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Biomedical subjects

R Arnon

Publications and source records attributed to R Arnon.

At least 73 records · Page 4Linked to original sources
PubMed1995

Monoclonal antibodies against acetylcholinesterase of Schistosoma mansoni: production and characterization.

Monoclonal antibodies (MAbs) were raised in mice against acetylcholinesterase (AChE, EC 3.1.1.7) of the parasite Schistosoma mansoni. Specific tests were used, in which the hybridoma culture supernatants were screened for MAbs capable of recognizing AChE. The MAbs were characterized by their recognition of different stages of the parasite life cycle, by their binding to epitopes of protein or of carbohydrate, and by their capability of blocking AChE activity of the intact parasites. Furthermore, the MAbs were tested for their cross-reaction with AChE derived from various species. One of the MAbs, termed SA31, showed strong cross-reactivity with invertebrate and vertebrate species, indicating some similarity of cross-reaction between schistosome and mammalian AChE. However, most of the schistosome AChE epitopes are not shared with vertebrate AChE. The specific interaction of three other MAbs with intact schistosomula resulted in a marked complement (C)-dependent cytotoxicity. Specific schistosome AChE epitopes might be suitable candidates for drug design and vaccine preparation.

Acetylcholinesterase↗
PubMed1995

Predictors of mortality in hospitalized patients with secondary upper gastrointestinal haemorrhage.

OBJECTIVES: To identify clinical, laboratory and endoscopic features of prognostic implication in patients who suffer an upper gastrointestinal haemorrhage whilst hospitalized for other causes. DESIGN/SETTING: A prospective longitudinal study of 125 consecutive cases (89 males, 36 females) seen during 1988-1991 in a tertiary care university hospital. MAIN OUTCOME MEASURES: The crude and adjusted relative risk of mortality associated with each of the various clinical, laboratory and endoscopic variables. RESULTS: The rates of endoscopic haemostasis, persistent or recurrent bleeding and surgery to control bleeding were 48, 37 and 12%, respectively; the overall mortality was 28%. A significantly increased risk of mortality was associated with shock prior to onset of bleeding, sepsis, renal failure, cirrhosis, encephalopathy, presence of red blood in the nasogastric aspirate or per rectum, thrombocytopenia, hypoalbuminaemia, elevation of serum bilirubin, aminotransferases or urea levels, endoscopic evidence of active bleeding, the application of endoscopic haemostasis, rebleeding, transfusion of > or = 6 units of blood, surgical treatment or any subsequent complication. Use of nonsteroidal anti-inflammatory drugs (27%) was associated with a decreased mortality risk (odds ratio 0.2; P = 0.03). A multivariate analysis showed that the features at presentation which were independently associated with an increased risk of mortality were: a history of cirrhosis, sepsis, shock prior to onset of bleeding, hypo-albuminaemia and elevated serum aminotransferases. CONCLUSION: The prognosis of secondary upper gastrointestinal haemorrhage depends on the underlying diseases and on the general condition of the patient, rather than on the actual cause of bleeding.

Aged↗
PubMed1995

Molecular biological aspects of alcohol-induced liver disease.

Molecular biological investigations have become a predominant methodology applied to the study of alcohol-induced liver disease. The enzymatic pathways responsible for ethanol metabolism, and their genetic as well as environmental control, have become the focus of detailed investigation. More recently, the significance of cytokines in the pathogenesis of alcohol-induced liver disease has also become a major area of speculation. This review focuses on the advances made in studies of two important enzymes responsible for alcohol metabolism, alcohol dehydrogenase and aldehyde dehydrogenase, as well as the investigation of the proinflammatory and profibrogenic cytokines involved in the process of hepatic fibrogenesis. The quality and quantity of new discoveries made in the field of alcohol-induced liver disease is impressive, especially when one realizes that molecular biological approaches have been employed in this area for only 15 years. However, in most cases the studies have been predominantly descriptive, with little direct relevance to the therapeutics of alcoholism and alcohol-induced organ injury. Because the groundwork has been laid, one hopes that the next 15 years will rectify this failure.

Alcohol Dehydrogenase↗
PubMed1995

Predictors of mortality in patients admitted to hospital for acute upper gastrointestinal hemorrhage.

