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Biomedical subjects

A M Young

Publications and source records attributed to A M Young.

At least 19 recordsLinked to original sources
PubMed2005

Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma.

PURPOSE: A proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens. PATIENTS AND METHODS: From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively. RESULTS: After commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS. CONCLUSION: We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.

Adult↗
PubMed2004

FTIR investigation of monomer polymerisation and polyacid neutralisation kinetics and mechanisms in various aesthetic dental restorative materials.

Diamond ATR FTIR has been used to quantify light catalysed polymerisation and polyacid neutralisation rates in various glass ionomer cements (GIC), resin-modified GICs (RMGIC) and compomers. At 150s after the start of light exposure, levels of methacrylate polymerisation on the lower surfaces of 1mm thick specimens were 97% and 98% for the RMGIC, Vitremer and Fuji II LC and 47% and 37% for the compomers, Compoglass and Dyract. After light exposure, polymerisation rates for the compomers decreased linearly with inverse time. By 50,000s Compoglass and Dyract were 62% and 51% polymerised. Initial rate of polyacid neutralisation in the GIC Shofu HIFI was 0.32 times that of Fuji IX GIC. Those in Vitremer, Fuji II LC, Compoglass and Dyract were 0.16, 0.09, 0.004 and 0.004 times that of Fuji IX. Excluding short initial periods, log of neutralisation rates decreased linearly with log-time. Average gradients were -1.35 for the GIC, -0.80 for the RMGIC and -0.59 for the compomers. By 50,000s, polyacid salt concentrations for the RMGIC and compomers were 0.41 and 0.016 times that of the GIC. Reaction mechanisms have been discussed and used to help interpret material mechanical properties, fluoride release rates and adhesion to tooth structure.

Compomers↗
PubMed2002

FTIR investigation of polymerisation and polyacid neutralisation kinetics in resin-modified glass-ionomer dental cements.

A new diamond ATR FTIR method has been developed to quantify the processes occurring in the resin-modified glass-ionomer cement (RMGIC). Fuji II LC (Improved), at 1 mm depth from the cement/water interface. With Fuji II LC (Improved) various changes in the spectra due to 90% monomer polymerisation were observed within 1 min after 20 s exposure to a dental light. Following polymerisation further different peak shifts with time were detected. Comparison with spectral changes seen during setting of the conventional glass-ionomer cement, Fuji IX, showed these could be assigned to water sorption and/or polyacid neutralisation. Any absorbance change due to the acid/glass reaction alone exhibited 2 linear regions when plotted against square root of time. Such behaviour suggests two separate diffusion mechanisms for acid neutralisation. The first faster one ceases at 30 or 150 min after mixing in Fuji IX and Fuji II LC (Improved), respectively. It was proposed that these were the times at which all the water (a required component of the reaction) in the original formulation is used up. The slower process was the same acid/glass reaction but initiated by water sorption. The initial rates of absorbance change due to acid neutralisation were 17 times faster for Fuji IX than Fuji II LC (Improved). By 4 days however, the total absorbance change due to acid neutralisation for Fuji IX was only 4 times that for Fuji II LC (Improved). Such results can help to explain changes in cement properties with time.

Glass Ionomer Cements↗
PubMed2001

Differential tolerance to antinociceptive effects of mu opioids during repeated treatment with etonitazene, morphine, or buprenorphine in rats.

RATIONALE: Repeated treatment experiments with high and low efficacy agonists provide critical insight into possible mechanisms underlying development of opioid tolerance. OBJECTIVE: Experiments in a tail-withdrawal assay tested the hypothesis that magnitude of tolerance to antinociceptive effects is inversely related to agonist relative efficacy in rats intermittently treated with etonitazene. morphine, or buprenorphine. METHODS: The antinociceptive effects of five mu opioid agonists were tested in male, Sprague-Dawley rats in a warm-water tail-withdrawal assay. To induce tolerance, escalating doses of the higher efficacy agonist etonitazene, the high efficacy agonist morphine, or the lower efficacy agonist buprenorphine were administered twice daily for 2-8 weeks. RESULTS: Etonitazene, etorphine, morphine, buprenorphine, and GPA 1657 [(1)-beta-2'-hydroxy-2,9-dimethyl-5-phenyl-6,7-benzomorphan] produced dose-dependent increases in tail-withdrawal latency until 100% maximum possible effect (%MPE) was obtained. Treatment with escalating doses of etonitazene, morphine, or buprenorphine produced greater tolerance to the lower efficacy agonists buprenorphine and GPA 1657 than to the higher efficacy agonists etonitazene, etorphine, and morphine. Treatment with buprenorphine, a lower efficacy agonist, produced greater tolerance than did treatment with equivalent doses of the higher efficacy agonists morphine or etonitazene. CONCLUSIONS: Taken together, these data suggest that magnitude of antinociceptive tolerance is inversely related to relative efficacy of mu agonists, with lower efficacy agonists being more susceptible to tolerance than are higher efficacy agonists under these intermittent dosing conditions.

