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Biomedical subjects

A M Thompson

Publications and source records attributed to A M Thompson.

At least 91 records · Page 5Linked to original sources
PubMed1994

Inhibition of antigen-induced contraction of guinea-pig airways by a leukotriene synthesis inhibitor, BAY x1005.

BAY x1005 ((R)-2-[4-quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid), an inhibitor of leukotriene synthesis, was evaluated, both in vitro and in vivo, for inhibition of antigen-induced airway contraction in the sensitised guinea-pig. Antigen (ovalbumin 0.001-10 micrograms/ml) challenge of tracheae in the presence of pyrilamine and indomethacin induced contractile responses which were inhibited by BAY x1005 with an IC50 value of 0.36 (0.2-0.8) microM. Using the same test system BAY x1005 (1 microM), ICI D2138 (0.3 microM) or AA 861 (1 microM) had similar inhibitory activities, whereas MK 886, MK 591, and Zileuton (A64077) all tested at 1 microM and REV 5901 (10 microM) had no significant effect. Using tracheae from non-sensitised (control) guinea-pigs the calcium ionophore A23187 (1 microM) induced a maximal contraction which was significantly inhibited by BAY x1005 at 1 microM, whereas MK 886 was only active at 3 microM. BAY x1005 tested at 10 microM and 3 microM had no effect against leukotriene D4- or KCl-induced contractions of guinea-pig tracheae respectively. In the anaesthetised ovalbumin sensitised guinea-pig BAY x1005 caused a dose-related inhibition of ovalbumin-induced bronchoconstriction, with approximate ID50 values of 0.85 mg/kg i.v. and 6.3 mg/kg p.o. In the same model MK 886, MK 591, AA 861 and ICI D2138 each given at 10 mg/kg p.o. had no significant inhibitory activity against antigen challenge. Six hours after administration BAY x1005 (10 mg/kg p.o.) was still effective against the antigen-induced response.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Lipoxygenase-Activating Proteins↗
PubMed1994

Tyrosine kinase inhibitors. 2. Synthesis of 2,2'-dithiobis(1H-indole-3-alkanamides) and investigation of their inhibitory activity against epidermal growth factor receptor and pp60v-src protein tyrosine kinases.

A series of amide analogues of the 2,2'-dithiobis(1H-indole-3-alkaonic acid) class of tyrosine kinase inhibitors have been prepared, by reaction of 1H-indole-3-alkanamides (8) with S2Cl2, and separation of the desired disulfides from the initial mixtures of mono-, di-, and trisulfides formed. These amides were evaluated in vitro against epidermal growth factor receptor and pp60v-src protein tyrosine kinases. Inhibitory activity against EGF receptor tyrosine kinase was chain-length dependent, with the propanamides being the most effective. Hydrogen bond donor capabilities in the amide function did not appear to be necessary, with an N-benzylamide being the most potent (IC50 = 0.85 microM). Further substitution on the benzyl ring did not increase potency, and substitution in the alpha-position of the propanamide side chain was acceptable. A water-soluble alpha-NH2 derivative showed good inhibitory activity toward the enzyme, was a potent inhibitor of cell growth in fibroblasts, and selectively inhibited intracellular tyrosine phosphorylation patterns. The nonreceptor kinase pp60v-src was in general much more sensitive than EGF receptor kinase to inhibition by these compounds, but with less pronounced structure-activity relationships.

3T3 Cells↗
PubMed1994

Expression of transforming growth factor beta mRNA isoforms in human breast cancer.

Using an RNAse protection assay, expression of messenger RNA for isoforms of TGF-beta was determined in a series of breast cancers. Of 50 tumours, 45 (90%) expressed TGF-beta 1 mRNA, 39 (78%) expressed TGF-beta 2, and 47 (94%) expressed TGF-beta 3. Patterns of expression varied between different tumours: 37 (74%) cancers expressed all three TGF-beta isoforms, ten (20%) expressed only two isoforms and two expressed TGF-beta 1 alone. One sample showed no evidence of TGF-beta mRNA expression. Although most breast cancers expressed mRNA for at least one isoform of TGF-beta, there were differences in patterns of mRNA expression between individual tumours. The relatively small number of tumours examined precluded detailed analysis between expression and other clinical parameters, but a significant association was identified between one aspect of isoform expression and lymph node status, in that the majority of tumours expressing all three isoforms were associated with lymph node involvement, whereas tumours without one or more isoform were usually lymph node negative (P = 0.025 by Fisher's exact test).

