25 trans-acting loci, including a potential post-translational regulation of stem cell factor by matrix metalloproteinase 9 and receptor-ligand pairs such as RANK-RANK ligand. Using public GWA study data, we further evaluate all 79 loci for their causal effect on coronary artery disease, and highlight several potentially causal associations. Overall, a majority of the plasma proteins studied showed evidence of regulation at the genetic level. Our results enable future studies of the causal architecture of human disease, which in turn should aid discovery of new drug targets.
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| 2. |
- Lindgren, Stefan, et al.
(author)
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Intravenous iron sucrose is superior to oral iron sulphate for correcting anaemia and restoring iron stores in IBD patients : A randomized, controlled, evaluator-blind, multicentre study
- 2009
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In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 44:7, s. 838-845
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Journal article (peer-reviewed)abstract
- Objective. Patients with inflammatory bowel disease (IBD) often have low iron stores or anaemia. There is controversy about whether iron should be supplemented orally or intravenously (i.v.). The purpose of this study was to investigate whether treatment with intravenous iron is superior to treatment with oral iron. The primary end-points were response and remaining anaemia at the end of treatment (EOT).Material and methods. Ninety-one patients with IBD and anaemia (B-Hb <115 g/L) were randomized to oral iron sulphate (n=46) or intravenous iron sucrose (n=45) treatment for 20 weeks.Results. Forty-three patients in the intravenous iron group completed the study compared to 35 patients in the oral iron group (p=0.0009). Only 22 patients (48%) tolerated the prescribed oral dose, and 52% reduced the dose or withdrew from treatment because of poor tolerance. At EOT, 47% patients in the oral iron group increased their B-Hb by ≥20 g/L, compared with 66% in the intravenous iron group (p=0.07). In the oral iron group, 41% still had anaemia versus 16% of the patients in the intravenous iron group (p=0.007), and 22% versus 42% reached their reference B-Hb level (p=0.04). Treatment with intravenous iron sucrose improved iron stores faster and more effectively than oral iron (p=0.002). Under treatment with intravenous iron, 74% of the patients had no anaemia and normal S-ferritin levels (>25 µg/L) at EOT compared with 48% of patients receiving oral iron (p=0.013).Conclusions. Treatment with intravenous iron sucrose is effective, safe, well tolerated and superior to oral iron in correcting haemoglobin and iron stores in patients with IBD.
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| 3. |
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| 4. |
- Adolfsson, Dan E., 1989-, et al.
(author)
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Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils
- 2020
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In: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 85:21, s. 14174-14189
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Journal article (other academic/artistic)abstract
- A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.
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| 5. |
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| 6. |
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| 7. |
- Bengtsson, Boel, et al.
(author)
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Perimetric probability maps to separate change caused by glaucoma from that caused by cataract
- 1997
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In: Acta Ophthalmologica Scandinavica. - 1395-3907. ; 75:2, s. 184-188
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Journal article (peer-reviewed)abstract
- We describe a new method for analysis of change in glaucomatous visual fields with the object to differentiate between changes caused by glaucoma from those caused by cataract, New pattern deviation change probability maps were developed from a prospectively collected glaucoma material and designed to be sensitive to changes in localized field loss, but to be unaffected by media-induced perimetric change. We compared the new change probability maps with the commercially available total deviation change probability maps in series of Humphrey perimetric tests in a glaucoma material of 43 eyes of 35 patients, who had undergone cataract surgery, When using the total deviation maps, considerable differences were seen between fields obtained before and after cataract surgery. Much smaller differences were seen when using the new change probability maps, that almost eliminated the common and disturbing effect of increasing cataract, This new tool could be of considerable help in differentiation between progressive glaucomatous visual field loss and deterioration caused by increasing media opacities.
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| 8. |
- Bergman, Peter, et al.
(author)
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Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial
- 2021
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In: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 74
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Journal article (peer-reviewed)abstract
- Background: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate safety and efficacy of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls.Methods: 539 study subjects (449 patients and 90 controls) were included. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/CAR T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection.Findings: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively.Interpretation: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. Rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups to improve immunity.
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| 9. |
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| 10. |
- Bi, Zhaoxia, et al.
(author)
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Self-assembled InN quantum dots on side facets of GaN nanowires
- 2018
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In: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 123:16
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Journal article (peer-reviewed)abstract
- Self-assembled, atomic diffusion controlled growth of InN quantum dots was realized on the side facets of dislocation-free and c-oriented GaN nanowires having a hexagonal cross-section. The nanowires were synthesized by selective area metal organic vapor phase epitaxy. A 3 Å thick InN wetting layer was observed after growth, on top of which the InN quantum dots formed, indicating self-assembly in the Stranski-Krastanow growth mode. We found that the InN quantum dots can be tuned to nucleate either preferentially at the edges between GaN nanowire side facets, or directly on the side facets by tuning the adatom migration by controlling the precursor supersaturation and growth temperature. Structural characterization by transmission electron microscopy and reciprocal space mapping show that the InN quantum dots are close to be fully relaxed (residual strain below 1%) and that the c-planes of the InN quantum dots are tilted with respect to the GaN core. The strain relaxes mainly by the formation of misfit dislocations, observed with a periodicity of 3.2 nm at the InN and GaN hetero-interface. The misfit dislocations introduce I1 type stacking faults (...ABABCBC...) in the InN quantum dots. Photoluminescence investigations of the InN quantum dots show that the emissions shift to higher energy with reduced quantum dot size, which we attribute to increased quantum confinement.
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| 11. |
- Bill-Axelson, Anna, et al.
