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Biomedical subjects

R A Wilcox

Publications and source records attributed to R A Wilcox.

At least 19 recordsLinked to original sources
PubMed2003

Reduction of medical error at the point-of-care using electronic clinical information delivery.

There is accumulating evidence that point-of-care delivery of clinical information such as evidence-based medicine, practice guidelines and drug information can streamline clinical practice and reduce preventable errors. In Australia, hospital-based physicians have -generally been slow to fully use these resources to enhance their clinical practice. Here we provide an introduction to the practical application of several hand-held and electronic information systems available to Australian physicians.

Computers, Handheld↗
PubMed2003

Persistent abnormality detected in the non-ictal electroencephalogram in primary generalised epilepsy.

OBJECTIVES: Gamma oscillations (30-100 Hz gamma electroencephalographic (EEG) activity) correlate with high frequency synchronous rhythmic bursting in assemblies of cerebral neurons participating in aspects of consciousness. Previous studies in a kainic acid animal model of epilepsy revealed increased intensity of gamma rhythms in background EEG preceding epileptiform discharges, leading the authors to test for intensified gamma EEG in humans with epilepsy. METHODS: 64 channel cortical EEG were recorded from 10 people with primary generalised epilepsy, 11 with partial epilepsy, and 20 controls during a quiescent mental state. Using standard methods of EEG analysis the strength of EEG rhythms (fast Fourier transformation) was quantified and the strengths of rhythms in the patient groups compared with with controls by unpaired t test at 1 Hz intervals from 1 Hz to 100 Hz. RESULTS: In patients with generalised epilepsy, there was a threefold to sevenfold increase in power of gamma EEG between 30 Hz and 100 Hz (p<0.01). Analysis of three unmedicated patients with primary generalised epilepsies revealed an additional 10-fold narrow band increase of power around 35 Hz-40 Hz (p<0.0001). There were no corresponding changes in patients with partial epilepsy. CONCLUSIONS: Increased gamma EEG is probably a marker of the underlying ion channel or neurotransmitter receptor dysfunction in primary generalised epilepsies and may also be a pathophysiological prerequisite for the development of seizures. The finding provides a new diagnostic approach and also links the pathophysiology of generalised epilepsies to emerging concepts of neuronal correlates of consciousness.

Adult↗
PubMed2001

B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production.

We describe here a newly identified member of the human B7 family, designated B7 homolog 3 (B7-H3), that shares 20-27% amino acid identity with other B7 family members. B7-H3 mRNA is not detectable in peripheral blood mononuclear cells, although it is found in various normal tissues and in several tumor cell lines. Expression of B7-H3 protein, however, can be induced on dendritic cells (DCs) and monocytes by inflammatory cytokines and a combination of phorbol myristate acetate (PMA) + ionomycin. Soluble B7-H3 protein binds a putative counter-receptor on activated T cells that is distinct from CD28, cytotoxic T lymphocyte antigen 4 (CTLA-4), inducible costimulator (ICOS) and PD-1. B7-H3 costimulates proliferation of both CD4+ and CD8+ T cells, enhances the induction of cytotoxic T cells and selectively stimulates interferon gamma (IFN-gamma) production in the presence of T cell receptor signaling. In contrast, inclusion of antisense B7-H3 oligonucleotides decreases the expression of B7-H3 on DCs and inhibits IFN-gamma production by DC-stimulated allogeneic T cells.Thus, we describe a newly identified costimulatory pathway that may participate in the regulation of cell-mediated immune responses.

Amino Acid Sequence↗
PubMed2001

Perceived barriers to rural nurse practitioner practice.

