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Sökning: WFRF:(Kristensen Anders)

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1.
  • Munch, Marie W., et al. (författare)
  • Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia The COVID STEROID 2 Randomized Trial
  • 2021
  • Ingår i: Journal of the American Medical Association (JAMA). - : AMER MEDICAL ASSOC. - 0098-7484 .- 1538-3598. ; 326:18, s. 1807-1817
  • Tidskriftsartikel (refereegranskat)abstract
    • Question What is the effect of 12 mg vs 6 mg of dexamethasone on the number of days alive without life support at 28 days in patients with COVID-19 and severe hypoxemia? Findings In this randomized trial that included 1000 patients with COVID-19 and severe hypoxemia, treatment with 12 mg/d of dexamethasone resulted in 22.0 days alive without life support at 28 days compared with 20.5 days in those receiving 6 mg/d of dexamethasone. This difference was not statistically significant. Meaning Compared with 6 mg of dexamethasone, 12 mg of dexamethasone did not statistically significantly reduce the number of days alive without life support at 28 days. This multicenter randomized clinical trial compares the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. IMPORTANCE A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. OBJECTIVE To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. INTERVENTIONS Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and >= 1 serious adverse reactions at 28 days). RESULTS Of the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]). CONCLUSIONS AND RELEVANCE Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.
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2.
  • Lagedal, Rickard, et al. (författare)
  • Impaired Antibody Response Is Associated with Histone-Release, Organ Dysfunction and Mortality in Critically Ill COVID-19 Patients
  • 2022
  • Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 11:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: the pathophysiologic mechanisms explaining differences in clinical outcomes following COVID-19 are not completely described. This study aims to investigate antibody responses in critically ill patients with COVID-19 in relation to inflammation, organ failure and 30-day survival. Methods: All patients with PCR-verified COVID-19 and gave consent, and who were admitted to a tertiary Intensive care unit (ICU) in Sweden during March-September 2020 were included. Demography, repeated blood samples and measures of organ function were collected. Analyses of anti-SARS-CoV-2 antibodies (IgM, IgA and IgG) in plasma were performed and correlated to patient outcome and biomarkers of inflammation and organ failure. Results: A total of 115 patients (median age 62 years, 77% male) were included prospectively. All patients developed severe respiratory dysfunction, and 59% were treated with invasive ventilation. Thirty-day mortality was 22.6% for all included patients. Patients negative for any anti-SARS-CoV-2 antibody in plasma during ICU admission had higher 30-day mortality compared to patients positive for antibodies. Patients positive for IgM had more ICU-, ventilator-, renal replacement therapy- and vasoactive medication-free days. IgA antibody concentrations correlated negatively with both SAPS3 and maximal SOFA-score and IgM-levels correlated negatively with SAPS3. Patients with antibody levels below the detection limit had higher plasma levels of extracellular histones on day 1 and elevated levels of kidney and cardiac biomarkers, but showed no signs of increased inflammation, complement activation or cytokine release. After adjusting for age, positive IgM and IgG antibodies were still associated with increased 30-day survival, with odds ratio (OR) 7.1 (1.5-34.4) and 4.2 (1.1-15.7), respectively. Conclusion: In patients with severe COVID-19 requiring intensive care, a poor antibody response is associated with organ failure, systemic histone release and increased 30-day mortality.
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3.
  • Bach, Anders, et al. (författare)
  • A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage
  • 2012
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:9, s. 3317-3322
  • Tidskriftsartikel (refereegranskat)abstract
    • Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.
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4.
  • Bach, Anders, et al. (författare)
  • Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95-NMDA receptor interaction
  • 2009
  • Ingår i: Angewandte Chemie International Edition. - : Wiley-VCH. - 1433-7851 .- 1521-3773. ; 48:51, s. 9685-9689
  • Tidskriftsartikel (refereegranskat)abstract
    • On the double: Dimerization of monomeric peptide ligands towards the PDZ domains of the protein PSD-95 (postsynaptic density 95) leads to potent inhibitors of protein-protein interactions with stability in blood plasma. Optimization of the length of the polyethylene glycol linker results in unprecedented affinity for inhibitors of the PDZ1-2 domain.
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5.
  • Behrens, Anders, et al. (författare)
  • The Computerized General Neuropsychological INPH Test (CoGNIT) revealed improvement in Idiopathic Normal Pressure Hydrocephalus (INPH) after shunt surgery
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • BackgroundWe have developed the COmputerized General Neuropsychological INPH Test (CoGNIT) dedicated for patients with idiopathic normal pressure hydrocephalus (INPH). Previously, validity and reliability of included tests have been established. The aim was to evaluate the battery’s sensitivity to detect cognitive changes after shunt surgery in INPH patients.MethodsPreoperatively, thirty-one INPH patients were given CoGNIT, which includes tests assessing memory, executive functions, attention, manual dexterity and psychomotor speed. CoGNIT also includes the Geriatric Depression Scale (GDS). Re-examination was done four months after shunt surgery. Scores and test completion were examined and compared to healthy elderly (n=44).ResultsPreoperative INPH test results were significantly lower in all tests compared to healthy. Improvements after shunt surgery were seen in all cognitive domains: memory (Ten-word list test, p<0,01), executive functions (Stroop incongruent, (p<0.05), attention (Two choice reaction test, p<0.01), psychomotor speed (Stroop congruent, p<0.05) and manual dexterity (Four- finger tapping, p<0.01). No ceiling effects were observed. Depressive symptoms were more common in INPH versus healthy and did not change postoperatively. Preoperatively 81 % of INPH patients completed at least eight of the nine included test.ConclusionsCoGNIT is sensitive to cognitive impairment and to investigate changes after shunt surgery in INPH. Completion rates are good. CoGNIT has a potential to be useful in the cognitive assessment of INPH. 
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6.
  • Behrens, Anders, et al. (författare)
  • The Computerized General Neuropsychological INPH Test revealed improvement in idiopathic normal pressure hydrocephalus after shunt surgery
  • 2020
  • Ingår i: Journal of Neurosurgery. - : AMER ASSOC NEUROLOGICAL SURGEONS. - 0022-3085 .- 1933-0693. ; 132:3, s. 733-740
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE The Computerized General Neuropsychological INPH Test (CoGNIT) provides the clinician and the researcher with standardized and accessible cognitive assessments in patients with idiopathic normal pressure hydrocephalus (INPH). CoGNIT includes tests of memory, executive functions, attention, manual dexterity, and psychomotor speed. Investigations of the validity and reliability of CoGNIT have been published previously. The aim of this study was to evaluate CoGNIT's sensitivity to cognitive change after shunt surgery in patients with INPH.METHODS Forty-one patients with INPH (median Mini-Mental State Examination score 26) were given CoGNIT preoperatively and at a postoperative follow-up 4 months after shunt surgery. Scores were compared to those of 44 healthy elderly control volunteers. CoGNIT was administered by either a nurse or an occupational therapist.RESULTS Improvement after shunt surgery was seen in all cognitive domains: memory (10-word list test, p < 0.01); executive functions (Stroop incongruent color and word test, p < 0.01); attention (2-choice reaction test, p < 0.01); psychomotor speed (Stroop congruent color and word test, p < 0.01); and manual dexterity (4-finger tapping, p < 0.01). No improvement was seen in the Mini-Mental State Examination score. Preoperative INPH test scores were significantly impaired compared to healthy control subjects (p < 0.001 for all tests).CONCLUSIONS In this study the feasibility for CoGNIT to detect a preoperative impairment and postoperative improvement in INPH was demonstrated. CoGNIT has the potential to become a valuable tool in clinical and research work.
