41.
Gullberg, Elisabet, et al.
(author)
Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis
2008
In: Laboratory investigation; a journal of technical methods and pathology. - New York, USA : Elsevier BV. - 1530-0307 .- 0023-6837. ; 88:11, s. 1215-26
Journal article (peer-reviewed) abstract
Crohn's disease is characterized by a defect in intestinal barrier function, where bacteria are considered the most important inflammation-driving factor. Enteric bacteria, including E. coli and Yersinia spp, affect tight junctions in enterocytes, but little is known about bacterial effects on the transcellular pathway. Our objective was to study the short-term effects of Y. pseudotuberculosis on uptake of nanoparticles across human villus epithelium. Monolayers of human colon epithelium-derived Caco-2 cells and biopsies of normal human ileum were studied after 2 h exposure to Y. pseudotuberculosis expressing (inv+) or lacking (inv-) the bacterial adhesion molecule, invasin. Transepithelial transport of fluorescent nanoparticles (markers of transcytosis) was quantified by flow cytometry, and mechanisms explored by using inhibitors of endocytosis. Epithelial expressions of beta1-integrin and particle uptake pathways were studied by confocal microscopy. The paracellular pathway was assessed by electrical resistance (TER), mannitol flux, and expression of tight junction proteins occludin and caludin-4 by confocal microscopy. Inv+ Y. pseudotuberculosis adhered to the apical surface of epithelial cells and induced transcytosis of exogenous nanoparticles across Caco-2 monolayers (30-fold increase, P<0.01) and ileal mucosa (268+/-47% of control; P<0.01), whereas inv bacteria had no effect on transcytosis. The transcytosis was concentration-, particle size- and temperature-dependent, and possibly mediated via macropinocytosis. Y. pseudotuberculosis also induced apical expression of beta1-integrin on epithelial cells. A slight drop in TER was seen after exposure to inv+ Y. pseudotuberculosis, whereas mannitol flux and tight junction protein expression was unchanged. In summary, Y. pseudotuberculosis induced apical expression of beta1-integrin and stimulated uptake of nanoparticles via invasin-dependent transcytosis in human intestinal epithelium. Our findings suggest that bacterial factors may initiate transcytosis of luminal exogenous particles across human ileal mucosa, thus presenting a novel mechanism of intestinal barrier dysfunction.
42.
43.
Jia, Juan, et al.
(author)
Lack of L-iduronic acid in heparan sulfate affects interaction with growth factors and cell signaling
2009
In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 284:23, s. 15942-15950
Journal article (peer-reviewed) abstract
Glucuronyl C5-epimerase (Hsepi) catalyzes the conversion of D-glucuronic acid to L-iduronic acid in heparan sulfate (HS) biosynthesis. Disruption of the Hsepi gene in mouse yielded a lethal phenotype with selective organ defects, but had remarkably little effect on other organ systems. We have approached the underlying mechanisms by examining the course and effects of FGF2 signaling in a mouse embryonic fibroblast (MEF) cell line derived from the Hsepi-/- mouse. The HS produced by these cells is devoid of IdoA residues, but shows upregulated N- and 6-O-sulfation compared to wildtype (WT) MEF HS. In medium fortified with 10% FCS the Hsepi-/- MEFs proliferated and migrated similar to WT cells. Under starvation conditions both cell types showed attenuated proliferation and migration, that could be restored by addition of FGF2 to WT cells whereas Hsepi-/- cells were resistant. Moreover, ERK phosphorylation following FGF2 stimulation was delayed in Hsepi-/- compared to WT cells. Assessment of HS-growth factor interaction by nitrocellulose filter trapping revealed strikingly aberrant binding property of FGF2 and glia-derived neurotropic factor (GDNF) to Hsepi-/- but not to WT HS. GDNF has a key role in kidney development, defective in Hsepi-/- mice. By contrast, Hsepi-/- and WT HS interacted similarly and in conventional mode with FGF10. These findings correlate defective function of growth factors with their mode of HS interaction, and may help explain the partly modest organ phenotypes observed after genetic ablation of selected enzymes in HS biosynthesis.
44.
45.
Lacroix, Brigitte, 1978-, et al.
