| 1. |
- Lukasik, J., et al.
(författare)
-
Discriminant analysis and secondary-beam charge recognition
- 2008
-
Ingår i: Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. - : Elsevier BV. - 0168-9002. ; 587:2-3, s. 413-419
-
Tidskriftsartikel (refereegranskat)abstract
- The discriminant-analysis method has been applied to optimize the exotic-beam charge recognition in a projectile fragmentation experiment. The experiment was carried out at the GSI using the fragment separator (FRS) to produce and select the relativistic secondary beams, and the ALADIN setup to measure their fragmentation products following collisions with Sn target nuclei. The beams of neutron poor isotopes around La-124 and Sn-107 were selected to study the isospin dependence of the limiting temperature of heavy nuclei by comparing with results for stable Sn-124 projectiles. A dedicated detector to measure the projectile charge upstream of the reaction target was not used, and alternative methods had to be developed. The presented method, based on the multivariate discriminant analysis, allowed to increase the efficacy of charge recognition up to about 90%, which was about 20% more than achieved with the simple scalar methods.
|
|
| 2. |
|
|
| 3. |
- Trautmann, W., et al.
(författare)
-
Isotopic dependence of the caloric curve
- 2009
-
Ingår i: Progress in Particle and Nuclear Physics. - : Elsevier BV. - 0146-6410. ; 62:2, s. 407-412
-
Tidskriftsartikel (refereegranskat)abstract
- Isotopic effects in projectile fragmentation at relativistic energies have been studied with the ALADIN forward spectrometer at SIS. Stable and radioactive Sn and La beams with an incident energy of 600 MeV per nucleon have been used in order to explore a wide range of isotopic compositions. Chemical freeze-out temperatures are found to be nearly invariant with respect to the A/Z ratio of the produced spectator sources, consistent with predictions for expanded systems. Consequences for the proposed interpretation of chemical breakup temperatures as representing the limiting temperatures predicted by microscopic models are discussed. (C) 2009 Elsevier B.V. All rights reserved.
|
|
| 4. |
- Pawlowski, P., et al.
(författare)
-
Neutron recognition in the LAND detector for large neutron multiplicity
- 2012
-
Ingår i: Nuclear Instruments and Methods in Physics Research, Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. - : Elsevier BV. - 0168-9002. ; 694, s. 47-54
-
Tidskriftsartikel (refereegranskat)abstract
- The performance of the LAND neutron detector is studied. Using an event-mixing technique based on one-neutron data obtained in the S107 experiment at the GSI laboratory, we test the efficiency of various analytic tools used to determine the multiplicity and kinematic properties of detected neutrons. A new algorithm developed recently for recognizing neutron showers from spectator decays in the ALADIN experiment S254 is described in detail. Its performance is assessed in comparison with other methods. The properties of the observed neutron events are used to estimate the detection efficiency of LAND in this experiment. (C) 2012 Elsevier B.V. All rights reserved.
|
|
| 5. |
- Pawłowski, P., et al.
(författare)
-
Neutrons from projectile fragmentation at 600 MeV/nucleon
- 2023
-
Ingår i: Physical Review C. - 2469-9993 .- 2469-9985. ; 108:4
-
Tidskriftsartikel (refereegranskat)abstract
- The neutron emission in projectile fragmentation at relativistic energies was studied with the Large-Area-Neutron-Detector LAND coupled to the ALADIN forward spectrometer at the GSI Schwerionen-Synchrotron (SIS). Stable Sn124 and radioactive Sn107 and La124 beams with an incident energy of 600 MeV/nucleon were used to explore the N/Z dependence of the identified neutron source. A cluster-recognition algorithm is applied for identifying individual particles within the hit distributions registered with LAND. The obtained momentum distributions are extrapolated over the full phase space occupied by the neutrons from the projectile-spectator source. The mean multiplicities of spectator neutrons reach values of up to about 11 and depend strongly on the isotopic composition of the projectile. An effective source temperature of T≈2-5 MeV, monotonically increasing with decreasing impact parameter, is deduced from the transverse momentum distributions. For the interpretation of the data, calculations with the statistical multifragmentation model were performed. The variety of excited projectile spectators assumed to decay statistically is represented by an ensemble of excited sources with parameters determined previously from the fragment production observed in the same experiments. The obtained agreement is very satisfactory for more peripheral collisions where, according to the model, neutrons are mainly emitted during the secondary decays of excited fragments. The neutron multiplicity in more central collisions is underestimated, indicating that other sources besides the modeled statistical breakup contribute to the observed neutron yield. The choice made for the symmetry-term coefficient of the liquid-drop description of produced fragments has a weak effect on the predicted neutron multiplicities.
|
|
| 6. |
|
|
| 7. |
- Vaduganathan, Muthiah, et al.