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7.
  • Chi, Celestine N., et al. (författare)
  • Deciphering the kinetic binding mechanism of dimeric ligands, using a potent plasma-stable dimeric inhibitor of postsynaptic density protein-95 as an example
  • 2010
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:36, s. 28252-28260
  • Tidskriftsartikel (refereegranskat)abstract
    • Dimeric ligands can be potent inhibitors of protein-protein or enzyme-substrate interactions. They have increased affinity and specificity towards their targets due to their ability to bind simultaneously to two binding sites and are therefore very attractive in drug design. However, few studies have addressed the kinetic mechanism of interaction of such bivalent ligands. We have investigated the binding interaction of a recently identified potent plasma-stable dimeric pentapeptide of PDZ1-2 of PSD-95 using protein engineering in combination with fluorescence polarisation, isothermal titration calorimetry and stopped-flow fluorimetry. Our experiments demonstrate that binding occurs via a two-step process, where an initial binding to either one of the two PDZ domains is followed by an intramolecular step, which produces the bidentate complex. We have determined all rate constants involved in the binding reaction and we also find evidence for a conformational transition of the complex. Our data demonstrate the importance of a slow dissociation for a successful dimeric ligand, but also highlight the possibility of optimizing the intramolecular association rate. The results may therefore aid the design of dimeric inhibitors in general.
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8.
  • Kjölhede, Karin, et al. (författare)
  • Glycemic, maternal and neonatal outcomes in women with type 1 diabetes using continuous glucose monitoring during pregnancy – Pump vs multiple daily injections, a secondary analysis of an observational cohort study
  • 2021
  • Ingår i: Acta Obstetricia et Gynecologica Scandinavica. - : Wiley. - 0001-6349 .- 1600-0412. ; 100:5, s. 927-933
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Continuous glucose monitoring (CGM) provides detailed information about glucose level fluctuations over time. The method is increasingly being used in pregnant women with type 1 diabetes. However, only one previous study compared CGM results related to pregnancy outcomes in women using insulin pumps with those administering multiple daily injections (MDI). We performed a secondary analysis of CGM metrics from an observational cohort of pregnant women with type 1 diabetes and compared insulin pump and MDI therapies in relation to maternal and neonatal outcomes. Material and methods: The study included 185 pregnant Swedish women with type 1 diabetes undergoing CGM throughout pregnancy. Women were divided according to insulin administration mode, ie MDI (n = 131) or pump (n = 54). A total of 91 women used real-time CGM and 94 women used intermittently viewed CGM. Maternal demographics and maternal and neonatal outcome data were collected from medical records. CGM data were analyzed according to predefined glycemic indices: mean glucose; standard deviation; percentage of time within, below and above glucose target range; mean amplitude of glycemic excursion; high and low glucose indices; and coefficient variation in percent. Associations between insulin administration mode and CGM data, on the one hand, and maternal and neonatal outcomes, on the other, were analyzed with analysis of covariance and logistic regression, respectively, adjusted for confounders. Results: There were no differences in maternal characteristics or glycemic indices between the MDI and pump groups, except for a longer duration of type 1 diabetes and higher frequencies of microangiopathy and real-time CGM among pump users. Despite improvement with each trimester, glucose levels remained suboptimal throughout pregnancy in both groups. There were no differences between the MDI and pump groups concerning the respective associations with any of the outcomes. The frequency of large for gestational age was high in both groups (MDI 49% vs pump 63%) and did not differ significantly. Conclusions: Pregnant women with type 1 diabetes did not differ in glycemic control or pregnancy outcome, related to MDI or pump administration of insulin. Glycemic control remained suboptimal throughout pregnancy, regardless of insulin administration mode.
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9.
  • Kristensen, Karl, et al. (författare)
  • Continuous glucose monitoring in pregnant women with type 1 diabetes : an observational cohort study of 186 pregnancies
  • 2019
  • Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 62:7, s. 1143-1153
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims/hypothesis: The aim of this study was to analyse patterns of continuous glucose monitoring (CGM) data for associations with large for gestational age (LGA) infants and an adverse neonatal composite outcome (NCO) in pregnancies in women with type 1 diabetes. Methods: This was an observational cohort study of 186 pregnant women with type 1 diabetes in Sweden. The interstitial glucose readings from 92 real-time (rt) CGM and 94 intermittently viewed (i) CGM devices were used to calculate mean glucose, SD, CV%, time spent in target range (3.5–7.8 mmol/l), mean amplitude of glucose excursions and also high and low blood glucose indices (HBGI and LBGI, respectively). Electronic records provided information on maternal demographics and neonatal outcomes. Associations between CGM indices and neonatal outcomes were analysed by stepwise logistic regression analysis adjusted for confounders. Results: The number of infants born LGA was similar in rtCGM and iCGM users (52% vs 53%). In the combined group, elevated mean glucose levels in the second and the third trimester were significantly associated with LGA (OR 1.53, 95% CI 1.12, 2.08, and OR 1.57, 95% CI 1.12, 2.19, respectively). Furthermore, a high percentage of time in target in the second and the third trimester was associated with lower risk of LGA (OR 0.96, 95% CI 0.94, 0.99 and OR 0.97, 95% CI 0.95, 1.00, respectively). The same associations were found for mean glucose and for time in target and the risk of NCO in all trimesters. SD was significantly associated with LGA in the second trimester and with NCO in the third trimester. Glucose patterns did not differ between rtCGM and iCGM users except that rtCGM users had lower LBGI and spent less time below target. Conclusions/interpretation: Higher mean glucose levels, higher SD and less time in target range were associated with increased risk of LGA and NCO. Despite the use of CGM throughout pregnancy, the day-to-day glucose control was not optimal and the incidence of LGA remained high.
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10.
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11.
  • Nissen, Klaus B., et al. (författare)
  • Targeting Protein-Protein Interactions with Trimeric Ligands : High Affinity Inhibitors of the MAGUK Protein Family
  • 2015
  • Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:2
  • Tidskriftsartikel (refereegranskat)abstract
    • PDZ domains in general, and those of PSD-95 in particular, are emerging as promising drug targets for diseases such as ischemic stroke. We have previously shown that dimeric ligands that simultaneously target PDZ1 and PDZ2 of PSD-95 are highly potent inhibitors of PSD-95. However, PSD-95 and the related MAGUK proteins contain three consecutive PDZ domains, hence we envisioned that targeting all three PDZ domains simultaneously would lead to more potent and potentially more specific interactions with the MAGUK proteins. Here we describe the design, synthesis and characterization of a series of trimeric ligands targeting all three PDZ domains of PSD-95 and the related MAGUK proteins, PSD93, SAP-97 and SAP-102. Using our dimeric ligands targeting the PDZ1-2 tandem as starting point, we designed novel trimeric ligands by introducing a PDZ3-binding peptide moiety via a cysteine-derivatized NPEG linker. The trimeric ligands generally displayed increased affinities compared to the dimeric ligands in fluorescence polarization binding experiments and optimized trimeric ligands showed low nanomolar inhibition towards the four MAGUK proteins, thus being the most potent inhibitors described. Kinetic experiments using stopped-flow spectrometry showed that the increase in affinity is caused by a decrease in the dissociation rate of the trimeric ligand as compared to the dimeric ligands, likely reflecting the lower probability of simultaneous dissociation of all three PDZ ligands. Thus, we have provided novel inhibitors of the MAGUK proteins with exceptionally high affinity, which can be used to further elucidate the therapeutic potential of these proteins.
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12.
