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Sökning: WFRF:(Malmqvist Ulf)

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  • Odeberg, J. M., et al. (författare)
  • UGT1A polymorphisms in a Swedish cohort and a human diversity panel, and the relation to bilirubin plasma levels in males and females
  • 2006
  • Ingår i: European Journal of Clinical Pharmacology. - : Springer. - 0031-6970 .- 1432-1041. ; 62:10, s. 829-837
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: The objective of this study was to investigate the prevalence of different polymorphisms and haplotypes associated with individual variations in pharmacokinetics and drug toxicity in the uridine-diphosphate glucuronosyl transferase (UGT) 1A gene in a Swedish cohort (248 healthy volunteers) and in 14 different ethnic groups. We also estimated UGT1A genotype-dependent glucuronidation efficiency using the endogenous substrate bilirubin as an indicator. Methods: Pyrosequencing-based genotyping assays were used to determine the different polymorphisms and haplotypes. Results: Haplotype analysis of the UGT1A1 (*1*28), UGT1A6 (*1*2), and UGT1A7(*1*2*3*4) allelic variants showed that three major haplotypes constituted 84% of the allelic variants in the cohort. We identified 15 haplotypes altogether from all groups, including previously undescribed haplotypes.Testing for the association of genotype and total bilirubin levels (nonfasting) in plasma disclosed that homozygous carriers of the TA allele, irrespective of haplotype combinations, had increased levels of bilirubin compared with noncarriers, but a gender-associated difference was observed. Conclusions: In a Swedish cohort, several genetic variants in the UGT1A gene are common, but prevalence in a population may differ because of ethnicity. A phenotype based on bilirubin levels has limitations in serving as an indicator of pharmacogenetic differences in glucuronidation due to the influence of gender. Because of possible substrate overlap regarding different UGT1A isoforms, determination of haplotypes of potential cis-acting polymorphisms in the UGT1A gene should be considered in pharmacogenetic association studies regarding drugs that undergo glucuronidation.
  • Ahlqvist, E., et al. (författare)
  • Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables
  • 2018
  • Ingår i: Lancet Diabetes & Endocrinology. - : Elsevier. - 2213-8587. ; 6:5, s. 361-369
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis. Methods We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA(1c), and homoeostatic model assessment 2 estimates of beta-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations. Findings We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes. Interpretation We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.
  • Arner, Anders, et al. (författare)
  • Calcium transients and the effect of a photolytically released calcium chelator during electrically induced contractions in rabbit rectococcygeus smooth muscle
  • 1998
  • Ingår i: Biophysical Journal. - : Cell Press. - 1542-0086 .- 0006-3495. ; 75:4, s. 1895-1903
  • Tidskriftsartikel (refereegranskat)abstract
    • Intracellular Ca2+ was determined with the fura-2 technique during electrically induced contractions in the rabbit rectococcygeus smooth muscle at 22 degreesC. The muscles were electrically activated to give short, reproducible contractions. Intracellular [Ca2+] increased during activation; the increase in [Ca2+] preceded force development by approximately 2 s. After cessation of stimulation Ca2+ fell, preceding the fall in force by approximately 4 s. The fluorescence properties of fura-2 were determined with time-resolved spectroscopy using synchrotron light at the MAX-storage ring, Lund, Sweden. The fluorescence decay of free fura-2 was best described by two exponential decays (time constants approximately 0.5 and 1.5 ns) at low Ca2+ (pCa 9). At high Ca2+ (pCa 4.5), fluorescence decay became slower and could be fitted by one exponential decay (1.9 ns). Time-resolved anisotropy of free fura-2 was characteristic of free rotational motion (correlation time 0.3 ns). Motion of fura-2 could be markedly inhibited by high concentrations of creatine kinase. Time-resolved spectroscopy measurements of muscle fibers loaded with fura-2 showed that the fluorescence lifetime of the probe was longer, suggesting an influence of the chemical environment. Anisotropy measurements revealed, however, that the probe was mobile in the cells. The Ca2+-dependence of contraction and relaxation was studied using a photolabile calcium chelator, diazo-2, which could be loaded into the muscle cells in a similar manner as fura-2. Photolysis of diazo-2 leads to an increase in its Ca2+-affinity and a fall in free Ca2+. When muscles that had been loaded with diazo-2 were illuminated with UV light flashes during the rising phase of contraction, the rate of contraction became slower, suggesting a close relation between intracellular Ca2+ and the cross-bridge interaction. In contrast, photolysis during relaxation did not influence the rate of force decay, suggesting that relaxation of these contractions is not determined by the rate of Ca2+ removal or due to an increased Ca2+ sensitivity, but instead is limited by other processes such as deactivation by dephosphorylation or detachment of tension-bearing cross-bridges, possibly regulated by thin filament systems.
