PubMed Health⌕ Search

Biomedical subjects

C M Richardson

Publications and source records attributed to C M Richardson.

At least 19 recordsLinked to original sources
PubMed2005

Cyclooxygenase-2 protein levels are independent of epidermal growth factor receptor expression or activation in operable non-small cell lung cancer.

UNLABELLED: Both cyclooxygenase (COX)-2 and epidermal growth factor receptor (EGFR) are thought to play important roles in the pathogenesis of non-small cell lung cancer (NSCLC). A number of in vitro studies have postulated a link between EGFR activation and subsequent COX-2 upregulation. The relationship between these factors has not been established in patients with NSCLC. COX-2 and EGFR expression were studied in 172 NSCLC specimens using standard immunohistochemical techniques. Western blotting was used to determine COX-2 and EGFR levels in five NSCLC cell lines. The effect of treatment with EGF on COX-2 expression in A549 cells was assessed. RESULTS: Both EGFR and COX-2 are overexpressed in NSCLC. The predominant pattern of COX-2 and EGFR staining was cytoplasmic. Membranous EGFR staining was seen in 23.3% of cases. There was no relationship between COX-2 and EGFR expression and survival or any clinicopathological features. No correlation was seen between EGFR expression and COX-2 expression in the immunohistochemical series or in the cell lines. Treatment with EGF did not upregulate COX-2 levels in A549 cells, either in serum free or serum-supplemented conditions. CONCLUSIONS: Although COX-2 and EGFR are over-expressed in NSCLC neither was of prognostic significance in this series of cases. There is no correlation between these two factors in either tumour samples or cell lines. Although these factors show no correlation in NSCLC, they remain potential, though independent targets for treatment.

Aged↗
PubMed2003

Excitatory effects of oxytocin and cholecystokinin on oxytocin neurones: differences between virgin, pregnant and lactating rats.

Extracellular recordings were made from supraoptic oxytocin (OT) neurones in rat brain slices to investigate the effect of reproductive state on their excitation by OT and cholecystokinin (CCK). Stable background activity was induced by local glutamate application, and OT neurones were identified by their continuous firing and opioid inhibition. The excitatory effect of OT (indicated by percentage neurones excited, peak increment in firing, and response magnitude) was maximal in lactating rats, intermediate in virgin, and lowest in pregnant animals. Excitation by CCK was high in both lactating and virgin rats but, as with OT tests, was minimal in the pregnant group. These adaptations in the responses to OT and CCK may help to ensure that the firing of OT neurones is appropriately regulated to meet changing demands for OT release.

Action Potentials↗
PubMed2003

Epidermal growth factor receptors and cyclooxygenase-2 in the pathogenesis of non-small cell lung cancer: potential targets for chemoprevention and systemic therapy.

The epidermal growth factor receptor (EGFR) is part of a family of plasma membrane receptor tyrosine kinases that control many important cellular functions, from growth and proliferation to cell death. Cyclooxygenase (COX)-2 is an enzyme which catalyses the conversion of arachidonic acid to prostagladins and thromboxane. It is induced by various inflammatory stimuli, including the pro-inflammatory cytokines, Interleukin (IL)-1beta, Tumour Necrosis Factor (TNF)-alpha and IL-2. Both EGFR and COX-2 are over-expressed in non-small cell lung cancer (NSCLC) and have been implicated in the early stages of tumourigenesis. This paper considers their roles in the development and progression of lung cancer, their potential interactions, and reviews the recent progress in cancer therapies that are directed toward these targets. An increasing body of evidence suggests that selective inhibitors of both EGFR and COX-2 are potential therapeutic agents for the treatment of NSCLC, in the adjuvant, metastatic and chemopreventative settings.

Carcinoma, Non-Small-Cell Lung↗
PubMed2002

Percutaneous lung biopsies: a survey of UK practice based on 5444 biopsies.

Percutaneous transthoracic lung biopsies are commonly performed for the investigation of lung masses. We describe current practice and complication rates in the UK. A postal questionnaire was sent to all centres in the British Thoracic Society directory. 157 replies (61% response rate) were received, providing data on 5444 biopsies. Mean number of biopsies performed per annum was 30.5 per centre; 8% of centres did not perform biopsies, 36% performed <25 biopsies per annum, 34% <50, 16% <100 and 6% >100. Consultant radiologists perform 91% of biopsies. Written consent was obtained at all centres. The operator obtained consent at 50% of centres. Written information for patients was provided at 35 (24%) centres. Biopsies are performed on a day case basis at 103 (71%) centres. Prior to biopsy the following were obtained routinely: CT scan (73% of centres), platelet count (73%), full clotting screen (70%), lung function (55%). Complications included pneumothorax (20.5% of biopsies), pneumothorax requiring chest drain (3.1%), haemoptysis (5.3%) and death (0.15%). The timing of post-procedure chest radiography was variable. Those centres that performed predominantly cutting needle biopsies had similar pneumothorax rates to centres performing mainly fine needle biopsies (18.9% vs 18.3%). There is great variation in practice throughout the UK. Most procedures are performed on a daycase basis. Small pneumothoraces are common but infrequently require treatment. National guidelines are needed to ensure consistency of standards.