(author)
A Pharmacodynamic Markov Mixed-Effects Model for Determining the Effect of Exposure to Certolizumab Pegol on the ACR20 Score in Patients With Rheumatoid Arthritis
2009
In: Clinical Pharmacology and Therapeutics. - : Nature Publishing Group. - 0009-9236 .- 1532-6535. ; 86:4, s. 387-395
Journal article (peer-reviewed) abstract
The American College of Rheumatology 20% preliminary definition of improvement of rheumatoid arthritis (ACR20) is widely used in clinical trials to assess response to treatment. The objective of this analysis was to develop an exposure-response model of ACR20 in subjects treated with certolizumab pegol, and to predict clinical outcome following various treatment schedules. At each visit, subjects were classified as being ACR20 responders, ACR20 non-responders, or having dropped out. A Markov mixed-effect model was developed to investigate the drug effect on the transitions between the 3 defined states. Increasing certolizumab pegol exposure predicted an increasing probability of becoming a responder and remaining a responder, as well as a reduced probability of dropping out of treatment. Simulations of the ACR20 response rate support dosing regimens of 400 mg at weeks 0, 2 and 4 followed by 200 mg every 2 weeks, or alternative maintenance regimen of 400 mg every 4 weeks.
46.
Le Bon, O., et al.
(author)
Personality profile and drug of choice; a multivariate analysis using Cloninger's TCI on heroin addicts, alcoholics, and a random population group
2004
In: Drug Alcohol Depend. - 0376-8716. ; 73:2, s. 175-82
Journal article (peer-reviewed) abstract
As personality may predispose, precipitate or perpetuate substance abuse and/or dependence, and as it is considered to remain stable across the years in a given subject, potential links with the drug of choice may help screen future patients before drug consumption. The present study compared three groups: 42 patients with heroin dependence (mean age: 31.2; standard deviation (SD): 5.5; 10 females), 37 patients with alcohol dependence (mean age 44.2; SD: 9.1; 9 females) and 83 subjects from a random population sample (mean age: 38.8; SD: 6.9; 20 females). Personality was measured by Cloninger's Temperament and Character Inventory (TCI). Pillai's MANCOVA with age as a covariate and gender as a cofactor was highly significant. Univariate ANOVA analyses using TCI dimensions as dependent variable showed most variables to vary in parallel for the two patient groups in comparison with controls. Post-hoc tests showed heroin patients to score higher in Novelty-Seeking and Self-Directedness than alcohol patients. Sub-dimensions Exploratory Excitability, Fear of the Uncertain, Responsibility, Congruent Second Nature and Transpersonal Identification were also significantly different in the two patient samples. Logistic regression showed Exploratory Excitability to segregate up to 76% of heroin patients from alcohol patients. In conclusion, personality profiles were linked to some preferential choice of drug and personality screening might be tested in preventive strategies.
47.
Lindegardh, N, et al.
(author)
Quantification of artemisinin in human plasma using liquid chromatography coupled to tandem mass spectrometry.
2009
In: Journal of pharmaceutical and biomedical analysis. - : Elsevier BV. - 1873-264X .- 0731-7085. ; 49:3, s. 768-73
Journal article (peer-reviewed) abstract
A liquid chromatographic tandem mass spectroscopy method for the quantification of artemisinin in human heparinised plasma has been developed and validated. The method uses Oasis HLB mu-elution solid phase extraction 96-well plates to facilitate a high throughput of 192 samples a day. Artesunate (internal standard) in a plasma-water solution was added to plasma (50 microL) before solid phase extraction. Artemisinin and its internal standard artesunate were analysed by liquid chromatography and MS/MS detection on a Hypersil Gold C18 (100 mm x 2.1 mm, 5 microm) column using a mobile phase containing acetonitrile-ammonium acetate 10mM pH 3.5 (50:50, v/v) at a flow rate of 0.5 mL/min. The method has been validated according to published FDA guidelines and showed excellent performance. The within-day, between-day and total precisions expressed as R.S.D., were lower than 8% at all tested quality control levels including the upper and lower limit of quantification. The limit of detection was 0.257 ng/mL for artemisinin and the calibration range was 1.03-762 ng/mL using 50 microL plasma. The method was free from matrix effects as demonstrated both graphically and quantitatively.
