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H Moore

Publications and source records attributed to H Moore.

At least 37 records · Page 2Linked to original sources
PubMed1998

Striatal extracellular dopamine levels in rats with haloperidol-induced depolarization block of substantia nigra dopamine neurons.

Correlations between substantia nigra (SN) dopamine (DA) cell activity and striatal extracellular DA were examined using simultaneous extracellular single-unit recordings and in vivo microdialysis performed in drug-naive rats and in rats treated repeatedly with haloperidol (HAL). Intact rats treated with HAL for 21-28 d exhibited significantly fewer active DA cells, indicating the presence of depolarization block (DB) in these cells. However, in rats that received surgical implantation of the microdialysis probe followed by a 24 hr recovery period, HAL-induced DA cell DB was reversed, as evidenced by a number of active DA neurons that was significantly higher than that in HAL-treated intact rats and similar to that of drug-naive rats. In contrast, using a modified probe implantation procedure that did not reverse SN DA neuron DB, we found striatal DA efflux to be significantly lower than in controls and significantly correlated with the reduction in DA neuron spike activity. Furthermore, although basal striatal DA efflux was independent of SN DA cell burst-firing activity in control rats, these variables were significantly correlated in rats with HAL-induced DA cell DB. Therefore, HAL-induced DB of SN DA neurons is disrupted by implantation of a microdialysis probe into the striatum using standard procedures. However, a modified microdialysis method that allowed reinstatement of DA neuron DB revealed that the HAL-induced inactivation of SN DA neurons was associated with significantly lower extracellular DA levels in the striatum. Moreover, the residual extracellular DA maintained in the presence of DB may, in part, depend on the burst-firing pattern of the noninactivated DA neurons in the SN.

Animals↗
PubMed1997

Transcytosis and surface presentation of IL-8 by venular endothelial cells.

Chemokines have been convincingly implicated in actuating inflammatory leukocyte emigration. To affect the circulating leukocytes, tissue-derived chemokines have to traverse the endothelial cells (ECs). This was thought to be accomplished by chemokine diffusion through the intercellular gaps. On the contrary, we show by electron microscopy that the prototype chemokine IL-8 is internalized by venular ECs abluminally and transcytosed to the luminal surface. Here, it is presented to the adherent leukocytes on the EC membrane, predominantly in association with the EC projections. The intact C terminus of IL-8, the molecule's "immobilization" domain, is required for the EC binding, transcytosis, and consequently, the in vivo proemigratory activity of IL-8, indicating that the described subcellular interactions of IL-8 with the ECs are functionally relevant.

Animals↗
PubMed1997

Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs.

Antipsychotic drugs used in the treatment of schizophrenia have in common the property of being dopamine-receptor antagonists. However, the rapid timecourse of receptor blockade produced upon drug administration does not correlate with the emergence of clinical actions, which typically require weeks of treatment to become manifest. Studies in rats have shown that repeated antipsychotic drug treatment results in a delayed inactivation of dopamine-neuron firing in the midbrain due to depolarization block. Furthermore, the therapeutic efficacy of antipsychotic drugs in humans correlates with their ability to induce depolarization block of mesolimbic dopamine neurons, whereas their potential to produce extrapyramidal side effects correlates with their propensity for inducing depolarization block in the nigrostriatal dopamine system. Therefore, dopamine-cell depolarization block is an effective model for evaluating antipsychotic drug efficacy, and provides a potential mechanism to account for their therapeutic impact on a dysregulated dopamine system.

Animals↗
PubMed1997

A phase I/II study of leucovorin, carboplatin and 5-fluorouracil (LCF) in patients with carcinoma of unknown primary site or advanced oesophagogastric/pancreatic adenocarcinomas.