Studies of barriers to nurse practitioner (NP) practice show similar results for more than 20 years. Comparisons of barriers to rural NP practice have not been performed. Descriptive data about perceived barriers to practice were collected from 292 NPs in one midwestern state (urban, 229; rural, 63; response rate, 60%). A primary barrier was a lack of understanding by the general public about the NP role, which respondents found was detrimental to practice success. Physicians also lacked knowledge about the NP role. Rural practice barriers also included lack of peer support, suggesting that isolation from other NPs detracted from practice success. Educating the public and health professionals about NP education, scope of practice, and roles continues to be necessary. Media campaigns can increase understanding of NP practice. Rural NPs can use electronic means to communicate with each other to decrease practice isolation. Removing barriers to practice remains an ongoing task to enhance rural nursing practice.

Adult↗
PubMed2000

Variable cytochrome P450 2D6 expression and metabolism of codeine and other opioid prodrugs: implications for the Australian anaesthetist.

Codeine is a popular opioid prodrug dependent on the activity of the specific cytochrome P450 enzyme 2D6 (CYP2D6). This enzyme catalyses the production of the potent analgesic metabolite morphine, but genetic studies have demonstrated that individuals from different ethnic groups exhibit considerable variability in the functional capacities of their expressed CYP2D6 enzymes, and pharmacological studies have shown many commonly prescribed drugs can reduce the action of CYP2D6 enzymes. These findings have significant clinical implications for the rational prescription of effective analgesia, especially in a multicultural country like Australia.

Analgesics, Opioid↗
PubMed1999

Evidence for the involvement of a small subregion of the endoplasmic reticulum in the inositol trisphosphate receptor-induced activation of Ca2+ inflow in rat hepatocytes.

The roles of a subregion of the endoplasmic reticulum (ER) and the cortical actin cytoskeleton in the mechanisms by which Ins(1,4,5)P3 induces the activation of store-operated Ca2+ channels (SOCs) in isolated rat hepatocytes were investigated. Adenophostin A, a potent agonist at Ins(1,4,5)P3 receptors, induced ER Ca2+ release and the activation of Ca2+ inflow. The concentration of adenophostin A that gave half-maximal stimulation of Ca2+ inflow (10 nM) was substantially lower than that (20 nM) which gave half-maximal ER Ca2+ release. A low concentration of adenophostin A (approx. 13 nM) caused near-maximal stimulation of Ca2+ inflow but only 20% of maximal ER Ca2+ release. Similar results were obtained using another Ins(1,4,5)P3-receptor agonist, 2-hydroxyethyl-alpha-d-glucopyranoside 2,3',4'-trisphosphate. Anti-type-1 Ins(1,4,5)P3-receptor monoclonal antibody 18A10 inhibited vasopressin-stimulated Ca2+ inflow but had no observable effect on vasopressin-induced ER Ca2+ release. Treatment with cytochalasin B at a concentration that partially disrupted the cortical actin cytoskeleton inhibited Ca2+ inflow and ER Ca2+ release induced by vasopressin by 73 and 45%, respectively. However, it did not substantially affect Ca2+ inflow and ER Ca2+ release induced by thapsigargin or 13 nM adenophostin A, intracellular Ca2+ release induced by ionomycin or Ins(1,4, 5)P3P4(5)-1-(2-nitrophenyl)ethyl ester ['caged' Ins(1,4,5)P3] or basal Ca2+ inflow. 1-(5-Chloronaphthalene-1-sulphonyl)homopiperazine, HCl (ML-9), an inhibitor of myosin light-chain kinase, also inhibited vasopressin-induced Ca2+ inflow and ER Ca2+ release by 53 and 44%, respectively, but had little effect on thapsigargin-induced Ca2+ inflow and ER Ca2+ release. Neither cytochalasin B nor ML-9 inhibited vasopressin-induced Ins(1,4,5)P3 formation. It is concluded that the activation of SOCs in rat hepatocytes induced by Ins(1,4,5)P3 requires the participation of a small region of the ER, which is distinguished from other regions of the ER by a different apparent affinity for Ins(1,4,5)P3 analogues and is associated with the plasma membrane through the actin skeleton. This conclusion is discussed briefly in relation to current hypotheses for the activation of SOCs.

