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2. |
- Hammarlund, Emma U., 1971-, et al.
(författare)
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A sulfidic driver for the end-Ordovician mass extinction
- 2012
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Ingår i: Earth and Planetary Science Letters. - : Elsevier BV. - 0012-821X .- 1385-013X. ; 331, s. 128-139
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Tidskriftsartikel (refereegranskat)abstract
- The end-Ordovician extinction consisted of two discrete pulses, both linked, in various ways, to glaciation at the South Pole. The first phase, starting just below the Normalograptus extraordinarius Zone, particularly affected nektonic and planktonic species, while the second pulse, associated with the Normalograptus persculptus Zone, was less selective. Glacially induced cooling and oxygenation are two of many suggested kill mechanisms for the end-Ordovician extinction, but a general consensus is lacking. We have used geochemical redox indicators, such as iron speciation, molybdenum concentrations, pyrite framboid size distribution and sulfur isotopes to analyze the geochemistry in three key Hirnantian sections. These indicators reveal that reducing conditions were occasionally present at all three sites before the first pulse of the end-Ordovician extinction, and that these conditions expanded towards the second pulse. Even though the N. extraordinarius Zone appears to have been a time of oxygenated deposition, pyrite is significantly enriched in 34S in our sections as well as in sections reported from South China. This suggests a widespread reduction in marine sulfate concentrations, which we attribute to an increase in pyrite burial during the early Hirnantian. The S-isotope excursion coincides with a major positive carbon isotope excursion indicating elevated rates of organic carbon burial as well. We argue that euxinic conditions prevailed and intensified in the early Hirnantian oceans, and that a concomitant global sea level lowering pushed the chemocline deeper than the depositional setting of our sites. In the N. persculptus Zone, an interval associated with a major sea level rise, our redox indicators suggests that euxinic conditions, and ferruginous in some places, encroached onto the continental shelves. In our model, the expansion of euxinic conditions during the N. extraordinarius Zone was generated by a reorganization of nutrient cycling during sea level fall, and we argue, overall, that these dynamics in ocean chemistry played an important role for the end-Ordovician mass extinction. During the first pulse of the extinction, euxinia and a steepened oxygen gradient in the water column caused habitat loss for deep-water benthic and nektonic organisms. During the second pulse, the transgression of anoxic water onto the continental shelves caused extinction in shallower habitats.
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3. |
- Kozik, Nevin P., et al.
(författare)
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Rapid marine oxygen variability : Driver of the Late Ordovician mass extinction
- 2022
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:46
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Tidskriftsartikel (refereegranskat)abstract
- The timing and connections between global cooling, marine redox conditions, and biotic turnover are underconstrained for the Late Ordovician. The second most severe mass extinction occurred at the end of the Ordovician period, resulting in ~85% loss of marine species between two extinction pulses. As the only “Big 5” extinction that occurred during icehouse conditions, this interval is an important modern analog to constrain environmental feedbacks. We present a previously unexplored thallium isotope records from two paleobasins that record global marine redox conditions and document two distinct and rapid excursions suggesting vacillating (de)oxygenation. The strong temporal link between these perturbations and extinctions highlights the possibility that dynamic marine oxygen fluctuations, rather than persistent, stable global anoxia, played a major role in driving the extinction. This evidence for rapid oxygen changes leading to mass extinction has important implications for modern deoxygenation and biodiversity declines.
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6. |
- Angelison, Leif, et al.