Carcinoma of unknown primary site (CUPS) accounts for 5-10% of all malignancies. Forty patients with metastatic CUPS or advanced oesophagogastric/pancreatic adenocarcinomas were recruited. Eligibility included ECOG performance status 0-2, minimum life expectancy of 3 months and measurable disease. The regimen consisted of bolus intravenous 5 fluorouracil (5-FU) and leucovorin (20 mg m-2) days 1-5 and carboplatin (AUC5) on day 3. The leucovorin/carboplatin/5-FU (LCF) was repeated every 4 weeks. The starting dose of 5-FU was 350 mg m-2 day-1 with escalation to 370 and then 400 mg m-2 day -1 after the toxicity at the previous level had been assessed. The maximum tolerated dose (MTD) was defined as the dosage of 5-FU that achieved 60% grade 3/4 toxicity. In addition, objective and symptomatic responses, quality of life and survival were assessed. The MTD of 5-FU in the LCF regimen was 370 mg m-2. The predominant toxicity was asymptomatic marrow toxicity. The 350 mg m-2 level was then expanded. There were two toxic deaths due to neutropenic sepsis, one at 370 mg m-2 after one course and one at 350 mg m-2 after four courses. The objective response rate was 25% with one complete response (CR) and nine partial responses (PRs). The median duration of response was 3.4 months (range 1-10). The CR and eight of the nine PRs were in CUPS patients. Twelve patients developed progressive disease on LCF. Median survival for all 40 patients was 7.8 months (10 months median survival for those treated at 350 mg m-2). The majority of patients described a symptomatic improvement with LCF chemotherapy. The recommended dose of 5-FU for future studies is 350 mg m-2 combined with leucovorin 20 mg m-2 and carboplatin (AUC5).

Adenocarcinoma↗
PubMed1997

A patch in the pectoral position lowers defibrillation threshold.

Implantable pacemaker cardioverter defibrillators are now available with biphasic waveforms, which have been shown to markedly improve defibrillation thresholds (DFTs). However, in a number of patients the DFT remains high. Also, DFT may increase after implantation, especially if antiarrhythmic drugs are added. We report on the use of a subcutaneous patch in the pectoral position in 15 patients receiving a transvenous defibrillator as a method of easily reducing the DFT. A 660-mm2 patch electrode was placed beneath the generator in a pocket created on the pectoral fascia. The energy required for defibrillation was lowered by 56% on average, and the system impedance was lowered by a mean of 25%. This maneuver allowed all patients to undergo a successful implant with adequate safety margin.

Defibrillators, Implantable↗
PubMed1996

Trans-synaptic stimulation of cortical acetylcholine release after partial 192 IgG-saporin-induced loss of cortical cholinergic afferents.

Environmental and pharmacological stimulation of cortical acetylcholine (ACh) efflux was determined in rats sustaining partial deafferentation of cortical cholinergic inputs. Rats were bilaterally infused with the selective cholinotoxin 192 IgG-saporin (0.005 microgram/0.5 microliter/site) into the frontoparietal cortex. In the first experiment, animals were pretrained to associate the onset of darkness with presentation of a palatable fruit cereal reward. The ability of this stimulus to enhance frontoparietal ACh efflux alone, and with the benzodiazepine receptor (BZR) weak inverse agonist ZK 93,426 (1.0 or 5.0 mg/kg, i.p.), was determined in lesioned and sham-lesioned rats. Intracortical infusions of 192 IgG-saporin reduced basal cortical ACh efflux by 47% of sham-lesioned values, consistent with reductions in the density of AChE-positive fibers. In spite of this deafferentation, ZK 93,426 produced a transient potentiation of the cortical ACh efflux induced by the darkness/cereal stimulus similar to that observed in control animals. In the second experiment, the ability of the more efficacious BZR partial inverse agonist FG 7142 (8.0 mg/kg, i.p.) to enhance basal cortical ACh efflux was compared in lesioned and sham-lesioned rats. Again, lesioned rats exhibited an increase comparable to control animals after FG 7142. This drug-induced stimulation of cortical ACh efflux was comparably and completely blocked in both groups by co-perfusion with tetrodotoxin (1.0 microM). These results suggest similarities in the modulation of cortical ACh efflux in intact and partially deafferented rats and indicate the potential of BZR inverse agonists for restoring transmission in animals with partial loss of cortical cholinergic inputs.

