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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Chew, Michelle, et al.
(författare)
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Depletion of myocardial glucose is observed during endotoxemic but not hemorrhagic shock in a porcine model
- 2013
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Ingår i: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535. ; 17:4
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Metabolic dysfunction is one of the hallmarks of sepsis yet little is known about local changes in key organs such as the heart. The aim of this study was to compare myocardial metabolic changes by direct measurements of substrates, such as glucose, lactate and pyruvate, using microdialysis (MD) in in-vivo porcine endotoxemic and hemorrhagic shock. To assess whether these changes were specific to the heart, we simultaneously investigated substrate levels in skeletal muscle. Methods Twenty-six female pigs were randomized to three groups: control (C) n = 8, endotoxemic shock (E) n = 9 and hemorrhagic shock (H) n = 9. Interstitial myocardial pyruvate, lactate and glucose were measured using MD. Skeletal muscle MD was also performed in all three groups. Results Marked decreases in myocardial glucose were observed in the E group but not in the H group compared to controls (mean difference (CI) in mmol/L: C versus E -1.5(-2.2 to -0.8), P < 0.001; H versus E -1.1(-1.8 to -0.4), P = 0.004; C versus H -0.4(-1.1 to 0.3), P = 0.282). Up to four-fold increases in myocardial pyruvate and three-fold increases in lactate were seen in both shock groups with no differences between the two types of shock. There was no evidence of myocardial anaerobic metabolism, with normal lactate: pyruvate (L:P) ratios seen in all animals regardless of the type of shock. In skeletal muscle, decreases in glucose concentrations were observed in the E group only (mean difference: C versus E -0.8(-1.4 to -0.3), P = 0.007). Although skeletal muscle lactate increased in both shock groups, this was accompanied by increases in pyruvate in the E group only (mean difference: C versus E 121(46 to 195), P = 0.003; H versus E 77(7 to 147), P = 0.032; C versus H 43(-30 to 43), P = 0.229). The L:P ratio was increased in skeletal muscle in response to hemorrhagic, but not endotoxemic, shock. Conclusions Endotoxemia, but not hemorrhage, induces a rapid decrease of myocardial glucose levels. Despite the decrease in glucose, myocardial lactate and pyruvate concentrations were elevated and not different than in hemorrhagic shock. In skeletal muscle, substrate patterns during endotoxemic shock mimicked those seen in myocardium. During hemorrhagic shock the skeletal muscle response was characterized by a lack of increase in pyruvate and higher L: P ratios. Hence, metabolic patterns in the myocardium during endotoxemic shock are different than those seen during hemorrhagic shock. Skeletal muscle and myocardium displayed similar substrate patterns during endotoxemic shock but differed during hemorrhagic shock.
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- Dhanani, Jayesh A, et al.
(författare)
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A research pathway for the study of the delivery and disposition of nebulised antibiotics: an incremental approach from in vitro to large animal models
- 2018
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Ingår i: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic.
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- Dhanani, Jayesh A., et al.
