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  • Sjöberg, Rickard L, et al. (författare)
  • Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene
  • 2006
  • Ingår i: International Journal of Neuropsychopharmacology. - Uppsala Univ, Cent Hosp Vasteras, Clin Res Ctr, S-72189 Vasteras, Sweden. Univ Uppsala, Pharmacol Unit, Dept Neurosci, Uppsala, Sweden. : CAMBRIDGE UNIV PRESS. - 1461-1457 .- 1469-5111. ; 9:4, s. 443-449
  • Tidskriftsartikel (refereegranskat)abstract
    • Previous research has demonstrated that a polymorphism in the serotonin transporter gene (5-HTTLPR) and adverse psychosocial circumstances interact to predict depression. The purpose of the present study was to explore the extent to which sex modulates these effects. Eighty-one boys and 119 girls (16-19 years old) were interviewed about psychosocial background variables and genotyped for the 5-HTT promoter polymorphism. There were two main results. First, boys and girls carrying the short 5-HTTLPR allele react to different kinds of environmental factors. Whereas males were affected by living in public housing rather than in own owned homes and by living with separated parents, females were affected by traumatic conflicts within the family. Second, the responses of males and females carrying the short 5-HTTLPR allele to environmental stress factors go in opposite directions. Thus, whereas females tend to develop depressive symptoms, males seem to be protected from depression. The results suggest that both the molecular and the psychosocial mechanisms underlying depression may differ between boys and girls.
  • Wallén-Mackenzie, Åsa, et al. (författare)
  • Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
  • 2009
  • Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
  • Tidskriftsartikel (refereegranskat)abstract
    • A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
  • Wallengren, Joanna, et al. (författare)
  • Local skin lesions in the rat after subcutaneous deposition of capsaicin
  • 2002
  • Ingår i: Skin Pharmacology and Applied Skin Physiology. - : Karger. - 1422-2868. ; 15:3, s. 154-165
  • Tidskriftsartikel (refereegranskat)abstract
    • Capsaicin is used to investigate the role of peripheral sensory nerve fibers. In previous studies of rats treated by injection of capsaicin into the skin of the neck, 'spontaneous' lesions in the head and neck region were observed. In this study, the course of development over time, the regional distribution and the innervation of capsaicin-induced dermal lesions were assessed in young male Sprague-Dawley rats. In one experiment, capsaicin was administered subcutaneously by injection in the skin of the neck. In a second experiment, capsaicin was injected in the back by a long needle that tunneled under the skin and allowed the capsaicin to be deposited in the subcutaneous fat of the neck. The density and the distribution of dermal nerve fibers were investigated by immunohistochemistry, using antisera against a panneuronal marker, protein gene product 9.5 (PGP), and calcitonin gene-related peptide (CGRP). In the first experiment, rats developed lesions in the neck area 11 days after injection. In the second experiment, lesions appeared in the skin of the back and occasionally in the neck area 10 days after injection. Development of lesions in the afflicted areas was paralleled by local reduction in the density of CGRP-immunoreactive (IR) nerve fibers, 80% in the first experiment and 72% in the second. The number of PGP-IR fibers was likewise reduced, by 39 and 41%, respectively. The density of the CGRP-IR fibers in the wound area was the same as in the adjacent, nonlesioned skin. The healing of the capsaicin-induced lesions was slow compared with surgical wounds in control animals. The wounds healed with hypertrophic scars. The healing process in the skin of the back was associated with the proliferation of CGRP-IR fibers. The study shows cutaneous lesions to appear in the region of the subcutaneous deposition of capsaicin. A uniform depletion of capsaicin-sensitive nerve fibers in the area of deposition suggests that an additional factor is needed to induce lesions. Possibly, impaired nociception in the afflicted area results in more vigorous grooming behavior and this, in turn, in a local skin damage.