(författare)
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Long-term outcome of infliximab treatment in chronic active ulcerative colitis : a Swedish multicentre study of 250 patients
- 2017
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Ingår i: Alimentary Pharmacology and Therapeutics. - : Wiley-Blackwell Publishing Inc.. - 0269-2813 .- 1365-2036. ; 45:4, s. 519-532
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Tidskriftsartikel (refereegranskat)abstract
- Background: Real-life long-term data on infliximab treatment in ulcerative colitis are limited.Aim: To study the long-term efficacy and safety of infliximab in chronic active ulcerative colitis and possible predictors of colectomy and response were also examined.Methods: A retrospective multi-centre study of infliximab treatment in 250 patients with chronic active ulcerative colitis with inclusion criteria: age ≥18 years, ambulatory treated, steroid-dependent or intolerant and/or immunomodulator refractory or intolerant.Results: Steroid-free clinical remission was achieved by 123/250 patients (49.2%) at 12 months and in 126/250 patients at a median follow-up of 2.9 years (50.4%). Primary response at 3 months was achieved by 190/250 (76.0%) patients and associated with a high probability of response 168/190 (88.4%) at 12 months and 143/190 (75.3%) at follow-up. Long-term rate of colectomy in primary responders was 6/190 (3.2%) at 12 months and 27/190 (14.2%) at last follow-up. Failure to achieve response at 3 months was associated with a high risk of subsequent colectomy, 29/60 (48.3%) at 12 months and 41/60 (68.3%) at follow-up. Response at 12 months was associated with a low risk of subsequent colectomy, 14/181 (7.7%) compared with non-response 19/34 (55.9%) (P < 0.0001). Non-response at 3 months was an independent predictor of subsequent colectomy (HR = 9.40, 95% CI = 5.10-17.35, P < 0.001). Concomitant azathioprine therapy did not influence outcome in terms of colectomy.Conclusions: Long-term efficacy of infliximab treatment in chronic active ulcerative colitis is excellent especially in patients who respond to induction treatment. Conversely, non-response at 3 months predicts a poor outcome, with a high risk of subsequent colectomy.
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7. |
- Berglund, B. E., et al.
(författare)
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Holocene forest dynamics and climate changes in the Abisko area, northern Sweden : the Sonesson model of vegetation history reconsidered and confirmed
- 1996
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Ingår i: Ecological Bulletins. - 0346-6868. ; 1996:1, s. 15-30
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Tidskriftsartikel (refereegranskat)abstract
- A new palaeoecological and palaeoclimatic project in the subalpine Abisko area, N Scandes, founded upon the pollen zone system defined by Sonesson is described. This model of vegetation history has been confirmed, although the chronology is partly revised. Sonesson's pollen diagrams are combined with new results from a lake sediment sequence at the tree-limit, which include sedimentologic, mineral magnetic, oxygen isotope and plant macrofossil studies. Since the deglaciation at c9000-8500 14C yr BP the vegetation of the Abisko area has generally been dominated by a subalpine birch Betula woodland tundra. The cliamte has generally been subarctic-oceanic since the deglaciation except for the period c.5500-3500 BP when temperate-continental conditions prevailed. This climatic development differs from the situation in the central Scandes.
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9. |
- Chaurasia, Chandra S., et al.
(författare)
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AAPS-FDA workshop white paper : microdialysis principles, application and regulatory perspectives
- 2007
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 24:5, s. 1014-1025
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Tidskriftsartikel (refereegranskat)abstract
- Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (microD) is the only tool available that explicitly provides data on the extracellular space. Although microD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of microD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of microD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on microD as a tool in drug research and development.
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10. |
- Chaurasia, Chandra S., et al.
(författare)
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AAPS-FDA Workshop White Paper : microdialysis principles, application, and regulatory perspectives
- 2007
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Ingår i: Journal of clinical pharmacology. - : Wiley. - 0091-2700 .- 1552-4604. ; 47:5, s. 589-603
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Tidskriftsartikel (refereegranskat)abstract
- Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (μD) is the only tool available that explicitly provides data on the extracellular space. Although μD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of μD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of μD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on μD as a tool in drug research and development.
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11. |
- Dahl, Tais W., et al.
(författare)
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Devonian rise in atmospheric oxygen correlated to the radiations of terrestrial plants and large predatory fish
- 2010
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:42, s. 17911-17915
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of Earth's biota is intimately linked to the oxygenation of the oceans and atmosphere. We use the isotopic composition and concentration of molybdenum (Mo) in sedimentary rocks to explore this relationship. Our results indicate two episodes of global ocean oxygenation. The first coincides with the emergence of the Ediacaran fauna, including large, motile bilaterian animals, ca. 550-560 million year ago (Ma), reinforcing previous geochemical indications that Earth surface oxygenation facilitated this radiation. The second, perhaps larger, oxygenation took place around 400 Ma, well after the initial rise of animals and, therefore, suggesting that early metazoans evolved in a relatively low oxygen environment. This later oxygenation correlates with the diversification of vascular plants, which likely contributed to increased oxygenation through the enhanced burial of organic carbon in sediments. It also correlates with a pronounced radiation of large predatory fish, animals with high oxygen demand. We thereby couple the redox history of the atmosphere and oceans to major events in animal evolution.