Animals↗
PubMed1998

New developments in the molecular pharmacology of the myo-inositol 1,4,5-trisphosphate receptor.

Receptor-mediated activation of phospholipase C to generate inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] is a ubiquitous signalling pathway in mammalian systems. A family of three IP3 receptor subtype monomers form functional tetramers, which act as effectors for Ins(1,4,5)P3, providing a ligand-gated channel that allows Ca2+ ions to move between cellular compartments. As IP3 receptors are located principally, although not exclusively, in the endoplasmic reticular membrane, Ins(1,4,5)P3 is considered to be a second messenger that mobilizes Ca2+ from intracellular stores. Ca2+ store mobilization by Ins(1,4,5)P3 can be shown to contribute to a variety of physiological and pathophysiological phenomena, and therefore the IP3 receptor represents a novel, potential pharmacological target. In this article, Rob Wilcox and colleagues review recent developments in IP3 receptor pharmacology, with particular emphasis on ligand molecular recognition by this receptor-channel complex. The potential for designing non-inositol phosphate-based agonists and antagonists is also discussed.

Animals↗
PubMed1997

Defining the minimal structural requirements for partial agonism at the type I myo-inositol 1,4,5-trisphosphate receptor.

The novel synthetic analogues D-3-fluoro-myo-inositol 1,5-bisphosphate-4-phosphorothioate, [3F-Ins(1,5)P2-4PS], D-3-fluoro-myo-inositol 1,4-bisphosphate-5-phosphorothioate [3F-Ins(1,4)P2-5PS], and D-3-fluoro-myo-inositol 1-phosphate-4,5-bisphosphorothioate [3F-Ins(1)P-(4,5)PS2] were utilised to define the structure-activity relationships which could produce partial agonism at the Ca2+ mobilising myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor. Based on prior structure-activity data we hypothesised that the minimal structural requirements for lns(1,4,5)P3 receptor partial agonism, were phosphorothioate substitution of the crucial vicinal 4,5-bisphosphate pair accompanied by another structural perturbation, such fluorination of 3-position of the myo-inositol ring. All the analogues fully displaced [3H]Ins(1,4,5)P3 from a single Ins(1,4,5)P3 binding site in pig cerebellar membranes [3F-Ins(1,5)P2-4PS (1C50 = 26 nM), 3F-Ins(1,4)P2-5PS (IC50 = 80 nM) and 3F-Ins(1)P-(4,5)PS2 (IC50 = 109 nM) cf. Ins(1,4,5)P3 (IC50 = 11 nM)]. In contrast, 3F-Ins(1,5)P2-4PS (IC50 = 424 nM) and 3F-Ins(1,4)P2-5PS (IC50 = 3579 nM) were weak full agonists at the Ca2+ mobilising Ins(1,4,5)P3 receptor of permeabilised SH-SY5Y neuroblastoma cells, being respectively 4- and 36-fold less potent than Ins(1,4,5)P3 (EC50 = 99 nM). While 3F-Ins(1)P-(4,5)PS2 (EC50 = 11345 nM) was a partial agonist releasing only 64.3 +/- 1.9% of the Ins(1,4,5)P3-sensitive intracellular Ca2+ pools. 3F-Ins(1)P-(4,5)PS2 was unique among the Ins(1,4,5)P3 receptor partial agonists so far identified in having a relatively high affinity for the Ins(1,4,5)P3 binding site, accompanied by a significant loss of intrinsic activity for Ca2+ mobilisation. This improved affinity was probably due to the retention of the 1-position phosphate, which enhances interaction with the Ins-(1,4,5)P3 receptor. 3F-Ins(1)P-(4,5)PS2 may be an important lead compound for the development of efficient Ins(1,4,5)P3 receptor antagonists.

Animals↗
PubMed1997

Binding and activity of the nine possible regioisomers of myo-inositol tetrakisphosphate at the inositol 1,4,5-trisphosphate receptor.

