Search PubMed⌕ Search

Biomedical subjects

R Arnon

Publications and source records attributed to R Arnon.

At least 109 records · Page 6Linked to original sources
PubMed1991

Effects of exogenous apo E-3 and of cholesterol-enriched meals on the cellular metabolism of human chylomicrons and their remnants.

The effects of exogenous apo E-3 and of cholesterol-enriched meals on the binding, cell association and proteolytic degradation of human chylomicrons and their remnants were determined in cultured human skin fibroblasts. Chylomicrons were prepared from plasma of normolipemic humans 4 h after a fat meal with normal or high cholesterol content. Remnants were obtained after incubation of chylomicrons with lipoprotein lipase in vitro. Cellular metabolism of chylomicrons was minimal, less than 10% that of LDL. Exogenous apo E-2 enhanced chylomicron metabolism by 3-4-fold. The cellular metabolism of remnants was 2.5-3.5-fold higher as compared to intact chylomicrons but their response to exogenous apo E-3 was considerably lower. The cellular metabolism of chylomicrons and chylomicron remnants obtained from subjects eating cholesterol-enriched fat meal was the highest either without or with added exogenous apo E-3. Yet, even in the preparation that exhibits the highest metabolic activity (apo E-3 enriched remnants from cholesterol-enriched meals) the absolute proteolytic degradation was about two-thirds that of LDL. We conclude that although LDL-receptors take up and degrade chylomicron remnants, the rate of catabolism of remnants by this route can not explain the rapid and complete remnant removal process as observed in vivo.

Adult↗
PubMed1991

Indirect immunotargeting of cis-Pt to human epidermoid carcinoma KB using the avidin-biotin system.

Cis-diamminedichloroplatinum (II) (cis-Pt) complexed to a carboxymethyl dextran-avidin conjugate was targeted to biotin-monoclonal antibody 108 (b-MAb 108). This MAb recognizes the extracellular domain of the epidermal growth factor receptor (EGF-R) on human epidermoid carcinoma (KB) cells over-expressing EGF-R. Cis-Pt-carboxymethyl-dextran-avidin (Pt-dex-Av) containing 60-90 M cis-Pt/M avidin was administered 24 hr following b-MAb108 containing 3-5 M biotin/M MAb. This treatment was potentially more effective in suppressing the growth of established KB tumor xenografts, or in inhibiting the development of lung metastases in nude mice, than free MAb 108, free drug or MAb 108 followed by drug. Replacing b-MAb 108 by unbiotinylated antibody or by b-MAb of a different specificity also yielded lower suppressive effects. The sequential administration of Pt-dex-Av following b-MAb was more effective than introduction of the Pt-dex-Av when already complexed to b-MAb 108. The results presented in this preliminary investigation suggest that Pt-dex-Av is specifically removed from the circulation by b-MAb 108 concentrated at the tumor site.

Animals↗
PubMed1991

Immunomodulation of experimental allergic encephalomyelitis by antibodies to the antigen-Ia complex.

Autoimmune diseases occur when T lymphocytes become activated on recognizing self antigen linked to the autologous class II molecule of the major histocompatibility complex (MHC). The resulting complex of antigen MHC T-cell receptor could be a target for treatment of autoimmune diseases. Studies in which each component is blocked separately might be limited by interference in non-relevant immune responses that either use the same set of T-cell-receptor V gene segments or are linked to the same MHC. We report here an attack by a specific antibody on the unique antigenic site formed by the binding of two components of the trimolecular complex, the autoantigen bound to the self MHC. We tested its effect in experimental allergic encephalomyelitis, an acute neurological autoimmune disease which is widely regarded as a model for autoimmune disorders and which is mediated by CD4+ T cells recognizing myelin basic protein (BP), or its peptides, in association with self Ia. We made monoclonal antibodies which bound only the complex of BP and I-As. These antibodies blocked the proliferative response in vitro to the encephalitogenic determinant of BP and reduced the response to intact BP, without affecting the response to a nonrelevant antigen-purified protein derivative of tuberculin presented on syngeneic macrophages. They also inhibited experimental allergic encephalomyelitis in H-2s mice. Hence, antibodies directed specifically to the autoantigen-Ia complex, may offer a highly selective and effective treatment in autoimmune diseases.