  • Wettermark, Bjoern, et al. (författare)
  • Secondary prevention in a large stroke population - A study of patients' purchase of recommended drugs
  • 2008
  • Ingår i: Stroke. - New York : American Heart Association. - 0039-2499 .- 1524-4628. ; 39:10, s. 2880-2885
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose - In this study, linked, anonymous data from The National Hospital Discharge Register and the Swedish Prescribed Drug Register were used for studying to what extent recommended drugs for secondary prevention after stroke and TIA were purchased by patients in the region of Stockholm, Sweden (2 million inhabitants). Methods - Data on purchased drugs for secondary stroke prevention during July 2005 to June 2006 by 17 902 patients > 18 years discharged after stroke or TIA during the period 1997 to June 2005 were analyzed by age, gender, and year of discharge. Results - Antiplatelets and warfarin were purchased by 87% of all stroke and 83% of all TIA patients, antihypertensives by 74% and 70%, and lipid lowering drugs by 41% and 39%, respectively. Conclusion - Time after discharge had only a minor influence on the proportion of patients purchasing the medicines.
  • Karypidis, A.-H., et al. (författare)
  • Deletion polymorphism of the UGT2B17 gene is associated with increased risk for prostate cancer and correlated to gene expression in the prostate
  • 2008
  • Ingår i: The Pharmacogenomics Journal. - Avenet, NJ : Nature Pub. Group. - 1470-269X .- 1473-1150. ; 8:2, s. 147-151
  • Tidskriftsartikel (refereegranskat)abstract
    • Metabolism of androgens includes glucuronidation, the major pathway of steroid elimination in several steroid target tissues. Glucuronidation is catalysed by UDP-glucuronosyltransferases (UGTs). UGT2B17 has been shown to be particularly active against androgens and is highly abundant in the prostate. Recently, we discovered that deletion of the UGT2B17 gene is associated with low or undetectable urinary testosterone levels. Here, we determined the phenotypic outcome of the deletion by quantifying the UGT2B17 mRNA expression in normal prostate tissues in individuals with different genotypes. Additionally, the frequency of UGT2B17 deletion polymorphism was studied in a Swedish population-based case–control study including 176 patients diagnosed with prostate cancer and 161 controls. We found that the individuals homozygous for the insertion allele expressed 30 times more UGT2B17 mRNA in prostate tissue than the heterozygotes. Carriers of the deletion allele had a significantly increased risk of prostate cancer (OR=2.07; 95% CI=1.32–3.25). In conclusion, these results show the UGT2B17 deletion polymorphism is associated with prostate cancer risk. 
  • Abdurahman, Samir, 1965-, et al. (författare)
  • Activity of the small modified amino acid alpha-hydroxy glycineamide on in vitro and in vivo human immunodeficiency virus type 1 capsid assembly and infectivity
  • 2008
  • Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 52:10, s. 3737-3744
  • Tidskriftsartikel (refereegranskat)abstract
    • Upon maturation of the human immunodeficiency virus type 1 (HIV-1) virion, proteolytic cleavage of the Gag precursor protein by the viral protease is followed by morphological changes of the capsid protein p24, which will ultimately transform the virus core from an immature spherical to a mature conical structure. Virion infectivity is critically dependent on the optimal semistability of the capsid cone structure. We have reported earlier that glycineamide (G-NH(2)), when added to the culture medium of infected cells, inhibits HIV-1 replication and that HIV-1 particles with aberrant core structures were formed. Here we show that it is not G-NH(2) itself but a metabolite thereof, alpha-hydroxy-glycineamide (alpha-HGA), that is responsible for the antiviral activity. We show that alpha-HGA inhibits the replication of clinical HIV-1 isolates with acquired resistance to reverse transcriptase and protease inhibitors but has no effect on the replication of any of 10 different RNA and DNA viruses. alpha-HGA affected the ability of the HIV-1 capsid protein to assemble into tubular or core structures in vitro and in vivo, probably by binding to the hinge region between the N- and C-terminal domains of the HIV-1 capsid protein as indicated by matrix-assisted laser desorption ionization-mass spectrometry results. As an antiviral compound, alpha-HGA has an unusually simple structure, a pronounced antiviral specificity, and a novel mechanism of antiviral action. As such, it might prove to be a lead compound for a new class of anti-HIV substances.
