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Biomedical subjects

A McCarthy

Publications and source records attributed to A McCarthy.

At least 55 records · Page 3Linked to original sources
PubMed1995

Nitric oxide synthase in human placenta and umbilical cord from normal, intrauterine growth-retarded and pre-eclamptic pregnancies.

1. It has been suggested that a deficiency of nitric oxide (NO) may explain many of the pathophysiological features of pre-eclampsia (PE) and intra-uterine (foetal) growth retardation (IUGR). To elucidate further the role of NO in the pathophysiology of pregnancy we have determined the relative amount and activity of NO synthase (NOS) in first trimester and normal-term placental tissues, as well as in the placenta and umbilical cord in pregnancies complicated by PE and IUGR, using NG-nitro-L-[2,3,4,5(-3)H]-arginine ([3H]-L-NOARG) binding, quantitative in vitro autoradiography, [3H]-arginine to [3H]-citrulline conversion and Western blotting. 2. Specific, high affinity (KD = 38 nM) [3H]-L-NOARG binding was demonstrated in the villous trophoblast of normal-term placentae. Binding was calcium-independent, stereoselective and exhibited a rank order of inhibition by NOS inhibitors and substrate (L-NOARG > or = L-NMMA > or = 7-NI > L-NAME > L-Arg > or = L-NIO > ADMA). 3. [3H]-L-NOARG binding density and NOS activity were both significantly greater in placental tissues from first trimester and PE or IUGR complicated pregnancies compared to normal-term placentae. 4. Western blotting, using an endothelial NOS peptide antiserum, demonstrated a approximately 140 KDa protein band in placental extracts and indicated that the amount of immunoreactive material was significantly greater in first trimester compared to normal-term placentae. 5. Specific [3H]-L-NOARG binding was also localized to the endothelial lining of umbilical arteries and veins, binding density being greater in the artery than the vein. [3H]-L-NOARG binding to the umbilical artery endothelium was significantly lower in PE and IUGR complicated pregnancies compared to normal-term controls. 6. The role of trophoblast-derived NO in human placental pathophysiology remains to be established, but differences in the amount of placental [3H]-L-NOARG binding, NOS activity and immunoreactive material indicate that expression of NOS in the villous trophoblast falls during pregnancy. Conversely, the apparent reduction in NOS in the umbilical artery endothelium in PE and IUGR complicated pregnancies may be indicative of endothelial dysfunction.

Adult↗
PubMed1994

Chromosomal localization of human genes for arylamine N-acetyltransferase.

Arylamine N-acetyltransferase is encoded at two loci, AAC-1 and AAC-2, on human chromosome 8. The products of the two loci are able to catalyse N-acetylation of arylamine carcinogens, such as benzidine and other xenobiotics. AAC-2 is polymorphic and individuals carrying the slow-acetylator phenotype are more susceptible to benzidine-induced bladder cancer. We have identified yeast artificial chromosome clones encoding AAC-1 and AAC-2 and have used the cloned DNAs as fluorescent probes for in situ hybridization. The hybridization patterns allow assignment of AAC-1 and AAC-2 to chromosome 8p21.3-23.1, a region in which deletions have been associated with bladder cancer [Knowles, Shaw and Proctor (1993) Oncogene 8, 1357-1364].

Arylamine N-Acetyltransferase↗
PubMed1994

Endothelial nitric oxide synthase in the human placenta: regional distribution and proposed regulatory role at the feto-maternal interface.

Feto-placental vessels lack innervation, hence control of this circulation is dependent on locally produced and circulating vasoactive factors. Functional studies have presented evidence that nitric oxide, a potent vasodilator and platelet anti-aggregating agent, may be generated into the feto-placental circulation, contributing to control of vascular tone. In view of the absence of nerves supplying the placenta the source of NO is likely to be endothelial. We have therefore investigated the localization of endothelial constitutive nitric oxide synthase (ecNOS) in human normal full-term placentae, using immunocytochemistry, with rabbit antiserum to a synthetic peptide, corresponding to amino acid residues 1172-1186 of human and bovine ecNOS. On Western blots of partially purified NO synthase extracted from placenta, the peptide antiserum reacted exclusively with a single protein band of approximately 135kDA. Immunoreactivity in tissue sections was localized to endothelium of umbilical artery and vein, and appeared uniform in sections at different levels along the cord. Staining in chorionic vessels was much more variable; it was present mainly in the larger vessels close to the cord where it had a patchy distribution. Staining was not seen in the endothelium of small feto-placental vessels. Strong immunoreactivity was evident in the syncytiotrophoblast of the placenta, although the intensity of staining was variable, being weaker along stem villi and strongest along terminal villi. The differential distribution and intensity of nitric oxide synthase immunoreactivity in the human placenta might indicate that locally produced, and in particular trophoblast-derived nitric oxide may play a pivotal role both in control of feto-placental vascular tone and as a platelet anti-aggregating agent in the utero-placental circulation.