(author)
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Radical prostatectomy versus watchful waiting in localized prostate cancer : the Scandinavian prostate cancer group-4 randomized trial
- 2008
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In: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 100:16, s. 1144-1154
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Journal article (peer-reviewed)abstract
- BACKGROUND: The benefit of radical prostatectomy in patients with early prostate cancer has been assessed in only one randomized trial. In 2005, we reported that radical prostatectomy improved prostate cancer survival compared with watchful waiting after a median of 8.2 years of follow-up. We now report results after 3 more years of follow-up.METHODS: From October 1, 1989, through February 28, 1999, 695 men with clinically localized prostate cancer were randomly assigned to radical prostatectomy (n = 347) or watchful waiting (n = 348). Follow-up was complete through December 31, 2006, with histopathologic review and blinded evaluation of causes of death. Relative risks (RRs) were estimated using the Cox proportional hazards model. Statistical tests were two-sided.RESULTS: During a median of 10.8 years of follow-up (range = 3 weeks to 17.2 years), 137 men in the surgery group and 156 in the watchful waiting group died (P = .09). For 47 of the 347 men (13.5%) who were randomly assigned to surgery and 68 of the 348 men (19.5%) who were not, death was due to prostate cancer. The difference in cumulative incidence of death due to prostate cancer remained stable after about 10 years of follow-up. At 12 years, 12.5% of the surgery group and 17.9% of the watchful waiting group had died of prostate cancer (difference = 5.4%, 95% confidence interval [CI] = 0.2 to 11.1%), for a relative risk of 0.65 (95% CI = 0.45 to 0.94; P = .03). The difference in cumulative incidence of distant metastases did not increase beyond 10 years of follow-up. At 12 years, 19.3% of men in the surgery group and 26% of men in the watchful waiting group had been diagnosed with distant metastases (difference = 6.7%, 95% CI = 0.2 to 13.2%), for a relative risk of 0.65 (95% CI = 0.47 to 0.88; P = .006). Among men who underwent radical prostatectomy, those with extracapsular tumor growth had 14 times the risk of prostate cancer death as those without it (RR = 14.2, 95% CI = 3.3 to 61.8; P < .001).CONCLUSION: Radical prostatectomy reduces prostate cancer mortality and risk of metastases with little or no further increase in benefit 10 or more years after surgery.
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| 12. |
- Binesse, Johan, et al.
(author)
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Roles of Reactive Oxygen Species-Degrading Enzymes of Francisella tularensis SCHU S4
- 2015
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In: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 83:6, s. 2255-2263
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Journal article (peer-reviewed)abstract
- Francisella tularensis is a facultative intracellular bacterium utilizing macrophages as its primary intracellular habitat and is therefore highly capable of resisting the effects of reactive oxygen species (ROS), potent mediators of the bactericidal activity of macrophages. We investigated the roles of enzymes presumed to be important for protection against ROS. Four mutants of the highly virulent SCHU S4 strain with deletions of the genes encoding catalase (katG), glutathione peroxidase (gpx), a DyP-type peroxidase (FTT0086), or double deletion of FTT0086 and katG showed much increased susceptibility to hydrogen peroxide (H2O2) and slightly increased susceptibility to paraquat but not to peroxynitrite (ONOO-) and displayed intact intramacrophage replication. Nevertheless, mice infected with the double deletion mutant showed significantly longer survival than SCHU S4-infected mice. Unlike the aforementioned mutants, deletion of the gene coding for alkyl-hydroperoxide reductase subunit C (ahpC) generated a mutant much more susceptible to paraquat and ONOO- but not to H2O2. It showed intact replication in J774 cells but impaired replication in bone marrow-derived macrophages and in internal organs of mice. The live vaccine strain, LVS, is more susceptible than virulent strains to ROS-mediated killing and possesses a truncated form of FTT0086. Expression of the SCHU S4 FTT0086 gene rendered LVS more resistant to H2O2, which demonstrates that the SCHU S4 strain possesses additional detoxifying mechanisms. Collectively, the results demonstrate that SCHU S4 ROS-detoxifying enzymes have overlapping functions, and therefore, deletion of one or the other does not critically impair the intracellular replication or virulence, although AhpC appears to have a unique function.
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| 13. |
- Bolin, Kristian, et al.
(author)
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Changes in the health status of the population
- 2008
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In: Simulating An Ageing Population. A Microsimulation Approach Applied to Sweden. (Contributions to Economic Analysis). ; , s. 85-114
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Book chapter (other academic/artistic)
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| 14. |
- Bolin, Kristian, et al.
(author)
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Early retirement
- 2008
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In: Simulating An Ageing Population. A Microsimulation Approach Applied to Sweden. (Contributions to Economic Analysis). ; , s. 143-199
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Book chapter (other academic/artistic)
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| 15. |
- Bolin, Kristian, et al.
(author)
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Sickness absence from work
- 2008
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In: Simulating An Ageing Population. A Microsimulation Approach Applied to Sweden. (Contributions to Economic Analysis). ; , s. 115-141
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Book chapter (other academic/artistic)
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| 16. |
- Bolin, Kristian, et al.
(author)
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Utilisation of inpatient care
- 2008
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In: Simulating An Ageing Population. A Microsimulation Approach Applied to Sweden. (Contributions to Economic Analysis). ; , s. 325-342
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Book chapter (other academic/artistic)
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| 17. |
- Eriksson, Anders, 1957, et al.
(author)
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Five mucosal transcripts of interest in ulcerative colitis identified by quantitative real-time PCR: a prospective study.
