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Biomedical subjects

R Arnon

Publications and source records attributed to R Arnon.

At least 127 records · Page 7Linked to original sources
PubMed1990

Heat-exercise performance of pyridostigmine-treated subjects wearing chemical protective clothing.

Pyridostigmine bromide is currently the pretreatment of choice for operation in a chemical warfare (CW) environment. Under CW conditions, subjects are exposed to thermal stress caused by CW protective clothing. This investigation was conducted to determine if pyridostigmine affects various physiological and biophysical parameters of human temperature regulation in subjects wearing CW protective clothing. Pyridostigmine was administered orally in a randomized double-blind cross-over study in four doses of 30 mg every 8 h. An average of 33% whole blood cholinesterase inhibition was induced in the pyridostigmine treated group 4 h after ingestion of last tablet. The subjects were exposed to 170 min exercise-heat stress (Tdb = 33 degrees C; rh = 60%) consisting of 60 min in a sitting position and two 50-min walks (1.39 m.s-1, 5% grade) separated by 10 min of rest. Non-evaporative heat exchange was significantly higher, -14.0 and -10.6 W.m-2 (p less than 0.03), for the pyridostigmine-treated subjects. No additional differences were found between treatments in the physiological responses and heat balance parameters at the end of exposure: heart rate (HR) was (mean +/- S.D.) 154 +/- 16 and 151 +/- 24 bpm, rectal temperature (Tre) was 39.0 +/- 0.4 and 38.9 +/- 0.2 degrees C, heat storage over the 2 h of exercise was 62 +/- 15 and 70 +/- 15 W.m-2, and sweat rate was 832 +/- 185 and 748 +/- 52 g.h-1, in the pyridostigmine and placebo treatments, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

[Clinical trial of copolymer 1 in multiple sclerosis].

A synthetic copolymer of amino acids, copolymer 1 (Cop 1), proved to be very effective in suppressing experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). It is 1 of a series of synthetic amino acid copolymers which simulate the basic protein constituent of the myelin sheath and the autoantigen responsible for induction of EAE. It cannot induce EAE but it does suppress it in a variety of animals. The immunological cross-reaction between Cop 1 and the basic protein is the basis for this suppressive activity. In view of the resemblance between EAE and MS, clinical trials with Cop 1 in MS were started. The first preliminary clinical trial was at this hospital and involved 4 patients with severe MS. A double-blind, randomized placebo-controlled pilot trial was carried on for 2 years in 50 patients with the exacerbating-remitting form of MS but with a Kurtzke Disability Status Scale rating of no more than 6. There were statistically significant differences in the number of patients with exacerbations in the placebo group, 23, as compared to only 16 in the Cop 1-treated group. As to exacerbations per patient, the 2-year averages were 2.7 and 0.6, respectively. Side-effects of Cop 1 were minimal. These results suggest that Cop 1 may be beneficial when given early in the exacerbating-remitting form of MS. Further trials, necessary to establish its efficacy in MS, are being run at the Albert Einstein College of Medicine in NY.

Amino Acids↗
PubMed1989

Blood levels and serum protein binding of cis-platinum(II) complexed to carboxymethyl-dextran.

Plasma levels and serum protein binding of cis-diamminedichloroplatinum(II) (cis-DDP) or cis-diamminediaquoplatinum(II) (cis-aq) complexed to carboxymethyl-dextran (CM-dex) with a molecular weight of 10,000 (T-10), 40,000 (T-40), and 250,000 (T-250) were investigated in BALB/c mice. Levels of active drug in the circulation after the i.v. or i.p. administration of the free or complexed drugs, as well as the loss of drug activity due to serum protein binding following incubation with mouse serum, were monitored by an antitumor in vitro assay using a drug-sensitive tumor cell line. Following i.v. injection of the complexes, active platinum(II) was maintained in the circulation at higher levels and for a longer period, whereas the free drug disappeared rapidly. The rate of disappearance of the complexed drug from the circulation was markedly influenced by the molecular size of the carrier CM-dex, since the retained amount of drug was considerably higher with the T-40 and T-250 complexes than with the T-10 complex. An i.p. injection resulted in a rapid and transient appearance of low levels of the free drugs in the blood, whereas in the case of the complexes, transport to the circulation was slower and their maintenance in the blood system was markedly higher. Serum protein binding was much slower with CM-dex-complexed drugs (regardless of the molecular size of the CM-dex carrier) than with the free drugs.