(författare)
-
Dronedarone for the treatment of atrial fibrillation with concomitant heart failure with preserved and mildly reduced ejection fraction : a post-hoc analysis of the ATHENA trial
- 2022
-
Ingår i: European Journal of Heart Failure. - : Wiley. - 1388-9842 .- 1879-0844. ; 24:6, s. 1094-1101
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: Limited therapeutic options are available for the management of atrial fibrillation/flutter (AF/AFL) with concomitant heart failure (HF) with preserved (HFpEF) and mildly reduced ejection fraction (HFmrEF). Dronedarone reduces the risk of cardiovascular events in patients with AF, but sparse data are available examining its role in patients with AF complicated by HFpEF and HFmrEF. Methods and results: ATHENA was an international, multicentre trial that randomized 4628 patients with paroxysmal or persistent AF/AFL and cardiovascular risk factors to dronedarone 400 mg twice daily versus placebo. We evaluated patients with (i) symptomatic HFpEF and HFmrEF (defined as left ventricular ejection fraction [LVEF] >40%, evidence of structural heart disease, and New York Heart Association class II/III or diuretic use), (ii) HF with reduced ejection fraction (HFrEF) or left ventricular dysfunction (LVEF ≤40%), and (iii) those without HF. We assessed effects of dronedarone versus placebo on death or cardiovascular hospitalization (primary endpoint), other key efficacy endpoints, and safety. Overall, 534 (12%) had HFpEF or HFmrEF, 422 (9%) had HFrEF or left ventricular dysfunction, and 3672 (79%) did not have HF. Patients with HFpEF and HFmrEF had a mean age of 73 ± 9 years, 37% were women, and had a mean LVEF of 57 ± 9%. Over a mean follow-up of 21 ± 5 months, dronedarone consistently reduced risk of death or cardiovascular hospitalization (hazard ratio 0.76; 95% confidence interval 0.69–0.84) without heterogeneity based on HF status (pinteraction >0.10). This risk reduction in the primary endpoint was consistent across the range of LVEF (as a continuous function) in HF without heterogeneity (pinteraction = 0.71). Rates of death, cardiovascular hospitalization, and HF hospitalization each directionally favoured dronedarone versus placebo in HFpEF and HFmrEF, but these treatment effects were not statistically significant in this subgroup. Conclusions: Dronedarone is associated with reduced cardiovascular events in patients with paroxysmal or persistent AF/AFL and HF across the spectrum of LVEF, including among those with HFpEF and HFmrEF. These data support a rationale for a future dedicated and powered clinical trial to affirm the net clinical benefit of dronedarone in this population.
|
|
| 8. |
- Beekman, Jan, et al.
(författare)
-
Long-term population trends and shifts in distribution of Bewick's swans cygnus columbianus bewickii wintering in northwest Europe
- 2020
-
Ingår i: Wildfowl. - 0954-6324. ; :69, s. 73-102
-
Tidskriftsartikel (refereegranskat)abstract
- Coordinated international censuses of the Northwest European Bewick's Swan Cygnus columbianus bewickii population have been undertaken across the swans' wintering range at c. 5-year intervals since 1984. During the early years of the study, numbers increased steadily to a peak of 29,780 individuals in January 1995, but then declined by 39.4% to 18,057 swans counted in January 2010 before showing a partial recovery to 20,149 recorded in January 2015. Changes in distribution across the wintering range were also recorded; a higher proportion of the population now remains in more easterly countries (notably Germany) in mid-winter, whilst only a handful of birds migrated to Ireland (at the western edge of the range) during the 2000s compared to >1,000 wintering there at the start of the study. Variation between censuses in the proportion of swans recorded in different parts of the range were attributable to weather conditions, with more swans wintering further north in warmer years. The overall percentage of cygnets recorded in each of the census years ranged from 9.6% in 2010 to 13.2% in 2005, with no obvious consistency over time in the distribution of cygnets across the wintering range. There were however changes between 1990 and 2015 in the swans' use of feeding habitats, with a decline in the proportion of birds on pasture and a corresponding increase in those on arable land. Decreases in the total population size and changes in distribution in the 21st century have implications for the designation and resultant protection of sites of international importance for the species.
|
|
| 9. |
- Cardell, M., et al.
(författare)
-
High resolution immunogold analysis reveals distinct subcellular compartmentation of protein kinase Cγ and δ in rat Purkinje cells
- 1997
-
Ingår i: Neuroscience. - 0306-4522. ; 82:3, s. 709-725
-
Tidskriftsartikel (refereegranskat)abstract
- High resolution immunogold cytochemistry was used to investigate the subcellular distribution of protein kinase Cγ and δ in Purkinje cells of the rat cerebellum. Postembedding incubation with an antibody raised to a peptide sequence near the C-terminus of protein kinase Cγ resulted in strong labelling along the dendrosomatic plasma membrane. A quantitative analysis indicated that this labelling reflected the existence of two pools of protein kinase Cγ; one membrane associated pool and one cytoplasmic pool located within 50 nm of the plasma membrane. The labelling along the plasma membrane showed a pronounced and abrupt increase when moving from the cell body into the axon initial segment. Gold particles signalling protein kinase Cγ were also enriched in putative Purkinje axon terminals in the dentate nucleus. The only organelle showing a consistent immunolabelling for protein kinase Cγ was the Golgi apparatus where the gold particles were restricted to the trans face. Protein kinase Cγ immunoreactivity also occurred in the Purkinje cell spines, with an enrichment in or near the postsynaptic density. Antibodies to protein kinase Cδ produced a very different labelling pattern in the Purkinje cells. Most of the gold particles were associated with rough endoplasmic reticulum, particularly with those cisternae that were located close to the nucleus or in the nuclear indentations. No significant protein kinase C5 immunolabelling was detected at the plasma membrane or in Purkinje cell spines. The present data point to a highly specific compartmentation of the two major protein kinase C isozyme in Purkinje cells and suggest that these isozymes act on different substrates and hence have different regulatory functions within these neurons.
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
- Cormier, Marc-André, et al.
(författare)
-
2H-fractionations during the biosynthesis of carbohydrates and lipids imprint a metabolic signal on the δ2H values of plant organic compounds
- 2018
-
Ingår i: New Phytologist. - : Wiley-Blackwell. - 0028-646X .- 1469-8137. ; 218:2, s. 479-491
-
Tidskriftsartikel (refereegranskat)abstract
- Hydrogen (H) isotope ratio (δ2H) analyses of plant organic compounds have been applied to assess ecohydrological processes in the environment despite a large part of the δ2H variability observed in plant compounds not being fully elucidated.We present a conceptual biochemical model based on empirical H isotope data that we generated in two complementary experiments that clarifies a large part of the unexplained variability in the δ2H values of plant organic compounds.The experiments demonstrate that information recorded in the δ2H values of plant organic compounds goes beyond hydrological signals and can also contain important information on the carbon and energy metabolism of plants. Our model explains where 2H‐fractionations occur in the biosynthesis of plant organic compounds and how these 2H‐fractionations are tightly coupled to a plant's carbon and energy metabolism. Our model also provides a mechanistic basis to introduce H isotopes in plant organic compounds as a new metabolic proxy for the carbon and energy metabolism of plants and ecosystems.Such a new metabolic proxy has the potential to be applied in a broad range of disciplines, including plant and ecosystem physiology, biogeochemistry and palaeoecology.
|
|
| 13. |
|
|
| 14. |
- Ehlers, Ina, 1984-, et al.
