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- Gautam, Narinder, et al.
(författare)
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Heparin-binding protein (HBP/CAP37): A missing link in neutrophil-evoked alteration of vascular permeability
- 2001
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1546-170X .- 1078-8956. ; 7:10, s. 1123-1127
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Tidskriftsartikel (refereegranskat)abstract
- Polymorphonuclear leukocyte infiltration into tissues in host defense and inflammatory diseasecauses increased vascular permeability and edema formation through unknown mechanisms.Here, we report the involvement of a paracrine mechanism in neutrophil-evoked alteration inendothelial barrier function. We show that upon neutrophil adhesion to the endothelial lining,leukocytic 2 integrin signaling triggers the release of neutrophil-borne heparin-binding protein(HBP), also known as CAP37/azurocidin, a member of the serprocidin family of neutrophilcationic proteins. HBP induced Ca++-dependent cytoskeletal rearrangement and intercellular gapformation in endothelial-cell monolayers in vitro, and increased macromolecular efflux in microvesselsin vivo. Moreover, selective inactivation of HBP prevented the neutrophils from inducingendothelial hyperpermeability. Our data suggest a fundamental role of neutrophil-derivedHBP in the vascular response to neutrophil trafficking in inflammation. Targeting this moleculein inflammatory disease conditions offers a new strategy for prevention of endothelial barrierdysfunction caused by misdirected leukocyte activation.
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- Kenne, Ellinor, et al.
(författare)
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Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice
- 2012
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Ingår i: Journal of Neuroinflammation. - : Springer Science and Business Media LLC. - 1742-2094. ; 9, s. 17-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Brain edema as a result of secondary injury following traumatic brain injury (TBI) is a major clinical concern. Neutrophils are known to cause increased vascular permeability leading to edema formation in peripheral tissue, but their role in the pathology following TBI remains unclear. Methods: In this study we used controlled cortical impact (CCI) as a model for TBI and investigated the role of neutrophils in the response to injury. The outcome of mice that were depleted of neutrophils using an anti-Gr-1 antibody was compared to that in mice with intact neutrophil count. The effect of neutrophil depletion on blood-brain barrier function was assessed by Evan's blue dye extravasation, and analysis of brain water content was used as a measurement of brain edema formation (24 and 48 hours after CCI). Lesion volume was measured 7 and 14 days after CCI. Immunohistochemistry was used to assess cell death, using a marker for cleaved caspase-3 at 24 hours after injury, and microglial/macrophage activation 7 days after CCI. Data were analyzed using Mann-Whitney test for non-parametric data. Results: Neutrophil depletion did not significantly affect Evan's blue extravasation at any time-point after CCI. However, neutrophil-depleted mice exhibited a decreased water content both at 24 and 48 hours after CCI indicating reduced edema formation. Furthermore, brain tissue loss was attenuated in neutropenic mice at 7 and 14 days after injury. Additionally, these mice had a significantly reduced number of activated microglia/macrophages 7 days after CCI, and of cleaved caspase-3 positive cells 24 h after injury. Conclusion: Our results suggest that neutrophils are involved in the edema formation, but not the extravasation of large proteins, as well as contributing to cell death and tissue loss following TBI in mice.
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| 9. |
- Lindbom, Lars, 1972-
(författare)
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Development, Application and Evaluation of Statistical Tools in Pharmacometric Data Analysis
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Pharmacometrics uses models based on pharmacology, physiology and disease for quantitative analysis of interactions between drugs and patients. The availability of software implementing modern statistical methods is important for efficient model building and evaluation throughout pharmacometric data analyses.The aim of this thesis was to facilitate the practical use of available and new statistical methods in the area of pharmacometric data analysis. This involved the development of suitable software tools that allows for efficient use of these methods, characterisation of basic properties and demonstration of their usefulness when applied to real world data. The thesis describes the implementation of a set of statistical methods (the bootstrap, jackknife, case-deletion diagnostics, log-likelihood profiling and stepwise covariate model building), made available as tools through the software Perl-speaks-NONMEM (PsN). The appropriateness of the methods and the consistency of the software tools were evaluated using a large selection of clinical and nonclinical data. Criteria based on clinical relevance were found to be useful components in automated stepwise covariate model building. Their ability to restrict the number of included parameter-covariate relationships while maintaining the predictive performance of the model was demonstrated using the antiarrythmic drug dofetilide. Log-likelihood profiling was shown to be equivalent to the bootstrap for calculating confidence intervals for fixed-effects parameters if an appropriate estimation method is used. The condition number of the covariance matrix for the parameter estimates was shown to be a good indicator of how well resampling methods behave when applied to pharmacometric data analyses using NONMEM. The software developed in this thesis equips modellers with an enhanced set of tools for efficient pharmacometric data analysis.
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| 12. |
- Lindbom, Lars, et al.
(författare)
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Perl-speaks-NONMEM (PsN) – a Perl module for NONMEM related programming
- 2004
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Ingår i: Computer Methods and Programs in Biomedicine. - : Elsevier BV. - 0169-2607 .- 1872-7565. ; 75:2, s. 85-94
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Tidskriftsartikel (refereegranskat)abstract
- The NONMEM program is the most widely used nonlinear regression software in population pharmacokinetic/pharmacodynamic (PK/PD) analyses. In this article we describe a programming library, Perl-speaks-NONMEM (PsN), intended for programmers that aim at using the computational capability of NONMEM in external applications. The library is object oriented and written in the programming language Perl. The classes of the library are built around NONMEM's data, model and output files. The specification of the NONMEM model is easily set or changed through the model and data file classes while the output from a model fit is accessed through the output file class. The classes have methods that help the programmer perform common repetitive tasks, e.g. summarising the output from a NONMEM run, setting the initial estimates of a model based on a previous run or truncating values over a certain threshold in the data file. PsN creates a basis for the development of high-level software using NONMEM as the regression tool.