  • Ahadi, Aylin, et al. (författare)
  • Simulation of Nanoindentation Response of Empty and Filled Viral Capsids
  • 2009
  • Ingår i: DCE Technical Memorandum. - 1901-7278. ; 11
  • Konferensbidrag (refereegranskat)abstract
    • The nanoindentation response of empty and filled viral capsids is modelled using three dimensional finite element analysis. Simulation with two different geometries, spherical and icosahedral, are performed using the finite element code Abaqus. The capsids are modeled as non-linear Hookean elastic and both small and large deformation analysis is performed. Force-indentation curves for three different viral capsids are directly compared to experimental data and the Young’s modulus is determined by calibrating the force-indentation curve to data from atomic force microscopy (AFM) experiments. Predictions are made for two additional viral capsids. The results from the simulation showed a good agreement with AFM data, see [1].
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13.
  • Ahnfeldt-Mollerup, Peder, et al. (författare)
  • Resource allocation and the burden of co-morbidities among patients diagnosed with chronic obstructive pulmonary disease : an observational cohort study from Danish general practice
  • 2016
  • Ingår i: BMC Health Services Research. - : Springer Science and Business Media LLC. - 1472-6963. ; 16:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Chronic obstructive pulmonary disease is a leading cause of mortality, and associated with increased healthcare utilization and healthcare expenditure. In several countries, morbidity-based systems have changed the way resources are allocated in general practice. In primary care, fee-for-services tariffs are often based on political negotiation rather than costing systems. The potential for comprehensive measures of patient morbidity to explain variation in negotiated expenditures for patients with chronic obstructive pulmonary disease has not previously been examined. The aim of this study is to analyze fee-for-service expenditure of patients diagnosed with chronic obstructive pulmonary disease visiting Danish general practice clinics and further to assess what proportion of fee-for-service expenditure variation was explained by patient morbidity and general practice clinic characteristics, respectively.METHODS: We used patient morbidity characteristics such as diagnostic markers and multi-morbidity adjustment based on adjusted clinical groups (ACGs) and fee-for-service expenditure for a sample of primary care patients for the year 2010. Our sample included 3,973 patients in 59 general practices. We used a multi-level approach.RESULTS: The average annual fee-for-service expenditure of caring for patients diagnosed with chronic obstructive pulmonary disease in general practice was about EUR 400 per patient. Variation in the expenditures was driven by multimorbidity characteristics up to 28 % where as characteristics such as age and gender only explained 5 %. Expenditures increased progressively with the degree of multimorbidity. In addition, expenditures were higher for patients who had diagnostic markers based on ICPC-2 (body systems and/or components such as infections and symptoms). Nevertheless, 9.8-15.4 % of the variation in expenditure was related to the clinic in which the patient was cared for.CONCLUSION: Patient morbidity and general practice clinic characteristics are significant patient-related fee-for-service expenditure drivers in chronic obstructive pulmonary disease care.
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14.
  • Aidas, Kestutis, et al. (författare)
  • The Dalton quantum chemistry program system
  • 2014
  • Ingår i: WIREs Computational Molecular Science. - : Wiley. - 1759-0876 .- 1759-0884. ; 4:3, s. 269-284
  • Tidskriftsartikel (refereegranskat)abstract
    • Dalton is a powerful general-purpose program system for the study of molecular electronic structure at the Hartree-Fock, Kohn-Sham, multiconfigurational self-consistent-field, MOller-Plesset, configuration-interaction, and coupled-cluster levels of theory. Apart from the total energy, a wide variety of molecular properties may be calculated using these electronic-structure models. Molecular gradients and Hessians are available for geometry optimizations, molecular dynamics, and vibrational studies, whereas magnetic resonance and optical activity can be studied in a gauge-origin-invariant manner. Frequency-dependent molecular properties can be calculated using linear, quadratic, and cubic response theory. A large number of singlet and triplet perturbation operators are available for the study of one-, two-, and three-photon processes. Environmental effects may be included using various dielectric-medium and quantum-mechanics/molecular-mechanics models. Large molecules may be studied using linear-scaling and massively parallel algorithms. Dalton is distributed at no cost from for a number of UNIX platforms.
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15.
  • Al-Karadaghi, Salam, et al. (författare)
  • A decade of progress in understanding the structural basis of protein synthesis
  • 2000
  • Ingår i: Progress in Biophysics and Molecular Biology. - 1873-1732. ; 73:2, s. 167-193
  • Forskningsöversikt (refereegranskat)abstract
    • The key reaction of protein synthesis, peptidyl transfer, is catalysed in all living organisms by the ribosome - an advanced and highly efficient molecular machine. During the last decade extensive X-ray crystallographic and NMR studies of the three-dimensional structure of ribosomal proteins, ribosomal RNA components and their complexes with ribosomal proteins, and of several translation factors in different functional states have taken us to a new level of understanding of the mechanism of function of the protein synthesis machinery. Among the new remarkable features revealed by structural studies, is the mimicry of the tRNA molecule by elongation factor G, ribosomal recycling factor and the eukaryotic release factor 1. Several other translation factors, for which three-dimensional structures are not yet known, are also expected to show some form of tRNA mimicry. The efforts of several crystallographic and biochemical groups have resulted in the determination by X-ray crystallography of the structures of the 30S and 50S subunits at moderate resolution, and of the structure of the 70S subunit both by X-ray crystallography and cryo-electron microscopy (EM). In addition, low resolution cryo-EM models of the ribosome with different translation factors and tRNA have been obtained. The new ribosomal models allowed for the first time a clear identification of the functional centres of the ribosome and of the binding sites for tRNA and ribosomal proteins with known three-dimensional structure. The new structural data have opened a way for the design of new experiments aimed at deeper understanding at an atomic level of the dynamics of the system.
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16.
  • Almered Olsson, Gunilla, 1951, et al. (författare)
  • Peri-Urban Food Production and Its Relation to Urban Resilience
  • 2016
  • Ingår i: Sustainability. - : MDPI AG. - 2071-1050. ; 8:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Food production on the urban-rural fringe is under pressure due to competing land uses. We discuss the potential to improve resilience for urban-rural regions by enhancing food production as part of multifunctional land use. Through studies of peri-urban land in the regions of Gothenburg (Sweden), Copenhagen (Denmark) and Gent (Belgium), recent developments are analysed. Arable farming has been declining since 2000 in all three areas due to urban expansion and recreational land use changes. In city plans, networks of protected areas and green spaces and their importance for human wellbeing have been acknowledged. Policies for farmland preservation in peri-urban settings exist, but strategies for local food production are not expressed in present planning documents. Among the diversity of peri-urban agricultural activities, peri-urban food production is a developing issue. However, the competing forms of land use and the continuing high dependence of urban food on global food systems and related resource flows reduces peri-urban food production and improvements in urban food security. The positive effects of local food production need to be supported by governance aiming to improve the urban-rural relationship. The paper discusses the resilience potential of connecting urban-rural regions and re-coupling agriculture to regional food production.
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17.
