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Biomedical subjects

L S Williams

Publications and source records attributed to L S Williams.

At least 91 records · Page 5Linked to original sources
PubMed1989

Interactive effects of peptidoleukotrienes and histamine on microvascular permeability and their involvement in experimental cutaneous and conjunctival immediate hypersensitivity.

The involvement of peptidoleukotrienes (LTs) in mediating the increase in microvascular permeability associated with experimental cutaneous immediate hypersensitivity was studied by examining the effect of SK&F 104353, a potent and selective LT-antagonist, on the response evoked by graded, intradermal injections of antigen. SK&F 104353, employed at doses that profoundly blocked LTC4, LTD4 and LTE4 responses, significantly reduced the response produced by experimental cutaneous immediate hypersensitivity. The response to the lowest antigen dose (0.1 microgram) was, however, entirely insusceptible to SK&F 104353. The effect of SK&F 104353 was also examined in combination with a pyrilamine-cimetidine dosing regimen sufficient to remove the histaminergic component of cutaneous immediate hypersensitivity. The non-histaminergic component associated with higher antigen doses (10 and 100 micrograms) was significantly reduced but not abolished by SK&F 104353; the non-histaminergic component associated with low antigen doses (0.1 and 1 microgram) was not susceptible to SK&F 104353. Thus, the increase in cutaneous microvascular permeability evoked by immediate hypersensitivity appears to comprise three components: (1) A histaminergic response apparent for all antigen doses; (2) a LT-mediated component which is manifest in response to high antigen doses; (3) a third, unidentified component that is present for the entire antigen dose-range but contributes less to the overall response when high antigen doses are used. A distinct non-histaminergic, non-leukotriene mediated component was not a feature of conjunctival immediate hypersensitivity. SK&F 104353 administered in combinatio with pyrilamine-cimetidine virtually abolished the response with a small residual remaining only for the highest antigen dose. In further contrast to cutaneous immediate hypersensitivity, SK&F 104353 alone was comparatively ineffective in type 1 allergic conjunctivitis. This difference in susceptibility to SK&F 104353 appears to reflect the type of histamine-LTD4 interactive effect on microvascular permeability. Histamine and LTD4 were additive in terms of cutaneous microvascular permeability. In the conjunctiva, histamine and LTD4 appeared mutually exclusive in that the level of response produced by the combination tended not to exceed that of the single component which caused the greater effect.

Animals↗
PubMed1989

Marked differential effects of prostanoid metabolites on rabbit intraocular pressure.

A comparison of the effects of the major metabolites of prostaglandins E2, F2 alpha, and D2 (PGE2, PGF2 alpha and PGD2) on rabbit intraocular pressure (IOP) revealed differences in potency relative to each other and the parent prostanoid. 15-Keto PGF2 alpha produced significant, dose-dependent decreases in IOP at 0.1 and 1% doses; responses of a similar magnitude were achieved with 0.01 and 0.1% PGF2 alpha indicating a 10-fold difference in potency between PGF2 alpha and its 15-keto metabolite. 13,14-Dihydro PGF2 alpha appeared slightly less active than 15-keto PGF2 alpha, whereas 13,14-dihydro-15-keto PGF2 alpha was almost 100-fold less potent than PGF2 alpha. PGE2 was approximately 100-fold more potent as an ocular hypotensive than its 15-keto and 13,14-dihydro-15-keto metabolites. 19(R)-OH PGF2 alpha did not alter IOP, whereas 19(R)-OH PGE2 was essentially equipotent to PGE2 as an ocular hypertensive without producing the typical subsequent decrease in IOP. The decrease in IOP evoked by active PGE2 and PGF2 alpha metabolites was of shorter duration than responses produced by the respective parent prostanoid. Although PGD2 was equipotent with PGE2 and PGF2 alpha, the 11-ketoreductase-derived metabolite (9 alpha, 11 beta-PGF2) exhibited little effect on IOP, and 13,14-dihydro-15-keto PGD2 was inactive. The thromboxane A2 (TxA2)-mimetic U-46619 and TxB2 did not significantly alter IOP.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1989

Prostaglandin F2 alpha effects on intraocular pressure negatively correlate with FP-receptor stimulation.

