Barriers to xenotransplantation.
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Animals↗
Biomedical subjects
S C Robson
Publications and source records attributed to S C Robson.
Fetal size and growth in Bangladeshi pregnancies.
A longitudinal study of 20 uncomplicated pregnancies in Bangladeshi women was undertaken. Fetal growth was investigated by serial ultrasound scans performed between 26 and 38 weeks of pregnancy. Repeated measurements of abdominal circumference and estimates of fetal weight were best described by a log quadratic equation. The coefficients were not significantly different from those obtained from a previously reported study of fetal growth in 67 uncomplicated pregnancies with healthy outcomes in white Anglo-Saxon women. Further comparison between the two groups showed that the mean abdominal circumference and estimates of fetal weight of the Bangladeshi fetuses were smaller at 28, 32 and 36 weeks' gestation. These results suggest that, although Bangladeshi fetuses appear to be smaller than Anglo-Saxon fetuses, they grow at a similar rate during the third trimester.
Abdomen↗
Role of neutrophil membrane proteases in fibrin degradation.
The cellular components of blood play a significant role in the breakdown of fibrin, with specific cellular adhesive processes allowing for accumulation of neutrophils within the fibrin clot. Fibrinolysis by elastase and cathepsin G, enzymes present within the azurophilic granules of the neutrophil, has previously been shown. Recent studies have demonstrated neutrophil-mediated fibrinogenolysis by a membrane-associated protease which suggests that proteases connected with the neutrophil membrane might also be capable of clot dissolution. Intact neutrophils were found to solubilize fibrin clots with the rate of fibrin solubilization being greater when the cells were incorporated into the clot than when the cells were added to preformed clots. Stimulation of intact neutrophils with phorbol ester upregulated this neutrophil-mediated fibrinolysis. Solubilization was detectable within 2 min of incubating the cells with fibrin clot, was always faster than that by neutrophil conditioned medium and lacked inhibition with lysosomal enzyme inhibitors. Neutrophil-mediated clot lysis was effected by membrane-associated serine proteases that migrated to apparent molecular weights of 501 kD, 398 kD, 316 kD, 245 kD and 209 kD on 3-13% SDS-PAGE. This degradation was distinct from that produced by plasmin, neutrophil lysosomal enzymes and purified human neutrophil elastase. The neutrophil membrane proteolytic systems were found to enhance the action of plasmin in clot solubilization. These results suggest neutrophil membrane proteolytic activity could assist thrombus dissolution and may be of particular value in assisting early clot dissolution by plasmin and when clot stabilization occurs through plasminogen activator inhibitor-1 (PAI-1) inhibition of plasminogen activation.
Cell Membrane↗
Blunted erythropoietin response to anaemia in tuberculosis.
The precise cause of the anaemia that is commonly associated with severe pulmonary tuberculosis (PTB) has not been elucidated. The role of erythropoietin (Epo), the central hormone regulating red cell formation, still awaits clarification. We therefore determined serum Epo levels in patients with PTB; group 1, haemoglobin less than 110 g/L, group 2, haemoglobin greater than 110 g/L; group 3, controls, consisted of matched individuals with uncomplicated iron deficiency; group 4, healthy volunteers. Peripheral blood monocytes were obtained from patients with PTB and the controls, cultured, and the supernatant fluid (SNF) harvested. Tumour necrosis factor alpha (TNF alpha) levels were determined in the SNF, which were then added in various dilutions to a hepatocellular carcinoma cell line (HepG2) capable of regulated EPO synthesis in vitro. The influence of this cytokine was defined by the addition of specific neutralising anti-TNF alpha antibodies in this assay system. Patients in group 1 had significantly lower Epo levels (54 + 11 mU/mL) compared with those in group 3 (142 +/- 41 mU/mL) (p < 0.01). Monocyte supernatants from patients in the anaemic PTB group had markedly elevated TNF alpha levels and significantly suppressed Epo output by HepG2 cells in vitro (p < 0.01). This inhibition was consistently abrogated by anti-TNF alpha antibodies. Serum Epo levels were inappropriately low in untreated PTB patients when compared with corresponding haemoglobin levels in iron deficient controls. This blunted response could be ascribed to release of TNF alpha or other cytokines by activated monocytes.