  • Angelin, Bo, et al. (författare)
  • Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver-selective thyroid hormone receptor agonist eprotirome
  • 2015
  • Ingår i: Journal of Internal Medicine. - : Wiley: 12 months. - 0954-6820 .- 1365-2796. ; 277:3, s. 331-342
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundLiver-selective thyromimetic agents could provide a new approach for treating dyslipidaemia. MethodsWe performed a multicentre, randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of eprotirome, a liver-selective thyroid hormone receptor agonist, in 98 patients with primary hypercholesterolaemia. After previous drug wash-out and dietary run-in, patients received 100 or 200gday(-1) eprotirome or placebo for 12weeks. The primary end-point was change in serum LDL cholesterol; secondary end-points included changes in other lipid parameters and safety measures. ResultsEprotirome treatment at 100 and 200g daily reduced serum LDL cholesterol levels by 235% and 31 +/- 4%, respectively, compared with 2 +/- 6% for placebo (Pless than0.0001). Similar reductions were seen in non-HDL cholesterol and apolipoprotein (apo) B, whereas serum levels of HDL cholesterol and apo A-I were unchanged. There were also considerable reductions in serum triglycerides and lipoprotein(a), in particular in patients with elevated levels at baseline. There was no evidence of adverse effects on heart or bone and no changes in serum thyrotropin or triiodothyronine, although the thyroxine level decreased. Low-grade increases in liver enzymes were evident in most patients. ConclusionIn hypercholesterolaemic patients, the liver-selective thyromimetic eprotirome decreased serum levels of atherogenic lipoproteins without signs of extra-hepatic side effects. Selective stimulation of hepatic thyroid hormone receptors may be an attractive way to modulate lipid metabolism in hyperlipidaemia.
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18.
  • Asif, Sana, M.D, PhD student, et al. (författare)
  • Immuno-Modulatory Effects of Dexamethasone in Severe COVID-19 : A Swedish Cohort Study
  • 2023
  • Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 11:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Dexamethasone (Dex) has been shown to decrease mortality in severe coronavirus disease 2019 (COVID-19), but the mechanism is not fully elucidated. We aimed to investigate the physiological and immunological effects associated with Dex administration in patients admitted to intensive care with severe COVID-19. A total of 216 adult COVID-19 patients were included-102 (47%) received Dex, 6 mg/day for 10 days, and 114 (53%) did not. Standard laboratory parameters, plasma expression of cytokines, endothelial markers, immunoglobulin (Ig) IgA, IgM, and IgG against SARS-CoV-2 were analyzed post-admission to intensive care. Patients treated with Dex had higher blood glucose but lower blood lactate, plasma cortisol, IgA, IgM, IgG, D-dimer, cytokines, syndecan-1, and E-selectin and received less organ support than those who did not receive Dex (Without-Dex). There was an association between Dex treatment and IL-17A, macrophage inflammatory protein 1 alpha, syndecan-1 as well as E-selectin in predicting 30-day mortality. Among a subgroup of patients who received Dex early, within 14 days of COVID-19 debut, the adjusted mortality risk was 0.4 (95% CI 0.2-0.8), i.e., 40% compared with Without-Dex. Dex administration in a cohort of critically ill COVID-19 patients resulted in altered immunological and physiologic responses, some of which were associated with mortality.
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19.
  • Ayres Pereira, Marina, et al. (författare)
  • Placental Sequestration of Plasmodium falciparum Malaria Parasites Is Mediated by the Interaction Between VAR2CSA and Chondroitin Sulfate A on Syndecan-1
  • 2016
  • Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 12:8
  • Tidskriftsartikel (refereegranskat)abstract
    • During placental malaria, Plasmodium falciparum infected erythrocytes sequester in the placenta, causing health problems for both the mother and fetus. The specific adherence is mediated by the VAR2CSA protein, which binds to placental chondroitin sulfate (CS) on chondroitin sulfate proteoglycans (CSPGs) in the placental syncytium. However, the identity of the CSPG core protein and the cellular impact of the interaction have remain elusive. In this study we identified the specific CSPG core protein to which the CS is attached, and characterized its exact placental location. VAR2CSA pull-down experiments using placental extracts from whole placenta or syncytiotrophoblast microvillous cell membranes showed three distinct CSPGs available for VAR2CSA adherence. Further examination of these three CSPGs by immunofluorescence and proximity ligation assays showed that syndecan-1 is the main receptor for VAR2CSA mediated placental adherence. We further show that the commonly used placental choriocarcinoma cell line, BeWo, express a different set of proteoglycans than those present on placental syncytiotrophoblast and may not be the most biologically relevant model to study placental malaria. Syncytial fusion of the BeWo cells, triggered by forskolin treatment, caused an increased expression of placental CS-modified syndecan-1. In line with this, we show that rVAR2 binding to placental CS impairs syndecan-1-related Src signaling in forskolin treated BeWo cells, but not in untreated cells.
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20.
  • Balslev, Soren, et al. (författare)
  • Microfluidic dye laser with compact, low-cost liquid dye dispenser
  • 2005
  • Ingår i: Micro Total Analysis Systems 2004. - 0854048960 ; , s. 375-377
  • Konferensbidrag (refereegranskat)abstract
    • We present a compact system consisting of a miniaturized fluid dispenser, delivering liquid laser dye to a micro-chip dye laser. This demonstrates the elimination of bulk fluid pumps for a microfluidic system by using a miniaturized, electrically and chemically inert dispenser, capable of delivering very low flow for extended periods of time.
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21.
  • Berkenstam, Anders, et al. (författare)
  • The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans
  • 2008
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 105:2, s. 663-667
  • Tidskriftsartikel (refereegranskat)abstract
    • Atherosclerotic cardiovascular disease is a major problem despite the availability of drugs that influence major risk factors. New treatments are needed, and there is growing interest in therapies that may have multiple actions. Thyroid hormone modulates several cardiovascular risk factors and delays atherosclerosis progression in humans. However, use of thyroid hormone is limited by side effects, especially in the heart. To overcome this limitation, pharmacologically selective thyromimetics that mimic metabolic effects of thyroid hormone and bypass side effects are under development. In animal models, such thyromimetics have been shown to stimulate cholesterol elimination through LDL and HDL pathways and decrease body weight without eliciting side effects. We report here studies on a selective thyromimetic [KB2115, (3-[[3,5-dibromo-4- [4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid)] in humans. In moderately overweight and hypercholesterolemic subjects KB2115 was found to be safe and well tolerated and elicited up to a 40% lowering of total and LDL cholesterol after 14 days of treatment. Bile acid synthesis was stimulated without evidence of increased cholesterol production, indicating that KB2115 induced net cholesterol excretion. KB2115 did not provoke detectable effects on the heart, suggesting that the pharmacological selectivity observed in animal models translates to humans. Thus, selective thyromimetics deserve further study as agents to treat dyslipidemia and other risk factors for atherosclerosis. © 2007 by The National Academy of Sciences of the USA.
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22.
  • Bhatt, Deepak L., et al. (författare)
  • Rationale, design and baseline characteristics of the effect of ticagrelor on health outcomes in diabetes mellitus patients Intervention study
  • 2019
  • Ingår i: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 42:5, s. 498-505
  • Tidskriftsartikel (refereegranskat)abstract
    • In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients >= 50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of >= 50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention.
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23.
  • Binzer-Panchal, Amrei, et al. (författare)
  • Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes
  • 2019
  • Ingår i: Clinical Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 1078-0432 .- 1557-3265. ; 25:7, s. 2155-2165
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort.Experimental Design: Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n = 50), copy-number variation (CNV, n = 40), cell morphometry (n = 39), and protein expression (n = 22). Gene ontology and network enrichment analysis were used to relate over-and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings.Results: Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multivariable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm(2) could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup. Conclusions: Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.
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24.
