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Biomedical subjects

J C Cooper

Publications and source records attributed to J C Cooper.

At least 19 recordsLinked to original sources
PubMed1996

Pharmacology of the nicotinic acetylcholine receptor from fetal rat muscle expressed in Xenopus oocytes.

The fetal rat muscle nicotinic acetylcholine receptor was expressed in Xenopus oocytes. Using the voltage-clamp technique, the response to a range of agonists was measured, listed in order of (decreasing) activity efficacy: anatoxin > or = epibatidine > acetylcholine > DMPP (1,1-dimethyl-4-phenylpiperazinium) > > cytisine > pyrantel > nicotine > coniine > tubocurare > lobeline. The agonist responses were compared with the steric and electrostatic properties of the molecules, using molecular modelling. Single-channel current were measured in outside-out patches for acetylcholine, nicotine, cytisine, anatoxin and epibatidine. The conductance of the single channels was independent of the type of agonist. The mean open times were characteristic of the agonist applied. Tubocurare, better known for its antagonist properties, was also a partial agonist. Single-channel currents were also observed for tubocurare, and for methyllycaconitine in patches with a very high density of the muscle nicotinic acetylcholine receptor, and these were blocked by alpha-bungarotoxin. The agonist properties of physostigmine, galanthamine and their methyl derivatives were also investigated. The conductance of the channels observed in outside-out patches was similar to that obtained for the classical agonists. The single-channel currents observed for physostigmine, galanthamine and their methyl derivatives were blocked by alpha-bungarotoxin, methyllycaconitine and mecamylamine, in contrast to previously reported studies on neuronal and adult muscle nicotinic acetylcholine receptors.

Acetylcholine↗
PubMed1996

Expression of prostacyclin and thromboxane synthases in placenta and placental bed after pre-eclamptic pregnancies.

Prostacyclin and thromboxane are potent antagonistic regulators of vascular tone and platelet aggregation. In pre-eclampsia, the ratio of their metabolites is decreased. Little is known about the local regulation of intrauterine prostacyclin and thromboxane production in this condition. Placenta and placental bed biopsies were obtained from uncomplicated and pre-eclamptic pregnancies. Prostacyclin synthase (PCS) and thromboxane synthase (TXS) and their mRNA's were localized by immunohistochemistry using monoclonal antibodies and in situ hybridization. Protein and mRNA levels were quantified by immunoblot and RNase protection assay. PCS-like immunoreactivity was found in endothelial cells and leiomyocytes, whereas fetal and maternal macrophages showed positive staining for TXS. Their mRNA was localized to trophoblast and endothelium, and TXS mRNA could also be detected in macrophages. Quantitative analysis showed no significant difference in intrauterine protein or mRNA expression after pre-eclampsia. The prostacyclin and thromboxane production seems to be compartmentalized within the uteroplacental unit. The expression of their synthesizing enzymes might be regulated post-transcriptionally. Additional regulation of prostaglandin production could be metabolically or on the substrate level and requires further elucidation.

Adult↗
PubMed1996

Maternal plasma levels of vascular endothelial growth factor in normotensive pregnancies and in pregnancies complicated by pre-eclampsia.

We have measured the level of vascular endothelial growth factor (VEGF) in maternal plasma during normotensive pregnancy and in pregnancies complicated by pre-eclampsia. VEGF was measured using a competitive enzyme immunoassay. Plasma VEGF was significantly elevated (P < 0.0001) in the pre-eclamptic group (median value 32.7 ng mL-1, range 10.3-64.0), compared with the normotensive group (median value 11.7 ng mL-1, range 6.3-24.3). VEGF is a potent regulator of endothelial cell function. The increased level found in women with pre-eclampsia indicates that VEGF may be involved in the maternal endothelial cell dysfunction associated with this condition. An increase in VEGF, a potent regulator of microvascular permeability, may also contribute to the extravasation of plasma proteins and the subsequent development of proteinuria, both characteristic features of pre-eclampsia.

Adolescent↗
PubMed1996

VEGF mRNA levels in placentae from pregnancies complicated by pre-eclampsia.