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12. |
- Dahl, Tais W., et al.
(författare)
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Reply to Butterfield : The Devonian radiation of large predatory fish coincided with elevated athospheric oxygen levels
- 2011
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:9, s. E29-
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Tidskriftsartikel (refereegranskat)abstract
- We welcome this opportunity to clarify the conclusions and implications of our recent publication in PNAS. Butterfield (1) raises four issues regarding the oxygenation of the Paleozoic Earth's surface and its correlation to animal evolution. Our geochemical and paleontological data supported ocean oxygenation in the Silurian-Early Devonian (2), a critical transition in Earth history that influenced biogeochemical cycles and biological systems. First, Butterfield suggests that evidence of charcoal in late Silurian rocks is incompatible with our claim that the earlier Paleozoic atmosphere had oxygen levels below 50% PAL (present-day atmospheric level). This counterargument rests on the assumption that the “fire window” of 62–166% PAL oxygen is well defined, but this is not the case (3).
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13. |
- Dahl, Tais W., et al.
(författare)
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Sulfidic anoxia in the oceans during the Late Ordovician mass extinctions – insights from molybdenum and uranium isotopic global redox proxies
- 2021
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Ingår i: Earth-Science Reviews. - : Elsevier BV. - 0012-8252. ; 220
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Forskningsöversikt (refereegranskat)abstract
- The Late Ordovician Mass Extinction wiped out 85% of animal species in two phases (LOME1 and LOME2). The kill mechanisms for the extinction phases are debated, but deteriorating climate and the expansion of marine anoxia appear to have been important factors. Nevertheless, the spatial extent and intensity of marine anoxia and its temporal relationship with the extinctions are not well understood. Here, we review existing global paleoredox proxy data based on molybdenum (Mo) and uranium (U) isotopes from four paleocontinents combined with new Mo isotope data from Dob's Linn, Scotland. Individually, these sedimentary records demonstrate significant redox fluctuations, but our coupled dynamic oceanic mass balance model for the evolution of the marine Mo and U cycles reveals that globally expansive ocean anoxia is best constrained by δ238U in carbonates from Anticosti Island that record expansive anoxia during LOME2. In addition, we consider periodic sulfidic anoxia developing in well-ventilated parts of the shallow oceans (e.g. during warmer periods with greater solar insolation) to have produced temporarily high seawater δ98Mo values during LOME1 in accordance with trends to high values observed in the sedimentary records. In this view, oceanic oxygen loss had a causal role during both extinction phases in the Late Ordovician.
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16. |
- Froese, Logan, et al.
(författare)
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The impact of sedative and vasopressor agents on cerebrovascular reactivity in severe traumatic brain injury
- 2023
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Ingår i: Intensive Care Medicine Experimental. - : Springer. - 2197-425X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study is to evaluate the impact of commonly administered sedatives (Propofol, Alfentanil, Fentanyl, and Midazolam) and vasopressor (Dobutamine, Ephedrine, Noradrenaline and Vasopressin) agents on cerebrovascular reactivity in moderate/severe TBI patients. Cerebrovascular reactivity, as a surrogate for cerebral autoregulation was assessed using the long pressure reactivity index (LPRx). We evaluated the data in two phases, first we assessed the minute-by-minute data relationships between different dosing amounts of continuous infusion agents and physiological variables using boxplots, multiple linear regression and ANOVA. Next, we assessed the relationship between continuous/bolus infusion agents and physiological variables, assessing pre-/post- dose of medication change in physiology using a Wilcoxon signed-ranked test. Finally, we evaluated sub-groups of data for each individual dose change per medication, focusing on key physiological thresholds and demographics.Results: Of the 475 patients with an average stay of 10 days resulting in over 3000 days of recorded information 367 (77.3%) were male with a median Glasgow coma score of 7 (4-9). The results of this retrospective observational study confirmed that the infusion of most administered agents do not impact cerebrovascular reactivity, which is confirmed by the multiple linear regression components having p value > 0.05. Incremental dose changes or bolus doses in these medications in general do not lead to significant changes in cerebrovascular reactivity (confirm by Wilcoxon signed-ranked p value > 0.05 for nearly all assessed relationships). Within the sub-group analysis that separated the data based on LPRx pre-dose, a significance between pre-/post-drug change in LPRx was seen, however this may be more of a result from patient state than drug impact.Conclusions: Overall, this study indicates that commonly administered agents with incremental dosing changes have no clinically significant influence on cerebrovascular reactivity in TBI (nor do they impair cerebrovascular reactivity). Though further investigation in a larger and more diverse TBI patient population is required.