  • Björck, Inger, et al. (författare)
  • Cereal grains for nutrition and health benefits: Overview of results from in vitro, animal and human studies in the HEALTHGRAIN project
  • 2012
  • Ingår i: Trends in Food Science & Technology. - : Elsevier BV. - 1879-3053 .- 0924-2244. ; 25:2, s. 87-100
  • Tidskriftsartikel (refereegranskat)abstract
    • Epidemiological studies have linked whole grain intake to the prevention of the metabolic syndrome, obesity and associated chronic diseases such as CVD and T2D. The Nutrition module within the HEALTHGRAIN project, included 10 partners and undertook in vitro, animal and humanin vivo studies with the overall aims of elucidating the components and mechanisms underlying the health benefits of cereal grains. This review summarises the major outcomes of these studies, including yet unpublished findings.
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25.
  • Bovinder Ylitalo, Erik, 1985- (författare)
  • Molecular heterogeneity of prostate cancer bone metastasis
  • 2018
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Castration-resistant prostate cancer (CRPC) develops after androgen deprivation therapy of advanced PC, often with metastatic growth in bone. Patients with metastatic CRPC have very poor prognosis. Growth of CRPC, in most but not all patients, seems to involve androgen receptor (AR) activity, despite castrate levels of serum testosterone. Multiple mechanisms behind AR activation in castrated patients have been described, such as AR amplification, AR mutations, expression of constitutively active AR variants, and intra-tumoral steroid synthesis. However, other mechanisms beside AR activation are also involved and CRPC patients with tumors circumventing the need for AR stimulation will probably not benefit from AR targeting therapies but will need alternative treatments.Available treatments for CRPC are chemotherapy, AR antagonists or inhibition of androgen-synthesis. Novel drugs are constantly under development and several new therapies has recently been approved for clinical use. These include, in addition to new AR targeting therapies also immunotherapy, osteoclast inhibitors and bone-targeting radiopharmaceuticals. Due to heterogeneous mechanisms behind CRPC and that newly developed therapies are based on different mechanisms of action, there are reasons to believe that CRPC patients show different therapy responses due to diverse molecular properties of individual tumors. Although there are promising prospects, no biomarkers are used today for patient stratification into different treatments. Another important aspect is that, when effective, any therapy will probably induce tumor responses that subsequently cause further molecular diversities and alternative paths for development of tumor relapse and castration-resistance. Such mechanisms are important to understand in order to develop new treatment strategies.In this thesis, global gene expression and methylation patterns were studied in bone metastases obtained from PC patients going through metastasis surgery for spinal cord compression. Gene expression patterns were analyzed by multivariate statistics and ontology analysis with the aim to identify subgroups of biological/pathological relevance. Interesting findings from array analysis were verified using qRT-PCR and immunohistochemical analysis. In addition, a xenograft mouse model was used to study the effects of abiraterone (steroidogenesis inhibitor) and cabazitaxel (taxane), and subsequently developed resistance mechanisms in the 22Rv1 PC cell line expressing high levels of AR-V7; a constitutively active AR splice variant associated with a poor prognosis and resistance to AR targeting therapies.In summary, results showed that the majority of CRPC bone metastases were AR-driven, defined from high levels of AR-regulated gene transcripts, while a smaller sub-group was non-AR-driven (paper I). AR-driven bone metastases had high metabolic activity in combination with downregulated immune responses while non-AR-driven cases had a more pronounced immune response (paper I) and higher bone cell activity (paper II). Paper III identified pronounced hypermethylation in primary prostate tumors probably causing a suppressed anti-tumor immune-response whereas metastases showed a different methylation pattern related to increased AR activity and patient outcome. In paper IV, 22Rv1 xenografts showed poor response to abiraterone and initially excellent response to cabazitaxel, but eventually resistance occurred probably due to an upregulation of the ABCB1 transporter protein. Anti-androgens partly reversed the resistance.In conclusion, we have identified molecular heterogeneities in clinical bone metastases associated with biological characteristics, which could perhaps be used both for stratifying patients into treatment modalities, and to aid in further development of effective therapies for CRPC.
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26.
  • Campos, Paula F., et al. (författare)
  • Ancient DNA sequences point to a large loss of mitochondrial genetic diversity in the saiga antelope (Saiga tatarica) since the Pleistocene
  • 2010
  • Ingår i: Molecular Ecology. - 0962-1083 .- 1365-294X. ; 19:22, s. 4863-4875
  • Tidskriftsartikel (refereegranskat)abstract
    • Prior to the Holocene, the range of the saiga antelope (Saiga tatarica) spanned from France to the Northwest Territories of Canada. Although its distribution subsequently contracted to the steppes of Central Asia, historical records indicate that it remained extremely abundant until the end of the Soviet Union, after which its populations were reduced by over 95%. We have analysed the mitochondrial control region sequence variation of 27 ancient and 38 modern specimens, to assay how the species' genetic diversity has changed since the Pleistocene. Phylogenetic analyses reveal the existence of two well-supported, and clearly distinct, clades of saiga. The first, spanning a time range from >49 500 C-14 ybp to the present, comprises all the modern specimens and ancient samples from the Northern Urals, Middle Urals and Northeast Yakutia. The second clade is exclusive to the Northern Urals and includes samples dating from between 40 400 to 10 250 C-14 ybp. Current genetic diversity is much lower than that present during the Pleistocene, an observation that data modelling using serial coalescent indicates cannot be explained by genetic drift in a population of constant size. Approximate Bayesian Computation analyses show the observed data is more compatible with a drastic population size reduction (c. 66-77%) following either a demographic bottleneck in the course of the Holocene or late Pleistocene, or a geographic fragmentation (followed by local extinction of one subpopulation) at the Holocene/Pleistocene transition.
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27.
  • Dengjel, Joern, et al. (författare)
  • Identification of Autophagosome-associated Proteins and Regulators by Quantitative Proteomic Analysis and Genetic Screens
  • 2012
  • Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 11:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Autophagy is one of the major intracellular catabolic pathways, but little is known about the composition of autophagosomes. To study the associated proteins, we isolated autophagosomes from human breast cancer cells using two different biochemical methods and three stimulus types: amino acid deprivation or rapamycin or concanamycin A treatment. The autophagosome- associated proteins were dependent on stimulus, but a core set of proteins was stimulus- independent. Remarkably, proteasomal proteins were abundant among the stimulus- independent common autophagosome- associated proteins, and the activation of autophagy significantly decreased the cellular proteasome level and activity supporting interplay between the two degradation pathways. A screen of yeast strains defective in the orthologs of the human genes encoding for a common set of autophagosome- associated proteins revealed several regulators of autophagy, including subunits of the retromer complex. The combined spatiotemporal proteomic and genetic data sets presented here provide a basis for further characterization of autophagosome biogenesis and cargo selection.
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28.
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29.
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30.
