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Biomedical subjects

M A King

Publications and source records attributed to M A King.

At least 19 recordsLinked to original sources
PubMed2001

Potentiation of opioid analgesia in dopamine2 receptor knock-out mice: evidence for a tonically active anti-opioid system.

Dopamine systems are intimately involved with opioid actions. Pharmacological studies suggest an important modulatory effect of dopamine and its receptors on opioid analgesia. We have now examined these interactions in a knock-out model in which the dopamine(2) (D(2)) receptor has been disrupted. Loss of D(2) receptors enhances, in a dose-dependent manner, the analgesic actions of the mu analgesic morphine, the kappa(1) agonist U50,488H and the kappa(3) analgesic naloxone benzoylhydrazone. The responses to the delta opioid analgesic [d-Pen(2),d-Pen(5)]enkephalin were unaffected in the knock-out animals. Loss of D(2) receptors also potentiated spinal orphanin FQ/nociceptin analgesia. Antisense studies using a probe targeting the D(2) receptor revealed results similar to those observed in the knock-out model. The modulatory actions of D(2) receptors were independent of final sigma receptor systems because the final sigma agonist (+)-pentazocine lowered opioid analgesia in all mice, including the D(2) knock-out group. Thus, dopamine D(2) receptors represent an additional, significant modulatory system that inhibits analgesic responses to mu and kappa opioids.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2001

Prolonged cortical silent period after transcranial magnetic stimulation in generalized epilepsy.

Transcranial magnetic stimulation (TMS) produces a cortical silent period (CSP) during a voluntary contraction. The duration of the CSP was used to assess the level of intracortical inhibition in patients with untreated idiopathic generalized epilepsy (IGE). Mean CSP duration was assessed at three TMS stimuli in 21 patients with IGE compared with 19 normal control subjects. Mean CSP duration was increased at all stimulus intensities, indicating that intracortical inhibition is increased in patients with IGE.

Adolescent↗
PubMed2001

Peroxide mediates ethanol-induced cytotoxicity in PC12 cells.

Pheochromocytoma (PC12) cell cultures exhibited a loss of cells and increase in intracellular oxidative stress when exposed to ethanol (EtOH) for 24 h. Catalase, an enzyme that hydrolyzes hydrogen peroxide (H(2)O(2)) to O(2) and H(2)O can attenuate EtOH-induced cell loss and oxidative stress in PC12 cells. This study provides the first clear evidence that oxidative stress in the form of elevated intracellular H(2)O(2) is a primary mechanism of EtOH neurotoxicity in PC12 cells.

Animals↗
PubMed2001

Matching prescription claims with medication data for nursing home residents: implications for prescriber feedback, drug utilisation studies and selection of prescription claims database.

Medication data retrieved from Australian Repatriation Pharmaceutical Benefits Scheme (RPBS) claims for 44 veterans residing in nursing homes and Pharmaceutical Benefits Scheme (PBS) claims for 898 nursing home residents were compared with medication data from nursing home records to determine the optimal time interval for retrieving claims data and its validity. Optimal matching was achieved using 12 weeks of RPBS claims data, with 60% of medications in the RPBS claims located in nursing home administration records, and 78% of medications administered to nursing home residents identified in RPBS claims. In comparison, 48% of medications administered to nursing home residents could be found in 12 weeks of PBS data, and 56% of medications present in PBS claims could be matched with nursing home administration records. RPBS claims data was superior to PBS, due to the larger number of scheduled items available to veterans and the veteran's file number, which acts as a unique identifier. These findings should be taken into account when using prescription claims data for medication histories, prescriber feedback, drug utilisation, intervention or epidemiological studies.

Databases, Factual↗
PubMed2001

The configurational dependence of binding free energies: a Poisson-Boltzmann study of Neuraminidase inhibitors.