Analgesics↗
PubMed2001

Presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor-mediated stimulation of glutamate and GABA release in the rat striatum in vivo: a dual-label microdialysis study.

The existence of presynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate autoreceptors on glutamate nerve terminals in vitro has recently been demonstrated using synaptosomal and brain slice preparations. In the present study we have used a modification of a rapid dual-label intracerebral microdialysis method, previously developed by Young and co-workers(80,81) for the study of presynaptic mechanisms of neurotransmitter release, to investigate whether presynaptic AMPA receptors also play a role in the control of striatal glutamate release in vivo. For comparative purposes, the action of locally applied AMPA on striatal GABA release in vivo was also monitored. Local application of AMPA (0.01-100 microM), by reverse dialysis, into the striatum resulted in concentration-dependent increases in the Ca(2+)-dependent efflux of both [3H]L-glutamate and [14C]GABA. Maximum responses reached 142.0+/-6.5% and 166.8+/-7.7% of basal efflux for [3H]L-glutamate and [14C]GABA, respectively. No marked behavioural changes were observed at any dose of the agonist. Unexpectedly, the AMPA-evoked responses were not potentiated by the AMPA receptor desensitization inhibitors cyclothiazide (10-100microM) or aniracetam (1mM). Consistent with this finding, AMPA-stimulated [3H]L-glutamate and [14C]GABA efflux were significantly attenuated by co-perfusion with the selective, competitive AMPA receptor antagonist 6-nitro-7-sulphamoylbenzo(F)quinoxaline-2,3-dione (100microM) but not 1-(aminophenyl)-4-methyl-7,8-methylendioxy-5H-2,3-benzodiazepine (100microM), a non-competitive AMPA receptor antagonist known to interact with the cyclothiazide site to control AMPA receptor function. The broad spectrum ionotropic glutamate receptor antagonist, kynurenic acid (100-1000microM) also markedly inhibited the AMPA-evoked responses in the striatum in vivo. None of the antagonists, when given alone, influenced basal efflux of [3H]L-glutamate suggesting a lack of tonic regulatory control of glutamate release via presynaptic AMPA-type autoreceptors in the rat striatum. These results demonstrate the presence of presynaptic AMPA receptors, of a novel cyclothiazide- and aniracetam-insensitive subtype, on presynaptic nerve terminals in the rat striatum in vivo, acting to enhance glutamate and GABA release. Our data support the concept of AMPA receptor heterogeneity in vivo, a finding which may facilitate the development of novel, more selective drugs for the treatment of a range of neurological disorders associated with abnormal cerebral glutamate release. The pharmacological profile of these novel presynaptic receptors is currently under investigation.

Animals↗
PubMed2001

Dealing with daily hassles: smoking and African-American adolescent girls.

PURPOSE: To examine cigarette use and its relationship to daily life hassles in an urban sample of African-American adolescent girls. METHODS: A sample of 105 African-American adolescent girls (mean age of 15.45 years) derived from a larger cross-sectional research project titled "Female Adolescent Substance Experience Study" funded by the National Institute of Drug Abuse comprised the sample. The sample was divided into adolescents who had ever smoked in their lifetime and adolescents who had never smoked before. Student's t-tests were conducted to determine whether there were differences between these groups on demographic characteristics and the number of daily life hassles. Pearson product moment correlations were also conducted to examine the association between age of smoking initiation and number of hassles. RESULTS: Less than 50% of the teenagers had ever smoked cigarettes in their lifetime, and of those who had ever smoked, the average age of initiation was 12.55 years (SD = 2.63). Furthermore, girls who had ever smoked, in contrast to girls who had never smoked, had a significantly greater number of daily life hassles, in general, and within the school/academic and family/economic domains in particular. Age of smoking initiation was negatively related to the number of hassles, indicating that girls who started to smoke at a younger age reported more hassles. CONCLUSIONS: These findings are discussed in terms of developing an understanding of gender and ethnic-specific correlates of smoking that can be used to better delineate the developmental smoking trajectory of African-American girls.

Adolescent↗
PubMed2001

Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin.