Acetylcholine↗
PubMed1996

Impacts of foot orthoses on pain and disability in rheumatoid arthritics.

Rheumatoid arthritis (RA) frequently causes foot pain and swelling that affect ambulation. Pharmaceutical management of pain and disability is standard in clinical practice. The use of functional posted foot orthoses, as an adjunct to pharmaceutical treatment, is a promising treatment for managing foot pain and disability in RA. Its effectiveness, however, has not been rigorously evaluated. We performed a double-blind clinical trial using foot orthoses vs. placebo orthoses in the management of the rheumatoid arthritic foot, while subjects continued customary treatment. On the basis of findings of no effect on disability and pain measures, this study indicates no benefit of functional posted foot orthoses over placebos.

Adolescent↗
PubMed1996

Neuronal mechanisms mediating drug-induced cognition enhancement: cognitive activity as a necessary intervening variable.

The conceptual foundations of a research aimed at the determination of potential neuronal, neuropharmacological, and behavioral/cognitive mechanisms mediating drug-induced cognition enhancement are discussed. The available evidence justifies a focus on attentional processes as a target for drug-induced cognition enhancement. Neuropharmacological mechanisms that may mediate drug-induced enhancement of attentional functions are proposed to interact necessarily with attention-associated neuronal activity. The elements of a transsynaptic approach to increase the excitability of basal forebrain cholinergic neurons and hence, attentional functions are discussed. Experimental tests of this hypothesis require the demonstration of interactions between cognition-induced increases in the activity of cortical cholinergic afferents and the effects of putative cognition enhancers. The available data illustrate that the effects of benzodiazepine receptor (BZR) agonists and inverse agonists on cortical acetylcholine (ACh) efflux interact with the state of activity in this system. The feasibility, potential heuristic power, and the experimental and conceptual problems of studies attempting to simultaneously assess drug effects on behavioral/cognitive abilities, ACh efflux, and neuronal activity have been revealed by an experiment intended to correlate performance in a task measuring sustained attention with medial prefrontal ACh efflux and medial prefrontal single-unit activity. The rational development of a psychopharmacology of cognition enhancers requires a union among behavioral/cognitive pharmacology, neuropharmacological and electrophysiological approaches.

Acetylcholine↗
PubMed1996

Safe intravenous antibiotic therapy at home: experience of a UK based programme.

Outpatient i.v. antibiotic therapy is well developed in the United States, largely because of pressures from third-party payers to reduce costs of medical care. We have developed an outpatient i.v. antibiotic programme in Oxford, that has evolved from a desire to provide high quality i.v. therapy to AIDS patients with cytomegalovirus retinitis. We describe the rationale of the service and report on our first two years' experience. We treated 67 consecutive patients (eight with HIV infection) at home with i.v. antibiotics. This resulted in a saving of 2275 hospital days for those patients without HIV infection. HIV positive patients received 69 months of home i.v. therapy. Minor intravascular catheter complications occurred in only five patients (7.5%). The only serious complications were three episodes of catheter-related sepsis (4.5%), all occurring in AIDS patients who had lines in for more than six months. We have shown that home i.v. antibiotic therapy can be delivered safely to patients with a wide variety of infectious problems using the existing network of community nurses in the National Health Service. Essential components to the programme include a multidisciplinary team working between the hospital and community and a written shared care protocol. Such a programme can result in reduced lengths of hospital stay and patient, community nurse and physician satisfaction.

Anti-Bacterial Agents↗
PubMed1995

Purine and pyrimidine nucleotides activate distinct signalling pathways in PC12 cells.

