Biomedical subjects

A M Young

Publications and source records attributed to A M Young.

At least 37 records · Page 2Linked to original sources

PubMed2000

On creating a workable signing environment: deaf and hearing perspectives.

This article studies teams of service providers in education and psychiatric services, in which a substantial number of both deaf and hearing people work together as colleagues. It focuses specifically on the challenges involved in cooperatively creating a signing work environment. Using a methodology that draws on the principles of ethnography, it identifies and explores the meaning constructions associated with signing at work, from deaf and hearing perspectives. Data were collected through interviews in three organizations all in the United Kingdom: two specialist psychiatric units for deaf adults and a school for deaf children. Forty-one informants participated (20 deaf, 21 hearing). Results show that from a deaf perspective, hearing people's use of sign language in their presence at work is closely associated with demonstrating personal respect, value, and confidence, and hearing colleagues' willingness to sign is more significant than their fluency. From a hearing perspective, results demonstrate that sign language use at work is closely associated with change, pressure, and the questioning of professional competence. The challenges involved in improving deaf/hearing relations are perceived from a deaf perspective as largely person-centered, and from a hearing perspective as primarily language-centered. The significance of organizational factors such as imbalances in power and status between deaf and hearing colleagues is explored in relation to the findings.

Journal Article↗

PubMed2000

Comparison of in vivo wear between polyethylene liners articulating with ceramic and cobalt-chrome femoral heads.

At yearly intervals we compared the radiological wear characteristics of 81 alumina ceramic femoral heads with a well-matched group of 43 cobalt-chrome femoral heads. Using a computer-assisted measurement system we assessed two-dimensional penetration of the head into the polyethylene liner. We used linear regression analysis of temporal data of the penetration of the head to calculate the true rates of polyethylene wear for both groups. At a mean of seven years the true rate of wear of the ceramic group was slightly greater (0.09 mm/year, SD 0.07) than that of the cobalt-chrome group (0.07 mm/year, SD 0.04). Despite the numerous theoretical advantages of ceramic over cobalt-chrome femoral heads, the wear performance in vivo of these components was similar.

Aged↗

PubMed2000

Characterization of long-term femoral-head-penetration rates. Association with and prediction of osteolysis.

BACKGROUND: We examined the relationship between long-term femoral-head-penetration patterns and osteolysis in a ten-year follow-up study of a well controlled patient population. The purposes of this study were to characterize the linearity of long-term head-penetration patterns over time, to describe the relationship between ten-year true wear rates and osteolysis, and to determine whether the occurrence of osteolysis at ten years could be predicted by penetration data obtained prior to five years. METHODS: Temporal femoral-head-penetration patterns were examined at a minimum of ten years after forty-eight primary total hip arthroplasties. The arthroplasties were performed with the use of an Arthropor acetabular cup (Joint Medical Products) and a thirty-two-millimeter-diameter cobalt-chromium femoral head (DePuy). Using a computer-assisted radiographic technique, we evaluated two-dimensional head penetration on serial annual radiographs. Linear regression analysis modeled penetration-versus-time data as a line for each patient. The slope of the regression line indicated the true wear rate for each patient. In a subgroup of thirty-four hips for which three annual radiographs had been made less than five years after the arthroplasty, we compared early head-penetration patterns with the later occurrence of osteolysis. RESULTS: For all forty-eight hips, the true wear rate averaged 0.18 millimeter per year (range, 0.01 to 0.44 millimeter per year) and temporal head-penetration patterns tended to be linear (mean r2 = 0.91 +/- 0.16). Osteolysis at ten years was strongly associated with increasing true wear rates (p < 0.001). Osteolysis did not develop in any of the nine hips with a true wear rate of less than 0.1 millimeter per year. However, osteolysis developed in nine (43 percent) of twenty-one hips with a rate between 0.1 and less than 0.2 millimeter per year, in eight of ten hips with a rate between 0.2 and 0.3 millimeter per year, and in all eight hips with a rate of greater than 0.3 millimeter per year. Evaluation of early true wear rates as a predictor of late osteolysis showed a similar relationship. CONCLUSIONS: This study demonstrates that true wear rates tend to be constant and that increased true wear is significantly associated with osteolysis at ten years after the operation. A similar relationship was also found at the early follow-up interval, indicating that early true wear rates (determined from serial radiographs) might enable orthopaedists to predict if patients are at risk for the development of osteolysis. CLINICAL RELEVANCE: On the basis of these findings, we use temporal femoral-head-penetration data in our practice to evaluate polyethylene inserts in asymptomatic patients, to estimate the time to component wear-through, and to adjust the frequency of follow-up evaluations for monitoring the development of osteolytic lesions in at-risk patients.

