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Biomedical subjects

R G Morris

Publications and source records attributed to R G Morris.

At least 163 records · Page 9Linked to original sources
PubMed1993

Stabilised p53 facilitates aneuploid clonal divergence in colorectal cancer.

Mutations in the p53 tumour suppressor gene are amongst the most frequent genetic abnormalities acquired in tumours. Recent studies in vitro suggest that mutant p53 destabilises the genome and facilitates development of aneuploidy. Here, in a study of 83 colorectal carcinomas, we demonstrate that alterations in p53 (detected by immunocytochemical stabilisation) precede and apparently facilitate divergence of aneuploid sub-clones. Aneuploidy in these tumours (but not those with normal p53) is predominantly in the subtetraploid range, suggesting that endoreduplication is important in its origin. This association with a specific phase of carcinoma progression is not shared by other commonly acquired genetic abnormalities in these tumours. These observations highlight the critical role of p53 in the regulation of abnormal chromosome replication and afford an explanation for the association between p53 abnormalities, aneuploidy and biological aggression in cancer.

Adenoma↗
PubMed1992

High-performance liquid chromatographic determination of sotalol in plasma. I. Application to the disposition of sotalol enantiomers in humans.

Two high-performance liquid chromatographic analytical methods have been developed for the measurement of dl-sotalol or d-sotalol and l-sotalol in plasma, using dl-atenolol as internal standard. Quantitation of dl-sotalol was carried out, following solid-phase extraction, on a 5-microns C18 reversed-phase column, with a mobile phase containing acetonitrile, ion-pairing reagent and distilled water, using ultraviolet detection at 235 nm. Quantitation of d-sotalol and l-sotalol was based on derivatisation with the chiral agent S-(-)-alpha-methylbenzyl isocyanate, followed by chromatographic separation on a 3-microns C18 reversed-phase column, with a mobile phase containing methanol, glacial acetic acid and distilled water, with fluorimetric detection at 220 nm excitation and 300 nm emission. A preliminary application of the latter method suggests that the disposition of sotalol in humans is not enantioselective.

Aged↗
PubMed1992

Smells are no surer: rapid improvement in olfactory discrimination is not due to the acquisition of a learning set.

The claim that rats can demonstrate the 'primate-like' learning capacity of learning set formation when trained with olfactory cues, rather than visual or auditory cues, has generated considerable interest in recent years. In this study, the claim is evaluated in detail by using a series of experimental and control procedures to determine whether rats do indeed develop the abstract 'win-stay, lose-shift' strategy which underlies learning set formation in monkeys. We report here that although exposure to a series of novel olfactory discrimination problems gives rise to progressive improvement in the rate of learning, it is not a necessary condition for the development of that rapid learning. Furthermore, even rats which fail to display progressive improvement in olfactory reversal learning show rapid learning on novel olfactory discrimination problems. Each of these findings suggests that although olfactory learning may be rapid, learning set formation does not occur over a short series of problems.

Animals↗
PubMed1992

Buspirone produces a dose-related impairment in spatial navigation.

Classical anxiolytic drugs and hippocampal lesions have common behavioural effects that include loss of place navigation in the water maze. The novel anxiolytic drug buspirone, unlike classical anxiolytic drugs, does not interact with GABA and is not muscle relaxant, sedative, hypnotic, anticonvulsant, or addictive. Buspirone affects hippocampal electrophysiology in a similar fashion to classical anxiolytics and so we predicted it would have similar effects on spatial navigation. Rats injected with buspirone (0.1-10.0 mg/kg, IP) showed a loss of acquisition of spatial navigation in the water maze that has a similar dose dependence to that reported for the effects of buspirone on the hippocampus. This finding demonstrates that the effects of anxiolytics on spatial navigation are not due to their side effects and supports the view that changes in hippocampal function may underlie some components of clinical anxiolytic action.

Animals↗
PubMed1992

Unbound plasma phenytoin concentrations measured using enzyme immunoassay technique on the cobas MIRA analyser--in vivo effect of valproic acid.

