| 11. |
- Antonov, D, et al.
(författare)
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HCV inhibiting macrocyclic phenylcarbamates
- 2008
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Patent (populärvet., debatt m.m.)abstract
- Compounds of the formula I: including a stereoisomer thereof, or an N-oxide, a pharmaceutically acceptable addition salt, or a pharmaceutically acceptable addition solvate thereof; useful as HCV inhibitors; processes for preparing these compounds as well as pharmaceutical compositions comprising these compounds as active ingredient.
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| 12. |
- Arvidsson, Alf, et al.
(författare)
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För Sverige i tiden?
- 2009
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Ingår i: Kulturella perspektiv - Svensk etnologisk tidskrift. - Umeå. - 1102-7908. ; 18:2, s. 2-8
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Tidskriftsartikel (refereegranskat)
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| 13. |
- Braun, Oscar, et al.
(författare)
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Residual platelet ADP reactivity after clopidogrel treatment is dependent on activation of both the unblocked P2Y(1) and the P2Y (12) receptor and is correlated with protein expression of P2Y (12).
- 2007
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Ingår i: Purinergic Signalling. - : Springer Science and Business Media LLC. - 1573-9546 .- 1573-9538. ; 3:3, s. 195-201
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Tidskriftsartikel (refereegranskat)abstract
- Two ADP receptors have been identified on human platelets: P2Y(1) and P2Y(12). The P2Y(12) receptor blocker clopidogrel is widely used to reduce the risks in acute coronary syndromes, but, currently, there is no P2Y(1) blocker in clinical use. Evidence for variable responses to clopidogrel has been described in several reports. The mechanistic explanation for this phenomenon is not fully understood. The aim of this study was to examine mechanisms responsible for variability of 2MeS-ADP, a stable ADP analogue, induced platelet reactivity in clopidogrel-treated patients. Platelet reactivity was assessed by flow cytometry measurements of P-selectin (CD62P) and activated GpIIb/IIIa complex (PAC-1). Residual 2MeS-ADP activation via the P2Y(12) and P2Y(1) receptors was determined by co-incubation with the selective antagonists AR-C69931 and MRS2179 in vitro. P2Y(1) and P2Y(12) receptor expression on both RNA and protein level were determined, as well as the P2Y(12) H1 or H2 haplotypes. Our data suggest that the residual platelet activation of 2MeS-ADP after clopidogrel treatment is partly due to an inadequate antagonistic effect of clopidogrel on the P2Y(12) receptor and partly due to activation of the P2Y(1) receptor, which is unaffected by clopidogrel. Moreover, a correlation between increased P2Y(12) protein expression on platelets and decreased response to clopidogrel was noticed, r(2)=0.43 (P<0.05). No correlation was found between P2Y(12) mRNA levels and clopidogrel resistance, indicating post-transcriptional mechanisms. To achieve additional ADP inhibition in platelets, antagonists directed at the P2Y(1) receptor could be more promising than the development of more potent P2Y(12) receptor antagonists.
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| 14. |
- Dimberg, Anna, et al.
(författare)
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Inhibition of monocytic differentiation by phosphorylation-deficient Stat1 is associated with impaired expression of Stat2, ICSBP/IRF8 and C/EBP epsilon
- 2006
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 64:3, s. 271-279
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Tidskriftsartikel (refereegranskat)abstract
- Monocytic differentiation is coordinated through the ordered activation of multiple signalling pathways, controlling transcription of specific subsets of genes that regulate the development of the mature phenotype. To identify key transcription factors involved in this process, we used the human monoblastic U-937 cell line as a model of monocytic differentiation. U-937 cells can be differentiated by treatment with all-trans retinoic acid (ATRA) and 1,25 alpha-dihydroxycholecalciferol (VitD3), resulting in G(0)/G(1)-arrested cells expressing monocytic surface markers. We have previously shown that ATRA-induced differentiation and cell cycle arrest specifically requires Stat1 activation, through phosphorylation of tyrosine 701 and serine 727. In this report, we used U-937 cells expressing phosphorylation-deficient mutants of Stat1 (Stat1Y701F and Stat1S727A) to determine myeloid-specific transcription factors that are activated downstream of Stat1 during induced monocytic differentiation. We demonstrate that ATRA-induced upregulation of Stat2, ICSBP/IRF8 and C/EBP epsilon, key transcription factors linked to myelomonocytic differentiation, is selectively impaired in cells expressing mutant Stat1. In contrast, ATRA-induced expression of PU.1, C/EBP alpha, C/EBP beta and IRF-1 was unaffected. Taken together, our data suggest that ATRA-induced regulation of Stat2, ICSBP and C/EBP epsilon is dependent on active Stat1, and that a failure to correctly regulate these transcription factors is associated with the inhibition of monocytic differentiation.