According to the current working classification for prostanoid receptors, the prostaglandin F2 alpha-sensitive receptor (FP-receptor) may be identified by comparing the rank order of activity of prostaglandin F2 alpha (PGF2 alpha) and its analogues. In order to further understand the pharmacology of PGF2 alpha-induced ocular hypotension, the intraocular pressure response to PGF2 alpha and selected analogues was compared with their rank order of activity in typical FP-receptor preparations such as contraction of the cat iris sphincter and affinity for corporal luteal membrane binding sites. The rank order of potency for decreasing intraocular pressure was as follows: PGF2 alpha greater than PGF1 alpha greater than 16-phenoxytetranor PGF2 alpha greater than 17-phenyltrinor PGF2 alpha = fluprostenol (inactive). For cat iris sphincter contraction, the rank order of potency appears to be fluprostenol = 17-phenyltrinor PGF2 alpha greater than 16-phenoxytetranor PGF2 alpha = PGF2 alpha greater than PGF1 alpha. The rank order of potency for PGF2 alpha analogues in decreasing intraocular pressure appears to negatively correlate with the rank order for cat iris sphincter contraction and literature values for corporal luteal membrane binding. It is concluded that the ocular hypotensive effect of PGF2 alpha is not mediated by the FP-receptor.

Administration, Topical↗
PubMed1988

Characterization of the conjunctival vasopermeability response to leukotrienes and their involvement in immediate hypersensitivity.

The microvascular permeability response of the guinea pig conjunctiva to sulfidopeptide leukotrienes (LTs) was quantified as extravasation of radiolabeled bovine serum albumin. The LTs were potent inducers of increased microvascular permeability, with relative potencies LTE4 greater than or equal to LTD4 greater than LTC4. The response to LTs was unaffected by indomethacin or a pyrilamine/cimetidine combination, but the LT antagonists FPL 55712 and SKF 102922 significantly inhibited the response to LTC4, LTD4 and LTE4. In guinea pigs actively sensitized to ovalbumin, topical ocular administration of ovalbumin markedly increased conjunctival microvascular permeability; this response was reduced by approximately 50% following histaminergic blockade by pyrilamine/cimetidine. FPL 55712 and SKF 102922 and the 5-lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) had no effect on the response to antigen when used alone. However, each agent significantly reduced the non-histaminergic component of the response when given in conjunction with pyrilamine/cimetidine. Thus, it appears that the immediate hypersensitivity response in guinea pig conjunctiva has a possible non-histaminergic component which is at least partly mediated by LTs.

Animals↗
PubMed1988

Synergistic effects of LTB4 and LTD4 on leukocyte emigration into the guinea pig conjunctiva.

Leukotrienes (LT) B4 and D4, alone and in combination, were topically applied to the eyes of guinea pigs, and their effects on conjunctival leukocyte infiltration studied. LTD4 potentiated the neutrophil response to LTB4, even though no neutrophil emigration was evoked by LTD4 itself over a dose range of 10-1000 ng. LTB4 alone at the 1-ng and 10-ng doses failed to evoke any leukocyte emigration, but significant numbers of neutrophils were observed at these concentrations when LTD4 (1-1000 ng) was present. Although a dose-dependent increase in neutrophil infiltration was observed for the 100-ng and 1000-ng doses of LTB4, cell counts were substantially higher with these doses in the presence of LTD4. Eosinophil numbers increased in a dose-related manner in response to LTB4 and LTD4 alone, with a greater response to LTD4. The addition of either 10 ng or 100 ng of LTB4 to graded doses of LTD4 (10-1000 ng) caused increased eosinophil numbers, the lower dose of LTB4 potentiating the response to LTD4 and the higher LTB4 dose showing no significant effect. The effects on leukocyte infiltration that were evoked by the LT combinations could not be explained simply on the basis of an increase in vascular permeability. Bradykinin (BK), a potent conjunctival microvascular permeability factor that does not elicit any leukocyte infiltration, did not significantly potentiate LTB4-induced eosinophil or neutrophil emigration. The synergistic effects of LTs on leukocyte emigration are also difficult to ascribe to hyperemia (ie, increased blood volume in the conjunctiva), because both LTB4 and LTD4 caused only very modest increases in conjunctival blood content, and BK, which did not potentiate the leukocytic responses to LTB4, caused marked increases in tissue blood content. High-dose LT combinations caused eosinophils, but not neutrophils, to migrate into the conjunctival epithelium and fragment, resulting in overt tissue damage. These results further suggest a synergistic interaction between LTB4 and LTD4 that directly alters leukocyte function. The relevance of these observations to a number of disease and trauma states is discussed.

Animals↗
PubMed1987

Dihydrolevobunolol is a potent ocular beta-adrenoceptor antagonist.