- 2008
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In: BMC gastroenterology. - 1471-230X. ; 8
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Journal article (peer-reviewed)abstract
- BACKGROUND: The cause and pathophysiology of ulcerative colitis are both mainly unknown. We have previously used whole-genome microarray technique on biopsies obtained from patients with ulcerative colitis to identify 5 changed mucosal transcripts. The aim of this study was to compare mucosal expressions of these five transcripts in ulcerative colitis patients vs. controls, along with the transcript expression in relation to the clinical ulcerative colitis status. METHODS: Colonic mucosal specimens from rectum and caecum were taken at ambulatory colonoscopy from ulcerative colitis patients (n = 49) with defined inflammatory activity and disease extension, and from controls (n = 67) without inflammatory bowel disease. The five mucosal transcripts aldolase B, elafin, MST-1, simNIPhom and SLC6A14 were analyzed using quantitative real-time PCR. RESULTS: Significant transcript differences in the rectal mucosa for all five transcripts were demonstrated in ulcerative colitis patients compared to controls. The grade of transcript expression was related to the clinical disease activity. CONCLUSION: The five gene transcripts were changed in patients with ulcerative colitis, and were related to the disease activity. The known biological function of some of the transcripts may contribute to the inflammatory features and indicate a possible role of microbes in ulcerative colitis. The findings may also contribute to our pathophysiological understanding of ulcerative colitis.
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| 18. |
- Folkersen, Lasse, et al.
(author)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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In: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
-
Journal article (peer-reviewed)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 19. |
- Fridolf, Karl, et al.
(author)
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Full Scale Tunnel Evacuation Experiment to Determine Appropriate Emergency Exit Portal Designs in Road Tunnels
- 2016
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In: Proceedings from the Seventh International Symposium on Tunnel Safety and Security. - 9789188349118 ; , s. 441-452
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Conference paper (other academic/artistic)abstract
- In this paper, the execution and results of an evacuation experiment that was conducted in a road tunnel in Stockholm in 2014 is presented. The primary objective of the experiment was to evaluate the effectiveness of different emergency exit portal designs, and other technical installations/aids in the tunnel, during a fire evacuation in smoke. Based on the results, it is concluded that the emergency exit portal design, which was developed and evaluated prior to the experiment, seems appropriate for the intended use. However, in order to increase the portal may be complemented with information signs on the wall opposite to the exit, way-finding signs including distances to the closest emergency exits on both tunnel walls, and a loudspeaker installation that can inform evacuating people about the location of the available exits.
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| 20. |
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| 21. |
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| 22. |
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| 23. |
- Hassellöv, Ida-Maja, 1974, et al.
(author)
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Miljörisker sjunkna vrak II. Undersökningsmetoder och miljöaspekter
- 2015
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Reports (other academic/artistic)abstract
- During 2015 the Swedish Maritime Administration continued the second phase of thegovernmental task Environmental risks from sunken wrecks which first report was finalized2014-10-31 (Dnr: 1399-14-01942-6).The main conclusions from the 2014 report remain; for future handling of potentially pollutingshipwrecks it is recommended that the Swedish Agency for Water and Marine Management isgiven a coordinating responsibility in close cooperation with other competent nationalauthorities, such as Swedish Maritime Administration, Swedish Coastguard, Swedish NationalMaritime Museums, the Geological Survey of Sweden, SMHI, Swedish EPA, and SwedishCivil Contingencies Agency. Through coordination of wreck related operations and activitieswithin the concerned competent authorities’ ordinary areas of responsibility, resourceefficiency is improved. The estimated extra cost for implementation of a national strategy forhandling of the wrecks are estimated to be 10-15 MSEK which should be allocated to thecompetent authorities by the Swedish Agency for Water and Marine Management.The conclusions from 2014 was reinforced during 2015, e.g. through the validation of the riskassessment model VRAKA, which is now available in a first operative version. Additionalecotoxicological experiments on the development of tolerance against PAHs in meiofauna andmicroorganism communities were conducted in a field study in Brofjorden. The mainconclusions from this work is that comprehensive analyzes of PAHs should include alkylatedPAHs, and that exposure to PAHs over time can lead to tolerance development in ammoniumoxidizing bacteria, at the expense of their ability to perform the essential ecosystem servicenitrification.Continued measurements of the bottom currents were made at the wrecks Villon and Skytteren,and at the dumping area west of Måseskär. Measurement series yielded important informationon how measuring equipment at the wreck can be deployed in an optimized way in futuremonitoring program; to calculate the possible spreading of pollution from a wreck, currentmeasurements should be performed upstream from the wreck site, while sensors for thedetection of, for example, oil should be put into the turbulence downstream of the wreck.The current measurement instruments (RDCP) deployed at the Måseskär dump site was trawledup after only three weeks of measurements, but still gave valuable information on the extensivebottom trawling that resuspend (stir up) sediments. Earlier geochemical surveys have shownsignificantly elevated arsenic concentrations in the area and sediment resuspension greatlyincreased the risk for spread of any contaminants in the area. Trawling is not prohibited in thearea, and the current lack of knowledge regarding potential effects on human health whenconsuming seafood from dump areas calls for reflection upon the suitability of trawling in thearea.In addition to the current measurements Swedish Maritime Administration and the SwedishNavy conducted hydrographic survey with multibeam and side scan sonar and ROVinvestigation of the wrecks in the dumping area at Måseskär. 28 wrecks were found, and ROVinvestigation showed cargo holds with dumped torpedoes or mines and other containers in some SjöfartsverketDnr: 1399-14-01942-156of the wrecks. There is some discrepancy between the previously measured elevated arsenicconcentrations in the Måseskär area and recently presented data from historical archives thatdoes not support the theory that chemical weapons were dumped in the area. However, there isa very good correlation between the dominant current direction in the area, and the highestmeasured arsenic concentrations in the area downstream of the wrecks, suggesting some formof arsenic source in the area.
