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Biomedical subjects

R E Kirsch

Publications and source records attributed to R E Kirsch.

At least 19 recordsLinked to original sources
PubMed1996

Hepatitis E in South Africa: evidence for sporadic spread and increased seroprevalence in rural areas.

Hepatitis E virus (HEV) is a major cause of non-A, non-B hepatitis in developing countries. Factors influencing sporadic spread of hepatitis E are unclear. We examined anti-HEV seroprevalence and demographic data from 407 urban and 360 rural black South African adults living in formal housing, squatter camps, or mud huts. Anti-HEV sero-prevalence ranged from 5.8% to 19.1% (mean 10.7%) in the different regions. Mean urban and rural rates were 6.6% and 15.3%, respectively (P = 0.0001). Rural mud hut dwellers, using unchlorinated river water, were at greater risk (17.4%) than rural villagers (5.3%; P = 0.008). A linear relation was found between seroprevalence and age, suggesting sporadic spread. The high prevalence in mud hut dwellers suggests that contaminated water plays a major role in HEV spread in South Africa. Routine chlorination or boiling of river drinking water before consumption may reduce HEV infection.

Adult↗
PubMed1996

Threshold effect of liver iron content on hepatic inflammation and fibrosis in hepatitis B and C.

BACKGROUND/AIMS: In hepatitis C, iron depletion may improve serum aminotransferases and the response to interferon, but it is not known whether inflammation and fibrosis correlate with hepatic iron content. Our aim was to establish whether hepatic iron content correlates with histological and serum indices of hepatic inflammation and fibrosis in hepatitis B and C. METHODS: Total hepatic iron was measured using computerized histomorphometry, and hepatic inflammation and fibrosis using a modified Knodell score, on histological slides from 31 patients with chronic hepatitis B and 38 with hepatitis C. RESULTS: Total hepatic iron was similar in the hepatitis B and C groups (0.82 +/- 1.72% and 0.56 +/- 1.12%; mean +/- SD). No iron was detectable in 11 patients with hepatitis B and 13 with hepatitis C. Alanine aminotransferase (85.96 +/- 67.1 vs 44.2 +/- 39.7 p < 0.05), aspartate aminotransferase (93.8 +/- 75.6 vs 47 +/- 33.5 IU/ml p < 0.05) and histological inflammatory score (9.33 +/- 3.51 vs 7.79 +/- 3.3 p = 0.07) were increased in those with stainable hepatic iron compared to those without. However, where iron was present, no association was found between the amount of hepatic iron and inflammatory or fibrosis scores. In hepatitis C, fibrosis was minimal in 77% of patients if iron was absent vs 24% with iron present, while marked fibrosis was present in 56% with iron vs 15% without iron (p < 0.01, Fisher's exact test). CONCLUSION: Hepatic iron is associated with increased hepatic inflammation in chronic hepatitis B and hepatitis C and with high fibrosis scores in hepatitis C. There is a threshold effect, and once present, increasing iron does not correlate with increasing inflammation or fibrosis.

Adolescent↗
PubMed1996

Inhibition of T cell mitogenesis by a novel anti-CD45R monoclonal antibody.

CD45 consists of a major family of membrane glycoproteins which have protein tyrosine phosphatase activity and regulate early activation events, progression and maturation signals in leucocytes. Various isoforms of CD45 (Mr 180-240 kDa) regulate sets of intermolecular associations between different surface receptors, and appear to be differentially expressed on B and T cells (namely CD45RA, B or CD45RO). We describe a novel IgG2a mAb directed against restricted and unique CD45R modified epitopes expressed preferentially on peripheral blood T cells. This anti-CD45R antibody (I(2)4c) at concentrations of 50 and 200 ng/mL inhibited mitogenic T cell lectin and anti-CD3-stimulated lymphocyte proliferation and blocked associated IL-2 secretion in vitro. Phorbol ester-stimulated mitogenesis was unaltered suggesting that the inhibition occurs independent of protein kinase C-mediated pathways. Western blotting and immunoprecipitation of purified cell lysates reveals that I(2)4c preferentially binds the higher Mr bands of CD45 expressed on T cells. Following T cell activation in vitro, the 190 kDa band became more predominant and an additional 130 kDa protein, possibly a proteolytic fragment was recognized. I(2)4c may inhibit T cell mitogenesis by direct effects on CD45R alone or by preventing interaction with other membrane-associated proteins and hence adhesive interactions with monocytes. Such interactions may however inhibit the initiation of signal transduction and, as a consequence, alter cellular activation by mitogenic lectins and anti-CD3 in vitro.