Adult↗
PubMed1994

Critical determination of the frequency of c-erbB-2 amplification in breast cancer.

Tissues from 323 methacarn-fixed and paraffin-embedded breast cancers were assessed for c-erbB-2 gene amplification by differential polymerase chain reaction (dPCR). The sensitivity of dPCR was ascertained using cell lines with c-erbB-2 amplification, and the relationship between dPCR ratio value and gene copy number was established. In clinical material the technique was not affected by the DNA contribution of normal tissue elements or by cancer DNA ploidy change. c-erbB-2 gene amplification was detected in 55% of invasive cancers and in 66% of in situ cancers. c-erbB-2 protein overexpression in breast cancer cells, as determined by specific immunohistochemistry, was only detected in 11% of invasive cancers and 43% of in situ cancers. Comparisons show that a substantial number of cancers with c-erbB-2 amplification lack detectable protein overexpression. This illustrates the complex nature of c-erbB-2 gene disregulation in cancer and suggests that multiple combinations of biological events and consequences are possible.

Aged↗
PubMed1994

Serotonin and serotonin receptors in the central auditory system.

Immunohistochemical and ligand-binding techniques were used to visualize the neurotransmitter serotonin and one of its receptors, the 5-HT1A subtype, in auditory nuclei of the brainstem. Serotonergic fibers and terminal endings were found in all auditory nuclei extending from the cochlear nucleus to the inferior colliculus, including the superior olivary complex and the nuclei of the lateral lemniscus. The density of the innervation varied between and within each nucleus. All serotonergic cell bodies were located outside the auditory nuclei. The 5-HT1A receptor subtype was found in the cochlear nucleus as well as in the inferior colliculus. With no serotonergic cell bodies present in the auditory nuclei, the present neuroanatomic and neurochemical findings support behavioral and neurophysiologic findings that the serotonergic system may modulate central auditory processing.

Animals↗
PubMed1993

Relationship of descending inferior colliculus projections to olivocochlear neurons.

With the objective of defining the relationship of descending inferior colliculus projections to the olivocochlear system in the guinea pig, inferior colliculus neurons were anterogradely labeled with Phaseolus vulgaris-leucoagglutinin and olivocochlear neurons were retrogradely labeled with horseradish peroxidase in the same brain sections. Inferior colliculus neurons were found to project to many nuclei and regions of the hindbrain where olivocochlear neurons reside. The most substantial of these descending projections was to the ipsilateral medioventral periolivary region. Fewer descending projections terminated in the ipsilateral ventral nucleus of the lateral lemniscus, superior paraolivary nucleus, and rostral periolivary region; and even fewer ipsilateral projections terminated in the area surrounding the lateral superior olive, caudal periolivary region, and the lateroventral periolivary region. Descending neurons of the inferior colliculus also project to the contralateral hindbrain first via the lateral lemniscus and then the trapezoid body, to terminate in the contralateral medioventral periolivary region, superior paraolivary nucleus, rostral periolivary region, and the ventral nucleus of the lateral lemniscus. In addition to the projections into these regions that contain olivocochlear neurons, there are varicosities of inferior colliculus neurons that appear to contact the olivocochlear neurons themselves, both ipsilaterally and contralaterally, especially, but not only, in the ipsilateral medioventral periolivary region. We therefore conclude that descending inferior colliculus neurons do provide input to olivocochlear neurons and that the input is not limited to olivocochlear neurons of the ipsilateral medioventral periolivary region. However, given the robust nature of the projection to the ipsilateral medioventral periolivary region and the paucity of contacts observed in that region, we also conclude that the olivocochlear neuron is not the major target of descending inferior colliculus projections.

