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Biomedical subjects

R E Kirsch

Publications and source records attributed to R E Kirsch.

At least 55 records · Page 3Linked to original sources
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↗
PubMed1994

Hepatitis E.

Explore the source record for details and available documents.

Female↗
PubMed1993

Fibrin and fibrinogen degradation products with an intact D-domain C-terminal gamma chain inhibit an early step in accessory cell-dependent lymphocyte mitogenesis.

Although the low molecular weight degradation products of fibrinogen (FgDP) and fibrin (FbDP) are known to inhibit lymphocyte blastogenesis, the effect of purified macro-molecular FgDP and FbDP (molecular weight, 90 to 200 Kd) is unclear. We have examined the effect of these latter FgDP and FbDP and find that products that contain the D domain inhibit lymphocyte proliferation in response to T-cell mitogens, allogeneic mononuclear leukocytes, and anti-CD3 in vitro. Plasmic digestion of D1 in the absence of calcium with removal of the C-terminal end of the gamma chain or disruption of the gamma-gamma C-terminal cross-link site of D-dimer (DD) by puffadder venom (PAV-D) abrogates their inhibitory potential. Prior incubation of monocytes with DD or D1 inhibits subsequent lymphocyte transformation. Binding studies with radiolabeled DD and PAV-D confirm that monocytes interact only with DD. This specific binding may be competitively inhibited by monoclonal antibodies to CD11b/CD18 or by peptide analogues of the C-terminal gamma chain of fibrinogen that mimic the adhesion recognition site of integrins. We postulate that DD and D1 bind to CD11b/CD18 on adherent monocytes and modulate lymphocyte activation. These products are typically present in the plasma of patients with disseminated intravascular coagulation with sepsis and could therefore influence inflammatory processes in vivo.

Antigen-Presenting Cells↗
PubMed1993

Immunological similarity between the 170 kD amoebic adherence glycoprotein and human beta 2 integrins.

Amoebiasis is an important cause of morbidity and mortality in developing countries. Virulence of Entamoeba histolytica depends on the trophozoite's being able to bind to colonic epithelium; binding is mediated by the 170 kD subunit of a 260 kD lectin. We found, by microcytofluorometry and western blotting studies, that this 170 kD subunit protein shares an epitope with human beta 2 integrins--a subfamily of cell-surface glycoproteins expressed exclusively on leucocytes and involved in many adhesive and signalling interactions. The immunological similarity between these proteins may explain the trophozoite's ability to bind to and invade colonic epithelium.

Amebiasis↗
PubMed1993

Disordered hemostasis in extrahepatic portal hypertension.

To assess the contribution of naturally occurring portal-systemic shunts to the coagulopathy of patients with liver disease, we studied laboratory parameters of hemostasis in 20 adult patients with extrahepatic portal hypertension, secondary to portal vein thrombosis, that had resulted in variceal bleeding. All extrahepatic portal hypertension patients had normal liver function and histological appearance. None had any evidence of preexisting coagulation disorders, and none had bled or undergone sclerotherapy in the 6 mo before study. Age- and gender-matched groups of 20 healthy individuals and 20 stable patients with cirrhosis and portal hypertension who had a history of variceal bleeding served as controls. Both patient groups had thrombocytopenia consistent with hypersplenism and portal hypertension. Prothrombin international normalized ratio (extrahepatic portal hypertension, 1.3 +/- 0.12; cirrhosis, 1.7 +/- 0.2; control, 1.02 +/- 0.06; p < 0.05) and partial thromboplastin time ratios (extrahepatic portal hypertension, 1.12 +/- 0.1; cirrhosis, 1.26 +/- 0.2; controls, 1.01 +/- 0.03; p < 0.05) were significantly prolonged in both patient groups. Extrahepatic portal hypertension and cirrhotic patient groups had significantly increased levels of serum total fibrin(ogen)-related antigen (extrahepatic portal hypertension, 818 +/- 150 ng/ml; cirrhosis, 454 +/- 52 ng/ml; controls, 124 +/- 7.3 ng/ml; p < 0.05), fibrin monomer (extrahepatic portal hypertension, 168.8 +/- 16.9 ng/ml; cirrhosis, 115.6 +/- 11.1 ng/ml; controls, 19.7 +/- 0.4 ng/ml; p < 0.05) and D-dimer (extrahepatic portal hypertension, 118 +/- 9.6 ng/ml; cirrhosis, 129 +/- 10 ng/ml; controls, 53.2 +/- 1.6 ng/ml; p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

The effect of oral activated charcoal on the course of congenital erythropoietic porphyria.