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17. |
- Gupta, Anubha, et al.
(författare)
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Peripheral and central H1 histamine receptor occupancy by levocetirizine, a non-sedating antihistamine; a time course study in the guinea pig
- 2007
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 151:7, s. 1129-1136
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: The H(1) receptor occupancy (H1RO) in brain is an indicator of central side effects of antihistamines. Here, we determined the kinetics of central and peripheral H1RO by levocetirizine in relation to its brain and plasma concentration, and investigated the role of the blood-brain barrier in any delay in brain H1RO. EXPERIMENTAL APPROACH: Concentration-time profiles in plasma and brain were obtained after 0.1 and 1 mg kg(-1) oral doses of levocetirizine in guinea pigs. H1RO in brain was measured ex vivo using [3H]-mepyramine and, in the periphery, by measuring the degree of inhibition of histamine-induced contractions of isolated guinea pig ileum. KEY RESULTS: The concentration-time profile of levocetirizine indicated lower levels (partition coefficient, K(p)=0.06-0.08), higher t(max) (2-4 h vs 1-1.5 h) and longer terminal half-life (4-5.6 h vs 2.1-2.8 h) in brain than plasma. The H1RO at 0.1 and 1 mg kg(-1) were 75% and 97%, respectively, at 1 hr in the periphery and, in the brain, were <20% and 28-67% respectively, at all time points studied. Brain H1RO vs plasma concentrations profile showed a delay, but not when compared to brain concentrations. CONCLUSIONS AND IMPLICATIONS: This study demonstrates an effective peripheral antihistamine effect of levocetirizine without central adverse effects at the dose close to human therapeutic dose. The slow increase in H1RO in the brain with time was caused by slow blood-brain barrier transport of levocetirizine. This demonstrates the importance of measuring time course of brain H1RO in relation to brain concentrations of drugs.
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18. |
- Hong, Erik, et al.
(författare)
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Critical thresholds of long-pressure reactivity index and impact of intracranial pressure monitoring methods in traumatic brain injury
- 2024
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Ingår i: Critical Care. - : Springer Nature. - 1364-8535 .- 1466-609X. ; 28:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Moderate-to-severe traumatic brain injury (TBI) has a global mortality rate of about 30%, resulting in acquired life-long disabilities in many survivors. To potentially improve outcomes in this TBI population, the management of secondary injuries, particularly the failure of cerebrovascular reactivity (assessed via the pressure reactivity index; PRx, a correlation between intracranial pressure (ICP) and mean arterial blood pressure (MAP)), has gained interest in the field. However, derivation of PRx requires high-resolution data and expensive technological solutions, as calculations use a short time-window, which has resulted in it being used in only a handful of centers worldwide. As a solution to this, low resolution (longer time-windows) PRx has been suggested, known as Long-PRx or LPRx. Though LPRx has been proposed little is known about the best methodology to derive this measure, with different thresholds and time-windows proposed. Furthermore, the impact of ICP monitoring on cerebrovascular reactivity measures is poorly understood. Hence, this observational study establishes critical thresholds of LPRx associated with long-term functional outcome, comparing different time-windows for calculating LPRx as well as evaluating LPRx determined through external ventricular drains (EVD) vs intraparenchymal pressure device (IPD) ICP monitoring.Methods: The study included a total of n = 435 TBI patients from the Karolinska University Hospital. Patients were dichotomized into alive vs. dead and favorable vs. unfavorable outcomes based on 1-year Glasgow Outcome Scale (GOS). Pearson's chi-square values were computed for incrementally increasing LPRx or ICP thresholds against outcome. The thresholds that generated the greatest chi-squared value for each LPRx or ICP parameter had the highest outcome discriminatory capacity. This methodology was also completed for the segmentation of the population based on EVD, IPD, and time of data recorded in hospital stay.Results: LPRx calculated with 10-120-min windows behaved similarly, with maximal chi-square values ranging at around a LPRx of 0.25-0.35, for both survival and favorable outcome. When investigating the temporal relations of LPRx derived thresholds, the first 4 days appeared to be the most associated with outcomes. The segmentation of the data based on intracranial monitoring found limited differences between EVD and IPD, with similar LPRx values around 0.3.Conclusion: Our work suggests that the underlying prognostic factors causing impairment in cerebrovascular reactivity can, to some degree, be detected using lower resolution PRx metrics (similar found thresholding values) with LPRx found clinically using as low as 10 min-by-minute samples of MAP and ICP. Furthermore, EVD derived LPRx with intermittent cerebrospinal fluid draining, seems to present similar outcome capacity as IPD. This low-resolution low sample LPRx method appears to be an adequate substitute for the clinical prognostic value of PRx and may be implemented independent of ICP monitoring method when PRx is not feasible, though further research is warranted.