Animals↗
PubMed1993

Tyrosine kinase inhibitors. 1. Structure-activity relationships for inhibition of epidermal growth factor receptor tyrosine kinase activity by 2,3-dihydro-2-thioxo-1H-indole-3-alkanoic acids and 2,2'-dithiobis(1H-indole-3-alkanoic acids).

A series of 2,3-dihydro-2-thioxo-1H-indole-3-alkanoic acids, and their methyl esters were prepared, the majority by oxidation of 1H-indole-3-alkanoic acids (DMSO/HCl), followed by thiation of the corresponding 2,3-dihydro-2-oxo-1H-indole-3-alkanoic acid esters. The monomeric thiones undergo facile and reversible oxidation to the corresponding 2,2'-dithiobis(1H-indole-3-alkanoic acids). The compounds were evaluated for their abilities to inhibit the tyrosine kinase activity of the epidermal growth factor receptor using a native complex contained in plasma membrane vesicles shed from cultured A431 cells, and to inhibit the growth of Swiss 3T3 mouse fibroblast in culture. Enzyme inhibitory activity is dependent on the length of the side chain, with propanoic acid derivatives showing the highest activity. The acids are generally significantly more potent than the corresponding esters, and the disulfides more active than the corresponding monomers. An ability to undergo the thione-thiol tautomerism necessary for dimerization is essential, with 3,3-disubstituted compounds being inactive. Overall, the data suggest that the disulfide is the more active form, with much of the activity of the monomeric thiones being due to varying degrees of conversion to the disulfide during the assay. In the growth inhibition assay, the methyl esters are more potent than their corresponding carboxylic acids, and the dimers are generally more potent than the monomers. The data show these compounds to be a novel and potent class of inhibitors of epidermal growth factor receptor tyrosine kinase activity.

Animals↗
PubMed1993

Allelic loss on a chromosome 17 in ductal carcinoma in situ of the breast.

Multiple tumor suppressor genes are implicated in the oncogenesis and progression of invasive carcinoma of the breast. To investigate the chronology of genetic changes we studied loss of heterozygosity on chromosome 17 in ductal carcinoma in situ, a preinvasive breast cancer. A microdissection technique was used to separate tumor from normal stromal cells prior to DNA extraction and loss of heterozygosity was assayed mainly using simple sequence repeat polymorphism markers and the polymerase chain reaction. Loss of heterozygosity on 17p was observed in 8 of 28 tumors (29%) when compared with normal control DNA, whereas no loss was seen on 17q, suggesting that at least one locus on 17p is involved early in the development of breast cancer.

Alleles↗
PubMed1993

Rural emergency medical volunteers and their communities: a demographic comparison.

This research compares the personal, household, and professional characteristics volunteer emergency medical service (EMS) providers in Ulster County, NY with those of the general population of this rural upstate county, using a survey instrument implemented by the author in conjunction with the 1990 U.S. Census data. A principal objective of this research was to identify the characteristics of these volunteers in order to support the recruitment and retention efforts of volunteer EMS organizations. Statistically significant deviations between these two sample populations include age distribution, maximum educational attainment, size of household, years in residence, type of employer, employing industry, occupation, household income, and commuting distance from work. Population differences for race, sex, marital status, household site, home ownership, housing costs, and in-county employment were not statistically significant. Additional data reported for the EMS volunteers include total emergency responses, active squad membership, length of service, level of medical qualifications, and intensity and nature of individual participation, age of recruitment, family involvement, tenure in the community, rates of household work participation, other volunteer activity, motivation, and receptivity to alternative incentive programs. The relevance of these data is interpreted with respect to the prospects for effective recruitment of volunteers, the level of commitment and retention of the volunteers, the degree of support which volunteers can expect from their communities, and the extent of cohesiveness and integration which volunteer EMS squads provide to their communities.

Adult↗
PubMed1993

A prospective study of the development of laterality: neonatal laterality in relation to perinatal factors and maternal behavior.