Amino Acid Oxidoreductases↗
PubMed1994

The Ward Daily Behaviour Scale.

BACKGROUND: The Ward Daily Behaviour Scale is a new rating instrument that can be used to measure all the daily noteworthy behaviour of patients of various ages and diagnoses on psychiatric wards. METHOD: The reliability and validity of the scale were tested on 40 patients. RESULTS: This instrument proved to be both reliable and valid for use on adult acute in-patient wards. CONCLUSIONS: The scale will be a valuable tool in a wide range of ward-based studies.

Activities of Daily Living↗
PubMed1994

Angiotensin II (AT1) vascular binding sites in human placentae from normal-term, preeclamptic and growth retarded pregnancies.

Angiotensin II (ANG II) is a potent vasoconstrictor in isolated human placental cotyledons and may contribute to the regulation of fetoplacental perfusion. We have used quantitative in vitro receptor autoradiography to examine antagonist ((Sar1,Ile8)-[125I]ANG II) and agonist ligand ([125I]ANG II) binding sites in normal-term, preeclamptic and fetal (intrauterine) growth retarded pregnancies. A similar distribution of binding sites was demonstrated using both ligands, localized to blood vessels in placental villi. Binding density was inversely related to vessel size, being significantly greater on microvessels in distal regions of the villous tree than on proximal vessels in main stem villi. Binding sites exhibited the characteristics of the AT1 class of ANG II receptor, ligand binding being sensitive to dithiothreitol, completely inhibited by nonpeptide AT1 antagonists (Losartan, EXP3174 and SKF108566) and not inhibited by the AT2 antagonist (PD123319). Guanine nucleotides also inhibited [125I]ANG II binding and abolished the high affinity component of agonist inhibition of (Ser1,Ile8)-[125I]ANG II binding, indicating G protein coupling. The capacity and affinity of the binding sites were significantly lower in placentae from pregnancies complicated by preeclampsia and intrauterine growth retardation compared to that in normal-term controls. These differences were apparently not due to prior receptor occupancy by endogenous ligand, but may reflect activation of the placental renin-angiotensin system and receptor down-regulation. Locally generated ANG II, acting via AT1 receptors, may contribute to the regulation of fetoplacental blood flow and influence placental perfusion in preeclamptic and growth retarded pregnancies.

Angiotensin II↗
PubMed1993

Determination of lipid hydroperoxides in native low-density lipoprotein by a chemiluminescent flow-injection assay.

Lipid hydroperoxides have been implicated in the pathogenesis of atherosclerosis. This work was therefore set up to obtain a fast and specific chemiluminescent assay for measuring hydroperoxides in native low-density lipoprotein (LDL). The apparatus was a complete HPLC system including two pumps, an autosampler, a computer and a chemiluminescent detector with a T-mixing coil in the place of the column. Samples were injected from the autosampler and mixed with luminescent reagent (3 microM luminol and 1 microM microperoxidase in 0.1 M carbonate buffer (pH 10)) in the T-piece. To generate a calibration curve, linoleic acid hydroperoxide was obtained by incubating soybean lipoxygenase with linoleic acid. The calculated conjugated diene concentration was in good agreement with the nominal linoleic acid hydroperoxide concentration. The chemiluminescence was linear with the amount of linoleic acid hydroperoxide injected and the detection limit was about 3 pmol linoleic acid hydroperoxide. The chemiluminescence induced by copper-oxidized LDL was linear with concentration; the detection limit, when compared with linoleic acid hydroperoxide, was similar. The reproducibility of the linoleic acid hydroperoxide and of oxidized LDL hydroperoxide was examined in single pools. The coefficient of variation on the triplicates of each pool was about 3%. The titre of the linoleic acid hydroperoxide and oxidized LDL peroxides was quite stable for at least 10 days when stored under argon at 4 degrees C in the presence of EDTA. The mean value of the LDL hydroperoxides in 16 control subjects was 145.20 +/- 98.81 pmol/mg LDL protein. In conclusion, the microperoxidase-luminol-dependent chemiluminescence flow-injection assay is a rapid, sensitive and selective method for measuring lipid hydroperoxides in native LDL.

Chromatography, High Pressure Liquid↗
PubMed1993

Differential localization of endothelin ETA and ETB binding sites in human placenta.

