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R G Morris

Publications and source records attributed to R G Morris.

At least 109 records · Page 6Linked to original sources

Reducing the cost of cyclosporin assays: modification of the EMIT 2000 method.

Cyclosporin is the leading immunosuppressant agent in organ transplantation, and therapeutic drug monitoring forms an integral part of patient management in most institutions. In the authors' laboratory, the cost of cyclosporin assays represents a major fraction of total consumable expenditure. At present, an average of 4,300 patient cyclosporin assays are performed annually using the EMIT 2000 method (Behring-Syva) on the Cobas Mira analyser (Roche), at a cost of AUD$50,000 in kits alone. As a means of reducing laboratory costs, the manufacturer's recommended method was modified by decreasing all of the reagent and sample volumes in the "Analytical" section of the Cobas Mira cyclosporin programme by 33%. Assay performance was monitored over a 10-month period and compared to that of the unmodified method. Calibration curves were stable, requiring a one-point correction on average of once every 12 days, and a full calibration once ever 1.7 months. Interassay variability was not different to that previously reported for the unchanged method, with mean (SD, CV) concentrations for trilevel quality control specimens of 86.5 micrograms/L (10.2, 11.9%), 185.9 micrograms/L (11.4, 6.2%) and 408.5 micrograms/l (28.9, 7.1%). From 24 specimens assayed in an international quality assurance programme, the results of 23 were within 1.2 SD of the group mean for the EMIT method, with an average bias of 0.8%. With the current modifications, we were able to perform an average of 105 patient assays per kit compared to the previous 71, equating to an annual saving the AUD$16,600.

Cyclosporine↗

Survey of cyclosporine therapeutic ranges, assay methodology, and use of 'sparing agents' in Australasian transplant centers.

Since its introduction in the 1980s, cyclosporine has become the major immunosuppressive drug used in organ transplantation. Despite widespread experience with this expensive agent, a number of controversial issues remain. These include the use of sparing agents to allow a lower dose of cyclosporine to be prescribed, specificity of assay method, and values quoted as therapeutic ranges. The authors surveyed organ transplant centers in Australia and New Zealand to ascertain local practices and found considerable variability in the use and dosage of sparing agents, cyclosporine assay method, and therapeutic ranges. The implications of these differences are discussed.

Adult↗

High-performance liquid chromatography quantitation of plasma lamotrigine concentrations: application measuring trough concentrations in patients with epilepsy.

Lamotrigine is a phenyltriazine anticonvulsant recently approved for clinical use. A high-performance liquid chromatographic (HPLC) method was developed using a silica column (5 microm) with an aqueous methanol mobile phase consisting of 94% methanol, 5.92% water, and 0.08% NH4H2PO4 adjusted to a final apparent pH of 4.0 and pumped at a flow rate of 1.0 ml/minute. Ultraviolet detection was carried out at a wavelength of 280 nm, and plasma samples were prepared for HPLC analysis by extraction into ethyl acetate after basification. Retention times for lamotrigine and its internal standard (BWA725C) were 10.3 and 11.2 minutes, respectively, and there was no chromatographic interference from other commonly coadministered anticonvulsants. Calibration curves were linear over a concentration range of 0.5 to 30 mg/l, with intra-assay and interassay coefficients of variation less than 8%. Assessment of assay performance in an international quality assurance program showed an average bias of 0.3% compared with the consensus mean. A review of 52 patient specimens showed that, if patients were grouped according to coadministered anticonvulsants, a significant correlation between lamotrigine dosage and concentration was evident in those coadministered valproate (in the absence of metabolic inducers) and in those coadministered a combination of valproate and inducers, but not in patients coadministered inducers alone. Mean (SD) trough concentrations were 9.2 (5.2), 2.8 (1.3), and 3.8 (2.8) mg/l in the valproate, inducer, and combination groups, respectively.

Anticonvulsants↗

Relation between cognitive dysfunction and pseudobulbar palsy in amyotrophic lateral sclerosis.

