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Biomedical subjects

M L Edwards

Publications and source records attributed to M L Edwards.

At least 37 records · Page 2Linked to original sources
PubMed1991

4',5'-unsaturated 5'-halogenated nucleosides. Mechanism-based and competitive inhibitors of S-adenosyl-L-homocysteine hydrolase.

The design and synthesis of (E)- and (Z)-5'-fluoro-4',5'-didehydro-5'-deoxyadenosine (6 and 13, respectively), a new class of mechanism-based inhibitors of S-adenosyl-L-homocysteine (SAH) hydrolase, is described. A number of analogues of 6 and 13 were synthesized in order to determine the structure-activity relationship necessary for inhibition of the enzyme. Substitution of chlorine for fluorine in 6 (i.e. 44), addition of an extra chlorine to the 5'-vinyl position (i.e. 51 and 52), modification of the 2'-hydroxyl group to the deoxy (34 and 35) and arabino (36 and 37) nucleosides provided competitive inhibitors of SAH hydrolase. Nucleosides 6 and 13, as well as 5'-deoxy-5',5'-difluoroadenosine (14) proved to be time-dependent inhibitors of SAH hydrolase. All three compounds are postulated to inhibit through the potent electrophile derived from oxidation of the 3'-hydroxyl of 6 or 13 to the ketone (i.e. 3 and/or the E-isomer). Consistent with the proposed mechanism of inactivation of SAH hydrolase by 6, 13, and 14 was the observation that incubation of purified rat liver SAH hydrolase with 6 resulted in release of 1 equiv of fluoride ion (by 19F NMR) and incubation with 14 resulted in release of 2 equiv of fluoride ion. The general synthetic route developed for the synthesis of the title nucleosides utilized the fluoro Pummerer reaction for the introduction of fluorine into the requisite precursors. Preliminary antiretroviral data from Moloney leukemia virus (MoLV) is presented and correlates with SAH hydrolase inhibition. Antiviral activity (IC50 against MoLV) ranged from 0.05 to 10 micrograms/mL.

Adenosylhomocysteinase↗
PubMed1991

Synthesis and DNA-binding properties of polyamine analogues.

The synthesis of a series of novel polyamine analogues is reported. The DNA binding of these compounds and a variety of other polyamines were compared with their IC50 values against HeLa cell. There seemed to be no apparent correlation between the DNA binding and toxicity against HeLa cells.

Alkylation↗
PubMed1991

Viscous carboxymethylcellulose in the prevention of epidural scar formation.

Six chemical agents were evaluated for their efficacy in preventing epidural scar formation following laminectomy in rabbits. One agent was carboxymethylcellulose and the other five agents represented various compositions of modified carboxymethylcellulose. Four weeks after laminectomy, spines were harvested and decalcified, and transverse sections were prepared for histologic analysis. Subjective evaluation suggested that two agents appeared to inhibit epidural scar formation compared with the untreated controls. Objective evaluation was performed by quantitating scar tissue area at the laminectomy site with a digitizing tablet. In agreement with the subjective evaluation, two agents were found to have significantly reduced epidural scar tissue area compared with the control (control = 0.418 +/- 0.16 SE mm2vs. Agent 2 = 0.067 +/- 0.02 [P less than 0.05] and Agent 5 = 0.089 +/- 0.02 [P less than 0.05]). Of the remaining four agents, one of which was the unmodified carboxymethylcellulose, none showed significant reduction in scar tissue formation. These findings indicate that viscous preparations of modified carboxymethylcellulose can act as a barrier against epidural scar formation following laminectomy.

Animals↗
PubMed1991

Transgenic plants and insect cells expressing the coat protein of arabis mosaic virus produce empty virus-like particles.

The 3' end of the RNA-2 of arabis mosaic virus (ArMV) was cloned and sequenced. The N-terminal amino acid sequence of the virion coat protein was determined by Edman degradation and the corresponding coding region identified. This gene was modified at the 5' and 3' ends by use of mismatched primers in the polymerase chain reaction (PCR), in order to facilitate the cloning of the gene, and to provide it with a methionine initiation codon. The modified cloned gene was expressed in transgenic plants, recombinant baculovirus-infected insect cells and bacteria. Both the insect cells and the plants expressing the modified coat protein gene contained empty virus-like particles (VLPs) similar to the empty virus shells found in plants infected with ArMV. These VLPs were not detected in the Escherichia coli expressing the coat protein. Analysis of the primary amino acid sequence in the ArMV coat protein revealed extensive regions of identity with that of grapevine fanleaf virus. Patterns in these identities may reflect a three-domain organization of the proteins.

