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Biomedical subjects

M J Slooff

Publications and source records attributed to M J Slooff.

At least 73 records · Page 4Linked to original sources
PubMed1997

Influence of 48 hours of cold storage in University of Wisconsin organ preservation solution on metabolic capacity of rat hepatocytes.

BACKGROUND/AIMS: Suspensions of isolated hepatocytes are a valuable tool to study liver functions. For optimal use of the isolated hepatocytes, methods are needed to preserve the hepatocytes while maintaining their viability, metabolic and transport functions. Until now, little has been known about the maintenance of the drug metabolism capacity and energy state, measured by the so-called energy charge (ATP+1/2ADP)/(ATP+ADP+AMP), in hepatocytes after storage in University of Wisconsin cold storage solution (UW). Consequently, we investigated whether UW, originally designed to preserve organs for transplantation, was suitable for preservation of isolated rat hepatocytes with respect to the maintenance of drug metabolism and levels of energy-rich substrates. METHODS: Viability of the isolated rat hepatocytes was determined by trypan blue exclusion, ATP content and energy charge after 24 and 48 h of storage in UW at 0 degrees C. Phase I and II metabolic functions of the cells were studied by measuring the cytochrome P450 content and the metabolic rate of lidocaine and 7-ethoxycoumarin. RESULTS: During 48 h of storage of hepatocytes in UW both phase I and phase II metabolism are preserved at control levels. After storage, the viability of the hepatocytes was not changed significantly, and the cells maintained proper cellular ATP content and overall energy charge. CONCLUSIONS: These results imply that hepatocytes from a single isolation can be stored in UW solution and used for metabolism experiments for 3 consecutive days, allowing a reduction in the use of experimental animals.

Animals↗
PubMed1997

High prevalence of hepatitis G virus after liver transplantation without apparent influence on long-term graft function.

BACKGROUND/AIMS: Hepatitis G virus is a recently characterized transfusion-transmissible RNA virus. Its pathogenicity remains to be established. We studied its prevalence in liver transplant patients and assessed the long-term influence on the liver graft. METHODS: Thirty-nine adult patients without hepatitis B or C were included; median follow-up was 8 years (range 1-17). Serum samples from before and late after transplantation were investigated for the presence of HGV-RNA. HGV-RNA was detected by cDNA-PCR, using primers from the NS3 region of the viral genome. The latest available yearly liver biopsy was assessed in a coded fashion according to established histological criteria. The outcome in the HGV-positive patients was compared with the outcome in the HGV-negative patients with respect to liver tests and liver histology. RESULTS: The prevalence before and after transplantation was 15.4 and 43.6%, respectively. Liver test results and liver histology did not differ between the HGV and non-HGV groups. In both groups more than 50% of the patients showed normal histology. Mild portal and/or lobular inflammation tended to be more prevalent in the non-HGV group (no statistical difference). CONCLUSIONS: HGV infection is highly prevalent in liver transplant patients. In the absence of co-infection with hepatitis B or C virus, no long-term negative influence on the graft occurs.

Adult↗
PubMed1997

Persistent unconjugated hyperbilirubinemia after liver transplantation due to an abnormal bilirubin UDP-glucuronosyltransferase gene promoter sequence in the donor.

BACKGROUND/AIMS: Gilbert's syndrome is genetically characterized by an extra TA element in the TATAA-box of the promotor region upstream of the bilirubin UDP-glucuronosyltransferase (UGT1A) coding region (Bosma et al. N Engl J Med 1995; 333: 1171-5). Persistent unconjugated hyperbilirubinemia is occasionally observed in liver transplant recipients with an otherwise normal liver function. We postulate that these patients could have received a liver from a donor with the Gilbert's syndrome genotype. Therefore, we investigated the UGT1A-gene TATAA-box in DNA from liver graft donors of jaundiced and non-jaundiced recipients. METHODS: DNA was obtained from stored donor lymphocytes and the number of TA elements in the TATAA-box of the UGT1A-gene promotor region was analyzed by polymerase chain-reaction. RESULTS: We observed two liver transplant recipients with persistent unconjugated hyperbilirubinemia. They received liver grafts from donors who were homozygous for an abnormal A(TA)7TAA-box in the UGT1A-gene. Four of 10 non-jaundiced recipients received livers from donors who were homozygous for the normal A(TA)6TAA-box and six received livers from donors who were heterozygous with a normal A(TA)6TAA-box on one allele and a prolonged A(TA)7TAA-box on the other allele. CONCLUSIONS: This study shows that liver graft recipients with persistent unconjugated hyperbilirubinemia may have received a liver from a donor with an abnormal TATAA-box in the bilirubin UGT1A-gene promotor region.

