| 1. |
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| 2. |
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| 3. |
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| 4. |
- Bentzen, B. H., et al.
(författare)
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Mechanisms of Action of the KCa2-Negative Modulator AP30663, a Novel Compound in Development for Treatment of Atrial Fibrillation in Man
- 2020
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Aims Small conductance Ca2+-activated K+ channels (SK channels, K(Ca)2) are a new target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of K(Ca)2 channels that is currently in clinical development for treatment of AF. The aim of this study is to present the electrophysiological profile and mechanism of action of AP30663 and its efficacy in prolonging atrial refractoriness in rodents, and by bioinformatic analysis investigate if genetic variants in KCNN2 or KCNN3 influence the expression level of these in human heart tissue. Methods and Results Whole-cell and inside-out patch-clamp recordings of heterologously expressed K(Ca)2 channels revealed that AP30663 inhibits K(Ca)2 channels with minor effects on other relevant cardiac ion channels. AP30663 modulates the K(Ca)2.3 channel by right-shifting the Ca2+-activation curve. In isolated guinea pig hearts AP30663 significantly prolonged the atrial effective refractory period (AERP) with minor effects on the QT-interval corrected for heart rate. Similarly, in anaesthetized rats 5 and 10 mg/kg of AP30663 changed the AERP to 130.7 +/- 5.4% and 189.9 +/- 18.6 of baseline values. The expression quantitative trait loci analyses revealed that the genome wide association studies for AF SNP rs13376333 in KCNN3 is associated with increased mRNA expression of KCNN3 in human atrial appendage tissue. Conclusions AP30663 is a novel negative allosteric modulator of K(Ca)2 channels that concentration-dependently prolonged rodent atrial refractoriness with minor effects on the QT-interval. Moreover, AF associated SNPs in KCNN3 influence KCNN3 mRNA expression in human atrial tissue. These properties support continued development of AP30663 for treatment of AF in man.
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| 5. |
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| 6. |
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| 7. |
- Holst, Anders G., et al.
(författare)
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Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial
- 2023
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Ingår i: Nature Medicine. - 1078-8956 .- 1546-170X.
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Tidskriftsartikel (refereegranskat)abstract
- Existing antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg−1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg−1 AP30663, 5 mg kg−1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg−1 and 5 mg kg−1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg−1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385 .
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| 8. |
- Menon, C., et al.
(författare)
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Defect density in non-selective and selective Si/SiGe structures
- 2002
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Ingår i: Journal of Crystal Growth. - 0022-0248 .- 1873-5002. ; 237, s. 259-263
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Tidskriftsartikel (refereegranskat)abstract
- The epitaxial quality of Si (non-selective or selective epitaxy)/SiGe (non-selective or selective epitaxy) structures applying Si2H2Cl2 or SiH4 as the Si source has been studied. High-resolution reciprocal lattice mapping and X-ray reflectivity measurements have been used to characterise the epitaxial quality and the interfacial defects, respectively. The surface morphology of the structures was studied by atomic force microscopy. It is shown that the generation of defects in non-selective SiGe layers is strongly dependent oil the thickness of the buffer layer. Moreover, the selective growth of a Si buffer layer requires a growth temperature above 770degreesC in order to obtain a smooth layer surface, which is beneficial for the succeeding growth of the SiGe layer. The surface can also be smoothed by an annealing treatment at 900degreesC for 40 s. This annealing step is crucial to remove the interfacial defects in the case of Si/SiGe structures grown with different Si sources.
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| 9. |
- Radamson, H. H., et al.
(författare)
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Growth of high frequency SiGe heterojunction bipolar transistors structures
- 2002
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Ingår i: Physica Scripta. - 0031-8949 .- 1402-4896. ; T101, s. 45-48
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Tidskriftsartikel (refereegranskat)abstract
- The growth of heterojuntion bipolar transistor structures using chemical vapor deposition has been investigated. Generation of defects in selectively or nonselectively grown collector layers using arsenic as the dopant has been studied. Minimizing the defect density in SiGe base layers by optimizing the growth rate has also been investigated in detail. High resolution reciprocal lattice mapping, atomic force microscopy and secondary ion mass spectrometry have been used as the main characterization tools.
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| 10. |
- Radamson, H. H., et al.