Biopsy↗
PubMed2000

Rational design of femtomolar inhibitors of isoleucyl tRNA synthetase from a binding model for pseudomonic acid-A.

This paper describes the design and characterization of novel inhibitors of IleRS, whose binding affinity approaches the tightest reported for noncovalent inhibition. Compounds were designed from a binding model for the natural product pseudomonic acid-A (PS-A) together with a detailed understanding of the reaction cycle of IleRS and characterization of the mode of binding of the reaction intermediate IleAMP. The interactions of the compounds with IleRS were characterized by inhibition of aminoacylation of tRNA or PP(i)/ATP exchange at supersaturating substrate concentration and by transient kinetics and calorimetry methods. A detailed understanding of the interaction of a comprehensive series of compounds with IleRS allowed the identification of key features and hence the design of exquisitely potent inhibitors. Predictions based on these results have been recently supported by a docking model based on the crystal structure of IleRS with PS-A [Silvian, L. F., Wang J. M., and Steitz T. A. (1999) Science 285 1074-1077].

Anti-Bacterial Agents↗
PubMed2000

Permissive effect of centrally administered oxytocin on the excitatory response of oxytocin neurones to ventral tegmental stimulation in the suckled lactating rat.

The mesencephalic ventral tegmentum has been implicated in the milk-ejection reflex and modulation of inputs from this region could provide a mechanism whereby central oxytocin facilitates synchronous bursting of oxytocin neurones during suckling. Experiments were therefore undertaken to investigate the effect of intracerebroventricular (i.c.v.) oxytocin on the response of oxytocin neurones to ventral tegmental stimulation. Oxytocin neurones were recorded in the supraoptic nucleus of urethane-anaesthetized lactating rats during suckling, and their response to single shock stimulation of the ventral tegmentum was monitored using peri-stimulus time-interval histograms. Before i.c.v. oxytocin, oxytocin neurones were either unresponsive to ventral tegmental stimulation, or displayed a small inhibition. However, after administration of oxytocin (2.2 ng i.c.v.), seven out of eight neurones tested displayed a pronounced excitatory response (onset latency 78.4 +/- 4.8 ms, duration 73.4 +/- 8.3 ms). This permissive effect on the excitatory response was only observed in the presence of suckling, and followed the same time course as facilitation of the milk-ejection reflex, being maximal immediately before each facilitated bursting response in the oxytocin neurones. The response to ventral tegmental stimulation remained unaltered after intraperitoneal administration of hypertonic saline to cause a generalized increase in the excitability of the oxytocin neurones. Moreover, i.c.v. oxytocin had no effect on the response of oxytocin neurones to stimulation of a descending input from the medial septum. In conclusion, administration of i.c.v. oxytocin has a selective permissive effect on the excitation of oxytocin neurones from the ventral tegmentum, and this supports previous in vitro studies suggesting that centrally released oxytocin may act as a modulator of afferent transmission to the magnocellular nuclei. This effect on the afferent excitation of oxytocin neurones may provide a mechanism whereby i.c.v. oxytocin facilitates suckling-evoked bursting activity.

Action Potentials↗
PubMed1999

Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response.

BACKGROUND: Treatment-resistance in schizophrenia remains a public health problem. Clozapine has been shown to be effective in about one third of this population, but carries with it medical risks and weekly blood draws. As olanzapine is a drug with a very similar biochemical profile to clozapine, it is important to evaluate whether non-response to olanzapine predicts clozapine non-response. METHODS: Forty-four treatment-resistant patients received eight weeks of olanzapine, either in a double-blind trial or subsequent open treatment at a mean daily dose of 25 mg/day. Two of 44 patients (5%) responded to olanzapine treatment. Patients who did not respond could then receive clozapine. Twenty-seven subsequently received an 8-week open trial of clozapine. RESULTS: Patients who did and did not receive clozapine did not differ demographically or in psychopathology. Eleven of 27 (41%) met a priori response criteria during clozapine treatment (mean dose 693 mg/day) after failing to respond to olanzapine. CONCLUSIONS: This study demonstrates that failure to respond to olanzapine treatment does not predict failure to clozapine. Treatment-resistant patients who fail on olanzapine may benefit from a subsequent trial of clozapine.

