Biomedical subjects

R G Morris

Publications and source records attributed to R G Morris.

At least 127 records · Page 7Linked to original sources

PubMed1996

Landmark stability: further studies pointing to a role in spatial learning.

Two experiments were conducted to investigate the possible role of landmark stability in spatial learning. Rats were trained to search in a large arena for food hidden at a consistent distance and direction from either a single radially symmetric landmark or an array of two landmarks. We varied the relative degree to which the landmark array and/or the cues of the training context predicted the location of food, without varying the conditional probability of food being available given either cue. Experiment 1 used vestibular disorientation to ensure control of search location by experimenter-controlled cues. The results showed that making either a single landmark or a cluster of two adjacent landmarks the sole spatial predictor of reward location reduced the accuracy of search compared to a condition where both the landmark array and context cues were reliable spatial predictors. Varying global landmark stability had no effect when training was conducted using an array of two landmarks located some distance from each other. Context cues, when tested alone, triggered very little searching in appropriate locations, and the absolute magnitude of control over search was insufficient to account for the superiority of stable landmarks. The better learning with a stable landmark, and the dependence of this effect on the geometrical arrangement of landmarks, points to the conditions of spatial learning involving additional principles to those of simple associative conditioning. Experiment 2 examined landmark stability using a single landmark and fixed directional cues in the absence of vestibular disorientation. This also revealed a relative advantage of landmark stability, but animals with a landmark that moved from trial to trial did show some evidence of learning. Context cues when tested alone had minimal influence. Parametric manipulation of landmark stability offers a novel way of influencing spatial learning and thus understanding better the process through which egocentric representations of perceived space are transformed into allocentric representations of the real world.

Animals↗

PubMed1996

Double dissociations of memory and executive functions in working memory tasks following frontal lobe excisions, temporal lobe excisions or amygdalo-hippocampectomy in man.

Thirty-two neurosurgical patients with unilateral or bilateral frontal lobe excisions, 41 patients with unilateral temporal lobe lesions and 19 patients who had undergone unilateral amygdalo-hippocampectomy were compared with matched controls on a computerized test of spatial working memory. A significant deficit was observed in the frontal lobe group, even at the least challenging level of task difficulty and this impairment was found to relate to the inefficient use of a particular searching strategy shown to improve performance on this task. In contrast, deficits in the temporal lobe group and the amygdalo-hippocampectomy group were only observed at the most difficult level of the task and in neither group could the deficit be related to the inefficient use of any particular searching strategy. In a follow-up study, the three patient groups were compared on analogous computerized tests of visual and verbal working memory. No deficits were observed in the frontal lobe group. By comparison, both the temporal lobe patients and the amygdalo-hippocampectomy group were significantly impaired in the visual working memory condition but not in the verbal working memory condition. These deficits were clearly evident at all levels of task difficulty and were not related to any particular searching strategy. The data are discussed in terms of the relative contributions of "executive' and "mnemonic' mechanisms to the contrasting, material dependent deficits observed in the frontal and temporal lobe groups.

Adult↗

PubMed1996

Enzyme-multiplied immunoassay (EMIT 2000) digoxin assay compared with fluorescence polarization immunoassay and amerlex 125I-radioimmunoassay at two Australian centers.

Digoxin assays in plasma from patients treated with the drug have played an integral role in its therapeutic management. Commercial digoxin immunoassays have been criticized for poor performance owing to various interferences and limited sensitivity. The present study compared the performance of a new enzyme-multiplied immunoassay technique (EMIT 2000) to fluorescence polarization immunoassay (FPIA) and radioimmunoassay (RIA) in two separate Australian centers. Comparisons were made using standard indices of precision and accuracy, samples taken from patients, quality-assurance samples, and cord blood samples from neonates, in which high concentrations of digoxin-like immunoreactive substances (DLIS) would be anticipated. The results confirmed satisfactory precision and accuracy for therapeutic drug monitoring purposes, a sensitivity of < 0.1 microgram/L, and very low DLIS interference, as assessed by assay of neonatal cord blood samples.

Anti-Arrhythmia Agents↗

PubMed1996

Drugs and brain death: drug assay perspectives.