(författare)
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Observed critical thickness in selectively and non-selectively grown Si1-xGex layers on patterned substrates
- 2002
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Ingår i: Physica Scripta. - 0031-8949 .- 1402-4896. ; T101, s. 42-44
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Tidskriftsartikel (refereegranskat)abstract
- Relaxation of SiGe layers grown selectively or non-selectively on oxide-patterned substrates using reduced pressure chemical vapor deposition was investigated. The influences of the buffer layer, the polycrystalline layer on the oxide and the opening size on the critical thickness for relaxation of SiGe layers have been studied in detail. High resolution reciprocal lattice mapping, atomic force microscopy and Normanski optical microscope have been used as the main characterization tools.
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| 11. |
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| 12. |
- Bentzen, Andreas, et al.
(författare)
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Mechanisms of diffusion-enhanced thermal stability of Si/Si1-xGex/Si heterostructures grown by chemical vapor deposition
- 2004
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Ingår i: Journal of Crystal Growth. - : Elsevier BV. - 0022-0248 .- 1873-5002. ; 261:1, s. 22-29
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Tidskriftsartikel (refereegranskat)abstract
- The thermal stability of doped Si/Si0.8Ge0.2/Si (n-p-n or p-n-p) structures grown by reduced pressure chemical vapor deposition has been studied in correlation with the dopant in- and out-diffusion, using high-resolution X-ray reciprocal lattice mapping and secondary ion mass spectrometry as the main characterization tools. Initially, by doping the strained Si0.8Ge0.2 layer with reasonable amounts of boron, phosphorus, or arsenic, the thermal stability of the structures is shown to be dramatically increased compared to intrinsic layers. Secondly, the results show that when the dopants are present only in the Si buffer and cap layers, intrinsic Si spacer layers are required to obtain a significant enhancement in the thermal stability. These spacers reduce the interfacial dopant concentration and act as barriers for direct injection of precipitates into the SiGe layers. Finally, p-n-p and n-p-n structures were studied showing a very good thermal stability, due to enhanced out-diffusion of dopants from the SiGe layer upon in-diffusion from the adjacent layers. By employing i-Si spacers, the boron out-diffusion in a n-p-n structure was reduced, giving rise to a degradation of the thermal stability of this structure.
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| 13. |
- Diness, J. G., et al.
(författare)
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Inhibition of K(Ca)2 Channels Decreased the Risk of Ventricular Arrhythmia in the Guinea Pig Heart During Induced Hypokalemia
- 2020
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background Hypokalemia reduces the cardiac repolarization reserve. This prolongs the QT-interval and increases the risk of ventricular arrhythmia; a risk that is exacerbated by administration of classical class 3 anti-arrhythmic agents. Small conductance Ca2+-activated K+-channels (K(Ca)2) are a promising new atrial selective target for treatment of atrial fibrillation. Under physiological conditions K(Ca)2 plays a minor role in ventricular repolarization. However, this might change under hypokalemia because of concomitant increases in ventriculay -60r intracellur Ca2+. Purpose To study the effects of pharmacological K(Ca)2 channel inhibition by the compounds AP14145, ICA, or AP30663 under hypokalemic conditions as compared to dofetilide and hypokalemia alone time-matched controls (TMC). Methods The current at +10 mV was compared in HEK293 cells stably expressing K(Ca)2.3 perfused first with normo- and then hypokalemic solutions (4 mM K+ and 2.5 mM K+, respectively). Guinea pig hearts were isolated and perfused with normokalemic (4 mM K+) Krebs-Henseleit solution, followed by perfusion with drug or vehicle control. The perfusion was then changed to hypokalemic solution (2.5 mM K+) in presence of drug. 30 animals were randomly assigned to 5 groups: ICA, AP14145, AP30663, dofetilide, or TMC. QT-interval, the interval from the peak to the end of the T wave (Tp-Te), ventricular effective refractory period (VERP), arrhythmia score, and ventricular fibrillation (VF) incidence were recorded. Results Hypokalemia slightly increased K(Ca)2.3 current compared to normokalemia. Application of K(Ca)2 channel inhibitors and dofetilide prolonged the QT interval corrected for heart rate. Dofetilide, but none of the K(Ca)2 channel inhibitors increased Tp-Te during hypokalemia. During hypokalemia 4/6 hearts in the TMC group developed VF (two spontaneously, two by S1S2 stimulation) whereas 5/6 hearts developed VF in the dofetilide group (two spontaneously, three by S1S2 stimulation). In comparison, 0/6, 1/6, and 1/6 hearts developed VF when treated with the K(Ca)2 channel inhibitors AP30663, ICA, or AP14145, respectively. Conclusion Hypokalemia was associated with an increased incidence of VF, an effect that also seen in the presence of dofetilide. In comparison, the structurally and functionally different K(Ca)2 channel inhibitors, ICA, AP14145, and AP30663 protected the heart from hypokalemia induced VF. These results support that K(Ca)2 inhibition may be associated with a better safety and tolerability profile than dofetilide.