OBJECTIVES: To examine the relation between cognitive dysfunction and pseudobulbar features in patients with amyotrophic lateral sclerosis (ALS). METHODS: The performance of two patient groups, ALS with pseudobulbar palsy (n = 24) and ALS without pseudobulbar palsy (n = 28), was compared with 28 healthy age matched controls on an extensive neuropsychological battery. Tests used were the national adult reading test, short form of the WAIS-R, recognition memory test, Kendrick object learning test, paired associate learning, Wisconsin card sorting test, verbal fluency, Stroop and negative priming tests, a random movement joystick test, and a computerised Tower of Hanoi test. RESULTS: Tests of executive function showed a pronounced deficit on written verbal fluency in both ALS groups in comparison to controls, which tended to be more prominent in patients with ALS with pseudobulbar palsy. The random movement joystick test (a non-verbal test of intrinsic movement generation) showed an impairment in the generation of random sequences in patients with pseudobulbar palsy only. The computerised Tower of Hanoi showed a subtle planning impairment (shorter planning times) in all the patients with ALS compared with controls on trials requiring more complex solutions. In addition the pseudobulbar patients displayed shorter planning times on complex trials, and tended to solve these trials less accurately. There was also evidence of a deficit for all patients with ALS in comparison with controls on total errors and number of categories achieved on the Wisconsin card sorting test and a strong tendency towards an impairment on a task of selective attention and cognitive inhibition (negative priming). A word recognition memory deficit was showed across both ALS groups. CONCLUSIONS: This study elicited cognitive deficits (involving predominantly executive processes, with some evidence of memory impairment) in patients with ALS and further strengthened the link between ALS and frontal lobe dysfunction, this being more prominent in patients with pseudobulbar palsy. However, cognitive impairments suggestive of extramotor cortical involvement were not exclusive to this subgroup.

Adult↗

Target concentration strategy for cyclosporin monitoring.

The target concentration concept has been proposed as a potential alternative to the established, and probably much abused, therapeutic range method of interpreting concentrations of therapeutic drugs in plasma, serum or blood when individualising drug dosages. This paper raises for debate the possibility of extending this alternative concept to immunosuppressant monitoring with cyclosporin, where there has been considerable difficulty in establishing therapeutic ranges which are widely accepted and applied. In its broader application, the target concentration strategy does present advantage to the clinician in precision, ability to calculate the dose directly from the target concentration and clearance, as well as a clearer concept of an optimal concentration (differentiating desired and adverse effects).

Cyclosporine↗

Identification of body parts in Alzheimer's disease: evidence for a body schema hypothesis.

This study examined the ability of patients with Alzheimer's Disease (AD) to perform a Body Part Identification (BPI) task, and also explored the relationship between BPI, intellectual level, severity of cognitive impairment and the general insight of patients into their disorder. The results showed that although AD patients are not always impaired on BPI, the degree of impairment correlates with the level of cognitive impairment measured using the Mini-Mental State Examination. The study also showed that BPI is not, however, associated with level of insight into their illness. Taken together these results provide support for the existence of a body schema that can be disrupted by AD, but is independent of the degree of insight into the illness.

Aged↗

Formulation of diltiazem affects cyclosporin-sparing activity.

OBJECTIVE: To consider the effect of changing from a conventional release formulation of diltiazem to the controlled diffusion diltiazem formulation on the cyclosporin-sparing effect in kidney transplant recipients. METHODS: Seven stable renal transplant recipients were studied on two separate occasions following at least 2 weeks stabilisation on either formulation. The order of administration of the two formulations was not randomised as all patients were already prescribed lower dosages of diltiazem before entering this phase of a larger study. The doses of diltiazem used were 90 mg (conventional release diltiazem) taken twice daily and 180 mg controlled diffusion diltiazem taken in the morning. RESULTS: Whilst there were no overall significant differences between the two formulations, the study demonstrated considerable interpatient variability when changing to the controlled diffusion formulation, particularly following the morning cyclosporin dose, with three patients showing a reduced cyclosporin AUC (30-60%) and one an increased cyclosporin AUC of 36%. CONCLUSION: A change in formulation of the cyclosporin-sparing agent may result in unpredictable alterations in cyclosporin concentrations and resultant clinical sequelae.

Adult↗

Drugs and brain death.

IN THE EARLY HOURS of the morning, a fit young man leaves a party, where drugs are reported to have been consumed, to walk home. A short time later he is found unconscious by the roadside, with severe head injuries. En route to hospital by ambulance, he suffers a cardiac arrest and is successfully resuscitated. On arrival at the Emergency Department he has obvious head injuries and is deeply unconscious, but shows spontaneous ventilatory movements. Available history is that he is a 20-year-old student with well-controlled epilepsy for which he takes phenytoin. It is not known how he sustained his injuries. Pupils are equal, small and react sluggishly to light. There is generalised flaccidity and an extensor-plantar response to painful stimuli. Skull x-rays show no fractures and computed tomography shows early cerebral oedema and scattered cerebral contusions with evidence of subarachnoid haemorrhage. He is transferred to the intensive care unit and measures to inhibit cerebral oedema, including mannitol, are commenced. An N-methyl-D-aspartate (NMDA) inhibitor is administered for neuroprotection and ventilatory support is commenced. Over the next 24 hours haemodynamic support is needed with fluid loading and vasopressors. A urine drug screen by Toxilab (Toxilab Incorporated, Irvine, Calif.) shortly after arrival shows the presence of phenytoin and morphine. The report states that the presence of benzodiazepines is suspected. Plasma phenytoin concentration at the time of arrival was 78 mumol/L (optimal range, 40-80 mumol/L). Forty hours after admission his condition has deteriorated. His pupils are at midposition, no longer reactive to light and his lower limbs exhibit only spinal reflexes. His relatives begin to prepare themselves for the fact he may not survive and raise the issue that he would have been keen to donate organs under such circumstances. What is the opinion regarding withdrawal of life support at this time?