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| 24. |
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| 25. |
- Holmquist Mengelbier, Linda, et al.
(author)
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Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.
- 2015
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Journal article (peer-reviewed)abstract
- Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.
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| 26. |
- Jonas, Örtegren, et al.
(author)
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Cone motion viscosity and optical second harmonic generation of ferroelectric liquid crystalline dendrimers
- 2001
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In: Liquid crystals (Print). - : Informa UK Limited. - 0267-8292 .- 1366-5855. ; 28:6, s. 861-868
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Journal article (peer-reviewed)abstract
- We report second harmonic generation in a ferroelectric liquid crystalline trimer and ferroelectric liquid crystalline dendrimers of first, second and third generation. Thin cells were filled with the compounds by capillary forces at elevated temperature, and cooled from the surface stabilized ferroelectric state to below the glass transition temperature, while kept in an electric field. The cone motion viscosity and the threshold electric field for unwinding of the helix axis of the chiral tilted smectic mesophases were studied separately at elevated temperature, and these data were used to optimize the preparation of the films. The measured response time was between 0.3 and 3 ms, which corresponds to a cone motion viscosity between 0.5 and 50 Pa s. Second harmonic generation was studied both at elevated temperature with an electric field and at room temperature with and without electric field. The first generation dendrimer exhibited a strong increase in the second order non-linear optical response with time at room temperature. The d(23)-coefficient of this dendrimer was approximately four times larger than for the other macromolecules and was 0.045 pm V-1. The relatively large d-coefficient of the first generation dendrimer is ascribed to crystallization, which improved the orientation of the molecular dipoles.
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| 27. |
- Lagou, Vasiliki, et al.
(author)
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Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability
- 2021
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Differences between sexes contribute to variation in the levels of fasting glucose and insulin. Epidemiological studies established a higher prevalence of impaired fasting glucose in men and impaired glucose tolerance in women, however, the genetic component underlying this phenomenon is not established. We assess sex-dimorphic (73,089/50,404 women and 67,506/47,806 men) and sex-combined (151,188/105,056 individuals) fasting glucose/fasting insulin genetic effects via genome-wide association study meta-analyses in individuals of European descent without diabetes. Here we report sex dimorphism in allelic effects on fasting insulin at IRS1 and ZNF12 loci, the latter showing higher RNA expression in whole blood in women compared to men. We also observe sex-homogeneous effects on fasting glucose at seven novel loci. Fasting insulin in women shows stronger genetic correlations than in men with waist-to-hip ratio and anorexia nervosa. Furthermore, waist-to-hip ratio is causally related to insulin resistance in women, but not in men. These results position dissection of metabolic and glycemic health sex dimorphism as a steppingstone for understanding differences in genetic effects between women and men in related phenotypes.
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| 28. |
- Lindgren, Göran, 1948-
(author)
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Studies in conflict economics and economic growth
- 2006
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Doctoral thesis (other academic/artistic)abstract
- “Armaments and Economic Performance”. The literature on military expenditure (milex) is scrutinized with respect to five areas. Investment is reduced when milex increases. Most studies have found economic growth hindered by higher milex. No clear association between milex and employment is found. However, the same amount of other public expenditure creates more jobs. There is some evidence for milex as counter-cyclical instrument in the US. The result for studies if milex is used in electoral cycles in the US is contradictory. Disaggregated data are emphasized as a possible solution to get more definite results.“The Economic Costs of Civil Wars”. The empirical studies of the economic costs of internal armed conflicts are divided into accounting and modelling methods. Cost is seen as the difference between the counterfactual production without conflict and the actual production. The average economic cost of internal armed conflict is a 3.7% yearly reduction of GDP. There are large differences between the estimates. One of the reasons for pursuing such studies is to give improved basis for more cost-effective post-conflict reconstruction, which is better achieved with an accounting method.“War and Economic Performance – Different Data, Different Conclusions?” This article studies the importance of armed conflict for economic growth by replicating an earlier analysis with new data on conflicts. The basic model investigates how conflicts in 1960-1974 affect economic growth in 1975-1989. Koubi finds that “wars are conducive to higher growth”. Koubi’s finding is confirmed when different conflict data is used in a similar research design.“The Role of External Factors in Economic Growth: A Comparative Analysis of Thailand and the Philippines 1950-1990”. Can differences in economic performance be explained by external factors? Both historical and regression analyses are utilised to answer the question. Three external factors are analysed: International trade, foreign direct investment, and external debt. In the regression analysis none of the external factors qualify as statistically significant. The historical analysis finds two external factors discriminating between the two countries. Thus, they might explain the differing growth rates of Thailand and the Philippines: Manufactured exports and external debt.
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| 29. |
- Lindgren, Helena, et al.