Animals↗
PubMed1989

Expression of Shiga toxin epitopes in E. coli immunological characterization.

Synthetic oligodeoxynucleotides encoding for two peptides corresponding to residues 9-21 and 19-31 in the amino acid sequence of the B subunit of Shiga toxin were prepared and inserted into pTOZ plasmid, in phase with the lacZ gene. The resultant vectors were used for transfection of E. coli. The bacteria containing the recombinant DNA expressed the respective peptides in the form of fusion proteins with beta-galactosidase. The N-terminal region of the Shiga toxin B subunit, containing the two peptides, was previously identified as a relevant epitope of the toxin, leading to the induction of neutralizing antibodies. The present study demonstrates that the bacterial extracts containing the fusion proteins as the products of the recombinant vectors, when used for immunization of rabbits, elicited a humoral immune response which was specific toward the respective peptides. Furthermore, the antibodies cross-reacted with the intact Shiga toxin.

Amino Acid Sequence↗
PubMed1989

Genetic control of immune response to a purified Schistosoma mansoni antigen. I. Effect of MHC class II antigens on the cellular, humoral and protective responses.

The influence of the I region of the major histocompatibility complex (MHC) on T-dependent immune responses against a purified schistosome antigen (9B antigen) was investigated. H-2 congenic mice expressing both I-A and I-E antigens (I-E+) showed a higher in-vitro proliferation to 9B antigen as compared to the recombinant strains expressing only I-A (I-E-). These two strains of mice differed both qualitatively and quantitatively in the humoral responses elicited by the purified antigen. Furthermore, in-vivo protection experiments showed that mice which do not express I-E molecules can be partially protected against the disease by prior immunization with the 9B antigen in contrast to their I-E expressing counterparts. The possible role of the I-E molecule in the immune responses elicited during Schistosoma mansoni infection is discussed.

Animals↗
PubMed1989

Genetic control of immune response to a purified Schistosoma mansoni antigen. II. Establishment and characterization of specific I-A and I-E restricted T-cell clones.

T-cell lines and clones specific for a partially protective schistosome antigen (9B antigen) were established from mice immunized with such antigen. The H-2 congenic strains B10.A which express both I-A and I-E class II gene products of the major histocompatibility complex (MHC) and B10.A(4R) which only express I-A molecules were used in these studies. The specific T-cell lines recognized the 9B antigen in the context of either A or E molecules, but both class II antigens were necessary for maximal stimulation of the T-cell lines in lymphocyte proliferation assays. T-cell clones were derived from these lines and their MHC restriction was investigated. Both I-A and I-E restricted clones could be isolated. All clones were specific for 9B antigen showing different degrees of cross-reactivity with a total schistosome extract (CA sonicate). A correlation between the fine specificity of the clones and the expression of class II antigens was demonstrated. Clones specific for 9B antigen, or which reacted to the same extent with 9B antigen and CA sonicate, were I-A restricted, whereas clones which proliferated more in the presence of CA sonicate were all I-E restricted. This suggests that I-E restricted clones recognize more cross-reactive epitopes than I-A restricted clones. These antigen-specific T-cell clones should provide a useful tool for examining the role of class II antigens in the modulation of protective immune response during Schistosoma mansoni infection.

Animals↗
PubMed1989

Suppression of experimental allergic encephalomyelitis by COP1--relevance to multiple sclerosis.

The evidence in this presentation clearly indicates that in the case of the model disease EAE, desensitization procedures are effective in suppressing the symptoms of the disease and in providing protection against it. The antigens used in our studies are all synthetic materials immunologically relevant to the myelin encephalitogenic protein, but not encephalitogenic themselves. The most effective of these materials is a random basic copolymer of alanine, glutamic acid, lysine and tyrosine, denoted COP 1. The finding that the suppressive polymers show immunological cross-reactivity with the encephalitogenic protein provides a logical basis for the explanation of their suppressive activity in terms of an immunological desensitization mechanism. Our studies suggest that the effectiveness of COP 1 in preventing EAE results from the production of antigen-suppressor T cells, and/or from blocking MBP-specific effector T cells. The results of the clinical trial presented here show demonstrable improvement in the COP 1-treated patients as compared with the placebo subjects, particularly for those patients with less severe MS at the start of the treatment. Thus, although the evidence supporting the antigenic role of MBP in MS is not strong, COP 1, a synthetic polypeptide simulating some of the properties of MBP, appears to be effective in altering the course of MS and is of potential value as a modality for the treatment of this disease.