Adult↗
PubMed1997

Splenic artery aneurysms in liver transplant patients. Liver Transplant Group.

BACKGROUND/AIMS: The purpose of the study was to investigate the incidence of and risk factors for splenic artery aneurysms in liver transplant patients. METHODS: Medical records and the pre- and 1-year postoperative angiograms of 337 liver transplant patients were reviewed to assess the presence and characteristics of these aneurysms. RESULTS: Forty-five patients with aneurysms were identified (13%): 41 cases in 242 adult patients (17%) and four (4%) in 95 children (p<0.01). The female-to-male ratio was 2:1. The majority of the aneurysms (87%) were located in the distal third of the splenic artery and the majority (87%) of the patients presented multiple aneurysms. In patients without portal hypertension no aneurysms were identified, whereas in 16% of the patients with portal hypertension aneurysms were found (p<0.001). In adult patients the incidence of splenic artery aneurysms was significantly higher in patients with parenchymal diseases than in patients with cholestatic diseases (p<0.0001). Two patients (4%) died due to rupture of the aneurysms. Control angiographies, 1 year after liver transplantation, showed no changes in size and number of the aneurysms, and no new aneurysms were identified. CONCLUSIONS: The incidence of splenic artery aneurysms in liver transplant patients is 13%. They are generally multiple and located in the distal third of the splenic artery. The incidence is higher in women and in patients with parenchymal liver disease and portal hypertension. The incidence of rupture was 4%.

Adolescent↗
PubMed1997

Changes in 31P-relaxation times during organ preservation: observations on cold stored human donor livers.

During cold preservation for transplantation the tissue hydration state changes. It is not known whether such changes lead to altered relaxation times of 31P nuclei with potential consequences for the quantification of tissue metabolites. Therefore, 31P spectroscopic and proton T1 relaxometric measurements were performed on 42 isolated human donor livers shortly before implantation. The results demonstrate that 31P T1 relaxation times change during preservation for clinical transplantation, thus quantification of tissue metabolites in cold stored donor livers may be in part dependent on the tissue hydration state. Furthermore, it appeared that changes in tissue hydration state especially affect the physico-chemical characteristics of the intracellular fluid compartment. This study indicates that reliable spectroscopic quantification of tissue metabolites, particularly during sequential spectroscopic measurements in cold stored donor organs is best warranted under fully relaxed conditions.

Adenosine↗
PubMed1997

Surgical treatment of giant haemangioma of the liver.

BACKGROUND: The treatment of giant symptomatic haemangioma of the liver is still controversial. This retrospective study reviewed the results of surgical treatment. METHODS: Twenty-eight patients with symptomatic giant haemangioma of the liver were treated by liver resection (n = 24) or liver transplantation (n = 4). The median diameter of the haemangiomas was 11 (range 5-20) cm. RESULTS: Complications occurred in five of the 24 patients treated by partial liver resection, although all survived and remain alive and well more than 2 years after surgery. In six patients there was residual haemangioma in the liver remnant which did not enlarge during the 2-year follow-up. In four patients the haemangioma was considered irresectable and liver transplantation was performed. One died after a 'two-stage' liver transplantation; the remaining three patients are alive and well, 1, 4 and 9 years after transplantation. CONCLUSION: Liver resection is the treatment of choice for giant haemangioma of the liver where possible. In selected cases liver transplantation is indicated.

Adolescent↗
PubMed1997

Acute liver failure: spontaneous recovery or transplantation?

BACKGROUND: Decision-making in acute liver failure. Acute liver failure is a disease with multiple organ involvement and a high mortality rate. Conservative management alone will only partly influence the outcome. The option of emergency liver transplantation has greatly improved survival rates, but unables spontaneous recovery. A set of prognostic criteria enables selection of patients who will benefit the most from emergency liver transplantation. METHODS: Retrospective review and survey of the Groningen results. RESULTS: Of 52 patients (33 adults and 19 children) admitted for acute liver failure 2 were beyond recovery and died, 9 were treated conservatively and recovered and 41 were listed for emergency liver transplantation because of an estimated survival rate < 20%. Of these, 3 died and 1 recovered spontaneously while waiting and 37 were transplanted. Survival rate for 41 patients listed for transplantation was 23 (56%) and was similar for children and adults. CONCLUSIONS: In patients with acute liver failure, management and decision-making in a specialized liver unit with the possibility of emergency liver transplantation is mandatory.