The ocular beta-adrenoceptor antagonist activity of dihydrolevobunolol (DHLB), the major ocular and systemic metabolite of levobunolol was investigated by determining its ability to block isoproterenol-induced ocular hypotension in normotensive rabbits. Topically-applied 0.001% and 0.01% DHLB virtually abolished the response to isoproterenol, indicating a beta-blocking potency similar to that of timolol. Thus, the ocular metabolism of levobunolol leads to the formation of a highly potent beta-adrenoceptor antagonist that may contribute to its clinical efficacy.

Adrenergic beta-Antagonists↗
PubMed1986

AIDS risk reduction: a community health education intervention for minority high risk group members.

During the past year, members of the Detroit Health Department health education staff have developed an Acquired Immunodeficiency Syndrome (AIDS) community education intervention. The intervention was designed in response to the growing public health problem of AIDS and the need to provide the community with accurate information regarding the transmission and prevention of the disease. The gap in AIDS education and information was particularly evident in the black community. In attempting to develop a comprehensive health education program, the staff encountered a number of barriers. Traditional antagonisms between the high-risk groups, homosexual and bisexual males and intravenous drug abusers, and the health department hampered the ability of the intervention team to design a clinic centered program. Concurrently, lack of access to the high-risk population and reactionary public sentiment toward the disease posed serious problems for developing community support for the implementation of an effective community-based program. The intervention team also found that traditional methodologies of health education program planning were inadequate. The staff lacked sufficient data on the beliefs and attitudes of the high-risk populations necessary to design relevant risk reduction activities. Recognizing our limited awareness and accessibility to the high risk groups, a strategy was developed to encourage members of the high-risk population to assume a leadership role in the development and implementation of the community-based program. The success of the Community Health Awareness Group (C-HAG) is, in part, a result of the willingness of high risk individuals to assume some responsibility in educating themselves and others. It also speaks to the efficacy of collaborative relationships between health workers and target populations when designing public health interventions.

Acquired Immunodeficiency Syndrome↗
PubMed1985

Control of isoleucine-valine biosynthesis in a valine-resistant mutant of Escherichia coli K-12 that simultaneously acquired azaleucine-resistance.

A mutant of Escherichia coli K-12 isolated as being growth resistant to L-valine (Valr) was shown also to exhibit growth resistance to 4-azaleucine (Azlr). Transductional analysis indicated that Azlr is cotransduced with Valr at a frequency of 100% and both are linked to leu, ara, and carA. This mutation conferring valine and azaleucine growth resistance resulted in increased levels of isoleucine and valine biosynthetic enzymes as well as those of valyl- and isoleucyl-tRNA synthetases during growth in minimal and enriched media. Acquisition of Vals/Azls results in the restoration of normal regulation of both classes of ilv enzymes and normal patterns of the tRNA Ile species. The overall regulatory patterns observed for individual isoleucine and valine gene products suggest differential participation of isoleucine and valine and/or isoleucyl- and valyl-tRNA's in control of expression of the respective structural genes.

Acetolactate Synthase↗
PubMed1984

Synthesis of the isoleucyl- and valyl-tRNA synthetases and the isoleucine-valine biosynthetic enzymes in a threonine deaminase regulatory mutant of Escherichia coli K-12.

A mutation in the structural gene for threonine deaminase, ilvA538 , results in lower than normal levels of the isoleucyl, valyl- and leucyl-tRNA synthetases. Moreover, this regulatory mutation decreases the level of expression of the ilv biosynthetic operons and renders their expression non-responsive to limitations of the branched-chain amino acids. In this paper, we present in vitro evidence for the inhibition of isoleucyl- and valyl-tRNA synthetase activity by threonine deaminase and 2-ketobutyrate, the product of the threonine deaminase reaction, through the formation of a high molecular weight complex of the three molecules. Based on these results, we propose a model to explain the regulation of the isoleucyl- and valyt -tRNA synthetases in which transient inhibition of the synthetase enzyme activities by threonine deaminase and 2-ketobutyrate increases the expression of ileS and valS , the structural genes for isoleucyl- and valyt -tRNA synthetase, respectively. Further, the results suggest that the hyperattenuated expression of the ilv biosynthetic operons is due to an increased rate of complex formation of valyl and isoleucyl-tRNA synthetases and the altered form of threonine deaminase of the ilvA538 mutant strain.

Amino Acyl-tRNA Synthetases↗
PubMed1984

Reversion of the effects of a threonine deaminase regulatory mutant by a mutation in ilvH in Escherichia coli K-12.