BACKGROUND: Quercetin is a naturally occurring flavonoid with many biological activities including inhibition of a number of tyrosine kinases. A phase I, dose-escalation trial of quercetin defined the maximum tolerated dose (MTD) as 1700 mg/m2 three weekly, but the vehicle, dimethyl sulphoxide (DMSO) is unsuitable for further clinical development of quercetin. PATIENTS AND METHODS: A water-soluble, pro-drug of quercetin (3'(N-carboxymethyl)carbomyl-3,4',5,7-tetrahydroxyflavone), QC12 has been synthesised. Six cancer patients received 400 mg of QC12 (equivalent to 298 mg of quercetin), orally on day 1 and intravenously (i.v.) in normal saline on day 14. RESULTS: Following oral administration of QC12 we were unable to detect QC12 or quercetin in plasma. After i.v. administration, we detected peak plasma concentrations of QC12 of 108.7 +/- 41.67 microMolar (microM). A two-compartment model with mean t(1/2)alpha of 0.31 +/- 0.27 hours and mean t(1/2)beta of 0.86 +/- 0.78 hours best described the concentration-time curves for QC12. The mean AUC was 44.54 +/- 13.0 microM.hour and mean volume of distribution (Vd) of 10.0 +/- 6.2 litres (l). Quercetin was found in all patients following i.v. infusion of QC12, with peak levels of quercetin 19.9 +/- 11.8 microM. The relative bioavailability of quercetin was estimated to be 20%-25% quercetin released from QC12. CONCLUSIONS: QC12 is not orally bioavailable. This water-soluble pro-drug warrants further clinical investigation; starting with a formal phase I, IV, dose-escalation study.

Adult↗
PubMed2001

Access conditions are crucial: comment on Lynch and Carroll (2001).

W. J. Lynch and M. E. Carroll (2001) sought to identify factors that control drug intake, that is, factors that decrease the avidity of drug seeking and drug taking while drug is obviously available. The review provides updated information about factors that regulate drug intake and a heuristic framework for future studies of regulatory processes throughout the natural history of a substance abuse disorder. In particular, the review suggests a productive framework for studies of transitions from early drug use to later abusive use. Forceful identification of factors that control the avidity of drug seeking and drug taking under the controlled conditions of the laboratory may encourage development of therapeutic interventions that capitalize on these factors for successful treatment of human drug abuse. Extending the analysis of regulation of intake to include factors that can be manipulated to reorganize behavior may improve the design of interventions to treat drug abuse.

Humans↗
PubMed2001

Prospective randomized comparison of dacarbazine (DTIC) versus DTIC plus interferon-alpha (IFN-alpha) in metastatic melanoma.

Dacarbazine (DTIC) has been the mainstay of chemotherapy for metastatic melanoma for over two decades, but only 15%-20% of patients respond and benefit is usually transient. Randomized studies combining DTIC with interferon-alpha (IFN-alpha) in advanced disease have so far been inconclusive in terms of response and survival. We report a randomized prospective pilot Phase III trial of DTIC +IFN-alpha in patients with metastatic melanoma. The primary endpoint was death. A total of 61 patients were randomized between April 1995 and April 1998. Differences in survival between groups were assessed using log-rank analysis. Quality of life was measured using the European Organization for Research on Treatment of Cancer QLQ C30 (+3) questionnaire. Fifty-seven patients died during the study. The median survival for patients receiving DTIC was 7.2 months (95% confidence interval (CI) 4.4-9.0); it was 4.8 months for DTIC + IFN-alpha (95% CI 2.0-8.0). There was no significant difference in survival between the two treatment arms (chi2 unadjusted = 0.15, P = 0.70; chi2 adjusted = 0.01, P = 0.91). The 6-month survival of those patients randomized to DTIC alone was 58% compared with 40% for those patients randomized to DTIC + IFN-alpha. There were no differences in quality of life between treatment groups. This study failed to demonstrate a survival benefit for patients receiving IFN-alpha in combination with DTIC. These results are inconclusive primarily owing to the small size of the trial. A meta-analysis is required to determine whether there is a role for the addition of IFN-alpha to DTIC in the treatment of this disease.

Adult↗
PubMed2001

Effect of radiographic quality on computer-assisted head penetration measurements.