BACKGROUND: We wanted to identify features of prognostic significance in patients admitted to hospital because of acute upper gastrointestinal (UGI) hemorrhage. METHODS: A prospective, longitudinal study of 321 consecutive cases admitted during 1988-91 was carried out. The relative risk of mortality associated with each of the background, laboratory, and endoscopic features and the hospital course was calculated. Multiple stepwise logistic regression was used to define factors independently associated with mortality. Two models were evaluated, the first based on the data at presentation (history, physical findings, initial laboratory data) and the second based on the first, plus the endoscopic and follow-up data. RESULTS: The overall mortality was 7.8%. At presentation the features associated with a significantly (p < 0.05) increased risk of mortality were (adjusted odds ratios in parentheses) age > or = 75 years (11.2), a history of cancer (12.1), blood in the gastric aspirate (9.6), and a systolic blood pressure < or = 90 mm Hg (6.4). The overall predictors of mortality were age > or = 75 years (12.7), blood in the gastric aspirate (18.9), serum creatinine level > or = 150 mumol/l (14.8), increased serum aminotransferase level (20.2), and persistent or recurrent bleeding (57.3). CONCLUSIONS: In patients admitted to hospital because of UGI hemorrhage the prognosis depends on age, underlying diseases, hemodynamic status, and the persistence or recurrence of bleeding. The causes of bleeding were not relevant to the prognosis.

Acute Disease↗
PubMed1994

Direct binding of myelin basic protein and synthetic copolymer 1 to class II major histocompatibility complex molecules on living antigen-presenting cells--specificity and promiscuity.

Copolymer 1 (Cop 1) is a synthetic basic random copolymer of amino acids that has been shown to be effective in suppression of experimental allergic encephalomyelitis and is being tested as a candidate drug for multiple sclerosis. It has been previously demonstrated that Cop 1 is immunologically cross-reactive with the autoantigen myelin basic protein (BP) and competitively inhibits the response to BP of T-cell lines and clones of different major histocompatibility complex (MHC) restrictions, of both mouse and human origin. In the present study we demonstrated the direct binding of Cop 1, using its biotinylated derivative, to MHC molecules on living antigen-presenting cells. Binding of biotinylated BP and peptide p84-102 (an immunodominant epitope of BP) was also demonstrated. Cop 1 and BP bound in a promiscuous manner to different types of antigen-presenting cells of various H-2 and HLA haplotypes. The specificity of the binding was confirmed by its inhibition with either the relevant anti-MHC class II antibodies or unlabeled analogs. Cop 1 exhibited the most extensive and fast binding to antigen-presenting cells. In addition, Cop 1 inhibited the binding of biotinylated derivatives of BP and of p84-102 to the MHC class II molecules and even displaced these antigens when already bound. Thus, these results suggest that Cop 1 indeed competes with BP for MHC binding and, thereby, inhibits T-cell responses to BP. The binding of Cop 1 to different DR alleles, probably because of its multiple MHC binding motifs, may indicate its potential as a broad-spectrum drug for multiple sclerosis.

Amino Acid Sequence↗
PubMed1994

Functional and antigenic similarities between a 94-kD protein of Schistosoma mansoni (SCIP-1) and human CD59.

Schistosomiasis is a parasitic disease affecting approximately 200 million people, primarily in the third world. Schistosoma mansoni, one of the causative agents of this disease, parasitize the human mesenteric and portal blood systems while successfully evading host immune responses. During parasite penetration into the mammalian host and shortly afterwards, the larvae rapidly convert from being sensitive to being resistant to C-mediated killing. Treatment of the C-resistant parasitic forms with trypsin renders the parasite susceptible to C attack, thus indicating the presence of C inhibitory protein(s) on the parasite surface. We describe here an intrinsic schistosome C inhibitory protein (SCIP-1) that exhibits antigenic and functional similarities with the human C-inhibitor CD59. Like CD59, SCIP-1 is capable of inhibiting formation of the C membrane attack complex (MAC), probably by binding to C8 and C9 of the C terminal pathway. In addition, SCIP-1 is apparently also membrane-anchored via glycosyl phosphatidylinositol as it can be specifically released with phosphatidylinositol-specific phospholipase C. Soluble SCIP-1, partially purified from Nonidet P-40 extracts of schistosome tegument is capable of inhibiting hemolysis of sensitized sheep erythrocytes and of rabbit erythrocytes by human C. Anti-human CD59 antibodies block this activity of SCIP-1 and in addition, upon binding to intact parasites, render them vulnerable to killing by human and guinea pig C. SCIP-1 is located on the surface of C-resistant forms of the parasite, i.e., 24-h cultured mechanical schistosomula and in vivo-derived adult worms as revealed by immunofluorescence and immunogold electron microscopy studies. These results identify one of the mechanisms schistosomes use to escape immune attack.

