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Biomedical subjects

M D Hall

Publications and source records attributed to M D Hall.

At least 19 recordsLinked to original sources
PubMed2002

Gabapentin-mediated inhibition of voltage-activated Ca2+ channel currents in cultured sensory neurones is dependent on culture conditions and channel subunit expression.

We have used the whole cell patch clamp method and fura-2 fluorescence imaging to study the actions of gabapentin (1-(aminoethyl) cyclohexane acetic acid) on voltage-activated Ca(2+) entry into neonatal cultured dorsal root ganglion (DRG) neurones and differentiated F-11 (embryonic rat DRG x neuroblastoma hybrid) cells. Gabapentin (2.5 microM) in contrast to GABA (10 microM) did not influence resting membrane potential or input resistance. In current clamp mode gabapentin failed to influence the properties of evoked single action potentials but did reduce the duration of action potentials prolonged by Ba(2+). Gabapentin attenuated high voltage-activated Ca(2+) channel currents in a dose- and voltage- dependent manner in DRG neurones and reduced Ca(2+) influx evoked by K(+) depolarisation in differentiated F-11 cells loaded with fura-2. The sensitivity of DRG neurones to gabapentin was not changed by the GABA(B) receptor antagonist saclofen but pertussis toxin pre-treatment reduced the inhibitory effects of gabapentin. Experiments following pre-treatment of DRG neurones with a PKA-activator and a PKA-inhibitor implicated change in phosphorylation state as a mechanism, which influenced gabapentin action. Sp- and Rp-analogues of cAMP significantly increased or decreased gabapentin-mediated inhibition of voltage-activated Ca(2+) channel currents. Culture conditions used to maintain DRG neurones and passage number of differentiated F-11 cells also influenced the sensitivity of Ca(2+) channels to gabapentin. We analysed the Ca(2+) channel subunits expressed in populations of DRG neurones and F-11 cells that responded to gabapentin had low sensitivity to gabapentin or were insensitive to gabapentin, by Quantitative TaqMan PCR. The data obtained from this analysis suggested that the relative abundance of the Ca(2+) channel beta(2) and alpha(2)delta subunit expressed was a key determinant of gabapentin sensitivity of both cultured DRG neurones and differentiated F-11 cells. In conclusion, gabapentin inhibited part of the high voltage-activated Ca(2+) current in neonatal rat cultured DRG neurones via a mechanism that was independent of GABA receptor activation, but was sensitive to pertussis toxin. Gabapentin responses identified in this study implicated Ca(2+) channel beta(2) subunit type as critically important to drug sensitivity and interactions with alpha(1) and alpha(2)delta subunits may be implicated in antihyperalgesic therapeutic action for this compound.

Acetates↗
PubMed2001

Calculation of the hydrophobicity of platinum drugs.

Models of the hydrophobicity of platinum drugs based on exposed surface areas of polar and nonpolar atoms are presented. For a total of 24 log P(oct) data, the best model resulted in a standard deviation of 0.35 over a range of more than 4 log units, with regression coefficients in broad agreement with previous models of log P(oct) for organic molecules. This model is used to compare log P(oct) to cell uptake for five platinum drugs and hence to establish an exponential relation between these parameters.

Antineoplastic Agents↗
PubMed2001

Illusory conjunctions of pitch and duration in unfamiliar tone sequences.

In 3 experiments, the authors examined short-term memory for pitch and duration in unfamiliar tone sequences. Participants were presented a target sequence consisting of 2 tones (Experiment 1) or 7 tones (Experiments 2 and 3) and then a probe tone. Participants indicated whether the probe tone matched 1 of the target tones in both pitch and duration. Error rates were relatively low if the probe tone matched 1 of the target tones or if it differed from target tones in pitch, duration, or both. Error rates were remarkably high, however, if the probe tone combined the pitch of 1 target tone with the duration of a different target tone. The results suggest that illusory conjunctions of these dimensions frequently occur. A mathematical model is presented that accounts for the relative contribution of pitch errors, duration errors, and illusory conjunctions of pitch and duration.

Adolescent↗
PubMed2000

Detection of the interleukin 18 family in rat brain by RT-PCR.

Interleukin 18, an inflammatory cytokine, mediates its effects by interaction with its receptor complex, consisting of the IL-18 receptor (IL-18R) and receptor accessory protein (AcPL). A functional inhibitor of IL-18, the IL-18 binding protein (IL-18BP), has been identified recently. This study reports the detection of IL-18, IL-18R, AcPL and IL-18BP mRNA expression in the brain of normal adult rats using RT-PCR.

Animals↗
PubMed2000

Evidence for auditory feature integration with spatially distributed items.