All 9 racemic regioisomers (15 enantiomerically) of myo-inositol tetrakisphosphates (IP4s): DL-Ins(1,2,4,5)P4 [A], DL-Ins(1,2,4,6)P4 [B], Ins(1,2,3,5)P4 [C], Ins(1,3,4,6)P4 [D], Ins(2,4,5,6)P4 [E], DL-Ins(1,3,4,5)P4 [F], DL-Ins(1,2,5,6)P4 [G], DL-Ins(1,2,3,4)P4 [H] and DL-Ins(1,4,5,6)P4 [I] [Chung S-K., Chang Y-T. Synthesis of all possible regioisomers of myo-inositol tetrakisphosphate. J Chem Soc Chem Commun 1995; 11-13] were investigated for their ability to bind to the D-myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] receptor in bovine adrenal cortical membranes, and for their ability to mobilize 45Ca2+ from Ins(1,4,5)P3-sensitive Ca2+ stores in permeabilized Chinese hamster ovary (CHO) cells. DL-Ins(1,2,4,5)P4 (Ki = 11 nM) bound to Ins(1,4,5)P3 receptors with an affinity only 2-fold lower than Ins(1,4,5)P3 (Ki = 6 nM). Ins(1,2,3,5)P4, Ins(1,3,4,6)P4, Ins(2,4,5,6)P4, DL-Ins(1,3,4,5)P4, DL-Ins(1,2,3,4)P4 and DL-Ins(1,4,5,6)P4 bound with affinities of between 0.4-0.7 microM. DL-Ins(1,2,4,6)P4 and DL-Ins(1,2,5,6)P4 bound to the Ins(1,4,5)P3 receptor with low affinity (approximately 2-3 microM). All but one of the IP4s mediated release of 45Ca2+ from stores of permeabilized CHO cells with a similar rank order of potency as that for Ins(1,4,5)P3 receptor binding, being between 16-fold and 50-fold less potent at releasing 45Ca2+ compared with their apparent binding affinities to the Ins(1,4,5)P3 receptor. The notable exception was Ins(1,2,3,5)P4, which showed an approximately 200-fold lower potency compared with its affinity for the Ins(1,4,5)P3 receptor. Ins(1,2,3,5)P4 may be a useful lead compound for the rational design of novel synthetic Ins(1,4,5)P3 analogues possessing structure-activity profiles with relatively high binding affinity, but low intrinsic efficacy, and hence partial agonists and antagonists at the Ins(1,4,5)P3 receptor.

Animals↗
PubMed1996

Stable overexpression of the type-1 inositol 1,4,5-trisphosphate receptor in L fibroblasts: subcellular distribution and functional consequences.

InsP3 receptor (InsP3R)/Ca(2+)-release channels differ markedly in abundance in different tissues/cell types and InsP3R expression levels may be modulated in response to a variety of external cues. Cell lines overexpressing InsP3Rs will provide useful models for the study of the influence of receptor density and subtype on InsP3-mediated Ca2+ signalling. We have investigated the properties of InsP3Rs in mouse L fibroblast cell lines transfected with either type-1 InsP3R cDNA (L15) or vector control (Lvec). L15 cells express approximately eightfold higher levels of the type-1 InsP3R protein than Lvec cells, as assessed by radioligand binding and immunoblotting. Increased expression was stable since it did not alter over ten cell passages. Both L15 and Lvec cells express predominantly the type-1 InsP3R isoform, indicating that functional differences in the InsP3-mediated Ca2+ signalling in these cell lines are due to alteration in the levels of receptor rather than changes in the isoform expressed. Type-1 InsP3R in L15 cells is largely associated with subcellular membrane fractions bearing the sarco/endoplasmic reticulum Ca2+ ATPase pump, appropriate for rapidly exchanging Ca2+ pools. Functionally, there is an approximately fourfold increase in the sensitivity of permeabilized L15-cell Ca2+ mobilization in response to increasing concentrations of Ins(1,4,5)P3. This study indicates that L15/ Lvec cells provide a suitable model for studying the effects of InsP3R expression level on InsP3-induced Ca2+ mobilization.