The role of extracellular nucleotides in intracellular signalling and neurosecretion was assessed in PC12 cells. Activation of phospholipase C and increased [Ca2+]i were mediated by purinoceptors with an agonist potency profile, ATP approximately UTP > 2-methylthioadenosine triphosphate (2-MeSATP), typical of P2U. ATP also evoked a rapid acidification followed by a more gradual alkalinization (measured with 2',7'-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF)), while UTP induced only a gradual alkalinization. The amiloride analogue 5-(N-ethyl-N-isopropyl)amiloride (EIPA) attenuated the alkalinization phase suggesting activation of the Na+/H+ exchanger by ATP and UTP. Using bisoxonol and [3H]tetraphenylphosphonium ([3H]TPP+) as potential-sensitive probes, we showed that while ATP rapidly depolarized PC12 cells in an Na(+)-dependent manner, UTP evoked a much reduced and delayed response. The potency profile (ATP approximately 2-MeSATP approximately adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) >> UTP, alpha, beta-methyleneATP) suggested involvement of a receptor subtype distinct from P2U. Secretion of endogenous dopamine was also assessed. Those nucleotides that induced depolarization (ATP, 2-MeSATP, ATP gamma S) were also the most potent secretagogues. UTP was ineffective. Our results suggest that ATP stimulates distinct purinoceptor subtypes and induces neurosecretion through the activation of multiple signalling pathways.

Adenosine Triphosphate↗
PubMed1995

Bidirectional modulation of cortical acetylcholine efflux by infusion of benzodiazepine receptor ligands into the basal forebrain.

In a previous in vivo microdialysis study in rats, it was found that cortical acetylcholine (ACh) efflux was reliably increased by a multimodal appetitive stimulus (onset of darkness with presentation of palatable food). Furthermore, this stimulated ACh efflux was significantly enhanced by systemic administration of a benzodiazepine receptor (BZR) weak inverse agonist and significantly reduced by a BZR full agonist. These effects contrasted with the minimal effects of BZR ligands on basal cortical ACh efflux in resting animals. The aim of the present study was to determine whether this modulation of stimulated cortical ACh efflux by BZR ligands was mediated within the basal forebrain. ACh efflux, measured with in vivo microdialysis, was stimulated by onset of darkness, an event which predicted delivery of palatable food. The BZR full inverse agonist, beta -CCM (3.0 micrograms/hemisphere) or the full agonist chlordiazepoxide (40.0 micrograms/hemisphere) was infused into the basal forebrain just prior to the darkness/food stimulus. Similar to previous results with systemic administration, the BZR full inverse agonist enhanced, while the full agonist reduced, stimulated cortical ACh efflux. These results demonstrate that the action of BZR ligands in the basal forebrain is sufficient for their modulation of cortical ACh release.

Acetylcholine↗
PubMed1995

Stimulation of cortical acetylcholine efflux by FG 7142 measured with repeated microdialysis sampling.

The effects of the benzodiazepine receptor partial inverse agonist beta-carboline FG 7142 on cortical ACh efflux were determined using in vivo microdialysis in freely-moving rats. Additionally, a within-subjects, repeated-dialysis experimental design (four microdialysis sessions; removable dialysis probe) was evaluated as a method for measuring changes in basal and FG 7142-stimulated ACh efflux in the frontoparietal cortex. FG 7142 (4.0, 8.0, and 16.0 mg/kg) produced a 150-470% increase in cortical ACh efflux, with a dose-dependent effect on the duration of the increase in efflux. Basal cortical ACh efflux was lower in session 4 than in session 1. However, the ability of FG 7142 to stimulate efflux was unchanged by repeated dialysis testing. The ability of tetrodotoxin (1.0 microM) to suppress both basal and FG 7142-stimulated ACh efflux was also unaffected by repeated dialysis testing. These results demonstrate that systemically administered benzodiazepine receptor inverse agonists stimulate cortical ACh efflux, and that repeated-measures experimental designs can be valid for determining certain changes in cortical ACh efflux with in vivo microdialysis.

Acetylcholine↗
PubMed1995

Fetal cytokine expression in utero detected by reverse transcriptase polymerase chain reaction.