Anemia↗
Haemostatic and immunological sequelae of portacaval shunt in rats.
We have evaluated the link between haemostatic abnormalities and immune dysfunction in liver disease by evaluating parameters of cellular and humoral immunity in conjunction with coagulation profiles in rats following portacaval anastomosis, induction of portal hypertension by portal vein stenosis or by sham surgical procedures. Twelve weeks following surgery, portacaval shunted rats were markedly anaemic (8.9 +/- 0.6 g/dl; controls 12.3 +/- 1.4 g/dl, p < 0.05), had low plasma fibrinogen levels (0.6 +/- 0.3 g/l, controls 2.5 +/- 0.2 g/l p < 0.05) and markedly elevated fibrin(ogen) degradation products (FDP) titres (1/40-1/80; controls < 1/10. p < 0.05). Portal vein stenosed rats were less anaemic (11.5 +/- 0.8 g/dl), had near normal fibrinogen levels (2.1 +/- 0.3 g/l) but elevated FDP levels (1/40-1/80). Both portacaval shunted and portal vein stenosed rats had elevated serum IgG levels (35.1 +/- 14.1 g/l; 29.2 +/- 13.9 g/l respectively; control values 20 +/- 5.9 g/l p < 0.05 for comparison with both experimental groups). Intrinsic lymphocyte proliferation to T and B cell mitogens was markedly depressed in the portacaval anastamosed rats when compared to controls. Serum factors inhibitory to control lymphocyte proliferation were noted in the shunted rats. Phagocytosis of complement and immunoglobulin sensitised sheep RBC by Kupffer cells purified from rats that had undergone portacaval shunting was markedly reduced (p < 0.05). The increased degree of phagocytosis following exposure to LPS-endotoxin (50 micrograms/ml) was proportionate in degree to the control group. Spontaneous release of bioactive lymphocyte activating factors (IL-1 and IL-6) by purified rat sinusoidal cell populations was decreased in the portacaval shunted group, and decreased still further following stimulation with LPS (50 micrograms/ml) in vitro. The observation that many of the haemostatic and immunological abnormalities associated with chronic liver disease are present in rats with surgically created portacaval shunts or with induced portal hypertension, lends credence to the hypothesis that shunting of portal blood is, at least in part, responsible for many of the systemic manifestations associated with chronic liver disease.
Animals↗
Third trimester fetal growth and umbilical venous blood concentrations of IGF-1, IGFBP-1, and growth hormone at term.
Insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-1 (IGFBP-1) and growth hormone (GH) concentrations were measured in umbilical venous blood after delivery of 78 term newborn infants. Three groups of pregnancies were prospectively identified during the third trimester, according to fetal size and subsequent fetal growth, assessed by repeated ultrasound scans. Fetal size was considered either appropriate for gestational age (AGA) or small for gestational age (SGA), according to whether the first ultrasound measurement of abdominal circumference was equal to or above, or below the tenth centile for gestational age, respectively. Subsequent fetal growth was quantified by the change in the standard deviation score of abdominal circumference measurements between the first and last scans before delivery. Fetal growth retardation (FGR) was defined as a (negative) change in SD score of greater than -1.5. Eighteen SGA fetuses with evidence of FGR had significantly lower IGF-1 (median 0.05 (range 0.0-0.24) U/ml) at delivery than 35 SGA fetuses with normal growth (median 0.13 (range 0.0-0.94) U/ml; P < 0.05) and 25 AGA fetuses with normal growth (median 0.31 (range 0.0-0.84) U/ml; P < 0.05). The median concentration in the SGA group with normal growth was also significantly lower than that of the AGA group with normal growth. There were no significant differences in IGFBP-1 or GH concentrations between the three groups. These observations indicate that umbilical blood concentrations at birth of IGF-1, but not IGFBP-1 or GH, relate to both fetal size and fetal growth during the third trimester of pregnancies reaching term.