1. The localization and differential distribution of endothelin (ET) receptor subtypes (ETA and ETB) was investigated in sections of human placenta by use of quantitative in vitro autoradiography and receptor selective ligands. 2. Specific, high density [125I]-ET-1 binding sites were localized to the decidua and foetal membranes as well as to arteries and veins in the chorionic plate and throughout the villous tree. Moderate to low density binding was found in the extravillous and villous trophoblast respectively. 3. [125I]-ET-1 binding sites exhibited a rank order of inhibition by unlabelled peptide sequences (ET-1 > ET-3 > [Ala3,11,18Nle7]-ET-1 > BQ123 > or = sarafotoxin 6c). However, in contrast to the monophasic inhibition curve of ET-1, the other sequences produced a significantly better fit to a two component inhibition curve suggesting the presence of a heterogeneous population of ET binding sites. 4. ETA and ETB receptors were distinguished by competitive inhibition of [125]-ET-1 binding with increasing concentrations of unlabelled ET-3, [Ala3,11,18Nle7]-ET-1, sarafotoxin 6c and BQ123 and by incubating sections with the ETB agonist, [125I]-BQ3020. ET receptor subtypes exhibited a differential distribution in the placenta. ETA type binding sites predominated (approximately 80% of the total) on veins and arteries in the chorionic plate. Veins in stem villi, blood vessels in distal regions of the villous tree and decidual cells displayed a high density (approximately 60-70% of the total) of the ETB receptor subtype. 5. No difference was detected in either the relative density of [125I]-ET-1 binding sites or the proportion of ETA to ETB sites in placentae from pregnancies complicated by pre-eclampsia compared with normal term controls.6. ET may have a local autocrine or paracrine role in the placenta, acting via specific receptors to influence foetoplacental blood flow and other aspects of placental function.

Adult↗
PubMed1992

Development of the left-right axis.

Left-right is not an axis in the conventional sense but rather two mirror-image proximodistal axes, upon which a quantal piece of positional information (leftness or rightness) is superimposed for laterally asymmetric organ development. We are attempting to establish the stages at which left-right is specified and determined, but this is complicated by the apparent loss of normal handed development in embryos that are cultured from pre-neural plate stages. Experiments suggest that left-right is determined by the first somite stage. The loss of normal left-right development in early cultures is probably not due to removal of some maternal signal, even though embryos do develop in vivo with their axes in a specific orientation relative to the uterus. The fact that there are two random embryonic axis orientations, 180 degrees opposed to one another, and that the axes of the two uterine horns are mirror-images of each other make it unlikely that the uterus could impart a sense of left-right to the embryo. The right ovary produces more eggs than the left one; this is reversed in iv/iv situs inversus mice. Analysis of iv/iv mice shows a correlation of left-right abnormalities with sex and close relationships between the abnormal left-right development of some organs, for example the heart and spleen, that have no obvious developmental connection.

Animals↗
PubMed1991

Development of handed body asymmetry in mammals.

We have proposed a three step model for the specification of left-right in mammalian embryos. The fundamental assumption is that handedness is imparted by an asymmetrical molecule. Conversion of molecular asymmetry to the cellular level gives a property to one side of the embryo to bias an otherwise random generation of an asymmetrical gradient which can be interpreted by developing organs. Rat embryos, treated at discrete stages, show a window of sensitivity for disruption of handedness, which may reflect the time of conversion/biasing. Heat shock and several chemicals cause left-right inversion in up to 50% of embryos exposed during neural groove formation. Earlier stages are less sensitive; no treatment begun after foregut pocket formation influences asymmetry. Evidence for cellular interactions in left-right specification comes from the apparent rescue of iv/iv mutant embryos in chimeras. We are looking for molecular left-right disparity before morphological asymmetry but detect no differences in two-dimensional protein profiles. Using an indirect measure, we find a right-left gradient of tissue oxygen in embryos at the 20-30 somite stage. This may reflect asymmetrical vasculature, as we have suggested to explain drug-induced asymmetrical limb malformations.

Animals↗
PubMed1991

Adaptation of postimplantation embryos to culture: membrane lipid synthesis and response to valproate.

