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- Olsson, Bob, 1969, et al.
(författare)
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T-cell-mediated cytotoxicity toward platelets in chronic idiopathic thrombocytopenic purpura.
- 2003
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 9:9, s. 1123-4
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Tidskriftsartikel (refereegranskat)abstract
- Chronic idiopathic thrombocytopenic purpura (ITP) is a bleeding disorder that is characterized by increased platelet destruction and is believed to be autoantibody mediated. In this study, CD3+ T cells from ITP patients had increased expression of genes involved in cell-mediated cytotoxicity. In addition, cytotoxic cell-mediated lysis of autologous platelets was shown in active ITP. Our data suggest that T-cell-mediated cytotoxicity is an alternative mechanism for platelet destruction in ITP.
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| 4. |
- Osterlund, Maria, et al.
(författare)
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Probing inhibitor-induced conformational changes along the interface between tissue factor and factor VIIa
- 2001
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 40:31, s. 9324-9328
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Tidskriftsartikel (refereegranskat)abstract
- Upon injury of a blood vessel, activated factor VII (FVIIa) forms a high-affinity complex with its allosteric regulator, tissue factor (TF), and initiates blood clotting. Active site-inhibited factor VIIa (FVIIai) binds to TF with even higher affinity. We compared the interactions of FVIIai and FVIIa with soluble TF (sTF). Six residues in sTF were individually selected for mutagenesis and site-directed labeling. The residues are distributed along the extensive binding interface, and were chosen because they are known to interact with the different domains of FVIIa. Fluorescent and spin probes were attached to engineered Cys residues to monitor local changes in hydrophobicity, accessibility, and rigidity in the sTF-FVIIa complex upon occupation of the active site of FVIIa. The results show that inhibition of FVIIa caused the structures around the positions in sTF that interact with the protease domain of FVIIa to become more rigid and less accessible to solvent. Thus, the presence of an active site inhibitor renders the interface in this region less flexible and more compact, whereas the interface between sTF and the light chain of FVIIa is unaffected by active site occupancy.
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- Andersson, Dick, et al.
(författare)
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Contribution of tryptophan residues to the CD spectrum of the extracellular domain of human tissue factor : Application in folding studies and prediction of secondary structure
- 2001
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Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 268:4, s. 1118-1128
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Tidskriftsartikel (refereegranskat)abstract
- The contribution to the circular dichroism (CD) spectrum made by each of the four Trp residues in the extracellular domain of human tissue factor, sTF (s designates soluble), was determined from difference CD spectra. The individual Trp CD spectra showed that all four residues contributed to the CD spectrum in almost the entire wavelength region investigated (180-305 nm). The sum of the individual spectra of each Trp residue in the near-UV region was qualitatively identical to the wild-type spectrum, clearly demonstrating that the Trp residues are the major contributors to the spectrum in this wavelength region. Trp CD bands interfere with the peptide bands in the far-UV region, leading to uncertainty in the predictions of the amounts of various types of secondary structure. Accordingly, the best prediction of secondary sTF structure content was achieved using a hypothetical Trp-free CD spectrum obtained after subtraction of all individual Trp spectra from the wild-type spectrum. The mutated Trp residues were also exploited as intrinsic probes to monitor the formation of local native-like tertiary structure by kinetic near-UV CD measurements. The global folding reaction was followed in parallel with a novel functional assay that registered the recovery of cofactor activity, i.e. stimulation of the amidolytic activity of Factor VIIa. From these measurements, it was found that sTF appears to regain FVIIa cofactor activity before the final side-chain packing of the Trp residues. The combined kinetic refolding results suggest that the compact asymmetric environments of the individual Trp residues in sTF are formed simultaneously, leading to the conclusion that the native tertiary structure of the whole protein is formed in a cooperative manner.
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- Bentzer, Peter, et al.
(författare)
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Low-Dose Prostacyclin Improves Cortical Perfusion following Experimental Brain Injury in the Rat.