  • Arner, Anders, et al. (författare)
  • Cross-bridge cycling in smooth muscle: a short review
  • 1998
  • Ingår i: Acta Physiologica Scandinavica. - : Wiley-Blackwell. - 0001-6772. ; 164:4, s. 363-372
  • Tidskriftsartikel (refereegranskat)abstract
    • This review is focused on the cross-bridge interaction of the organized contractile system of smooth muscle fibres. By using chemically skinned preparations the different enzymatic reactions of actin-myosin interaction have been associated with mechanical events. A rigor state has been identified in smooth muscle and the binding of ATP causes dissociation of rigor cross-bridges at rates slightly slower than those in skeletal muscle, but fast enough not to be rate-limiting for cross-bridge turn over in the muscle fibre. The release of inorganic phosphate (Pi) is associated with force generation, and this process is not rate-limiting for maximal shortening velocity (Vmax) in the fully activated muscle. The binding of ADP to myosin is strong in the smooth muscle contractile system, a property that might be associated with the generally slow cross-bridge turn over. Both force and Vmax are modulated by the extent of myosin light chain phosphorylation. Low levels of activation are considered to be associated with the recruitment of slowly cycling dephosphorylated cross-bridges which reduces shortening velocity. The attachment of these cross-bridge states in skinned smooth muscles can be regulated by cooperative mechanisms and thin filament associated systems. Smooth muscles exhibit a large diversity in their Vmax and the individual smooth muscle tissue can alter its Vmax under physiological conditions. The diversity and the long-term modulation of phenotype are associated with changes in myosin heavy and light chain isoform expression.
  • Bonnevier, Johan, et al. (författare)
  • Sustained norepinephrine contraction in the rat portal vein is lost when Ca(2+) is replaced with Sr(2+).
  • 2002
  • Ingår i: American Journal of Physiology: Cell Physiology. - : American Physiological Society. - 1522-1563 .- 0363-6143. ; 282:4, s. 845-852
  • Tidskriftsartikel (refereegranskat)abstract
    • Agonist-induced activation of smooth muscle involves a rise in intracellular Ca(2+) concentration and sensitization of myosin light chain phosphorylation to Ca(2+). Sr(2+) can enter through Ca(2+) channels, be sequestered and released from sarcoplasmic reticulum, and replace Ca(2+) in activation of myosin light chain phosphorylation. Sr(2+) cannot replace Ca(2+) in facilitation of agonist-activated Ca(2+)-dependent nonselective cation channels. It is not known whether Sr(2+) can replace Ca(2+) in small G protein-mediated sensitization of phosphorylation. To explore mechanisms involved in alpha-receptor-activated contractions in smooth muscle, effects of replacing Ca(2+) with Sr(2+) were examined in rat portal vein. Norepinephrine (NE) at
  • Hjortswang, Henrik, et al. (författare)
  • Contractile properties of ureters from rats with infravesical urinary outlet obstruction
  • 1998
  • Ingår i: Urological Research. - : Springer. - 0300-5623. ; 26:5, s. 337-342
  • Tidskriftsartikel (refereegranskat)abstract
    • Mechanical properties of ureters from rats with infravesical urinary outflow obstruction were studied in vitro. Urinary outflow obstruction was created by partial ligation of the urethra in female rats. After 10 days a marked hypertrophy of the urinary bladder and a dilatation of the ureters were observed. Proximal and distal segments of the ureters from these animals were isolated and mounted in a wire myograph for force registration. Comparisons were made with ureters from control rats. The ureters from the rats with urinary outflow obstruction exhibited a large increase in lumen diameter and an unchanged thickness of the muscle layer. These data suggest that the dilatation of the ureters is associated with growth of the smooth muscle in the wall. All ureter preparations were relaxed in normal physiological salt solution. When the extracellular K+ concentration was increased to 20 mM the dilated ureters became spontaneously active. At [K+] in the range 20-40 mM in the presence of noradrenaline (10(-5) M) all ureters exhibited high-frequency spontaneous contractions. The dilated ureters had a lower frequency of spontaneous contractions and a higher force. The results show a pronounced remodelling of the ureter wall following infravesical outlet obstruction. The structural changes were associated with alterations in the contraction pattern of the preparations, most probably reflecting changes in the excitation-contraction coupling of the growing cells.
