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Sökning: WFRF:(Olsson Bengt) > (2000-2004)

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1.
  • Eriksson, Ulf G, et al. (författare)
  • Pharmacokinetics of melagatran and the effect on ex vivo coagulation time in orthopaedic surgery patients receiving subcutaneous melagatran and oral ximelagatran : a population model analysis
  • 2003
  • Ingår i: Clinical Pharmacokinetics. - 0312-5963 .- 1179-1926. ; 42:7, s. 687-701
  • Forskningsöversikt (refereegranskat)abstract
    • OBJECTIVE: Ximelagatran, an oral direct thrombin inhibitor, is rapidly bioconverted to melagatran, its active form. The objective of this population analysis was to characterise the pharmacokinetics of melagatran and its effect on activated partial thromboplastin time (APTT), an ex vivo measure of coagulation time, in orthopaedic surgery patients sequentially receiving subcutaneous melagatran and oral ximelagatran as prophylaxis for venous thromboembolism. To support the design of a pivotal dose-finding study, the impact of individualised dosage based on bodyweight and calculated creatinine clearance was examined. DESIGN AND METHODS: Pooled data obtained in three small dose-guiding studies were analysed. The patients received twice-daily administration, with either subcutaneous melagatran alone or a sequential regimen of subcutaneous melagatran followed by oral ximelagatran, for 8-11 days starting just before initiation of surgery. Nonlinear mixed-effects modelling was used to evaluate rich data of melagatran pharmacokinetics (3326 observations) and the pharmacodynamic effect on APTT (2319 observations) in samples from 216 patients collected in the three dose-guiding trials. The pharmacokinetic and pharmacodynamic models were validated using sparse data collected in a subgroup of 319 patients enrolled in the pivotal dose-finding trial. The impact of individualised dosage on pharmacokinetic and pharmacodynamic variability was evaluated by simulations of the pharmacokinetic-pharmacodynamic model. RESULTS: The pharmacokinetics of melagatran were well described by a one-compartment model with first-order absorption after both subcutaneous melagatran and oral ximelagatran. Melagatran clearance was correlated with renal function, assessed as calculated creatinine clearance. The median population clearance (creatinine clearance 70 mL/min) was 5.3 and 22.9 L/h for the subcutaneous and oral formulations, respectively. The bioavailability of melagatran after oral ximelagatran relative to subcutaneous melagatran was 23%. The volume of distribution was influenced by bodyweight. For a patient with a bodyweight of 75kg, the median population estimates were 15.5 and 159L for the subcutaneous and oral formulations, respectively. The relationship between APTT and melagatran plasma concentration was well described by a power function, with a steeper slope during and early after surgery but no influence by any covariates. Simulations demonstrated that individualised dosage based on creatinine clearance or bodyweight had no clinically relevant impact on the variability in melagatran pharmacokinetics or on the effect on APTT. CONCLUSIONS: The relatively low impact of individualised dosage on the pharmacokinetic and pharmacodynamic variability of melagatran supported the use of a fixed-dose regimen in the studied population of orthopaedic surgery patients, including those with mild to moderate renal impairment.
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2.
  • Littorin, Bengt, et al. (författare)
  • Family characteristics and life events before the onset of autoimmune type 1 diabetes in young adults : A nationwide study
  • 2001
  • Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 24:6, s. 1033-1037
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE - To elucidate whether family characteristics and stressful life events were associated with onset of autoimmune type 1 diabetes in young adults. RESEARCH DESIGN AND METHODS - This investigation was based on a nationwide study (Diabetes Incidence Study in Sweden) of newly diagnosed patients aged 15-34 years. Patients clinically classified as type 1 diabetic with antibodies to islet cells and/or to GAD65 were compared with age- and sex-matched control subjects via questionnaire. The questionnaire covered diabetes heredity, social environment, educational level, and life events experienced during the 12 months before diagnosis. RESULTS - The rate of response was 82% for the diabetic patients and 65% for the control subjects. Questionnaires from 349 diabetic patients and 979 control subjects were considered. Diabetes in relatives was more frequent in the patients (odds ratio [OR] 2.6) who were born in Sweden and whose mothers were of Swedish origin. No major stress factors were detected in the diabetic patients, however, in comparison with the control subjects, the diabetic patients had experienced fewer conflicts with their parents and had less often broken contacts with friends. CONCLUSIONS - Young adults with recent-onset type 1 diabetes were more exposed to heredity for diabetes, but no major prediabetic stress factors were detected. Our study does not directly support the concept that psychosocial stressful life events are involved in the development of autoimmune type 1 diabetes in young adults.