  • Bengtsson, Jörgen, et al. (författare)
  • The influence of age on the distribution of morphine and morphine-3-glucuronide across the blood-brain barrier in sheep
  • 2009
  • Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 157:6, s. 96-1085
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND PURPOSE: The effect of age on the distribution of morphine and morphine-3-glucuronide (M3G) across the blood-brain barrier (BBB) was studied in a sheep model utilizing intracerebral microdialysis. The effect of neonatal asphyxia on brain drug distribution was also studied.EXPERIMENTAL APPROACH: Microdialysis probes were inserted into the cortex, striatum and blood of 11 lambs (127 gestation days) and six ewes. Morphine, 1 mg x kg(-1), was intravenously administered as a 10 min constant infusion. Microdialysis and blood samples were collected for up to 360 min and analysed using liquid chromatography-tandem mass spectrometry. The half-life, clearance, volume of distribution, unbound drug brain : blood distribution ratio (K(p,uu)) and unbound drug volume of distribution in brain (V(u,brain)) were estimated.KEY RESULTS: Morphine K(p,uu) was 1.19 and 1.89 for the sheep and premature lambs, respectively, indicating that active influx into the brain decreases with age. Induced asphyxia did not affect transport of morphine or M3G across the BBB. Morphine V(u,brain) measurements were higher in sheep than in premature lambs. The M3G K(p,uu) values were 0.27 and 0.17 in sheep and premature lambs, indicating a net efflux from the brain in both groups.CONCLUSIONS AND IMPLICATIONS: The morphine K(p,uu) was above unity, indicating active transport into the brain; influx was significantly higher in premature lambs than in adult sheep. These results in sheep differ from those in humans, rats, mice and pigs where a net efflux of morphine from the brain is observed.
  • Granberg, Lizette, et al. (författare)
  • CYP1A1 and CYP1B1 in blood-brain interfaces : CYP1A1-dependent bioactivation of 7,12-dimethylbenz(a)anthracene in endothelial cells.
  • 2003
  • Ingår i: Drug Metabolism And Disposition. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556 .- 1521-009X. ; 31:3, s. 259-265
  • Tidskriftsartikel (refereegranskat)abstract
    • Immunohistochemistry and autoradiography were used to identify sites of the cytochrome P450 enzymes (P450) 1A1 and 1B1 expression and activation of 7,12-dimethylbenz(a)anthracene (DMBA), in the brain of rodents pretreated with the aryl hydrocarbon receptor (AhR) agonists beta-naphthoflavone (BNF), 3,3',4,4',5-pentachlorobiphenyl or vehicle. Immunohistochemistry revealed that CYP1A1 was preferentially induced in endothelial cells (EC) in the choroid plexus, in veins in the leptomeninges, and in cerebral veins of AhR agonist-pretreated mice. No induction occurred in cerebral capillary EC. In vehicle-treated mice no localization of CYP1A1 in EC was observed. CYP1B1 was expressed in smooth muscle cells of arteries in the leptomeninges, in cerebral arteries/arterioles and to a low extent in ependymal cells of AhR agonist- and vehicle-treated mice. No CYP1B1 was detected in capillary loops of the choroid plexus or in cerebral capillaries. Following administration of [(3)H]DMBA to BNF-pretreated mice, a marked irreversible binding in EC of the choroid plexus and of veins in the leptomeninges was observed but not in cerebral capillaries. In vehicle-treated mice, there was no [(3)H]DMBA-binding at these sites. Furthermore, a high level of irreversibly bound [(3)H]DMBA occurred in EC at these sites in precision-cut mouse/rat brain slices and in excised blood-brain interfaces incubated with [(3)H]DMBA. Since [(3)H]DMBA binding sites corresponded with the sites of CYP1A1 induction, we conclude that rodents express a constitutively low but highly inducible and functional CYP1A1 in EC of some of the blood-brain interfaces. The role of CYP1A1/1B1 and environmental pollutants in the etiology of cerebrovascular disease needs further consideration.
  • Gullberg, Elisabet, et al. (författare)
  • Yersinia pseudotuberculosis induces transcytosis of nanoparticles across human intestinal villus epithelium via invasin-dependent macropinocytosis
  • 2008
  • Ingår i: Laboratory investigation; a journal of technical methods and pathology. - New York, USA : Springer Science and Business Media LLC. - 1530-0307 .- 0023-6837. ; 88:11, s. 1215-26
  • Tidskriftsartikel (refereegranskat)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.
  • Jia, Juan, et al. (författare)
  • Lack of L-iduronic acid in heparan sulfate affects interaction with growth factors and cell signaling
  • 2009
  • Ingår i: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 284:23, s. 15942-15950
  • Tidskriftsartikel (refereegranskat)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.
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