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| 16. |
- Persson, Kristin, et al.
(författare)
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Severe lung lesions caused by Salmonella are prevented by inhibition of the contact system
- 2000
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 192:10, s. 1415-1424
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Tidskriftsartikel (refereegranskat)abstract
- Vascular damage induced by trauma, inflammation, or infection results in an alteration of the endothelium from a nonactivated to a procoagulant, vasoconstrictive, and proinflammatory state, and can lead to life-threatening complications. Here we report that activation of the contact system by Salmonella leads to massive infiltration of red blood cells and fibrin deposition in the lungs of infected rats. These pulmonary lesions were prevented when the infected animals were treated with H-D-Pro-Phe-Arg-chloromethylketone, an inhibitor of coagulation factor XII and plasma kallikrein, suggesting that inhibition of contact system activation could be used therapeutically in severe infectious disease.
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| 17. |
- Tehler, Henrik, et al.
(författare)
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Evidence-based disaster risk management : A scoping review focusing on risk, resilience and vulnerability assessment
- 2024
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Ingår i: Progress in Disaster Science. - : Elsevier. - 2590-0617. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- A plethora of methods exist to aid decision-making in mitigating disaster risk, many of which fall into the categories of risk, vulnerability and/or resilience assessment methods. The objective of the present study is to provide an overview of these methods, with a particular focus on evidence that supports their practical implementation. A scoping study of scientific literature reveal 97 distinct methods. Despite the growing interest in publishing new methods, there seems to be a lack of focus on demonstrating their effectiveness in practice. The few contributions that do include some forms of evaluation typically do so by comparing the method’s output with disaster data, by contrasting it with the output of other methods, by having experts evaluate the structure of the method, or by testing the method in practice and evaluating its usage. To further strengthen the relevance of research on this topic, increased attention should be paid to this matter. A good starting point would be to use the ways of evaluation identified in this study and systematically present evidence regarding the practical usefulness of methods for risk, vulnerability and/or resilience assessment.
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| 18. |
- Tunblad, Karin, et al.
(författare)
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The use of clinical irrelevance criteria in covariate model building with application to dofetilide pharmacokinetic data
- 2008
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 35:5, s. 503-526
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Tidskriftsartikel (refereegranskat)abstract
- To characterise the pharmacokinetics of dofetilide in patients and to identify clinically relevant parameter-covariate relationships. To investigate three different modelling strategies in covariate model building using dofetilide as an example: (1) using statistical criteria only or in combination with clinical irrelevance criteria for covariate selection, (2) applying covariate effects on total clearance or separately on non-renal and renal clearances and (3) using separate data sets for covariate selection and parameter estimation. Pooled concentration-time data (1,445 patients, 10,133 observations) from phase III clinical trials was used. A population pharmacokinetic model was developed using NONMEM. Stepwise covariate model building was applied to identify important covariates using the strategies described above. Inclusion and exclusion of covariates using clinical irrelevance was based on reduction in interindividual variability and changes in parameters at the extremes of the covariate distribution. Parametric separation of the elimination pathways was accomplished using creatinine clearance as an indicator of renal function. The pooled data was split in three parts which were used for covariate selection, parameter estimation and evaluation of predictive performance. Parameter estimations were done using the first-order (FO) and the first-order conditional estimation (FOCE) methods. A one-compartment model with first order absorption adequately described the data. Using clinical irrelevance criteria resulted in models containing less parameter-covariate relationships with a minor loss in predictive power. A larger number of covariates were found significant when the elimination was divided into a renal part and a non-renal part, but no gain in predictive power could be seen with this data set. The FO and FOCE estimation methods gave almost identical final covariate model structures with similar predictive performance. Clinical irrelevance criteria may be valuable for practical reasons since stricter inclusion/exclusion criteria shortens the run times of the covariate model building procedure and because only the covariates important for the predictive performance are included in the model.
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| 19. |
- Yrlid, Ulf, 1971, et al.
(författare)
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Endothelial repair is dependent on CD11c(+) leukocytes to establish regrowing endothelial sheets with high cellular density
- 2019
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 105:1, s. 195-202
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial injury makes the vessel wall vulnerable to cardiovascular diseases. Injured endothelium regenerates by collective sheet migration, that is, the endothelial cells coordinate their motion and regrow as a sheet of cells with retained cell-cell contacts into the wounded area. Leukocytes appear to be involved in endothelial repair in vivo; however, little is known about their identity and role in the reparative sheet migration process. To address these questions, we developed a high-quality en face technique that enables visualizing of leukocytes and endothelial cells simultaneously following an endoluminal scratch wound injury of the mouse carotid artery. We discovered that regrowing endothelium forms a broad proliferative front accompanied by CD11c(+) leukocytes. Functionally, the leukocytes were dispensable for the initial migratory response of the regrowing endothelial sheet, but critical for the subsequent formation and maintenance of a front zone with high cellular density. Marker expression analyses, genetic fate mapping, phagocyte targeting experiments, and mouse knock-out experiments indicate that the CD11c(+) leukocytes were mononuclear phagocytes with an origin from both Ly6C(high) and Ly6C(low) monocytes. In conclusion, CD11c(+) mononuclear phagocytes are essential for a proper endothelial regrowth following arterial endoluminal scratch injury. Promoting the endothelial-preserving function of CD11c(+) leukocytes may be a strategy to enhance endothelial repair following surgical and endovascular procedures.
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