The linear finite difference Poisson-Boltzmann (FDPB) equation is applied to the calculation of the electrostatic binding free energies of a group of inhibitors to the Neuraminidase enzyme. An ensemble of enzyme-inhibitor complex conformations was generated using Monte Carlo simulations and the electrostatic binding free energies of subtly different configurations of the enzyme-inhibitor complexes were calculated. It was seen that the binding free energies calculated using FDPB depend strongly on the configuration of the complex taken from the ensemble. This configurational dependence was investigated in detail in the electrostatic hydration free energies of the inhibitors. Differences in hydration energies of up to 7 kcal mol(-1) were obtained for root mean square (RMS) structural deviations of only 0.5 A. To verify the result, the grid size and parameter dependence of the calculated hydration free energies were systematically investigated. This showed that the absolute hydration free energies calculated using the FDPB equation were very sensitive to the values of key parameters, but that the configurational dependence of the free energies was independent of the parameters chosen. Thus just as molecular mechanics energies are very sensitive to configuration, and single-structure values are not typically used to score binding free energies, single FDPB energies should be treated with the same caution.

Binding Sites↗
PubMed2001

Transgene delivery with a cationic lipid in the presence of amyloid beta (betaAP) peptide.

The ability of a cationic lipid to deliver plasmid DNA (pDNA) in presence of the neurotoxic fragment of amyloid beta-peptide was evaluated. Pre-treatment of cells with betaAP (25-35) peptide resulted in a modest increase in transgene expression. When betaAP (25-35) peptide was mixed with the pDNA/liposome complex and used, the complexes lost their ability to transfect. However, the reverse sequenced betaAP (35-25) peptide demonstrated no significant differences in transgene expression in pre-treated cells, and in cells where betaAP (35-25) peptide was mixed with pDNA/liposome complexes and transfected. The amount of pDNA delivered to the cells was decreased in presence of betaAP (25-35) as measured with flow cytometry using fluorescently labeled liposomes. The decreased endocytosis may be due to their rod-like structure formation as demonstrated by electron microscopy and atomic force microscopy (AFM). These results demonstrate that betaAP (25-35) peptide may interfere with gene delivery with cationic systems.

Amyloid beta-Peptides↗
PubMed2001

Multidisciplinary case conference reviews: improving outcomes for nursing home residents, carers and health professionals.

AIM OF STUDY: This study sought to determine whether multidisciplinary case conference reviews improved outcomes for nursing home residents, and the effects of this team approach to resident care on carers, including the hands-on carers employed by the nursing home, and health professionals. METHOD: 245 residents of three Canberra nursing homes were enrolled in this non-randomised controlled trial. The intervention consisted of sessions of three case conference reviews held between 10/4/96 and 4/12/96. These sessions were attended by the General Practitioners (GPs) of the residents discussed, the GP project officer from the ACT Division of General Practice, a clinical pharmacist, senior nursing staff, other health professionals e.g. physiotherapist, and occasionally the resident concerned or their representative. At each review, a case presentation by the resident's GP was followed by a multidisciplinary discussion of all aspects, medical and non-medical, of the resident's care. The review concluded with a management plan for the resident. In total 75 residents were reviewed. MAIN OUTCOME MEASURES: Medication use and cost, and mortality. RESULTS: One month after the reviews were completed comparisons between those who were reviewed and those who were not showed non-significant reductions in medication orders, medication cost, and mortality in the reviewed group. Many of the 92 recommendations in the management plans that were carried out benefited the residents (n = 37) and/or carers (n = 24). The responses of the GPs and the Directors of Nursing to the reviews were overwhelmingly positive. CONCLUSION: Recommendations arising from multidisciplinary case conferences were carried out to the benefit of patients and carers. Given the support shown by key stakeholders, multidisciplinary conferences should be used more.

Aged↗
PubMed2001

Outcomes of a randomized controlled trial of a clinical pharmacy intervention in 52 nursing homes.