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3.
  • Olsson, Emma, 1974- (författare)
  • Many-body Problems in the Theory of Stellar Collapse and Neutron Stars
  • 2004
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • When modelling the collapse of massive stars leading to supernova explosions and the cooling of neutron stars, understanding the microphysical processes, such as the interaction of neutrinos within a dense medium are of vital importance. The interaction of neutrinos with nucleons (neutrons and protons) is altered by the presence of the medium, compared to the same process with free nucleons. Neutrino scattering and production processes may be characterized in terms of the excitations that are created or destroyed in the nuclear medium. One way to analyse the effects of the medium is by using Landau's theory of normal Fermi liquids. This theory gives simple relationships between physical quantities such as the spin susceptibility or the response to a weak interaction probe in terms of Landau parameters, that are measures of the interaction between quasiparticles. One problem when using Landau Fermi liquid theory for nucleon matter is that the interaction has a tensor component. The tensor interaction does not conserve the total spin and, as a consequence, there are generally contributions to long-wavelength response functions from states that have more than one quasiparticle-quasihole pair in the intermediate state. Such contributions cannot be calculated in terms of Landau parameters alone, since in the usual formulation of Landau theory, only singlepair excitations are considered. In this thesis three problems are addressed. First, we obtain bounds on the contributions from more than one quasiparticle-quasihole pair by using sum-rule arguments. Second, we derive expressions for static response functions allowing for the tensor components of the interaction. We analyse which the most important effects are on the static response of nucleon matter, and find that the major contributions comes from renormalization of coupling constants and transitions to states with more than one quasiparticle-quasihole pair. Third, we show how contributions to the dynamical response coming from states containing two quasiparticle-quasihole pairs may be evaluated in terms of Landau theory if one allows for the effect of collisions in the Landau kinetic equation. We consider the case of asymmetric nuclear matter, and our work goes beyond earlier works in that they contain the effects of collisions in addition to those of the mean field.
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5.
  • Törn, Carina, et al. (författare)
  • Combinations of beta cell specific autoantibodies at diagnosis of diabetes in young adults reflects different courses of beta cell damage
  • 2001
  • Ingår i: Autoimmunity. - 0891-6934. ; 33:2, s. 115-120
  • Tidskriftsartikel (refereegranskat)abstract
    • To explore the natural course of beta cell function in recent onset diabetes, a subgroup (n = 157) of all incident cases (n = 879) 15-34 years old. 1992-1993 in Sweden. and with positivity for at least one autoantibody of islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA) or tyrosine phosphatase antibodies (1A-2A) were followed prospectively thr the first four years with annual analysis of C-peptide. The aim was to relate the course of beta cell function, measured as C-peptide, in early diabetes with the presence of different islet autoantibodies at diagnosis. We found that patients positive for ICA alone (n = 11 ) had significantly higher C-peptide levels both at diagnosis and during the first three years compared with the other patients (n = 146; p = 0.022, p < 0.001, p = 0.004 and p = 0.0022). Patients positive for GADA alone or in combination with other antibodies (n = 125) had significantly lower C-peptide during the first three years after diagnosis compared with the other patients (n = 32. p < 0.001, p = 0.0011 and p = 0.0136). Patients with two or three autoantibodies had C-peptide levels similar to levels found in patients positive only for GADA. However. after four years, there were no significant differences between any of the groups of different autoantibody combinations. At diagnosis. 55% (86/157) of the patients had C-peptide: levels above the lower normal range of 0.25 nmol/l, but the frequency of patients with beta cell Function above this level decreased after two years to 41% (65/157; p = 0.035) and after four years to 22% (35/157; p = 0.0041).
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6.
