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Biomedical subjects

M Levi

Publications and source records attributed to M Levi.

At least 163 records · Page 9Linked to original sources
PubMed1999

Humoral and cell-mediated immune responses in humans to the NSP4 enterotoxin of rotavirus.

Rotavirus nonstructural protein NSP4 has recently been suggested to function as a viral enterotoxin and play a role in the pathophysiological mechanism whereby rotaviruses induce diarrhea. The ability of rotavirus NSP4 to stimulate a humoral immune response was examined in naturally infected children and adults, rotavirus vaccinated children, as well as a cellular immune response in adults. In this study, 10 of 10 naturally infected children and 9 of 10 rotavirus-vaccinated children showed a weak humoral IgG immune response to recombinant NSP4 (rNSP4) and/or a synthetic peptide corresponding to residues 114-134 of NSP4. Modest serum IgG antibody responses were detected in 20 of 20 adults. A cellular immune response to rNSP4 and/or NSP4(114-134) were detected in 8 of 10 adults measured either as a T-cell proliferative response (7 of 10), an increased production of IL-2 (6 of 10), or increased production of interferon-gamma (8 of 10). These results indicate that NSP4 induces a humoral immune response in humans and show for the first time that NSP4 stimulates a cellular immune response, possibly including cytolytic T-cells.

Adult↗
PubMed1999

Low-molecular weight heparins in venous and arterial thrombotic disease.

INTRODUCTION: Since the introduction of low-molecular-weight heparins (LMWHs) in the early 1980's, the use of these compounds has been extensively investigated as a substitute for unfractionated heparin (UFH) in patients with venous and arterial thrombotic diseases. LMWHs have several advantages as compared to UFH, such as the subcutaneous route of administration, the predictable anticoagulant response and the lack of the need for laboratory monitoring. The present systematic review evaluates randomised clinical trials which investigated the efficacy and safety of LMWH in the acute treatment of venous thromboembolism, myocardial infarction, unstable coronary syndromes and ischemic stroke. METHODS: A computerised and manual search was performed to identify all relevant clinical trials. All randomised studies, with an a priori defined study population, clinical outcome measurement and adequate follow-up, were reviewed by two independent assessors. Whenever possible a common effect estimate of the included studies was calculated. RESULTS: Thirteen studies in approximately 4000 patients with acute venous thromboembolism revealed an odds ratio for the 3-month recurrent thromboembolism rate and major bleeding complications during exposure of 0.77 (C.I. 0.57-1.04) and 0.61 (C.I. 0.39-0.95), respectively, in favour of LMWH as compared to UFH. In patients with acute myocardial infarction, one study suggested a reduction in the incidence of reinfarction and cardiac death in LMWH recipients compared to UFH, while a placebo-controlled study revealed no beneficial effect of LMWH on these outcomes. In six studies including over 7000 patients with acute unstable coronary syndromes, there was an odds ratio for recurrent angina, myocardial infarction, urgent revascularisation and major bleedings of 0.88 (C.I. 0.76-1.01), 0.84 (C.I. 0.69-1.01), 0.83 (C.I. 0.70-0.99), 1.09 (C.I. 0.70-1.70), respectively, in favour of LMWH compared to UFH. The three studies comparing LMWH treatment with placebo in approximately 1000 patients with acute ischemic stroke revealed an odds ratio for the 10-day recurrent stroke, death or disability after 3 months and major bleeding complications of 0.68 (C.I. 0.41-1.13), 0.94 (C.I. 0.78-1.15), 2.92 (C.I. 1.88-4.55), respectively. CONCLUSION: Fixed-dose subcutaneous LMWH appears to be a safe and effective alternative for dose-adjusted intravenous heparin in the treatment of patients with acute venous thrombotic disease as well as in patients with acute unstable coronary syndromes. The effectiveness of LMWH in patients with acute myocardial infarction remains unclear. There seems to be no beneficial effect of LMWH treatment as compared to placebo in patients with acute ischemic stroke, while the risk of major bleeding was clearly increased.

Fibrinolytic Agents↗
PubMed1998

Rapid analysis of epitope-paratope interactions between HIV-1 and a 17-amino-acid neutralizing microantibody by electrospray ionization mass spectrometry.