The environment of the conceptus in culture is quite different from that in utero. It is likely that the embryo adapts to this environment in various ways, but little is known of adaptation, nor of its significance to mechanistic studies using embryo culture. To illustrate this area, we summarize data from two comparative studies: of membrane lipid synthesis by conceptuses in culture and in utero, and of the morphologic response of conceptuses to valproate in these two environments. The synthesis of the major membrane lipids, cholesterol and phospholipids, is significantly affected by culture. De novo synthesis of cholesterol progressively increases during culture, compared to equivalent stages in utero. In contrast, phospholipid synthesis decreases in culture. Cultured conceptuses were morphologically similar to those in utero, suggesting that apparent structural normality does not guarantee biochemical activity equivalent to that in vivo. Conceptuses exposed to valproate in vivo showed a wide range of severity of defects. Those abnormalities that apparently permit survival to term seem relatively subtle, while more severe defects (as usually reported in culture studies) appear to be lethal. Subtle defects, very similar to those induced in vivo, can be reproduced in culture, but only with short-term, not continuous, exposure. We have previously proposed that valproate may interfere with embryonic lipid synthesis. Thus, despite lipid synthetic pathways adapting to the culture environment, the response to valproate in vitro, can mimic that in utero, with appropriate exposure conditions.

Animals↗
PubMed1991

Experimental observations on the specificity of Strigea falconispalumbi (Trematoda: Strigeidae) toward planorbid first intermediate hosts.

Planorbis planorbis, Planorbarius corneus and Biomphalaria alexandrina (Egyptian strain) were ascertained as new experimental first intermediate hosts, thus bringing the total number of planorbid experimental first intermediate hosts to eight. The highest degree of compatibility was exhibited with P. planorbis (infection prevalence 80%) followed by P. corneus (46.6%), whereas B. alexandrina (as snail species not occurring in the geographical range of S. falconispalumbi) showed the lowest degree of compatibility (23.3%).

Animals↗
PubMed1990

The development of handed asymmetry in aggregation chimeras of situs inversus mutant and wild-type mouse embryo.

Mutant iv/iv mice develop as if they have no sense of left and right, so the development of asymmetry is random: half normal, half as a mirror-image of normal, situs inversus. We have made aggregation chimeras of 8-cell stage iv/iv and +/+ embryos, transferred them into pseudopregnant mice, and examined their phenotype on day 10 of gestation. The contribution of mutant and wild-type cells to tissues of the embryo was estimated by strain-specific isozyme (GPI-1) analysis. We have also performed reciprocal embryo transfers, iv/iv blastocysts into +/+ mice, and vice versa. These transfers show that the development of handed asymmetry is determined by embryonic genotype, and is unaffected by the maternal environment (at least after day 3), or by the procedures of embryo collection, culture and transfer. Our observations on the development of 21 viable chimeric embryos show that neither iv/iv nor +/+ cells are dominant. All embryos (12) with less than 50% contribution of iv/iv cells to the heart developed with normal situs. Of 9 embryos with greater than 50% iv/iv cells, only 2 developed with inverted situs. These findings suggests that there was partial 'rescue' of embryos by some influence of normal over mutant cells. However, we cannot, statistically, exclude an alternative interpretation that cells are behaving autonomously. Interestingly, the embryos that developed with inverted situs were unique in having greater than two thirds contribution of iv/iv cells to both the heart and the visceral yolk-sac.

Animals↗
PubMed1989

The development of asymmetry: the sidedness of drug-induced limb abnormalities is reversed in situs inversus mice.

We are studying the development of handedness, in particular the relationships between handed structures with bilateral symmetry, for example the limbs, and those with lateral asymmetry, such as the heart, lungs and gut. Asymmetric (unilateral) developmental limb abnormalities can be induced by chemical treatment of mouse embryos, either in utero by acetazolamide, or in culture by misonidazole. We have examined these effects in mice homozygous for the iv gene. The development of bilateral symmetry in iv/iv mice is normal, but the control of asymmetry appears to be random, that is 50% develop normally (situs solitus), 50% with laterally inverted viscera (situs inversus). We find that the handedness of induced asymmetric limb defects is highly correlated with embryonic visceral situs. Right limb defects are induced in situs solitus embryos, left-sided defects in situs inversus. This suggests that the mechanism of induction of asymmetric defects is not related to any intrinsic difference between the development of left and right limbs, but is connected to visceral asymmetry. In addition, the high correlation of limb defects with situs was observed in culture as well as in utero suggesting that the maternal environment plays no role in the development of asymmetry.

Acetazolamide↗
PubMed1988

Fatal recurrence of neuroleptic malignant syndrome.

The clinical features of a fatal case of the neuroleptic malignant syndrome are presented. The fatal episode was a recurrence of the syndrome after a milder episode 3 months earlier. Prescription of neuroleptics was continued unchanged following the latter, as a correct diagnosis was not made at the time. The case emphasises the importance of early recognition of the syndrome and the possibility of spontaneous remission of symptoms despite continued neuroleptic treatment.

Adult↗