Recent auditory research using sequentially presented, spatially fixed tones has found evidence that, as in vision for simultaneous, spatially distributed objects, attention appears to be important for the integration of perceptual features that enable the identification of auditory events. The present investigation extended these findings to arrays of simultaneously presented, spatially distributed musical tones. In the primary tasks, listeners were required to search for specific cued conjunctions of values for the features of pitch and instrument timbre. In secondary tasks, listeners were required to search for a single cued value of either the pitch or the timbre feature. In the primary tasks, listeners made frequent errors in reporting the presence or absence of target conjunctions. Probability modeling, derived from the visual search literature, revealed that the error rates in the primary tasks reflected the relatively infrequent failure to correctly identify pitch or timbre features, plus the far more frequent illusory conjunction of separately presented pitch and timbre features. Estimates of illusory conjunction rate ranged from 23% to 40%. Thus, a process must exist in audition that integrates separately registered features. The implications of the results for the processing of isolated auditory features, as well as auditory events defined by conjunctions of features, are discussed.

Auditory Perception↗
PubMed1999

Expression and characterisation of human and rat CRF2alpha receptors.

Rat and human CRF2alpha receptors were expressed in CHO-pro5 cells and stable cell lines generated. Each receptor was characterised using [125I][tyr0]sauvagine and results compared to CRF1 receptors expressed in the same parental cell line. Under identical assay conditions, [125I][tyr0]sauvagine labelled both CRF1 and CRF2alpha receptors with high affinity. The level of expression varied from 103 fmol/mg membrane protein to 1842 fmol/mg membrane protein (rat CRF1 receptors and rat CRF2 receptors, respectively). It was possible to establish robust scintillation proximity assays (SPA) using wheat germ agglutinin (WGA) SPA beads to trap membrane protein. The success of the SPA assay format was dependent on the level of receptor expression observed. The rank order of affinities of a series of peptide CRF receptor agonists and antagonists was similar to that described in the literature for the two receptor subtypes as determined using radioligand binding and cAMP accumulation. No pharmacological differences were apparent between rat and human cloned receptors with the exception of alpha-helical CRF-(9-41). This peptide exhibited 10-fold higher affinity for rat CRF2alpha receptors as compared to human CRF2alpha receptors. PD 173307, PD 173602 and PD 174239 exhibited high affinity and selectivity for human CRF1 receptors, and as such represent useful tools for probing CRF receptor function.

Amphibian Proteins↗
PubMed1999

The interleukin-1 type I receptor is expressed in human hypothalamus.

Several lines of evidence suggest that interleukin-1 (IL-1) acts directly on the central nervous system, probably within the hypothalamus, causing effects such as fever, activation of the immune response and sickness behaviour. IL-1 has also been shown to be involved in the aetiology of several neuronal diseases, including neurodegeneration, stroke and Alzheimer's disease. However, the question as to whether the full-length type I IL-1 receptor (IL-1RI) is expressed in the human hypothalamus has yet to be addressed. Using the polymerase chain reaction, we cloned a full-length cDNA encoding the human hypothalamic IL-1RI from human hypothalamic cDNA. The DNA sequence of the human hypothalamic receptor was identical to that of the human fibroblast IL-1RI. The IL-1RI receptor protein was detected in astrocytes of normal human hypothalamic brain sections using immunocytochemical techniques. To ascertain that the cloned receptor was functional, Chinese hamster ovary (CHO) cells were transfected with a plasmid vector containing the IL-1RI coding region. IL-1RI-mediated-signal transduction was assessed by microphysiometry and activation of p38 MAP (mitogen-activated protein) kinase. We report the first demonstration that both the type I IL-1 transcript and the protein are expressed in the human hypothalamus. The receptor was expressed in a stable CHO cell line, providing a tool with which to embark on a thorough analysis of the signalling mechanisms mediated by IL-1 via this receptor.

Animals↗
PubMed1999

Corticotropin-releasing factor type 1 and type 2alpha receptors regulate phosphorylation of calcium/cyclic adenosine 3',5'-monophosphate response element-binding protein and activation of p42/p44 mitogen-activated protein kinase.

