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- Akyürek, L M, et al.
(författare)
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Tolerance induction ameliorates allograft vasculopathy in rat aortic transplants. Influence of Fas-mediated apoptosis.
- 1998
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Ingår i: The Journal of clinical investigation. - 0021-9738. ; 101:12, s. 2889-99
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Tidskriftsartikel (refereegranskat)abstract
- Based on successful induction of donor-specific unresponsiveness by alloantigenic stimulation in several animal models of acute rejection, we hypothesized that similar immune manipulations would also inhibit the evolution of chronic rejection and transplant vasculopathy. To induce immune tolerance, DA rats received a PVG heart allograft and were immunosuppressed with cyclosporine for 30 d. At day 100 the animals were challenged with a PVG aortic allograft after either 1 or 18 h of cold ischemia. 8 wk after the aortic transplantation, the grafts were investigated for morphological changes, infiltrating cells, apoptosis, and Fas-Fas ligand expression. Control allografts showed advanced transplant arteriosclerosis, whereas tolerance-induced aortic allografts displayed reduced neointimal formation, less medial atrophy, fewer apoptotic cells, and fewer Fas- and FasL-expressing cells. Prolonged ischemic storage time did not profoundly alter the morphological changes of the allografts. Fas expression was found in T cells, macrophages, vascular smooth muscle cells, and endothelial cells, whereas FasL was expressed mainly by T cells and macrophages. FasL mRNA expression was evident throughout the entire allograft wall. In conclusion, induction of allospecific tolerance can effectively prevent transplant arteriosclerosis. Cold ischemia damage does not abrogate the beneficial effect of tolerance, but creates a separate identity of mainly endothelial lesions. Furthermore, Fas-mediated apoptosis appears to be involved in the pathological lesions seen in chronic rejection.
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| 4. |
- Hammarlund-Udenaes, Margareta, et al.
(författare)
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Drug equilibration across the blood-brain barrier : pharmacokinetic considerations based on the microdialysis method
- 1997
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Ingår i: Pharmaceutical research. - 0724-8741 .- 1573-904X. ; 14:2, s. 128-134
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The purpose of the study was to investigate the influence of different rates of transport into and out of the brain, including passive and active transport, on unbound brain concentrations and profile in relation to the blood concentration profile. Special emphasis is put on hydrophilic drugs. METHODS: Simulations were performed with a model including one body compartment and one brain compartment, with linear or saturable transport into and out of the brain. Comparisons were made with experimental results from microdialysis (MD) studies. RESULTS: Three features were evident when combining the MD results: 1) equilibration across the blood-brain barrier (BBB) is rapid, 2) half-life is similar in brain and blood for most drugs, and 3) unbound brain concentrations seldom reach the level of unbound blood concentrations. A low concentration ratio brain:blood is not mainly caused by a low influx, but rather by different influx and efflux clearances. Active transport out of the brain can explain the results, but also active transport into the brain under certain conditions. A small volume of distribution in brain vs. that in the rest of the body contributes to a rapid equilibration and similar half-lives. CONCLUSIONS: Assumptions of slow equilibration of hydrophilic drugs and similar unbound concentrations across the BBB at steady state are contradicted. The results are more in line with recent findings on the presence of P-glycoprotein and other transport mechanisms at the BBB. Non-passive transport across the BBB seems to be the case for almost all drugs studies with MD so far.
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| 5. |
- Lange, D, et al.
(författare)
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Expression of TGF-beta related Smad proteins in human epithelial skin tumors.
- 1999
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Ingår i: International journal of oncology. - 1019-6439. ; 14:6, s. 1049-56
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Tidskriftsartikel (refereegranskat)abstract
- Members of the transforming growth factor (TGF)-beta family regulate cell growth and differentiation activating intracellular Smad proteins. Their role in skin and skin tumorigenesis is not well understood. Therefore we investigated the expression of TGF-beta type I receptor (TbetaR-I) and Smad-proteins involved in the TGF-beta-pathway, e.g. Smad2, Smad3, Smad4, Smad6 and Smad7. We examined the effects of TGF-beta1, -beta2, BMP2, BMP7 on five epithelial cell lines in vitro. TGF-beta1-mediated growth inhibition of HaCaT and HSC4 were observed with half maximal effects at approximately 7 pg ml-1 and 20 pg ml-1, respectively. However, malignant HSC2 and A431 cells were unresponsive to TGF-beta1. A differentiation was seen after 5 days in HaCaT and HSC4 cells only. We compared the reactivity with specific antisera against TbetaR-I and Smad proteins among the different skin tumors: seborrheic keratoses (SK), actinic keratoses (AK), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). There were statistically significant differences of the ratio between the expression in tumor and that in non-tumorous epithelial cells in each tissue specimen. There was a tendency for the lower level of TbetaR-I expression of SCC compared with SK (p=0.08). This was accompanied by the decreased expression of the TbetaR-I. We found a markedly decreased expression of all antigens in BCC. conversion of normal keratinocytes to tumorigenic cells may in part be due to an acquisition of resistance to TGF-beta and loss of expression of intracellular signalling Smad proteins.
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| 7. |
- Lange, J, et al.
(författare)
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Gelation behaviour during chainwise crosslinking polymerisation of methacrylate resins
- 1999
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Ingår i: Polymer. - 0032-3861 .- 1873-2291. ; 40, s. 5699-5707
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Tidskriftsartikel (refereegranskat)abstract
- The gelation process in chainwise crosslinking polymerisation of methacrylate resins with average functionalities of 2.1-50 (1.05-25 methacrylate groups/molecule) was investigated using dynamic mechanical analysis. For all systems a crossover in tan delta (tan delta independent of frequency) was observed at gelation. The gel time was found to decrease with increasing functionality of the system. Within the measured frequency ranges, power law behaviour for the dynamic modulus was observed at the gel point in all systems. A value of the power law exponent n of 0.4 +/- 0.2 to 0.6 +/- 0.1 (increasing with increasing functionality of the system) was determined for gelation during reactions at T greater than or equal to T-g infinity. This trend suggests that the differences in screening between the systems dominate over the difference in fractal dimension. For reaction temperatures below T-g infinity a value of n = 0.3 +/- 01 was obtained, which was attributed to the influence of micro-vitrification. (C) 1999 Elsevier Science Ltd. All rights reserved.
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