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Biomedical subjects

H Giles

Publications and source records attributed to H Giles.

16 recordsLinked to original sources
PubMed1992

Inotropic polyazapentalene sulmazole analogues.

Aryl substituted 1H-imidazo[1,2-a]imidazole 8, imidazo[2,1-b]thiazole 9, 1,4-dihydroimidazo[4,5-d]imidazole 11, and 1(2),4-dihydroimidazo[4,5-c]pyrazoles 12-17 have been prepared. An X-ray crystallographic study confirmed the structure of 8 and showed this analogue to exist as the 1H-tautomer. These heterocycles were evaluated as inotropic agents and analogues 12, 15, and 17 found to display inotropic properties which were less potent in vitro, but more potent in vivo, than those of sulmazole. Structure-activity relationships are discussed.

Animals↗
PubMed1992

Type-1 and type-2 astrocytes are distinct targets for prostaglandins D2, E2, and F2 alpha.

Accumulating evidence has revealed that astrocytes are potential targets for various neurotransmitters. Here we investigated the effects of prostaglandins (PGs) on signal transduction in purified primary cultures of rat type-1 and type-2 astrocytes. PGF2 alpha, PGD2, and 9 alpha,11 beta-PGF2, a metabolite of PGD2 and a stereoisomer of PGF2 alpha, evoked a rapid rise in the intracellular Ca2+ concentration ([Ca2+]i) in type-1, but not in type-2, astrocytes. STA2, a stable analogue of thromboxane A2, was less effective, and PGE2 showed little effect. The PG-induced rise in [Ca2+]i was not blocked by an antagonist of either PGD2 receptor or thromboxane A2 receptor. PGF2 alpha and 9 alpha,11 beta-PGF2 stimulated rapid formation of inositol trisphosphate followed by inositol bisphosphate and inositol monophosphate. On the other hand, PGE2 increased the intracellular level of cyclic AMP in type-2 astrocytes, rather than in type-1 astrocytes. The potency of PGs for cyclic AMP formation was in the following order: PGE2 greater than PGE1 greater than or equal to STA2 much greater than iloprost, a stable analogue of PGI2. PGD2 and PGF2 alpha had no effect on cyclic AMP formation. These results demonstrate that type-1 astrocytes preferentially express PGF2 alpha receptors, the activation of which leads to phosphoinositide metabolism and [Ca2+]i elevation, whereas type-2 astrocytes possess PGE receptors that are linked to cyclic AMP formation.

Animals↗
PubMed1992

The effect of a prostaglandin DP-receptor partial agonist (192C86) on platelet aggregation and the cardiovascular system in healthy volunteers.

1. PGD2 (DP)-receptors mediate inhibition of platelet aggregation and vasodilatation. If receptor reserve were greater on platelets it might be possible to separate these effects. To determine whether such a difference in receptor reserve exists, we have examined the effects of a highly selective DP-receptor partial agonist 192C86 on platelet aggregation and the cardiovascular system in healthy volunteers. 2. Using an open, dose-escalating study design, four male volunteers received constant rate intravenous infusions of 192C86 for up to 60 min. Ex vivo platelet aggregation to ADP and collagen in platelet-rich plasma (PRP) and whole blood (WB) was studied at baseline, after 15, 30 and 60 min of each infusion and at 180 min post-infusion. Heart rate (HR), systolic and diastolic (DBP) blood pressure were measured at frequent intervals. Adverse experiences were monitored by checklist. Facial flushing was assessed by the volunteer using a visual analogue scale, by an observer using a numerical scale and by full-face colour photographs. Blood was taken for assay of plasma 192C86 concentrations by radio-immunoassay (r.i.a.). 3. 192C86 (0.007-0.058 micrograms kg-1 min-1) inhibited platelet aggregation to ADP and collagen both in PRP and WB in a dose-dependent manner. However, this was always accompanied by a decrease in DBP, increase in HR and facial flushing. Plasma concentrations of 192C86 were at or below the limits of sensitivity of the r.i.a. (0.5 ng ml-1). 4. The highest infusion rate was stopped after 20 min due to symptomatic hypotension on standing.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Inhibition of endothelium-dependent vasorelaxation by arginine analogues: a pharmacological analysis of agonist and tissue dependence.