Animals↗
PubMed1991

Phosphatidylinositol-specific phospholipase C induces biosynthesis of acetylcholinesterase via diacylglycerol in Schistosoma mansoni.

We have previously shown that two ectoenzymes, acetylcholinesterase (AChE) and alkaline phosphatase, are released from the surface and from particulate fractions of the parasite Schistosoma mansoni, by a phosphatidylinositol-specific phospholipase C (PtdIns-PLC) of bacterial origin. Exposure to PtdIns-PLC not only removes large amounts of AChE from the surface of intact, viable Schistosoma in culture, but is accompanied by a concomitant increase in overall levels of AChE in the parasite. The same phenomenon is observed with PtdIns-PLC from two different bacterial sources; Staphylococcus aureus and Bacillus thuringiensis. The increase in AChE levels may be ascribed to de novo synthesis since exposure to PtdIns-PLC, in the presence of the protein-synthesis inhibitor cycloheximide, totally blocked the increase in AChE activity. Furthermore, PtdIns-PLC induced an increased incorporation of [35S]methionine into the AChE immunoprecipitated by a specific anti-AChE serum. This increase is selective for AChE, since total protein synthesis remained almost unchanged after PtdIns-PLC addition, and little or no effect was observed on the enzymatic activity of alkaline phosphatase, which is also glycophosphatidylinositol anchored. Since cleavage of the phosphatidylinositol anchor by PtdIns-PLC should liberate diacylglycerol, which may act as second messenger, we investigated the effect of exogenous diacylglycerols on the synthesis of AChE in S. mansoni. Three different diacylglycerols were tested as possible inducers of AChE activity in the parasite. Both 1-oleoyl-2-acetyl-sn-glycerol and 1,2-dimyristoyl-sn-glycerol were able to increase AChE activity by 35-40% at concentrations of 25 micrograms/ml. A higher concentration of 1,2-dioctanoyl-sn-glycerol (70 micrograms/ml) was needed to produce an equivalent effect. Moreover, addition of phorbol-12-myristate-13-acetate, together with the calcium ionophore A23187, produced a similar increase in AChE activity. Finally, polymixin B, a specific inhibitor of protein kinase C, partially blocked the increase in AChE activity induced by PtdIns-PLC. Our results suggest the involvement of glycophosphatidyl membrane-anchor breakdown products as putative second messengers in the parasite S. mansoni.

Acetylcholinesterase↗
PubMed1991

Acetylcholinesterase from Schistosoma mansoni: immunological characterization.

The enzyme acetylcholinesterase (AChE) is present in the trematode Schistosoma mansoni, which infects humans and causes a severe disease called schistosomiasis or Bilharzia. We have purified this enzyme and raised polyclonal antibodies against it. The specificity of these antibodies against the schistosome enzyme was demonstrated by their capacity to precipitate exclusively AChE activity from cercariae extract and to recognize the 8S molecular form of the parasite's AChE. On the other hand, they did not cross-react at all with AChE from human erythrocytes. By employing immunogold electron microscopy, AChE was located on the surface, in the membranal bodies of the tegument and in the muscles of schistosomula. The antibodies raised against the purified AChE of S. mansoni are of protective value, as they led to efficient complement-mediated killing of schistosomula in vitro. It was also demonstrated that antibodies specific towards S. mansoni AChE are present in the sera of mice and of human patients infected with the parasite, suggesting that this enzyme partakes in the immune response towards the parasite during infection. These cumulative data, particularly the schistosomicidal activity of the antibodies and their lack of cross-reactivity with human AChE, are of significance in the consideration of the S. mansoni AChE for vaccination purposes.

Acetylcholinesterase↗
PubMed1991

Immuno-parasitological parameters in schistosomiasis--a perspective view of a vaccine-oriented immunochemist.