AIMS: To evaluate whether a year long clinical pharmacy program involving development of professional relationships, nurse education on medication issues, and individualized medication reviews could change drug use, mortality and morbidity in nursing home residents. METHODS: A cluster randomised controlled trial, where an intervention home was matched to three control homes, was used to examine the effect of the clinical pharmacy intervention on resident outcomes. The study involved 905 residents in 13 intervention nursing homes and 2325 residents in 39 control nursing homes in south-east Queensland and north-east New South Wales, Australia. The outcome measures were: continuous drug use data from government prescription subsidy claims, cross-sectional drug use data on prescribed and administered medications, deaths and morbidity indices (hospitalization rates, adverse events and disability indices). RESULTS: This intervention resulted in a reduction in drug use with no change in morbidity indices or survival. Differences in nursing home characteristics, as defined by cluster analysis with SUDAAN, negated intervention-related apparent significant improvements in survival. The use of benzodiazepines, nonsteroidal anti-inflammatory drugs, laxatives, histamine H2-receptor antagonists and antacids was significantly reduced in the intervention group, whereas the use of digoxin and diuretics remained similar to controls. Overall, drug use in the intervention group was reduced by 14.8% relative to the controls, equivalent to an annual prescription saving of A64 dollars per resident (approximately 25 pound sterling). CONCLUSIONS: This intervention improved nursing home resident outcomes related to changes in drug use and drug-related expenditure. The continuing divergence in both drug use and survival at the end of the study suggests that the difference would have been more significant in a larger and longer study, and even more so using additional instruments specific for measuring outcomes related to changes in drug use.

Age Distribution↗
PubMed2001

Health-related quality of life in narcolepsy.

Narcolepsy is a chronic sleep disorder characterised by symptoms of excessive daytime sleepiness and cataplexy. The aim of this study was to describe the health-related quality of life of people with narcolepsy residing in the UK. The study comprised a postal survey of 500 members of the UK narcolepsy patient association, which included amongst other questions the UK Short Form 36 (SF-36), the Beck Depression Inventory (BDI), and the Ullanlinna Narcolepsy Scale (UNS). A total of 305 questionnaires were included in the final analysis. The results showed that the subjects had significantly lower median scores on all eight domains of the SF-36 than normative data, and scored particularly poorly for the domains of role physical, energy/vitality, and social functioning. The BDI indicated that 56.9% of subjects had some degree of depression. In addition, many individuals described limitations on their education, home, work and social life caused by their symptoms. There was little difference between the groups receiving different types of medication. This study is the largest of its type in the UK, although the limitations of using a sample from a patient association have been recognised. The results are consistent with studies of narcolepsy in other countries in demonstrating the extensive impact of this disorder on health-related quality of life.

Adolescent↗
PubMed2001

Resolution recovery for list-mode reconstruction in SPECT.

The purpose of the study was to evaluate the resolution recovery in the list-mode iterative reconstruction algorithm (LMIRA) for SPECT. In this study we compare the performance of the proposed method with other iterative resolution recovery methods for different noise levels. We developed an iterative reconstruction method which uses list-mode data instead of binned data. The new algorithm makes use of a more accurate model of the collimator structure. We compared the SPECT list-mode reconstruction with MLEM, OSEM and RBI, all including resolution recovery. For the evaluation we used Gaussian shaped sources with different FWHM at three different locations and three noise levels. For these distributions we calculated the reconstructed images for a different number of iterations. The absolute error for the reconstructed images was used to evaluate the performance. The performance of all four methods is comparable for the sources located in the centre of the field of view. For the sources located out of the centre, the error of the list-mode method is significantly lower than that of the other methods. Splitting the system model into a separate object-dependent and detector-dependent module gives us a flexible reconstruction method. With this we can very easily adapt the resolution recovery to different collimator types.

Algorithms↗
PubMed2001

An interior point iterative maximum-likelihood reconstruction algorithm incorporating upper and lower bounds with application to SPECT transmission imaging.

The algorithm we consider here is a block-iterative (or ordered subset) version of the interior point algorithm for transmission reconstruction. Our algorithm is an interior point method because each vector of the iterative sequence [x(k)], k = 0, 1, 2, ... satisfies the constraints a(j) < x(j)k < b(j), j = 1, ..., J. Because it is a block-iterative algorithm that reconstructs the transmission attenuation map and places constraints above and below the pixel values of the reconstructed image, we call it the BITAB method. Computer simulations using the three-dimensional mathematical cardiac and torso phantom, reveal that the BITAB algorithm in conjunction with reasonably selected prior upper and lower bounds has the potential to improve the accuracy of the reconstructed attenuation coefficients from truncated fan beam transmission projections. By suitably selecting the bounds, it is possible to restrict the over estimation of coefficients outside the fully sampled region, that results from reconstructing truncated fan beam projections with iterative transmission algorithms such as the maximum-likelihood gradient type algorithm.