OBJECTIVE: To measure the mRNA levels of vascular endothelial growth factor and its receptor in the placenta following delivery after uncomplicated pregnancy and after pregnancies complicated by pre-eclampsia. SETTING: Rosie Maternity Hospital, Cambridge. MATERIAL: Placental biopsies were obtained following delivery by caesarean section in 23 cases of pregnancy presenting at a range of gestational ages with pre-eclampsia. These were compared with biopsies from 20 appropriately matched women with uncomplicated pregnancies. MAIN OUTCOME MEASURE: mRNA levels of vascular endothelial growth factor (VEGF) and its receptor the fins-like tyrosine kinase (flt), were quantified in total RNA isolated from placental biopsies using the RNAse protection assay. The amount of RNA was compared with that of the housekeeping gene glyceraldehyde 3-phosphate dehydrogenase (GAPDH), used as a standard. Results were expressed as arbitrary optical density units of VEGF/GAPDH and flt/GAPDH. RESULTS: In both control and pre-eclamptic women regression analysis showed that the level of mRNA encoding VEGF declined significantly with gestational age (P < 0.0001). However, levels of VEGF mRNA were significantly lower in the pre-eclamptic women compared with the control women (P < 0.023). CONCLUSIONS: This study provides evidence of an abnormality of growth factor expression in the placenta during pregnancies complicated by pre-eclampsia. Such placentae exhibit deficient growth and differentiation of terminal villi and reduced fetal capillary branching and reduced levels of VEGF could well account for these morphometric changes. This finding provides a molecular explanation for this abnormal placental development and points to VEGF as a factor in the aetiology of pre-eclampsia and its complications.

Adolescent↗
PubMed1995

Physostigmine, galanthamine and codeine act as 'noncompetitive nicotinic receptor agonists' on clonal rat pheochromocytoma cells.

The acetylcholine esterase inhibitor (-)-physostigmine has been shown to act as agonist on nicotinic acetylcholine receptors from muscle and brain, by binding to sites on the alpha-polypeptide that are distinct from those for the natural transmitter acetylcholine (Schröder et al., 1994). In the present report we show that (-)-physostigmine, galanthamine, and the morphine derivative codeine activate single-channel currents in outside-out patches excised from clonal rat pheochromocytoma (PC12) cells. Although several lines of evidence demonstrate that the three alkaloids act on the same channels as acetylcholine, the competitive nicotinic antagonist methyllycaconitine only inhibited channel activation by acetylcholine but not by (-)-physostigmine, galanthamine or codeine. In contrast, the monoclonal antibody FK1, which competitively inhibits (-)-physostigmine binding to nicotinic acetylcholine receptors, did not affect channel activation by acetylcholine but inhibited activation by (-)-physostigmine, galanthamine and codeine. The three alkaloids therefore act via binding sites distinct from those for acetylcholine, in a 'noncompetitive' fashion. The potency of (-)-physostigmine and related compounds to act as a noncompetitive agonist is unrelated to the level of acetylcholine esterase inhibition induced by these drugs. (-)-Physostigmine, galanthamine and codeine do not evoke sizable whole-cell currents, which is due to the combined effects of low open-channel probability, slow onset and slow inactivation of response. In contrast, they sensitize PC12 cell nicotinic receptors in their submaximal response to acetylcholine. While the abundance of nicotinic acetylcholine receptor isoforms expressed in PC12 cells excludes identification of specific nicotinic acetylcholine receptor subtypes that interact with noncompetitive agonists, the identical patterns of single-channel current amplitudes observed with acetylcholine and with noncompetitive agonists suggested that all PC12 cell nicotinic acetylcholine receptor subtypes that respond to acetylcholine also respond to noncompetitive agonist. The action of noncompetitive agonists therefore seems to be highly conserved between nicotinic acetylcholine receptor subtypes, in agreement with the high level of structural conservation in the sequence region harboring major elements of this site.

Acetylcholine↗
PubMed1995

Localization of vascular endothelial growth factor and its receptor, flt, in human placenta and decidua by immunohistochemistry.

Vascular endothelial growth factor is a secreted angiogenic growth factor the mRNA of which is present in the placenta. The mRNA encoding the vascular endothelial growth factor receptor, flt, has also been demonstrated in placenta, with trophoblast appearing to be a novel site of flt expression. We investigated the expression of both vascular endothelial growth factor and flt-like immunoreactivity in first trimester and term placentae. In the first trimester, vascular endothelial growth factor immunoreactivity was localized to placental macrophages (Hofbauer cells), and in decidua, to glandular epithelium and maternal macrophages. In the term placenta, vascular endothelial growth factor immunoreactivity was present in extravillous trophoblast and in extracellular material. Flt immunoreactivity was demonstrated on extravillous trophoblast in first trimester and term, and on Hofbauer cells within placental villi. This complex pattern of both vascular endothelial growth factor and flt-like immunoreactivity suggests that vascular endothelial growth factor may be involved not only in the regulation of placental angiogenesis, but also in trophoblast invasion.