Amino Acid Sequence↗
PubMed1991

1,10-bis(guanidino)decane inhibits N-methyl-D-aspartate responses in vitro and in vivo.

This study evaluated the interaction of the arcaine analog 1,10-bis(guanidino)decane (BG10) with the NMDA receptor. BG10 inhibited [3H]dizocilpine binding to well-washed rat brain membranes with an apparent affinity of 1.3 microM. The inhibition was not competitive with respect to glutamate or glycine, but was significantly altered by spermidine. However, unlike arcaine, BG10 slowed the dissociation of [3H]dizocilpine. BG10 also inhibited [3H]glycine binding at similar concentrations. BG10 inhibited N-methyl-D-aspartate (NMDA) and glycine-induced increases in intracellular Ca++ in cultured rat brain neurons monitored using the fluorescent dye, fura-2 (IC50 3 microM). This inhibition was not competitive with NMDA or glycine and could not be reversed by either spermidine or arcaine. BG10 also noncompetitively inhibited NMDA-stimulated cyclic GMP production in cerebellar slices from mouse brain. Finally, BG10 administered i.p. reduced harmaline-stimulated, NMDA-dependent cyclic GMP accumulation in mouse cerebellum in vivo (ED50 12.3 mg/kg). These data demonstrate that BG10 is a novel and effective NMDA receptor antagonist in vitro and in vivo.

Animals↗
PubMed1990

Potentiation of natural killer cell activity and tumor immunity by diacetylputrescine.

The objective of the present investigation was to evaluate the immunomodulating properties of tetramethylenebisacetamide (N,N' 1-diacetylputrescine, DAP), a known inducer of cellular differentiation. We examined the effect of DAP administration in vivo on splenic and nonadherent peritoneal natural killer (NK) cell activity. A single i.p. injection of DAP (100 mg/kg) enhanced cytolytic activity directed against YAC-1 and MCA-38 tumor target cells 2- to 3-fold. Cytolytic activity peaked 3 days following DAP injection. DAP treatment increased the frequency of asialo-GM1-positive splenocytes to 15% compared with 5% for vehicle treated controls. Furthermore, cytolytic activity could be eliminated by treatment with anti-asialo-GM1 antibodies and complement. Lysis of NK-resistant P815 and EL4 tumor target cells was not observed in leukocytes from DAP-treated mice. DAP treatment of mice given injections i.p. of MCA-38 tumor cells increased survival time of the mice by 37%, curing 10% of the animals of the tumor. DAP treatment of mice given injections intrasplenically of MCA-38 tumor cells reduced both the number and the size of the hepatic metastases. The antitumor effect of DAP in vivo could be eliminated by pretreating mice with anti-asialo-GM1 antibodies or utilizing NK cell deficient beige (bg/bg) mice. These results indicate that the observed anti-tumor activity of DAP is mediated, at least in part, by NK cells.

Adenocarcinoma↗
PubMed1990

Bis(benzyl)polyamine analogs as novel substrates for polyamine oxidase.

N,N'-Bis(benzyl)polyamine analogs were found to be substrates for highly purified polyamine oxidase. Metabolism of these analogs was apparently dependent on molecular O2 and resulted in the formation of benzaldehyde, H2O2, and a polyamine analog with free terminal amines. The debenzylation reaction was optimal between pH 9 and 10, identical to the pH optimum for polyamine oxidase activity when N1-acetylspermine was used as the substrate. On a molecular sieve column the debenzylating activity co-eluted with N1-acetylspermine oxidizing activity, at an apparent molecular mass of approximately 65 kDa. The purified enzyme also appeared to have a molecular mass of approximately 65 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Debenzylation of the bis(benzyl)polyamines was competitively inhibited by N1-acetylspermine and N1-acetylspermidine. The specific irreversible inhibitor of polyamine oxidase, N1,N4-bis(buta-2,3-dienyl)butanediamine also inhibited the debenzylation, whereas inhibitors of diamine and monoamine oxidases did not. The evolution of benzaldehyde from bis(benzyl)polyamine analogs by polyamine oxidase allowed the development of a simple rapid spectrophotometric assay for use in the measurement of polyamine oxidase activity in partially purified tissue or cell extracts. Further, metabolism of a bis(benzyl)polyamine analog by polyamine oxidase was found to be an important element in the growth inhibitory properties of the compound in a mouse model of malaria.