Adult↗

Microsatellite instability and the role of hMSH2 in sporadic colorectalcancer.

Microsatellite instability (MSI) occurs in most tumours from patients with hereditary non-polyposis colorectal cancer (HNPCC) and in around 17% of sporadic colorectal cancers. Germline defects in mismatch repair (MMR) genes are responsible for the majority of large HNPCC families, with hMSH2 accounting for at least 50%. MMR gene defects also occur in a small proportion of sporadic colorectal tumours with MSI. Here we report a systematic analysis of mismatch repair deficiency in 215 Scottish patients with sporadic colorectal tumours. We found that 16.4% of tumours exhibited MSI; survival analysis by Cox proportional hazards method showed a substantial survival advantage for patients with tumours showing MSI, independent of other prognostic factors. Tumours with MSI were screened for hMSH2 mutations and although 61% were found to have alterations, of these only 1/24 was exonic. The majority of these changes were reductions in length at intronic mononucleotide tracts and we postulate that these alterations are the result of a genetic defect elsewhere, although they may compromise hMSH2 function as a second step in tumourigenesis. Our findings indicate that instability confers an improved prognosis in colorectal cancer and, despite the fact that these two groups of tumours share similar biological characteristics, the genetic basis of HNPCC and sporadic colorectal cancer with MSI is different.

Base Sequence↗

Normal spatial learning despite regional inhibition of LTP in mice lacking Thy-1.

The process of learning involves stable changes in synaptic efficacy for which long-term potentiation (LTP) provides a widely adopted mammalian model. Synaptic modification induced by learning or LTP may involve the action of cell adhesion molecules. One such candidate is the ubiquitous neuronal glycoprotein Thy-1. In mice in which the gene encoding Thy-1 has been inactivated, we find a regionally selective impairment of LTP in vivo in the hippocampal formation: LTP is normal in area CA1 but strongly inhibited in the dentate gyrus. Spatial learning by Thy-1-deficient mice, as assessed in the watermaze, is unimpaired. Thus LTP in the cortical input to the dentate gyrus seems not to be required for spatial learning.

Animals↗

Ki-ras mutations in adenomas: a characteristic of cancer-bearing colorectal mucosa.

Activating mutations in the Ki-ras2 oncogene are frequently observed in sporadic colorectal adenomas and their incidence is reported to rise in large and tubulovillous adenomas to values close to those in carcinomas. This study shows that this property is a feature of adenomas growing in large bowel that has already demonstrated its propensity to engender malignant tumours: i.e., bowel in which there is a synchronous carcinoma. Adenomas from cancer-free bowel do not share this high incidence of Ki-ras mutations. This difference in mutation incidence between adenomas from cancer-free and cancer-bearing patients does not appear to derive from sampling bias relative to adenoma size, site, or patient age, nor is it found in another gene (APC) known to be of importance in adenoma formation. Large, dysplastic adenomas from cancer-bearing bowel, however, are particularly liable to carry Ki-ras mutations when they arise in patients over 70 years old. The observations suggest that the role of Ki-ras mutations may be more subtle than merely enhancing adenoma growth. Adenoma cells of cancer-prone individuals may suffer more mutational events than those in persons selected as cancer-free.

Adenoma↗

Functional magnetic resonance image analysis of a large-scale neurocognitive network.