Embryonic and Fetal Development↗
Role of endothelial cells in transplantation.
Endothelial cell activation with accompanying vascular inflammatory changes is considered central to the experimental manifestations of both hyperacute and delayed xenograft rejection responses. Natural xenoreactive antibodies directed at alpha-galactosyl residues of xenogeneic glycoproteins and glycolipids, with associated complement activation via the classical pathway, are considered major immediate mediators of graft endothelial cell injury in the clinically relevant discordant swine to primate combinations. In delayed xenograft rejection processes, where recipients are treated prophylactically to ameliorate these initial events, activation of infiltrating mononuclear phagocytes and natural killer cells are associated with ongoing endothelial cell activation processes, procoagulant generation and vascular thrombosis. Allograft hyperacute rejection is observed when vascularised organs are transplanted to sensitized individuals with high levels of cytotoxic antibodies. Less dramatic forms of humoral allograft rejection (termed accelerated or vascular rejection) and the more common cell-mediated endothelialitis are associated with significant graft damage. Endothelial cell activation is also linked with graft preservation injury, forms of chronic rejection and delayed graft loss. Experimental work is currently being directed at the control of hyperacute rejection, the close understanding of endothelial cell thromboregulation in both transplanted xeno- and allografts and the development of novel therapeutic agents including gene therapy and the possible use of organs from transgenic animals.
Cell Transplantation↗
Acid-base changes after severe birth acidaemia.
The aim of this study was to assess prospectively acid-base changes after severe birth acidaemia. Fourty-five term babies with severe acidaemia (median umbilical artery pH 6.99 [Range 6.74-7.05], mean base deficit 16.3 [SD 3.7] mmol/l) were prospectively identified. Pathological cardiotocographs were present in 32 (71%) prior to delivery and 39 (87%) were delivered operatively; 27 for fetal distress. Sixteen required intubation. At one hour of age, median pH was 7.29 [Range 7.04-7.45] and the change in pH correlated with one hour pCO2 (r = 0.62 p < 0.001). pH measurements were obtained in 11 of the 16 babies with a 1 hour pH < or = 7.25 and all values had recovered by this time. Five of this group were receiving oxygen. Of the 11 babies admitted to NICU, 1 died and 3 had evidence of encephalopathy, all of which were normal at follow-up [2-12 months]. Recovery of pH after severe birth acidaemia was evident at 1 hour of age and would appear to be complete by 4 hours.
Acid-Base Imbalance↗
Hematopoietic stem cell markers are expressed by ductal plate and bile duct cells in developing human liver.
The identification of ductal plate cells as likely progenitors for bile duct epithelium and hepatocytes and their possible reappearance as oval cells in the regenerating liver have generated much interest in their pluripotential capacities. We have examined the distribution of three hematopoietic stem cell markers, c-kit, CD34, and CD33 in addition to laminin, the standard cytokeratin markers CAM 5.2, CK 18, and CK 7 and the oval cell marker OV-6 in fetal liver during various stages of development. Hematopoietic stem cell markers were expressed in ductal plate cells in a pattern similar to the early cytokeratin markers CAM 5.2 and CK 18. Cells stained strongly for these early cytokeratin markers until 22 weeks. Thereafter, the expression of these markers decreased while positivity for CK 7 increased. Bile duct cells showed a distribution of hematopoietic and cytokeratin markers resembling that of ductal plate cells. Both ductal plate cells and bile duct cells expressed OV-6 strongly throughout development. This study showed similarity between hepatic and bile duct precursors and bone marrow stem cells. The comparable distribution of markers in bile duct epithelium and ductal plate cells may imply fewer transitional stages between ductal plate cells and bile duct epithelium than between the putative stem cells and hepatocytes.