(author)
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Mechanisms of heme utilization by Francisella tularensis
- 2015
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:3
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Journal article (peer-reviewed)abstract
- Francisella tularensis is a highly virulent facultative intracellular pathogen causing the severe disease tularemia in mammals. As for other bacteria, iron is essential for its growth but very few mechanisms for iron acquisition have been identified. Here, we analyzed if and how F. tularensis can utilize heme, a major source of iron in vivo. This is by no means obvious since the bacterium lacks components of traditional heme-uptake systems. We show that SCHU S4, the prototypic strain of subspecies tularensis, grew in vitro with heme as the sole iron source. By screening a SCHU S4 transposon insertion library, 16 genes were identified as important to efficiently utilize heme, two of which were required to avoid heme toxicity. None of the identified genes appeared to encode components of a potential heme-uptake apparatus. Analysis of SCHU S4 deletion mutants revealed that each of the components FeoB, the siderophore system, and FupA, contributed to the heme-dependent growth. In the case of the former two systems, iron acquisition was impaired, whereas the absence of FupA did not affect iron uptake but led to abnormally high binding of iron to macromolecules. Overall, the present study demonstrates that heme supports growth of F. tularensis and that the requirements for the utilization are highly complex and to some extent novel.
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| 30. |
- Lindgren, Petter, et al.
(author)
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A likelihood ratio-based approach for improved source attribution in microbiological forensic investigations
- 2019
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In: Forensic Science International. - : Elsevier. - 0379-0738 .- 1872-6283. ; 302
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Journal article (peer-reviewed)abstract
- A common objective in microbial forensic investigations is to identify the origin of a recovered pathogenic bacterium by DNA sequencing. However, there is currently no consensus about how degrees of belief in such origin hypotheses should be quantified, interpreted, and communicated to wider audiences. To fill this gap, we have developed a concept based on calculating probabilistic evidential values for microbial forensic hypotheses. The likelihood-ratio method underpinning this concept is widely used in other forensic fields, such as human DNA matching, where results are readily interpretable and have been successfully communicated in juridical hearings. The concept was applied to two case scenarios of interest in microbial forensics: (1) identifying source cultures among series of very similar cultures generated by parallel serial passage of the Tier 1 pathogen Francisella tularensis, and (2) finding the production facilities of strains isolated in a real disease outbreak caused by the human pathogen Listeria monocytogenes. Evidence values for the studied hypotheses were computed based on signatures derived from whole genome sequencing data, including deep-sequenced low-frequency variants and structural variants such as duplications and deletions acquired during serial passages. In the F. tularensis case study, we were able to correctly assign fictive evidence samples to the correct culture batches of origin on the basis of structural variant data. By setting up relevant hypotheses and using data on cultivated batch sources to define the reference populations under each hypothesis, evidential values could be calculated. The results show that extremely similar strains can be separated on the basis of amplified mutational patterns identified by high-throughput sequencing. In the L. monocytogenes scenario, analyses of whole genome sequence data conclusively assigned the clinical samples to specific sources of origin, and conclusions were formulated to facilitate communication of the findings. Taken together, these findings demonstrate the potential of using bacterial whole genome sequencing data, including data on both low frequency SNP signatures and structural variants, to calculate evidence values that facilitate interpretation and communication of the results. The concept could be applied in diverse scenarios, including both epidemiological and forensic source tracking of bacterial infectious disease outbreaks.
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| 31. |
- Locke, Adam E, et al.
(author)
-
Genetic studies of body mass index yield new insights for obesity biology.
- 2015
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
-
Journal article (peer-reviewed)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 32. |
- Nyberg, Martin, et al.
(author)
-
PCA3 as a diagnostic marker for prostate cancer: A validation study on a Swedish patient population.
- 2010
-
In: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 1651-2065 .- 0036-5599. ; 44, s. 378-383
-
Journal article (peer-reviewed)abstract
- Abstract Objective. Prostate cancer antigen 3 in urine (uPCA3) has been shown to perform better than total prostate-specific antigen in serum (tPSA) to predict prostate cancer (PCa) detection. The aim of this study was to validate the diagnostic precision of uPCA3 in a mixed set of patients with no previous history of PCa, including patients with previous negative biopsies. Material and methods. The study included 62 men scheduled for prostate biopsy at Skåne University Hospital Malmö, Sweden. Urine samples were obtained according to the Progensa™ uPCA3 assay. Logistic regression and receiver operating characteristic curves were used to test associations between levels of biomarkers and prostate cancer. Results. According to pathological examination of core needle biopsies, PCa was found in 18 out of 62 patients. A one-step increase in uPCA3 was associated with an increase in the odds of cancer of 1.026 (p = 0.005). Differences in the odds ratio between uPCA3 and tPSA were not statistically significant. A model using both markers did not increase prediction of event. Areas under the curve for uPCA3, tPSA and a model combining uPCA3 and tPSA did not differ significantly. No significant correlation was found between uPCA3 and tPSA or prostate volume. Conclusion. In this small set of mixed patients uPCA3 alone and tPSA performed equally well as diagnostic markers for PCa. A combination of the two markers did not improve the diagnostic performance. This study does not support a role for the uPCA3 urine test to replace or be added to tPSA in PCa detection.
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| 33. |
- Ortegren, J., et al.
(author)
-
Improved thermal stability of pyroelectric polymers by crosslinking of ferroelectric liquid crystals
- 2001
-
In: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1089-5647 .- 1520-6106 .- 1520-5207. ; 105:42, s. 10223-10227
-
Journal article (peer-reviewed)abstract
- Monofunctional ferroelectric liquid crystalline monomers and a blend of monofunctional/lbifunctional ferroelectric liquid crystalline monomers were photopolymerized, yielding a side-chain liquid crystalline polymer and a cross-linked polymer, respectively. The cross-linked polymer exhibited higher thermal stability than the side-chain liquid crystalline polymer and was pyroelectric up to 170 degreesC, whereas the side-chain liquid crystalline polymer lost most of its pyroelectricity at 38 degreesC. It is shown by electrooptic and birefringence measurements that cross-linking in the unwound SmC* phase prevented the reoccurrence of the helical superstructure.
