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- Ericzon, B G, et al.
(författare)
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Secretion and composition of bile after human liver transplantation : studies on the effects of cyclosporine and tacrolimus
- 1997
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 63:1, s. 74-80
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Tidskriftsartikel (refereegranskat)abstract
- Cyclosporine (CsA) and tacrolimus (FK506) have recently been reported to inhibit canalicular transport of bile acids in vitro and thereby possibly induce cholestasis. A relative reduction of chenodeoxycholic acid (CDCA) has been observed after liver transplantation when CsA is used as immunosuppressant. We tested the hypothesis that CsA induces cholestasis and reduces CDCA secretion as compared with treatment with monoclonal antibodies (OKT3), and that CsA differs from FK506 with regard to its effects on biliary lipid secretion.Bile flow, biliary lipid secretion rates, and biliary bile acid composition were determined during the first 10 days after transplantation in 29 liver transplant recipients. Two prospective randomized studies were performed that compared CsA and OKT3 and compared CsA- and FK506-based regimens. In study 1, bile acid output averaged 0.75±0.15 µmol/min in the CsA I group and 0.54±0.11 µmol/min in the OKT3 group on postoperative day 1. Bile flow and bile acid output then increased, and there was no significant difference between the two groups. The relative proportion of CDCA decreased to the same extent in both groups. In study 2, mean bile acid outputs on postoperative day 1 were 0.57±0.26 µmol/min and 0.55±0.15 µmol/min in the CsA 2 and FK506 groups, respectively. The following increase in bile acid secretion was significantly larger in the FK506 group. After transplantation, the relative proportion of CDCA decreased with time in both groups, but the reduction was more rapid in the FK506 group.In conclusion, CsA did not inhibit bile secretion during short-term treatment after liver transplantation. Compared with patients given CsA-based treatment, patients with FK506-based treatment recovered bile secretion more rapidly.
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- Hägglund, H, et al.
(författare)
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Treatment of hepatic venoocclusive disease with recombinant human tissue plasminogen activator or orthotopic liver transplantation after allogeneic bone marrow transplantation
- 1996
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 62:8, s. 1076-1080
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Tidskriftsartikel (refereegranskat)abstract
- Ten allogeneic bone marrow transplant (BMT) recipients with hepatic venoocclusive disease (VOD) were treated with recombinant human tissue plasminogen activator (rt-PA). Two of them subsequently underwent orthotopic liver transplantation (OLT). One additional patient with VOD underwent OLT without prior rt-PA treatment. Treatment with rt-PA was started a median of 14 (1--35) days after BMT. The dose of rt-PA given to adults was 10-50 mg i.v. and that given to children was 3-10 mg i.v. Treatment was given for 2-4 days. In three patients, the dose was administered over a longer period or it was repeated. Four patients responded to rt-PA therapy and six did not. Eight patients suffered from hemorrhages, one intracranial and three gastrointestinal. Four patients required blood transfusions. Four had minor subcutaneous hemorrhages and/or epistaxis. One patient died of intracranial hemorrhage and five from hepatic and/or multiorgan failure. Two patients treated with rt-PA, 10 mg/day for 4 days, are alive; one is alive and well 3 months after BMT, the other has relapsed after 7 months. The three patients undergoing OLT died of chronic hepatic failure, cerebral edema, and pneumonia. Our experience suggests that rt-PA should not be administered in high doses and that the treatment should not be given over a longer period, because of the risk of severe hemorrhages.
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- Lilja, Helene, et al.