  • Törn, Carina, et al. (författare)
  • Glutamic acid decarboxylase antibodies (GADA) is the most important factor for prediction of insulin therapy within 3 years in young adult diabetic patients not classified as Type 1 diabetes on clinical grounds
  • 2000
  • Ingår i: Diabetes/Metabolism Research and Reviews. - 1520-7552 .- 1520-7560. ; 16:6, s. 442-447
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Differentiation between Type 1 and Type 2 diabetes in adults is difficult at diagnosis. In this study we tested the hypothesis that autoantibodies at diagnosis are predictive for insulin treatment within 3 years in patients initially not classified as Type 1 diabetes. Methods In a nationwide population-based study, blood samples were obtained from 764 patients, all diagnosed with diabetes during a 2-year period. At diagnosis, 583 (76%) were classified as Type 1, 110 (14%) as Type 2 and 71 (9.3%) could not be classified. Results Among patients not classified as Type 1 diabetes, 52 (47%) of Type 2 and 42 (59%) of unclassified patients were positive for islet cell antibodies CICA), glutamic acid decarboxylase antibodies (GADA) or tyrosine phosphatase antibodies (IA-2A). These patients (n=94) had lower body mass index (BMI) (p<0.001) and lower C-peptide (p<0.001) compared to the autoantibody negative patients (n=87). Compared to clinically classified Type 1 diabetes patients positive for autoantibodies (n=477), they have higher BMI (p<0.001), higher C-peptide (p<0.001) and the same levels of ICA, GADA and IA-2A. After 3 years, 93% of autoantibody positive patients initially not classified as Type 1 were on insulin. When ICA, GADA, IA-2A, BMI and C-peptide were tested in a multiple logistic regression, only GADA was signiificant for insulin treatment within 3 years (OR = 18.8; 95% CI 1.8-191) in patients treated with diet or oral drugs at diagnosis. Conclusions A correct classification is difficult in adult diabetic patients. The presence of pancreatic autoantibodies, especially GADA, at diagnosis of diabetes are highly predictive for insulin therapy within 3 years from diagnosis.
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7.
  • Andersson, Agneta, et al. (författare)
  • Fatty acid profile of skeletal muscle phospholipids in trained and untrained young men
  • 2000
  • Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - 0193-1849 .- 1522-1555. ; 279:4, s. E744-E751
  • Tidskriftsartikel (refereegranskat)abstract
    • Endurance trained (n = 14) and untrained young men (n = 15) were compared regarding the fatty acid profile of the vastus lateralis muscle after 8 wk on diets with a similar fatty acid composition. The skeletal muscle phospholipids in the trained group contained lower proportions of palmitic acid (16:0) (-12.4%, P < 0.001) and di-homo-gamma-linolenic acid [20:3(n-6)] (-15.3%, P = 0.018), a lower n-6-to-n-3 ratio (-42.0%, P = 0.015), higher proportions of stearic acid (18:0) (+9.8%, P = 0.004) and sum of n-3 polyunsaturated fatty acids (+33.8%, P = 0.009), and a higher ratio between 20:4(n-6) to 20:3(n-6) (+18.4%, P = 0.006) compared with those in the untrained group. The group differences in 16:0, 20:3(n-6), 18:0/16:0, and 20:4(n-6)/20:3(n-6) were independent of fiber-type distribution. The trained group also showed a lower proportion of 16:0 (-7.9%, P < 0.001) in skeletal muscle triglycerides irrespective of fiber type. In conclusion, the fatty acid profile of the skeletal muscle differed between trained and untrained individuals, although the dietary fatty acid composition was similar. This difference was not explained by different fiber-type distribution alone but appears to be a direct consequence of changes in fatty acid metabolism due to the higher level of physical activity.
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8.
  • Ares, Mikko, et al. (författare)
  • Decreased inducibility of TNF expression in lipid-loaded macrophages.
  • 2002
  • Ingår i: BMC Immunology. - 1471-2172. ; 3:1, s. 13-13
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Inflammation and immune responses are considered to be very important in the pathogenesis of atherosclerosis. Lipid accumulation in macrophages of the arterial intima is a characteristic feature of atherosclerosis which can influence the inflammatory potential of macrophages. We studied the effects of lipid loading on the regulation of TNF expression in human monocyte-derived macrophages. RESULTS: In macrophages incubated with acetylated low density lipoprotein (ac-LDL) for 2 days, mRNA expression of TNF in cells stimulated with TNF decreased by 75%. In cell cultures stimulated over night with IL-1beta, lipid loading decreased secretion of TNF into culture medium by 48%. These results suggest that lipid accumulation in macrophages makes them less responsive to inflammatory stimuli. Decreased basal activity and inducibility of transcription factor AP-1 was observed in lipid-loaded cells, suggesting a mechanism for the suppression of cytokine expression. NF-kappaB binding activity and inducibility were only marginally affected by ac-LDL. LDL and ac-LDL did not activate PPARgamma. In contrast, oxidized LDL stimulated AP-1 and PPARgamma but inhibited NF-kappaB, indicating that the effects of lipid loading with ac-LDL were not due to oxidation of lipids. CONCLUSIONS: Accumulation of lipid, mainly cholesterol, results in down-regulation of TNF expression in macrophages. Since monocytes are known to be activated by cell adhesion, these results suggest that foam cells in atherosclerotic plaques may contribute less potently to an inflammatory reaction than newly arrived monocytes/macrophages.
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