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| 34. |
- Plan, Anders, et al.
(author)
-
Exceptional preservation of reidite in the Rochechouart impact structure, France: New insights into shock deformation and phase transition of zircon
- 2021
-
In: Meteoritics and Planetary Science. - : Wiley. - 1086-9379 .- 1945-5100. ; 56:10, s. 1795-1828
-
Journal article (peer-reviewed)abstract
- Reidite, the high-pressure zircon (ZrSiO4) polymorph, is a diagnostic indicator of impact events. Natural records of reidite are, however, scarce, occurring mainly as micrometer-sized lamellae, granules, and dendrites. Here, we present a unique sequence of shocked zircon grains found within a clast from the Chassenon suevitic breccia (shock stageIII) from the ~200 Ma, 20–50 km wide Rochechouart impact structure in France. Our study comprises detailed characterization with scanning electron microscopy coupled with electron backscatter diffraction with the goal of investigating the stability and response of ZrSiO4 under extreme P–T conditions. The shocked zircon grains have preserved various amounts of reidite ranging from 4% up to complete conversion. The grains contain various variants of reidite, including the common habits: lamellae and granular reidite. In addition, three novel variants have been identified: blade, wedge, and massive domains. Several of these crosscut and offset each other, revealing that reidite can form at multiple stages during an impact event. Our data provide evidence that reidite can be preserved in impactites to a much greater extent than previously documented. We have further characterized reversion products of reidite in the form of fully recrystallized granular zircon grains and minute domains of granular zircon in reidite-bearing grains that occur in close relationship to reidite. Neoblasts in these grains have a distinct crystallography that is the result of systematic inheritance of reidite. We interpret that the fully granular grains have formed from prolonged exposure of temperatures in excess of 1200 °C. Reidite-bearing grains with granular domains might signify swift quenching from temperatures close to 1200 °C. Grains subjected to these specific conditions therefore underwent partial zircon-to-reidite reversion, instead of full grain recrystallization. Based on our ZrSiO4 microstructural constraints, we decipher the grains evolution at specific P–T conditions related to different impact stages, offering further understanding of the behavior of ZrSiO4 during shock.
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| 35. |
- Scott, Robert A., et al.
(author)
-
Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
- 2012
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
-
Journal article (peer-reviewed)abstract
- Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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| 36. |
- Shungin, Dmitry, et al.
(author)
-
New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
-
Journal article (peer-reviewed)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 37. |
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| 38. |
- Syed Khaja, Azharuddin Sajid, et al.
(author)
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Elevated level of wnt5a protein in localized prostate cancer tissue is associated with better outcome.
- 2011
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:10
-
Journal article (peer-reviewed)abstract
- Wnt5a is a non-canonical secreted glycoprotein of the Wnt family that plays an important role in cancer development and progression. Previous studies report that Wnt5a is upregulated in prostate cancer and suggested that Wnt5a affects migration and invasion of prostate tumor cell. This study aimed to evaluate the prognostic value of Wnt5a protein expression in prostate cancer tissue and its potential to predict outcome after radical prostatectomy in patients with localized prostate cancer.
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| 39. |
- Twine, Susan, et al.
(author)
-
A mutant of Francisella tularensis strain SCHU S4 lacking the ability to express a 58-kilodalton protein is attenuated for virulence and is an effective live vaccine
- 2005
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In: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 73:12, s. 8345-8352
-
Journal article (peer-reviewed)abstract
- Francisella tularensis subsp. tularensis (type A) strain SCHU S4 is a prototypic strain of the pathogen that is highly virulent for humans and other mammals. Its intradermal (i.d.) 50% lethal dose (LD50) for mice is <10 CFU. We discovered a spontaneous mutant, designated FSC043, of SCHU S4 with an i.d. LD50 of >10(8) CFU. FSC043 effectively vaccinated mice against challenge with a highly virulent type A strain, and the protective efficacy was at least as good as that of F. tularensis LVS, an empirically attenuated strain which has been used as an efficacious human vaccine. Comparative proteomics was used to identify two proteins of unknown function that were identified as defective in LVS and FSC043, and deletion mutants of SCHU S4 were created for each of the two encoding genes. One mutant, the DeltaFTT0918 strain, failed to express a 58-kDa protein, had an i.d. LD50 of approximately 10(5) CFU, and was found to be less capable than SCHU S4 of growing in peritoneal mouse macrophages. Mice that recovered from sublethal infection with the DeltaFTT0918 mutant survived when challenged 2 months later with >100 LD50s of the highly virulent type A strain FSC033. This is the first report of the generation of defined mutants of F. tularensis subsp. tularensis and their use as live vaccines.