The ability to make any meaningful interpretation of a drug assay result is very dependent upon a knowledge of the limitations of the method(s) used (sensitivity, specificity etc.), and the concentration that may be measured in plasma and its relationship to CNS effects. We need more information about 'critical' concentrations for each drug and sedation in the setting of the brain-injured patient before meaningful interpretation can be applied to such data. While the above discussion is critical of screen-type assays, the alternative specific assays are not easily provided for, as obviously the resourcing of laboratories to be able to deliver such specialized services for a range of therapeutic drugs, in addition to 'social' drugs or other toxins (e.g. glues, pesticides, solvents, environmental substances etc), becomes an increasingly complex issue in the current economic climate. Hence, the analytical laboratory can offer valuable support to the clinical team however, the interpretation of such results must be assessed in the light of many limitations of such assay methods and not seen as the 'gold standard' for assessment of brain function.

Brain Death↗

PubMed1996

Dextromoramide pharmacokinetics following sublingual administration.

The extent of absorption and other pharmacokinetic parameters of dextromoramide following sublingual administration were assessed in five patients receiving chronic opioid analgesia. The use of the standard 5 mg tablet formulation was associated with negligible absorption in two patients, a prolonged time to peak concentration in the other three and substantial variability in clearance. The study concluded that the standard tablet formulation cannot be recommended for sublingual use where reliable, rapid onset analgesia is required.

Absorption↗

PubMed1996

Diltiazem does not always increase blood cyclosporin concentration.

The pharmacokinetic interaction between the calcium channel blocking drug, diltiazem (DTZ), the antifungal agent itraconazole (ICZ) and the immunosuppressive drug cyclosporin (CsA) was studied in a patient with a single lung transplant. The CsA area under curve estimations demonstrated a significant increase when ICZ was co-prescribed (5836 micrograms l-1 h vs 8159 micrograms l-1 h) but no increase when DTZ was co-prescribed with CsA (5836 micrograms l-1 h vs 5069 micrograms l-1 h). Despite widespread use as a CsA-sparing agent, DTZ does not always increase CsA concentrations.

Calcium Channel Blockers↗

PubMed1995

A novel cytochrome P450 expressed primarily in brain.

hct-1 (hippocampal transcript) was detected in a differential screen of a rat hippocampal cDNA library. Expression of hct-1 was enriched in the formation but was also detected in rat liver and kidney, though at much lower levels; expression was barely detectable in testis, ovary, and adrenal. In liver, unlike brain, expression was sexually dimorphic; hepatic expression was greatly reduced in female rats. In mouse, brain expression was widespread, with the highest levels being detected in corpus callosum; only low levels were detected in liver. Sequence analysis of rat and mouse hct-1 cDNAs revealed extensive homologies with cytochrome P450s (CYPs), a diverse family of heme-binding monooxygenases that metabolize a range of substrates including steroids, fatty acids, and xenobiotics. Among the CYPs, hct-1 is most similar (39% at the amino acid sequence) to cholesterol 7 alpha-hydroxylase (CYP7) and contains a postulated steroidogenic domain present in other steroid-metabolizing CYPs but clearly represents a type of CYP not previously reported. Genomic Southern analysis suggests that a single gene corresponding to hct-1 is present in mouse, rat, and human. hct-1 is unusual in that, unlike all other CYPs described, the primary site of expression is in the brain. Similarity to CYP7 and other steroid-metabolizing CYPs may argue that hct-1 (CYP7B) plays a role in steroid metabolism in brain, notable because of the documented ability of brain-derived steroids (neurosteroids) to modulate cognitive function in vivo.

Amino Acid Sequence↗

PubMed1995

Distinct components of spatial learning revealed by prior training and NMDA receptor blockade.

Synaptic plasticity dependent on N-methyl-D-aspartate (NMDA) receptors is thought to underlie certain types of learning and memory. In support of this, both hippocampal long-term potentiation and spatial learning in a watermaze are impaired by blocking NMDA receptors with a selective antagonist D(-)-2-amino-5-phosphonovaleric acid (AP5) or by a mutation in one of the receptor subunits. Here we report, however, that the AP5-induced learning deficit can be almost completely prevented if rats are pretrained in a different watermaze before administration of the drug. This is not because of stimulus generalization, and occurs despite learning of the second task remaining hippocampus dependent. An AP5-induced learning deficit is, however, still seen if the animals are pretrained using a non-spatial task. Thus, despite its procedural simplicity, the watermaze may involve multiple cognitive processes with distinct pharmacological properties; although required for some component of spatial learning, NMDA receptors may not be required for encoding the spatial representation of a specific environment.

2-Amino-5-phosphonovalerate↗

PubMed1995

Spatial learning with a minislab in the dorsal hippocampus.