(författare)
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Lung Pharmacokinetics of Tobramycin by Intravenous and Nebulized Dosing in a Mechanically Ventilated Healthy Ovine Model
- 2019
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Ingår i: Anesthesiology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0003-3022 .- 1528-1175. ; 131:2, s. 344-355
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Tidskriftsartikel (refereegranskat)abstract
- Editors PerspectiveWhat We Already Know about This Topic For most bacterial pneumonia, the lung interstitium is considered to be the site of infection, and adequate antibiotic concentrations are important for drug effect Despite systemic antibiotic therapy, therapeutic failure is common, perhaps due to poor lung penetration, and resulting low interstitial space fluid antibiotic concentrations Increasing systemic antibiotic doses in order to increase interstitial space fluid antibiotic concentrations could lead to toxicities such as nephrotoxicity What This Article Tells Us That Is New In a mechanically ventilated healthy large animal model, nebulized tobramycin produced higher peak lung interstitial space fluid concentrations, as well as higher initial epithelial lining fluid concentrations, with lower plasma concentrations than were observed after intravenous administration due to more extensive lung penetration Background: Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Methods: Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. Results: The peak lung interstitial space fluid concentrations were lower with intravenous tobramycin 20.2 mg/l (interquartile range, 12 mg/l, 26.2 mg/l) versus the nebulized route 48.3 mg/l (interquartile range, 8.7 mg/l, 513 mg/l), P = 0.002. For nebulized tobramycin, the median epithelial lining fluid concentrations were higher than the interstitial space fluid concentrations at 1 h (1,637; interquartile range, 650, 1,781, vs. 16 mg/l, interquartile range, 7, 86, P amp;lt; 0.001) and 6 h (48, interquartile range, 17, 93, vs. 4 mg/l, interquartile range, 2, 9, P amp;lt; 0.001). For intravenous tobramycin, the median epithelial lining fluid concentrations were lower than the interstitial space fluid concentrations at 1 h (0.19, interquartile range, 0.11, 0.31, vs. 18.5 mg/l, interquartile range, 9.8, 23.4, P amp;lt; 0.001) and 6 h (0.34, interquartile range, 0.2, 0.48, vs. 3.2 mg/l, interquartile range, 0.9, 4.4, P amp;lt; 0.001). Conclusions: Compared with intravenous tobramycin, nebulized tobramycin achieved higher lung interstitial fluid and epithelial lining fluid concentrations without increasing systemic concentrations.
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| 6. |
- Dhanani, Jayesh A, et al.
(författare)
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Recovery rates of combination antibiotic therapy using in vitro microdialysis simulating in vivo conditions
- 2018
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Ingår i: Journal of pharmaceutical analysis. - : Elsevier BV. - 2214-0883 .- 2095-1779. ; 8:6, s. 407-412
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Tidskriftsartikel (refereegranskat)abstract
- Microdialysis is a technique used to measure the unbound antibiotic concentration in the interstitial spaces, the target site of action. In vitro recovery studies are essential to calibrating the microdialysis system for in vivo studies. The effect of a combination of antibiotics on recovery into microdialysate requires investigation. In vitro microdialysis recovery studies were conducted on a combination of vancomycin and tobramycin, in a simulated in vivo model. Comparison was made between recoveries for three different concentrations and three different perfusate flow rates. The overall relative recovery for vancomycin was lower than that of tobramycin. For tobramycin, a concentration of 20µg/mL and flow rate of 1.0µL/min had the best recovery. A concentration of 5.0µg/mL and flow rate of 1.0µL/min yielded maximal recovery for vancomycin. Large molecular size and higher protein binding resulted in lower relative recoveries for vancomycin. Perfusate flow rates and drug concentrations affected the relative recovery when a combination of vancomycin and tobramycin was tested. Low perfusate flow rates were associated with higher recovery rates. For combination antibiotic measurement which includes agents that are highly protein bound, in vitro studies performed prior to in vivo studies may ensure the reliable measurement of unbound concentrations.
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| 8. |
- Ersmark, Erik, et al.
(författare)
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Population demography and genetic diversity in the Pleistocene cave lion
- 2015
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Ingår i: Open Quaternary. - : Ubiquity Press, Ltd.. - 2055-298X. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- With a range that covered most of northern Eurasia and parts of North America, the cave lion (Panthera spelaea) was one of the most widespread carnivores of the Late Pleistocene. Earlier ancient DNA analyses have shown that it is distinct from modern lions, and have suggested a demographic decline in Beringia during marine isotope stage 3 (MIS 3). Here, we further investigate the Late Pleistocene population dynamics in more detail by combining a powerful algorithm that couples MCMC with coalescent simulations under an approximate Bayesian computation framework. We use an ancient DNA dataset of previously published (n = 34) and new radiocarbon dated specimens (n = 14). Phylogenetic and network analyses based on the mitochondrial control region and the ATP8 gene identified two major haplogroups, one of which appears to vanish around 41,000 cal a BP. The approximate Bayesian computation analysis suggested a decline in effective population size (Ne) in Beringia of at least a 2-fold magnitude that began approximately 47,000 cal a BP, followed by an increase in Ne, most likely around 18,000 cal a BP. The cave lion went through a demographic bottleneck during MIS 3, which may have lasted for several tens of thousands of years, and only recovered shortly before the species' extinction. Several other large mammal species display similar declines in genetic diversity in Beringia during MIS 3, suggesting that major environmental changes might have affected megafaunal populations during this time period.