Adult↗
PubMed1999

Molecular recognition of tyrosinyl adenylate analogues by prokaryotic tyrosyl tRNA synthetases.

Molecular modelling and synthetic studies have been carried out on tyrosinyl adenylate and analogues to probe the interactions seen in the active site of the X-ray crystal structure of tyrosyl tRNA synthetase from Bacillus stearothermophilus, and to search for new inhibitors of this enzyme. Micromolar and sub-micromolar inhibitors of tyrosyl tRNA synthetases from both B. stearothermophilus and Staphylococcus aureus have been synthesised. The importance of the adenine ring to the binding of tyrosinyl adenylate to the enzyme, and the importance of water-mediated hydrogen bonding interactions, have been highlighted. The inhibition data has been further supported by homology modelling with the S. aureus enzyme, and by ligand docking studies.

Adenine↗
PubMed1998

Supraoptic oxytocin and vasopressin neurones show differential sensitivity to the neurosteroid pregnenolone sulphate.

The neurosteroid pregnenolone sulphate (PS) interacts allosterically with ionotropic glutamate receptors and thereby could be an important modulator of activity within the hypothalamic magnocellular nuclei. The present in-vitro study therefore examined the effect of perifusion of PS (100 microM) on activity of supraoptic oxytocin (OT) and vasopressin (VP) neurones, in which firing was stimulated by local application of glutamate, NMDA or AMPA. In the presence of locally applied glutamate, PS significantly potentiated firing in putative VP neurones, but had little effect on putative OT neurones. In both cell types, PS increased firing in the presence of NMDA and depressed firing in the presence of AMPA. The action of PS on glutamate- and NMDA-stimulated firing was unaffected by addition of the GABA(A) receptor antagonist, picrotoxin (50 microM). The suppressive action of PS on AMPA-stimulated firing was, however, reversed by picrotoxin and therefore probably requires intact GABAergic transmission for its expression. When putative VP neurones were stimulated by local application of K+, in the presence of picrotoxin, PS evoked a small increase in the ongoing activity, although this did not reach significance. When the glutamate receptor antagonists, NBQX (20 microM) and AP5 (40 microM), were included in the medium, no change in K+ -stimulated firing was observed. Hence PS has no effect on activity of putative VP neurones in the absence of exogenous and endogenous glutamate excitation. In conclusion, PS selectively potentiates glutamate-stimulated activity in putative VP neurones, probably via NMDA receptors, thus providing a mechanism whereby this neurosteroid might exert rapid non-genomic effects on VP secretion. The lack of effect of PS in putative OT neurones probably relates to the relatively small involvement of NMDA receptors in mediating glutamate excitation in this cell type.

Animals↗
PubMed1998

Ethics and employee benefits.

The following article attempts to bring to light the many questions and thoughts regarding ethical behavior as it relates to the employee benefits profession. Rather than dictating to the reader all the answers regarding ethics, the article demonstrates the different ways various situations can be interpreted. It leaves open the choices available to employee benefits professionals, while compelling us to confront the difficult decisions we must face when dealing with employees, employers and insurance companies.

Ethics, Institutional↗
PubMed1997

Glutamate excitation of oxytocin neurones in vitro involves predominantly non-NMDA receptors.

Experiments were undertaken to compare effects of the NMDA and non-NMDA receptor antagonists, AP5 (40 microM) and NBQX (10 microM), on glutamate-induced firing in supraoptic oxytocin (OT) and vasopressin (VP) neurones in vitro. In putative OT neurones NBQX caused a significantly greater reduction in firing than AP5, whilst in putative VP neurones both antagonists reduced activity powerfully and to a similar extent. The relatively small effect of AP5 in putative OT neurones was unaffected by the removal of extracellular magnesium. These results suggest that glutamate-induced firing in putative OT neurones is predominantly controlled by non-NMDA receptors.

2-Amino-5-phosphonovalerate↗
PubMed1997

The neurosteroid pregnenolone sulphate enhances NMDA-induced phasic firing of vasopressin neurones in the rat supraoptic nucleus.

