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D C West

Publications and source records attributed to D C West.

At least 55 records · Page 3Linked to original sources
PubMed1993

Single axon excitatory postsynaptic potentials in neocortical interneurons exhibit pronounced paired pulse facilitation.

In slices of adult rat somatosensory/motor cortex, paired recordings were made from pyramidal and non-pyramidal neurons. Single axon excitatory postsynaptic potentials evoked in the non-pyramidal neuron by action potentials in the pyramidal neuron were large and fast and demonstrated large fluctuations in amplitude, with coefficients of variation between 0.1 and 1.25. Excitatory postsynaptic potential amplitude distributions included a large number of apparent failures of transmission as well as some extremely large events. This contrasted dramatically with the relatively narrow distribution of amplitudes for pyramid-pyramid connections in neocortex. Excitatory postsynaptic potentials increased in amplitude with postsynaptic membrane hyperpolarization. Very small changes in the coefficient of variation when mean amplitudes increased substantially were consistent with the increase being due to a change in quantal amplitude. These excitatory postsynaptic potentials displayed profound paired pulse facilitation. Moreover, third and fourth spikes in a presynaptic burst also evoked large responses. This facilitation was associated with a decrease in the proportion of apparent failures in transmission and a change in the shape of the excitatory postsynaptic potential amplitude distribution, both indicative of an increase in the probability of transmitter release. However a large change in the mean amplitude was not associated with a similar change in the inverse square of the coefficient of variation. The result of this third test, taken in isolation, might therefore suggest that quantal amplitude had increased with paired-pulse facilitation. However, of the three tests applied, this last is the most heavily model-dependent and produced a result inconsistent with the results of the other two tests. The possibility is therefore discussed that both the shape of the excitatory postsynaptic potential amplitude distribution and the failure of coefficient of variation analysis to detect an apparently presynaptic change might result from the release at these synapses being poorly fit by a simple model. Based on a more complex model of synaptic release proposed by Faber and Korn [Faber and Korn (1991) Biophys. J. 60, 1288-1294] and a hypothesis proposed by Scharfman et al. [Scharfman et al. (1990) Neuroscience 37, 693-707], two hypotheses arising from the present study are discussed: (i) that branch point failure contributes to the pattern of synaptic activation at these connections; and (ii) that both presynaptic pyramidal firing pattern and axonal geometry contribute to the selection of the type of postsynaptic neurone preferentially activated.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Large, deep layer pyramid-pyramid single axon EPSPs in slices of rat motor cortex display paired pulse and frequency-dependent depression, mediated presynaptically and self-facilitation, mediated postsynaptically.

1. In slices of rat sensorimotor cortex, dual intracellular recordings were obtained from 1,952 pairs of deep layer pyramidal neurons. Where action potentials in one neurone elicited excitatory postsynaptic potentials (EPSPs, n = 56) in the other, responses to different presynaptic firing rates and patterns and at different postsynaptic membrane potentials were recorded and on some occasions both neurons were filled with biocytin. 2. Slices were fixed, sectioned again at 60 microns, and incubated with Avidin horseradish peroxidase (HRP), which was then visualized using the 3,3'-diaminobenzidine tetrahydrochloride (DAB) method. All neurones reported here that were identified histologically were pyramidal cells with their somata in the deep layers (V and VI). 3. One in 70 of the tests performed revealed a synaptic connection, 25 of which were studied in detail. Mean EPSP amplitude was 1.67 +/- 1.66 (SD) mV, with some single sweep events as large as 9 mV. For some of the smaller EPSPs the amplitude distributions contained a clear peak around 0 mV, the coefficient of variation (CV) was large, and paired pulse facilitation was apparent. EPSPs with large average amplitudes displayed no apparent failures of transmission, EPSP amplitudes were fairly evenly distributed around the mean, CVs were small, and paired pulse depression was apparent in 2.5 mM extracellular Ca2+. When single sweeps were selected according to the size of the first EPSP, large second EPSPs were found to follow small first EPSPs and small second EPSPs to follow large first EPSPs. Paired pulse effects appeared, in the majority of tests, to be due to a change in presynaptic release probability. 4. Two EPSPs were recorded in three different extracellular Ca2+ concentrations. In 1 mM Ca2+, the first EPSP of a short interval pair was small and paired pulse facilitation was apparent. In 5 mM Ca2+, first EPSPs were between 2.5 and 4 times larger than in 1 mM Ca2+ and paired pulse depression was apparent. In all Ca2+ concentrations however, averaged third and fourth EPSPs of brief bursts were of similar amplitudes and smaller than second EPSPs. If presynaptic inhibition does contribute to paired pulse effects here, it is not overcome by a combination of raised extracellular Ca2+ and repetitive presynaptic firing. 5. These EPSPs displayed a wide range of time courses. The mean 10-90% rise time was 2.49 +/- 1.08 ms, the mean width at half amplitude was 15.39 +/- 5.42 ms (n = 22), and the mean EPSP latency was 1.59 +/- 0.68 ms (n = 18). (ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Stage III neuroblastoma over 1 year of age at diagnosis: improved survival with intensive multimodality therapy including multiple alkylating agents.