Progress in therapeutic or prophylactic immune intervention in HIV-1 infections may only come about with a detailed understanding at the molecular/atomic level of how antibodies neutralize (inactivate) virus infectivity. Currently information on the molecular aspects of antibody-virus interaction comes predominantly from X-ray crystallography, a process that is dependent on the production of suitable crystals. NMR can also be valuable but is complex and time consuming, while mass spectrometry has been limited to matrix-assisted laser-desorption ionization (MALDI) analysis of peptides eluted from the cognate antibody. Here, we have used electrospray ionization mass spectrometry (ESI-MS) to detect directly the interactions of a novel 17-amino-acid microantibody (MicroAb) that has HIV-1-inhibitory activity, and peptides representing the V3 regions of primary HIV-1 strains isolated from Brazil (clade B) and Africa (clade A). The MicroAb is based on the third complementarity-determining region of the heavy chain (CDR-H3) of a murine monoclonal IGGI (F58) specific for the V3 loop of the gp120 envelope glycoprotein of HIV-1. ESI-MS proved to be rapid (taking < 3 h for the entire analysis), sensitive (analytes at 2 mmol/ml), and accurate (RMM estimation to 0.01-0.1%). With it, we showed that the MicroAb forms complexes with the V3 peptides, implying that its antiviral activity is mediated by binding directly to the virus particle. In addition, through controlled protease digestion of the V3 peptides, we concluded that the CDR-H3 MicroAb bound to RKXXXIGPGR, a region similar to the epitope of the whole IgG as determined by ELISA. We believe that the approach exemplified here will be applicable generally to the identification of groups involved in receptor-ligand interactions.

Amino Acid Sequence↗
PubMed1998

Activation of clotting factor XI without detectable contact activation in experimental human endotoxemia.

Evidence of factor XI (FXI) activation in vivo is scarce. In addition, it remains uncertain whether thrombin, factor XIIa (FXIIa), or perhaps another protease is responsible for FXI conversion. We investigated the activation of FXI in eight healthy volunteers after infusion of a low dose of endotoxin (4 ng/kg of body weight). Activation of prekallikrein FXII, FXI, and prothrombin was measured with sensitive enzyme-linked immunosorbent assays (ELISAs), and FXI activation was measured with a novel enzyme capture assay that detects noncomplexed FXIa. Activation of FXI was apparent with a significant plasma peak level of noncomplexed FXIa of 10 to 11 pmol/L at 1 and 2 hours after endotoxin infusion, followed by a gradual increase in FXIa-FXIa inhibitor complexes, measured in the ELISAs, with a summit of 11 to 15 pmol/L at 6 and 24 hours, respectively. In accordance with previous studies, thrombin generation was detected 1 hour after endotoxin infusion to become maximal after 3 to 4 hours. In contrast, we did not find any evidence of contact activation, because markers of activation of prekallikrein and FXII remained undetectable. From the FXIa data a theoretical model was constructed which suggested that inhibition of FXIa does not take place in the plasma compartment, but is localized on a surface. These data provide the first evidence for FXI activation in low-grade endotoxemia and suggest that FXI is activated independently of FXII.

Adult↗
PubMed1998

Linomide suppresses chronic-relapsing experimental autoimmune encephalomyelitis in DA rats.

Linomide (quinoline-3-carboxamide) is a synthetic immunomodulator that suppresses several experimental autoimmune diseases. Here we report the effects of Linomide on chronic progressive and/or relapsing experimental autoimmune encephalomyelitis (PR-EAE), a CD4+ T cell mediated animal model of multiple sclerosis (MS). PR-EAE induced in DA rats by inoculation with homogenized guinea pig spinal cord and Freund's complete adjuvant, was strongly suppressed by Linomide administered daily subcutaneously from the day of inoculation. Linomide dose-dependently delayed the interval between immunization and onset of clinical PR-EAE, reduced severity and relapse of clinical PR-EAE, and shortened clinical PR-EAE. These clinical effects were associated with the down-modulation of CNS antigen-induced T cell responses and production of proinflammatory cytokines (IFN-gamma and TNF-alpha) as well as with upregulation of IL-4 (except in spleen MNC), IL-10 and TGF-beta in both spleen MNC and the spinal cord. These effects indicate that Linomide can suppress PR-EAE and may mediate its suppressive effects by regulation of cytokines.

Adjuvants, Immunologic↗
PubMed1998

[Recombinant factor VIIa (eptacog alfa): a new therapeutic option for patients with severe bleeding disorder due to inhibitory antibodies against a coagulation factor].