Antigens, CD↗
Degradation of fibronectin in association with vascular endothelial disruption in preeclampsia.
The objectives of this study were (1) To assess human umbilical cord vein endothelial cell (HUVEC) fibronectin (Fn) content and integrity in patients with preeclampsia and (2) to investigate the ability of Fn and Fn fragments (FnDP) to disrupt endothelial cell attachment to an Fn matrix through modulation of plasminogen activator activity. Intact Fn was released from normal cord veins, while Fn and FnDP (70 and 21 kd) were released from cord veins in culture from patients with severe preeclampsia. Factor VIII and Fn immunostaining of normal cord sections revealed endothelial integrity and low Fn content, while immunostaining of cord sections from patients with preeclampsia revealed a disrupted endothelium and high concentrations of Fn. Both intact Fn and FnDP isolated from patient plasma or prepared by plasmin digestion of pure Fn had no effect on chromium 51 release from HUVECs. These FnDP, but not intact Fn, stimulated HUVEC urokinase plasminogen activator production within 2 hours (p < 0.05) and caused a time- and concentration-dependent detachment and disruption of the HUVEC monolayers and HUVEC-mediated degradation of immobilized iodine 125-labeled Fn underneath the HUVEC monolayer (p < 0.02) after 2 hours. This 125I-labeled Fn release was enhanced by plasminogen and inhibited by aprotinin. Thus FnDP appear to cause endothelial cell disruption that may be due to plasmin generation in vitro.
Adult↗
Xenotransplantation: endothelial cell activation and beyond.
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Animals↗
A cost-to-benefit analysis of blood products used during the initiation of an orthotopic liver transplantation programme.
Orthotopic transplantation is the treatment of choice for selected patients with end-stage post-necrotic and cholestatic liver diseases. These individuals typically have disturbed haemostasis, which reflects both impaired hepatic synthesis of clotting factors and disseminated intravascular coagulation compounded by large-volume transfusions of blood products occasionally required during surgery. The latter contribute significantly to the cost of this procedure, but may approximate the cumulative consumption of that required for the support of patients in liver failure. Perspective is provided by prospective analysis of data from the first 10 patients in the current programme. There were striking, if transient, intra-operative changes in standard laboratory parameters of coagulation and fibrinolysis; all patients were readily controlled with replacement therapy administered according to serial haemostatic measurements combined with clinical judgement. In most patients these values had stabilised within 24 hours of surgery. Those with post-necrotic liver cirrhosis had the most marked degrees of hepatic dysfunction, reflected in more profound haemostatic disturbances; these patients required the largest amounts of blood products. Inclusive median costs for the first year were estimated at R35,000 and for the first 5 years at R60,000, with 80% of the patients expected to be alive between 5 and 10 years later and enjoying an excellent quality of life. These figures contrast with those estimated for optimal medical and non-transplant surgical management following variceal bleeding as a major complication of liver disease (R30,000 for the first year and R70,000 at 3 years). In addition, the latter patients would usually be unable to work and have a poor quality of life with minimal likelihood of survival beyond this point. We conclude that with a multidisciplinary approach in an academic centre, surgical replacement of the irreversibly damaged liver in properly selected patients is no more expensive and has a better outcome than acceptable alternative approaches.
Adult↗
Fibrinogenolysis by a neutrophil membrane protease generates an A alpha 1-21 fragment.