PURPOSE: A nonrandomized, single-arm trial was conducted to assess the efficacy of multimodality therapy including intensive chemotherapy with multiple alkylating agents in the treatment of children with Evans stage III neuroblastoma older than 1 year at diagnosis. PATIENTS AND METHODS: Twenty-five patients with a median age of 18 months at diagnosis were treated with multimodality therapy including surgery and chemotherapy using either nitrogen mustard (mechlorethamine), doxorubicin, cisplatin, dacarbazine (DTIC), vincristine, and cyclophosphamide (MADDOC) or cisplatin and cyclophosphamide induction followed by maintenance MADDOC (induction MADDOC) protocols. Sixteen of 25 patients also received radiotherapy to the tumor bed and primary lymph nodes. Event-free survival (EFS) was compared with that reported previously in the literature. N-myc amplification was evaluated prospectively and the Shimada classification was evaluated retrospectively as potential prognostic factors. RESULTS: We report a 72% EFS (95% confidence interval +/- 18%) with a median follow-up of 85 months. EFS was significantly worse for patients with tumors demonstrating N-myc amplification (P = .018). Patients classified as favorable according to the Shimada system experienced a significantly better EFS (P = .04), but unfavorable patients still maintained a 60% EFS. CONCLUSION: Intensive multimodality treatment including MADDOC and induction MADDOC chemotherapy provides a very good EFS for children older than 1 year who have stage III neuroblastoma. Children classified as favorable according to the Shimada system have a better prognosis. Patients whose tumors demonstrate N-myc amplification have a poor prognosis despite therapy.

Alkylating Agents↗
PubMed1992

Does hyaluronan have a role in endothelial cell proliferation of the synovium?

Hyaluranate (HA) is a major constituent of synovial fluid, but its concentration and molecular size differ in normal and inflamed joints. HA can induce or inhibit angiogenesis depending on both its size and its concentration. Endothelial-cell endocytose-labeled macromolecular HA and HA oligosaccharides and binding studies have identified an HA-specific receptor on the endothelial cell surface (KD, 10(-10) mol/L; approximately 2,000/cell). The molecular weight of HA-binding proteins was found to be 90 to 125, 78, and 46 kd.

Animals↗
PubMed1992

Push-pull cannula for localized application of drugs and sampling of medium, combined with electrophysiological recordings in an interface slice chamber.

These experiments combined electrophysiological recordings from hippocampal slices with application of drugs to and sampling of extracellular fluid from a restricted region of the slice using a push-pull cannula placed under the slice in an interface chamber. Stable and apparently normal extracellular and intracellular recordings could be obtained directly over the tip of the cannula and solutions changed without disturbing the recording. Relatively rapid effects (1-5 min) were observed when TTX, CNQX, or medium containing 50 mM K+ were applied via the cannula and recovery from these effects was achieved. In addition, effects were restricted to the immediate vicinity of the cannula; neurones recorded several hundred micrometers away were apparently unaffected. Samples of extracellular fluid obtained as minute fractions during the application of high K+ containing medium contained higher concentrations of GABA, aspartate and glutamate than control fractions but the same levels of other amino acids, e.g., isoleucine and leucine. With appropriate design of push-pull cannula and recording chamber, therefore, stable electrophysiological recordings can be combined with localized extracellular fluid sampling and rapid and localized application of test solutions in an interface slice chamber.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1991

TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.

Previously we described joining of DNA in the beta T cell receptor gene to DNA of an uncharacterized locus in a t(7;9)(q34;q34.3) chromosomal translocation from a case of human T lymphoblastic leukemia (T-ALL). We now show that the locus on chromosome 9 contains a gene highly homologous to the Drosophila gene Notch. Transcripts of the human gene, for which we propose the name TAN-1, and its murine counterpart are present in many normal human fetal and adult mouse tissues, but are most abundant in lymphoid tissues. In t(7;9)(q34;q34.3) translocations from three cases of T-ALL, the breakpoints occur within 100 bp of an intron in TAN-1, resulting in truncation of TAN-1 transcripts. These observations suggest that TAN-1 may be important for normal lymphocyte function and that alteration of TAN-1 may play a role in the pathogenesis of some T cell neoplasms.