(författare)
-
Limited suppression of photorespiration by 20th century atmospheric CO2 increase in trees worldwide
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Forests are a key component of the global carbon and hydrological cycle and forest responses to environmental drivers create important feedbacks to these cycles. Photosynthetic efficiency of most forest tree species is strongly limited by photorespiration, a side reaction using O2 instead of CO2 as substrate, leading to a carbon loss for the plant. Photorespiration occurs in all trees and is reduced under elevated CO2 concentrations and increased under elevated temperature. Because the CO2 concentration of the atmosphere has increased in past decades, long-lived trees may have benefited from reduced photorespiration, but the temperature increase would have been a compensating detriment; but direct quantification of long-term changes in metabolic fluxes is lacking. Realistic forecasting of responses of trees and forests to future CO2 and temperature demands quantifying the reduction of photorespiration. In twelve tree species from five continents, we observe that photorespiration has been reduced by the CO2 increase during the past century, but for most the reduction is smaller than predicted from plant responses in CO2 alone. Comparison with data from a combined CO2 and temperature manipulation experiment shows that the reduced response can be explained by increases in leaf temperatures, which might result directly from increased air temperatures or indirectly from reduced transpirative cooling. These data suggest that global warming has already inhibited plant fertilization by increasing CO2, and that biomass increases may have been smaller than deduced from measurements of the heavy carbon isotope 13C. Observation of this centennial metabolic shift in tree physiology worldwide provides new insights into forest-climate feedbacks and can be used to improve coupled climate-vegetation models.
|
|
| 15. |
- Fabritz, Larissa, et al.
(författare)
-
Dynamic risk assessment to improve quality of care in patients with atrial fibrillation : the 7th AFNET/EHRA Consensus Conference
- 2021
-
Ingår i: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 23:3, s. 329-344
-
Tidskriftsartikel (refereegranskat)abstract
- AimsThe risk of developing atrial fibrillation (AF) and its complications continues to increase, despite good progress in preventing AF-related strokes.Methods and resultsThis article summarizes the outcomes of the 7th Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA) held in Lisbon in March 2019. Sixty-five international AF specialists met to present new data and find consensus on pressing issues in AF prevention, management and future research to improve care for patients with AF and prevent AF-related complications. This article is the main outcome of an interactive, iterative discussion between breakout specialist groups and the meeting plenary. AF patients have dynamic risk profiles requiring repeated assessment and risk-based therapy stratification to optimize quality of care. Interrogation of deeply phenotyped datasets with outcomes will lead to a better understanding of the cardiac and systemic effects of AF, interacting with comorbidities and predisposing factors, enabling stratified therapy. New proposals include an algorithm for the acute management of patients with AF and heart failure, a call for a refined, data-driven assessment of stroke risk, suggestions for anticoagulation use in special populations, and a call for rhythm control therapy selection based on risk of AF recurrence.ConclusionThe remaining morbidity and mortality in patients with AF needs better characterization. Likely drivers of the remaining AF-related problems are AF burden, potentially treatable by rhythm control therapy, and concomitant conditions, potentially treatable by treating these conditions. Identifying the drivers of AF-related complications holds promise for stratified therapy.
|
|
| 16. |
|
|
| 17. |
- Francardo, Veronica, et al.
(författare)
-
Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism
- 2014
-
Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 137, s. 1998-2014
-
Tidskriftsartikel (refereegranskat)abstract
- Sigma-1 receptor ligands may have neuroprotective and neurorestorative properties. In a mouse model of parkinsonism, Francardo et al. show that chronic treatment with the sigma-1 receptor agonist PRE-084 increases the density of striatal dopaminergic fibres and improves forelimb use. Boosting sigma-1 receptor activity may have disease-modifying effects in ParkinsonA ' s disease.The sigma-1 receptor, an endoplasmic reticulum-associated molecular chaperone, is attracting great interest as a potential target for neuroprotective treatments. We provide the first evidence that pharmacological modulation of this protein produces functional neurorestoration in experimental parkinsonism. Mice with intrastriatal 6-hydroxydopamine lesions were treated daily with the selective sigma-1 receptor agonist, PRE-084, for 5 weeks. At the dose of 0.3 mg/kg/day, PRE-084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation of neurotrophic factors (BDNF and GDNF) and their downstream effector pathways (extracellular signal regulated kinases 1/2 and Akt). No treatment-induced behavioural-histological restoration occurred in sigma-1 receptor knockout mice subjected to 6-hydroxydopamine lesions and treated with PRE-084. Immunoreactivity for the sigma-1 receptor protein was evident in both astrocytes and neurons in the substantia nigra and the striatum, and its intracellular distribution was modulated by PRE-084 (the treatment resulted in a wider intracellular distribution of the protein). Our results suggest that sigma-1 receptor regulates endogenous defence and plasticity mechanisms in experimental parkinsonism. Boosting the activity of this protein may have disease-modifying effects in Parkinson's disease.
|
|
| 18. |
- Gandhi, Sampada K., et al.