Many "higher-order" mental functions are subserved by large-scale neurocognitive networks comprising several spatially distributed and functionally specialized brain regions. We here report statistical and graphical methods of functional magnetic resonance imaging data analysis which can be used to elucidate the functional relationships (i.e., connectivity and distance) between elements of a neurocognitive network in a single subject. Data were acquired from a normal right-handed volunteer during periodic performance of a task which demanded visual and semantic processing of words and subvocalization of a decision about the meaning of each word. Major regional foci of activation were identified (by sinusoidal regression modeling and spatiotemporal randomization tests) in left extrastriate cortex, angular gyrus, supramarginal gyrus, superior and middle temporal gyri, lateral premotor cortex, and Broca's area. Principal component (PC) analysis was initially undertaken by singular value decomposition (SVD) of the "raw" time series observed at 170 activated voxels. This revealed a large functional distance (negative connectivity) between visual processing systems and all other brain regions in the space of the first PC. SVD of a matrix of fitted time series, and a matrix of six sinusoidal regression parameters estimated at each activated voxel, were developed as less noisy (more informative) alternatives to SVD of the "raw" data. Canonical variate analysis of denoised data was then used to clarify functional relationships between the major regional foci. Visual input analysis systems (extrastriate cortex and angular gyrus) were colocalized in the space of the first canonical variate (CV) and significantly separated from all other brain regions. Semantic analysis systems (supramarginal and temporal gyri) were colocalized and significantly separated in the space of the second CV from the subvocal output system (Broca's area). These results are provisionally interpreted in terms of underlying hemodynamic events and cognitive psychological theory.

Adult↗

Deficits in spatial working memory after unilateral temporal lobectomy in man.

Forty neurosurgical patients and 20 controls were tested on a series of computerized tasks (the executive golf, structured golf and rotate tasks) designed to investigate spatial working memory. As defined by Olton [Spatial Abilities, Academic Press, New York, 1982], spatial working memory involves the encoding of specific and contextual information within the spatial domain. Right temporal lobectomy patients were significantly impaired on all three tasks, while the left temporal lobectomy patients showed a less significant overall impairment only on the structured golf task. Although there was no statistically significant differences between the two patient groups on the three tasks, the results point towards a robust deficit in spatial memory associated with right temporal lobectomy. The results provide further evidence for the role of the mesial temporal lobe structures in the processing and encoding of spatial information.

Adult↗

Spatial working memory and strategy formation in patients with frontal lobe excisions.

Spatial working memory was investigated in 20 patients with unilateral neurosurgical excisions of the frontal cortex (UFL), nine with right (RFL) and eleven with left lesions (LFL), comparing their performance to a matched control group. Spatial memory was tested using the Executive Golf Task, a test that also measures spatial strategy formation. Overall the UFL were significantly impaired, the greatest impairment being found in the RFL group. The difference between the RFL and LFL groups was abolished when a measure of strategy formation was used as a covariate in the analysis. A further test of spatial working memory, the Owl Spatial Working Memory Task, which prevents the use of a spatial strategy, showed a significant and equivalent impairment in both the RFL and LFL patients. The data are consistent with neuropsychological and functional neuroimaging investigations supporting the role of the pre-frontal cortex in spatial working memory.

Adult↗

Decreased NGFI-A gene expression in the hippocampus of cognitively impaired aged rats.

Hippocampal NGFI-A gene expression is increased following the induction of long-term potentiation, a form of activity-dependent synaptic plasticity that has been implicated in learning. In this study, we show a positive correlation between spatial learning and the constitutive expression of NGFI-A mRNA, selectively in CA1 pyramidal neurons. NGFI-A mRNA expression decreased with age in CA1, CA2 and neocortex. Long-term amitriptyline treatment, which improved spatial learning in young rats, had no significant effects on NGFI-A mRNA levels. Whether hippocampal NGFI-A plays a direct role in the mechanism of learning and memory remains to be determined.

Aging↗

Further studies of the role of hippocampal synaptic plasticity in spatial learning: is hippocampal LTP a mechanism for automatically recording attended experience?

Rats trained as normal animals on a delayed matching-to-place task until they were fully familiar with the environment and the strategy required for effective performance were treated with a CSF or D-AP5 at a dose shown to be sufficient to block LTP in vivo. A striking delay-dependent impairment was observed in the AP5-treated animals. These findings indicate that 1-trial event memory depends on NMDA receptors.

2-Amino-5-phosphonovalerate↗

Episodic memory dysfunction during sodium amytal testing of epileptic patients in relation to posterior cerebral artery perfusion.

The effect of filling of the posterior cerebral artery (PCA) on memory performance during the intracarotid sodium amytal test (IAP) was investigated in 57 patients with unilateral temporal epileptic seizure foci under consideration for surgical therapy. Memory functioning was tested following injection of the internal carotid artery contralateral and ipsilateral to the side of seizure focus. In both cases, patients with PCA filling observed using conventional angiography showed a greater memory deficit, although this effect was more robust with contralateral injections. In a subsample of patients with left hemisphere dominance for language, the effect of PCA filling on memory performance was only significant when the right hemisphere was injected. The implications of these findings are discussed in terms of the validity of the IAP test and the different factors that need to be taken into account when interpreting IAP memory performance.

Adult↗