Adolescent↗
PubMed1997

Poor initial graft function after orthotopic liver transplantation: can it be predicted and does it affect outcome? An analysis of 125 adult primary transplantations.

Donor liver shortage is a persistent problem in liver transplantation. A more liberal donor acceptance policy may be a possible solution. However, this might put recipients at risk for initial poor function or even non-function of the graft. Therefore risk factors for initial graft dysfunction should be identified, preferably by using an uniform definition of primary graft dysfunction or non-function. We retrospectively analysed 125 adult liver transplantations in order to identify risk factors for initial poor function and primary non-function. Donor, recipient pretransplant and surgical parameters were evaluated. Since there is no consensus on the criteria of dysfunction we used two definitions known from literature. No risk factors for postoperative dysfunction could be identified for either of the two definition sets. Furthermore, the definition set that included ALAT, prothrombin time and bile production in the first 72 h to identify poor graft function showed no relation with graft or recipient outcome. The other set, using ASAT and prothrombin time, determined from day 2 to day 7, showed that patients with a primary dysfunction had significantly higher morbidity and mortality compared to patients with a well functioning graft. We conclude that initial poor function after liver transplantation remains unpredictable, irrespective of the way it is defined. Moreover, our analysis shows that initial poor function can also develop in recipients that receive 'non-marginal' grafts without prolonged ischemia times. These results may support a more liberal selection of donor livers.

Adolescent↗
PubMed1996

Comparison of T cell responses in patients with a long-term surviving renal allograft versus a long-term surviving liver allograft. It's a different world.

The aim of the present study was to analyze whether acquired transplantation tolerance had developed in patients with a long-term surviving renal or liver allograft. Analysis of antidonor cytotoxic T cell precursor frequencies was performed in 31 renal allograft recipients and 9 liver allograft recipients with good graft function 2 years after transplantation. The results demonstrated that, before transplantation, normal antidonor T cell responses were generated in both groups of patients. Two years after transplantation, donor-specific CTL nonresponsiveness had developed in a minority of the renal transplant recipients. In contrast, 8 out of 9 liver transplant recipients showed donor-specific mixed lymphocyte culture and CTL nonresponsiveness. These findings indicate that development of donor-specific T cell nonresponsiveness is not a common event after kidney transplantation, whereas liver transplantation seems to induce, at least in vitro, a state of donor-specific T cell nonresponsiveness.

Cytotoxicity, Immunologic↗
PubMed1996

Tissue pH in cold-stored human donor livers preserved in University of Wisconsin solution. A noninavasive clinical study with 31P-magnetic resonance spectroscopy.

It is not known whether the tissue acidosis that accompanies cold storage is the beginning of irreversible cell injury, ultimately leading to cell death, or whether it is a natural "protective" mechanism for cells to survive hypoxic periods. To answer this question, the tissue pH of 45 cold-stored human donor livers preserved in University of Wisconsin solution (UW) was assessed shortly before implantation using noninvasive 31P magnetic resonance spectroscopy. We conclude that tissue pH during cold storage may be partly dependent upon hepatic glycogen stores and donor age. The wide range of tissue pH values that was observed at the time of implantation does not result in significant effects on cellular damage after transplantation. This indicates that tissue pH is not a major determinant for the viability of UW solution-preserved human donor livers, as indicated by postoperative hepatocellular damage and liver synthesis function. The membrane stabilizing and buffering capacity of UW solution appears to protect liver viability against tissue acidosis. Our results also indicate that liver tissue pH can be lower than has been previously assumed in the literature without significant adverse effects on liver viability.

Adenosine↗
PubMed1996

Bile acids suppress the secretion of very-low-density lipoprotein by human hepatocytes in primary culture.