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19. |
- Ilyashuk, Elena A., et al.
(författare)
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Holocene climate variability on the Kola Peninsula, Russian Subarctic, based on aquatic invertebrate records from lake sediments
- 2013
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Ingår i: Quaternary Research. - : Cambridge University Press (CUP). - 0033-5894 .- 1096-0287. ; 79:3, s. 350-361
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Tidskriftsartikel (refereegranskat)abstract
- Sedimentary records of invertebrate assemblages were obtained from a small lake in the Khibiny Mountains, Kola Peninsula. Together with a quantitative chironomid-based reconstruction of mean July air temperature, these data provide evidence of Holocene climate variability in the western sector of the Russian Subarctic. The results suggest that the amplitude of climate change was more pronounced in the interior mountain area than near the White Sea coast. A chironomid-based temperature reconstruction reflects a warming trend in the early Holocene, interrupted by a transient cooling at ca. 8500-8000 cal yr BP with a maximum drop in temperature (ca. 1 degrees C) around 8200 cal yr BP. The regional Holocene Thermal Maximum, characterized by maximum warmth and dryness occurred at ca. 7900-5400 cal yr BP. During this period, July temperatures were at least 1 C higher than at present. The relatively warm and dry climate persisted until ca. 4000 cal yr BP, when a pronounced neoglacial cooling was initiated. Minimum temperatures, ca. 1-2 degrees C lower than at present, were inferred at ca. 3200-3000 cal yr BP. Faunal shifts in the stratigraphic profile imply also that the late-Holocene cooling was followed by a general increase in effective moisture. (C) 2013 University of Washington. Published by Elsevier Inc. All rights reserved.
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20. |
- Kjebon, Olle, et al.
(författare)
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1.55 μm buried heterostructure laser via regrowth of semi-insulating InP:Fe around vertical mesas fabricated by reactive ion etching using methane and hydrogen
- 1991
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 59:3, s. 235-255
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Tidskriftsartikel (refereegranskat)abstract
- A GaInAsP/InP Fabry-Perot-type buried-heterostructure quantum well laser operating at 1.55 μm has been realized utilizing iron-doped semi-insulating InP around vertical mesas fabricated by reactive ion etching using methane and hydrogen. A maximum cw output power of 19 mW has been achieved on as-cleaved chips of 300 μm length with a quantum efficiency of 21% per facet. Threshold currents lie between 20 and 25 mA. As low as 2 Ω series resistance has been measured despite an ohmic contact area not exceeding that of the 2-μm-wide mesa. A 3 dB bandwidth of 7.5 GHz at 12 mW output power is obtained from the small-signal frequency modulation measurements.
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22. |
- Ljótsson, B., et al.