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| 40. |
- Williamsson, Ia
(author)
-
Establishment Patterns of Model Diffusion Theory
- 2023
-
Doctoral thesis (other academic/artistic)abstract
- Information technology is now part of almost every product and service, and the ever-increasing rate of technology and software development demands an appropriate software development process model. The model, whichdescribes the software development process, plays a crucial role for success in software projects. Models are constantly produced and refined in academia and practice, but models from academia tend to remain unused in practice, or take a long time to reach practice. Currently there is a lack of knowledge on how models are transferred or diffused in and between academia and practice, which is the knowledge gap that this study aims to investigate.The research purpose has thus been to investigate and ground a theory about the diffusion of software process models in and between academia and practice. The study is based on data collected from 31 informants, from both academia and practice, and analyzed with a grounded theory method approach. The Diffusion of Innovation theory was consulted during theory development, and the perceived model characteristics, complexity, ando bservability are seen as distinguishing differences between the theories.The resulting grounded theory, “Establishment Patterns of Model Diffusion” describes four important areas, and how they affect each other ina model diffusion situation. The areas are: Motivation; Establishment; Usage; and Quality. How model diffusion takes place depends on the are as themselves, on the prevailing conditions, on the knowledge at hand and on how the areas are evaluated. This shows multi-faceted, time-dependent, and unpredictable patterns for model diffusion. The patterns include experience of model use, the past and future context of use, the characteristics of the model, requirements in the working process, individuals’ empowerment, availability of multiple models, composition of project groups, and the group members’ private and business networks.The findings have several implications. For academia, the benefits may be in the awareness of the multiple patterns for model diffusion and software process improvements, which cannot be separated from each other. Models are constantly adopted and simultaneously modified in practice. Practice may benefit from an awareness of the multiple patterns for model diffusionand sources of experience and knowledge, and how to make use of the existing knowledge capital strategically. Both academia and practice may also benefit from increased cooperation, each contributing their unique experience, and consequently increasing relevance for practice in the diffusion of models, and in developing and receiving research results in a useful format.
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| 41. |
- Örtegren, Jonas, et al.
(author)
-
Time-dependent nonlinear optical properties of pyroelectric liquid crystalline polymers
- 1999
-
In: Macromolecular Symposia. - : Wiley. - 1022-1360 .- 1521-3900. ; 148, s. 179-195
-
Journal article (peer-reviewed)abstract
- Highly oriented pyroelectric liquid-crystalline polymers were prepared by photopolymerization under the influence of a static electric field from binary mixtures of two acrylate monomers exhibiting chiral smectic C mesomorphism. Both monomers contained nitro groups to yield second order nonlinear optical properties (second harmonic generation) and one of the monomers had two functional groups to yield a crosslinked polymer. The room temperature second order nonlinear susceptibility of the polymers showed during the first two hours a 10 % decrease after which it remained constant during the next 48 days. At elevated temperatures there was a significant difference in the nonlinear optical properties over time between crosslinked and uncrosslinked polymers. The uncrosslinked polymer showed a pronounced loss of second order nonlinear optical activity with time at ≥38°C. The crosslinked polymer showed a much smaller and basically a temperature independent decrease rate in the second order nonlinear optical properties at all the ageing temperatures (23-130°C). Both the loss in mesogen order parameter, very evident for the uncrosslinked polymer, and conformational changes occurring within the mesogens (β mechanism), may account for the observations made.
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| 42. |
- Adler, Jan-Olof, et al.
(author)
-
The upgraded photon tagging facility at the MAX IV Laboratory
- 2013
-
In: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - : Elsevier BV. - 0167-5087 .- 0168-9002. ; 715, s. 1-10
-
Journal article (peer-reviewed)abstract
- A description is given of the upgraded photon tagging facility at the MAX IV Laboratory. Two magnetic spectrometers are used to momentum analyze post-bremsstrahlung electrons. The tagged photon range extends from 10 to 180 MeV with an energy resolution of about 300 keV. The system has been operated at rates up to 4 x 10(6) photons s(-1) MeV (-1). Different diagnostic tools are described as well as the experimental program.
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| 43. |
- Aftab, Muhammad Usman, et al.
(author)
-
Towards A Distributed Ledger Based Verifiable Trusted Protocol for VANET
- 2021
-
In: 2021 International Conference on Digital Futures and Transformative Technologies, ICoDT2 2021. - : Institute of Electrical and Electronics Engineers Inc.. - 9781665412858
-
Conference paper (peer-reviewed)abstract
- To ensure traffic safety and proper operation of vehicular networks, safety messages or beacons are periodically broadcasted in Vehicular Adhoc Networks (VANETs) to neighboring nodes and road side units (RSU). Thus, authenticity and integrity of received messages along with the trust in source nodes is crucial and highly required in applications where a failure can result in life-threatening situations. Several digital signature based approaches have been described in literature to achieve the authenticity of these messages. In these schemes, scenarios having high level of vehicle density are handled by RSU where aggregated signature verification is done. However, most of these schemes are centralized and PKI based where our goal is to develop a decentralized dynamic system. Along with authenticity and integrity, trust management plays an important role in VANETs which enables ways for secure and verified communication. A number of trust management models have been proposed but it is still an ongoing matter of interest, similarly authentication which is a vital security service to have during communication is not mostly present in the literature work related to trust management systems. This paper proposes a secure and publicly verifiable communication scheme for VANET which achieves source authentication, message authentication, non repudiation, integrity and public verifiability. All of these are achieved through digital signatures, Hash Message Authentication Code (HMAC) technique and logging mechanism which is aided by blockchain technology.
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| 44. |
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| 45. |
- Agnér, Ulf, et al.
(author)
-
Bredäng : Miljonprogrammets föregångare
- 2018
-
Reports (other academic/artistic)abstract
- Denna publikation är ett resultat av läsåret 2017-2018 i kursen Restaureringskonst vid Kungl. Konsthögskolan, arkitekturavdelningen. Årets tema var bostadsarkitektur. Förvalta, förädla, förvanska? Under läsåret undersöktes bostadsarkitekturen som kulturarv, hur bostadshus och bostadsområden förvaltas, förädlas alternativt förvanskas genom restaureringsåtgärder, förtätningar och omvandlingar. II läsårets projektstudie ingick fem bostadsområden i södra Stockholm, utvalda för att representera varsin epok i 1900-talets bostadsutveckling. En projektgrupp för varje bostadsområde gjorde studier i olika skalor, från den utvalda lägenhetens detaljer, trapphuset och bostadshuset, gården och gatan till stadsdelsnivån.