48.
Lundälv, Jörgen, 1966
(author)
Bioterrorism och media
2004
Book (other academic/artistic) abstract
Attacker med biologiska och kemiska preparat är ett nytt hot mot institutioner i världen bl.a massmedia. I USA har ett antal medieföretag attackerats med brev som visat sig innehålla mjältbrand. I Sverige utsätts medier för hot och risker med jämna mellanrum. Denna guide om säkerhet och beredskap ger ny kunskap om vad bioterrorism innebär och vilka hotbilder som finns mot medieföretag i Sverige. Den vänder sig också till informationsstrateger vid myndigheter och företag liksom till hälso- och sjukvårdspersonal med intresse för epidemiologiska frågor. Guiden inleds med företal av Gorm Albrechtsen, f.d. chefredaktör vid Herning Folkeblad i Danmark som utsatts för misstänkta pulverbrev samt av Åke Sellström, avdelningschef vid Totalförsvarets forskningsinstitut (FOI) och expert på biologiska och kemiska vapen.
49.
Löfmark, Sonja, et al.
(author)
Clindamycin-induced enrichment and long-term persistence of resistant Bacteroides spp. and resistance genes
2006
In: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 58:6, s. 1160-1167
Journal article (peer-reviewed) abstract
Objectives: The aim was to study the long-term consequences of 1 week clindamycin administration regarding selection and persistence of resistance, resistance determinants and diversity of the Bacteroides spp. in the intestinal microflora. Methods: A total of 1306 Bacteroides isolates were collected from constitutively cultured faecal samples during a 2 year period from eight healthy volunteers. The strains were identified by biochemical and genotyping methods. MIC values were determined by the agar dilution method and presence of resistance genes was screened by real-time PCR. Results: Ecological changes in the intestinal microflora persisting up to 24 months were recorded after a 7 day clindamycin administration to four healthy volunteers. Compared to a control group, not exposed to clindamycin, an enrichment and stabilization of resistant Bacteroides strains and resistance determinants were discovered up to 2 years after clindamycin exposure. Conclusions: The results indicate that even a short-term antibiotic administration can cause long-term alterations in the commensal microbiota of individual subjects, detectable 2 years after dosing. The recorded selection and persistence of resistant strains and resistance genes, illustrates the importance of increasing our knowledge of the role of the abundant intestinal microbial community as a reservoir for spread of resistance.
50.
Magnusson, Marie, et al.
(author)
Effects of pentoxifylline and its metabolites on platelet aggregation in whole blood from healthy humans
2008
In: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 581:3, s. 290-5
Journal article (peer-reviewed) abstract
It is known that pentoxifylline inhibits platelet aggregation in vitro, but the effects from pentoxifylline and its main metabolites: 3,7-dimetyl-1(5 hydroxyhexyl)xanthine (R-M1 and S-M1), 3,7-dimetyl -1(4-carboxybutyl)xanthine (M4), 3,7-dimetyl -1(3-carboxypropyl)xanthine (M5), on platelet aggregation in whole blood in vitro and in vivo have not been studied. We found that pentoxifylline, rac-M1, R-M1, S-M1 and M4 significantly inhibit ADP induced platelet aggregation in whole blood in vitro in a concentration-dependent manner, R-M1 being the most potent followed by rac-M1, S-M1, pentoxifylline, and M4. In this series of experiments the effects on aggregation induced ATP-release were less pronounced and were only significant after treatment with pentoxifylline, rac-M1 and R-M1, but the potency order appears to be the same. Since the metabolites are not available for use in humans, and also since each substance would be extensively metabolised in vivo, we made an attempt to estimate the relative contribution of each substance to the total effect of pentoxifylline in vivo. Previously published concentrations of pentoxifylline and these metabolites in humans, after administration of pentoxifylline, were used in combination with the potency ratios from this study. The findings from these calculations were that the main effect in vivo comes from S-M1 followed by pentoxifylline, the other metabolites contribute less than 10% each. In conclusion: in the following potency order R-M1, rac-M1, pentoxifylline, S-M1 and M4 all have significant effects on platelet aggregation in whole blood in vitro. However, it appears that the main effects in vivo are caused by S-M1 and pentoxifylline.