(författare)
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Provoking symptoms to relieve symptoms : A randomized controlled dismantling study of exposure therapy in irritable bowel syndrome
- 2014
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Ingår i: Behaviour Research and Therapy. - : Elsevier. - 0005-7967 .- 1873-622X. ; 55:1, s. 27-39
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Tidskriftsartikel (refereegranskat)abstract
- An internet-delivered cognitive behavioral treatment (ICBT) based on systematic exposure exercises has previously shown beneficial effects for patients with irritable bowel syndrome (IBS). Exposure exercises may be perceived as difficult for patients to perform because of the elicited short-term distress and clinicians may be reluctant to use these interventions. The aim of this study was to compare ICBT with the same protocol without systematic exposure (ICBT-WE) to assess if exposure had any incremental value. This randomized controlled dismantling study included 309 participants diagnosed with IBS. The treatment interventions lasted for 10 weeks and included online therapist contact. ICBT-WE comprised mindfulness, work with life values, acceptance, and encouraged reduced avoidance behaviors, while ICBT also included systematic exposure to IBS symptoms and related situations. Severity of IBS symptoms was measured with the Gastrointestinal Symptom Rating Scale-IBS version (GSRS-IBS). The between-group Cohen's don GSRS-IBS was 0.47(95% CI: 0.23-0.70) at post-treatment and 0.48 (95% CI: 0.20-0.76) at 6-month follow-up, favoring ICBT. We conclude that the systematic exposure included in the ICBT protocol has incremental effects over the other components in the protocol. This study provides evidence for the utility of exposure exercises in psychological treatments for IBS.
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23. |
- Loryan, Irena, 1977-, et al.
(författare)
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Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development
- 2017
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Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 14:12, s. 4362-4373
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Tidskriftsartikel (refereegranskat)abstract
- Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fold lower lysosomal trapping capacity. No signs of PLD were seen with GRT2. The different profile of GRT2 relative to GRT1 is due to a structural change resulting in a reduced basicity of one amino group. Hence, by distinct chemical modifications, undesired lysosomal trapping can be separated from desired drug delivery into different organs. In summary, assessment of intracellular unbound concentrations was instrumental in delineating the intercompound and intertissue differences in PLD induction in vivo and could be applied for identification of potential lysosomotropic compounds in drug development.
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24. |
- Löndahl, Magnus, et al.
(författare)
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A prospective study: hyperbaric oxygen therapy in diabetics with chronic foot ulcers
- 2006
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Ingår i: Journal of Wound Care. - 0969-0700. ; 15:10, s. 457-459
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Tidskriftsartikel (refereegranskat)abstract
- Research suggests that hyperbaric oxygen therapy may have beneficial effects on ulcer healing and amputation rates in diabetic patients. This paper describes the design of a study that is evaluating its effects on chronic diabetic foot ulcers.
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25. |
- Möller, Per, et al.
(författare)
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Deglaciation history and subsequent lake dynamics in the Siljan region, south-central Sweden, based on new LiDAR evidence and sediment records
- 2022
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Ingår i: Earth Surface Processes and Landforms. - : Wiley. - 0197-9337 .- 1096-9837. ; 47, s. 3515-3545
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Tidskriftsartikel (refereegranskat)abstract
- The Siljan region hosts Europe´s largest impact structure. The high-relief landscape, with a central granite dome bordered by lake basins, contains an array of glacial and shore-level landforms. We investigated its deglaciation history by mapping and analysing landforms on high resolution LiDAR-based Digital Surface Models coupled with well-dated sediment successions from peat and lake sediment cores. The granite dome and bordering areas are characterized by streamlined terrain and ribbed moraine with a streamlined overprint. These suggest an ice-flow direction from NNW with wet-based thermal conditions prior to deglaciation. During its retreat, the ice sheet was split into thinner plateau ice and thicker basin ice. Sets of low-gradient glaciofluvial erosion channels suggest intense ice-lateral meltwater drainage across gradually ice-freed slopes, while 'down-the-slope' erosion channels and eskers show meltwater drainage from stagnated plateau ice. Thick basin ice receded with a subaqueous margin across the deep Siljan–Orsasjön Basin c. 10,700–10,500 cal. BP. During ice recession the ingression of the Baltic Ancylus Lake led to diachronous formation of highest shoreline marks, from c. 207 m in the south to c. 220 m a.s.l. in the north. Differential uplift resulted in shallowing of the water body, which led to the isolation of the Siljan–Orsasjön Basin from the Baltic Basin at c. 9800 cal. BP. The post-isolation water body – the ‘Ancient Lake Siljan' – was drained through the ancient Åkerö Channel with a water level at 168–169 m a.s.l. during c. 1000 years. A later rerouting of the outlet to the present course was initiated at c. 8800 cal. BP, which led to a lake-level lowering of 6–7 m to today’s level of Lake Siljan (c. 162 m a.s.l.). This study shows the strength of an integrated methodological approach for deciphering the evolution of a complex landscape, combining highly resolved geomorphological analysis with well-dated sediment successions.
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