Animals↗
PubMed1990

Polyamine analogues with antitumor activity.

A series of tetraamines derived from 1,8-diaminooctane was prepared and tested as antitumor agents. The reaction of 1,8-diaminooctane with acrylonitrile gave N,N'-bis(cyanoethyl)-1,8-diaminooctane, which was reduced to tetraamine 20. Alkylation of the terminal nitrogen atoms of the tetra-Boc derivative of this compound by methyl or ethyl halide followed by removal of the Boc groups gave the bis(alkyl)polyamines 26a and 26b, respectively. These three compounds exhibit promising antitumor activity in the mouse L1210 leukemia model. Coadministration of a polyamine oxidase inhibitor potentiated the antitumor activity.

Animals↗
PubMed1990

Chalcones: a new class of antimitotic agents.

A series of chalcones was evaluated as antimitotic agents. One of these, (E)-1-(2,5-dimethoxyphenyl)-3-[4-(dimethylamino)phenyl]-2-methyl-2-pr open- 1-one) (73), was found to be an effective antimitotic agent at a concentration of 4 nM in an in vitro HeLa cell test system. When evaluated in experimental tumor models in vivo, this compound exhibited antitumor activity against L1210 leukemia and B16 melanoma.

Antineoplastic Agents↗
PubMed1990

Acoustic validation of phonological knowledge and its relationship to treatment.

The speech of 4 phonologically disordered children with place and voicing errors affecting initial stop consonants was described through phonological and acoustic analyses. Productions of target voiced and voiceless alveolar and velar stops were transcribed and acoustically analyzed before and after treatment that was administered on a predetermined contrast. Three of the children produced significant, although largely imperceptible, differences in VOT for a given stop when it represented different adult stops. The presence of productive phonological knowledge, as inferred from acoustic data, facilitated rapid generalization of correct production of the treated contrast. In the absence of acoustically determined productive knowledge, a longer treatment period was necessary to achieve a lower level of production accuracy on the same treated contrast. Sources of speech sound errors for the 4 children were hypothesized by comparing the children's underlying representations determined from both acoustic and descriptive phonological data.

Child, Preschool↗
PubMed1990

Comorbidity of stuttering and disordered phonology in young children.

Young stutterers frequently exhibit concomitant speech and/or language disorders. The co-occurrence of these disorders is, however, not yet well understood. The purpose of this paper is to introduce the notion of "comorbidity" as it relates to the field of speech-language pathology: specifically, to discuss comorbidity (coexistence) of stuttering and disordered phonology in young children. Literature on concomitant speech and language disorders in young stutterers is reviewed, with special reference to the prevalence of articulatory/phonological disorders in young stutterers. Future research on the coexistence of two speech and language disorders is encouraged, as well as the consideration of diagnostic treatment and prognostic implications for children who exhibit both stuttering and disordered phonology as opposed to children who exhibit each disorder in isolation.

Child↗
PubMed1989

Bis(benzyl)polyamine analogs inhibit the growth of chloroquine-resistant human malaria parasites (Plasmodium falciparum) in vitro and in combination with alpha-difluoromethylornithine cure murine malaria.

A number of bis(benzyl)polyamine analogs were found to be potent inhibitors of both chloroquine-resistant and chloroquine-sensitive strains of the human malaria parasite Plasmodium falciparum in vitro (IC50 values = 0.2-14 microM). Administration of one of the compounds, MDL 27695, which is N,N'-bis(3-[(phenylmethyl)amino]propyl)-1,7-diaminoheptane (C6H5CH2NH(CH2)3NH(CH2)7NH(CH2)3NHCH2C6H5), at 10-15 mg/kg i.p. three times per day for 3 days in combination with 2% alpha-difluoromethylornithine (DFMO; eflornithine) in drinking water effected cures of 47/54 mice infected with Plasmodium berghei. Cured mice were found to be immune upon rechallenge with the same P. berghei strain 4 months after the initial infection and drug-induced cure. MDL 27695 rapidly inhibited the incorporation of [3H]hypoxanthine into P. falciparum RNA and DNA, whereas the incorporation of [3H]isoleucine was not affected until much later. We conclude, therefore, that the major cytotoxic event may be direct binding of MDL 27695 to DNA with subsequent disruption of macromolecular biosynthesis and cell death. These compounds offer a lead in the search for new agents for chemotherapy of malaria.