  • Erlström, Mikael, et al. (författare)
  • Stratigraphy and geothermal assessment of Mesozoic sandstone reservoirs in the Öresund Basin - exemplified by well data and seismic profiles
  • 2018
  • Ingår i: Bulletin of the Geological Society of Denmark. - 0011-6297. ; 66, s. 123-149
  • Tidskriftsartikel (refereegranskat)abstract
    • The Øresund Basin in the transnational area between Sweden and Denmark forms a marginal part of the Danish Basin. The structural outline and stratigraphy of the Mesozoic succession is described, and a novel interpretation and description of the subsurface geology and geothermal potential in the North Sjælland Half-graben is presented. The subsurface bedrock in the basin includes several Mesozoic intervals with potential geothermal sandstone reservoirs. Parts of the succession fulfill specific geological requirements about distribution, composition and quality of the sandstones. A characterisation of these is presently of great interest in the attempt to identify geothermal reservoirs suitable for district heating purposes. The results presented in this paper include for the first time a comprehensive description of the stratigraphic intervals as well as the characteristics of the potential Mesozoic geothermal reservoirs in the Øresund region, including their distribution, composition and physical properties. This is illustrated by seismic cross-sections and well sections. In addition, results from analyses and evaluations of porosity, permeability, formation fluids and temperature are presented. Six potential geothermal reservoirs in the Mesozoic succession are described and assessed. Primary focus is placed on the characteristics of the reservoirs in the Lower Triassic and Rhaetian–Lower Jurassic succession. The study shows that the Mesozoic reservoir sandstones vary considerably with respect to porosity and permeability. Values range between 5–25% for the pre-Rhaetian Triassic sandstones, but are commonly > 25% for the Rhaetian–Lower Jurassic and Lower Cretaceous sandstones. The corresponding permeability rarely reaches above 500 mD for the pre-Rhaetian Triassic reservoirs, but often reach >1 Darcy for the Rhaetian–Lower Jurassic and the Lower Cretaceous sandstones. The interpreted formation temperatures for the reservoirs in the Øresund Basin are: 45–50°C at 1500 m, 60–70°C at 2000 m and 70–90°C at 2500 m depth . The combined results provide a geological framework for making site specific predictions regarding appraisal of viable geothermal projects for district heating purposes in the region as well as reducing the risk of unsuccessful wells
  •  
31.
  • Fedorov, R V, et al. (författare)
  • Structure of ribosomal protein TL5 complexed with RNA provides new insights into the CTC family of stress proteins
  • 2001
  • Ingår i: Acta Crystallographica. Section D: Biological Crystallography. - 1399-0047. ; D57:7, s. 968-976
  • Tidskriftsartikel (refereegranskat)abstract
    • The crystal structure of Thermus thermophilus ribosomal protein TL5 in complex with a fragment of Escherichia coli 5S rRNA has been determined at 2.3 Å resolution. The protein consists of two domains. The structure of the N-terminal domain is close to the structure of E. coli ribosomal protein L25, but the C-terminal domain represents a new fold composed of seven -strands connected by long loops. TL5 binds to the RNA through its N-terminal domain, whereas the C-terminal domain is not included in this interaction. Cd2+ ions, the presence of which improved the crystal quality significantly, bind only to the protein component of the complex and stabilize the protein molecule itself and the interactions between the two molecules in the asymmetric unit of the crystal. The TL5 sequence reveals homology to the so-called general stress protein CTC. The hydrophobic cores which stabilize both TL5 domains are highly conserved in CTC proteins. Thus, all CTC proteins may fold with a topology close to that of TL5.
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32.
  • Flores-Morales, Amilcar, et al. (författare)
  • Proteogenomic characterization of patient-derived xenografts highlights the role of REST in neuroendocrine differentiation of castration-resistant prostate cancer
  • 2019
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 25:2, s. 595-608
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: An increasing number of castration-resistant prostate cancer (CRPC) tumors exhibit neuroendocrine (NE) features. NE prostate cancer (NEPC) has poor prognosis, and its development is poorly understood. Experimental Design: We applied mass spectrometry–based proteomics to a unique set of 17 prostate cancer patient–derived xenografts (PDX) to characterize the effects of castration in vivo, and the proteome differences between NEPC and prostate adenocarcinomas. Genome-wide profiling of REST-occupied regions in prostate cancer cells was correlated to the expression changes in vivo to investigate the role of the transcriptional repressor REST in castration-induced NEPC differentiation. Results: An average of 4,881 proteins were identified and quantified from each PDX. Proteins related to neurogenesis, cell-cycle regulation, and DNA repair were found upregulated and elevated in NEPC, while the reduced levels of proteins involved in mitochondrial functions suggested a prevalent glycolytic metabolism of NEPC tumors. Integration of the REST chromatin bound regions with expression changes indicated a direct role of REST in regulating neuronal gene expression in prostate cancer cells. Mechanistically, depletion of REST led to cell-cycle arrest in G1, which could be rescued by p53 knockdown. Finally, the expression of the REST-regulated gene secretagogin (SCGN) correlated with an increased risk of suffering disease relapse after radical prostatectomy. Conclusions: This study presents the first deep characterization of the proteome of NEPC and suggests that concomitant inhibition of REST and the p53 pathway would promote NEPC. We also identify SCGN as a novel prognostic marker in prostate cancer.
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33.
  • Guiomar, N., et al. (författare)
  • Typology and distribution of small farms in Europe : Towards a better picture
  • 2018
  • Ingår i: Land use policy. - : Elsevier BV. - 0264-8377 .- 1873-5754. ; 75, s. 784-798
  • Tidskriftsartikel (refereegranskat)abstract
    • The contribution of small farms to local food supply, food security and food sovereignty is widely acknowledged at a global level. In the particular case of Europe, they often are seen as an alternative to large and specialised farms. Assessing the real role of small farms has been limited by a lack of information, as small farms are frequently omitted from agricultural censuses and national statistics. It is also well acknowledged that small farms differ widely, and are distributed according to different spatial patterns across Europe, fulfilling different roles according to the agriculture and territorial characteristics of each region. This paper presents the result of a novel classification of small farms at NUTS-3 level in Europe, according to the relevance of small farms in the agricultural and territorial context of each region, and based on a typology of small farms considering different dimensions of farm size. The maps presented result from an extensive data collection and variables selected according to European wide expert judgement, analysed with advanced cluster procedures. The results provide a fine grained picture of the role of small farms at the regional level in Europe today, and are expected to support further data analysis and targeted policy intervention.
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34.
  • Gülfe, Anders, et al. (författare)
  • Efficacy and drug survival of anti-tumour necrosis factor-alpha therapies in patients with non-radiographic axial spondyloarthritis: an observational cohort study from Southern Sweden.
  • 2014
  • Ingår i: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 43:6, s. 493-497
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: To evaluate the efficacy and drug survival of anti-tumour necrosis factor (anti-TNF) therapy in non-radiographic axial spondyloarthritis (nr-axSpA) patients treated in clinical practice in Southern Sweden. Method: In this cohort study we prospectively included 112 patients with nr-axSpA and high disease activity as well as inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs) receiving their first course of anti-TNF therapy. Patients fulfilling modified New York criteria for ankylosing spondylitis (AS) were excluded. The Assessment of SpondyloArthritis International Society (ASAS) criteria for axial SpA were fulfilled by 77% (n = 86) of the included patients. Results: At baseline, the median age of the cohort was 38 years, 59% were males, 79% of the patients had imaging suggestive of sacroiliitis (primarily inflammation on magnetic resonance imaging, MRI), 71% were HLA-B27 positive, and the median disease duration was 6 years and 10 months. At 6 months of follow-up, the median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) decreased from 5.6 to 3.2 (p = 0.002), the Bath Ankylosing Spondylitis Functional Index (BASFI) decreased from 3.9 to 1.8 (p = 0.005), and C-reactive protein (CRP) level decreased from 4.4 to 1.7 mg/L (p = 0.001). After 1 year of treatment the Kaplan-Meier estimated drug survival was 76%, and at 2 years of follow-up this value decreased to 65%. Patients with inflammatory MRI findings at baseline had significantly better drug survival [hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.10-0.55, p = 0.001]. Male sex was also associated with higher drug survival (HR 0.45, 95% CI 0.24-0.85, p = 0.011). CRP level at baseline was not associated with drug survival. Conclusions: Anti-TNF treatment of patients with nr-axSpA in clinical practice resulted in reduced BASDAI and BASFI scores and good drug survival. The results from this study suggest that male gender and positive imaging at baseline are associated with a favourable treatment course.
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35.
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36.
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37.