Animals↗
PubMed1996

A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria.

Variegate porphyria (VP), a low-penetrant autosomal dominant inherited disorder of haem metabolism, is characterised by photosensitivity (Fig. 1) and a propensity to develop acute neuropsychiatric attacks with abdominal pain, vomiting, constipation, tachycardia, hypertension, psychiatric symptoms and, in the worst cases, quadriplegia. Acute attacks, often precipitated by inappropriate drug therapy, are potentially fatal. While earlier workers thought the distal haem biosynthetic enzyme ferrochelatase may be involved in the genesis of VP, it was shown in the early 1980's, and is now accepted, that VP is associated with decreased protoporphyrinogen oxidase activity (PPO) (E.C.1.3.3.4). VP prevalence is much higher in South Africa than elsewhere; probably due to a founder effect with patients descending from a 17th century Dutch immigrant. PPO cDNAs from Bacillus subtilis, Myxococcus xanthus, human placenta and mouse liver have been cloned, sequenced and expressed. Human and mouse cDNAs consist of open reading frames 1431 nucleotides long, encoding a 477 amino acid protein. The human PPO gene contains thirteen exons, spanning approximately 4.5 kb. We have identified a C to T transition in codon 59 (in exon 3) resulting in an arginine to tryptophan substitution (R59W). A protein expressed from an in vitro-mutagenized PPO construct exhibits substantially less activity than the wild type. The R59W mutation was present in 43 of 45 patients with VP from 26 of 27 South African families investigated, but not in 34 unaffected relatives or 9 unrelated British patients with PPO deficiency. Since at least one of these families is descended from the founder of South African VP, this defect may represent the founder gene defect associated causally with VP in South Africa.

Amino Acid Sequence↗
PubMed1996

Nonopsonic binding of Mycobacterium tuberculosis to human complement receptor type 3 expressed in Chinese hamster ovary cells.

Nonopsonic invasion of mononuclear phagocytes by Mycobacterium tuberculosis is likely important in the establishment of a primary infection in the lung. M. tuberculosis binds to a variety of phagocyte receptors, of which the mannose receptor and complement receptor type 3 (CR3) may support nonopsonic binding. CR3, a beta2 integrin, is a target for diverse intracellular pathogens, but its role in nonopsonic binding remains uncertain. We have examined the binding of M. tuberculosis H37Rv to human CR3 heterologously expressed in Chinese hamster ovary (CHO) cells, thereby circumventing the problems of competing receptors and endogenously synthesized complement, which are inherent in studies with mononuclear phagocytes. The surface expression of CD11b and CD18 was assessed by immunofluorescence, immunobead binding, flow cytometry, and immunoprecipitation with anti-CD11b and anti-CD18 monoclonal antibodies (MAbs). The functional activity of the surface-expressed CD11b/CD18 (CR3) heterodimer was confirmed by rosetting with C3bi-coated microspheres. We found that M. tuberculosis bound four- to fivefold more avidly to CR3-expressing CHO cells than to wild-type cells and, importantly, that this binding was at similar levels in the presence of fresh or heat-inactivated human or bovine serum or no serum. In contrast, Mycobacterium smegmatis bound poorly to CR3-expressing CHO cells in the absence of serum, but after opsonization in serum, binding was comparable to that of M. tuberculosis. The binding of M. tuberculosis to the transfected CHO cells was CR3 specific, as it was inhibited by anti-CR3 MAbs, particularly the anti-CD11b MAbs LM2/1 (I domain epitope) and OKM1 (C-terminal epitope), neither of which inhibit C3bi binding. MAb 2LPM19c, which recognizes the C3bi-binding site on CD11b, had little or no effect on M. tuberculosis binding. The converse was found for the binding of opsonized M. smegmatis, which was strongly inhibited by 2LPM19c but unaffected by LM2/1 or OKM1. CR3-specific binding was also evidenced by the failure of M. tuberculosis to bind to CHO cells transfected with an irrelevant surface protein (angiotensin-converting enzyme) in the presence or absence of serum. We conclude that the binding of M. tuberculosis H37Rv to CR3 expressed in CHO cells is predominantly nonopsonic and that the organism likely expresses a ligand that binds directly to CR3.