Animals↗
PubMed1994

Schistosoma mansoni: isolation and characterization of Smpi56, a novel serine protease inhibitor.

Tegumental extracts from adult worms of Schistosoma mansoni contain an inhibitory activity to the S. mansoni 28-kDa serine protease and to pancreatic elastase. By using biotinylated elastase and streptavidin-agarose, the postulated protease inhibitor has been isolated from the crude worm extract in a single step. Monospecific rabbit antibodies raised against the protease inhibitor have immunoprecipitated a 56-kDa [35S]Met-labeled serine protease inhibitor which was designated Smpi56 (S. mansoni protease inhibitor, 56 kDa). Smpi56 binds tightly to and inhibits the 28-kDa protease of S. mansoni and pancreatic and neutrophil elastase but not papain, pepsin, thrombin, trypsin, chymotrypsin, proteinase K, urokinase and acetylcholinesterase. The biological function of Smpi56 is still not known, but in view of its elastase inhibitory activity it may be speculated that the parasite is employing Smpi56 to protect itself from activated neutrophils. Smpi56 may also potentially protect the parasite from its endogenous 28-kDa protease.

Animals↗
PubMed1994

The amount of acetylcholinesterase on the parasite surface reflects the differential sensitivity of schistosome species to metrifonate.

Acetylcholinesterase (AChE) is present in all stages of the life-cycle of schistosomes and is located in muscle and on the surface of the parasite. Metrifonate is a drug that inhibits AChE. We compared the AChEs from three schistosome species (Schistosoma mansoni, Schistosoma haematobium and Schistosoma bovis) that have different susceptibilities to metrifonate in vivo. Sensitivities to AChE inhibitors were similar. The subunits of AChE were 110 kDa and 76 kDa and the dominant molecular form of AChE was a G2 form in all three species. This was the major form on the tegument while additional molecular forms were associated with the internal tissues. Differences in relative amounts of AChE activity between these species were found in the adults but not in the schistosomula. At the adult stage the major difference between species lay in the relative amounts of AChE activity in their teguments. S. haematobium teguments carried 20 times and S. bovis 6.9 times the activity present on S. mansoni teguments. These quantitative differences associate with the relative sensitivities of these species to metrifonate.

Acetylcholinesterase↗
PubMed1994

Enhancement of anti-Shigella lipopolysaccharide (LPS) response by addition of the cholera toxin B subunit to oral and intranasal proteosome-Shigella flexneri 2a LPS vaccines.

Addition of the cholera toxin B subunit to oral and intranasal proteosome-Shigella flexneri 2a lipopolysaccharide vaccines improved their immunogenicities. Enhancement of anti-O-Shigella immunoglobulin A levels was most evident in lung lavages following oral immunization and in lung and intestinal fluids when suboptimal doses were used with either immunization route.

Administration, Intranasal↗
PubMed1994

Inhibition of carbon tetrachloride-induced liver injury by liposomes containing vitamin E.

We tested a variety of antioxidants as possible therapeutic agents in an acute CCl4 mouse model of hepatotoxicity. Liver damage, gauged by the amount of serum aminotransferase released into the blood, morphological changes, lethal dose response, and presence of thiobarbituric acid-reactive substances (TBARS), were significantly inhibited in a dose-dependent manner by liposomes containing vitamin E (LVE) or by Rocavit E, a water-soluble emulsion of alpha-tocopherol. Serum aminotransferase levels in LVE- or Rocavit E-treated animals were always > 10-fold lower than levels in corresponding CCl4 controls. Other liposome-associated antioxidants, butylated hydroxytoluene, vitamin E succinate, catalase, desferoxamine, superoxide dismutase, and ascorbic acid 6-palmitate, were also able to elicit a decrease in damage; however, they were substantially less effective. Intravenous therapy with LVE decreased mortality by nearly 90% when a lethal dose of CCl4 was given. When the biodistribution of the liposomes was examined, it was determined that the vast majority were localized in the Kupffer cell population. This approach of delivering nontoxic therapeutic agents selectively to the liver offers a variety of clinical applications in humans.