We have determined the volume and location of hippocampal tissue required for normal acquisition of a spatial memory task. Ibotenic acid was used to make bilateral symmetric lesions of 20-100% of hippocampal volume. Even a small transverse block (minislab) of the hippocampus (down to 26% of the total) could support spatial learning in a water maze, provided it was at the septal (dorsal) pole of the hippocampus. Lesions of the septal pole, leaving 60% of the hippocampi intact, caused a learning deficit, although normal electrophysiological responses, synaptic plasticity, and preserved acetylcholinesterase staining argue for adequate function of the remaining tissue. Thus, with an otherwise normal brain, hippocampal-dependent spatial learning only requires a minislab of dorsal hippocampal tissue.

Acetylcholinesterase↗

PubMed1995

Glucocorticoids, hippocampal corticosteroid receptor gene expression and antidepressant treatment: relationship with spatial learning in young and aged rats.

The emergence of cognitive deficits in a subgroup of aged rats is associated with increased hypothalamic-pituitary-adrenal axis activity, decreased hippocampal mineralocorticoid and/or glucocorticoid receptor gene expression and neuronal loss. Short-term treatment with antidepressant drugs in young rats increases hippocampal corticosteroid receptor gene expression. In this study, the effects of chronic antidepressant administration on hippocampal mineralocorticoid and glucocorticoid receptor gene expression and spatial memory in young and aged rats were investigated. Young (eight months) and old (22 +/- 1 months) Lister-hooded rats were ranked according to watermaze performance. Matched pairs of rats were treated with amitriptyline (10 mg/kg) or saline daily for nine weeks, then reassessed in the watermaze. Amitriptyline significantly improved spatial memory in the young rats (33% increase in transfer test time) and increased hippocampal mineralocorticoid, but not glucocorticoid receptor messenger RNA expression. By contrast, in aged rats, amitriptyline had no effect on spatial memory or hippocampal corticosteroid receptor gene expression, either in cognitively unimpaired or cognitively-impaired animals. In aged rats, basal plasma corticosterone levels, which were significantly higher than in young animals, correlated negatively with spatial memory, while hippocampal glucocorticoid receptor mRNA expression correlated negatively with plasma corticosterone levels and positively with spatial memory. Amitriptyline had no significant effect on basal morning plasma corticosterone levels in either young or aged rats, but significantly decreased evening corticosterone levels in aged rats. Our data support the notion that corticosterone exerts a concentration-dependent biphasic influence, via selective activation of hippocampal mineralocorticoid and glucocorticoid receptor, on spatial memory. Amitriptyline improves spatial memory in young rats and increases hippocampal mineralocorticoid receptor gene expression. The lack of amitriptyline effect on spatial memory in aged rats may reflect decreased plasticity of both the synaptic processes underlying spatial memory and the regulation of hippocampal mineralocorticoid/glucocorticoid receptor expression, with mineralocorticoid receptors fully occupied due to elevated basal plasma corticosterone levels (in part a consequence of inadequate glucocorticoid receptor function).

Aging↗

PubMed1995

Problem solving in schizophrenia: a specific deficit in planning ability.

The study investigated problem solving ability in schizophrenia. Thirty DSM-IIIR schizophrenic patients and 27 matched normal controls were tested on the Three-Dimensional Computerised Tower of London Test (3-D CTL Test) (Morris et al., 1993). The patients took significantly more moves to solve a series of problems and solved significantly fewer problems in the predetermined minimum number of moves. The patients response times, as measured using a control version of the task (the 3-D CTL Control), were longer than those of the controls. However, when latencies were adjusted to take into account the slower responses overall, the patients planning times were not significantly increased. Inaccurate planning, as defined by taking more moves, did not correlate with either positive or negative symptoms, but the response times tended to be longer in patients who had more negative symptoms. The findings suggest that there is a deficit in problem solving activity in schizophrenia that may be associated with translating 'willed intentions' into action, independent of slower motor speed.

Adult↗

PubMed1995

Cognitive features of psychotic states arising in late life (late paraphrenia).