(författare)
-
Risk of Major Bleeding in Patients With Atrial Fibrillation Taking Dronedarone in Combination With a Direct Acting Oral Anticoagulant (From a U.S. Claims Database)
- 2021
-
Ingår i: American Journal of Cardiology. - : Elsevier BV. - 0002-9149. ; 159, s. 79-86
-
Tidskriftsartikel (refereegranskat)abstract
- Dronedarone may increase exposure and the risk of major bleeding when prescribed with a direct oral anticoagulant (DOAC). This retrospective cohort study examined the risk of the first occurrence of major bleeding (hospitalization or emergency room visit for gastrointestinal [GI] bleeding, intracranial hemorrhage [ICH], or bleeding at other sites) among new users of apixaban, dabigatran, and rivaroxaban in patients with AF ≥18 years (January 1, 2007 to September 30, 2017) from the United States Truven Health MarketScan claims, comparing concomitant users of dronedarone to DOAC alone users in patients with atrial fibrillation (AF). No increased risk of major bleeding was associated with use of dronedarone and apixaban (adjusted Hazard Ratio [aHR]: 0.69 [95% confidence interval [CI]: 0.40, 1.17], p = 0.16), a modestly increased risk of GI bleeding but not overall bleeding was associated with use of dronedarone and dabigatran (aHR bleeding: 1.18 [95% CI: 0.89, 1.56], p = 0.26; aHR GI bleeding: 1.40 [95% CI: 1.01, 1.93]; p = 0.04) and an increased risk of overall bleeding, driven by GI bleeding, was associated with use of dronedarone and rivaroxaban (aHR bleeding: 1.31 [95% CI: 1.01, 1.69]; p = 0.04; aHR GI bleeding: 1.39 [95% CI: 0.98, 1.95]; p = 0.06), compared to each DOAC respectively. There was no increased risk of ICH associated with combined use of dronedarone and any DOAC. Prospective analyses, preferably randomized controlled studies, are needed to further explore the risk of major bleeding with concomitant use of DOACs and CYP3A4/P-gp inhibitors such as dronedarone.
|
|
| 19. |
- Handelsman, Yehuda, et al.
(författare)
-
Impact of dronedarone on patients with atrial fibrillation and diabetes : A sub-analysis of the ATHENA and EURIDIS/ADONIS studies
- 2022
-
Ingår i: Journal of Diabetes and its Complications. - : Elsevier BV. - 1056-8727. ; 36:7
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: This post hoc analysis evaluated efficacy and safety of dronedarone in atrial fibrillation (AF) and atrial flutter (AFL) patients with/without diabetes. Methods: Patients were categorized according to baseline diabetes status. Time-to-event analyses were performed using Kaplan-Meier method. Hazard-ratios were assessed using Cox models. Results: 945/4628 (dronedarone = 482; placebo = 463) patients in ATHENA and 215/1237 (dronedarone = 148; placebo = 67) patients in EURIDIS/ADONIS studies had diabetes. In ATHENA, there were higher rates of CV hospitalization/death in patients with diabetes (39.5%) than without diabetes (34.7%). Incidence of first CV hospitalization/death was lower in patients with diabetes treated with dronedarone (35.1%) than placebo (44.1%), and time to this event was longer in those treated with dronedarone than placebo (log-rank p = 0.005). Median AF/AFL recurrence time was longer in patients treated with dronedarone than placebo in patients with diabetes (ATHENA: 722 vs 527 days, log-rank p = 0.004; EURIDIS/ADONIS: 100 vs 23 days, log-rank p = 0.15) or without diabetes (ATHENA: 741 vs 492 days, log-rank p < 0.0001; EURIDIS/ADONIS: 120 vs 59 days, log-rank p = 0.0002). Occurrence of any treatment-related adverse events with dronedarone was similar for patients with/without diabetes and was comparable to placebo. Conclusions: Dronedarone reduced incidence of CV hospitalization/death, AF/AFL recurrence and increased time to these events in AF/AFL patients with/without diabetes. Trial registration: Not applicable, as it was a post hoc analysis. This article is based on previously conducted studies (ATHENA: NCT00174785, EURIDIS: NCT00259428, and ADONIS: NCT00259376).
|
|
| 20. |
- Labaf, A., et al.
(författare)
-
Predictive accuracies of CHA2DS2-VASc and HAS-BLED, and anticoagulation quality in relation to thromboemblism and bleeding in patients with mechanical heart valves
- 2013
-
Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 34:Supplement: 1, s. 379-379
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: The variability of international normalized ratio (INR) is considered a risk factor in patients with mechanical heart valves (MHV)and INR target range still remains unestablished. CHA2DS2-VASc andHAS-BLED are risk stratification schemas designed for atrial fibrillation. Their ability to discriminate thromboembolism (TE) and bleeding for patients with MHV have never been investigated.Methods: We conducted a complete study of all patients with MHV followed in two centres. A total of 407 and 140 patients respectively were followed between 2008-2011. Data on INR, time in therapeutic range (TTR), variability, CHA2DS2-VASc and HAS-BLED were extracted.Results: The mean (±SD) age in centre 1 and 2 were 70 (14) and 61 (14) respectively. The target INR range for all MHV was 2-4 in centre 1 and 2-3 in centre 2 and mean INR was 2.9 (0.31) and 2.6 (0.19) respectively. The incidence of TE was 3.4 per 100 patient-years in centre 1 and 1.4 per 100 patient-years in centre 2, p=0.035, and for major bleeding 4.9 per 100 patient-years and 1.7 per 100 patient-years respectively, p=0.005. TheHAS-BLED score correlated well with bleeding, with area under the curveof 0.63 (95% confidence interval [CI]: 0.57-0.70). CHA2DS2-VASc had 0.56 (95% CI: 0.48-0.64) for TE. Adding atrial fibrillation as a risk factor did not improve the c statistic. INR variability (SD), comparing the 3rd tertile with the first had (Odds ratio [OR]: 4.05; 95% [CI]: 2.09-7.84) for major bleeding and (OR: 2.01; 95% [CI]: 1.0-3.99) for TE. INR SD was higher with a higher mean INR and target range 2-4 (p<0.001) andindependently predicted bleeding.Conclusion: HAS-BLED predicted bleeding with discriminatory ability similar to previous reports to atrial fibrillation whilst CHA2DS2-VAScpredictive ability for TE was modest. Higher INR intensity is associated with higher variability, which correlates to primarily bleeding, but also TE. Some of the difference between the groups considering TE can be accounted for more significant risk factors in the centre 1 cohort. A more narrow INR target range could be recommended to reduce variability ofanticoagulation.
|
|
| 21. |
- Lauritzen, M., et al.