It has been almost 10 years since we became involved in research on schistosomiasis. With a background of many years of research on structure-function relationships in protein antigens and a wide experience in the development of peptide-based synthetic vaccines, I was intrigued by the complexity of the immunological aspects of host-parasite relation and the unique capacity of parasites to evade the immune response of their hosts. Being of very ancient lineage, schistosomes, which evolved from blood flukes during the Permian era, had two hundred million years of evolution to their advantage, to perfect their survival strategies. As a result, they are capable of circumventing the immunological machinery of the mammalian host and may consequently survive in it for decades. It seemed to us that an understanding, at least in part, of these processes, was a prerequisite for any attempt to enhance the capacity of the host to mount effective immunity, the long-range goal of such studies being the development of an efficient vaccine. In this review I have attempted to summarize the various approaches pursued in our laboratory towards this goal. This is definitely not a comprehensive review, and I had no intention of covering the vast literature in this field, except for that closely relevant to the discussed topics. This is rather a perspective review summarizing our own findings concerning different aspects of the biological, biochemical and immunological properties of Schistosoma mansoni, and their contribution toward the global effort of the research on schistosomiasis.

Acetylcholinesterase↗
PubMed1991

Zidovudine toxicity to murine bone marrow may be affected by the exact frequency of drug administration.

Zidovudine (azidothymidine, AZT) toxicity to the bone marrow (BM) is a major hindrance to its widespread clinical application in the treatment of the acquired immunodeficiency syndrome (AIDS). In this work we verify the prediction of a mathematical model that cytotoxicity to the host can be reduced when the frequency of drug administration is an integer multiple of the target cell average cycle time (ca. 7 h in murine BM cells). We report in vivo experiments in mice showing that a 7-h frequency of AZT administration is significantly less toxic than other frequencies when peripheral blood parameters and the proportion of BM cells arrested at the S-phase gate of the DNA content distribution are considered.

Animals↗
PubMed1991

The effects of glucose polymer beverage ingestion during prolonged outdoor exercise in the heat.

The aim of this study was to examine the effect of ingestion of a glucose polymer drink on fluid and metabolic balance during a 30 km outdoor march in the heat (ambient temperature, 26-31 degrees C; relative humidity, 53-34%). The subjects were randomly assigned to one of three groups: 7.2% glucose polymer-electrolyte beverage (GP) (N = 16), flavored sweetened placebo drink (SP) (N = 15), and tap water (TW) (N = 18). The subjects in the three groups consumed similar volumes of fluid, and no differences were found in sweat rate and percent dehydration. Changes in plasma volume were smaller, though not statistically significant, for GP than for SP and TW (-2.8%, -5.4%, -9.4%, respectively). Changes in sodium concentrations and serum osmolality were similar in the three groups. Subjects consuming GP maintained during exercise a significantly higher (P less than 0.001) blood glucose concentration (range: 6.5-7.4 mmol.l-1) than the SP and TW groups. They were also found to have increased levels of serum insulin (29.3 +/- 18.5 mU.l-1) and no change in serum free fatty acids (0.52 +/- 0.19 mmol.l-1). In contrast, subjects ingesting SP or TW had significantly elevated (P less than 0.001) concentrations of free fatty acids (range: 1.35-1.74 mmol.l-1) compared with subjects consuming GP (0.35-0.52 mmol.l-1), with no significant change in blood glucose and serum insulin levels over the exercise period. We conclude that highly trained endurance athletes may maintain a higher blood glucose level by consuming GP during prolonged exercise in the heat without impairing fluid replacement.

Adult↗
PubMed1990

Tissue distribution of avidin and streptavidin injected to mice. Effect of avidin carbohydrate, streptavidin truncation and exogenous biotin.

Radioionated avidin and streptavidin were characterized for their biodistribution and tissue association in Balb/c mice, in comparison to their interaction with cells in vitro. Binding of avidin to spleen and bone-marrow cells in vitro was up to 20-fold higher than that of streptavidin, but when tested in vivo avidin clearance from blood and tissues was considerably faster than that of streptavidin. Levels of avidin at 24 h after an intravenous injection were below 1% (of the injected dose/mass tissue) in most organs. Non-glycosylated avidin was similar in its biodistribution to native avidin. Native streptavidin exhibited higher and prolonged tissue association with 5-10% levels in lung, liver, spleen, kidney and blood, whereas its truncated form showed low tissue levels (1-3%) but a remarkably high affinity to the kidney (80%). Exogenous biotin did not affect streptavidin distribution in vivo but caused a 2-7-fold increase in the retention of avidin (but not non-glycodylated avidin) in some of the organs.