  • Löfgren, Mia, et al. (författare)
  • Substrate and product dependence of force and shortening in fast and slow smooth muscle
  • 2001
  • Ingår i: Journal of General Physiology. - : Rockefeller Institute for Medical Research. - 0022-1295. ; 117:5, s. 407-418
  • Tidskriftsartikel (refereegranskat)abstract
    • To explore the molecular mechanisms responsible for the variation in smooth muscle contractile kinetics, the influence of MgATP, MgADP, and inorganic phosphate (P(i)) on force and shortening velocity in thiophosphorylated "fast" (taenia coli: maximal shortening velocity Vmax = 0.11 ML/s) and "slow" (aorta: Vmax = 0.015 ML/s) smooth muscle from the guinea pig were compared. P(i) inhibited active force with minor effects on the V(max). In the taenia coli, 20 mM P(i) inhibited force by 25%. In the aorta, the effect was markedly less (< 10%), suggesting differences between fast and slow smooth muscles in the binding of P(i) or in the relative population of P(i) binding states during cycling. Lowering of MgATP reduced force and V(max). The aorta was less sensitive to reduction in MgATP (Km for Vmax: 80 microM) than the taenia coli (Km for Vmax: 350 microM). Thus, velocity is controlled by steps preceding the ATP binding and cross-bridge dissociation, and a weaker binding of ATP is not responsible for the lower V(max) in the slow muscle. MgADP inhibited force and V(max). Saturating concentrations of ADP did not completely inhibit maximal shortening velocity. The effect of ADP on Vmax was observed at lower concentrations in the aorta compared with the taenia coli, suggesting that the ADP binding to phosphorylated and cycling cross-bridges is stronger in slow compared with fast smooth muscle.
  • Malmqvist, Ulf, et al. (författare)
  • Female pig urethral tone is dependent on Rho guanosine triphosphatases and Rho-associated kinase.
  • 2004
  • Ingår i: Journal of Urology. - : Lippincott Williams & Wilkins. - 1527-3792 .- 0022-5347. ; 171:5, s. 1955-1958
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Circular smooth muscle of the urethra generates spontaneous myogenic tone of relevance for the maintenance of continence. We tested if Rho guanosine triphosphatases (GTPases) and Rho-associated kinase (ROK) are involved in the generation of urethral tone. MATERIALS AND METHODS: Small circular strips of female pig urethra were dissected out and mounted for recording isometric force. The effect of pharmacological agents known to modulate the activity of Rho GTPases or ROK was examined. The intracellular calcium concentration was measured using fura-2. RESULTS: Urethral tone was abolished by removing extracellular calcium or by adding the calcium antagonist felodipine. The decrease in force was closely related to a decrease in intracellular calcium concentration, indicating that tone depends on membrane associated mechanisms. Toxin B, which inactivates Rho GTPases, and Y 27632, which inhibits ROK, completely abolished tone in the female pig urethra. The latter effect occurred without any change in the intracellular calcium concentration. CONCLUSIONS: The results suggests that urethral tone depends on activity in G-protein coupled pathways and inhibition of this activity is sufficient for urethral tone relaxation. Thus, to our knowledge a new pathway in the generation of urethral tone, which might be acted on by autonomic nerves during micturition, has been identified.