  • Gülfe, Anders, et al. (författare)
  • Rapid and sustained health utility gain in anti-TNF treated inflammatory arthritis. Observational data during seven years in southern Sweden.
  • 2010
  • Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 69:2, s. 352-357
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and other spondylarthritides (SpA) impose great impact on the individual in addition to the costs on society, which may be reduced by effective pharmacological treatment. Industry independent health economic studies should complement studies sponsored by industry. OBJECTIVE: To study secular trends in baseline health utilities in patients commencing TNF blockade for arthritis in clinical practice over 7 years; to address utility changes during treatment; to investigate the influence of previous treatment courses; to study the feasibility of health utility measures, and to compare them across diagnostic entities. METHODS: /B> EuroQoL 5 Dimensions (EQ-5D) utility data were collected from a structured clinical follow-up program of anti-TNF treated patients with RA (N=2554), PsA (N=574) or SpA (N=586). Time trends were calculated. Completer analysis was used. RESULTS: /B> There were weak or non-significant secular trends for increasing baseline utilities over time for RA, PsA and SpA. Maximum gain in utilities occurred already after 2 weeks for all diagnoses and remained stable for patients remaining on therapy. First and second anti-TNF courses performed similarly. CONCLUSIONS: Utilities at inclusion remained largely unchanged for RA, PsA and SpA over 7 years. Improvement occurred early during treatment and not beyond 6 weeks at the group level. Improvement during the first course was not consistently greater than the second. There were no major differences between RA, PsA and SpA. EQ-5D proved feasible and applicable across these diagnoses. These "real world" data may be useful for health economic modelling.
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38.
  • Gülfe, Anders, et al. (författare)
  • Six and 12 Weeks Treatment Response Predicts Continuation of Tumor Necrosis Factor Blockade in Rheumatoid Arthritis: An Observational Cohort Study from Southern Sweden.
  • 2009
  • Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 36, s. 517-521
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To investigate if treatment response predicts continuation of anti-tumor necrosis factor (TNF) treatment in patients with rheumatoid arthritis (RA). METHODS: We investigated if treatment response and/or achieving a certain activity state at 6 weeks or 3 months predicts continuation of treatment in an observational cohort of 1789 anti-TNF-naive patients with established RA disease from southern Sweden. RESULTS: Response to treatment at 6 weeks at overall/American College of Rheumatology (ACR20) or good/major level (except ACR70) significantly predicted drug continuation. Response according to all criteria sets at overall/ACR20 and at good/major/ACR70 level predicted drug continuation at 3 months, as did achieving low disease activity at 3 months irrespective of activity index applied. Remaining in a high disease activity state predicted drug discontinuation at both timepoints and according to all criteria sets. CONCLUSION: Response criteria may be useful aids in deciding on continuation of TNF blockade in RA as early as after 6 weeks of treatment. The various criteria sets perform similarly.
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39.
  • Gülfe, Anders, et al. (författare)
  • Utility-based outcomes made easy: The number needed per QALY gained (NNQ). Observational cohort study from Southern Sweden of TNF blockade in inflammatory arthritis.
  • 2010
  • Ingår i: Arthritis Care and Research. - : Wiley. - 2151-4658 .- 2151-464X. ; 62:10, s. 1399-1406
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE.: To introduce a novel, simple, utility based outcome measure, the Number Needed per Quality adjusted life year (QALY) gained (NNQ), and to apply it in clinical practice in anti-TNF treated patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondylarthritis (SpA). METHODS.: The NNQ is the number of patients one has to treat in order to gain 1 QALY. It is calculated as the inverted value of the utility gain (area under curve) over 1 year in a cohort subjected to an intervention. EuroQoL-5-dimensions (EQ-5D) utility data from the South Swedish Arthritis Treatment Register was used. RESULTS.: 1001 RA, 241 PsA, and 255 SpA patients were eligible for the study. First, 2(nd) and 3(rd) treatment courses were studied. For RA, NNQ was 4.5, 6.4 and 5.2 for 1(st), 2(nd) and 3(rd) courses, respectively. For PsA and SpA, NNQ was 4.2-4.5 irrespective of treatment order. Treatment groups with N<50 were not analysed. During the study period 2002-2007, there were no secular trends of utility gains. CONCLUSION.: The NNQ is an easily derived and understandable, utility based outcome measure that may be useful for stakeholders, decision makers as well as for clinicians. It was readily applied in this study of TNF blockade across 3 arthritis diagnoses. NNQ varied little over diagnoses and treatment course order, with a possible exception in 2(nd) treatment course in RA.
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40.
  • Hallberg, Håkan, et al. (författare)
  • Modeling of Continuous Dynamic Recrystallization in Aluminum
  • 2009
  • Ingår i: DCE Technical Memorandum No. 11. - 1901-7278. ; 11, s. 59-62
  • Konferensbidrag (refereegranskat)abstract
    • A constitutive model is presented, considering grain size refinement through continuous dynamic recrystallization together with an evolving dislocation density. The grain refinement is allowed to influence both the evolution of the dislocation density and the rate dependence of the material. The model is calibrated against experimental data on aluminum and numerical simulations of equal channel angular pressing (ECAP) material processing illustrates the capabilities of the model.
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41.
  • Hansen, Lea B.S., et al. (författare)
  • A low-gluten diet induces changes in the intestinal microbiome of healthy Danish adults
  • 2018
  • Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • © 2018, The Author(s). Adherence to a low-gluten diet has become increasingly common in parts of the general population. However, the effects of reducing gluten-rich food items including wheat, barley and rye cereals in healthy adults are unclear. Here, we undertook a randomised, controlled, cross-over trial involving 60 middle-aged Danish adults without known disorders with two 8-week interventions comparing a low-gluten diet (2 g gluten per day) and a high-gluten diet (18 g gluten per day), separated by a washout period of at least six weeks with habitual diet (12 g gluten per day). We find that, in comparison with a high-gluten diet, a low-gluten diet induces moderate changes in the intestinal microbiome, reduces fasting and postprandial hydrogen exhalation, and leads to improvements in self-reported bloating. These observations suggest that most of the effects of a low-gluten diet in non-coeliac adults may be driven by qualitative changes in dietary fibres.
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42.
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43.
  • Hay-Schmidt, Anders, et al. (författare)
  • Prenatal exposure to paracetamol/acetaminophen and precursor aniline impairs masculinisation of male brain and behaviour
  • 2017
  • Ingår i: Reproduction. - : Bioscientifica. - 1470-1626 .- 1476-3990. ; 154:2, s. 145-152
  • Tidskriftsartikel (refereegranskat)abstract
    • Paracetamol/acetaminophen (N-Acetyl-p-Aminophenol; APAP) is the preferred analgesic for pain relief and fever during pregnancy. It has therefore caused concern that several studies have reported that prenatal exposure to APAP results in developmental alterations in both the reproductive tract and the brain. Genitals and nervous system of male mammals are actively masculinised during foetal development and early postnatal life by the combined actions of prostaglandins and androgens, resulting in the male-typical reproductive behaviour seen in adulthood. Both androgens and prostaglandins are known to be inhibited by APAP. Through intrauterine exposure experiments in C57BL/6 mice, we found that exposure to APAP decreased neuronal number in the sexually dimorphic nucleus (SDN) of the preoptic area (POA) in the anterior hypothalamus of male adult offspring. Likewise, exposure to the environmental pollutant and precursor of APAP, aniline, resulted in a similar reduction. Decrease in neuronal number in the SDNPOA is associated with reductions in male sexual behaviour. Consistent with the changes, male mice exposed in uteri to APAP exhibited changes in urinary marking behaviour as adults and had a less aggressive territorial display towards intruders of the same gender. Additionally, exposed males had reduced intromissions and ejaculations during mating with females in oestrus. Together, these data suggest that prenatal exposure to APAP may impair male sexual behaviour in adulthood by disrupting the sexual neurobehavioral programming. These findings add to the growing body of evidence suggesting the need to limit the widespread exposure and use of APAP by pregnant women.