In a strain carrying an ilvA538 mutation, the ilvGEDA operon expression is decreased (hyperattenuated) and the activity and/or expression of isoleucyl- and valyl- tRNA synthetases is decreased. We have isolated two revertants of ilvA538 owing to mutations in the ilvH gene, whose product is acetohydroxy acid synthase III. The regulatory properties of these revertants are consistent with a dual role for threonine deaminase as an effector of the ilvGEDA operon and the isoleucyl- and valyl- tRNA synthetase structural genes.

Amino Acyl-tRNA Synthetases↗
PubMed1982

Altered regulation of isoleucine-valine biosynthesis in a hisW mutant of Salmonella typhimurium.

Control of isoleucine-valine biosynthesis was examined in the cold-sensitive hisW3333 mutant strain of Salmonella typhimurium. During growth at the permissive temperature (37 degrees C), the isoleucine-valine (ilv) biosynthetic enzyme levels of the hisW mutant were two- to fourfold below these levels in an isogenic hisW+ strain. Upon a reduction in growth temperature to partially permissive (30 degrees C), the synthesis of these enzymes in the hisW mutant was further reduced. However, synthesis of the ilv enzymes was responsive to the repression signal(s) caused by the addition of excess amounts of isoleucine, valine, and leucine to the hisW mutants. Such a "super-repressed" phenotype as that observed in this hisW mutant is similar to that previously shown for the hisU1820 mutant, but was different from the regulatory response of the hisT1504 mutant strain. Moreover, by the use of growth-rate-limiting amounts of the branched-chain amino acids, it was shown that this hisW mutant generally did not increase the synthesis of the ilv enzymes as did the hisW+ strain. Overall, these results are in agreement with the hypothesis that the hisW mutant is less responsive to ilv specific attenuation control than is the hisW+ strain and suggest that this limited regulatory response is due to an alteration in the amount or structure of an element essential to attenuation control of the ilv operons.

Acetolactate Synthase↗
PubMed1982

Characterization of a cold-sensitive hisW mutant of Salmonella typhimurium.

Previous studies of hisW mutants of Salmonella typhimurium have led to the suggestion that such strains are defective in tRNA maturation. (J. E. Brenchley and J. Ingraham, J. Bacteriol. 114:528-536, 1973). In this study, we report that one hisW strain is defective in the accumulation of all stable RNA species. Polyacrylamide gel electrophoresis of radiolabeled RNA indicated tha at the nonpermissive temperature (20 degrees C) all stable RNa species in the cold-sensitive hisW3333 mutant were synthesized and rapidly degraded. We propose that the cold sensitivity of this strain is caused by such a restriction in stable RNA accumulation at low temperature. In vitro and in vivo studies demonstrated that the RNA degraded in this strain was synthesized de novo and was not preexisting RNA. Furthermore, physiological and genetic recovery from the cold-sensitive hisW phenotype resulted in relatively normal RNA synthesis and accumulation. Thus, the RNA alterations observed in this strain were not explained by defects in a tRNA modification enzyme. Rather, these findings suggest the existence of defective RNA processing and that a control mechanism for the overall synthesis or accumulation of stable RNA species is altered in the hisW3333 mutant.

Gene Expression Regulation↗
PubMed1979

ilvU, a locus in Escherichia coli affecting the derepression of isoleucyl-tRNA synthetase and the RPC-5 chromatographic profiles of tRNAIle and tRNAVal.

A mutation in the ilvU locus of Escherichia coli has led to a complex phenotype that included resistance to thiaisoleucine, a loss of derepressibility of isoleucyl tRNA synthetase, and an alteration of the RPC-5 chromatographic profile of the branched-chain aminoacyl-tRNA's. The alterations were manifest in an increase in the amount of Species 2 of both tRNAIle and tRNAVal at the expense of Species 1. A similar alteration, but independent of (and additive to) that caused by the ilvU mutation, was observed upon limitation of either isoleucine or valine. The shift in profile caused by limitation was also independent of the reduced growth rate or the derepression of the isoleucine and valine biosynthetic enzymes that also result from limitation. During chloramphenicol treatment nearly all tRNAIle and tRNAVal formed appears as species 2. Upon recovery from chloramphenicol, Species 2 of both acceptors are converted to Species 1. It is proposed that the ilvU product not only allows derepression of isoleucyl-tRNA synthetase but also retards the conversion of tRNA2Ile to tRNA1Ile and that of tRNA2Val to tRNA1Val. The mutated ilvU loci abolish the derepression and are more efficient in retarding the conversion.

Amino Acyl-tRNA Synthetases↗