  • Malmqvist, Ulf, et al. (författare)
  • Kinetics of contraction in depolarized smooth muscle from guinea-pig taenia coli after photodestruction of nifedipine
  • 1999
  • Ingår i: Journal of Physiology. - : The Physiological Society. - 1469-7793. ; 519519 Pt 1:1, s. 213-221
  • Tidskriftsartikel (refereegranskat)abstract
    • 1. The time course and kinetics of force development following activation by opening of L-type Ca2+ channels was investigated using photodestruction of the Ca2+ channel blocker nifedipine in smooth muscle from the guinea-pig taenia coli. 2. In muscles activated using high K+ and Ca2+ and subsequently inhibited with nifedipine, photodestruction of the drug using a strong ultraviolet light flash initiated a rapid contraction. The force initiated by photodestruction of nifedipine reached near-maximal levels. This procedure eliminates diffusional delays and can thus be used to investigate the kinetics of depolarization-induced contractions. 3. The rate of force development of contractions initiated by photodestruction of nifedipine was slower than that observed in maximally thiophosphorylated skinned fibres. This suggests the rate of force development is limited by activation steps in the activation cascade prior to the force generation of the cross-bridge system. 4. The rate of force development and the plateau force were dependent on the extracellular [CaCl2] suggesting that the intracellular [Ca2+] determines the rate of phosphorylation and force development. The delay between illumination and increase in force was about 300 ms. The delay was similar at low and high extracellular [CaCl2] indicating that buffering by superficial sarcoplasmatic reticulum does not introduce a delay in force development following activation of Ca2+ channels in this muscle.
  • Malmqvist, Ulf, et al. (författare)
  • Regulation of force and shortening velocity by calcium and myosin phosphorylation in chemically skinned smooth muscle
  • 1996
  • Ingår i: Pflügers Archiv. - : Springer. - 0031-6768. ; 433:1-2, s. 42-48
  • Tidskriftsartikel (refereegranskat)abstract
    • The phosphatase inhibitor okadaic acid (OA) was used to study the relationship between [Ca2+], rates of phosphorylation/dephosphorylation and the mechanical properties of smooth muscle fibres. Force/velocity relationships were determined with the isotonic quick release technique in chemically skinned guinea-pig taenia coli muscles at 22 degrees C. In the maximally thiophosphorylated muscle neither OA (10 microM) nor Ca2+ (increase from pCa 9.0 to pCa 4.5) influenced the force-velocity relationship. When the degree of activation was altered by varying [Ca2+] in the presence of 0.5 microM calmodulin, both force and the maximal shortening velocity (Vmax) were altered. At pCa 5.75, at which force was about 35% of the maximal at pCa 4.5, Vmax was 55% of the maximal value. When OA was introduced into fibres at pCa 6.0, force was increased from less than 5% to 100% of the maximal force obtained in pCa 4.5. The relationship between the degree of myosin light chain phosphorylation and force was similar in the two types of activation; varied [OA] at constant [Ca2+] and at varied [Ca2+]. The relation between force and Vmax when the degree of activation was altered with OA was almost identical to that obtained with varied [Ca2+]. The results show that Ca2+ and OA do not influence force or Vmax in the maximally phosphorylated state and suggest that the level of myosin light chain phosphorylation is the major factor determining Vmax. The finding that the relationship between force and Vmax was similar when activation was altered with OA and Ca2+ suggests, however, that alterations in the absolute rates of phosphorylation and dephosphorylation at a constant phosphorylation level do not influence the mechanical properties of the skinned smooth muscle fibres.
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