1. Isolated rings of rabbit external jugular vein (RbJV) and rat thoracic aorta (RA) were used to study the effect of the NO synthase inhibitor L-NG-nitroarginine methyl ester (L-NAME) on muscarinic and 5-hydroxytryptamine (5-HT) receptor-stimulated, endothelium-dependent vascular relaxations. 2. In RbJV relaxations produced by the endothelial 5-HT receptor agonist alpha-methyl-5-HT were potently and non-surmountably inhibited by L-NAME (10 microM), whereas acetylcholine relaxations in this tissue were unaffected by this concentration of inhibitor. By contrast, acetylcholine relaxations in RA were virtually abolished by 10 microM L-NAME. In each case an equivalent concentration of D-NAME was without effect on agonist-induced relaxations. 3. The different effect of L-NAME on acetylcholine relaxations in RbJV and RA was not due to muscarinic receptor differences. Affinity estimates for acetylcholine (pKA = 6.12 +/- 0.09; 6.09 +/- 0.08 respectively) and for 4-diphenyl-acetoxy-N-methylpiperidine methobromide (4-DAMP, pKB = 9.01 +2- 0.012; 9.24 +/- 0.16 respectively) indicated that the receptors in both tissues belong to the same M3 class. Tissue differences resulting from the release of a cyclo-oxygenase product or a glibenclamide-sensitive K(+)-channel-linked hyperpolarizing factor were also ruled out by selective inhibition of these pathways. 4. When phenoxybenzamine was used to reduce the efficacy of acetylcholine in RbJV so that it behaved as a partial agonist in this tissue, L-NAME (10 microM) now produced non-surmountable inhibition of relaxation responses. In untreated tissues the same concentration of L-NAME also profoundly inhibited responses produced by butyrylcholine and pilocarpine, both of which behave as partial agonists at the M3 receptor in RbJV. 5. A simple model was developed which describes the theoretical behaviour of receptor-stimulated synthesis and release of NO. The model predicts that competitive inhibition of NO formation results in parallel displacements of the agonist response curve in the case of high efficacy agonist, but right-shift with concomitant depression of the curve maximum in the case of low efficacy agonists. Simulations based on the model showed reasonable agreement with the experimental data. 6. It is concluded that analogues of L-arginine demonstrate tissue- and agonist-dependence in terms of their ability to inhibit receptor-mediated events involving the liberation of NO. This behaviour can reflect differences in agonist efficacy in the receptor systems being studied, a possibility that should be ruled out before apparent resistance to inhibition is taken as evidence for the involvement of heterogeneous endothelium-derived relaxing factors (EDRFs).

Acetylcholine↗
PubMed1992

Classification of platelet and vascular prostaglandin D2 (DP) receptors: estimation of affinities and relative efficacies for a series of novel bicyclic ligands. With an appendix on goodness-of-fit analyses.

1. The DP receptors located on platelets and vasculature were examined in a human washed platelet preparation and in isolated rings of rabbit external jugular vein. 2. A series of eight novel bicyclic compounds were studied for their effects in the two assays. Seven produced agonism, inhibition of aggregation or vascular relaxation, and one compound was 'silent' in both assays. 3. The operational model of agonism (Black & Leff, 1983) was fitted simultaneously to concentration-effect curve data for the seven agonist compounds. The affinity and efficacy estimates so obtained were tested for similarity between the two tissues by analysis of variance, showing that the model could be fitted to both sets of data by assuming the same relative affinity and efficacy values. However, absolute affinity estimates were consistently lower in the vascular preparation. 4. Analysis of two of the seven agonists as antagonists was also possible. This provided pKB estimates which supported the agonist affinity estimates. The eighth compound was also analysed as an antagonist. It, like the other seven, demonstrated a difference in affinity between the two tissues. 5. The results of this study support the view that platelet and vascular DP receptors are similar, assuming that the systematic difference in affinity estimates for the series of compounds between the two tissues is the consequence of receptor micro-environment and/or accessory binding site differences.

Algorithms↗
PubMed1992

Intergenerational talk and communication with older people.

A program of research conducted within an anti-agism paradigm demonstrates that young people process and respond to the speech of older people in stereotypical ways. Such conclusions result from studies using a variety of research methods. Experimental studies demonstrate that older-sounding speech triggers age schematic responses and that young people tend to use agist strategies of information seeking and compliance gaining from older people, while interactive studies explore how stereotypes and age identities are co-produced by young and old people in conversation. We use lifespan and intercultural perspectives to argue that the communicative patterns we observe in our studies are in some senses and contexts counterproductive in both the long and short term, in that they can reproduce negative attitudes toward aging as well as inhibit successful aging.