Animals↗
PubMed1996

Fibronectin fragments cause an underestimation of plasma fibronectin levels in severe pre-eclampsia.

Elevated fibronectin (Fn) concentrations in plasma from pregnant women have been suggested to be predictive for the development of pre-eclampsia. However, reported correlations between Fn concentration with gestational age or disease severity appear to be confounded by several variables. Our finding of degradation products of Fn in plasma from patients with severe pre-eclampsia led to a study of whether their presence could influence immunological and functional measurements of intact plasma Fn. Plasma samples (10 control pregnant and 10 severe pre-eclampsia patients) were studied for the presence of intact Fn and fragments by SDS-PAGE and Western blotting. Percentages of immunoreactive Fn fragmentation in control plasma (9.37 +/- 6.7%) and severe pre-eclampsia plasma (62.57 +/- 7.0%) were determined by densitometric scanning. Immunoassays by ELISA were performed on normal plasma samples and on purified Fn in the absence or presence of plasma digests of pure Fn. Artefactual underestimations of Fn concentration occurred in the presence of Fn fragments. The percentage underestimation increased with increasing digestion times (1 h, 46.52 +/- 3.69%; 3 h, 77.5 +/- 7.18%; 4 h, 100%) and with increasing concentrations of Fn digest products (1h) added to normal plasma samples (n = 10) (40 micrograms, 23 +/- 8.1%; 125 micrograms, 36.33 +/- 5.1%; 250 micrograms, 43.66 +/- 6.5%). The underestimation of Fn concentration in the presence of Fn fragments suggests that ELISAs for Fn may be unreliable and thus lose their predictive value in these patients. Opsonic activities of control pregnant and severe pre-eclamptic plasma were determined by gelatin-latex agglutination assay. The ratios of opsonic activity to Fn concentration in plasma from patients with pre-eclampsia were significantly lower than those of control pregnant plasma samples (p < 0.008). The impaired gelatin-latex agglutination of Fn in pre-eclamptic plasma suggests that Fn fragmentation could have biological sequelae in vivo.

Blotting, Western↗
PubMed1995

Treatment of acute myocardial infarction with streptokinase does not appear to modulate circulating neutrophil function.

The administration of thrombolytic therapy is the most common method of achieving patency of the occluded coronary artery in patients with acute myocardial infarction (AMI). However, thrombolytic agents and the byproducts of fibrinolysis have the potential to affect neutrophil activation and thus function, thereby augmenting myocardial damage further. This study assessed the effect of streptokinase administration on the function of circulating neutrophils in patients with AMI. For this neutrophil adherence to human umbilical vein endothelial cells, homotypic neutrophil aggregation, and CD11b and L-selectin expression on the neutrophil membrane prior to and 1 h and 6 h after thrombolytic therapy was monitored. The study population included patients with AMI who received aspirin and streptokinase, and healthy laboratory workers who received aspirin only; all subjects acted as their own controls. Circulating fibrin degradation products and white cells were markedly raised following administration of streptokinase. No significant differences in neutrophil adherence to endothelium, homotypic neutrophil interactions, and CD11b or L-selectin expression were demonstrated between neutrophils, either pre- or post-thrombolytic therapy in the infarct group, or between neutrophils from the infarct group and from the control group. It was concluded that streptokinase produces an abrupt neutrophil leukocytosis together with a marked increase in circulating levels of fibrin degradation products. The assay systems used were unable to show significant sequential changes in circulating neutrophil adhesion and L-selectin or CD11b expression in patients with AMI following thrombolytic therapy or when these patients were compared with controls.

CD18 Antigens↗
PubMed1995

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↗
PubMed1995

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↗
PubMed1995

Serum angiotensin-converting enzyme activity, concentration, and specific activity in granulomatous interstitial lung disease, tuberculosis, and COPD.