In 2 patients with severe haemorrhage (a 63-year-old man with haemophilia A (the factor VIII level was 29%) and a 44-year-old woman), of an inhibitory antibody against factor VIII was diagnosed. The development of recombinant factor VIIa (eptacog alpha) has made available a new therapeutic option for patients with an inhibitory antibody against a coagulation factor. Both patients were treated successfully with the new factor after other forms of treatment had failed. The new concept of the coagulation cascade on which the treatment with eptacog alpha is based assumes that the lack of an amplifying loop in the coagulation which takes place via factor IX (in combination with factor VIII) can be compensated by extra stimulation of the principal route (tissue factor-factor VIIa --> factor X) by pharmacological amounts of factor VIIa.

Adult↗
PubMed1998

Treatment with P2 protein peptide 57-81 by nasal route is effective in Lewis rat experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is a CD4+ T cell-mediated autoimmune disorder of the peripheral nervous system (PNS) that can be actively induced in susceptible animal species and strains by active immunization with PNS myelin + Freund's complete adjuvant (FCA). EAN represents an animal model for studying the immunopathogenesis and treatment of Guillain-Barré syndrome (GBS), which is a major inflammatory demyelinating disease of the PNS in humans. Here, we report that treatment by nasal administration of the neuritogenic peptide 57-81 of the PNS myelin component, P2 protein, dose-dependently suppressed EAN severity and shortened clinical EAN. Clinical EAN relapse induced by rechallenge with BPM + FCA was also prevented in EAN rats receiving high dose P2 peptide. P2 peptide induced suppression of EAN was associated with PNS antigen specific T cell hyporesponsiveness reflected by lymphocyte proliferation, numbers of PNS antigen-reactive IFN-gamma secreting and IFN-gamma mRNA expressing lymph node cells, but elevated levels of PNS antigen reactive TGF-beta mRNA secreting cells. Reduced CD4+ T cell and macrophage infiltrations within the PNS were also observed. Based on these observations, nasal autoantigen administration should be further evaluated, considering its possible future use in GBS.

Administration, Intranasal↗
PubMed1998

Synthetic peptides fail to induce nasal tolerance to experimental autoimmune myasthenia gravis.

Nasal administration of Torpedo acetylcholine receptor (AChR) to Lewis rats prior to induction of experimental autoimmune myasthenia gravis (EAMG) is highly efficient in prevention of clinical weakness, and suppression of AChR-specific T and B cell responses. To identify possible antigenic determinants within the receptor which can modulate EAMG and anti-AChR response, we evaluated the effects of nasal administration of alpha 61-76, alpha 100-116, alpha 146-162, delta 354-367, and alpha 261-277 of Torpedo AChR at different doses on the tolerance induction against EAMG irrespective if given at lower, the same or higher doses than whole Torpedo AChR protein, that was confirmed to be highly efficient as tolerogen to EAMG. None of these peptides, neither administrated alone nor in combination, induced tolerance to EAMG. Peptide administration did not affect the levels or affinities of anti-AChR antibodies when compared with non-tolerized control EAMG rats, while administration of whole AChR protein affected both variables. The results may indicate that the T and B cell heterogeneity of AChR epitopes makes it difficult to induce tolerance using synthetic peptide.

Animals↗
PubMed1998

Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes.

Like obese humans, Zucker diabetic fatty (ZDF) rats exhibit early beta cell compensation for insulin resistance (4-fold beta cell hyperplasia) followed by decompensation (>50% loss of beta cells). In prediabetic and diabetic ZDF islets, apoptosis measured by DNA laddering is increased 3- and >7-fold, respectively, compared with lean ZDF controls. Ceramide, a fatty acid-containing messenger in cytokine-induced apoptosis, was significantly increased (P < 0.01) in prediabetic and diabetic islets. Free fatty acids (FFAs) in plasma are high (>1 mM) in prediabetic and diabetic ZDF rats; therefore, we cultured prediabetic islets in 1 mM FFA. DNA laddering rose to 19.6% vs. 4.6% in lean control islets, preceded by an 82% increase in ceramide. C2-Ceramide without FFA induced DNA laddering, but fumonisin B1, a ceramide synthetase inhibitor, completely blocked FFA-induced DNA laddering in cultured ZDF islets. [3H]Palmitate incorporation in [3H]ceramide in ZDF islets was twice that of controls, but [3H]palmitate oxidation was 77% less. Triacsin C, an inhibitor of fatty acyl-CoA synthetase, and troglitazone, an enhancer of FFA oxidation in ZDF islets, both blocked DNA laddering. These agents also reduced inducible nitric oxide (NO) synthase mRNA and NO production, which are involved in FFA-induced apoptosis. In ZDF obesity, beta cell apoptosis is induced by increased FFA via de novo ceramide formation and increased NO production.