- 2003
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Ingår i: Journal of Neurotrauma. - : Mary Ann Liebert Inc. - 1557-9042 .- 0897-7151. ; 20:5, s. 447-461
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Tidskriftsartikel (refereegranskat)abstract
- It was recently shown that prostacyclin at a low dose reduces cortical cell death following brain trauma in the rat. Conceivably, prostacyclin with its vasodilatory, anti-aggregatory, anti-adhesive and permeability-reducing properties improved a compromised perfusion caused by post-traumatic vasoconstriction, microthrombosis and increased microvascular permeability. The objective of the present study was therefore to investigate the hemodynamic effects of low-dose prostacyclin in the traumatized rat cortex. Following a fluid percussion brain injury or a sham procedure, animals were treated with a continuous intravenous infusion of prostacyclin of 1 or 2 ng x kg(-1) x min(-1), or vehicle. Blood flow ([(14)C]-iodoantipyrine), the permeability-surface area product (PS) for [(51)Cr]-EDTA, and brain water content were measured after 3 or 48 h of treatment. Blood flow values in the injured cortex were transiently reduced to 0.42 +/- 0.2 mL x min(-1) in the vehicle group 3 h following trauma from a corresponding value of about 1.6 mL x min(-1) in the sham group, with recovery of blood flow after 48 h. Prostacyclin treatment caused a dose-dependent increase in blood flow which reached statistical significance 48 h following trauma. Brain water content and PS increased in the injured cortex post trauma and the higher dose of prostacyclin increased these parameters further at 48 h compared to the vehicle group (p < 0.05). The latter effects of prostacyclin cannot be attributed to an increase in permeability, as prostacyclin did not influence PS or brain water content following sham trauma. In fact prostacyclin has been shown to have permeability-decreasing properties. We conclude that prostacyclin improves cortical perfusion following brain trauma. The simultaneous aggravation of brain edema can be explained by an increased surface area, perhaps in combination with increased capillary hydrostatic pressure.
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- Carlsson, Per-Ola, et al.
(författare)
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Chronically decreased oxygen tension in rat pancreatic islets transplantedunder the kidney capsule
- 2000
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 69:5, s. 761-766
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A factor of potential importance in the failure of islet grafts is poor or inadequate engraftment of the islets in the implantation organ. This study measured the oxygen tension and blood perfusion in 1-, 2-, and 9-month-old islet grafts. METHODS: The partial pressure of oxygen was measured in pancreatic islets transplanted beneath the renal capsule of diabetic and nondiabetic recipient rats with a modified Clark electrode (outer tip diameter 2-6 microm). The size of the graft (250 islets) was by purpose not large enough to cure the diabetic recipients. The oxygen tension in islets within the pancreas was also recorded. Blood perfusion was measured with the laser-Doppler technique. RESULTS: Within native pancreatic islets, the partial pressure of oxygen was approximately 40 mm Hg (n=8). In islets transplanted to nondiabetic animals, the oxygen tension was approximately 6-7 mm Hg 1, 2, and 9 months posttransplantation. No differences could be seen between the different time points after transplantation. In the diabetic recipients, an even more pronounced decrease in graft tissue oxygen tension was recorded. The mean oxygen tension in the superficial renal cortex surrounding the implanted islets was similar in all groups (approximately 15 mm Hg). Intravenous administration of glucose (0.1 gxkg(-1)x min(-1)) did not affect the oxygen tension in any of the investigated tissues. The islet graft blood flow was similar in all groups, measuring approximately 50% of the blood flow in the kidney cortex. CONCLUSION: The oxygen tension in islets implanted beneath the kidney capsule is markedly lower than in native islets up to 9 months after transplantation. Moreover, persistent hyperglycemia in the recipient causes an even further decrease in graft oxygen tension, despite similar blood perfusion. To what extent this may contribute to islet graft failure remains to be determined.
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- Eriksson, Ola, et al.