Algorithms↗
PubMed2001

Estrogens decrease reperfusion-associated cortical ischemic damage: an MRI analysis in a transient focal ischemia model.

BACKGROUND AND PURPOSE: Early identification of irreversible cerebral ischemia is critical in defining strategies that influence neuronal survival after stroke. We used MRI to investigate the effects of 17beta-estradiol (E2) on the temporal evolution of focal ischemia. METHODS: Female rats were ovariectomized and divided into 1 of 2 groups: ovariectomy alone (OVX; n=4) or ovariectomy with estrogen replacement (OVX+E2; n=3). Both groups were then subjected to 1-hour middle cerebral artery occlusion (MCAO), with the use of a standardized endovascular monofilament model, followed by reperfusion. Sequential diffusion-weighted (DWI) and T2-weighted (T2WI) MRI were obtained during and after the MCAO. In separate groups of animals (n=5 for OVX and OVX+E2), cerebral blood flow (CBF) was measured by laser-Doppler methods before, during, and after occlusion. RESULTS: DWI detected similar lesion characteristics during MCAO in both groups. In the OVX group, lesion size did not change during reperfusion, but the signal intensity ratio increased early and stabilized during the latter stages. In contrast, DWI lesion size decreased during reperfusion in OVX+E2 rats by 50% to 60% (P<0.05), a size reduction almost exclusively limited to cortical regions. During MCAO, the signal intensity ratio in OVX+E2 rats was reduced compared with OVX rats. Reperfusion further attenuated the signal intensity ratio in cortical but not subcortical regions (P<0.05 versus OVX). T2WI revealed no lesions in either group during MCAO, but it detected lesion sizes similar to that of DWI during reperfusion. Furthermore, similar patterns and magnitudes of estrogen treatment-related decrease in lesion size were noted after reperfusion. T2WI demonstrated less intense signal intensity ratio changes in both groups compared with DWI. There were no differences in CBF between groups either during occlusion, early reperfusion, or 1 day after reperfusion. CONCLUSIONS: This study strongly suggests that estrogens selectively protect cortical tissue from ischemic damage during MCAO and that this protection is exerted during both the occlusion and reperfusion phases of ischemia and does not involve an estrogen-related change in CBF.

Animals↗
PubMed2000

Definition of the anterior choroidal artery territory in rats using intraluminal occluding technique.

This manuscript delineates the territory of the anterior choroidal artery (AChA) in rats, as defined by the induction of an AChA infarction. By advancing a 0.24-mm surgical suture up the internal carotid artery (ICA) to a point 0.5-2 mm proximal to the middle cerebral artery (MCA) origin, the AChA could be occluded and a reliable AChA distribution infarction was produced in 62% (23/37) of animals. The infarct volume, as defined by TTC staining, was 55+/-7 mm(3). Maps of the infarction, generated by measuring the entire area of overlapping coronal slices, demonstrated that the internal capsule was always damaged. Other areas that might be affected included the hippocampus, thalamus, amygdaloid complex, piriform cortex, dorsal caudatoputamen, and lateral ventricular wall. Positioning the coated suture proximal to the AChA produced a much smaller infarct involving the medial and lateral hypothalamus, preoptic region, optic chiasm, and marginal region of the internal capsule near to the lateral hypothalamus exempt from AChA territory damage. A causative relationship between AChA occlusion and a deep cerebral infarct centered on the internal capsule was further established by: (1) identifying the AChA on the non-ischemic side with colored silicone perfusion, and subsequent similar delineation on the ischemic side, and (2) delineating infarction in the silicone perfused AChA region using hematoxylin and eosin staining and the TUNEL method. The AChA usually originated from the ICA (91% of cases), 1.75+/-0.12 mm proximal to the MCA bifurcation. Approximately 27% of the AChAs had periamygdaloid branch(es) on its initial segment.