The administration of oral activated charcoal to two patients with congenital erythropoietic porphyria has previously been reported to result in a marked reduction in plasma and urinary porphyrin concentrations and in one case, clinical remission. We describe an additional case in which the use of charcoal was associated with an apparent exacerbation of the biochemical activity of the disease following an initial period of remission. This result is unexpected, and currently unexplained. We conclude that charcoal therapy in porphyria may not be without risk, and should be used with caution.

Administration, Oral↗
PubMed1993

Secretion of interleukin-6 by peripheral blood mononuclear cells from patients with pulmonary tuberculosis and their contacts.

The acute phase response, cell-mediated immunity and delayed type hypersensitivity in pulmonary tuberculosis (TB) may be mediated and regulated by the synthesis and release of interleukins 1 and 6 (IL-1, IL-6) and tumour necrosis factor (TNF) alpha. To examine this, peripheral blood mononuclear cells (PBMC) from TB patients, healthy controls and socially matched controls were cultured in the presence or absence of 5 micrograms/ml lipopolysaccharide-endotoxin (LPS) for 48 hours. IL-6 in the supernatant fluids (SNF) was measured using biological and immunoassays. Spontaneous release of functionally active IL-6 was significantly increased in PBMC SNF of TB patients when compared with both healthy controls and socially matched controls (median values of 4265, 356 and 1245 pg/10(6) cells respectively, p < 0.001). PBMC of social controls produced markedly more IL-6 than those of healthy controls (p < 0.001). LPS stimulated IL-6 production showed similar patterns for TB patients, healthy and social controls (median values of 6806, 1291 and 2667 pg/10(6) cells respectively, p < 0.001). In all three groups, LPS-stimulated cells produced significantly more IL-6 than non-stimulated cultures (p < 0.001). Constitutive production of IL-6 by PBMC from TB patients implies pre-activation of cells and suggests that IL-6 may be important in the regulation of the acute phase response in TB. Discrepant IL-6 release between the two control groups may be secondary to subclinical mycobacterial infection with non-specific immunological activation in the social controls.

Adolescent↗
PubMed1993

Serial measurements of circulating tissue plasminogen activator and fibrin(ogen) degradation products predict outcome in gestational proteinuric hypertension.

Gestational proteinuric hypertension (GPH), a major cause of maternal death, may be characterised by hypertension and proteinuria alone or may progress to disturbed coagulation and multiorgan failure. Since the condition can only be reversed by termination of pregnancy, there is a need for reliable indicators of severity. We found circulating levels of tissue plasminogen activator (tPA) (27.98 +/- 2.12 v. 7.17 +/- 0.81 ng/ml, mean +/- SEM), fibrin(ogen) degradation products (FDP) (7.55 +/- 1.99 v. 1.92 +/- 0.47 micrograms/ml) and fibronectin (221 +/- 15.2 v. 120 +/- 15.2 micrograms/ml) to be significantly increased in 21 patients with severe GPH when compared with 21 normotensive, age- and gestational age-matched pregnant controls. More importantly, patients who developed severe GPH showed a progressive increase in tPA and FDP levels with time. This was in contrast to patients who had hypertension and proteinuria alone, in whom tPA and FDP concentrations did not increase. Parallel measurements did not reveal a fall in platelet count or an increase in urinary protein excretion in patients who subsequently progressed to severe disease. Our findings may be of assistance to clinicians faced with the need to prolong pregnancy in patients with GPH in order to ensure fetal viability.

Enzyme-Linked Immunosorbent Assay↗