Animals↗
PubMed1996

Quantal calcium release in electropermeabilized SH-SY5Y neuroblastoma cells perfused with myo-inositol 1,4,5-trisphosphate.

Continuous perfusion of immobilized electropermeabilized SH-SY5Y neuroblastoma cells was utilised as a novel approach to the assessment of incremental activation and inactivation of myo-inositol 1,4,5-trisphosphate (IP3)-induced calcium (Ca2+) mobilisation (IICM). SH-SY5Y cells when stimulated with sub-optimal IP3 exhibited a rapid concentration dependent activation of Ca2+ mobilization followed by a partial inactivation. Although this partial inactivation allowed net Ca2+ mobilized to be stringently returned to basal levels, a concentration-dependent depletion of the store was maintained while ever perfusion with the stimulating IP3 concentration was sustained. This partial inactivation of IP3-induced quantal Ca2+ release (QCR) was only compromised if cells, with replete Ca2+ stores, were perfused with supra-maximally effective concentrations of IP3 (5-10 microM). Thus, at supra-optimal IP3 concentrations, a reproducible plateau of Ca2+ release lying 50-150 nM above the basal Ca2+ concentration was observed. Feedback on IP3R sensitivity by gross cytosolic Ca2+ levels could be eliminated as the sustained and exclusive mediator of incremental activation/inactivation cycle of IICM in SH-SY5Y cells, since released Ca2+ was perfused away from the immobilized cells. Thus, while ever the cells were continuously perfused with IP3, impressive incremental inactivation was apparent. Additionally, IP3R partial agonists were found to exhibit lower intrinsic activity for both activation and inactivation of QCR, suggesting that ligand-induced inactivation of the IP3R was more important than inactivation mechanisms reliant on either Ca2+ flux through the channel and/or calcium store depletion. Therefore, we suggest that, in perfused SH-SY5Y cells, the most parsimonious explanation of our data is that IP3 binding probably activates and then partially inactivates its receptor in a concentration-dependent fashion to produce the QCR phenomenon.

Calcium↗
PubMed1995

Asymptomatic carotid artery stenosis and stroke in patients undergoing cardiopulmonary bypass.

PURPOSE: This study was undertaken to assess the natural history of carotid artery stenosis in patients undergoing cardiopulmonary bypass (CPB) at a Veterans Administration Medical Center. METHODS: Between January 1989 and August 1993, all patients undergoing CPB were offered preoperative carotid artery ultrasound screening as part of an investigative protocol. Patients were monitored in-hospital for the occurrence of perioperative neurologic deficit. RESULTS: A total of 582 patients underwent carotid artery ultrasound screening. Greater than 50% stenosis or occlusion of one or both internal carotid arteries was present in 130 patients (22%), with 80% or greater stenosis or occlusion of one or both arteries present in 70 patients (12%). In-hospital stroke or death occurred in 12 (2.1%) and 36 (6.2%) patients, respectively. Of the 12 strokes, five were global and seven were hemispheric in distribution. Of the five patients who had global events, none had evidence of carotid artery stenosis. However, of the seven patients who had hemispheric events, five had significant 50% or greater stenosis or occlusion of the internal carotid artery ipsilateral to the hemispheric stroke. Therefore the presence of carotid artery stenosis or occlusion was significantly associated with hemispheric stroke (no stenosis 0.34% vs stenosis 3.8%; p = 0.0072). Furthermore, the risk of hemispheric stroke in patients with unilateral 80% to 99% stenosis, bilateral 50% to 99% stenosis, or unilateral occlusion with contralateral 50% or greater stenosis was 5.3% (4 of 75). No strokes occurred in patients with unilateral 50% to 79% stenosis (n = 52). CONCLUSIONS: It is concluded that carotid atherosclerosis is a risk factor for hemispheric stroke in patients undergoing CPB.

Adult↗