Animals↗
PubMed1988

Proteases secreted by transforming schistosomula of Schistosoma mansoni promote resistance to killing by complement.

Early events in the transformation of schistosomula of Schistosoma mansoni include shedding of the glycocalyx and conversion of the parasite from sensitive to resistant to complement-mediated killing. This is accompanied by a release of proteolytic activity which occurs at the same rate as the first two phenomena and is also complete within 1 h of culture at 37 degrees C in defined synthetic medium. Two serine proteases, of 28 kDa and a 60 kDa, were purified to homogeneity from the culture medium of transforming schistosomula; the purification steps and the initial characterization of these proteases are reported elsewhere. Both proteases accelerated the release of surface molecules from the schistosomula; however, the effect of the 28-kDa protease was much more pronounced. Qualitative analysis of the material cleaved from the schistosomula by the purified proteases on SDS-PAGE revealed a fragmentation pattern identical with that of the material shed spontaneously from transforming schistosomula. This strongly suggests that the 28-kDa and 60-kDa proteases contribute physiologically to the release of the schistosomular surface molecules including the high Mr glycocalyx. The activity of the two proteases was inhibited by PMSF. Freshly transformed schistosomula treated shortly with the purified 28-kDa protease produced a lower C consumption and became more refractory to C killing. Both consumption and killing were mediated by the alternative pathway of C in the absence of antibodies. These results postulate a role for proteases secreted by transforming schistosomula in the release of schistosomular surface molecules which activate C. This may serve as an escape mechanism from C damage employed by transforming schistosomula.

Animals↗
PubMed1988

NMR study of the complexes between a synthetic peptide derived from the B subunit of cholera toxin and three monoclonal antibodies against it.

The contact interactions between a synthetic peptide and three different anti-peptide monoclonal antibodies have been studied by nuclear magnetic resonance (NMR). The synthetic peptide is CTP3 (residues 50-64 of the B subunit of cholera toxin) suggested as a possible epitope for synthetic vaccine against cholera. The hybridoma cell lines TE33 and TE32 derived after immunization with CTP3 produce antibodies cross-reactive with the native toxin. The cell line TE34 produces anti-CTP3 antibodies that do not bind the toxin. Selective deuteriation of the antibodies has been used to simplify the proton NMR spectra and to assign resonances to specific types of amino acids. The difference spectra between the proton NMR spectrum of the peptide-Fab complex and that of Fab indicate that the combining site structures of TE32 and TE33 are very similar but differ considerably from the combining site structure of TE34. By magnetization transfer experiments with selectively deuteriated Fab fragment of the antibody, we have found that in TE32 and TE33 the histidine residue of the peptide is buried in a hydrophobic pocket of the antibody combining site, formed by a tryptophan and two tyrosine residues. The hydrophobic nature of the pocket is further demonstrated by the lack of any pH titration effect on the chemical shift of the C4H of the bound peptide histidine. In contrast, for TE34 we have found only one tyrosine residue in contact with the histidine of the peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1988

Isotype restriction of murine antibodies towards the loop region of hen's egg white lysozyme.

Monoclonal antibodies specific for the loop determinant (residues 64-80) of hen's egg white lysozyme demonstrated an immunoglobulin class restriction. Only IgM response against the loop could be evoked in mice, irrespective of whether the immunogen was the intact native lysozyme as such, or the loop peptide covalently conjugated to a synthetic carrier, poly-DL-alanyl-poly-L-lysine (A-L). Despite the fact that in polyclonal antisera from mice immunized with lysozyme, the ELISA-titre of anti-loop reactivity was very low, 26% of the total anti-lysozyme response could be accounted for by the loop when expressed as the percentage of anti-lysozyme hybridoma colonies producing monoclonal antibodies reactive with the loop. The results can be interpreted either as determinant controlled isotype restriction, or alternatively, as an affinity restriction leading to the phenomenon that antibodies of isotypes other than IgM are formed, but are of too low avidity to be detected by the ELISA method.