The existence of a relationship between bile acid and triacylglycerol metabolism in humans has been established, but the underlying mechanism and its physiological relevance have remained unclear. We have studied the effects of bile acids on the secretion of very-low-density lipoprotein (VLDL)-associated triacylglycerol, using [3H]glycerol labeling technique, and apolipoprotein B (apoB) in human hepatocytes in primary culture. Human hepatocytes secrete nascent VLDL with an average diameter of about 40 nm. Lipid composition of the particles resembles that reported for plasma VLDL, with the exception of a markedly lower cholesterylester content. In 24-hour cultured human hepatocytes, physiological (i.e., portal) concentrations of taurocholic acid (10 to 200 mumol/L) suppressed [3H]triacylglycerol secretion dose dependently. The degree of inhibition highly correlated (r = .87, P < .01) with taurocholic acid content of the cells of different preparations (n = 7). ApoB secretion was inhibited by taurocholic acid to a similar extent as [3H]triacylglycerol secretion (r = .93, P < .01). Lipid composition of secreted VLDL particles did not change during taurocholic acid-induced suppression. No effects on intracellular apoB, [3H]triacylglycerol, triacylglycerol, and cholesterol mass were observed, nor did taurocholic acid affect protein synthesis, albumin secretion, or lactate dehydrogenase (LDH) release. Cellular cholesteryl ester (CHE) mass, however, was markedly reduced. Our results show that bile acids strongly interfere with the assembly or secretion of VLDL particles by human hepatocytes, suggesting a physiological function of the enterohepatic circulation of bile acids in the regulation of postprandial serum lipid levels.

Adult↗
PubMed1996

Cytomegalovirus infection does not increase the risk of vanishing bile duct syndrome after liver transplantation.

Cytomegalovirus (CMV) infection and HLA-DR sharing have been reported to be associated with the development of vanishing bile duct syndrome (VBDS) after liver transplantation. We retrospectively analyzed the importance of these risk factors for VBDS in 126 consecutive recipients of a first transplant. In contrast to previous studies, CMV was monitored strictly using the antigenemia assay, a quantitative marker of the viral load. Patient and graft survival were comparable in patients with and without CMV infection. The incidence of VBDS was low, regardless of the CMV infection status or degree of HLA-DR sharing. Improvements in the early diagnosis and treatment of CMV infection may have eliminated its negative influence on graft survival.

Bile Duct Diseases↗
PubMed1996

Incidence, risk factors, and outcome of antithymocyte globulin treatment of steroid-resistant rejection after liver transplantation.

We retrospectively analyzed the incidence and outcome of steroid-resistant rejection (SRR) during the first 6 months after OLT in 126 patients receiving triple immunosuppression. A total of 95 patients either did not experience acute rejection at all or had acute rejection that subsided without additional treatment. A total of 31 patients had biopsy-proven acute rejection that required therapy: 18 patients had acute rejection that responded to steroid therapy (steroid-sensitive rejection, SSR); the remaining 13 patients had SRR and received ATG. At the onset of acute rejection, no differences in clinical, biochemical, or immunological parameters were present between patients with SSR and SRR. However, the histological grade of acute rejection in the initial biopsy was higher in patients with SRR (P = 0.05). ATG treatment was effective in 10 of the 13 patients and was not associated with an increased incidence of opportunistic infections. Patient and graft survival rates at 2 years were comparable in the three groups. These data show that the incidence of SRR during the first 6 months after OLT is low, and that its treatment with ATG is both effective and well tolerated.

Adult↗
PubMed1996

Analysis of growth in children after orthotopic liver transplantation.

Growth after pediatric liver transplantation is an important factor in determining the quality of life. We collected data on height, skeletal age, and liver function of 45 consecutive pediatric transplant recipients and assessed the influence of primary diagnosis, liver function, and immunosuppressive regimen on their growth. Height and skeletal age were plotted as median standard deviation scores versus years post-transplantation. Growth, in terms of both height and skeletal age, were continuous without catch-up growth. Primary diagnosis was found to have no influence on height and poor liver function had a negative effect on both height and skeletal growth. A higher alternate day prednisolone maintenance dose also had negative effect on skeletal growth. Thus, it can be concluded that a pretransplant lack of growth will not be restored and is an indication for early transplantation in end-stage liver disease, especially in younger children.

Adolescent↗
PubMed1996

Bone loss after liver transplantation is not prevented by cyclical etidronate, calcium and alphacalcidol. The Liver Transplant Group, Groningen.