(författare)
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Fetal rat hepatocytes : Isolation, characterization and transplantation in the Nagase analbuminernic rats
- 1997
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Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 64:9, s. 1240-1248
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Tidskriftsartikel (refereegranskat)abstract
- Background. In contrast to adult hepatocytes, fetal hepatocytes (FH) are thought to be highly proliferative, less immunogenic, and resistant to cryopreservation and ischemic injury. These qualities could enhance FH engraftment, proliferation, and gene transfer requiring active DNA synthesis, Methods. Rat FH were obtained using the nonperfusion collagenase/DNase digestion method, Free and cultured cells were studied using electron microscopy, fluorescence-activated cell sorting, and Northern analysis using alpha-fetoprotein and albumin as markers of hepatocyte lineage, DNA synthetic activity was measured in quiescent and mitogen-stimulated fetal and adult hepatocytes by [H-3]thymidine incorporation, Susceptibility of cultured FH to retrovirally mediated gene transfer was studied using an amphotropic retroviral vector carrying the Escherichia coli lac-Z gene, Nagase analbuminemic rats were used as recipients to study the effects of intraportal FH transplantation, Analysis of serum albumin was carried out by enzyme-linked immunosorbent assay. Results, In fetal liver, 87+/-2%? of the cells showed morphological and molecular features of hepatocytes. DNA synthetic activity in nonstimulated cultured FH was 10 times greater than the maximal hepatocyte growth factor-driven response in adult rat hepatocytes., A total of 5-15% FH stained positive for X-gal; results of transduction in adult hepatocyte cultures were negative. In Nagase analbuminemic rat recipients, FH produced significant amounts of albumin only when a hepatic regenerative stimulus was applied. Immunohistochemistry confirmed presence of albumin-positive hepatocytes, Conclusions, Fetal rat liver from the late gestation period is highly enriched with hepatocyte progenitors, They are highly proliferative and susceptible to retroviral transduction and can engraft and function in the adult rat liver if transplanted under a hepatic regenerative stimulus.
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- Suhr, O B, et al.
(författare)
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Impact of autonomic neuropathy on circulatory instability during liver transplantation for familial amyloidotic polyneuropathy.
- 1997
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337 .- 1534-6080. ; 63:5, s. 675-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Circulatory instability with severe hypotension frequently complicates liver transplantation in patients with familial amyloidotic polyneuropathy. Autonomic dysfunction is found early in the course of the disease by analysis of beat-to-beat heart rate variability (HRV). The aim of the present study was to investigate the impact of autonomic neuropathy on intraoperative circulatory instability during liver transplantation for familial amyloidotic polyneuropathy.METHODS: Twenty-two patients were evaluated at the Department of Medicine, Umea University Hospital, by spectral analysis of HRV and later received liver transplants at Huddinge University Hospital. The low-and high-frequency bands obtained by spectral analysis of HRV in the supine and upright positions, respectively, were used as representative of sympathetic and parasympathetic activity. Circulatory instability during transplantation was defined as a fall in systolic arterial blood pressure below 70 mmHg for more than 5 min during the preanhepatic phase.RESULTS: Both arrhythmia preventing spectral analysis of HRV and a sympathetic variability peak below 2.5 mHz2 were significantly more common among patients with intraoperative circulatory instability (P=0.03 and 0. 004, respectively). A diminished increase in pulse rate when tilting the patients from the supine to the upright position was also more pronounced among patients with circulatory instability (P<0.05).CONCLUSIONS: The majority of patients who will develop circulatory instability with a pronounced fall in arterial blood pressure can be identified by Poincare plots of R-R intervals and spectral analysis of HRV. A low sympathetic peak or arrhythmia precluding spectral analysis of HRV is significantly related to operative circulatory instability.
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- Wahlberg, Jeanette, 1969-, et al.
(författare)
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Evidence of a negative feedback system regulating the total beta-cell volume in nondiabetic rats that received pancreas transplants
- 1998
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Ingår i: Transplantation. - : Lippincott Williams & Wilkins. - 0041-1337 .- 1534-6080. ; 66:10, s. 1392-1394
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The aim of the present study was to investigate the long-term regulation of pancreatic beta-cell volume after pancreas transplantation into adult rats.METHODS: A syngeneic pancreaticoduodenal transplantation was made in normoglycemic Wistar-Furth rats. By this means, the recipients doubled their pancreatic islet volume. Nine months after transplantation, the total beta-cell volume was measured in serial pancreatic sections immunostained for insulin from both the native and transplanted pancreata, and in the native pancreas of age-matched Wistar-Furth rats that did not receive transplants.RESULTS: No changes in the volume of individual beta-cells were seen. A 50% decrease in total beta-cell volume was observed in both the native and transplanted pancreas when compared with that of age-matched controls. However, the combined beta-cell volumes of the native and transplanted pancreas in the rats that received transplants were similar to those of the native pancreas in control animals. No signs of increased apoptosis in any of the glands could be seen during the first postoperative week or after 9 months.CONCLUSIONS: These findings provide evidence of a negative feedback system, which regulates the total beta-cell volume to the levels seen in age-matched rats that did not receive transplants. The underlying mechanisms for the decreased beta-cell volume are unknown, but may involve a diminished replicatory rate of the beta-cells.