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| 14. |
- Diness, J. G., et al.
(författare)
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The KCa2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs
- 2020
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To describe the effects of the KCa2 channel inhibitor AP30663 in pigs regarding tolerability, cardiac electrophysiology, pharmacokinetics, atrial functional selectivity, effectiveness in cardioversion of tachy-pacing induced vernakalant-resistant atrial fibrillation (AF), and prevention of reinduction of AF. Methods and Results: Six healthy pigs with implanted pacemakers and equipped with a Holter monitor were used to compare the effects of increasing doses (0, 5, 10, 15, 20, and 25 mg/kg) of AP30663 on the right atrial effective refractory period (AERP) and on various ECG parameters, including the QT interval. Ten pigs with implanted neurostimulators were long-term atrially tachypaced (A-TP) until sustained vernakalant-resistant AF was present. 20 mg/kg AP30663 was tested to discover if it could successfully convert vernakalant-resistant AF to sinus rhythm (SR) and protect against reinduction of AF. Seven anesthetized pigs were used for pharmacokinetic experiments. Two pigs received an infusion of 20 mg/kg AP30663 over 60 min while five pigs received 5 mg/kg AP30663 over 30 min. Blood samples were collected before, during, and after infusion on AP30663. AP30663 was well-tolerated and prominently increased the AERP in pigs with little effect on ventricular repolarization. Furthermore, it converted A-TP induced AF that had become unresponsive to vernakalant, and it prevented reinduction of AF in pigs. Both a >30 ms increase of the AERP and conversion of AF occurred in different pigs at a free plasma concentration level of around 1.0–1.4 µM of AP30663, which was achieved at a dose level of 5 mg/kg. Conclusion: AP30663 has shown properties in animals that would be of clinical interest in man. © Copyright © 2020 Diness, Kirchhoff, Speerschneider, Abildgaard, Edvardsson, Sørensen, Grunnet and Bentzen.
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| 15. |
- Eskelund, Christian W., et al.
(författare)
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15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2) : prolonged remissions without survival plateau
- 2016
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 175:3, s. 410-418
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Tidskriftsartikel (refereegranskat)abstract
- In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 114years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 127 and 85years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.
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| 16. |
- Eskelund, Christian Winther, et al.
(författare)
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Detailed Long-Term Follow-Up of Patients Who Relapsed After the Nordic Mantle Cell Lymphoma Trials : MCL2 and MCL3
- 2021
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Ingår i: HemaSphere. - : Wolters Kluwer. - 2572-9241. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is an incurable disease with a highly variable clinical course. The prognosis after relapse is generally poor, and no standard of care exists. We investigated the postrelapse outcomes of 149 patients who were initially treated in the Nordic Lymphoma Group trials, MCL2 or MCL3, both representing intensive cytarabine-containing frontline regimens including autologous stem cell transplant. Patients with progression of disease before 24 months (POD24, n = 51, 34%) displayed a median overall survival of 6.6 months compared with 46 months for patients with later POD (n = 98, 66%; P < 0.001). MCL international prognostic index, cell proliferation marker, blastoid morphology, and TP53 mutations showed independent prognostic value irrespective of POD24, and in a combined, exploratory risk score, patients with 0, 1, 2-3, or 4-5 high-risk markers, respectively, displayed a 5-year overall survival of 62%, 39%, 31%, and 0%. By a comparison of median progression-free survival of the different salvage therapies in the relapse setting, bendamustine-rituximab was superior to all other combination chemotherapy regimens; however, it was also associated with longer responses to last line of therapy. Collectively, we confirm the prognostic impact of POD24 and highlight the relevance of other biomarkers, and we emphasize the importance of novel therapies for patients with high-risk features at first POD.
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| 17. |
- Gal, P., et al.