This communication describes a modification of the total plasma phenytoin enzyme immunoassay technique (EMIT) run on the Cobas MIRA analyser that allows quantitation of unbound phenytoin concentrations in human plasma for routine therapeutic drug monitoring (TDM) purposes. An application of this method is also presented to consider the previously described protein binding drug interaction with concomitantly administered valproic acid in patients with epilepsy. The coefficients of variation for the unbound phenytoin assay ranged from 7.5 to 9.6% and the assay had a reproducibility and accuracy similar to the total phenytoin assay, acceptable for routine TDM. Phenytoin protein binding was linear over a range of total plasma concentrations of 3-65 mg/L. Patients also receiving valproic acid (nine patients, 105 specimens) had a significantly (p less than 0.0001) greater mean +/- SD unbound phenytoin fraction (13.3 +/- 3.1%) compared to nine patients (110 specimens) not receiving valproic acid (8.3 +/- 1.6%). There was also a significant correlation (p less than 0.001) between plasma valproic acid concentration and unbound phenytoin fraction, which resulted in greater intrasubject variability in phenytoin protein binding.

Blood Proteins↗
PubMed1992

Specific enzyme-multiplied immunoassay and fluorescence polarization immunoassay for cyclosporin compared with Cyclotrac [125I]radioimmunoassay.

The analysis of cyclosporin-A (CsA) has proved a valuable adjunct to clinical care of patients who have received organ grafts. The measurement of CsA in whole blood by specific methods has recently taken a new direction with the introduction of a range of rapid methods, including a homogeneous enzyme immunoassay technique (EMIT) and a monoclonal fluorescence polarization immunoassay (FPIA). The present paper compares these two methods with the established Cyclotrac specific [125I]RIA (radioimmunoassay) using both commercial CsA-spiked control material as well as a group of 60 patient specimens (predominantly renal transplants). While each of the new methods showed acceptable precision and accuracy with the commercial quality control material, significant differences were demonstrated with patient specimens, such that FPIA was 12.5% greater than [125I]RIA (p less than 0.0001), which was in turn 5.9% greater than EMIT (p = 0.007). These data suggested that the FPIA may have residual CsA-metabolite interference and that the EMIT method was the most "specific" for parent CsA of the three tested, potentially therefore more comparable to high-performance liquid chromatography (HPLC).

Antibodies, Monoclonal↗
PubMed1992

Memory after treatment for acute lymphoblastic leukaemia.

Long term survivors of acute lymphoblastic leukaemia (ALL) often experience cognitive difficulties, which may be related to impairment of memory function. Memory ability has been studied in a group of survivors of ALL along with sibling controls and in children who have received treatment for other forms of cancer. Children in the ALL group were found to have significant deficits in memory function in tasks which required the application of strategic planning behaviour. These deficits are potentially remediable by educational strategies.

Adolescent↗
PubMed1992

The apoptosis endonuclease and its regulation.

Activation of an endogenous endonuclease has been observed in conjunction with the structural changes of apoptosis in a wide variety of cell types and circumstances. The endonuclease is present constitutively in some cells (e.g. rodent cortical thymocytes) in which apoptosis is readily triggered by many unrelated stimuli, but is inducible in others. Purification of this enzyme is an objective of some importance in apoptosis research, as it might act as a marker of susceptibility to apoptosis and lead to better understanding of the regulation of the process as a whole. Early data suggest that the thymocyte endonuclease is an anionic protein of molecular weight greater than 110 kDa, with a pH optimum of 7.5 and a double-strand cleavage preference. Its activity, and the induction of apoptosis as a whole, is regulated by several familiar cellular proto-oncogenes and oncosuppressor genes, including c-myc, Ha-ras, bcl-2 and p53.

Animals↗
PubMed1992

The NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) impairs spatial learning and LTP in vivo at intracerebral concentrations comparable to those that block LTP in vitro.