Even the most sophisticated computer-assisted radiographic techniques of measuring femoral head penetration into the polyethylene liner depend on the quality of the radiograph being evaluated, which varies greatly in clinical settings. The authors of this study sought to determine how the accuracy and reproducibility of three commercially available computer-assisted measurement systems differed when measuring optimal radiographs (with sharply defined component edges) and suboptimal radiographs (with less well defined edges). Using three computer-assisted measurement systems, the authors measured head penetration on simulated and clinical hip radiographs. All systems calculated head penetration as the movement of the head center relative to the cup center. To define the periphery of the prosthetic head and cup, one method (System One) used the human eye and a digitizing tablet, whereas the other two methods (System Two and System Three) used digital edge detection algorithms. For simulated hip radiographs, error was calculated as the absolute value of the difference between the known amount of head penetration, determined by a coordinate measuring machine, and the amount of penetration determined by the software. Three way analysis of variance showed a significant difference in absolute error among the three measurement techniques. System One had a significantly smaller absolute error (0.11 +/- 0.06 mm) than did System Two (0.25 +/- 0.25 mm) and System Three (0.19 +/- 0.13 mm). In addition, three-way analysis of variance showed that optimal radiographs were associated with a significantly lower absolute error (0.14 +/- 0.09 mm) than were suboptimal radiographs (0.23 +/- 0.22 mm). For optimal radiographs, there was no significant difference in error among the three measurement methods; all systems were accurate and reproducible. However, for suboptimal radiographs absolute error increased and varied widely, and a significant difference among the methods existed. These data show the susceptibility of head penetration measurements to radiographic technique and underscore the importance of good quality radiographs for all analyses of head penetration.

Analysis of Variance↗
PubMed2001

Reflections on validity and epistemology in a study of working relations between deaf and hearing professionals.

In this article, a research study that examined the working relationships between Deaf and hearing professionals in health and educational services in the United Kingdom is addressed. These service providers worked in bilingual organizations where both British Sign Language and English were used and in which Deaf people's identity as a cultural-linguistic minority was accepted. The focus of this article is on issues of validity and epistemology that arose for the Deaf and hearing research team in the course of this study. In particular, it examines the influence of identity attributions on the research process for researchers operating within a context of historical oppression, minority language use and legitimization of research knowledge, and challenges to the interpretative analysis used in the study that arose from the dynamics of majority-minority power relations in the wider social world.

Communication↗
PubMed2001

Social isolation and sexual abuse among women who smoke crack.

The purpose of this study was to explore the prevalence of social isolation and its relationship to sexual trauma in a sample of Black women who smoke crack cocaine. Using a convenience sample of 115 Black women with a history of smoking crack cocaine, participants were interviewed for 2 to 4 hours and asked a variety of questions about their health, relationships, sexuality, and drug use. Bivariate and multivariate logistical regressions were used to predict whether the women reported being socially isolated. While social isolation was not necessarily a common experience among the sample, it was found that women who had been sexually abused were three times more likely to report being socially isolated than women who had not been sexually abused. In addition, social isolation was more common among women who had been abused by a family member, who had been abused when they were young, and who had been abused for a long period of time. However, multivariate analyses revealed that the age at which the sexual trauma occurred was the most salient predictor of social isolation in adulthood. Implications for drug treatment are discussed.

Adolescent↗
PubMed2000

Discriminative stimulus effects of two doses of fentanyl in rats: pharmacological selectivity and effect of training dose on agonist and antagonist effects of mu opioids.

RATIONALE: Discriminative stimulus effects of mu opioids vary systematically as a function of training dose. Differences among training doses may arise from multiple mechanisms. OBJECTIVES: In vivo apparent pA(2) analyses were used to examine the contributions of opioid mechanisms to stimulus control by low and high training doses of the mu opioid fentanyl. METHODS: Saline and one of two doses of fentanyl, administered s.c., were established as discriminative stimuli in two groups of rats (low training dose group: 0.01 mg/kg; high training dose group: 0.04 mg/kg). Generalization tests and in vivo apparent pA(2) analyses were used to evaluate receptor mechanisms of stimulus control. RESULTS: Fentanyl, etonitazene, methadone, and morphine evoked full fentanyl generalization in both groups but were more potent in the low-dose group. Spiradoline and d-amphetamine did not evoke generalization in either group. Naltrexone antagonized stimulus and rate-altering effects of fentanyl in both groups, with apparent pA(2) values of 7. 6 in the low-dose group and 7.5 in the high-dose group. Nalbuphine and nalorphine evoked full generalization in the low-dose group but less than 40% generalization in the high-dose group. In the high-dose group, nalbuphine and nalorphine antagonized the stimulus and rate-altering effects of fentanyl with apparent pA(2) values of 5.3 and 6.1, respectively, demonstrating lower efficacy mu actions. CONCLUSIONS: Changes in fentanyl training dose preserved the mu opioid selectivity of stimulus control but altered the intensity of the transduced mu opioid stimulus required for generalization. These differences in intensity of the fentanyl stimulus determined whether low efficacy mu opioids would evoke or antagonize fentanyl generalization.