Adult↗
PubMed1991

A comparative study of the prostanoid receptor profile of 9 alpha 11 beta-prostaglandin F2 and prostaglandin D2.

1. The aim of this study was to determine the receptor profile of 9 alpha 11 beta-prostaglandin F2 (PGF2) and compare it with that of its parent, prostaglandin D2 (PGD2). The experiments were designed to overcome the problems associated with the presence of multiple prostanoid receptor sub-types in most tissues; the lack of selective antagonists for each receptor means that conclusions regarding efficacy at FP and EP2 receptors must remain provisional. 2. At DP receptors in human platelets and rabbit jugular vein, PGD2 was a full agonist, p[A50] 7.02 +/- 0.09 and 6.60 +/- 0.12 respectively. 9 alpha 11 beta-PGF2 was approximately 30-60 fold less potent than PGD2. 3. 9 alpha 11 beta-PGF2 was a full agonist in the FP receptor containing preparation, cat iris sphincter (p [A50] 7.35 +/- 0.09) comparable in potency to PGD2 (p[A50] 7.15 +/- 0.19). Likewise the two prostanoids showed similar potency at the TP receptor in guinea-pig aorta (9 alpha 11 beta-PGF2 p[A50] 6.00 +/- 0.07; PGD2 6.24 +/- 0.08). 4. 9 alpha 11 beta-PGF2 and PGD2 had efficacy but low potency at EP1 receptors (guinea-pig oesophageal muscularis mucosa) and demonstrated 2000-3000 fold lower potency than PGE2 (p[A50] 8.35 +/- 0.09). Similarly, in the EP2 receptor-containing preparation, cat trachea, 9 alpha 11 beta-PGF2 was 3500 fold less potent and PGD2 700 fold less potent than PGE2 (p[A50] 8.06 +/- 0.26). 5. 9 alpha 11 beta-PGF2 and PGD2 (10 microM) were without affinity at the IP receptors on human platelets and had no agonist action in the EP3 receptor containing preparation, guinea-pig vas deferens. 6. 9 alpha 11 beta,-PGF2 is a major metabolite of PGD2 in vivo and this conversion clearly represents an inactivation step since 9 alpha 11 beta-PGF2 is of considerably lower potency than PGD2 at DP receptors. However, it is of similar potency to PGD2 at TP, FP, EP1 and EP2 receptors and it may, therefore, contribute to the biological effects which follow PGD2 administration or endogenous synthesis; its actions at these receptors are likely to be similar to those of PGD2 itself.

Animals↗
PubMed1991

Information-seeking triggered by age.

Age labels may lead to the seeking of age-stereotypic information from target individuals. Using Carver and de la Garza's information-seeking procedure (which asked respondents to judge the relative importance of various kinds of information they would glean from drivers involved in an automobile accident for assigning accident responsibility), but extending it to a wider life span (16 to 91 years of age) and to both genders, we generalized earlier findings to a similar undergraduate sample (n = 437) in another country. Also demonstrated for the first time is the fact that ageist information-seeking across the life span was independent of the driver's gender, the participant's age, and the participant's gender. Specifically, participants wanted to know from younger drivers about their driving conduct (whether they had been drunk and speeding), and from older drivers about their capacity for driving (mental competence, vision, and health). The seeking of environmental information (car safety and road conditions) did not vary with the age of driver in any systematic way.

Accidents, Traffic↗
PubMed1977

Intra-amniotic injection of thyroxine (T4Y to a human fetus. Evidence for conversion of T4 to reverse T3.