The 600 kDa neutrophil membrane neutral protease, which had been shown to generate bioactive peptides from the acute-phase reactant C-reactive protein, has now been shown to have fibrinogenolytic activity that is distinct from fibrinogenolysis by plasmin and neutrophil lysosomal enzymes. This protease gradually reduces the apparent molecular mass of fibrinogen (340 kDa) to non-clottable products and generates terminal products with apparent molecular mass values of 270 kDa, 200 kDa, 100 kDa and less than 40 kDa through cleavage of all three of the constituent chains. Characteristics of fibrinogenolysis by this neutrophil protease are cleavage of the bond between amino acids valine and glutamic acid at positions 21 and 22 respectively from the N-terminus of the A alpha chain to release an A alpha 1-21 peptide, digestion of the B beta chain at positions within the C-terminus, and proteolysis of the bond between amino acids isoleucine and glycine at positions 394 and 395 respectively from the N-terminus of the gamma chain. This generates products that lack anticoagulant activity. The thrombin clotting time of the product with an apparent molecular mass of 330 kDa was prolonged, although clot formation was still observed. Loss of coagulability and inability to clot was found with further degradation of fibrinogen to an apparent molecular mass of 290 kDa. Activity of this neutrophil membrane protease in vivo could be important for the regulation of fibrin deposition at sites of inflammation, and may contribute to the reported plasma levels of the A alpha 1-21 peptide.
Amino Acid Sequence↗
Primary sclerosing cholangitis. Requiem for biliary drainage operations?
OBJECTIVE: To review the outcome of a consecutive number of patients with primary sclerosing cholangitis (PSC) treated at one institution to define prognostic variables and determine the influence of surgery on outcome. DESIGN: Case series of patients with PSC seen in Cape Town, South Africa, between 1981 and 1991. SETTING: Tertiary referral center. PATIENTS: Thirty-six patients with PSC were studied. Diagnosis was based on cholangiographic findings of multiple strictures of the bile ducts together with compatible clinical and biochemical features. Thirty-two patients were followed up prospectively for up to 9 years. MAIN OUTCOME MEASURES: Patient outcome was defined as good (stable or slowly progressive disease) or poor (death or liver transplantation). RESULTS: During the follow-up period, seven patients with PSC died and two underwent liver transplantation. Actuarial survival at 5 years was 52%. An increased serum bilirubin concentration was the only variable at presentation that independently predicted a poor outcome. Cholangiography was unhelpful in predicting patient outcome. Six patients who developed obstructive jaundice associated with advanced liver disease underwent biliary drainage operations for surgically correctable strictures, but this did not seem to prevent progression of the disease. Two patients who progressed to end-stage liver disease went on to have liver transplantation and were alive with functioning grafts at 7 and 14 months, respectively. CONCLUSIONS: Symptomatic PSC is a progressive disorder with a poor prognosis. Our experience suggests that patients with advanced liver disease caused by PSC should be considered directly for liver transplantation rather than biliary bypass operations.
Adolescent↗
The influence of cyclosporine A therapy on sex hormone levels in pre- and post-menopausal women with primary biliary cirrhosis.
The mechanism underlying sex hormone disturbances in post-menopausal women with primary biliary cirrhosis is unclear, but these alterations may occur as a consequence of liver disease. As cyclosporine may have some therapeutic potential is this condition, we have evaluated short-term alterations in plasma sex hormone levels in 11 pre- and 19 post-menopausal women with primary biliary cirrhosis following randomisation to cyclosporine A or placebo therapy. Baseline sex hormone binding globulin levels were markedly depressed in all pre-menopausal women but were elevated for the post-menopausal group when compared to standard reference ranges. Testosterone and dihydrotestosterone levels were low or markedly depressed in both patient groups. Androstendione concentrations tended to be higher than the normal range in the post-menopausal group. Oestradiol levels were within the normal range for the pre-menopausal group but were relatively higher in the post-menopausal group than in other normal post-menopausal women. Cyclosporine A therapy resulted in significant decreases in sex hormone binding globulin levels (26.6 +/- 5.0 to 16.2 +/- 4.6 nmol/l; p < 0.05) in the premenopausal group and reduction in total (336 +/- 163 to 140 +/- 132 pmol/l; p < 0.01) and free (6 +/- 5 to 2 +/- 3 pmol/l; p < 0.05) oestradiol levels in the post-menopausal group at 6 months. There were no significant alterations in other hormonal parameters. No temporal changes occurred in the placebo group. Cyclosporine A therefore induces significant but variable sex hormone changes in both pre- and post-menopausal women with primary biliary cirrhosis.