Animals↗
PubMed2000

Insulin-like growth factor-binding protein-3 modulates expression of Bax and Bcl-2 and potentiates p53-independent radiation-induced apoptosis in human breast cancer cells.

We report that transfection of insulin-like growth factor-binding protein-3 (IGFBP-3) cDNA in human breast cancer cell lines expressing either mutant p53 (T47D) or wild-type p53 (MCF-7) induces apoptosis. IGFBP-3 also increases the ratio of pro-apoptotic to anti-apoptotic members of the Bcl-2 family. In MCF-7, an increase in Bad and Bax protein expression and a decrease in Bcl-x(L) protein and Bcl-2 protein and mRNA were observed. In T47D, Bax and Bad proteins were up-regulated; Bcl-2 protein is undetectable in these cells. As T47D expresses mutant p53 protein, these modulations of pro-apoptotic proteins and induction of apoptosis are independent of p53. The effect of IGFBP-3 on the response of T47D to ionizing radiation (IR) was examined. These cells do not G(1) arrest in response to IR and are relatively radioresistant. Transfection of IGFBP-3 increased the radiosensitivity of T47D and increased IR-induced apoptosis but did not effect a rapid G(1) arrest. IR also caused a much greater increase in Bax protein in IGFBP-3 transfectants compared with vector controls. Thus, IGFBP-3 increases the expression of pro-apoptotic proteins and apoptosis both basally and in response to IR, suggesting it may be a p53-independent effector of apoptosis in breast cancer cells via its modulation of the Bax:Bcl-2 protein ratio.

Apoptosis↗
PubMed2000

Detection of dead cells and measurement of cell killing by flow cytometry.

A flow cytometer can quickly perform numerous quantitative, sensitive measurements on each individual cell within a large, heterogeneous population. The modern commercially available analytical instruments, which can be found in most hospitals, pathology laboratories, and cell biology research laboratories in the industrially developed countries, can now routinely measure fluorescence simultaneously at four different wavelengths, in addition to light scatter in two directions, at rates of thousands of cells per second. Thus, flow cytometry provides a powerful and versatile approach to the measurement of cell death and cell killing. However, it is important to stress that the biological nature of the phenomenon under investigation will determine which assay is appropriate, and at what stage in the process of cell killing it should be applied. This consideration is particularly important in the study of drug- or cell-mediated cytotoxicity.

Animals↗
PubMed2000

There is substantial nuclear and cellular disintegration before detectable phosphatidylserine exposure during the camptothecin-induced apoptosis of HL-60 cells.

BACKGROUND: An early sign of apoptosis in many cells is the appearance of phosphatidylserine (PS) on the outside of the plasma membrane, whilst the cells still retain the ability to exclude DNA-binding molecules such as propidium iodide and 7-aminoactinomycin D (7-AAD). The protein annexin V binds preferentially to PS and has often been used to monitor the early phase of apoptosis. There have been some conflicting results concerning whether annexin V binds to camptothecin (CAM)-treated HL-60 cells, a commonly used model for apoptosis. We investigated the effects of culturing HL-60 cells for up to 8 h with a range of CAM concentrations. METHODS: We used flow cytometry to measure cellular light scatter, annexin V-FITC binding, and 7-AAD uptake, and DNA content after fixation and permeabilization. We also used microscopy to examine the morphology of cells (both unsorted and sorted according to their light scatter) after cytocentrifugation. RESULTS: We found that CAM caused the rapid appearance of low light scatter apoptotic bodies. Even among cells with "normal" light scatter, there was widespread DNA cleavage and nuclear fragmentation by 3 h. The percentage of apoptotic bodies peaked at about 4 h and it was only afterward that annexin V binding could be detected to both intact cells and to apoptotic bodies. When they first appeared, the intact annexin V+ cells had S-phase DNA content. CONCLUSIONS: During CAM-induced apoptosis of HL-60 cells, the external exposure of PS can either precede or follow DNA cleavage, which suggests that PS exposure is not always an indicator of early apoptosis.

Annexin A5↗