The cognitive performance of 47 elderly psychotic patients with onset of symptoms in late life (late paraphrenia) was compared to that of 33 controls matched for age, sex, ethnic origin, number of years of education, and pre-morbid IQ as measured by the NART. Neuropsychological indices of general cognitive functioning (MMSE, CAMCOG, WAIS-R verbal and performance scores) showed that patients were performing the tasks at a significantly lower level than controls. Patients also showed a trend to have a lower span capacity than controls, particularly at the spatial span subtest. There was no obvious impairment of learning as measured by the digit and spatial recurring span tasks nor of simultaneous matching-to-sample ability. However, patients' performance on a delayed-matching-to-sample procedure was significantly worse than that of controls. In addition, patients performed worse than controls on the Recognition Memory Test for Faces, but not for Words. Finally, the performance of patients on tests assessing executive functioning (Verbal Fluency Test, Computerized Extra and Intra-Dimensional Shift Task, Computerized Spatial Working Memory Task, and Computerized Tower of London Task) was consistently worse than that of controls. These results suggest that psychotic states arising in late life are predominantly associated with a decline on measures of general cognitive ability and executive functioning. The neuropsychological meaning of these findings is discussed in the light of cognitive models of psychotic symptoms, as well as of schizophrenia and dementia research. We concluded that the lack of a clear pattern of impairment among these patients may be the result of their clinical and cognitive diversity.

Aged↗

PubMed1995

Clinical and cognitive diversity of psychotic states arising in late life (late paraphrenia).

This study aimed to explore the heterogeneity of paranoid psychosis with onset in late life by using cognitive factors in a centroid method of cluster analysis. Forty-seven subjects were allocated to two different clusters, the first with 24 (51.1%) and the second with 23 (48.9%) patients. Their cognitive attainment was evaluated against the performance of 33 elderly controls, all groups being matched for age, sex, and the numbers of years of education. Patients in cluster 2 showed a pattern of widespread cognitive impairment, which involved general measures of cognitive performance (MMSE, CAMCOG, WAIS-R verbal and performance scores), memory (digit and spatial span, delayed matching-to-sample, recognition memory for words and faces), and executive functions (verbal fluency, extra and intra-dimensional shift ability, spatial working memory, and planning). In contrast, patients in cluster 1 were only impaired on their extra-dimensional set shift and planning abilities, suggesting a more specific and restricted executive functioning deficit. We also analysed the impact that the use of antipsychotic medication could have had on patients' cognitive performance, which was shown to be negligible. In addition, there was no difference between the clusters with regard to the number of patients using neuroleptics, suggesting that the medication was unlikely to have introduced a performance bias in the two patient clusters. The validity of the subdivision of these patients into two separate groups was further supported by other clinical findings. Patients in cluster 1 exhibited more severe psychotic symptoms, as measured by the SAPS, than their counterparts in cluster 2, and were also more likely to display first-rank symptoms of Schneider. Conversely, cluster 2 membership was strongly associated with the presence of neurological signs and negative symptoms. We suggest that psychotic states arising in late life are a heterogeneous condition that may be best divided in two: 'type A', including patients with a wide range of psychotic symptoms, mild increase in the frequency of neurological signs, and cognitive deficits restricted to executive functions, and 'type B', which includes patients with less complex psychotic symptoms associated with a marked increase in the frequency of neurological signs and generalized cognitive impairment. The basis for this subdivision and the prospect for future studies are discussed.

Aged↗

PubMed1995

Recognition memory for words and faces following unilateral temporal lobectomy.

The study tested the ability of the Warrington Recognition Memory Test (1984) to discriminate between patients with left and right temporal lobe lesions. Forty-seven patients who had undergone unilateral temporal lobectomy (TL) (23 right- and 24 left-sided operations) were tested on the two components of the test, recognition memory for words (RMW) and recognition memory for faces (RMF). The results show that the right TL group were significantly worse than the left TL group on RMF. Conversely, the left TL group were significantly worse on the RMW test, confirming earlier results relating to material-specific deficits in long-term memory following TL. The RMF test was relatively sensitive and specific in detecting significant impairments associated with right TL, but the RMW proved much less sensitive to the effects of left TL. RMW and RMF discrepancy scores were found not to discriminate well between the two groups of patients.

Adult↗

PubMed1995

Cloning of a bovine renal epithelial Na+ channel subunit.