(författare)
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First Clinical Study with AP30663-a K(Ca)2 Channel Inhibitor in Development for Conversion of Atrial Fibrillation
- 2020
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Ingår i: Cts-Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 13:6, s. 1336-1344
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Tidskriftsartikel (refereegranskat)abstract
- Pharmacological cardioversion of atrial fibrillation (AF) is frequently inefficacious. AP30663, a small conductance Ca(2+)activated K+(K(Ca)2) channel blocker, prolonged the atrial effective refractory period in preclinical studies and subsequently converted AF into normal sinus rhythm. This first-in-human study evaluated the safety and tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) effects were explored. Forty-seven healthy male volunteers (23.7 +/- 3.0 years) received AP30663 intravenously in ascending doses. Due to infusion site reactions, changes to the formulation and administration were implemented in the latter 24 volunteers. Extractions from a 24-hour continuous electrocardiogram were used to evaluate the PD effect of AP30663. Data were analyzed with a repeated measure analysis of covariance, noncompartmental analysis, and concentration-effect analysis. In total, 33 of 34 adverse events considered related to AP30663 exposure were related to the infusion site, mild in severity, and temporary in nature, although full recovery took up to 110 days. After formulation and administration changes, the local infusion site reaction remained, but the median duration was shorter despite higher dose levels. AP30663 displayed a less than dose proportional increase in peak plasma concentration (C-max) and a terminal half-life of around 5 hours. In healthy volunteers, no effect of AP30663 was observed on electrocardiographic parameters, other than a concentration-dependent effect on the corrected QT Fridericia's formula interval (+18.8 +/- 4.3 ms for the highest dose level compared with time matched placebo). In conclusion, administration of AP30663, a novel K(Ca)2 channel inhibitor, was safe and well-tolerated systemically in humans, supporting further development in patients with AF undergoing cardioversion.
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| 18. |
- Geisler, Christian H., et al.
(författare)
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Nordic MCL2 trial update : six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC plus autologous stem-cell support: still very long survival but late relapses do occur
- 2012
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 158:3, s. 355-362
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Tidskriftsartikel (refereegranskat)abstract
- Mantle cell lymphoma (MCL) is a heterogenic non-Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early based on the median observation time of 4 years results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event-free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6.5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median event-free survival of 7.4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki-67-expression were the only independent prognostic factors. Subdivided by the MIPI-Biological Index (MIPI + Ki-67, MIPI-B), more than 70% of patients with low-intermediate MIPI-B were alive at 10 years, but only 23% of the patients with high MIPI-B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk-adapted treatment strategy for MCL.
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| 19. |
- Glimelius, Bengt, et al.
(författare)
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Adjuvant chemotherapy in colorectal cancer: a joint analysis of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group
- 2005
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Ingår i: Acta Oncol. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 44:8, s. 904-12
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Tidskriftsartikel (refereegranskat)abstract
- Due to uncertainties regarding clinically meaningful gains from adjuvant chemotherapy after colorectal cancer surgery, several Nordic Groups in the early 1990s initiated randomised trials to prove or reject such gains. This report gives the joint analyses after a minimum 5-year follow-up. Between October 1991 and December 1997, 2 224 patients under 76 years of age with colorectal cancer stages II and III were randomised to surgery alone (n = 1 121) or adjuvant chemotherapy (n = 1 103) which varied between trials (5FU/levamisole for 12 months, n = 444; 5FU/leucovorin for 4-5 months according to either a modified Mayo Clinic schedule (n = 262) or the Nordic schedule (n = 397). Some centres also randomised patients treated with 5FU/leucovorin to+/-levamisole). A total of 812 patients had colon cancer stage II, 708 colon cancer stage III, 323 rectal cancer stage II and 368 rectal cancer stage III. All analyses were according to intention-to-treat. No statistically significant difference in overall survival, stratified for country or region, could be found in any group of patients according to stage or site. In colon cancer stage III, an absolute difference of 7% (p = 0.15), favouring chemotherapy, was seen. The present analyses corroborate a small but clinically meaningful survival gain from adjuvant chemotherapy in colon cancer stage III, but not in the other presentations.
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| 20. |
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| 21. |
- Kolstad, Arne, et al.