CRF exerts a key neuroregulatory control on the function of the hypothalamic-pituitary-adrenal axis. These effects are thought to be mediated primarily through activation of Gs-coupled plasma membrane receptors. In the present study, we investigated the effects of activation of CRF receptors by sauvagine on signaling pathways that converge on phosphorylation of the transcription factor calcium/cAMP response element-binding protein (CREB). Studies were undertaken using CHO cell lines transfected with either rat CRF-1 or CRF-2alpha receptors. Signaling pathways were investigated using immunocytochemical, Western blot, and imaging techniques. Treatment with sauvagine increased phosphorylation of p42/p44, but not of p38 or stress-activated protein kinase (SAPK)/JUN N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases correlating with increased p42/p44 MAP kinase activity. Mobilization of intracellular Ca2+ stores was observed in cells treated with high concentrations (100 nM, 1 microM) of sauvagine. A time- and dose-dependent increase in phosphorylation of the transcription factor CREB was observed in cultures treated with sauvagine. Phosphorylation of CREB occurred at lower concentrations of sauvagine than those required to mobilize intracellular calcium stores, and phosphorylation was not blocked by the mitogen-activated protein kinase kinase inhibitor PD98059 at a concentration (1 microM) that fully inhibited phosphorylation of MAP kinase. Cotreatment of cultures with the protein kinase A inhibitor H89 (10 microM) blocked fully the stimulatory actions of sauvagine (0.1 nM, 1 nM) on phosphorylation of CREB, but not those on phosphorylation of MAP kinase. Phosphorylation of MAP kinase was partially blocked by the phosphoinositide 3-kinase inhibitor LY294002 (5 microM) and by the phosphoinositide-phospholipase C inhibitor U73122 (10 microM). These data demonstrate that cAMP-, Ca2+-, and MAP kinase-dependent signaling pathways are activated by stimulation of CRF-1 and CRF-2alpha receptors. However, in these cells, only protein kinase A-dependent pathways contribute significantly to enhanced phosphorylation of CREB. These represent the first reported observations of CRF receptor-mediated phosphorylation of the transcription factor CREB and activation of MAP kinase signal transduction pathways.

Amphibian Proteins↗
PubMed1998

Cloning of rat brain interleukin-18 cDNA.

The interleukin-1 (IL-1) family comprises IL-1 alpha and IL-1 beta and an endogenous IL-1 receptor antagonist (IL-1ra). IL-1 has diverse actions in the brain and has been implicated in both acute and chronic neurodegeneration. However, neither IL-1 alpha nor IL-1 beta are neurotoxic per se in vivo, so other IL-1 related ligands may be important in neurodegeneration. The cytokine interleukin-18 (also called interferon gamma inducing factor, IGIF) was first isolated from the liver of mice during toxic shock. It was later proposed as a member of the IL-1 family, based on protein sequence homology with IL-1 beta and IL-1ra, and has tentatively been called IL-1 gamma. We cloned IL-18 from adult rat brain and demonstrated, by RT-PCR, that it is expressed constitutively in cerebellum, hippocampus, hypothalamus, cortex and striatum. Rat brain IL-18 shows close homology to mouse and human IL-18, and to the recently published sequence from the rat adrenal gland. Mouse pro-IL-18 and pro-IL-1 beta are processed by caspase-1. We demonstrate that caspase-1 also cleaves rat IL-18 in vitro and that the caspase inhibitor, zVAD-DCB inhibits this cleavage.

Adrenal Glands↗
PubMed1998

Influence of prosodic boundaries on comprehension of spoken English sentences.

Three experiments investigated the role of prosody in the comprehension of auditory sentences. In Exp. 1 an analysis of three novice talkers and one expert talker verified the production parameters of one type of syntactic ambiguity and showed that pitch cues were more prominent than duration cues. In Exp. 2, 16 listeners used prosodic information to make consistent decisions reliably about phrase boundaries. In Exp. 3, 40 participants listened to sentences in which prosody was inconsistent with later morphosyntactic information, indicated their understanding, and then judged whether a visual target was related to the meaning of the sentence. Inconsistent prosody slowed comprehension and contributed to slower, less accurate judgments of sentence meaning. This suggests that prosodic information contributes to the perception of spoken language and can affect comprehension even when the syntactic structure indicated by prosody is contradicted by subsequent morphosyntactic information.

Adult↗
PubMed1996

Bombesin receptors in the brain.

We have shown that in the central nervous system BN receptors are closely associated with 5-HT systems. On a subpopulation of dorsal raphe neurons, NMB receptors are able to depolarize cells by reducing gK+. In one of the target regions of the dorsal raphe 5-HT neurons, the SCN, we have also shown that neurons are excited by BN-related peptides. In the SCN, the GRP receptors excite neurons by two different mechanisms: closure of gK+ and opening of an unidentified cation conductance. Expression of human BN receptors from the brain in CHO cells or Xenopus oocytes shows a very similar pharmacological profile to that seen in the rat brain slice preparations. In the CHO cell line, following BN receptor activation, a major second-messenger path involves hydrolysis of PIP2 by phospholipases to yield IP3, which releases Ca2+ from intracellular stores. In the oocyte expression system, a similar second messenger pathway is clearly apparent, and Ca2+-sensitive gCl- represents the last phase in a cascade of events. The final phase of the mechanism of action in the artificial systems does not involve gK+, suggesting a different second messenger cascade to that in neurons. However, the involvement of phospholipases and their phospholipid products have not been excluded in neurons.

Amino Acid Sequence↗
PubMed1996

Letting go.