This series of experiments investigated whether the NMDA receptor antagonist D-2-amino-5-phosphonopentanoate (D-AP5) could induce impairments of spatial learning across a dose range comparable to its impairment of hippocampal long-term potentiation (LTP) in vivo. Estimations of the extracellular concentration of D-AP5 in hippocampus using microdialysis were also made to compare whether these impairments occur at concentrations similar to those required to impair LTP in the in vitro hippocampal slice. Rats were chronically infused with D-AP5 into the lateral ventricle at a range of concentrations (0-50 mM) via osmotic minipumps. They were first trained to find and escape onto a hidden platform in an open-field water maze task. After the behavioral learning, they were anesthetized with urethane and an attempt was made to evoke and monitor hippocampal LTP. Extracellular samples of D-AP5 in hippocampus were then taken using microdialysis, and finally, the animals were killed and tissue samples dissected. The microdialysis and tissue samples were analyzed for D-AP5 content using HPLC with fluorescence detection. The results established, first, that D-AP5 impairs spatial learning in a linear dose-dependent manner, highly correlated with its corresponding impairment of hippocampal LTP in vivo. No concentration of D-AP5 was observed to block LTP without affecting learning. Second, the microdialysis estimates indicated that, subject to certain assumptions, D-AP5 causes these impairments at extracellular concentrations comparable to those that impair LTP in vitro. Third, comparison of the whole tissue and microdialysis samples revealed a concentration ratio of approximately 30:1, indicating that 97% of the intracerebral D-AP5 is inaccessible to the dialysis probes. Infusion of 20 mM EGTA was found to cause a sevenfold increase in D-AP5 in the dialysis perfusates, suggesting that at least part of the inaccessible D-AP5 is trapped by a calcium-dependent mechanism. Two further behavioral control studies indicated that the D-AP5-induced impairment of spatial learning is unlikely to be secondary to a drug-induced motor disturbance, and that the performance of the D-AP5 group whose concentration was just sufficient to block hippocampal LTP completely was statistically indistinguishable from that of a group of rats with bilateral hippocampal lesions induced by ibotenic acid. Taken together, these findings offer support for the hypothesis that activation of NMDA receptors is necessary for certain kinds of learning.

2-Amino-5-phosphonovalerate↗
PubMed1991

Intracerebral distribution of DL-2-amino-phosphonopentanoic acid (AP5) and the dissociation of different types of learning.

Chronic intraventricular infusion of the selective NMDA receptor antagonist AP5 appears to cause an impairment of spatial but not visual discrimination learning. However, Goddard (1986) has questioned whether this dissociation in task-selectivity reflects a difference in the underlying neural mechanisms or differential drug diffusion. Two experiments conducted to address this issue established (a) that chronic intraventricular infusion of AP5, at a dose sufficient to cause a spatial learning impairment, results in a relatively uniform distribution of the drug across the brain, and (b) that chronic bilateral intracortical infusion at sites very close to visual cortex also fails to impair visual discrimination learning. These findings argue against differential diffusion being a major cause of the sensitivity of spatial but not visual discrimination tasks to AP5, and raises the possibility that representational and procedural memory tasks may depend upon distinct cell-biological mechanisms of plasticity.

2-Amino-5-phosphonovalerate↗
PubMed1991

Disposition of epirubicin and metabolites with repeated courses to cancer patients.

Thirteen cancer patients were studied following a total of 41 courses of epirubicin (EPI) (38-50 mg.m-2, mean 49.2 mg.m-2, administered by a 60 min infusion), together with other cancer chemotherapeutic agents. The aim was to consider the disposition of EPI and metabolites following subsequent courses as it has been reported that doxorubicin (the 4'-epimer parent of EPI) clearance is increased following the first administration. We have observed that EPI-glucuronide accounted for a mean 78.0%, epirubicinol 0.2% and epirubicinol-glucuronide 19.3% and that parent EPI accounted for only 2.4% of the EPI-compounds measured (mean of all patients and courses) for the 3 h period immediately following the infusion. These data confirm the rapid metabolism of EPI and the dominance of the glucuronidation metabolite pathway (which is not available to doxorubicin) and are compared with the metabolite profile observed in other reports. Large inter- and intra-individual variability in area under the plasma concentration/time curve were observed with no clear evidence of any consistent directional trend for such fluctuations, suggesting that factors contributing to EPI disposition are multivariate.

Adult↗
PubMed1991

Improved high-performance liquid chromatography assay for atenolol in plasma and urine using fluorescence detection.