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- Arnadottir, Margret, et al.
(författare)
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Hyperhomocysteinemia in cyclosporine-treated renal transplant recipients
- 1996
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Ingår i: Transplantation. - 1534-6080. ; 61:3, s. 509-512
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Tidskriftsartikel (refereegranskat)abstract
- Moderate hyperhomocysteinemia, an independent cardiovascular risk factor, has been reported in renal transplant recipients. In the present study, plasma concentrations of total homocysteine were significantly increased in 120 renal transplant recipients as compared with 60 healthy controls (19.0 +/- 6.9 vs. 11.6 +/- 2.8 mumol/L, P < 0.0001) and as compared with 53 patients without a transplant but with a comparable degree of renal failure (19.0 +/- 6.9 vs. 16.0 4.9 mumol/L, P < 0.01). There was a significant inverse correlation between glomerular filtration rates and plasma homocysteine concentrations in the renal transplant recipients (r = -0.52, P < 0.0001). Groups of renal transplant recipients, with and without cyclosporine, and renal patients without a transplant were studied; these groups were comparable regarding age, sex distribution, glomerular filtration rate, and folate and vitamin B12 concentrations. Renal transplant recipients on cyclosporine had significantly higher plasma homocysteine concentrations than those not on cyclosporine (19.5 +/- 7.6 vs. 16.2 +/- 4.8 mumol/L, P < 0.05), and the patients without a transplant (19.5 +/- 7.6 vs. 16.0 +/- 4.9 mumol/L, P < 0.01). Thus, the hyperhomocysteinemia of renal transplant recipients not treated with cyclosporine, and that of renal patients without a transplant probably is explained by the same mechanism: renal insufficiency. An additional mechanism seems to operate in renal transplant recipients treated with cyclosporine. The lack of correlation between the concentrations of plasma homocysteine and red cell folate in these patients suggests that cyclosporine interferes with folate-assisted remethylation of homocysteine. Plasma homocysteine concentrations were significantly increased in 24 patients with a history of atherosclerotic complications as compared with the remaining 96 renal transplant recipients (20.8 +/- 4.4 vs. 18.5 +/- 7.3 mumol/L, P < 0.01).
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- Chen, Daxin, et al.
(författare)
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Regulated inhibition of coagulation by porcine endothelial cells expressing P-selectin-tagged hirudin and tissue factor pathway inhibitor fusion proteins
- 1999
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337. ; 68:6, s. 832-839
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Tidskriftsartikel (refereegranskat)abstract
- Background. Thrombotic vascular occlusion resulting in infarction occurs during hyperacute rejection of allografts transplanted into sensitized patients and remains a major problem in experimental xenotransplantation. A similar process is also found in disorders of diverse etiology including atherosclerosis, vasculitis, and disseminated intravascular coagulation. Methods. We have previously constructed two membrane-tethered anticoagulant fusion proteins based on human tissue factor pathway inhibitor and the leech anticoagulant hirudin and demonstrated their functional efficacy in vitro. These constructs have now been modified by the addition of a P-selectin sequence to the cytoplasmic tail to localize them in Weibel-palade bodies. They have been transfected into Weibel-palade body-positive endothelial cells isolated from the inferior vena cava of normal pigs. Results. In resting endothelial cells, fusion protein expression colocalized with P-selectin and was confined to Weibel-palade bodies. These cells had a procoagulant phenotype in recalcified human plasma. However, after activation with phorbol ester the anticoagulant proteins were rapidly relocated to the cell surface where they specifically inhibited the clotting of human plasma. Conclusions. Novel anticoagulant molecules may prove useful therapeutic agents for gene therapy in thrombotic disease and postangioplasty or for transgenic expression in animals whose organs may be used for clinical xenotransplantation. Expression in vascular endothelial cells may be regulated by inclusion of P-selectin cytoplasmic sequence, to restrict cell surface expression to activated endothelium.
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- Fehrman-Ekholm, I, et al.
(författare)
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Follow-up of living kidney donors from 1964-1995.
- 1999
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Ingår i: TRANSPLANTATION. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337. ; 67:7, s. S188-S188
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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- FehrmanEkholm, I, et al.