(författare)
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ORWARE : a simulation tool for waste management
- 2002
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Ingår i: Resources, Conservation and Recycling. - 0921-3449 .- 1879-0658. ; 36:4, s. 287-307
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Tidskriftsartikel (refereegranskat)abstract
- A simulation model, ORWARE (ORganic WAste REsearch) is described. The model is mainly used as a tool for researchers in environmental systems analysis of waste management. It is a computer-based model for calculation of substance flows, environmental impacts, and costs of waste management. The model covers, despite the name, both organic and inorganic fractions in municipal waste. The model consists of a number of separate submodels, which describes a process in a real waste management system. The submodels may be combined to design a complete waste management system. Based on principles from life cycle assessment the model also comprises compensatory processes for conventional production of e.g. electricity, district heating and fertiliser. The compensatory system is included in order to fulfil the functional units, i.e. benefits from the waste management that are kept constant in the evaluation of different scenarios. ORWARE generates data on emissions, which are aggregated into different environmental impact categories, e.g. the greenhouse effect, acidification and eutrophication. Throughout the model all physical flows are described by the same variable vector, consisting of up to 50 substances. The extensive vector facilitates a thorough analysis of the results, but involves some difficulties in acquiring relevant data. Scientists have used ORWARE for 8 years in different case studies for model testing and practical application in the society. The aims have e.g. been to evaluate waste management plans and to optimise energy recovery from waste.
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| 31. |
- Erixon, Martin, et al.
(författare)
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PD fluids contain high concentrations of cytotoxic GDPs directly after sterilization
- 2004
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Ingår i: Peritoneal Dialysis International. - 1718-4304. ; 24:4, s. 392-398
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Glucose degradation products (GDPs) in peritoneal dialysis (PD) fluids are cytotoxic and affect the survival of the peritoneal membrane. One of the most reactive GDPs in PD fluids is 3,4-dideoxyglucosone-3-ene (3,4-DGE). 3,4-DGE has been reported as an intermediate between 3-deoxyglucosone (3-DG) and 5-hydroxymethyl furaldehyde (5-HMF) during degradation of glucose. In PD fluids, 3,4-DGE exists in a temperature-dependent equilibrium with a pool of unidentified substances. The aim of this study was to explore this equilibrium and its temperature dependence during the first months of storage after the sterilization procedure. Methods: GDPs and inhibition of cell growth (ICG) were measured directly after sterilization of the PD fluid and during storage at different temperatures for 60 days. The following GDPs were analyzed: 3-DG, 3,4-DGE, 5-HMF, formaldehyde, acetaldehyde, glyoxal, and methylglyoxal. Results: Immediately after sterilization, the concentration of 3,4-DGE was 125 mumol/L. During the first weeks of storage, it decreased by about 80%. At the same time, the 3-DG concentration increased. None of the other GDPs were significantly affected. Cytotoxicity correlated well with the concentration of 3,4-DGE. When pure 3,4-DGE was substituted for the lost amount of 3,4-DGE after 30 days of storage, the initial ICG was almost completely regained. Conclusions: Heat sterilization of PD fluids promotes the formation of large quantities of 3,4-DGE, rendering the fluid highly cytotoxic. During storage, the main part of 3,4-DGE is reversibly converted in a temperature-dependent manner to a less cytotoxic pool, consisting mainly of 3-DG. Cytotoxicity seems to be dependent exclusively on 3,4-DGE. In order to avoid higher levels of 3,4-DGE concentrations, PD fluids should not be used too soon after sterilization and should not be stored at temperatures above room temperature.
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| 43. |
- Lundberg, Peter, et al.
(författare)
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Detection of neural activity in functional MRI using canonical correlation analysis.
- 2001
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- A novel method for detecting neural activity in functional magnetic resonance imaging (fMRI) data is introduced. It is based on canonical correlation analysis (CCA), which is a multivariate extension of the univariate correlation analysis widely used in fMRI. To detect homogeneous regions of activity, the method combines a subspace modeling of the hemodynamic response and the use of spatial relationships. The spatial correlation that undoubtedly exists in fMR images is completely ignored when univariate methods such as as t-tests, F-tests, and ordinary correlation analysis are used. Such methods are for this reason very sensitive to noise, leading to difficulties in detecting activation and significant contributions of false activations. In addition, the proposed CCA method also makes it possible to detect activated brain regions based not only on thresholding a correlation coefficient, but also on physiological parameters such as temporal shape and delay of the hemodynamic response. Excellent performance on real fMRI data is demonstrated. Magn Reson Med 45:323-330, 2001
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| 46. |
- Mattsson, Göran, et al.