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44.
  • Hollestelle, Antoinette, et al. (författare)
  • No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
  • 2016
  • Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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45.
  • Holm, Karin, et al. (författare)
  • The role of Fusobacterium necrophorum in pharyngotonsillitis – A review
  • 2016
  • Ingår i: Anaerobe. - : Elsevier BV. - 1075-9964. ; 42, s. 89-97
  • Forskningsöversikt (refereegranskat)abstract
    • Fusobacterium necrophorum is a gram-negative anaerobic bacterium that is the causative agent of the invasive disease Lemierre's syndrome. In addition, it is also associated with peritonsillar abscess formation and otitis media in small children. Recent research has shown that F. necrophorum may be involved in pharyngotonsillitis especially in adolescent and young adults and that it may be the second most common bacterial cause of pharyngotonsillitis after Streptococcus pyogenes (Group A streptococci). Peritonsillar abscesses and Lemierre's syndrome due to F. necrophorum are also found in this age group, suggesting that they may be complications of F. necrophorum pharyngotonsillitis. In this review we present the present knowledge about the role of F. necrophorum in pharyngotonsillitis with special emphasis on the age distribution. We argue that F. necrophorum is an important pathogen involved in pharyngotonsillitis in the age group of 13–40 years of age and we urge clinical microbiology labs to set up the appropriate techniques to be able to detect F. necrophorum from throat swabs.
  •  
46.
  • Holm, Karin, et al. (författare)
  • Three variants of the leukotoxin gene in human isolates of Fusobacterium necrophorum subspecies funduliforme
  • 2017
  • Ingår i: Anaerobe. - : Elsevier BV. - 1075-9964. ; 45, s. 129-132
  • Tidskriftsartikel (refereegranskat)abstract
    • Leukotoxin is a well-known virulence factor of animal isolates of Fusobacterium necrophorum subspecies necrophorum, and is also expressed by animal isolates of subspecies funduliforme, whereas its presence in isolates from humans has not been fully established. In this study we found that the leukotoxin gene was present in all tested F. necrophorum isolates from humans. Three sequence variants were found, two of which have not been described previously. The sequence types correlated to source of infection. Further studies are needed to examine the role of the leukotoxin in human infections.
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47.
  •  
48.
  • Karlsson, Johan, et al. (författare)
  • National EQ-5D tariffs and quality-adjusted life-year estimation: comparison of UK, US and Danish utilities in south Swedish rheumatoid arthritis patients.
  • 2011
  • Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 70, s. 2163-2166
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To study how the choice of national EQ-5D tariff may affect utility and incremental quality-adjusted life-year (QALY) estimates. METHODS: South Swedish rheumatoid arthritis patients in an observational study, starting and continuing anti-tumour necrosis factor (TNF) monotherapy (n=54) or anti-TNF plus methotrexate (n=215) for 1 year during May 2002 to April 2009, were included. EQ-5D questionnaires were completed at baseline, 3, 6 and 12 months. Utilities and accumulated QALY were compared using the UK, US and Danish EQ-5D tariffs. Utilities for all 243 possible EQ-5D health states were also compared. RESULTS: US utilities were generally higher than UK, with Danish falling in between. A substantial 1-year mean utility improvement was seen in both study groups using all tariffs (UK 0.28 vs 0.29; US 0.18 vs 0.19; Danish 0.20 vs 0.22). Adjusting for baseline differences between groups, the incremental QALY gain of combined treatment was 0.09 using the UK tariff, while 0.06 according to both US and Danish tariffs. Inter-tariff disagreement in utility and accumulated QALY varied irregularly across the range of utilities. CONCLUSIONS: Applying different national EQ-5D tariffs to the same data may result in substantially different incremental QALY estimates, crucial knowledge when interpreting cost-utility analyses. Studies using different tariffs cannot be directly compared.
  •  
49.
  • Karlsson, JA, et al. (författare)
  • Treatment response to a second or third TNF-inhibitor in RA: results from the South Swedish Arthritis Treatment Group Register.
  • 2008
  • Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 47:4, s. 507-513
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives. To study treatment response rates of RA patients undergoing second- and third-line anti-TNF therapy and to identify baseline predictors of response to second-line treatment. Methods. RA patients monitored in a prospective, observational study, having switched anti-TNF therapy once (first-time switchers, n = 337) or twice (second-time switchers, n = 36)-i.e. following failures with one antibody- and one receptor-type agent-between March 1999 and December 2006, were studied. Treatment responses at 3 months were assessed by the ACR and European League Against Rheumatism (EULAR) response criteria. Predictive potentials for response to second-line treatment of demographics, baseline disease activity measures, disease and treatment characteristics were analysed using logistic regression. Results. ACR20 response was met by 51% of first-time and 35% of second-time switchers. Corresponding ACR50 rates were 27 and 18%; EULAR overall rates (EULAR good or moderate response) 71 and 58%; EULAR good rates 25 and 9% and 28-joint disease activity score (DAS28) remission rates 16 and 6%. Identified baseline predictors of response to second-line treatment were lower age and HAQ scores, elevated DAS28 values and having ceased the former anti-TNF treatment due to adverse events rather than inefficacy. No variable was predictive for all examined response criteria. Conclusions. Response rates of first-time anti-TNF switchers are somewhat below those of anti-TNF naïve RA patients, while the markedly inferior response rates of second-time switchers suggest other therapeutic options to be considered in this situation. Identified baseline predictors of response may be useful indicators to second-line anti-TNF therapy, but vary depending on the response criteria set studied.
  •  
50.
  • Kjaergaard, Benedict, et al. (författare)
  • A porcine model of massive, totally occlusive, pulmonary embolism
  • 2009
  • Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 124:2, s. 226-9
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: A reliable, animal model of massive, totally occlusive, pulmonary embolism (PE) is lacking. OBJECTIVES: To design an animal model of totally occlusive PE and to challenge the model by a plasminogen activator. METHODS: In eight anaesthetized pigs (approximately 90 kg) a massive preformed autologous thrombus was injected into the caval vein. One animal was autopsied to assess the extent of injected clot, whereas in the other animals extracorporeal life support (ECLS) was initiated and continued for three hours. These animals received 100 mg rt-PA. Blood gases, coagulation tests, creatine kinase (CK), lactate dehydrogenase (LDH), end-tidal CO2, systemic and pulmonary artery blood pressures and flow were registered. RESULTS: All animals went into circulatory arrest within 2 minutes after injection of the thrombus. In the animal where ECLS was not started, autopsy relieved a totally occlusive embolus of the pulmonary artery. The ECLS maintained a systemic blood flow of 6-8 L/min with adequate oxygenation and CO2-removal. However, lactate increased and base-excess became negative. Ddimer increased, fibrinogen decreased, and CK and LDH increased. All seven animals were weaned from ECLS. Despite the rt-PA treatment, the animals had at that time low end tidal CO2/PaCO2 ratio and increased mean pulmonary arterial pressure, suggesting a significant amount of embolic material remaining in the pulmonary artery. CONCLUSION: This model of massive, totally occlusive, pulmonary embolism mimics well fatal PE seen in the clinic, and has the potential for use in testing of new therapeutic interventions.
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