131I (150 mCi) was inadvertently given to a woman during week 10 to 11 of her gestation. When referred, fetal size was estimated at 31 to 32 weeks' gestation. Because of the potential risk of fetal hypothyroidism, an amniocentesis, with an injection of 500 mug of thyroxine, was performed weekly from week 33 until delivery. T4, T3, thyrodi-stimulating hormone (TSH), and rT3 were measured in amniotic fluid samples obtained at 33, 36, and 37 weeks. Maternal serum T4 was measured on the day of delivery. T4, T3, and TSH concentrations were measured in cord blood and during the neonatal period. The concentration of T4 in amniotic fluid (AF) was within the normal range at 32 weeks (prior to thyroxine); AF T3 and TSH were not detectable. The concentration of AF rT3 at 32 weeks also was normal (160 ng. per deciliter) and increased markedly after beginning intra-amniotic T4 injections; AF T4 increased modestly, but the AF T3 level remained unmeasurable. The concentration of T4 in cord serum obtained within 24 hours of the last amniotic fluid thyroxine injection, was in the hyperthyroid range and the TSH level was low. The cord serum T3 level was at the upper range of normal. The infant's serum T4 and T3 both increased during the first 24 hours. The male infant developed normally and serum T4 and TSH concentrations were normal at 4 months of age. The data indicate: (1) that T4 injected into AF is absorbed by the human fetus, (2) that AF rT3 concentration increases markedly after the AF T4 injection, whereas AF T3 levels do not increase, and (3) that the neonatal TSH surge is not entirely suppressed by hyperthyroid levels of cord serum T4.

Adult↗
PubMed1977

Detection of errors in methylmalonyl-CoA metabolism by using amniotic fluid.

We report a method for rapid prenatal detection of methylmalonic acidemia, consisting of measuring methylmalonly-CoA mutase (EC 5.4.99.2) activity in non-cultured amniotic cells and measuring the concentration of methylmalonate in the amniotic fluid. Immediate stabilization of the mutase activity in the non-cultured amniotic cell by its coenzyme adenosycobalamin, and use of methylmalonyl-CoA with high specific activity gives mutase activity comparable to that of cultured amniotic cells or normal fibroblasts. Consequently, findings of low mutase activity and a hight concentration of methylmalonate in the amniotic fluid allows accurate diagnosis of the vitamin B12-nonresponsive form of methylmalonic acidemia. These results can be obtained in two days. For the vitamin B12-responsive form, the correct diagnosis depends upon finding amniotic fluid methylmalonate, because cells from these patients will display normal methylmalony-CoA mutase activity after adenosylcobalamin is added. Problems in interpreting data on bloody samples and the limitations of the method are discussed.

Amniotic Fluid↗
PubMed1977

Development of sex-trait stereotypes among young children in the United Staes, England, and Ireland.

The Sex Stereotype Measure II (SSM II), a 32-item revision of the Williams, Bennett, and Best Sex Stereotype Measure, was developed to assess children's knowledge of conventional, sex-trait stereotypes defined by American university students. The procedure employed brief stories and human figure silhouettes which were individually administered to 5- and 8-year-old children in the United States, England, and Ireland and group administered to 11-year-olds in the United States. In the United States, knowledge of sex-trait stereotypes was found to develop in a linear fashion between the ages of 5 and 11, with more male traits than female traits being known at each age level. Cross-nationally, there was a high degree of similarity in the nature of the sex stereotypes being learned by the children in the 3 countries, although the rate of learning appeared slower among the Irish children. In all countries there was a clear progression in sex-stereotype learning from age 5 to age 8. English boys had greater knowledge of stereotypes than English girls, but this was not true in Ireland and the United States. Generally, knowledge of male stereotype traits appeared to develop earlier while knowledge of the female traits increased more rapidly between ages 5 and 8. The similarity in sex-stereotype learning in the 3 countries is discussed, and studies in progress in other countries of greater cultural diversity are noted.

Behavior↗
PubMed1976

A simple, rapid method for prenatal detection of defects in propionate metabolism.

Incorporation of radiolabel from propionate-1(-14)C into protein (TCA insoluble material) in fibroblasts or amniotic fluid cells, provides a rapid, simple means of detecting fetuses with inborn errors of propionate metabolism using small numbers of cells. Controls were easily differentiated from mutant lines over differing media pH conditions. This method was successfully used to diagnose correctly a normal fetus at risk for methylmalonic acidemia. This method can be used as an adjunct in diagnosis, but cannot replace direct enzyme analysis.

Amniotic Fluid↗
PubMed1975

Propionate metabolism in fetal livers of 15 to 19 weeks' gestation.

Extracts of hepatic tissue obtained from saline-induced abortuses were analyzed for methylmalonyl CoA carbonylmutase (MM) and propionyl CoA carboxylase (PC) activity. MM activity was similar to control values, which suggests that abortion material may be used to confirm the prenatal diagnosis of methylmalonic acidemia. Confirmation of a presumptive propionic acidemia diagnosis is more tenuous due to the instability of PC and the possibility that saline may induce PC activity.

Abortion, Induced↗