Adult↗
A 15-year experience of injection sclerotherapy in adult patients with extrahepatic portal venous obstruction.
OBJECTIVE: The authors report a 15-year experience with injection sclerotherapy in the management of adult and teenage patients with esophageal varices due to extrahepatic portal venous obstruction (EHPVO). SUMMARY BACKGROUND DATA: Extrahepatic portal venous obstruction is an uncommon cause of esophageal varices and is associated with normal liver function. Effective control of variceal bleeding is the major factor influencing survival. The results of surgery have been unsatisfactory, and therefore, more conservative management policies have been adopted. METHODS: Fifty-five patients with proven EHPVO underwent repeated injection sclerotherapy via either a modified rigid esophagoscope under general anaesthesia or a fiber-optic endoscope under light sedation, using ethanolamine oleate as the sclerosant. RESULTS: Esophageal varices were eradicated in 44 patients after a median number 6 injections (range 1-17) over a mean of 12.5 months (range 1-48). The mean follow-up was 6.8 years (range 1.1-14.6 years). Eleven patients were admitted on eighteen occasions with bleeding from esophageal varices before eradication and there were seven bleeding episodes in six patients from recurrent varices after initial eradication. Complications related to sclerotherapy included injection site leak (6), stenosis (11) and mucosal ulceration (32) during 362 injection sclerotherapy episodes. Four patients died during the study period. CONCLUSIONS: Injection scelotherapy is the treatment of choice in most patients with EHPVO.
Adult↗
Malignant obstructive cholangiopathies mimicking primary sclerosing cholangitis.
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Adolescent↗
Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1 beta, IL-6 and plasminogen activator inhibitors from monocytes in vitro.
Disseminated intravascular coagulation, characterized by circulating fibrin(ogen) degradation products (FDP), is associated with both acute and chronic inflammatory conditions. Since the association of FDP with monocytes could influence the release of cytokines and other regulatory proteins with significant clinical ramifications, we have studied cytokine synthesis and release following the interaction of D-dimer (DD), a terminal degradation product of fibrin, with human monocytes in vitro. Adherent peripheral blood monocytes were incubated with purified DD for 24 and 48 h and secreted or cell-associated IL-1 beta and IL-6 antigen levels and activity determined. DD (50 micrograms/ml) boosted the secretion of IL-1 beta antigen from median control levels of 659 pg/ml to 2704 pg/ml and that of IL-6 antigen from 806 pg/ml to > 3000 pg/ml at 48 h (P < 0.05). Similar increases in extracellular biologically active IL-1 and IL-6 were observed. Although DD increased cell associated IL-1 beta antigen levels from median values of 188 to 1600 pg/106 cells and IL-6 antigen from 660 to 2215 pg/106 cells (P < 0.05), cell-associated IL-1 functional activity decreased from control levels of 98 inhibitor units/ml to 65 units/ml for cells exposed to DD. Secreted plasminogen activator inhibitor (PAI) bioactivity and PAI type 2 antigen levels were significantly increased following exposure of monocytes to DD. This may explain the decreased cell associated IL-1 activity observed in our study as PAI are known to inhibit biologically active membrane bound IL-1. Our finding that DD enhances monocyte release of biologically active cytokines suggests the presence of positive feedback pathways for fibrinogen synthesis by hepatocytes. Furthermore, the association of monocytes with DD may potentiate localized coagulation processes by subsequent alterations in pericellular proteolysis.
Antifibrinolytic Agents↗