PubMed Health⌕ Search

Biomedical subjects

T Dickinson

Publications and source records attributed to T Dickinson.

16 recordsLinked to original sources
PubMed2001

Complete genome sequence of a virulent isolate of Streptococcus pneumoniae.

The 2,160,837-base pair genome sequence of an isolate of Streptococcus pneumoniae, a Gram-positive pathogen that causes pneumonia, bacteremia, meningitis, and otitis media, contains 2236 predicted coding regions; of these, 1440 (64%) were assigned a biological role. Approximately 5% of the genome is composed of insertion sequences that may contribute to genome rearrangements through uptake of foreign DNA. Extracellular enzyme systems for the metabolism of polysaccharides and hexosamines provide a substantial source of carbon and nitrogen for S. pneumoniae and also damage host tissues and facilitate colonization. A motif identified within the signal peptide of proteins is potentially involved in targeting these proteins to the cell surface of low-guanine/cytosine (GC) Gram-positive species. Several surface-exposed proteins that may serve as potential vaccine candidates were identified. Comparative genome hybridization with DNA arrays revealed strain differences in S. pneumoniae that could contribute to differences in virulence and antigenicity.

Antigens, Bacterial↗
PubMed2001

The Comprehensive Microbial Resource.

One challenge presented by large-scale genome sequencing efforts is effective display of uniform information to the scientific community. The Comprehensive Microbial Resource (CMR) contains robust annotation of all complete microbial genomes and allows for a wide variety of data retrievals. The bacterial information has been placed on the Web at http://www.tigr.org/CMR for retrieval using standard web browsing technology. Retrievals can be based on protein properties such as molecular weight or hydrophobicity, GC-content, functional role assignments and taxonomy. The CMR also has special web-based tools to allow data mining using pre-run homology searches, whole genome dot-plots, batch downloading and traversal across genomes using a variety of datatypes.

Bacteria↗
PubMed2001

Non-opioid actions of lamotrigine within the rat dorsal horn after inflammation and neuropathic nerve damage.

Some opioid-resistant pain conditions can be alleviated by voltage-dependent Na(+) channel blockers such as lamotrigine. The mu-opioid-receptor agonist morphine can modulate cation entry into cells to affect overall cellular excitability, an effect which can in turn be endogenously antagonised by the neuropeptide cholecystokinin (CCK). However, lamotrigine may also modulate cellular excitability by non-specifically blocking voltage-dependent ion channels. We have looked for interactions of lamotrigine with the opioid/CCK pathway within the spinal dorsal horn, to rule out the possibility that lamotrigine may attenuate nociceptive responses via actions on this pathway. Both lamotrigine and the mu-opioid agonist DAMGO inhibited mustard oil-evoked cell firing by approximately 50% compared with control levels. Co-application of CCK8S reversed DAMGO-, but not lamotrigine-induced inhibition of cell firing and this reversal was prevented with the selective CCK(B) receptor antagonist PD 135158. Although lamotrigine inhibited both brush- and cold-evoked cell firing in neuropathic animals, lamotrigine inhibition of mustard oil-evoked cell firing in the same animals was not significantly greater than that observed in controls. These results suggest that the antinociceptive properties of lamotrigine within the spinal dorsal horn are unlikely to be mediated via interactions with the opioid/CCK pathway.

Action Potentials↗
PubMed2001

Inhibition of neointima formation in an organ culture of human saphenous vein: a comparison of dual endothelin-converting enzyme/neutral endopeptidase and selective neutral endopeptidase inhibition.