Decidua↗
PubMed1995

Growth factors in pregnancy.

The role of growth factors in pregnancy is a rapidly expanding subject. With the advent of molecular biological techniques more and more detailed information is available to the researcher. This review does not attempt to be exhaustive in its coverage of growth factors in pregnancy, rather it tries to give a brief taste of the possible roles that they may play in pregnancy by considering three specific factors, leukaemia inhibitory factor, colony stimulating factor-1 and vascular endothelial growth factor.

Animals↗
PubMed1994

Structural studies on porphobilinogen deaminase.

The X-ray crystallographic analysis of porphobilinogen deaminase (hydroxymethylbilane synthase, EC 4.3.1.8) shows the polypeptide chain folded into three domains, (1) N-terminal, (2) central and (3) C-terminal, of approximately equal size. Domains 1 and 2 have a similar overall topology, a modified doubly wound parallel beta-sheet. Domain 3 is an open-faced three-stranded antiparallel beta-sheet, with one face covered by three alpha-helices. The active site is located between domains 1 and 2. The dipyrromethane cofactor linked to cysteine 242 protrudes from domain 3 into the mouth of the cleft. Flexible segments between domains 1 and 2 are thought to have a role in a hinge mechanism, facilitating conformational changes. The cleft is lined with positively charged, highly conserved, arginine residues which form ion pairs with the acidic side chains of the cofactor. Aspartic acid 84 has been identified as a critical catalytic residue both by its proximity to the cofactor pyrrole ring nitrogen and by structural and kinetic studies of the Asp-84-->Glu mutant protein. The active site arginine residues have been altered by site-directed mutagenesis to histidine residues. The mutant proteins have been studied crystallographically in order to reconcile the functional changes in the polymerization reaction with structural changes in the enzyme.

Crystallography, X-Ray↗
PubMed1994

Health and Nutrition Examination Survey of 1971-75: Part I. Ear and race effects in hearing.

The Health and Nutrition Examination Survey of 1971-75 contains unique hearing data because its design permits generalization to noninstitutionalized civilians in the continental United States. Air-conduction thresholds and their relationships to age, ear, gender, frequency, and race were examined in unscreened 25- to 74-year-olds. Although the observed effects of age, gender, and frequency were expected, three aspects of the results were remarkable. First, there was support for previous observations that older females have poorer low-frequency hearing. Second, there was an ear effect among white males who had poorer 2 and 4 kHz mean thresholds on the left at all ages. Third, there was a pattern of poorer mean thresholds for blacks that was particularly evident in comparisons between black and white females.

Adult↗
PubMed1994

Health and Nutrition Examination Survey of 1971-75: Part II. Tinnitus, subjective hearing loss, and well-being.

The Health and Nutrition Examination Survey of 1971-75 contains valuable information because it provides unbiased estimates of the state of hearing in the general population. Here, three facets of the subjective aspects of hearing loss are examined: frequent and bothersome tinnitus, ratings of hearing, and general well-being. The period prevalence of frequent, bothersome tinnitus varied with race and gender (13 to 17%) with higher rates among blacks and females. The mean air-conduction thresholds (0.5 to 4 kHz) of those reporting frequent and bothersome tinnitus did not exceed 32 dB HL. Mean audiograms associated with those who rated both ears good, fair, poor, or deaf were significantly different from each other. Mean poorer ear audiograms for those rating one ear as good were significantly better than those for comparable symmetrical ratings. Last, there was no clear, consistent relationship between audiometric thresholds and measures of well-being.

Acoustic Stimulation↗
PubMed1992

Otologic complaints in temporomandibular joint syndrome.

Complaints of diminished hearing or reduced speech discrimination frequently accompany temporomandibular dysfunction. There is no consensus as to the mechanism of their occurrence or the alteration of these symptoms with the treatment. We studied 12 subjects with internal derangement of the temporomandibular joint (treated surgically) and nine subjects with myofascial pain disorder (treated medically), and we found no difference between the groups in pretreatment audiometric findings or in their degree of otologic symptoms. Similarly, there were no differences in posttreatment audiometric measures and there were no significant treatment effects. Furthermore, there was no correlation between subjects' complaints of reduced hearing sensitivity or discrimination and audiometric results. The apparently significant reduction in symptoms experienced by some subjects in the absence of audiometric change suggests the operation of unmeasured factors in their response to treatment.

Adolescent↗