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| 15. |
- Doverhag, Christina, 1979, et al.
(författare)
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Pharmacological and genetic inhibition of NADPH oxidase does not reduce brain damage in different models of perinatal brain injury in newborn mice
- 2008
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 1095-953X .- 0969-9961. ; 31:1, s. 133-44
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Inflammation and reactive oxygen species (ROS) are important in the development of perinatal brain injury. The ROS-generating enzyme NADPH oxidase (Nox2) is present in inflammatory cells and contributes to brain injury in adult animal models. HYPOTHESIS: NADPH oxidase contributes to ROS formation and development of injury in the immature brain and inhibition of NADPH oxidase attenuates perinatal brain injury. METHODS: We used animal models of term hypoxia-ischemia (HI) (P9 mice) as well as ibotenate-induced excitotoxic injury (P5 mice) mimicking features of periventricular leukomalacia in preterm infants. In vitro microglia cell cultures were used to investigate NADPH oxidase-dependent ROS formation. In vivo we determined the impact 1) of HI on NADPH oxidase gene expression 2) of genetic (gp91-phox/Nox2 knock-out) and 3) of pharmacological NADPH oxidase inhibition on HI-induced injury and NMDA receptor-mediated excitotoxic injury, respectively. Endpoints were ROS formation, oxidative stress, apoptosis, inflammation and extent of injury. RESULTS: Hypoxia-ischemia increased NADPH oxidase subunits mRNA expression in total brain tissue in vivo. In vitro ibotenate increased NADPH oxidase-dependent formation of reactive oxygen species in microglia. In vivo the inhibition of NADPH oxidase did not reduce the extent of brain injury in any of the animal models. In contrast, the injury was increased by inhibition of NADPH oxidase and genetic inhibition was associated with an increased level of galectin-3 and IL-1beta. CONCLUSION: NADPH oxidase is upregulated after hypoxia-ischemia and activated microglia cells are a possible source of Nox2-derived ROS. In contrast to findings in adult brain, NADPH oxidase does not significantly contribute to the pathogenesis of perinatal brain injury. Results obtained in adult animals cannot be transferred to newborns and inhibition of NADPH oxidase should not be used in attempts to attenuate injury.
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| 16. |
- Elvin, Anders, et al.
(författare)
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Decreased muscle blood flow in fibromyalgia patients during standardised muscle exercise : a contrast media enhanced colour Doppler study.
- 2006
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Ingår i: European Journal of Pain. - : Wiley. - 1090-3801 .- 1532-2149. ; 10:2, s. 137-44
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the study was to investigate if contrast enhanced ultrasound (US) imaging of muscular blood flow during and following exercise could detect alterations in vascularity in fibromyalgia (FM) patients. Ten FM patients and 10 matched controls were examined with US during standardised static and directly following static and dynamic muscular contractions of the infraspinatus muscle. Doppler ultrasound evaluation was performed before and after the administration of ultrasound contrast media. The FM patients had lower magnitude of muscle vascularity following dynamic (p<0.001) and during (p<0.002) static exercise compared to controls. The immediate flow response to muscular activity was not only of a lower magnitude, but also of a shorter duration in FM patients following dynamic exercise (p<0.001) and during static exercise (p<0.01). There were no statistically significant group differences in blood flow intensity or duration following static contraction. In conclusion, contrast enhanced US was found useful to study real-time muscle blood flow changes during and following standardised, low-intensity exercise in FM patients and healthy controls. Our results support the suggestion that muscle ischemia can contribute to pain in FM, possibly by maintaining the central nervous changes such as central sensitisation/disinhibition. US with contrast can be a new valuable approach to assess muscle perfusion in pain patients during standardised exercise.
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| 17. |
- Hultberg, Björn, et al.
(författare)
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Homocystein--markör för kärlsjukdom hos aldre med psykisk sjukdom.