(författare)
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Evidence of Functional Impairment of Syngeneically Transplanted Mouse Pancreatic Islets Retrieved from the Liver
- 2004
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 53:4, s. 948-954
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Tidskriftsartikel (refereegranskat)abstract
- A drawback in pancreatic islet transplantation is the large number of islets needed to obtain insulin independence in patients with diabetes. This most likely reflects extensive posttransplantation islet cell death and functional impairment of the remaining endocrine cells. We aimed to develop an experimental method to retrieve transplanted islets from the mouse liver, which would enable comparisons of transplanted and endogenous islets and provide valuable information on functional changes induced by intraportal transplantation. Transplanted islets were obtained by retrograde perfusion of the liver with collagenase. The identity of retrieved tissue as transplanted islets was confirmed by intravital staining, immunohistochemistry, and electron microscopy. The retrieved islets, irrespective of whether they had resided in diabetic or nondiabetic recipients, had a markedly lower insulin content and glucose-stimulated insulin release when compared with isolated endogenous islets. The glucose oxidation rate was also markedly lower in the retrieved islets, suggesting mitochondrial dysfunction. These disturbances in insulin content, insulin release, and glucose oxidation rate were not reversed by a few days of culture after retrieval. The results implicate changes in islet function after intraportal transplantation. Such dysfunction may contribute to the high number of islets needed for successful transplantation in diabetic individuals.
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- Musi, Barbara, et al.
(författare)
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Biocompatibility of peritoneal dialysis fluids: long-term exposure of nonuremic rats.
- 2004
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Ingår i: Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. - 0896-8608. ; 24:1, s. 37-47
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Long-term peritoneal dialysis (PD) leads to structural and functional changes in the peritoneum. The aim of the present study was to investigate the long-term effects of PD fluid components, glucose and glucose degradation products (GDP), and lactate-buffered solution on morphology and transport characteristics in a nonuremic rat model. METHODS: Rats were subjected to two daily intraperitoneal injections (20 mL/day) during 12 weeks of one of the following: commercial PD fluid (Gambrosol, 4%; Gambro AB, Lund, Sweden), commercial PD fluid with low GDP levels (Gambrosol trio, 4%; Gambro AB), sterile-filtered PD fluid (4%) without GDP, or a glucose-free lactate-buffered PD fluid. Punctured and untreated controls were used. Following exposure, the rats underwent a single 4-hour PD dwell (30 mL, 4% glucose) to determine peritoneal function. Additionally, submesothelial tissue thickness, percentage of high mesothelial cells (perpendicular diameter > 2 microm), vascular density, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF) beta1 mRNA expression were determined. Submesothelial collagen concentration was estimated by van Gieson staining. RESULTS: Submesothelial tissue thickness and vascular density, mediated by VEGF and TGFbeta production, in the diaphragmatic peritoneum increased significantly in rats exposed to any PD fluid. Gambrosol induced a marked increased fibrosis of the hepatic peritoneum. A significant increase in high mesothelial cells was observed in the Gambrosol group only. Net ultrafiltration was reduced in the Gambrosol and in the glucose-free groups compared to untreated controls. Small solute transport was unchanged, but all groups exposed to fluids showed significantly increased lymph flow. CONCLUSIONS: Our results show that long-term exposure to different components of PD fluids leads to mesothelial cell damage, submesothelial fibrosis, and neoangiogenesis. Mesothelial cell damage could be connected to the presence of GDP; the other changes were similar for all fluids. Peritoneal transport characteristics did not change in any consistent way and the neoangiogenesis observed was not paralleled by increased solute transport.
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