Amino Acid Sequence↗
PubMed1991

Angiogenesis in wound healing.

Angiogenesis is an essential component of wound healing. Vessel growth is controlled by the local actions of chemical mediators, the extracellular matrix, metabolic gradients, and physical forces. Manipulation of some of these factors can improve healing in experimental wounds. The clinical potential and specific application of 'angiomodulatory' strategies are discussed.

Angiogenesis Inducing Agents↗
PubMed1990

A comparison of the sensitivity to photodynamic treatment of endothelial and tumour cells in different proliferative states.

Bovine aorta endothelial and human colon adenocarcinoma (WiDr) cells were exposed to haematoporphyrin derivative plus light. Cell survival was determined using a [3H]thymidine incorporation and a clonogenic assay for both cell types. The endothelial cells were more sensitive to photodynamic treatment. This could be explained in terms of increased drug uptake into the endothelial cells despite there being no difference in cell volume between the cells. For both tumour and endothelial cells, exponentially growing cells were more sensitive to photodynamic treatment than plateau-phase cells. This was associated with a reduction in drug uptake into plateau-phase endothelial cells. However, there was no difference in uptake into exponentially growing and plateau-phase WiDr cells.

Animals↗
PubMed1990

Factors affecting slow regular firing in the suprachiasmatic nucleus in vitro.

In isolated slices of hypothalamus, suprachiasmatic nucleus (SCN) neurons were recorded intracellularly. Blockade of Ca++ channels increased spike duration, eliminating an early component of the afterhyperpolarization (AHP) that followed evoked spikes. The duration and reversal potential of AHPs were, however, unaffected, suggesting that only an early, fast component of the AHP was Ca(++)-dependent. Unlike other central neurons that exhibit pacemaker activity, therefore, SCN neurons do not display a pronounced, long-lasting Ca(++)-dependent AHP. Extracellular Ba++ and intracellular Cs+ both revealed slow depolarizing potentials evoked either by depolarizing current injection, or by repolarization following large hyperpolarizations. They had different effects on the shape of spikes and the AHPs that followed them, however. Cs+, which blocks almost all K+ channels, dramatically reduced resting potential, greatly increased spike duration (to tens of milliseconds), and blocked AHPs completely. In contrast, Ba++ had little effect on resting potential and produced only a small increase in spike duration, depressing an early Ca(++)-dependent component and a later Ca(++)-independent component of the AHP. The relatively weak pacemaker activity of SCN neurons appears to involve voltage-dependent activation of at least one slowly inactivating inward current, which brings the cells to firing threshold and maintains tonic firing; both Ca(++)-dependent and Ca(++)-independent K+ channels, which repolarize cells after spikes and maintain interspike intervals; and Ca++ channels, which contribute to activation of Ca(++)-activated K+ currents and may also contribute to slow depolarizing potentials. In the absence of powerful synaptic inputs, SCN neurons express a pacemaker activity that is sufficient to maintain an impressively regular firing pattern. Slow, repetitive activation of optic input, however, increases local circuit activity to such an extent that the normal pacemaker potentials are overridden and firing patterns are altered. Since SCN neurons are very small and have large input resistances, they are particularly susceptible to synaptic input.

Animals↗
PubMed1989

Sera of children with renal tumours contain low-molecular-mass hyaluronic acid.

The molecular mass of hyaluronic acid (HA) rather than its serum concentration alone may be a hallmark of certain types of malignancy. A radiometric assay was used to measure HA levels in 35 children with renal tumours [33 Wilms' tumours and 2 bone metastasizing renal tumours of childhood (BMRTC)] and 20 normal siblings of children with cancer. The HA level in the sera of normal children was barely detectable and had a molecular mass of 1-5 x 10(5). In both Wilms' and BMRTC patients, very high levels of HA were found in preoperative serum samples; these fell dramatically following surgical excision of the tumours. A novel finding of our study was the presence of low-molecular-mass HA (similar to the angiogenic fragments of HA) in the sera of BMRTC patients. In contrast, high-molecular-mass HA (which is not angiogenic) was found in the sera of Wilms' patients (2 x 10(6) kDa). Following surgery in BMRTC patients, not only did serum HA levels fall to a value within normal ranges, but also the HA which remained was of high molecular mass.

Adolescent↗
PubMed1989

Hyaluronan and angiogenesis.