Animals↗
PubMed1988

Acetylcholinesterase in Schistosoma mansoni is anchored to the membrane via covalently attached phosphatidylinositol.

Two enzymes, alkaline phosphatase and acetylcholinesterase (AChE), have been shown previously to be components of the surface of the trematode parasite Schistosoma mansoni. In this study we report that both these enzymes and other serine hydrolases are susceptible to release from the S. mansoni tegumental membrane by a phosphatidylinositol-specific phospholipase C (PIPLC) of bacterial origin. These data suggest that AChE and alkaline phosphatase of S. mansoni, as in higher organisms, are anchored to the membrane via covalently attached phosphatidylinositol. The release of AChE from the vesicular fraction of the parasite with PIPLC occurs in a concentration-dependent manner. Sucrose gradient centrifugation of the PIPLC-released AChE showed a single 8.3 S molecular form, similar to that observed for AChE solubilized by Triton X-100. PIPLC removed large amounts of AChE from the surface of intact schistosomula in culture, with no impairment of the viability of the parasite. In this case, an increase in the overall levels of AChE in the intact parasite was observed after addition of PIPLC.

Acetylcholinesterase↗
PubMed1988

Purification and characterization of proteases secreted by transforming schistosomula of Schistosoma mansoni.

Schistosomula of Schistosoma mansoni which are mechanically transformed at 4 degrees C and are then incubated at 37 degrees C in defined medium spontaneously secrete two proteases, a major one of 28 kDa and a minor one of 60 kDa. These were purified by ion exchange chromatography on DEAE-cellulose and gel filtration on Ultrogel AcA 54 with yields of 33% and 29%, respectively. Both appeared as single bands by silver staining following sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis. The 28 kDa protease is a glycoprotein that has a pI of 11 or higher and an optimal activity around pH 9.0. It cleaves casein, gelatin and human C3 and C3b. It is metal-ion independent and is inhibited by diisopropyl fluorophosphate, phenylmethanesulfonyl fluoride, soy-bean trypsin inhibitor, alpha 1 antitrypsin, Zn2+ ions, sodium dodecyl sulphate and normal human serum. The 60 kDa protease is a glycoprotein with a pI of 9.2. It can also cleave casein and gelatin and its activity is inhibited by phenylmethanesulfonyl fluoride but not by diisopropyl fluorophosphate or sodium dodecyl sulphate. We suggest that these proteases may play a role during cercarial penetration of the skin and in shedding of the cercarial glycocalyx.

Animals↗
PubMed1988

Specific inhibition of the T-cell response to myelin basic protein by the synthetic copolymer Cop 1.

Cop 1 is a synthetic basic random copolymer of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine in a residue molar ratio of 6.0:1.9:4.7:1.0 and with a molecular weight of 21,000 which proved to be effective in specific suppression of experimental allergic encephalomyelitis and has been proposed as a candidate drug against multiple sclerosis. In the present study we further investigated the mechanism of Cop 1 suppressive activity and tested whether Cop 1 could inhibit the specific T-cell response to myelin basic protein (BP). Eight BP-specific T-cell lines and clones with various H-2 restrictions and antigenic specificities were used. The responses of all these lines and clones to BP, as followed by both cell proliferation and interleukin 2 secretion assays, were affected by Cop 1. For one line, a direct cross proliferation with Cop 1 was observed, whereas in the other seven lines and clones, Cop 1 specifically inhibited the responses to BP in a competitive dose-dependent manner. The inhibition of the response to BP is specific to Cop 1, as D-Cop 1 and another random acidic polymer, poly(Tyr,Glu,Ala) (TGA), both of which were previously demonstrated to be ineffective in suppression of experimental allergic encephalomyelitis, did not inhibit the response to BP. Furthermore, Cop 1 specifically inhibited only the response of the T-cell lines and clones to BP. It did not inhibit their response to the mitogen Con A, nor did it inhibit the responses of the purified protein derivative-specific T-cell line and clone. These results suggest that Cop 1 may be effective in suppression of experimental allergic encephalomyelitis, not only because of the selective stimulation of suppressor T cells, as we have previously demonstrated, but also by specific inhibition of BP-specific effector T cells.

Animals↗