The effect of the neurosteroid pregnenolone sulphate (PS) on N-methyl-D-aspartate (NMDA)-induced phasic firing of supraoptic vasopressin (VP) neurones was studied in rat hypothalamic slices in vitro. In VP neurones which were induced to fire phasically by continuous perifusion with NMDA (9-30 microM), addition of 100 microM PS to the incubation medium significantly increased overall spike frequency, with a rise in both proportion of time active and intraburst firing rate. A similar effect was seen during picrotoxin block of GABAergic transmission. No significant change in NMDA-induced phasic firing was observed with 100 microM dehydroepiandrosterone sulphate. VP neurones became silent in the absence of NMDA, and under these conditions PS had no effect. In conclusion, PS increases NMDA-induced phasic firing in VP neurones, providing a mechanism whereby this neurosteroid may participate in the regulation of VP secretion.

Animals↗
PubMed1997

ATP acting on P2Y receptors triggers calcium mobilization in Schwann cells at the neuroelectrocyte junction in skate.

Schwann cells are integral cellular components of the dense cholinergic presynaptic plexus (nerve plate) which innervates each electrocyte in skate electric organ. Using the Ca2+-sensitive dye fura-2, we have followed the response in these cells to various chemical challenges. In K+ depolarized nerve plates nerve terminals consistently responded with a rapid and sustained Ca2+ signal. Schwann cell responses to depolarization were rarely seen but, when observed, were always delayed in onset when compared to nerve terminal response (6-10 s later). The possibility that these responses were triggered by mediators released from nerve terminals was tested by direct application of candidate substances. Schwann cells were found to respond to adenosine triphosphate and adenosine diphosphate with a biphasic increase of intracellular Ca2+ concentration, a rapid peak response being followed in the majority of cells by a sustained plateau phase. In the absence of external Ca2+ only the transient peak response was observed. Depletion of internal Ca2+ stores with thapsigargin completely inhibited the adenosine triphosphate-stimulated rise in Schwann cell Ca2+. The response to adenosine triphosphate was concentration-dependent (EC50 2.8 microM) and was reversibly blocked by two antagonists of P2 purinoceptors: suramin and reactive blue 2. Adenosine diphosphate and 2-methylthio-adenosine triphosphate were equipotent with adenosine triphosphate and at high concentrations (100 microM) diadenosine tetraphosphate produced responses comparable to low concentrations of adenosine triphosphate. Adenosine, adenosine monophosphate, the alpha beta-methylene analogues of adenosine triphosphate and adenosine diphosphate, uridine triphosphate, cytidine triphosphate and guanosine triphosphate were without significant effect. These results show that, in skate electric organ Schwann cells, the release of Ca2+ from intracellular stores is triggered by adenosine triphosphate acting on P(2gamma) receptors and suggest that Schwann cells may be targets for synaptically-released adenosine triphosphate in the electric organ model of the neuromuscular junction.

Acetylcholine↗
PubMed1996

Inhibition of acetylcholine release from presynaptic terminals of skate electric organ by calcium channel antagonists: a detailed pharmacological study.

Release of acetylcholine (ACh) from the presynaptic terminals in skate electric organ was tested for its sensitivity to calcium channel antagonists. A pharmacological profile was established by measuring inhibition of K(+)-stimulated release of [3H]ACh from prelabelled tissue slices. Peptide antagonists of N-type (omega-conotoxins GVIA and MVIIA) and P-type (omega-agatoxin-IVA) channels had no effect, whereas both omega-conotoxins MVIIC and SVIB produced concentration-dependent inhibition and could completely block ACh release. omega-Conotoxin GVIA and omega-agatoxin IVA did not attenuate the block by omega-conotoxin MVIIC. The inorganic ions, Cd2+ and Ni2+, also produced a full inhibition of release (Cd2+ > > Ni2+) and Gd3+ a partial one. Drugs targeting L-type channels (diltiazem, nifedipine and verapamil) at low microM concentrations and a synthetic analogue of the polyamine toxin from funnel web spider venom (sFTX) at 1 mM were all non-inhibitory. Inhibition by omega-conotoxins MVIIC (IC50 25 nM) and SVIB (IC50 500 nM) was reversible and modulated by external concentrations of Ca2+. Inhibitory potency was increased by lowering and decreased by elevating external Ca2+. This "antagonistic" effect of Ca2+ was also seen with Cd2+ inhibition. The inhibitory potency of omega-conotoxin MVIIC was unaffected by predepolarisation. End plate potentials generated by release of endogenous ACh in electrically-stimulated slices were also reversibly blocked by Cd2+ and omega-conotoxins MVIIC and SVIB but were unaffected by omega-conotoxin GVIA and omega-agatoxin IVA. It is concluded that ACh release in skate electric organ depends on presynaptic calcium channels which have different pharmacological properties from established sub-types.

Acetylcholine↗