PURPOSE: Endothelin-1 (ET-1) has been implicated in a variety of vascular pathologic conditions, although there is considerable controversy as to whether such effects are mediated by the ET-(A) or ET-(B) receptor. This study investigated whether inhibition of big ET-1 processing by inhibition of endothelin-converting enzyme (ECE) could, therefore, offer an alternative therapeutic strategy in the prevention of vein graft intimal hyperplasia. METHODS: Human saphenous vein (3 equal segments from 10 patients) were maintained in organ culture for 14 days with either 50 micromol/L CGS 26303 (a dual ECE/neutral endopeptidase [NEP] inhibitor), 50 micromol/L CGS 24592 (a selective NEP inhibitor), or vehicle (control). They were then processed for immunostaining and neointimal thickness measurements, and conditioned media was collected for enzyme-linked immunosorbent assay analysis. RESULTS: Neointimal thickness in the ECE/NEP-inhibited veins did not differ significantly from that of control segments. However, there was a highly significant augmentation in the NEP-inhibited segments, consistent with an inhibition of ET-1 degradation (median difference, 16.8; 95% CI, -23.5, -10.4; P =.002, Wilcoxon). ECE immunostaining was reduced in the ECE/NEP-inhibited veins, although ET-1 staining was also present. ET-1 expression was intense in the thickened neointimas of NEP-inhibited veins, which also showed significant ECE staining. Elevated levels of big ET-1 were measured in the ECE/NEP-inhibited veins, consistent with reduced ECE activity. However, mature ET-1 was still detectable in these segments. CONCLUSION: There is a requirement for potent and selective inhibitors of ECE to evaluate fully the potential therapeutic benefits of blocking ET-1 biosynthesis. The use of dual inhibitors complicates the interpretation of results, because the observed response is likely to be a combination of both ECE and NEP inhibition.

Aspartic Acid Endopeptidases↗
PubMed2000

Raised levels of plasma big endothelin 1 in patients with colorectal cancer.

BACKGROUND: The aim was to assess the role of plasma Big Endothelin (ET) 1 levels as a marker of disease presence and stage in colorectal adenocarcinoma. METHODS: Big ET-1 was measured in the plasma of 37 patients with colorectal cancer. Preoperative systemic plasma levels of Big ET-1 in patients with cancer were compared with levels in 20 age- and sex-matched controls. Portal plasma samples were collected at operation in addition to peripheral venous samples. Immunohistochemical staining for Big ET-1 was performed on a selection of primary tumour specimens and liver metastases. RESULTS: Median (range) preoperative systemic plasma levels of Big ET-1 were significantly higher in patients with cancer than in controls (1.0 (0.3-9.7) versus 0.2 (0.0-6.0) fmol/ml; P = 0.0001). Intraoperative portal plasma levels of Big ET-1 were significantly higher in patients with Dukes' 'D' disease than in patients with Dukes' A, B and C disease (2.1 (1.4-10.0) versus 1.2 (0.3-6.6) fmol/ml; P = 0. 01). Similarly, systemic plasma levels were significantly higher in patients with Dukes' 'D' disease than in those with localized disease (1.9 (1.2-9.7) versus 1.2 (0.2-8.3) fmol/ml; P = 0.01). The presence of microvascular invasion in the tumour specimens was associated with a significantly raised portal plasma level of Big ET-1 (1.6 (1.5-2.1) versus 1.1 (0.8-1.3) fmol/ml; P = 0.04). Immunohistochemistry localized Big ET-1 to the cancer epithelial cells. CONCLUSION: The plasma level of Big ET-1 is significantly raised in patients with colorectal cancer. Patients with liver metastases have significantly higher levels than those with localized disease.

Adenocarcinoma↗
PubMed1999

The role of VIP/PACAP receptor subtypes in spinal somatosensory processing in rats with an experimental peripheral mononeuropathy.