Cytokine expression at the maternal-fetal interface is well documented. Some authors have postulated the existence of a bidirectional cytokine signaling mechanism that is critical to the maintenance of normal pregnancy. The role of the fetus (versus fetally derived placental tissues) in this process is unknown. Using reverse transcription polymerase chain reaction techniques, we studied paired maternal and fetal samples from 16 pregnancies (including two twin pregnancies) for the presence of tumor necrosis factor-alpha and IL-1 beta mRNA. We demonstrate that mRNA for both of these cytokines can be detected in both maternal and fetal blood as early as the 21st wk of gestation. These results support a potential role for the fetus in the bidirectional cytokine signaling of pregnancy.

Base Sequence↗
PubMed1994

Monoamine activity in anterior hypothalamus of guinea pig pups separated from their mothers.

Brief isolation in a novel environment increased the ratios of 3-methoxy-4-hydroxyphenylethylene glycol to norepinephrine (MHPG:NE) and dihydroxyphenylacetic acid to dopamine (DOPAC:DA) in the anterior hypothalamus of guinea pig pups. Ratios were significantly elevated after 90 min of isolation and for MHPG:NE, after 30 min of isolation; changes were due to increases in MHPG and DOPAC. Home cage isolation produced no change in any measure of catecholamine activity. No changes in levels of serotonin or its metabolite were observed. In 1 experiment, resting levels of NE and DOPAC:DA were predictive of the rate of separation-induced vocalization. Maternal separation in the context of novelty increases hypothalamic NE and DA activity; however, both isolation and novelty are required because neither maternal separation in the home cage nor exposure to a novel cage together with the mother had any discernible effect.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Bidirectional modulation of stimulated cortical acetylcholine release by benzodiazepine receptor ligands.

In vivo microdialysis was used to determine the ability of benzodiazepine receptor (BZR) ligands to modulate stimulated cortical acetylcholine (ACh) efflux in awake, freely-moving Fischer-344/BNNia rats. Cortical ACh efflux was reliably enhanced during presentation of a complex stimulus (exposure to darkness coupled with presentation of a small amount of palatable food) in animals entrained with that stimulus. Administration of the BZR selective inverse agonist ZK 93,426 (5.0 mg/kg, i.p.) potentiated the ability of the darkness/food stimulus to enhance efflux, whereas administration of the BZR full agonist, chlordiazepoxide (5.0 mg/kg, i.p.) blocked the enhancement. The interaction of the BZR ligands with the entrained stimulus in affecting cortical ACh efflux was not secondary to effects on motor activity. These results, combined with results from a previous study, suggest that modulation of cortical ACh efflux by BZR ligands is bidirectional and dependent on the level of activity within cortical cholinergic neurons. This relationship enables the trans-synaptic stimulation of cortical ACh transmission by BZR inverse agonists to be most effective during behavioral activities which recruit the basal forebrain cholinergic system.

Acetylcholine↗
PubMed1992

Age-dependent modulation of in vivo cortical acetylcholine release by benzodiazepine receptor ligands.

In vivo microdialysis was utilized to determine the effects of benzodiazepine receptor (BZR) ligands on cortical acetylcholine (ACh) release in awake young and aged rats. There were no significant differences in baseline cortical ACh release as a function of age. While administration of the BZR selective inverse agonist ZK 93 426 increased ACh release in both groups of animals, the aged rats exhibited a greater stimulation. Unexpectedly, under the present testing conditions, the BZR agonist chlordiazepoxide (CDP) had no systematic effect on ACh release in either group. The presence or absence of these drug effects or drug-age interactions was not secondary to the impact of these compounds on behavioral activity. Cortical ACh release could also be stimulated by turning off the lights in the observation room or by the systemic administration of scopolamine. Aged rats were at least as able as their younger counterparts to respond to these manipulations with increased release. These results suggest that basal and stimulated release of cortical ACh is not impaired at the ages studied. Moreover, selective inverse BZR agonists may be a potent way of trans-synaptically stimulating cortical cholinergic transmission.

Acetylcholine↗