(författare)
-
Cortical spreading depression is associated with arachidonic acid accumulation and preservation of energy charge
- 1990
-
Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 10:1, s. 115-122
-
Tidskriftsartikel (refereegranskat)abstract
- The present study aimed to study the relation between the release of arachidonic acid (AA) and the energy state in cerebral cortices of rats during single episodes of cortical spreading depression (CSD). The changes in concentrations of AA, labile phosphate compounds [ATP, ADP, AMP, and phosphocreatine (PCr)], and glycolytic metabolites (lactate, pyruvate, glucose, and glycogen) were studied during and following the large change of the local direct current (DC) potential. Free AA increased markedly during the DC shift, continued to increase during the subsequent 3 min, and returned to control levels at 4-5 min after CSD. PCr decreased by 38% in the first minutes following the DC shift, while ADP increased by 38%. Both returned to normal within a few minutes. ATP, AMP, and energy charge remained constant throughout the experimental period. Glucose decreased by 47% and glycogen by 34% for a few minutes following CSD, while lactate increased by 105% at 2-3 min and by 77% at 4-5 min after CSD. The metabolites returned to control levels at 10 min after CSD. Considering the constant energy charge at all time points during CSD, it is suggested that the AA rise reflects augmented phospholipase activity due to either increased intracellular [Ca2+] or receptor stimulation or both. The possibility that N-methyl-D-aspartate receptors play a role in the release of AA, and that free AA in turn could be part of the mechanism of CSD, is discussed.
|
|
| 22. |
- Lobo, Andrea C., et al.
(författare)
-
Cleavage of the vesicular glutamate transporters under excitotoxic conditions
- 2011
-
Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 44:3, s. 292-303
-
Tidskriftsartikel (refereegranskat)abstract
- Glutamate is loaded into synaptic vesicles by vesicular glutamate transporters (VGLUTs), and alterations in the transporters expression directly regulate neurotransmitter release. We investigated changes in VGLUT1 and VGLUT2 protein levels after ischemic and excitotoxic insults. The results show that VGLUT2 is cleaved by calpains after excitotoxic stimulation of hippocampal neurons with glutamate, whereas VGLUT1 is downregulated to a lower extent VGLUT2 was also cleaved by calpains after oxygen/glucose deprivation (OGD), and downregulated after middle cerebral artery occlusion (MCAO) and intrahippocampal injection of kainate. In contrast, VGLUT1 was not affected after OGD. Incubation of isolated synaptic vesicles with recombinant calpain also induced VGLUT2 cleavage, with a little effect observed for VGLUT1. N-terminal sequencing analysis showed that calpain cleaves VGLUT2 in the C-terminus, at Asn(534) and Lys(542). The truncated GFP-VGWT2 forms were found to a great extent in non-synaptic regions along neurites, when compared to GFP-VGLUT2. These findings show that excitotoxic and ischemic insults downregulate VGLUT2, which is likely to affect glutamatergic transmission and cell death, especially in the neonatal period when the transporter is expressed at higher levels. (C) 2011 Elsevier Inc. All rights reserved.
|
|
| 23. |
- Matsumoto, S, et al.
(författare)
-
Persistent phosphorylation of synaptic proteins following middle cerebral artery occlusion
- 2002
-
Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016 .- 0271-678X. ; 22:9, s. 1107-1113
-
Tidskriftsartikel (refereegranskat)abstract
- Transient cerebral ischemia following I to 2 hours of middle cerebral artery occlusion (MCAO) in the rat leads to infarction, which can be diminished by synaptic transmission modulators, implying aberrant cell signaling in the pathogenetic process. The authors report here changes in the levels of tyrosine phosphorylated proteins (PTyr) and calcium calmodulin kinase II (CaMKII) phosphorylation of Thr 286, in synaptosomal, particulate, and cytosolic fractions of different cortical areas following I or 2 hours of MCAO, or 2 hours of MCAO followed by 2 hours of reperfusion. At the end of 2-hour MCAO, PTyr, and in particular the pp180, indicative of NR2A/B subunit, increased in the synaptosomal fraction in less ischemic areas while it decreased in more severe ischemic regions. During reperfusion, phosphorylation increased at least 2 fold in, reperfused areas, During 2 hours of MCAO, the phosphorylation of CaMKII increased 8- to 10-fold in the synaptosomal fraction in all ischemic brain regions. During reperfusion, the phospho-CaMKII levels remained elevated by approximately 300%, compared with the contralateral hemisphere (control). There was no increase in phospho-CaMKII in the cytosolic fraction at any time during, or following ischemia in any of the brain regions examined. The authors conclude that both tyrosine kinase coupled pathways, as well as CaMKII-mediated cellular processes associated with synaptic activity, are strongly activated during and particularly following MCAO. These results support the hypothesis that aberrant cell signaling may contribute to ischemic cell death and dysfunction, and that selective modulators of cell signaling may be targets for pharmacological intervention against ischemic brain damage.
|
|
| 24. |
- Matsumoto, S, et al.
(författare)
-
Restricted clinical efficacy of cyclosporin A on rat transient middle cerebral artery occlusion
- 2002
-
Ingår i: Life Sciences. - 1879-0631. ; 72:4-5, s. 591-600
-
Tidskriftsartikel (refereegranskat)abstract
- The immunosuppressant cyclosporin A (CsA) has been shown to have neuroprotective action. The inhibition of both calcineurin activation and mitochondrial permeability transition pore (mtPTP) opening are considered the primary neuroprotective mechanisms of CsA. Here we have evaluated the effect of CsA on significantly reducing infarct size induced by transient middle cerebral artery occlusion (MCAO) in rats, and examined variable therapeutic applications for brain infarction. Experimental rats were divided into 12 groups according to: CsA administration time (immediately after occlusion or immediately after reperfusion); dosage (between 10 and 50 mg/kg); route (i.v. or i.p.); and with or without needle insertion, which hypothetically disrupts the blood brain barrier (BBB). Neuroprotective effects of CsA were hardly noticeable when administered immediately after occlusion or by i.v. injection. By needle insertion, CsA administration significantly reduced infarct size, although vehicle treatment also reduced infarct size compared with nontreatment animals, i.e. no needle insertion. These results suggest that needle insertion allows endogenous neuroprotective substances to pass into the brain. Furthermore, single dosages over 30 mg/kg CsA were excessive and negated potential neuroprotective effects. However, two i.p. administrations of 20 mg/kg CsA immediately and 24 hrs after reperfusion significantly ameliorated the infarct size compared to the vehicle-treated group. We conclude that CsA exhibits significant neuroprotective activity, although its therapeutic application for stroke may be limited by very strict and precise management requirements.
|
|
| 25. |
|
|
| 26. |
- Pundi, Krishna, et al.