(författare)
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Nordic MCL-3 study : 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma
- 2014
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 123:19, s. 2953-2959
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Tidskriftsartikel (refereegranskat)abstract
- The main objective of the MCL3 study was to improve outcome for patients not in CR before transplant by adding (90)Y-ibritumomab-tiuxetan (Zevalin) to the high-dose regimen. 160 consecutive, untreated stage II-IV MCL patients < 66 years received rituximab (R)- maxi-CHOP alternating with R-high-dose Ara-C (6 cycles total), followed by high-dose BEAM or BEAC and autologous stem cell transplantation 2005-2009. Zevalin (0.4 mCi/kg) was given to responders in only CRu/PR prior to high-dose therapy. The overall response rate (ORR) pre-transplant was 97%. After a median follow-up of 4.4 years the outcome did not differ from that of the historic control, the MCL2 trial with the same treatment except for Zevalin. Overall (OS), event free (EFS), and progression-free survival (PFS) at 4 years were 78, 62 and 71%, respectively. For patients in CRu/PR before transplant who received Zevalin duration of response was shorter than in the CR group. Inferior PFS, EFS- and OS were predicted by PET-positivity pre-transplant and detectable minimal residual disease (MRD) before and after transplant. In conclusion, a positive PET prior to transplant and MRD are strong predictors of outcome. Late intensification with Zevalin may be too late to improve the outcome of patients not in CR before transplant.
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| 22. |
- Liin, Sara, et al.
(författare)
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Fatty acid analogue N-arachidonoyl taurine restores function of I-Ks channels with diverse long QT mutations
- 2016
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Ingår i: eLIFE. - : ELIFE SCIENCES PUBLICATIONS LTD. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- About 300 loss-of-function mutations in the I-Ks channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved I-Ks channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.
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| 23. |
- Liin, Sara, et al.
(författare)
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Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac I-Ks channel
- 2015
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:18, s. 5714-5719
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Tidskriftsartikel (refereegranskat)abstract
- Polyunsaturated fatty acids (PUFAs) affect cardiac excitability. Kv7.1 and the beta-subunit KCNE1 form the cardiac I-Ks channel that is central for cardiac repolarization. In this study, we explore the prospects of PUFAs as I-Ks channel modulators. We report that PUFAs open Kv7.1 via an electrostatic mechanism. Both the polyunsaturated acyl tail and the negatively charged carboxyl head group are required for PUFAs to open Kv7.1. We further show that KCNE1 coexpression abolishes the PUFA effect on Kv7.1 by promoting PUFA protonation. PUFA analogs with a decreased pK(a) value, to preserve their negative charge at neutral pH, restore the sensitivity to open I-Ks channels. PUFA analogs with a positively charged head group inhibit I-Ks channels. These different PUFA analogs could be developed into drugs to treat cardiac arrhythmias. In support of this possibility, we show that PUFA analogs act antiarrhythmically in embryonic rat cardiomyocytes and in isolated perfused hearts from guinea pig.
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| 24. |
- Liin, Sara, et al.
(författare)
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Polyunsaturated fatty acids are potent openers of human M-channels expressed in Xenopus laevis oocytes
- 2016
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Ingår i: Acta Physiologica. - : WILEY-BLACKWELL. - 1748-1708 .- 1748-1716. ; 218:1, s. 28-37
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Polyunsaturated fatty acids have been reported to reduce neuronal excitability, in part by promoting inactivation of voltage-gated sodium and calcium channels. Effects on neuronal potassium channels are less explored and experimental data ambiguous. The aim of this study was to investigate anti-excitable effects of polyunsaturated fatty acids on the neuronal M-channel, important for setting the resting membrane potential in hippocampal and dorsal root ganglion neurones. Methods: Effects of fatty acids and fatty acid analogues on mouse dorsal root ganglion neurones and on the human KV7.2/3 channel expressed in Xenopus laevis oocytes were studied using electrophysiology. Results: Extracellular application of physiologically relevant concentrations of the polyunsaturated fatty acid docosahexaenoic acid hyperpolarized the resting membrane potential (-2.4 mV by 30 mu M) and increased the threshold current to evoke action potentials in dorsal root ganglion neurones. The polyunsaturated fatty acids docosahexaenoic acid, alpha-linolenic acid and eicosapentaenoic acid facilitated opening of the human M-channel, comprised of the heteromeric human KV7.2/3 channel expressed in Xenopus oocytes, by shifting the conductance-vs.-voltage curve towards more negative voltages (by -7.4 to -11.3 mV by 70 mu M). Uncharged docosahexaenoic acid methyl ester and monounsaturated oleic acid did not facilitate opening of the human KV7.2/3 channel. Conclusions: These findings suggest that circulating polyunsaturated fatty acids, with a minimum requirement of multiple double bonds and a charged carboxyl group, dampen excitability by opening neuronal M-channels. Collectively, our data bring light to the molecular targets of polyunsaturated fatty acids and thus a possible mechanism by which polyunsaturated fatty acids reduce neuronal excitability.