A bovine homologue of the rat and human epithelial Na+ channel subunits, alpha-rENaC and alpha-hENaC, was cloned. The cDNA clone, termed alpha-bENaC, was isolated from a bovine renal papillary collecting duct cDNA expression library. The bovine cDNA is 3,584 base pairs (bp) long, has an open reading frame of 2,094 bp encoding a 697-amino acid protein, and is 75-85% homologous to its rat and human counterparts. In vitro translation of the transcribed cRNA yields an 80-kDa polypeptide and one at 92 kDa in the presence of pancreatic microsomes. The clone exhibits consensus sequences for N-linked glycosylation and for phosphorylation by protein kinase C, but not for protein kinase A. After expression in Xenopus laevis oocytes, a small amiloride-sensitive Na+ conductance that exhibited inward rectification and a reversal potential greater than +30 mV, consistent with the predicted equilibrium potential for Na+, was identified. The expressed alpha-bENaC-associated Na+ current was not responsive to elevations in adenosine 3',5'-cyclic monophosphate but could be stimulated by phorbol 12-myristate 13-acetate, an activator of protein kinase C. alpha-bENaC also formed amiloride-sensitive chimeric channels when coexpressed with the rat beta- and gamma-ENaC subunits in Xenopus oocytes. alpha-bENaC therefore represents a novel isoform of a growing family of epithelial Na+ channels.

Amino Acid Sequence↗

PubMed1994

Hippocampal corticosteroid receptor mRNA expression and spatial learning in the aged Wistar rat.

The expression of mineralocorticoid (MR) and glucocorticoid receptor (GR) mRNA in the hippocampus of aged (18-24 months) and young (7 months) Wistar rats in relation to spatial learning in the water maze was investigated. All aged rats showed impaired performance of the task to locate a hidden platform compared to young controls, but the Wistar strain as a whole showed inferior performance to a group of young Lister hooded controls (added for the purposes of comparison) with even young Wistar rats apparently failing to learn platform location. The aged Wistar rats spent nearly 70% of their time near the side walls of the pool throughout the 5 days of training, while the young Wistar controls showed a gradual reduction in the percentage time spent there. MR and GR mRNA expression were unaltered in any hippocampal subregion in aged rats compared to young controls. Plasma corticosterone levels were also unchanged in aged rats. These results show that alterations in hippocampal corticosteroid receptor gene expression are not an inevitable consequence of aging in the rat, but that aging may be associated with strategy changes in the performance of a spatial learning task that are independent of glucocorticoid hypersecretion or alterations in hippocampal corticosteroid receptor mRNA expression.

Aging↗

PubMed1994

Intracerebroventricular injection of a nitric oxide synthase inhibitor does not affect long-term slope potentiation in vivo.

Although there is evidence from in vitro studies to suggest that NO synthesis may be involved in the induction of hippocampal LTP, other in vitro studies and experiments conducted in vivo have provided conflicting results. In agreement with previous work conducted in this laboratory using an i.p. route of administration, this paper reports that i.c.v. injections of the NO synthase inhibitor, N omego-nitro-L-arginine methyl ester (L-NAME), at a dose sufficient to inhibit hippocampal NO synthase by 90-95%, failed to block the induction of LTP in the dentate gyrus in vivo (as measured by the change in the slope of the early rising phase of the field EPSP). The failure to block LTP occurred following both a strong and a weak tetanus. L-NAME injections did, however, result in a small but transient increase in the baseline slope of the field EPSP, a more prolonged enhancement of the baseline population spike, and a significant attenuation of spike potentiation induced by a strong tetanus. These results offer no support for the hypothesis that NO synthase is required for the induction of the synaptic component of LTP, but do suggest a role for NO in the control of cell excitability in the hippocampus.

Amino Acid Oxidoreductases↗

PubMed1994

Loss of heterozygosity of MCC is not associated with mutation of the retained allele in sporadic colorectal cancer.

The adenomatous polyposis coli (APC) gene, which transmits familial adenomatous polyposis, is frequently mutated in sporadic colorectal tumours. Acquired somatic mutations have also been reported in a second gene, mutated in colorectal cancer (MCC), which lies within 500 kb of APC on chromosome 5q21 and has thus been implicated in tumour development. Further evidence for an oncosuppressor gene other than APC on chromosome 5q comes from recent studies of lung, renal and hepatic cancers in which there is loss of heterozygosity of 5q21 but no somatic APC mutations. To investigate the relative importance of APC and MCC in sporadic colorectal cancer, we have assessed the extent of 5q21 allelic loss in 80 carcinomas. All informative tumours exhibiting allelic loss had deletions which included both APC and MCC. In 21 tumours with loss of heterozygosity in MCC we have screened the entire coding region of the gene for mutation of the retained allele and found no evidence for mutation. The data indicate that independent loss of MCC is a rare event, and that in cases where allele loss occurs mutation of the retained allele is uncommon. This suggests that MCC does not function as an independent tumour suppressor in the majority of colorectal cancers.

Alleles↗