After orthotopic liver transplantation (OLT) bone mass rapidly declines and vertebral fracture rate increases. We studied bone loss and parameters of bone turnover in 53 consecutive patients. In an attempt to reduce bone loss the patients were prophylactically treated with cyclical etidronate in addition to daily 1 alpha-hydroxyvitamin D3 and calcium. During the first 3 months after transplantation median lumbar spinal bone mineral density (BMD) decreased 4.5%; subsequently no significant changes occurred. Median hip BMD continued to fall during the first post-transplantation year and deteriorated 7% over the whole study period. New vertebral fractures were seen in 25% of the patients, which is not lower than previously reported rates in patients not receiving cyclical etidronate. Parathyroid hormone levels increased after OLT (p = 0.01), but remained within normal ranges. Urinary hydroxyproline levels were increased and normalized in the second half-year after OLT. Elevated fasting calciuria increased further after OLT. 1,25-Dihydroxy-vitamin D3 levels were lowered pre-OLT (25 vs 66 pmol/ 1, p < 0.001) and normalized at 3 months after OLT. Serum osteocalcin concentrations remained unchanged and were reduced compared with levels in healthy controls. In summary, increased bone resorption occurs after OLT with persistent decreased bone formation, leading to vertebral fracture in 25% of patients. Etidronate, 1 alpha-calcidol and calcium treatment did not prevent bone loss.

Absorptiometry, Photon↗
PubMed1996

Adenosine triphosphate-dependent copper transport in human liver.

BACKGROUND/AIM: The recent cloning and sequencing of the Wilson disease gene indicates that hepatic copper (Cu) transport is mediated by a P-type ATPase. The location of this Cu-transporting protein within the hepatocyte is not known; in view of its proposed function and current concepts of hepatic Cu transport, it may reside in intracellular membranes (endoplasmic reticulum (ER), lysosomes) and/or in the bile canalicular membrane. The objective of this study was to establish characteristics and localization of ATP-dependent Cu transport in human liver. METHODS: We have investigated Cu transport in vesicles of human liver plasma membranes showing a gradual increase in enrichment of canalicular domain markers: i.e. basolateral liver plasma membranes (blLPM), a mixed population of basolateral and canalicular (XLPM) and canalicular liver plasma membranes (cLPM). RESULTS: In the presence of ATP (4 mM) and an ATP-regenerating system, uptake of radiolabeled Cu (64Cu, 10 microM) into cLPM vesicles and, to a lesser extent, into blLPM and XLPM was clearly stimulated when compared to control AMP values. Initial uptake rates of ATP-dependent Cu transport were 5.6, 7.8 and 13.7 nmol.min-1.mg-1 protein for blLPM, XLPM and cLPM, respectively, and showed no relationship with marker enzyme activity of ER and lysosomes (glucose-6-phosphatase and acid-phosphatase, respectively). Leucine aminopeptidase activity, as a marker for the cLPM, significantly correlated with ATP-dependent uptake rates measured in different membrane preparations: r = 0.70 (n = 9, p < 0.05). Estimated K(m) and Vmax values of ATP-dependent Cu uptake were 49.5 microM and 36.9 nmol.min-1.mg-1 protein, respectively. CONCLUSION: This study provides biochemical evidence for the presence of an ATP-dependent Cu transport system in human liver (cCOP), mainly localized at the canalicular domain of the hepatocytic plasma membrane.

Adenosine Triphosphate↗
PubMed1996

Doppler ultrasound of the hepatic artery and vein performed daily in the first two weeks after orthotopic liver transplantation. Useful for the diagnosis of acute rejection?

RATIONALE AND OBJECTIVES: To analyze changes in Doppler ultrasound variables in relation to liver biopsy findings for the diagnosis of acute rejection after orthotopic liver transplantation (OLT), the authors performed in a prospective study 316 Doppler ultrasound examinations in the first 2 weeks after OLT on 23 patients. METHODS: Recordings were obtained daily from the hepatic artery (resistive index [RI]) and hepatic vein (damping index [DI]). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi-square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection. RESULTS: Serial Doppler ultrasound examinations showed a significant increase in the RI in 11 of 22 patients (50%); the 23rd patient was excluded because of hepatic artery thrombosis. Despite an agreement in 15 of 22 patients (68%) no statistically significant correlation could be found (positive predictive value 6/11 = 55%; negative predictive value 9/11 = 82%; chi-square = 3.14; P > 0.05). A significant increase in the DI was observed in 14 of 23 patients (61%). However, no statistically significant correlation could be found as well with this parameter (positive predictive value 6/14 = 43%; negative predictive value 6/9 = 67%; chi-square = 0.00; P > 0.05). CONCLUSION: Serial Doppler ultrasound examinations were not helpful in predicting acute rejection.

Acute Disease↗