(författare)
-
Dronedarone Versus Sotalol in Antiarrhythmic Drug-Naive Veterans With Atrial Fibrillation
- 2023
-
Ingår i: Circulation: Arrhythmia and Electrophysiology. - 1941-3149. ; 16:8, s. 456-467
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sotalol and dronedarone are both used for maintenance of sinus rhythm for patients with atrial fibrillation. However, while sotalol requires initial monitoring for QT prolongation and proarrhythmia, dronedarone does not. These treatments can be used in comparable patients, but their safety and effectiveness have not been compared head to head. Therefore, we retrospectively evaluated the effectiveness and safety using data from a large health care system. METHODS: Using Veterans Health Administration data, we identified 11 296 antiarrhythmic drug-naive patients with atrial fibrillation prescribed dronedarone or sotalol in 2012 or later. We excluded patients with prior conduction disease, pacemakers or implantable cardioverter-defibrillators, ventricular arrhythmia, cancer, renal failure, liver disease, or heart failure. We used natural language processing to identify and compare baseline left ventricular ejection fraction between treatment arms. We used 1:1 propensity score matching, based on patient demographics, comorbidities, and medications, and Cox regression to compare strategies. To evaluate residual confounding, we performed falsification analysis with nonplausible outcomes. RESULTS: The matched cohort comprised 6212 patients (3106 dronedarone and 3106 sotalol; mean [±SD] age, 71±10 years; 2.5% female; mean [±SD] CHA2DS2-VASC, 2±1.3). The mean (±SD) left ventricular ejection fraction was 55±11 and 58±10 for dronedarone and sotalol users, correspondingly. Dronedarone, compared with sotalol, did not demonstrate a significant association with risk of cardiovascular hospitalization (hazard ratio, 1.03 [95% CI, 0.88-1.21]) or all-cause mortality (hazard ratio, 0.89 [95% CI, 0.68-1.16]). However, dronedarone was associated with significantly lower risk of ventricular proarrhythmic events (hazard ratio, 0.53 [95% CI, 0.38-0.74]) and symptomatic bradycardia (hazard ratio, 0.56 [95% CI, 0.37-0.87]). The primary findings were stable across sensitivity analyses. Falsification analyses were not significant. CONCLUSIONS: Dronedarone, compared with sotalol, was associated with a lower risk of ventricular proarrhythmic events and conduction disorders while having no difference in risk of incident cardiovascular hospitalization and mortality. These observational data provide the basis for prospective efficacy and safety trials.
|
|
| 27. |
- Reynolds, Matthew R., et al.
(författare)
-
Novel methodology for the evaluation of symptoms reported by patients with newly diagnosed atrial fibrillation : Application of natural language processing to electronic medical records data
- 2023
-
Ingår i: Journal of Cardiovascular Electrophysiology. - : Wiley. - 1045-3873 .- 1540-8167. ; 34:4, s. 790-799
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Understanding symptom patterns in atrial fibrillation (AF) can help in disease management. We report on the application of natural language processing (NLP) to electronic medical records (EMRs) to capture symptom reports in patients with newly diagnosed (incident) AF. Methods and Results: This observational retrospective study included adult patients with an index diagnosis of incident AF during January 1, 2016 through June 30, 2018, in the Optum datasets. The baseline and follow-up periods were 1 year before/after the index date, respectively. The primary objective was identification of the following predefined symptom reports: dyspnea or shortness of breath; syncope, presyncope, lightheadedness, or dizziness; chest pain; fatigue; and palpitations. In an exploratory analysis, the incidence rates of symptom reports and cardiovascular hospitalization were assessed in propensity-matched patient cohorts with incident AF receiving first-line dronedarone or sotalol. Among 30 447 patients with an index AF diagnosis, the NLP algorithm identified at least 1 predefined symptom in 9734 (31.9%) patients. The incidence rate of symptom reports was highest at 0–3 months post-diagnosis and lower at >3–6 and >6–12 months (pre-defined timepoints). Across all time periods, the most common symptoms were dyspnea or shortness of breath, followed by syncope, presyncope, lightheadedness, or dizziness. Similar temporal patterns of symptom reports were observed among patients with prescriptions for dronedarone or sotalol as first-line treatment. Conclusion: This study illustrates that NLP can be applied to EMR data to characterize symptom reports in patients with incident AF, and the potential for these methods to inform comparative effectiveness.
|
|
| 28. |
- Sakai, Takao, et al.
(författare)
-
Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis
- 2001
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 7:3, s. 324-330
-
Tidskriftsartikel (refereegranskat)abstract
- Fibronectin performs essential roles in embryonic development and is prominently expressed during tissue repair. Two forms of fibronectin have been Identified: plasma fibronectin (pFn), which Is expressed by hepatocytes and secreted In soluble form into plasma; and cellular fibronectin (cFn), an insoluble form expressed locally by fibroblasts and other cell types and deposited and assembled into the extracellular matrix. To investigate the role of pFn in vivo, we generated pfn-deficient adult mice using Cre-loxP conditional gene-knockout technology. Here we show that pfn-deficient mice show increased neuronal apoptosis and larger Infarction areas following transient focal cerebral ischemia. However, pFn is dispensable for skin-wound healing and hemostasis.
|
|
| 29. |
- Schnabel, Renate B, et al.