Animals↗
PubMed1987

Virulence for guinea pigs of tubercle bacilli isolated from the sputum of participants in the BCG trial, Chingleput District, South India.

This study, conducted in Madras, India and in Madison, Wisconsin, USA, was concerned with the virulence of isolates of Mycobacterium tuberculosis obtained from the sputum of individuals living in the Chingleput district of south India. The following results were obtained. 1. The findings of Mitchison with respect to the predominance of low virulence for guinea pigs among isolates from persons living Madras, were confirmed on isolates from the sputum of residents of the Chingleput district. 2. A high correlation was found between the log10 number of tubercle bacilli recovered from the spleen of guinea pigs infected intramuscularly with 1.0 mg of tubercle bacilli and the root index of virulence. 3. A high correlation was found between the log10 number of tubercle bacilli recovered from the spleen of guinea pigs infected intramuscularly with 1.0 mg of tubercle bacilli and the number recovered from the spleen of guinea pigs infected by the respiratory route with 5-10 tubercle bacilli. 4. Relatively low correlations were found between RIV and the susceptibility of isolates to thiophene-2 carboxylic acid hydrazide or to hydrogen peroxide.

Animals↗
PubMed1987

Clinical application of two phonologically based treatment procedures.

Two phonological process-based treatment procedures were applied in an ongoing clinical program. Subjects were 4 children aged 3:1, 3:8, 4:1, and 5:1. Two subjects were assigned to a minimal pairs contrasting procedure, and 2 were assigned to a modified cycles procedure based on results of a detailed phonological analysis. All children demonstrated marked changes in their phonological systems as shown by the results of pretreatment and follow-up generalization probes. Correct production generalized to sounds affected by the treatment process that were not a focus of training. Correct production of untrained sounds lagged behind that of trained sounds for all subjects. Results support the hypothesis that articulation remediation is enhanced by treating phonological processes as well as the notion that the acquisition of phonology is a gradual process. Both treatment procedures used in this study were found to be effective and efficient, as evidenced by the elimination of up to three phonological processes within 2 1/2 months for each subject.

Articulation Disorders↗
PubMed1985

Exogenous reinfection in experimental airborne tuberculosis.

This study of experimental airborne tuberculosis in which guinea pigs were infected with tubercle bacilli of low and high virulence, provides no support for hypotheses suggesting that a second or third exposure to tubercle bacilli leads to an adverse effect on host response to the first infecting strain or to the reinfecting strain. The principal influence of the first infection was to protect against a subsequent infection. This protection was most evident as inhibition of the spread of bacilli from the lungs to the spleen. The first infection appeared to exert less influence on events at the site of reimplantation of organisms in the lungs.

Air Microbiology↗
PubMed1985

Plant virus detection using a new form of indirect ELISA.

A novel form of indirect enzyme-linked immunosorbent assay (ELISA) has been devised for the detection of viruses in plants. The method uses protein A in two applications to sandwich antibody-antigen-antibody layers. The first applied layer of protein A prepares the plate for the coating antibody layer. The second layer of protein A is conjugated to the enzyme and detects the second antibody layer. The orientation of the IgG induced in the coating layer of antibody prevents later unwanted reaction with the conjugated protein A. Using seven antisera, protein A sandwich ELISA (PAS-ELISA) detected homologous virus isolates in standard dilutions of infected plant homogenates at A405 values which were at least one absorbance unit greater than those of healthy controls. The PAS-ELISA method was more sensitive than the direct double antibody sandwich form of ELISA (DAS-ELISA), e.g. not only were A405 values for homologous reactions greater in PAS-ELISA but also an antiserum to a birch isolate of cherry leaf roll virus detected four related isolates with the new method against only one with DAS-ELISA. However, dilution end points for the homologous virus were about the same in both methods. In a practical application, PAS-ELISA detected prune dwarf virus in 18-36% of tested Prunus avium seeds.

Animals↗