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| 46. |
- Ahlgren, Bengt, et al.
(author)
-
Demo: Experimental Feasibility Study of CCN-lite on Contiki Motes for IoT Data Streams
- 2016
-
In: Proceedings of the 3rd ACM Conference on Information-Centric Networking. - New York, NY, USA : ACM. - 9781450344678 ; , s. 221-222
-
Conference paper (peer-reviewed)abstract
- Many IoT applications are inherently information-centric, making it advantageous to use ICN transport. We demonstrate CCN-lite ported to run on Contiki sensor motes with limited processing and storage resources. We show a method for mapping streams of sensor data to a stream of immutable CCN named data objects, and an adaptive probing method to find the newest value. We also demonstrate interoperation between MQTT and CCN via a gateway. A higher level goal is to use ICN as an open interface for accessing IoT data.
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| 47. |
- Ahlinder, Jon, et al.
(author)
-
Increased knowledge of Francisella genus diversity highlights the benefits of optimised DNA-based assays
- 2012
-
In: BMC Microbiology. - : Springer Science and Business Media LLC. - 1471-2180. ; 12, s. 220-
-
Journal article (peer-reviewed)abstract
- Background: Recent advances in sequencing technologies offer promising tools for generating large numbers of genomes, larger typing databases and improved mapping of environmental bacterial diversity. However, DNA-based methods for the detection of Francisella were developed with limited knowledge about genetic diversity. This, together with the high sequence identity between several Francisella species, means there is a high risk of false identification and detection of the highly virulent pathogen Francisella tularensis. Moreover, phylogenetic reconstructions using single or limited numbers of marker sequences often result in incorrect tree topologies and inferred evolutionary distances. The recent growth in publicly accessible whole-genome sequences now allows evaluation of published genetic markers to determine optimal combinations of markers that minimise both time and laboratory costs. Results: In the present study, we evaluated 38 previously published DNA markers and the corresponding PCR primers against 42 genomes representing the currently known diversity of the genus Francisella. The results highlight that PCR assays for Francisella tularensis are often complicated by low specificity, resulting in a high probability of false positives. A method to select a set of one to seven markers for obtaining optimal phylogenetic resolution or diagnostic accuracy is presented. Conclusions: Current multiple-locus sequence-typing systems and detection assays of Francisella, could be improved by redesigning some of the primers and reselecting typing markers. The use of only a few optimally selected sequence-typing markers allows construction of phylogenetic topologies with almost the same accuracy as topologies based on whole-genome sequences.
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| 48. |
- Ahlsén, Göran, et al.
(author)
-
Resistance profiles of cyclic and linear inhibitors of HIV-1 protease
- 2002
-
In: Antiviral Chemistry & Chemotherapy. - 0956-3202 .- 2040-2066. ; 13:1, s. 27-37
-
Journal article (peer-reviewed)abstract
- Resistance to anti-HIV protease drugs is a major problem in the design of AIDS drugs with long-term efficacy. To identify structural features associated with a certain resistance profile, the inhibitory properties of a series of symmetric and asymmetric cyclic sulfamide, cyclic urea and linear transition-state analogue inhibitors of HIV-1 protease were investigated using wild-type and mutant enzyme. To allow a detailed structure-inhibition analysis, enzyme with single, double, triple and quadruple combinations of G48V, V82A, 184V and L90M substitutions was used. Kinetic analysis of the mutants revealed that catalytic efficiency was 1-30% of that for the wild-type enzyme, a consequence of reduced kcat in all cases and an increased KM for all mutants except for the G48V enzyme. The overall structure-inhibitory profiles of the cyclic compounds were similar, and the inhibition of the V82A, 184V and G48V/L90M mutants were less efficient than of the wild-type enzyme. The greatest increase in Ki was generally observed for the 184V mutant and least for the G48V/L90M mutant, and additional combinations of mutations did not result in improved inhibition profiles for the cyclic compounds. An extended analysis of additional mutants, and including a set of linear compounds, showed that the profile was unique for each compound, and did not reveal any general structural features associated with a certain inhibition profile. The effects of structural modifications in the inhibitors, or of mutations, were not additive and they differed depending on their context. The results demonstrate the difficulties in predicting resistance, even for closely related compounds, and designing compounds with improved resistance profiles.
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| 49. |
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| 50. |
- Almer, Sven, 1938-, et al.
(author)
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Handläggning av svårt skov av ulcerös kolit. In: Löfberg R (ed): Inflammatorisk tarmsjukdom.
- 2010
-
In: Läkartidningen. - 0023-7205 .- 1652-7518. ; 106:45, s. 62-75
-
Journal article (peer-reviewed)abstract
- Patienter med svårt skov av ulcerös kolit bör vårdas på sjukhus och handläggas av gastroenterolog och kolorektal kirurg i nära samarbete.Skovets svårighetsgrad kan underskattas, varför noggrann bedömning av inflammationens utbredning och svårighetsgrad enligt validerade kriterier är viktigt.Intravenös behandling med kortikosteroider är en av hörnstenarna i den akuta behandlingen.Patienter som inte förbättras på denna behandling, bör erbjudas medicinsk »rescue-behandling« eller kolektomi.Infliximab har visats vara en effektiv rescue-behandling och kan minska behovet av kolektomi inom de första 3 månaderna och upp till 3 år.
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