Animals↗
PubMed1990

Complement regulation on the surface of cultured schistosomula and adult worms of Schistosoma mansoni.

Cercaria and freshly prepared schistosomula of Schistosoma mansoni are highly sensitive to complement. However, early in their maturation, the schistosomula become resistant to complement killing. This conversion is preceded by a rapid and massive release of several acetabular proteases and of the glycocalyx coat. Thus, shedding of the glycocalyx which is a major immunogen and a strong activator of the alternative pathway of complement permits the parasite to escape immune damage. Mechanically transformed schistosomula, which were cultured in a defined synthetic medium and developed complement resistance, could be converted by proteolysis to complement sensitivity. Trypsin and pronase markedly increased the susceptibility of cultured schistosomula to complement. The trypsin-induced complement sensitivity persisted for at least 19 h without recovery of resistance. Similar treatment with trypsin produced complete killing of adult worms by complement in absence of antibodies. Efficient killing was obtained with normal human serum (NHS), with normal guinea pig serum (GpS), and with C4-depleted HS and C4-deficient GpS indicating that the killing was mediated by the cytolytic alternative pathway of complement. Larger quantities of C3b with intact alpha' chain could be demonstrated on trypsin-treated than on non-treated schistosomula. Antibodies which were raised in rabbits by immunization with the trypsin-released material bound to cultured (non-treated) schistosomula and to adult worms, and induced their killing in GpS and C4-deficient GpS. These results suggest that following release of the glycocalyx, the transforming schistosomula of S. mansoni spontaneously express a complement regulatory protein(s). A similar regulator is postulated to be present on the surface of adult worms. Such regulatory molecules may serve as good targets for immunotherapy, since antibodies directed to them will inhibit their regulatory activity and thus potentiate in vivo the lytic action of complement.

Animals↗
PubMed1990

Effect of pyridostigmine on the exercise-heat response of man.

The effect of pyridostigmine on thermoregulatory responses was evaluated during exercise and heat stress. Eight heat acclimated, young adult male subjects received four doses of pyridostigmine (30 mg) or identical placebo tablets every 8 h, in a double blind, randomized, cross-over trial. A 30.3%, SD 4.6% inhibition of the circulating cholinesterase (ChE) activity was induced in the pyridostigmine-treated group. The subjects were exposed to 170-min exercise and heat-stress (dry bulb temperature, 33 degrees C; relative humidity 60%) consisting of 60 min in a sitting position and two bouts of 50-min walking (1.39 m.s-1, 5% gradient) which were separated by 10-min rest periods. No differences were found between treatments in the physiological responses and heat balance parameters at the end of exposure: heart rate (fc) was 141 beats.min-1, SD 16 and 150 beats.min-1, SD 12, rectal temperature (Tre) was 38.5 degrees C, SD 0.4 degrees and 38.6 degrees C, SD 0.3 degrees, heat storage was 60 W.m-2, SD 16 and 59 W.m-2, SD 15 and sweat rate was 678 g.h-1, SD 184 and 661 g.h-1, SD 133, in the pyridostigmine and placebo treatments, respectively. The changes in Tre and fc over the heat-exercise period were parallel in both study and control groups. Pyridostigmine caused a slight slowing of fc (5 beats.min-1) which was consistent throughout the entire exposure (P less than 0.001) but was of no clinical significance. The overall change in fc was similar for both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Effects of lovastatin therapy on LDL receptor activity in circulating monocytes and on structure and composition of plasma lipoproteins.

The effect of lovastatin therapy on LDL-receptor activity in fresh monocytes and on the structure and composition of lipoproteins was determined in 9 patients with familial hypercholesterolemia (FH) and 8 patients with non-familial hypercholesterolemia (NFH). Lovastatin reduced LDL-cholesterol levels by 34.8 and 47.5%, respectively, in the 2 groups of patients, and plasma apo B levels by 33.3 and 42.5%. LDL receptor activity in fresh monocytes increased by 53% and 86% respectively. HDL-cholesterol and plasma apo A-I levels increased only in the NFH group, by 10.2 and 7.1%. Lipoproteins were separated by centrifugation on a zonal rotor. Except for the intermediate density lipoprotein (IDL) fraction, no changes were observed in the structure and composition of the various lipoproteins. The investigations thus demonstrated that lovastatin therapy is associated with a measurable and significant increase of LDL-receptor activity in circulating monocytes that may contribute to the lipid lowering action of the drug.