(författare)
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Kidney donors live longer
- 1997
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337. ; 64:7, s. 976-978
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Tidskriftsartikel (refereegranskat)
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- FehrmanEkholm, I, et al.
(författare)
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Reasons for not accepting living kidney donors
- 1996
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Ingår i: Transplantation. - : Ovid Technologies (Wolters Kluwer Health). - 0041-1337. ; 61:8, s. 1264-1265
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Tidskriftsartikel (refereegranskat)
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- Larsson, Lena C, et al.
(författare)
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Discordant neural tissue xenografts survive longer in immunoglobulin deficient mice
- 1999
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Ingår i: Transplantation. - 0041-1337. ; 68:8, s. 60-1153
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The immune response against discordant xenografts in the brain is incompletely understood and remains a major obstacle for future clinical applications of xenogeneic neural tissue transplants in neurodegenerative disorders. To determine the role of antibodies in the rejection process, we compared graft survival and immune reactions between immunoglobulin deficient (IgKO) and normal mice.METHODS: A cell suspension of embryonic porcine ventral mesencephalon was injected into the striatum of adult normal and IgKO mice. Graft sizes and number of infiltrating CD4- and CD8-positive lymphocytes were determined by stereological methods at 4 days and 2, 4, and 6 weeks after the transplants. Microglial accumulation was determined using the optical densitometrical method. Intraparenchymal deposition of IgG was investigated at 4 days and 2 weeks.RESULTS: The majority of IgKO mice had surviving grafts for up to 4 weeks, whereas survival was minimal in control mice beyond 4 days. Graft sizes differed significantly between IgKO and control mice at 2 weeks (P<0.01, Kruskal Wallis ANOVA, followed by Mann Whitney test). The majority of infiltrating lymphocytes were CD4-positive in control mice but CD8-positive in IgKO mice. Microglial accumulation was strong around surviving grafts in IgKO mice at 4 weeks. Prominent staining of IgG, diffuse in the transplanted hemisphere and specific on grafted neurons, was found in control mice.CONCLUSIONS: Our results suggest that immunoglobulins play an initiating role in rejection of discordant neural xenografts. After a prolonged graft survival of approximately 4 weeks, a cellular response with a large proportion CD8-positive cells leads to rejection in IgKO mice.
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- Mattsson Hultén, Lillemor, 1951, et al.
(författare)
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Butylated hydroxytoluene and N-acetylcysteine attenuates tumor necrosis factor-alpha (TNF-alpha) secretion and TNF-alpha mRNA expression in alveolar macrophages from human lung transplant recipients in vitro
- 1998
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Ingår i: Transplantation. - 0041-1337. ; 66:3, s. 364-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a polypeptide cytokine principally produced by macrophages/monocytes and commonly associated with inflammatory conditions. The present study was designed to investigate whether the antioxidants butylated hydroxytoluene (BHT) and N-acetylcysteine (NAC) modified TNF-alpha production in stimulated and unstimulated alveolar macrophages from lung transplant recipients in vitro. METHODS: The effects of BHT and NAC on TNF-alpha production were studied both with and without lipopolysaccharide (LPS) activation of alveolar macrophages from bronchoalveolar lavage fluid. TNF-alpha was quantitated in cell culture medium using an enzyme-linked immunosorbent assay. TNF-alpha mRNA expression was analyzed by quantitative reverse transcription-polymerase chain reaction on total RNA extracted from the incubated alveolar macrophages. RESULTS: In unstimulated alveolar macrophages, TNF-alpha levels were significantly reduced by incubation with BHT or NAC. When alveolar macrophages from patients with cytomegalovirus infection were incubated with BHT, TNF-alpha secretion was significantly lowered. A significant reduction of TNF-alpha levels in LPS-stimulated alveolar macrophages was obtained in the presence of BHT or NAC. Our data from quantitative reverse transcription-polymerase chain reaction showed that the observed decrease in protein levels of TNF-alpha was associated with a decrease in TNF-alpha mRNA expression. CONCLUSIONS: Our results indicate that antioxidant treatment may be an effective step to lower the inflammatory process caused by cytomegalovirus infection or in endotoxin (LPS)-activated macrophages. The therapeutic use of antioxidant compounds could, therefore, be of interest in conditions such as lung transplantation, in which oxidative stress and inflammation can contribute significantly to the loss of allograft function.
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