Animals↗
PubMed1994

Upper gastrointestinal hemorrhage. Comparison of the causes and prognosis in primary and secondary bleeders.

BACKGROUND: Hemorrhage from the upper gastrointestinal (UGI) tract is defined as primary when it is the cause of admission to hospital and as secondary when it complicates the course of patients admitted to hospital for other causes. The objective of this study was to compare the background features, course, and outcome of patients with primary and secondary bleeding. METHODS: All patients who underwent upper endoscopy because of acute UGI bleeding during 1988-91 in a tertiary care university hospital were studied longitudinally. The background features of primary bleeders (n = 321) were compared with those of secondary bleeders (n = 125). From the primary bleeders, a group was matched to the secondary bleeders by age, sex, use of nonsteroidal anti-inflammatory drugs (NSAIDs), and liver disease. The laboratory and endoscopic findings, hospital course, and mortality were compared in the two groups. RESULTS: Secondary bleeders were on the average 5 years older than primary bleeders and were significantly more likely to have ischemic heart disease, chronic lung disease, and chronic renal failure. Use of corticosteroids, H2 blockers, antacids, and anticoagulants in this group was significantly more prevalent, whereas the use of NSAIDs was similar in the two groups. The case-control analysis showed a similar distribution of the causes of bleeding in the two groups. However, rebleeding, endoscopic hemostasis, and complications were more frequent in secondary bleeders. The mortality in secondary bleeders was 28%, compared with 10% in matched primary bleeders, for a relative risk of 3.8 (p = 0.0002). CONCLUSION: Secondary hemorrhage is associated with an increased mortality, which is related to the underlying diseases and not to a difference in the causes of bleeding.

Acute Disease↗
PubMed1994

Anti-nuclear antibodies associated with schistosomiasis and anti-schistosomal antibodies associated with SLE.

Various autoantibodies to nuclear antigens were detected by ELISA in pooled sera of 15 ICR mice 9 weeks after infection with schistosoma. The binding of this serum with acute infection to cercarial extract was inhibited by prior incubation of the sera with DNA, polynucleotides and cercarial extract. Sera from 9 BALB/c mice with experimentally induced lupus, reacted with cercarial extract. No binding was noted with normal mouse sera (NMS). Similarly, sera of SLE patients (N = 113) reacted with the parasite extracts in a higher incidence (14.2%) compared to NHS (3.7%) (P < 0.05). Immunoblot analysis showed common features to SLE sera reacting with two antigenic "groups". The first are antigens that also were recognized by sera of mice infected with schistosomiasis (60, 85, and 94 kDa cercarial proteins). The second group entailed proteins that bound with SLE sera only (10-18 kDa, 29 kDa and 52 kDa). It can be concluded that antinuclear autoantibodies can be found in sera of acute infected mice with schistosomiasis, while SLE sera may react with 3 schistosomal extracts in a higher incidence than NHS (P < 0.05). These results suggest an autoimmune response in schistosomiasis. It is possible that a parasite infection (as bilharzia) may be one of the "trigger" mechanisms for SLE in a subject with the suitable immunogenetic and hormonal background.

Animals↗
PubMed1994

Immunospecific drug design--prospects for treatment of autoimmune diseases.

Recent advances in elucidating the activation and regulation of the autoimmune processes have provided new approaches for selective immunotherapy. Three different strategies are described: autoantigen-based therapy utilizing immunospecifically designed macromolecules and peptides, T-suppressor lines and clones, as well as antibodies specific to the antigen-MHC complex. These modalities, the efficacy of which has been demonstrated for experimental allergic encephalomyelitis, may be adapted to other experimental as well as human autoimmune diseases.

Animals↗
PubMed1994

Upper gastrointestinal endoscopy in the pediatric patient.