(författare)
-
Early diagnosis and better rhythm management to improve outcomes in patients with atrial fibrillation : the 8th AFNET/EHRA consensus conference
- 2023
-
Ingår i: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 25:1, s. 6-27
-
Tidskriftsartikel (refereegranskat)abstract
- Despite marked progress in the management of atrial fibrillation (AF), detecting AF remains difficult and AF-related complications cause unacceptable morbidity and mortality even on optimal current therapy. This document summarizes the key outcomes of the 8th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Eighty-three international experts met in Hamburg for 2 days in October 2021. Results of the interdisciplinary, hybrid discussions in breakout groups and the plenary based on recently published and unpublished observations are summarized in this consensus paper to support improved care for patients with AF by guiding prevention, individualized management, and research strategies. The main outcomes are (i) new evidence supports a simple, scalable, and pragmatic population-based AF screening pathway; (ii) rhythm management is evolving from therapy aimed at improving symptoms to an integrated domain in the prevention of AF-related outcomes, especially in patients with recently diagnosed AF; (iii) improved characterization of atrial cardiomyopathy may help to identify patients in need for therapy; (iv) standardized assessment of cognitive function in patients with AF could lead to improvement in patient outcomes; and (v) artificial intelligence (AI) can support all of the above aims, but requires advanced interdisciplinary knowledge and collaboration as well as a better medico-legal framework. Implementation of new evidence-based approaches to AF screening and rhythm management can improve outcomes in patients with AF. Additional benefits are possible with further efforts to identify and target atrial cardiomyopathy and cognitive impairment, which can be facilitated by AI.
|
|
| 30. |
- Shamloo, M., et al.
(författare)
-
Activation of the extracellular signal-regulated protein kinase cascade in the hippocampal CA1 region in a rat model of global cerebral ischemic preconditioning
- 1999
-
Ingår i: Neuroscience. - 0306-4522. ; 93:1, s. 81-88
-
Tidskriftsartikel (refereegranskat)abstract
- A short period of sublethal preconditioning ischemia (3 min) followed by two days of reperfusion provides almost complete protection against ischemic cell death induced by a second (9 min) lethal ischemic episode. Here, we have investigated the extracellular signal-regulated protein kinase kinase and extracellular signal-regulated protein kinase, two kinases known to activate gene transcription and to be of importance for cell survival, after sublethal preconditioning ischemia in the rat hippocampal CA1 region. The activation levels of these two kinases were also studied after a second ischemic episode both in preconditioned and nonconditioned brains. An increased phosphorylation of the extracellular signal-regulated protein kinase kinase was found in neuronal cell bodies, particularly in the nucleus, 30 min, 4 h and two days of reperfusion after preconditioning ischemia. Two days after preconditioning ischemia both extracellular signal-regulated protein kinase kinase and extracellular signal-regulated protein kinase were markedly phosphorylated. During the early reperfusion period (30 min) after the second ischemic insult the phosphorylation levels of these two kinases were increased in both nonconditioned and preconditioned brains. In the late reperfusion time (one day), the phosphorylation levels of the extracellular signal-regulated protein kinase kinase and extracellular signal-regulated protein kinase were decreased in preconditioned brains, but remained elevated in nonconditioned brains. We conclude that phosphorylation of the extracellular signal-regulated protein kinase kinase and extracellular signal-regulated protein kinase after sublethal ischemia correlates with the neuroprotection induced by preconditioning, possibly by transcriptional activation of neuroprotective genes. Also, preconditioning enhances normalization of the disturbed cell signaling through the extracellular signal-regulated protein kinase cascade induced by lethal ischemia.
|
|
| 31. |
- Singh, Jagmeet P., et al.
(författare)
-
Phased target trial design and meta-analysis in a head-to-head treatment comparison
- 2023
-
Ingår i: Pharmacoepidemiology and Drug Safety. - : John Wiley & Sons. - 1053-8569 .- 1099-1557. ; 32:Suppl. 1, s. 444-444
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: For conditions with rare clinical outcomes, real-world treatment comparisons are challenging to design and prone to confounding.Objectives: To present a robust methodologic approach for rigorous and transparent assessment of rare outcomes using real-world data.Methods: We emulated a target trial using an active comparator, new-user design to compare dronedarone to sotalol for rhythm control in atrial fibrillation (AF) as both are recommended for similar patient phenotypes. Using one protocol, a pre-specified stepwise approach was implemented across 4 datasets (Optum CDM; IBM MarketScan; Veterans Affairs Electronic Health Records; Swedish National Patient Register). Meta-analysis was used to ensure sufficient capture of specific, rare primary outcomes (cardiovascular (CV) hospitalization and ventricular proarrhythmia) and to evaluate consistency of findings across patient populations. Steps 1–3 focused on cohort selection, propensity score matching (PSM), baseline equipoise and residual confounding assessment via negative control outcome analyses. In steps 4–6, outcomes in the individual cohorts were analyzed using an as-treated approach and Cox proportional hazards models. Step 7 included a heterogeneity assessment, meta-analysis using fixed effects models, and hypothesis testing using a hierarchical approach. In step 8, sensitivity analyses, including E-values and Inverse Probability of Censoring Weighting, were conducted to verify the robustness of findings.Results: In step 1, 35,467 sotalol and 27,955 dronedarone patients with AF who were antiarrhythmic drug-naive were identified across databases. In steps 2–3, 23,275 dronedarone patients were PS-matched to 23,275 sotalol patients. Baseline covariates were well-balanced and little-to-no residual confounding was observed via the negative control analyses. Individual HRs were estimated in steps 4–6, and, when no significant heterogeneity between databases was observed, hazard ratios (HRs) were pooled across datasets in step 7. For example, for CV hospitalization, dronedarone was superior to sotalol with no heterogeneity (HR: 0.91; 95% CI: 0.85, 0.97; Cochran Q p-value: 0.32). Eleven sensitivity analyses were conducted in step 8 and confirmed that findings were generally robust.Conclusions: An active comparator, new-user design using the target trial approach coupled with meta-analysis generated consistent findings across databases and countries using one protocol. Similar methods, including a pre-specified stepwise approach, negative control outcome, and tests for robustness should be considered for real-world studies where specific, rare outcomes need to be examined in a rigorous and transparent way.
|
|
| 32. |
- Thind, Munveer, et al.