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| 25. |
- Menon, C, et al.
(författare)
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Loading effect in SiGe layers grown by dichlorosilane- and silane-based epitaxy
- 2001
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Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 90:9, s. 4805-4809
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of the loading effect in Si1-xGex layers (0 less than or equal tox less than or equal to 20%) versus growth parameters has been investigated for selective and nonselective growth using silane- and dichlorosilane-based epitaxy. Various methods have been examined in order to reduce the loading effect, and their influence on the defect density will be further discussed. High-resolution x-ray diffraction and atomic force microscopy were applied as the main tools in these investigations. It is shown that SiGe epitaxy is strongly sensitive to the opening size on the patterned substrates. This dependence is affected by the chemistry of the deposition. This effect can be decreased by adding HCl to the gas mixture or decreasing the growth rate. Meanwhile, adding HCl during the growth of SiGe layers or using a low growth rate decreases the epitaxial quality of the layers. Depositing a Si seed layer prior to the growth of the SiGe layer reduces the loading effect without degrading the epitaxial quality of the layer.
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| 26. |
- Olafsen, Anja H., et al.
(författare)
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Muligheter og utfordringer ved fjernarbeid og hybride arbeidsordninger post‑pandemi
- 2023
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Ingår i: Magma - Tidsskrift for økonomi og ledelse. - : Cappelen Damm Akademisk. - 1500-0788 .- 1500-6069. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Med oppblomstringen av fjernarbeid og hybride arbeidsordninger for store deler av den norske arbeidsstyrken er det viktig med kunnskap om hvordan dette nye arbeidslivet ser ut og oppleves. Basert på et landsrepresentativt utvalg av 3 633 norske arbeidstakere med mulighet for fjernarbeid har vi undersøkt omfanget av fjernarbeid og forskjeller i ansattes opplevelse av jobbdesign, ledelse, jobbatferd samt arbeidsrelatert og generell helse basert på arbeidssted. Resultatene viser at det fortsatt er utstrakt bruk av fjernarbeid også i tiden etter pandemien. Mange benytter seg av hybride arbeidsordninger hvor noen dager tilbringes på kontoret og noen dager tilbringes hjemme, og den nye normalen ser ut til å være 1–2 dager fjernarbeid per uke. Videre er det en tendens til at fjernarbeidere har en noe mer positiv opplevelse av jobbdesign og ledelse, men dette gjelder i hovedsak for ansatte som bruker hybride arbeidsordninger, da fulltids fjernarbeid også synes å ha noen negative aspekter. Effektstørrelsene for forskjellene som er identifisert er imidlertid generelt små, og resultatene varierer en del ved sammenligning av omfang av fjernarbeid. En tydeligere tendens er at ansatte som benytter fjernarbeid skårer lavere på arbeidsrelatert og generell helse. Spesielt utfordrende er balansen mellom arbeid og privatliv. Basert på resultatene diskuterer vi muligheter og utfordringer ved fjernarbeid og hybride arbeidsordninger for å sikre ansattes jobbatferd og arbeidsrelaterte og generelle helse.
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| 27. |
- Olafsen, Anja H., et al.
(författare)
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The paradox of remote work : when employee wishes and wellbeing collide
- 2024
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Ingår i: Human Resource Development International. - : Routledge. - 1367-8868 .- 1469-8374.
