The hepatitis G virus/GBV-C is associated with glomerulonephritis.
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Female↗
Biomedical subjects
R E Kirsch
Publications and source records attributed to R E Kirsch.
Autonomic neuropathy in extra-hepatic portal vein thrombosis: evidence for impaired autonomic reflex arc.
BACKGROUND/AIMS: Autonomic dysfunction is common in cirrhosis, and may be associated with increased mortality and hyperdynamic circulatory changes. Our aim was to investigate whether autonomic disturbances occur in extrahepatic portal vein thrombosis and their correlation with hemodynamic abnormalities. PATIENTS AND METHODS: Heart rate variation in response to standing, deep breathing, and Valsalva maneuver, and blood pressure response to sustained handgrip and to standing, were studied in 16 subjects with portal vein thrombosis (10 males, 30.8+/-2.8 years: mean+/-SE), 12 with cirrhosis (7 males, 52+/-2.3 years), and 10 healthy controls (7 males, 30.8+/-3.0 years). Supine resting, and 10- and 30-min standing epinephrine and norepinephrine levels were measured and results correlated with cardiac output. RESULTS: Autonomic dysfunction occurred in 62% of portal vein thrombosis and 75% of cirrhosis subjects, but in no controls (p<0.02). Similarly, postural hypotension occurred in portal vein thrombosis (-10.25+/-0.65 mmHg, p=0.003) and cirrhosis (-7.42+/-0.82 mmHg, p=0.007) but not in controls. All groups had similar baseline epinephrine and norepinephrine concentrations. Epinephrine increased significantly in controls (45%, p<0.01 and 49%, p<0.02) after 10 of 30 min standing but not in the portal vein thrombosis or the cirrhotic group, and norepinephrine increased after 10 and 30 min standing in cirrhotics (128%, p<0.004 and 130%, p<0.008) and controls (129%, p<0.002 and 116%, p<0.004), but not portal vein thrombosis (34.5% and 39%, NS vs baseline). Portal vein thrombosis and cirrhosis groups had increased cardiac output (4441+/-509 and 3262+/-292) vs controls (1763+/-212 ml/min/m2, p<0.002), but there was no correlation with autonomic neuropathy or with catecholamine levels. CONCLUSIONS: Autonomic dysfunction and impaired catecholamine response to orthostatic stress occur commonly in portal vein thrombosis and suggest an impairment of the autonomic reflex arc, but changes do not correlate with hemodynamic abnormalities.
Adult↗
Doctors and the TRC--confronting our past.
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Ethics, Medical↗
Variegate porphyria in South Africa, 1688-1996--new developments in an old disease.
Variegate porphyria, an autosomal dominant inherited trait resulting in decreased activity of protoporphyrinogen oxidase, the penultimate haem biosynthetic enzyme, is characterised clinically by photosensitive skin disease and a propensity to acute neurovisceral crises. The disease has an exceptionally high frequency in South Africa, owing to a founder effect. The specific mutation in the protoporphyrinogen oxidase gene sequence which represents this founder gene has been identified. Genetic diagnosis is therefore now possible in families in whom the gene defect is known. However, the exact nature and degree of activity of the porphyria can only be determined by detailed quantitative biochemical analysis of excreted porphyrins. The relative contributions of the acute attack and the skin disease to the total disease burden of patients with variegate porphyria is not static, and in South Africa there have been significant changes over the past 25 years, with fewer patients presenting with acute attacks, leaving a greater proportion to present with skin disease or to remain asymptomatic with the diagnosis being made in the laboratory. The most common precipitating cause of the acute attack of VP is administration of porphyrinogenic drugs. Specific suppression of haem synthesis with intravenous haem arginate is the most useful treatment of a moderate or severe acute attack. Although cutaneous lesions are limited to the sun-exposed areas, management of the skin disease of VP remains inadequate.
Animals↗
Hepatitis C virus infection rate in volunteer blood donors from the Western Cape--comparison of screening tests and PCR.