Apolipoproteins↗
PubMed1990

Carboxy-terminal peptides from the B subunit of Shiga toxin induce a local and parenteral protective effect.

Two synthetic peptides corresponding to overlapping sequences from the C-terminus of the B chain of Shiga toxin were prepared and characterized. These peptides consisted of residues 54-67 and 57-67 in the protein sequence. This region coincides with the major peak of surface area residues, as predicted from a computer-derived plot. For the purpose of immunization, the peptides were either conjugated with a protein or a synthetic carrier, or were polymerized. Polyclonal antibodies against these peptides derivatives, induced in rabbits, recognized the homologous peptides and cross-reacted with the intact toxin. These antibodies were capable of neutralizing the various biological activities of the toxin, namely the cytotoxic, enterotoxic and neurotoxic activities. Active immunization of mice with the peptide derivatives protected them from the lethal effect of the toxin. Moreover, oral immunization of rats led to inhibition of fluid secretion in ligated ileal loops into which toxin was injected. This effect was paralleled by the induction of high levels of specific anti-peptide IgA antibodies in the serum after bile duct ligation.

Administration, Oral↗
PubMed1990

Androgenic response to long-term physical training in male subjects.

An increase in endogenous androgen production has been observed following long-term physical training and the beneficial effects of training have been attributed in part to this phenomenon. Other investigators, however, found, in contrast lower testosterone levels in trained compared with untrained subjects. The purpose of the present study was to follow the long-term changes in total testosterone (T) and cortisol (C) levels in intensely training individuals. The changes in the body's anabolic state, induced by intense long-term physical training, were determined using the plasma resting T/C ratio. T and C levels of 35 young untrained subjects were measured at 6 week intervals during 18 weeks of strenuous physical training. All samples were drawn within one half hour of awaking (05.30-06.00). Mean serum T levels increased significantly at 6 weeks (28.7%, p less than 0.02) and decreased significantly at 12 weeks (20.6%, p less than 0.02), but did not differ at 18 weeks compared with levels before training was commenced (mean +/- SE, 16.9 +/- 0.2, 21.8 +/- 0.3, 12.8 +/- 0.2 and 17.3 +/- 0.2 nmol/l at 0, 6, 12, and 18 weeks, respectively). Mean serum C was increased significantly (21.3%, p less than 0.005) at 18 weeks (463.5 +/- 19.3, 507.7 +/- 22.1, 480.1 +/- 19.3, and 565.6 +/- 22.1 nmol/l). T/C ratio decreased significantly after 12 and 18 weeks of training. Our results do not support an association between reduced total testosterone levels and prolonged training. However, hypercorticolism with a relative catabolic state may occur.

Adaptation, Physiological↗
PubMed1990

Schistosoma mansoni: localization of the 28 kDa secreted protease in cercaria.

Monospecific rabbit antibodies were utilized to localize the 28 kDa serine protease which is released from transforming schistosomula of Schistosoma mansoni in cercariae and freshly transformed schistosomula. This protease exerts two postulated activities, degradation of connective tissue proteins thus promoting skin penetration and release of the cercarial glycocalyx leading to accelerated schistosomular transformation. Upon immunogold labelling of cercarial cryosections, the 28 kDa protease was found stored in both the preacetabular and postacetabular glands. This enzyme was also detected in the cercarial glycocalyx by immunogold and immunofluorescence labelling and by its proteolytic activity. Following transformation and shedding of the glycocalyx, the same 28 kDa protease was found on the surface membrane of transformed schistosomula which are resistant to immune damage. It is suggested that the 28 kDa membrane protease which cleaves in vitro the complement proteins C3, C3b and C9, may promote in vivo immunoresistance of S. mansoni.

Animals↗