Analgesics, Opioid↗
PubMed2000

Use of Raman spectroscopy in the characterisation of the acid-base reaction in glass-ionomer cements.

Raman spectra of various combinations of glass-ionomer cement components have been compared with those of the reactants and the salts of polyacrylic and tartaric acids. The components consisted of a fast-setting acid-degradable dental glass (containing, inter alia, oxides of Si, Al, Ca, Ba and Na), polyacrylic acid (PAA) and/or tartaric acid (TA). On the addition of water to the glass and tartaric acid, Raman spectroscopy indicated loss of acid and production of tartrate salts within seconds of mixing. Mixtures containing the glass, PAA and water in mass ratios 2:1:(0.1-4) reacted to form polyacrylate salts. The maximum fraction of unreacted PAA was found to decrease linearly with initial water/PAA mass ratio to a minimum of approximately 20% when this ratio exceeds 1.5. The data are consistent with 5.6 moles of water being required when each mole of acidic groups is neutralised. In newly prepared cements containing glass, water, polyacrylic and tartaric acids, polyacrylic acid and its salts, in both ionised and solid state form, can be detected. After about 1 h, however, Raman peaks associated with ionised species disappear.

Acrylic Resins↗
PubMed2000

Modulation of latent inhibition in the rat by altered dopamine transmission in the nucleus accumbens at the time of conditioning.

Latent inhibition describes a process by which pre-exposure of a stimulus without consequence retards the learning of subsequent conditioned associations with that stimulus. It is well established that latent inhibition in rats is impaired by increased dopamine function and potentiated by reduced dopamine function. Previous evidence has suggested that these effects are modulated via the meso-accumbens dopamine projections. We have now undertaken three experiments to examine this issue directly, especially in the light of one study in which latent inhibition was reported to be unaffected by direct injection of amphetamine into the accumbens. Latent inhibition was studied using the effect of pre-exposure of a tone stimulus on the subsequent formation of a conditioned emotional response to the tone. 6-Hydroxydopamine-induced lesions of dopamine terminals in the nucleus accumbens resulted in potentiation of latent inhibition. Bilateral local injections of the dopamine antagonist haloperidol into the nucleus accumbens (0.5 microg/side) before conditioning also potentiated latent inhibition. Moreover, such injections were able to reverse the disruptive effect of systemic amphetamine (1mg/kg, i.p.) on latent inhibition. Bilateral local injection of amphetamine (5 microg/side) into the nucleus accumbens before conditioning was able to disrupt latent inhibition, provided that it was preceded by a systemic injection of amphetamine (1mg/kg) 24h earlier.We conclude that the attenuation of latent inhibition by increased dopamine function in the nucleus accumbens is brought about by impulse-dependent release of the neurotransmitter occurring at the time of conditioning. The previously reported failure to disrupt latent inhibition with intra-accumbens amphetamine is probably due to impulse-independent release of dopamine. The implications of these conclusions for theories linking disrupted latent inhibition to the attentional deficits in schizophrenia, and to the dopamine theory of this disorder, are discussed.

Amphetamine↗
PubMed2000

A phase II study of the 5-lipoxygenase inhibitor, CV6504, in advanced pancreatic cancer: correlation of clinical data with pharmacokinetic and pharmacodynamic endpoints.

PURPOSE: Primary objective was to determine response rate of patients with advanced pancreatic cancer to a novel lipoxygenase and thromboxane A2 synthetase inhibitor (CV6504); secondary objectives included estimation of pharmacokinetics of CV6504, target-enzyme inhibition, safety and tolerance, quality of life and survival. PATIENTS AND METHODS: Thirty-one patients with advanced pancreatic cancer were planned to receive CV6504, 100 mg TDS, orally for three months, at which point CT scans were performed to assess therapeutic response rates. Steady state concentrations of CV6504 and thromboxane B2 (an indirect measure of thromboxane A2 synthetase (TA2S) inhibition) were made. Of the 31 patients entered into the study, 23 were considered fully evaluable for response. RESULTS: The drug was well tolerated with few side effects; no partial or complete responses were seen, but 10 patients had stable disease at 3 months; quality of life was maintained during therapy; mean CV6504 steady state plasma concentrations of 14 +/- 6 ng/ml resulting in 75 +/- 18% inhibition of TA2S were achieved; median-survival time for all patients considered eligible for assessment of efficacy was 36.6 weeks after the initial dose of study medication. The actuarial one-year survival was approximately 25%. CONCLUSION: CV6504 inhibits its target enzyme in vivo, maintains stable disease in 32% of evaluable patients and is well tolerated.

Antineoplastic Agents↗