Peripheral nerve damage often results in the development of chronic pain states, resistant to classical analgesics. Since vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are up-regulated in dorsal root ganglion cells following peripheral nerve injury, we investigated the expression and influence of VPAC1, VPAC2 and PAC1 receptors in rat spinal dorsal horn following a chronic constriction injury (CCI). Electrophysiological studies revealed that selective antagonists of VPAC1, VPAC2 and PAC1 receptors inhibit mustard oil-, but not brush-induced activity of dorsal horn neurones in CCI animals, while cold-induced neuronal activity was attenuated by VPAC1 and PAC1, but not VPAC2 receptor antagonists. Ionophoresis of selective agonists for the receptor subtypes revealed that the VPAC2 receptor agonist excited twice as many cells in CCI compared to normal animals, while the number of cells excited by the VPAC1 receptor agonist decreased and responses to PACAP-38 remained unchanged. In situ hybridisation histochemistry (ISHH) confirmed an increase in the expression of VPAC2 receptor mRNA within the ipsilateral dorsal horn following neuropathy, while VPAC1 receptor mRNA was seen to decrease and that for PAC1 receptors remained unchanged. These data indicate that VIP/PACAP receptors may be important regulatory factors in neuropathic pain states.

Animals↗
PubMed1999

VIP and PACAP: very important in pain?

Neuropathic pain arising from direct trauma to, or compression injury of, peripheral nerves is a common clinical problem. It is characterized by the development of abnormal pain states (spontaneous pain, hyperalgesia, allodynia), which can persist long after the initial injury has resolved. The underlying mechanisms are poorly understood and, as a consequence, treatment is often unsatisfactory. Some of the main contributing factors are thought to be the morphological and phenotypic changes that occur centrally, including alterations in the expression of neurotransmitters and their associated receptors, both in the dorsal root ganglia and in the spinal dorsal horn. This article focuses on the functional role of the two structurally related peptides VIP and PACAP within the spinal cord, and their possible contribution to the altered transmission of sensory information in neuropathic conditions.

Animals↗
PubMed1998

Antisense ablation of type I metabotropic glutamate receptor mGluR1 inhibits spinal nociceptive transmission.

Electrophysiological and behavioral studies point to a role of group I metabotropic glutamate receptors (mGluR1 and mGluR5) in mediating spinal nociceptive responses in rats. However, antagonists with a high degree of specificity for each of these sites are not yet available. We, therefore, examined the effects of antisense deletion of spinal mGluR1 expression in assays of behavioral analgesia and of electrophysiological responses of dorsal horn neurons. Rats treated with an mGluR1 antisense oligonucleotide reagent, delivered continuously to the intrathecal space of the lumbar spinal cord, developed marked analgesia as measured by an increase in the latency to tail-flick (55 degreesC) over a period of 4-7 d. This correlated with a selective reduction in mGluR1, but not mGluR5, immunoreactivity in the superficial dorsal horn compared with untreated control rats, in parallel with a significant reduction in the proportion of neurons activated by the mGluR group I agonist 3, 5-dihydroxyphenylglycine (DHPG), whereas the proportion of cells excited by the mGluR5 agonist, trans-azetidine-2,4-dicarboxylic acid (t-ADA) remained unaffected. In contrast, rats treated with mGluR1 sense or mismatch probes showed none of these changes compared with untreated, control rats. Furthermore, multireceptive dorsal horn neurons in mGluR1 antisense-treated rats were strongly excited by innocuous stimuli to their peripheral receptive fields, but showed severe reductions in their sustained excitatory responses to the selective C-fiber activator mustard oil and in responses to DHPG.

Animals↗
PubMed1998

Optical sensor arrays for odor recognition.

Optical sensor arrays containing fluorescent solvatochromatic dyes immobilized in a plurality of polymers generate information-rich responses upon exposure to organic vapors. The response profiles are used to train a variety of computational networks such that subsequent exposure of the array to the vapors enables them to be classified and/or quantified. A number of strategies can be taken to enhance sensitivity and to increase sensor diversity.

Animals↗
PubMed1997

Behavioural and electrophysiological evidence supporting a role for group I metabotropic glutamate receptors in the mediation of nociceptive inputs to the rat spinal cord.