During a 4 year period (January 1988 to December 1991), 237 pediatric patients (mean age +/- SD, 9.75 +/- 5.17 years) underwent 289 upper gastrointestinal endoscopies. Premedication was used in only 102 of the endoscopic examinations, mostly in children between 2 and 10 years of age. Patients who were examined without sedation tolerated the procedure well. Abdominal pain was the most frequent indication, accounting for 57.4% of all procedures. Gastritis, esophagitis, duodenitis and duodenal ulcer were the most common endoscopic findings. Seventy-five endoscopies were performed to obtain small bowel biopsies. We found this procedure to be easy and safe and preferable to capsule biopsies. In our experience, upper gastrointestinal endoscopy with or without sedation is a safe and effective diagnostic procedure in the pediatric age group.

Adolescent↗
PubMed1993

[Rubber-band ligation of esophageal and cardiac varices].

Esophageal sclerotherapy was the treatment of choice for bleeding esophageal varices in the past decade. It is effective for treating acute variceal bleeding, as well as eradicating esophageal varices for secondary prevention of bleeding. However, in more than 20% of patients sclerotherapy involves complications, some of which are serious. The high complication rate suggested the development of a new method that should be at least as effective and as easy to perform as sclerotherapy, but with fewer complications and side-effects. Endoscopic variceal ligation was developed at the University of Colorado and described in 1986. It is reported to control active variceal bleeding in about 90% of patients, and to eradicate varices in about 80% of surviving patients. Complications are rare. We have adapted the method in our unit and here describe out preliminary experience in 11 patients.

Esophageal and Gastric Varices↗
PubMed1993

T suppressor hybridomas and interleukin-2-dependent lines induced by copolymer 1 or by spinal cord homogenate down-regulate experimental allergic encephalomyelitis.

Suppressor T (Ts) hybridomas and interleukin-2-dependent T cell lines were established from spleens of mice, which had been rendered unresponsive to experimental allergic encephalomyelitis (EAE) either by mouse spinal cord homogenate or by the synthetic suppressant copolymer 1 (Cop 1). The Ts hybridoma supernatants and the Ts line cells specifically suppressed the in vitro response to the encephalitogenic myelin basic protein (BP), as indicated by inhibition of both the proliferation and interleukin-2-secretion responses of a BP-specific T cell line. Moreover, these Ts cells prevented the development of actively induced EAE in vivo. All hybridomas and lines were most effective when injected at the time of disease induction, thus suggesting that they operate as effector suppressor cells, and functionally inhibit encephalitogenic responses. The data presented here suggest that the suppressor cells are stimulated by the protective epitopes included in the BP as well as in the Cop 1 molecules and that they play an active role in the regulation of EAE. The generation of Ts lines and hybridomas, which have been induced by Cop 1, establish the specific stimulation of suppressor cells to EAE as a mechanism underlying the therapeutic activity of Cop 1.

Animals↗
PubMed1993

Disparate effects of a triglyceride lowering diet and of bezafibrate on the HDL system: a study in patients with hypertriglyceridaemia and low HDL-cholesterol levels.

The response of plasma triglyceride and of the high density lipoprotein (HDL) system to a triglyceride lowering diet and to a bezafibrate was compared in a group of 24 human subjects with mild to moderate hypertriglyceridaemia and low HDL-cholesterol levels. Post-heparin plasma lipoprotein (LPL) and hepatic (HL) lipase activities were determined before the initiation of the study and at the end of the diet (12 weeks) and bezafibrate (12 weeks) periods. HDL structure and composition were determined on a zonal centrifugation system at the end of the diet and bezafibrate periods. Diet caused a 9-20% reduction of plasma triglycerides but there was no change in LPL, HL or HDL levels. The individual responses between plasma triglycerides and HDL cholesterol levels however were highly correlated (r = 0.60 to 0.78). Combined diet plus bezafibrate therapy caused a further 38% decrease of plasma triglycerides with a 28% increase of HDL-cholesterol and a 47% increase of LPL activity. HDL3 density decreased and the contribution of cholesteryl ester to the HDL mass was increased while the contribution of proteins and triglycerides decreased. In the majority of the subjects (61%) HDL cholesterol levels increased by 20% or more and in these subjects the change of HDL was highly correlated with the change of the LPL/HL ratio (r = 0.74) but not with the change of the plasma triglyceride levels. In the remaining subjects (39%), HDL cholesterol levels remained unchanged or increased by less than 20%. The change of HDL cholesterol levels in these subjects was unrelated to the decrease of plasma triglycerides or the change of post-heparin lipase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Bezafibrate↗