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Brain Neoplasms↗
PubMed1995

The effect of post-operative diet on recovery in the first twelve hours after tonsillectomy and adenoidectomy.

The effect of post-operative diet selection on the recovery rate of 100 children ages 3-17 years undergoing tonsillectomy and adenoidectomy (T & A) was studied. In the first 12 h after T & A children were allowed either a 'restricted' diet of only soft foods and liquids or a 'non-restricted' diet of foods preselected and usually eaten by the child. Parental evaluation of the child's general well being, pain level and nausea were evaluated. The number of episodes of emesis, doses of acetominophen and the list of foods and drinks consumed were also recorded. No significant differences in any aspect of recovery were noted between groups. However, a trend towards decreased nausea and parental perception of a more successful general recovery was noted at 12 h in the 'non-restricted' group. Children in the 'non-restricted' group were able to eat foods more often associated with their regular diet. No child from either group experienced any immediate or delayed complications. Implications for children and their families undergoing T & A are discussed.

Acetaminophen↗
PubMed1995

Within-category discrimination of musical chords: perceptual magnet or anchor?

Recent speech research has begun to evaluate the internal structure of categories. In one such study, Kuhl (1991) found that discrimination was poorer for vowel stimuli that were more representative of the category (prototype, or P, set) than it was for less representative stimuli (nonprototype, or NP, set). This finding was interpreted as indicating that a category prototype may function as a "perceptual magnet", effectively decreasing perceptual distance, and thus discriminability, between stimuli. The present study examines the function of prototypes in a musical category--another natural, but nonspeech category. Paralleling the Kuhl study, representative (P) and less representative (NP) sets of major triad stimuli were constructed, based on equal temperament. Musically experienced subjects rated the stimuli in each set for a goodness as a major triad, with the highest rated stimulus serving as a prototype standard for a subsequent discrimination task. Results from the discrimination task demonstrated better performance in the P context than in the NP context. The current nonspeech results indicate that a prototype functions as an anchor rather than a magnet. In addition to providing a natural, nonspeech standard for comparison with speech findings, the results provide some important insights into the nature of musical categories.

Humans↗
PubMed1994

Crystallization of catechol-1,2 dioxygenase from Pseudomonas arvilla C-1.

The metalloenzyme catechol 1,2-dioxygenase from Pseudomonas arvilla C-1 consists of three isozymes formed by combinations of two non-identical subunits; alpha alpha, alpha beta and beta beta; with molecular masses of 59,000, 63,000 and 67,000 Da, respectively. The alpha alpha isozyme crystallizes in the orthorhombic space group C222(1) with unit cell dimensions a = 62.7 A, b = 71.5 A, c = 187.1 A. The rectangular plates diffract to 2.6 A resolution. This is the first dioxygenase to be crystallized that uses catechol as a substrate. Comparison of the structure of this enzyme with protocatechuate 3,4-dioxygenase will provide basic information about the mechanisms of subunit association, substrate selectivity, and the origins of metabolic diversity in enzymes.

Catechol 1,2-Dioxygenase↗
PubMed1993

Crystal structure of a ternary complex of Escherichia coli malate dehydrogenase citrate and NAD at 1.9 A resolution.

The structure of malate dehydrogenase from Escherichia coli complexed with the substrate analog, citrate and the cofactor NAD, has been determined by X-ray crystallography. A monoclinic crystal of the malate dehydrogenase, grown in citrate buffer, was soaked in 10 mM NAD solution and found to be isomorphous with the apo-form. The X-ray data extended to 1.9 A, nearly the same resolution limit as the apo-enzyme crystals. The ternary complex of malate dehydrogenase has very few conformational differences from that of the pseudo binary complex of enzyme with bound citrate. In addition, the NAD molecule has a very similar conformation to the NAD as found in the crystal structure of the cytosolic eukaryotic malate dehydrogenase. Similar hydrogen bond interactions are made by both enzymes from polar groups belonging to the NAD. Such interactions include hydrogen bonds from the ribose oxygens and the phosphate oxygens, to backbone amide and carbonyl atoms of the protein and to side-chains of a select few conserved hydrophilic residues. The only notable difference occurs in the active site region where the nicotinamide moiety is obstructed from further entering the active site by the C-6 carbonyl atoms of citrate. In this position there are no direct polar interactions between the protein and the nicotinamide moiety. Energy minimization of the structure with malate substituted for citrate in the active site shows that the nicotinamide moiety assumes the same position in the active site as the NAD in cytosolic malate dehydrogenase. The carboxamide atoms of the energy minimized model make significant hydrogen bond interactions with the catalytic residue, H177, and with the main-chain atoms of I117 and V146 in the vicinity of the active site, while the position of the rest of the cofactor remains unchanged.

Binding Sites↗