Angiotensin-converting enzyme (ACE) activity in serum is used as an aid to the diagnosis and follow-up of patients with sarcoidosis. A theoretical limitation of measurements of activity is that these may be affected by the presence of pharmacologic or endogenous inhibitors of ACE. Immunoassays of ACE concentration avoid this problem and, when combined with tests of ACE activity, permit calculation of specific activity of ACE. In this study, we set out to develop a sensitive radioimmunoassay for ACE to compare results obtained with this method with results of ACE activity and calculated ACE specific activity in patients suffering from a variety of lung diseases. In a group of control subjects (n = 32), the ACE concentration was 453.7 +/- 159.8 (SD) ng/mL; 95% confidence interval (CI), 398.34 to 509.06, but levels were significantly elevated in sarcoidosis (979.3 +/- 558.6 ng/mL; 95% CI, 827.5 to 1,131.1; n = 51; p < 0.001 vs control subjects), silicosis (646.5 +/- 239.1 ng/mL; 95% CI, 544.2 to 748.8; n = 21; p < 0.01), and miliary tuberculosis (647.0 +/- 217.1 ng/mL; 95% CI, 551.9 to 742.1; n = 29; p < 0.01). The levels were normal in COPD, interstitial pulmonary fibrosis, and active cavitary pulmonary tuberculosis. The overall correlation between ACE activity and concentration measurements was strong (r = 0.93). No evidence of endogenous ACE inhibition was observed in any of the disease categories studied except in COPD where an elevation of ACE specific activity was observed, raising the possibility that in this condition different isozymes of ACE with higher specific activity might be released.

Adult↗
PubMed1995

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↗
PubMed1995

Is dietary erucic acid hepatotoxic in pregnancy? An experimental study in rats and hamsters.

The hypothesis that dietary erucic acid may contribute to the pathogenesis of intrahepatic cholestasis of pregnancy has been examined in pregnant rats and hamsters after prolonged feeding of diets containing 25% rapeseed oil rich in erucic acid (40% of fatty acids) or corn oil, without erucic acid. Both dietary oils were well tolerated, although weight gain was 17% to 20% less in animals receiving rapeseed oil. Rats and hamsters were studied on the last day of pregnancy and compared with age- and diet-matched nonpregnant animals. Histological examination showed no major morphologic abnormalities in liver, heart, kidneys, and adrenals. Similar microscopic deposits of fat were found in the livers and hearts of pregnant hamsters of both dietary groups. Chromatographic analysis of fatty acids in liver, heart, and kidney homogenates of hamsters and in isolated rat liver cells reflected the fatty acid composition of the dietary oils: oleic (18:1) and linoleic (18:2) acids were among the predominant fatty acids. Erucic acid was found in a higher proportion in the heart (14% by weight of total fatty acids) than in the liver (3%) and kidneys (3%) of animals fed rapeseed oil. Bile flow and biliary lipid composition was similar in rats and hamsters fed rapeseed or corn oil. Bile flow tended to be less in pregnant than in nonpregnant animals. Pregnant hamsters fed rapeseed oil tended to have the lowest bile flow. The lithogenic index of bile was slightly decreased in pregnant rats and increased in pregnant hamsters, although these proportional changes were similar for both diets. In all circumstances the lithogenic index remained below a value of 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1994

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↗
PubMed1994

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↗
PubMed1994

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↗
PubMed1994

Inhibition of mammalian protoporphyrinogen oxidase by acifluorfen.

We have studied the kinetics of the inhibition of mitochondrial protoporphyrinogen oxidase (PPO) from liver and placenta of 3 mammalian species by the diphenyl ether herbicide acifluorfen (AF). AF competitively inhibited PPO from human liver and placenta, mouse liver and pig placenta with respect to its substrate protoporphyrinogen. In contrast, mixed-type inhibition was shown for pig liver. The differing results shown in pig liver may point to structural differences in PPO derived from different species and tissues. We have also compared the effects of AF on the function of PPO in human lymphoblasts from normal subjects and those with variegate porphyria, an inherited disorder of PPO. Competitive inhibition was shown for both and there were no significant differences in the values of Ks or Ki.

Animals↗