As part of an investigation of the development of laterality, 150 neonates were tested for bilateral asymmetries in behavior. Palmar and plantar grasping, and head-turning preference were measured, and observations were made of the way mothers held their babies and laid them in their cribs. Overall, right head-turning predominated. However, the side on which the baby had been lain pre-test markedly affected head-turning behavior: 120 of 147 babies turned predominantly to the right after lying on the right, whereas only 75 did so after lying on their left side (p < .001). There was no predominant asymmetry in the population in palmar or plantar grasping. These findings are explored in relation to perinatal factors and maternal behavior.

Female↗
PubMed1993

Allele loss from 5q21 (APC/MCC) and 18q21 (DCC) and DCC mRNA expression in breast cancer.

Thirty-four primary, untreated sporadic breast cancers were examined for loss of heterozygosity (LOH) at tumour suppressor loci involved in colorectal cancer: APC/MCC at 5q21 and DCC at 18q21. LOH was identified in 28% informative patients at 5q21 and 31% at 18q21. LOH at 5q21 and 18q21 was compared with allele loss at 17p13 and concurrent LOH at two or more of the loci was noted in 24% of tumours. Expression of a 12 kb DCC mRNA was demonstrated in 14/34 (42%) of the cancers and in all five tumours with LOH at the DCC locus there was an additional 11 kb DCC mRNA. Abnormalities of three loci involved in colorectal cancer (5q21, 17p13 and 18q21) therefore also occur in sporadic breast cancer. The accumulation of such genetic abnormalities may confer a growth advantage important in the development of breast cancer.

Alleles↗
PubMed1993

pS2 is an independent factor of good prognosis in primary breast cancer.

In breast cancer, oestrogen regulated genes, such as pS2, may be expressed in well differentiated tumours with a good prognosis. We have examined pS2 mRNA expression in 78 primary, untreated breast cancers and related pS2 expression to disease behaviour and known prognostic factors. pS2 mRNA expression was detected in 25/78 (32%) of cancers and was significantly associated with a moderate/high oestrogen receptor content (P = 0.045, Chi Square test). pS2 mRNA expression was associated with freedom from disease at median 31 months clinical and radiological follow-up (P = 0.015, Fisher's exact test, odds ratio 8.6). Using multiple logistic regression analysis of six potential prognostic factors only pathological axillary node status (P < 0.01) and pS2 mRNA expression (P < 0.05) provided independent prognostic information. Furthermore, pS2 was associated with a good prognosis in the axillary node positive patients where only 1/13 (8%) with pS2 mRNA expression compared with 13/29 (45%) without detectable expression had recurrence of their disease. These data provides strong support for pS2 as a useful independent prognostic factor in primary breast cancer.

Adult↗
PubMed1993

Issues in the consumer choice of health care coverage plans.

Developing and implementing successful marketing strategies for prepaid health care coverage plans is becoming an important issue as managers of these plans struggle to remain competitive in the market place. This paper provides insight into the reasons why consumers make choices among varying types of health care coverage plans. Some suggestions are made to plan managers for incorporating these results into the development of marketing strategies for prepaid health care coverage plans.

Arkansas↗
PubMed1992

The oxidizing capacity of the earth's atmosphere: probable past and future changes.

The principal oxidants in the lower atmosphere are ozone (O3) and two by-products of O3 photodissociation, the hydroxyl radical (OH) and hydrogen peroxide (H2O2). A number of critical atmospheric chemical problems depend on the earth's "oxidizing capacity," which is essentially the global burden of these oxidants. There is limited direct evidence for changes in the earth's oxidizing capacity since recent preindustrial times when, because of industrial and population growth, increasing amounts of O3 precursor trace gases (carbon monoxide, nitrogen oxides, and hydrocarbons) have been released into the atmosphere. The concentrations of O3 and possibly H2O2 have increased over large regions. Models predict that tropospheric O3 will increase approximately 0.3 to 1% per year over the next 50 years with both positive and negative trends possible for OH and H2O2. Models and the observational network for oxidants are improving, but validation of global models is still at an early stage.

Atmosphere↗