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| 9. |
- Frantz, Laurent A. F., et al.
(författare)
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Ancient pigs reveal a near-complete genomic turnover following their introduction to Europe
- 2019
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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. ; 116:35, s. 17231-17238
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Tidskriftsartikel (refereegranskat)abstract
- Archaeological evidence indicates that pig domestication had begun by similar to 10,500 y before the present ( BP) in the Near East, and mitochondrial DNA ( mtDNA) suggests that pigs arrived in Europe alongside farmers similar to 8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.
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| 11. |
- McKay, James D., et al.
(författare)
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Lung cancer susceptibility locus at 5p15.33
- 2008
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 40:12, s. 1404-1406
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Tidskriftsartikel (refereegranskat)abstract
- We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P - 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.
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| 12. |
- Rocklöv, Joacim, et al.
(författare)
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On the estimation of heat-intensity and heat-duration effects in time series models of temperature-related mortality in Stockholm, Sweden
- 2012
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Ingår i: Environmental Health. - 1476-069X. ; 11, s. 23-
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Tidskriftsartikel (refereegranskat)abstract
- Background: We examine the effect of heat waves on mortality, over and above what would be predicted on the basis of temperature alone.Methods: Present modeling approaches may not fully capture extra effects relating to heat wave duration, possibly because the mechanisms of action and the population at risk are different under more extreme conditions. Modeling such extra effects can be achieved using the commonly left-out effect-modification between the lags of temperature in distributed lag models.Results: Using data from Stockholm, Sweden, and a variety of modeling approaches, we found that heat wave effects amount to a stable and statistically significant 8.1-11.6% increase in excess deaths per heat wave day. The effects explicitly relating to heat wave duration (2.0-3.9% excess deaths per day) were more sensitive to the degrees of freedom allowed for in the overall temperature-mortality relationship. However, allowing for a very large number of degrees of freedom indicated over-fitting the overall temperature-mortality relationship.Conclusions: Modeling additional heat wave effects, e. g. between lag effect-modification, can give a better description of the effects from extreme temperatures, particularly in the non-elderly population. We speculate that it is biologically plausible to differentiate effects from heat and heat wave duration.
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| 13. |
- Schulz, Robert, et al.
(författare)
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Is the future of peer review automated?
- 2022
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Ingår i: BMC Research Notes. - : Springer Nature. - 1756-0500. ; 15:1
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The rising rate of preprints and publications, combined with persistent inadequate reporting practices and problems with study design and execution, have strained the traditional peer review system. Automated screening tools could potentially enhance peer review by helping authors, journal editors, and reviewers to identify beneficial practices and common problems in preprints or submitted manuscripts. Tools can screen many papers quickly, and may be particularly helpful in assessing compliance with journal policies and with straightforward items in reporting guidelines. However, existing tools cannot understand or interpret the paper in the context of the scientific literature. Tools cannot yet determine whether the methods used are suitable to answer the research question, or whether the data support the authors' conclusions. Editors and peer reviewers are essential for assessing journal fit and the overall quality of a paper, including the experimental design, the soundness of the study's conclusions, potential impact and innovation. Automated screening tools cannot replace peer review, but may aid authors, reviewers, and editors in improving scientific papers. Strategies for responsible use of automated tools in peer review may include setting performance criteria for tools, transparently reporting tool performance and use, and training users to interpret reports.
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