An improved assay for racemic atenolol (AT) concentrations in human plasma and urine is described using a high-performance liquid chromatographic method with fluorescence detection. The method has a sensitivity limit of 0.5 micrograms/L in plasma with acceptable within- and between-run reproducibilities, and demonstrated linearity at concentrations up to 2,000 micrograms/L. A pilot clinical evaluation of the assay was undertaken on 56 trough plasma specimens from 36 outpatients on established AT therapy. Atenolol concentrations in these patients showed large variations at all prescribed doses, including undetectable levels in four patients (revealing unsuspected noncompliance). Because of its sensitivity and applicability to urinary analysis, the method can be used for pharmacokinetic studies and, under certain circumstances, may be valuable in clinical therapeutic drug monitoring.

Adult↗
PubMed1991

MCC, a candidate familial polyposis gene in 5q.21, shows frequent allele loss in colorectal and lung cancer.

MCC is a gene located within human chromosome band 5q.21 that shows somatically acquired mutations in colorectal cancer, and may be identical to the gene responsible for inheritance of familial adenomatous polyposis. Here we demonstrate that alleles contiguous with or within MCC are deleted in a high proportion of sporadic colorectal carcinomas. Of 106 carcinomas that were informative concurrently at close-flanking sites both centromeric and telomeric to MCC, 41.5% showed acquired allele loss contiguous with MCC. Evidence is presented to show that the true frequency of loss of MCC alleles is higher still. In contrast, allele losses in chromosome 5 that were incompatible with involvement of MCC were very rare (2% of a total series of 201 informative tumours). Interstitial deletion was the commonest mechanism of allele loss, and L5.71-3, a probe known to include coding sequences of MCC, marks the most consistently deleted site. Moreover mapping of chromosome breakpoints with six probes within 5q.21 sited the common critical deletion in a 2.5 Mb region which included L5.71-3. However use of L5.71-3 itself suggested that critical deleted regions may lie on either side of the probed sequence. The simplest explanation for this unexpected finding is that MCC itself is the essential deleted gene, the lost exons lying sometimes centromeric to, sometimes telomeric to and occasionally within the region detected by L5.71-3. Tumours in which MCC-related alleles were lost by interstitial deletion were in general larger than those with other mechanisms of acquired homozygosity (e.g. mitotic recombination), but there were no other obvious associations with clinicopathological features. Between 20% and 25% of lung cancers also showed acquired allele losses contiguous with MCC. The significance of this observation is still to be determined, as lung tumours show allele losses at many other sites, but the specificity of the probes used in this study does establish that the 5q.21 losses in these tumours are compatible with involvement of MCC.

Adenomatous Polyposis Coli↗
PubMed1991

Gender differences in carers of dementia sufferers.

Recent research shows that the demands of the caregiving role are experienced differently by men and women. Both the subjective and the objective strain and burden appear to be greater in female carers of dementia sufferers, and factors that influence this include differences in role expectations and coping strategies. These findings have implications for the provision of services for dementia sufferers and their carers.

Adaptation, Psychological↗
PubMed1990

Hippocampal synaptic plasticity and NMDA receptors: a role in information storage?

There has recently been renewed interest in the idea that alterations in synaptic efficacy may be the neural basis of information storage. Particular attention has been focused upon long-term potentiation (LTP), a long-lasting, but experimentally induced synaptic change whose physiological properties point to it being a candidate memory mechanism. However, considerations of storage capacity and the possibility of concomitant activity-dependent synaptic depression make it unlikely that individual learning experiences will give rise to gross changes in field potentials similar to those that occur in LTP, even if learning and LTP utilize common neural mechanisms. One way of investigating the functional significance of LTP is to use selective antagonists of those excitatory amino acid receptors whose activation is essential for its induction. This paper discusses various design requirements for such experiments and reviews work indicating that the N-methyl-D-aspartate receptor antagonist AP5 causes a behaviourally selective learning impairment having certain common features to the behavioural profile seen after hippocampal lesions. Two new studies are described whose results show that AP5 has no effect upon the retrieval of previously established memories, and that the dose-response profile of the impairment of spatial learning occurs across a range of extracellular concentrations in hippocampus for which receptor selectivity exists. These experiments show that activation of NMDA receptors is essential for certain kinds of learning.

Animals↗