Remodelling tissues, in both normal and pathological situations, show a greatly increased synthesis and turnover of hyaluronan. An essential part of these processes is new blood vessel formation. Whereas native hyaluronan has been reported to inhibit angiogenesis in vivo, partial degradation products (4-25 disaccharide units) have been found to stimulate angiogenesis in several in vivo systems. Examination of the effect of hyaluronan and its oligosaccharides on cultured cells suggests that these effects are due to the direct action of hyaluronan on endothelial cells. Native HA inhibits endothelial cell proliferation and disrupts cell-cell/cell-substrate interactions at physiological concentration. Angiogenic oligosaccharides induce both endothelial proliferation and migration, possibly via a receptor-mediated mechanism. Thus the metabolic state of hyaluronan could have profound effects on tissue neovascularization.

Animals↗
PubMed1989

The effect of hyaluronate and its oligosaccharides on endothelial cell proliferation and monolayer integrity.

Hyaluronidase treatment of hyaluronic acid produced a series of oligosaccharides. Those between 3 and 16 disaccharides in length stimulated angiogenesis in vivo and the proliferation of tissue cultured endothelial cells in vitro. This effect appears to be cell type specific, as no stimulation of fibroblasts or smooth muscle cells was observed. Endothelial cells were found to endocytose both high- and low-molecular-mass hyaluronate, which might be receptor mediated. Fibroblasts and smooth muscle cells, cultured under the same conditions, showed negligible uptake of hyaluronate. Thus, the cell-specific effects may be due to the differences in internalization of hyaluronate. High-molecular-weight hyaluronate both inhibited endothelial cell proliferation and disrupted newly formed monolayers. These data are consistent with the ability of hyaluronate to inhibit new blood vessel formation in vivo and also suggest that hyaluronate metabolism plays a pivotal role in the regulation of angiogenesis.

Animals↗
PubMed1989

A local circuit neocortical synapse that operates via both NMDA and non-NMDA receptors.

1. In slices of rat neocortex, spike triggered averaging was employed to record in one neurone the excitatory postsynaptic potential (e.p.s.p.) generated by a spike in another, neighbouring neurone. When recorded at different membrane potentials, some of these e.p.s.ps exhibited a voltage relation typical of neuronal responses to N-methyl-D-aspartate (NMDA). 2. Selective NMDA antagonists reduced the amplitude of these e.p.s.ps, but had little effect on their early rising phase. In contrast, a less selective excitatory amino acid antagonist reduced all phases of the e.p.s.p. 3. By analyzing single axon e.p.s.ps we have been able to establish that the synaptic input to one cortical cell, delivered by a single presynaptic cortical cell, operates simultaneously via NMDA and non-NMDA amino acid receptors.

2-Amino-5-phosphonovalerate↗
PubMed1989

Spinal antinociceptive actions and naloxone reversibility of intravenous mu- and kappa-opioids in spinalized rats: potency mismatch with values reported for spinal administration.

1. The relative spinal effectiveness of mu- and kappa-opioids has been assessed by their intravenous potencies on nociceptive responses (heat and/or pinch) of single motoneurones recorded in alpha-chloralose anaesthetized, spinalized rats. 2. The depressant actions of both mu- and kappa-opioids were reversed by low intravenous doses of naloxone (10 to 100 micrograms kg-1). When tested at a dose of 1 microgram kg-1 i.v., naloxone antagonized the effects of the mu-agonist morphine but had no effect on the kappa-opioid U-50,488. This provides further support for the theory that the actions of mu- and kappa-ligands were mediated at different subclasses of opioid receptor but highlights the difficulties in using antagonists with poor receptor selectivity to differentiate between mu- and kappa-receptor-mediated effects in vivo. 3. The molar potency rations of fentanyl: morphine:U-50,488: tifluadom for thermal and mechanical nociceptive responses were 620: 1.0:0.74:5.7 and 520:1.0:0.56:7.7 respectively. These potency ratios, as well as the absolute potencies, agree well with those reported in several behavioural studies in which systemic administration of agonists was used in non-thermal tests. 4. The agonist potency values obtained in this study contrast with those reported for local spinal administration. By this route, the potency of lipophilic opioids (e.g. fentanyl, U-50,488 and tifluadom) relative to hydrophilic opioids (e.g. morphine) is much reduced, implying that activity of intrathecally administered opioids is more dependent on the physico-chemical properties of the agonists used than on the relative abundance in the spinal cord of functional opioid receptors of the mu- and kappa-subtypes. This conclusion indicates that the results with locally applied opioids should not be used to assess spinal opioid receptor function.

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