Animals↗
PubMed1998

Seroreactivity to HIV-1 V3 subtypes A to H peptides of Argentinian HIV-positive sera.

Serologic assays could be useful for determining circulating subtypes in different geographic regions. A total of 175 serum samples from the same number of Argentinian HIV-infected patients from Buenos Aires and Rosario were tested against a panel of peptides representing V3 consensus subtypes A through H. A V3 peptide enzyme immunoassay was used for screening the sera. Most sera were reactive with peptides representing subtypes B (58.28%), F (13.14%), and A (8.57%). Cross-reactivity between the remainder of the peptides was observed. Genotypes of eight patients from Rosario were determined and compared with serotyping. Results showed that seven of eight genotyped patients reacted with their respective consensus B peptide and one reacted with consensus B and F. V3 peptide serology proved to be useful for determining HIV-1 clades circulating in Argentina.

Amino Acid Sequence↗
PubMed1998

Enhancement of rabbit jugular vein thrombolysis by neutralization of factor XI. In vivo evidence for a role of factor XI as an anti-fibrinolytic factor.

Recent in vitro studies have shown that fibrinolytic activity may be attenuated by a thrombin-activatable fibrinolysis inhibitor (TAFI), which is activated by thrombin, generated via the intrinsic pathway of coagulation in a factor XI-dependent way. Thus factor XI may play a role in the regulation of endogenous fibrinolysis. The aim of this study was to investigate the effect of in vivo inhibition of factor XI and TAFI in an experimental thrombosis model in rabbits. Incorporation of anti-factor XI antibodies in jugular vein thrombi resulted in an almost twofold increase in endogenous thrombolysis compared with a control antibody. A similar effect was observed when the anti-factor XI antibody was administered systemically. Inhibition of TAFI activity also resulted in a twofold increase in clot lysis whereas inhibition of both factor XI and TAFI activity had no additional effect. Thus, we provide the first in vivo evidence for enhanced thrombolysis through inhibition of clotting factor XI, demonstrating a novel role for the intrinsic pathway of coagulation. Furthermore we demonstrate that inhibition of TAFI had a similar effect on thrombolysis. We postulate that inhibition of factor XI activity enhances thrombolysis because of diminished indirect activation of TAFI.

Animals↗
PubMed1998

Continuous infusion of recombinant factor VIIa in patients with haemophilia and inhibitors. Experience in The Netherlands and Belgium.

BACKGROUND: Initial clinical experience with recombinant factor VIIa (rVIIa) for treatment of haemophilia patients with inhibitors against factor VIII or IX has been obtained by administration of rVIIa by repeated intravenous bolus injections. However, continuous infusion of rVIIa may be a more appropriate administration method if prolonged treatment is indicated. METHODS: We have surveyed and analysed the initial experience with continuous infusion of rVIIa in the Netherlands and Belgium. RESULTS: Five hospitals treated 7 haemophilia patients with inhibitors on 9 different occasions (4 bleedings, 5 surgical interventions) by continuous infusion of rVIIa over a total of 59 days. Haemostatic coverage was considered effective in 8 out of 9 cases and partially effective in 1 case. Continuous infusion of rVIIa was aimed at rVIIa target plasma levels of 10 U/ml and a decrease in prothrombin time (PT) of 3 s compared to control levels. This was obtained by an initial bolus injection of 90 micrograms/kg prior to continuous infusion of rVIIa at doses between 30-6 micrograms/kg/h (mean 17.5 micrograms/kg/h). A conventional one-stage factor VII coagulation assay, often used in combination with a PT, was satisfactory in monitoring rVIIa treatment. The additional clinical value of anti-fibrinolytic and anti-thrombophlebitic treatment was unclear. CONCLUSION: In our experience, rVIIa appeared to be efficacious and safe when administered by continuous infusion. Continuous infusion of rVIIa is more convenient than bolus injections or rVIIa, easy to monitor and provides a cost reduction of > 50%. These advantages make continuous infusion an attractive administration method for prolonged treatment with rVIIa.

Adult↗
PubMed1998

Acute hepatitis in a patient using a Chinese herbal tea--a case report.

A case is presented of reversible acute hepatitis in a patient using a Chinese herbal tea. Upon identification of the tea mixture Aristolochia species, including A. debilis, which contains the highly toxic aristolochic acid, could be identified. We conclude that the acute hepatitis as described in this patient is most likely to be caused by (one of) the active ingredients of the Chinese herbal tea. Furthermore, this case illustrates that so-called natural products can cause unexpected severe adverse reactions.

Acute Disease↗