INTRODUCTION: Hepatitis C virus (HCV) antibody seroprevalence studies overestimate the true infection rate. No data exist on the incidence of HCV or its clinical features in blood donors of sub-Saharan Africa. AIMS: To establish the true incidence of HCV infection in volunteer blood donors in the Western Cape, and compare risk factors and clinical and biochemical features of viraemic and non-viraemic subjects. METHODS: All donors attending the Western Province Blood Transfusion Service between December 1992 and August 1994 were screened prospectively for anti-HCV using the Abbott second-generation assay. Positive donors were evaluated clinically and biochemically. Their sera were examined for HCV-RNA by the polymerase chain reaction (PCR). RESULTS: Of 66314 donors screened, 275 (0.41%) were anti-HCV-positive. Of these 13.6% were PCR-positive (0.056% of all donors). PCR-positive patients had more risk factors for HCV acquisition (P < 0.01), symptoms of hepatitis (P = 0.02) and clinical signs of liver disease (P = 0.05) and higher alanine (P < 0.0001) and aspartate aminotransferase levels (P < 0.0001) than PCR-negative donors. However, clinical and biochemical features did not discriminate adequately between PCR-positive and negative donors. Liver biopsies performed in 9 of 13 PCR-positive cases showed mild inflammation, but no cirrhosis.
Blood Donors↗
A jaundiced look at the management of hepatitis?
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Acetaminophen↗
Halothane hepatitis in a South African population--frequency and the influence of gender and ethnicity.
AIM: To review post-anaesthetic hepatitis in a South African population, given that halothane use is restricted in other countries because of the high mortality and morbidity of its associated type II (idiosyncratic) hepatitis, even though it is still widely used in South Africa. STUDY DESIGN: Descriptive, retrospective analysis. PATIENTS AND METHODS: Hepatitis cases that occurred after inhalational anaesthetic use were identified by means of a computer search of Groote Schuur Hospital records, 1980-1994. Cases of hepatitis caused by circulatory failure and viral hepatitis were excluded. RESULTS: Twenty-six episodes occurred in 22 patients (mean age 49.05 years, range 32-65 years), of whom 15 were women. This gave an estimated incidence of 3.53/100,000 anaesthetics (95% confidence interval 2.06-5.0/100,000). All had pyrexia (mean 38.7 +/- 0.72 degrees C), malaise, anorexia or nausea and vomiting, with onset a mean of 4.27 +/- 3.5 days after exposure. Jaundice occurred in 86%, rash in 13.6%; 17 patients (77%) were obese. Alanine and aspartate aminotransferase levels were raised 47.49 +/- 61.8 and 55.9 +/- 54.5 times the upper limit of normal. Seven patients died and 1 underwent liver transplantation. Hepatitis occurred after the first exposure in only 2 patients (9%). Men and women had a similar risk, but the estimated relative risk for whites v. black or coloured patients was 3.33 (95% confidence interval 1.45-7.23; P = 0.003) controlling for gender. Awareness of the condition was suboptimal, and in 3 patients re-exposure to halothane occurred after an initial episode of typical halothane hepatitis. CONCLUSION: Halothane hepatitis remains a major cause of morbidity and mortality in South Africa. It is more common in whites, but there was no gender-related excess risk.
Adult↗
High prevalence of GBV-C hepatitis G virus infection in a rural South African population.
A novel virus, GBV-C/hepatitis G virus (GBV-C/HGV), has been cloned and characterised recently. GBV-C/HGV global epidemiology and risk factors for acquisition are currently unclear. We aimed to establish the determinants of this infection in a rural South African (SA) population. The study population included two samples, namely a community-based sample, and consenting persons from a nonspecialist outpatient department in the same district. A questionnaire regarding demographic details and putative risk factors was administered; blood samples were taken on which a polymerase chain reaction (PCR) was performed for both 5'NCR and NS5a regions of GBV-C/HGV using commercially available primers and probes. Two hundred and forty-nine people were studied with a mean GBV-C/HGV prevalence of 10.4%. Outpatient department and community prevalences differed significantly (18.0% and 6.3%, respectively, P = 0.004). GBV-C/HGV infection was associated with excessive alcohol consumption (P = 0.02; OR, 4.18) and a lack of waterborne sewerage (P = 0.04). PCR amplification of the NS5a region of all but two South African GBV-C/HGV positive samples showed poor reactivity. The prevalence of GBV-C/HGV in rural SA appears to be higher than that reported from Europe and North America. Infection appeared to be associated with excess alcohol intake and a history of previous blood transfusion. The discrepant NS5a and 5'NCR PCR sensitivity in this study raises the possibility of genetic differences in southern African GBV-C/HGV.
Adolescent↗
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↗
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↗
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↗
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↗
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↗
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↗
National strategy for the prevention and management of transfusion-associated hepatitis.
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Antiviral Agents↗
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↗
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↗
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↗