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Tidskriftsartikel (refereegranskat)abstract
- The aftermath of the COVID-19 pandemic has witnessed a surge in remote work, ushering in a ‘new normal’ whose nuances and ramifications are yet to be fully understood. In a recent study, leveraging data from a large representative panel study of Norwegian workers, we explored the prevalence of remote work, identified the demographic profiles of remote workers, and investigated their work experiences. This exploration extends to contrasting the experiences of those in home offices with their non-remote counterparts, focusing on work-related health and performance outcomes. The findings reveal a paradox where remote work, despite its perceived benefits, holds potential downsides, particularly in terms of work-life conflict and occupational health. This article aims to shed light on these less-discussed adverse effects, challenging the predominantly positive narrative surrounding remote work. We contend that there is a perceptual bias amongst employees who may overemphasise the positives of remote work, while our data indicate that its implications are not uniformly beneficial. Incorporating insights from related literature, we discuss these findings in the broader context of remote work’s impact on wellbeing and organisational dynamics, contributing a balanced perspective to the ongoing discourse on post-pandemic work arrangements.
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| 28. |
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| 29. |
- Shah, N., et al.
(författare)
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Governing health data across changing contexts : A focus group study of citizen’s views in England, Iceland, and Sweden
- 2021
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Ingår i: International Journal of Medical Informatics. - : Elsevier. - 1386-5056 .- 1872-8243. ; 156
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe governance structures associated with health data are evolving in response to advances in digital technologies that enable new ways of capturing, using, and sharing different types of data. Increasingly, health data moves between different contexts such as from healthcare to research, or to commerce and marketing. Crossing these contextual boundaries has the potential to violate societal expectations about the appropriate use of health data and diminish public trust. Understanding citizens’ views on the acceptability of and preferences for data use in different contexts is essential for developing information governance policies in these new contexts.MethodsFocus group design presenting data sharing scenarios in England, Iceland, and Sweden.ResultsSeventy-one participants were recruited. Participants supported the need for data to help understand the observable world, improve medical research, the quality of public services, and to benefit society. However, participants consistently identified the lack of information, transparency and control as barriers to trusting organisations to use data in a way that they considered appropriate. There was considerable support for fair and transparent data sharing practices where all parties benefitted.ConclusionData governance policy should involve all stakeholders’ perspectives on an ongoing basis, to inform and implement changes to health data sharing practices that accord with stakeholder views. The Findings showed that (1) data should be used for ethical purposes even when there was commercial interest; (2) data subjects and/or public institutions that provide and share data should also receive benefits from the sharing of data; (3) third parties use of data requires greater transparency and accountability than currently exists, (4) there should be greater information provided to empower data subjects.
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| 30. |
- Skarsfeldt, Mark, et al.
(författare)
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Polyunsaturated fatty acid-derivedI(Ks)channel activators shorten the QT interval ex-vivo and in-vivo
- 2020
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Ingår i: Acta Physiologica. - : WILEY. - 1748-1708 .- 1748-1716. ; 229:4
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Tidskriftsartikel (refereegranskat)abstract
- Aim We aimed to assess the ability of natural and modified polyunsaturated fatty acids (PUFAs) to shorten QT interval in ex-vivo and in-vivo guinea pig hearts. Methods The effect of one natural (docosahexaenoic acid [DHA]) and three modified (linoleoyl glycine [Lin-GLY], docosahexaenoyl glycine [DHA-GLY], N-arachidonoyl taurine [N-AT]) PUFAs on ventricular action potential duration (APD) and QT interval was studied in a E4031 drug-induced long QT2 model of ex-vivo guinea pig hearts. The effect of DHA-GLY on QT interval was also studied in in-vivo guinea pig hearts upon intravenous administration. The effect of modified PUFAs onI(Ks)was studied usingXenopus laevisoocytes expressing human KCNQ1 and KCNE1. Results All tested PUFAs shortened ADP and QT interval in ex-vivo guinea pig hearts, however, with different ability in restoring baseline APD/QT interval with specific modified PUFAs being most efficacious. Despite comparable ability in activating the human KCNQ1/KCNE1 channel, Lin-GLY was not as effective in shortening APD/QT interval as DHA-GLY in ex-vivo hearts. By constructing a guinea pig-like KCNE1, we found Lin-GLY to induce less activating effect compared with DHA-GLY on human KCNQ1 co-expressed with guinea pig-like KCNE1. Docosahexaenoyl glycine was studied in more detail and was found to shorten QT interval in in-vivo guinea pig hearts. Conclusion Our results show that specific PUFAs shorten QT interval in guinea pig hearts. The tendency of modified PUFAs with pronouncedI(Ks)channel activating effect to better restore QT interval suggests that modifying PUFAs to target theI(Ks)channel is a means to improve the QT-shortening effect.
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| 31. |
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