(författare)
-
Dronedarone treatment following cardioversion in patients with atrial fibrillation/flutter : A post hoc analysis of the EURIDIS and ADONIS trials
- 2020
-
Ingår i: Journal of Cardiovascular Electrophysiology. - : Wiley. - 1045-3873 .- 1540-8167. ; 31:5, s. 1022-1030
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: The phase 3 EURIDIS and ADONIS studies evaluated dronedarone for atrial fibrillation (AF)/atrial flutter (AFL) recurrence in patients with nonpermanent AF. Here we assessed whether patient characteristics and/or treatment outcomes in these studies differed based on the need for cardioversion before randomization. Methods: Time to adjudicated first AF/AFL recurrence, symptomatic recurrence, cardiovascular hospitalization/death, and AF hospitalization, and safety were assessed by cardioversion status. Results: Of 1237 patients randomized (2:1 dronedarone:placebo), 364 required baseline cardioversion (dronedarone 243, placebo 121). Patients requiring cardioversion had a greater prevalence of cardiovascular comorbidities and shorter times to first AF/AFL recurrence compared with those not requiring cardioversion. Dronedarone was associated with longer median time to first AF/AFL recurrence vs placebo regardless of cardioversion status (cardioversion: 50 vs 15 days, hazard ratio [HR] 0.76; 95% confidence interval [CI], 0.59-0.97; P =.02; non-cardioversion: 150 vs 77 days, HR 0.76; 95% CI, 0.64-0.90; P <.01). Dronedarone was similarly associated with prolonged median time to symptomatic recurrence vs placebo in the cardioversion (347 vs 87 days, HR 0.65; 95% CI, 0.49-0.87) and non-cardioversion (288 vs 120 days, HR 0.74; 95% CI, 0.62-0.90) populations. Risk of cardiovascular hospitalization/death and first AF hospitalization was lower with dronedarone vs placebo regardless of cardioversion status, but differences were not statistically significant. The safety of dronedarone was similar in both groups. Conclusion: Patients requiring baseline cardioversion represent a distinct population, having more underlying cardiovascular disease and experiencing a shorter time to AF/AFL recurrences. Dronedarone was associated with improved efficacy vs placebo regardless of cardioversion status.
|
|
| 33. |
|
|
| 34. |
- Wieloch, Tadeusz, et al.
(författare)
-
Mitochondrial Permeability Transition in the CNS - Composition, Regulation, and Pathophysiological Relevance
- 2007
-
Ingår i: Handbook of Neurochemistry and Molecular Neurobiology - Brain Energetics. Integration of Molecular and Cellular Processes. - Boston, MA : Springer US. - 9780387303666 ; , s. 667-702
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Mitochondrial permeability transition (MPT) is induced in isolated brain mitochondria by calcium and oxidants and is inhibited by adenine nucleotides. When induced, MPT is associated with equilibration of solutes of <1500 Da across the inner mitochondrial membrane. A persistent induction of MPT depolarizes the inner membrane and causes cessation of ATP synthesis, swelling of the matrix, and bursting of the mitochondrial membranes. The rupture of the membranes releases calcium stored in the mitochondrial matrix and apoptogenic factors from the intermembrane space, leading to cell death. MPT has been implicated in acute brain injury and neurodegenerative disease since inhibitors of MPT such as cyclosporin A (CsA) are brain protective. Whether MPT has a physiological role is unclear, but MPT may be important in calcium homeostasis under conditions of excessive neuronal activity.
|
|
| 35. |
- Xu, Yuan, et al.
(författare)
-
Reimport of carbon from cytosolic and vacuolar sugar pools into the Calvin–Benson cycle explains photosynthesis labeling anomalies
- 2022
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:11
-
Tidskriftsartikel (refereegranskat)abstract
- Photosynthesis metabolites are quickly labeled when 13CO2 is fed to leaves, but the time course of labeling reveals additional contributing processes involved in the metabolic dynamics of photosynthesis. The existence of three such processes is demonstrated, and a metabolic flux model is developed to explore and characterize them. The model is consistent with a slow return of carbon from cytosolic and vacuolar sugars into the Calvin–Benson cycle through the oxidative pentose phosphate pathway. Our results provide insight into how carbon assimilation is integrated into the metabolic network of photosynthetic cells with implications for global carbon fluxes.
|
|
| 36. |
- Zhang, E., et al.
(författare)
-
Influence of MK-801 on brain extracellular calcium and potassium activities in severe hypoglycemia
- 1990
-
Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 0271-678X .- 1559-7016. ; 10:1, s. 136-139
-
Tidskriftsartikel (refereegranskat)abstract
- The purpose of the present study was to examine the effect of blockade of N-methyl-D-aspartate (NMDA) receptors on the depolarization associated with severe hypoglycemia, which is commonly preceded by one or a few transient depolarizations reminiscent of cortical spreading depression (CSD). In the cerebral cortices of rats [K+](e) and [Ca2+](e) were measured with ion-selective microelectrodes. NMDA blockade was achieved by injection of MK801 in doses that block CSD. In control rats, the latency from the time point when blood glucose reached minimal levels to onset of ionic shifts was 33.2 ± 3.5 min, and [K+](e) rose from 3.2 ± 0.2 to 55 ± 5 mM. All variables remained unchanged in rats treated with MK801. In another four rats treated with MK801, [Ca2+](e) declined from 1.06 ± 0.22 to 0.12 ± 0.02 mM. Plasma glucose measurements indicated that the cortex depolarized at a plasma glucose concentration between 0.7 and 0.8 mM, i.e., within a narrow range, suggesting a threshold phenomenon. In conclusion, activation of NMDA receptors seems of minor importance for hypoglycemic depolarization. The ionic transients that precede the persistent hypoglycemic depolarization are probably mediated by mechanisms distinct from those of electrically induced CSD.
|
|