A combined study of behavioural and electrophysiological tests was carried out in order to assess the role of metabotropic glutamate receptors (mGluRs) in mediating sensory inputs to the spinal cord of the rat. In the behavioural study the responses of conscious animals, with or without carrageenan-induced inflammation, to noxious mechanical and thermal stimuli were observed both before and after the intrathecal administration of mGluR antagonists L(+)-2-amino-3-phosphonopropionic acid (L-AP3) and (S)-4-carboxy-3-hydroxyphenylglycine (CHPG). It was found that the mGluR antagonist (S)-CHPG was capable of increasing both mechanical threshold and thermal latency in both groups of animals, and L-AP3 did so in those with inflammation induced in their hindpaw. Following this study, the responses of single lamina III-V dorsal horn neurons to an innocuous A beta fibre brush stimulus and a noxious C fibre (mustard oil) stimulus were extracellularly recorded and the effect of ionophoretically applied drugs was examined. Cyclothiazide (CTZ), a selective antagonist at mGluR1, markedly reduced the activity evoked by mustard oil, but not that elicited by brushing of the receptive field. Activity induced in dorsal horn neurons by ionophoresing various mGluR subgroup agonists was examined. CTZ successfully inhibited the activity evoked by group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG). In comparison to the neurons which responded to the ionophoresis of DHPG, less were activated by the selective mGluR5 agonist trans-azetidine dicarboxylic acid (t-ADA). Together these results indicate that group I mGlu receptors, in particular mGluR1, play a crucial role in mediating nociception, particularly following a sustained noxious input.

Alanine↗
PubMed1997

Evidence for roles of vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) receptors in modulating the responses of rat dorsal horn neurons to sensory inputs.

The extracellularly recorded electrophysiological activity of single multireceptive dorsal horn neurons was markedly increased by ionophoretic administration of vasoactive intestinal polypeptide (VIP) or pituitary adenylate cyclase activating polypeptide (PACAP)-38. Some cells responded selectively to PACAP-38 (suggesting mediation by a PACAP receptor), whereas others responded to both VIP and PACAP-38 (suggesting a VIP1 and/or VIP2 receptor). Most non-nociceptive cells were unaffected by PACAP-38 and all were unaffected by VIP. The selectivity of VIP/PACAP receptor antagonists was established on cloned rat VIP1, VIP2 and PACAP receptors in vitro before their utilization to indicate the likely involvement of VIP1, and possibly PACAP receptors, in VIP- and PACAP-38-mediated responses of dorsal horn neurons. The VIP/PACAP receptor antagonists inhibited responses of multireceptive cells to sustained innocuous (brush) and noxious (mustard oil) stimuli, with a selectivity suggesting the involvement of VIP1 and PACAP receptors, although the participation by VIP2 receptors cannot be excluded. These data implicate both VIP and PACAP in regulating the basal responsiveness of multireceptive dorsal horn neurons to sensory stimuli.

Animals↗
PubMed1995

The involvement of metabotropic glutamate receptors and their intracellular signalling pathways in sustained nociceptive transmission in rat dorsal horn neurons.

The excitatory responses of individual dorsal horn neurons to cutaneous brush, repeated application of the C-fibre-selective chemical algogen, mustard oil, or to ionophoretic (1S,3R)-ACPD [a metabotropic glutamate receptor (mGluR) agonist] were monitored by extracellular recording. We have previously shown that the responses of dorsal horn neurons to mustard oil are inhibited by several selective antagonists of mGluRs. Effects of ionophoresis of the mGluR antagonists (R,S)-CHPG and L-AP3 and a range of selective inhibitors of intracellular signalling pathways were examined on evoked responses here. The results suggest that protein kinase C, phospholipase A2 and perhaps Ca2+/calmodulin kinase II play a role in mediating the sustained elevated activity of dorsal horn neurons that is incrementally elicited by repeated application of mustard oil, but probably make little contribution to sustained brush-evoked activity. Concurrence in the sensitivity of mustard oil- and (1S,3R)-ACPD-evoked activity to (R,S)-CHPG, L-AP3 and to inhibitors of intracellular signalling pathways, suggests that mGluRs are an important origin of these intracellular signals required for sustained nociception.

Animals↗