- 2008
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Ingår i: Läkartidningen. - 0023-7205. ; 105:38, s. 2576-2578
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Forskningsöversikt (refereegranskat)abstract
- Many studies have reported higher total plasma homocysteine (tHcy) in elderly patients with mental illness than in control subjects. There are many different determinants of plasma tHcy concentration, including age, cobalamin/folate status, renal function and the presence of vascular disease. The presence of vascular disease may contribute to cognitive impairment. We have investigated elderly patients with regard to plasma tHcy and the presence of vascular disease. Clarification of the role of vascular risk factors in mental illness is important because most are modifiable, in contrast to other risk factors such as age and genetics. The main findings in our studies imply that elevated plasma tHcy concentration in elderly patients with mental illness is mainly associated with the presence of vascular disease and is not related to the specific psychogeriatric diagnosis. Furthermore, it seems possible that the control of conventional vascular risk factors could be guided by the level of plasma tHcy, serum cystatin C, and serum N-terminal pro-brain natriuretic peptide. Patients with an elevation of any of these parameters could be selected for a lower target level of vascular risk factors such as blood pressure cholesterol etc. than conventional target levels.
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| 18. |
- Kivling, Anna, et al.
(författare)
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Diverse FOXP3 Expression in Children with Type 1 Diabetes and Celiac Disease
- 2008
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1150, s. 273-277
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Tidskriftsartikel (refereegranskat)abstract
- Imbalance between different types of T lymphocytes, such as T helper (Th) and regulatory T cells (Tregs), has been reported to play a part in the pathogenesis behind such autoimmune diseases as type 1 diabetes (T1D) and celiac disease (CD). Defects in Tregs are proposed to at least partly explain the imbalance of Th cells found in children with immunologic diseases. Peripheral blood mononuclear cells from 24 children with T1D and/or CD, and reference children (that is, those without any of these diseases) were stimulated with disease-associated antigens (insulin, gluten, transglutaminase [tTG]), and phytohemagglutinin (PHA). The mRNA expression of the Treg-associated marker FOXP3 was analyzed with multiplex real-time RT-PCR. Children with T1D showed both a low spontaneous (P < 0.05) and PHA-induced (P < 0.01) expression of FOXP3 mRNA compared to children with CD. Children with T1D also had a low PHA-induced FOXP3 mRNA expression compared to the group of children diagnosed with both T1D and CD (P < 0.05). Spontaneous (P < 0.05) and PHA-induced (P < 0.05) FOXP3 mRNA expression was high in children with CD compared to reference children. In contrast, stimulation with insulin tended to induce high FOXP3 mRNA expression in T1D children compared to reference children (P = 0.057). In conclusion, children with only T1D generally showed a lower FOXP3 mRNA expression than did children with CD, or with T1D in combination with CD, which suggests impaired regulation of the immune system in children with T1D.
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| 19. |
- Kårehed, Karin, et al.
(författare)
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IFN-gamma-induced upregulation of Fc gamma-receptor-I during activation of monocytic cells requires the PKR and NF kappa B pathways
- 2007
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Ingår i: Molecular Immunology. - : Elsevier BV. - 0161-5890 .- 1872-9142. ; 44:4, s. 615-624
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Tidskriftsartikel (refereegranskat)abstract
- Interferon (IFN)-gamma is a potent activator of macrophages, increasing the cells capacity to perform specific functions during inflammation and immune response. In this report we use IFN-gamma-induced upregulation of the high affinity receptor for IgG (Fc gamma RI/CD64) in the human monocytic cell line U-937 as a model for monocytic activation. We show that upregulation of Fc gamma RI is dependent on signals mediated by the dsRNA-dependent kinase PKR, and the transcription factor NF kappa B. silencing of PKR expression by siRNA or inhibition of PKR by 2-aminopurine (2-AP) potently blocks the IFN-gamma-induced transcriptional activation of the Fc gamma RI promoter. We find that the serine 727 phosphorylation of Stat1, required for full IFN-gamma-induced Fc gamma RI promoter activity, is dependent on PKR. We further show that IFN-gamma induction of Fc gamma RI upregulation is dependent on the NF kappa B pathway, as evidenced by inhibition of NF kappa B using a phosphorylation defective I kappa B alpha (S32A/S36A) mutant, or inhibiting the IKB-kinase (IKK) by treatment with BMS345541. Our results suggest that IFN-gamma-induced increase of Fc gamma RI expression requires the integration of two signalling events: PKR-dependent Stat1 serine 727 phosphorylation, and activation of NF kappa B.
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| 20. |
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