Adult↗

PubMed1999

Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine.

Galactose-targeted delivery of macromolecules and drug conjugates to asialoglycoprotein receptor (ASGPR) positive cells has been widely documented in animals, although targeting in humans has never been demonstrated. In this study we report the pharmacokinetics and imaging determined in the first patient enrolled in a phase I clinical study of the poly[N-(2-hydroxypropyl)methacrylamide] copolymer bearing doxorubicin and galactosamine, known as PK2. Gradient high performance liquid chromatography (HPLC) evaluation of plasma and urine has been combined with 123I-based imaging to show biphasic clearance of the drug from the plasma (half-lives of 78+/-1 and 990+/-15), and approximately 30% delivery of the drug to the hepatic region, as determined by planar whole body imaging at 24 h. This patient has a multifocal hepatoma, and single photon emission computed tomography (SPECT) analysis showed a ratio of tumour tissue to normal liver uptake of approximately 1:3, at 24 h. On the basis of this patient, effective hepatic targeting can be achieved following an intravenous dose of 20 mg/m2 doxorubicin as PK2, however the therapeutic usefulness of this targeted drug has yet to be established.

Antibiotics, Antineoplastic↗

PubMed1999

Contoured elastic-membrane microvalves for microfluidic network integration.

A contoured elastic-membrane microvalve is presented that enables integrated microfluidic processing at the network level. This method takes advantage of two ideas to improve performance: flexible elastic membranes (which enable high-performance shutoff and reduced footprint), and three-dimensionally contoured valve geometries (which reduce dead volume, improve fluidic priming, and reduce susceptibility to cavitation at high fluid velocities). We describe the use of laser-induced etching for microfluidic manifold fabrication, discuss the nonlinear load-deflection behavior of elastic membranes that can occur below 30 psi, and present flow-rate data for microvalves under inlet pressures of 0-20 psi with zero applied membrane pressure. Valve-closure data for inlet pressures of 0-30 psi are presented for fully assembled microvalve structures. The microvalve structures under test were capable of turning off flows of > 20 microL/s. These flow rates were shown to be limited by inlet and outlet flow resistances and not by the valve structure itself, so that higher maximum flow rate capabilities should be readily achieved.

Computer-Aided Design↗

PubMed1999

Can pharmacokinetic monitoring improve clinical use of fluorouracil?

Fluorouracil is used clinically against a variety of solid tumors. It is a prodrug that undergoes a series of intracellular conversions to active cytotoxic species. There is wide interindividual variability in fluorouracil metabolism; furthermore, it has nonlinear kinetics that make it relatively more difficult to predict plasma concentrations after brief infusions compared with prolonged infusions. There is an increasing body of evidence that relates plasma fluorouracil concentrations to toxicity and effectiveness, and consequently there may be a definable mathematical relationship that describes a 'therapeutic window'. Dose nomograms and pharmacokinetic models based on limited sampling strategies have been developed, as have empirical dose escalation schedules based on multivariate analysis of the determinants of toxicity, The utility of these approaches should be tested in properly powered, prospective, randomised trials.

Age Factors↗

PubMed1998

Dopamine release in the amygdaloid complex of the rat, studied by brain microdialysis.

The dopaminergic projection from the ventral tegmental area to the amygdaloid complex may be modulatory on the processes of associative learning in the latter region. We measured dopamine in four different amygdaloid subfields in the rat, using brain microdialysis. Extracellular levels of dopamine in two sites in the lateral nucleus were not consistently measurable, even after treatment with amphetamine. However, basal dopamine levels were measurable in more medial locations (basolateral and central nuclei), with higher concentrations in the caudal than in the rostral probe placement, and were increased around 3-fold by systemic amphetamine. Similarly, dopamine levels in caudal-medial amygdala were increased by local potassium stimulation and by mild footshock in a calcium-dependent manner, indicating a neurotransmitter origin.

Amphetamine↗

PubMed1998

In vivo apparent affinity and efficacy estimates for mu opiates in a rat tail-withdrawal assay.

Experiments in a rat tail-withdrawal assay tested the hypothesis that the magnitude and pattern of antagonism of mu opiate agonists by the insurmountable mu opioid antagonist clocinnamox are inversely related to agonist efficacy. In addition, these experiments examined whether this antagonism could be quantified to yield apparent affinity and efficacy estimates for the pharmacological characterization of five opiate agonists. Etonitazene, etorphine, morphine, buprenorphine, and GPA 1657 produced dose-dependent increases in tail-withdrawal latency until 100% maximum possible effect (%MPE) was obtained. Morphine required a higher dose of clocinnamox for a 50% reduction in maximal antinociceptive effect than did buprenorphine or GPA 1657. In contrast, no dose of clocinnamox tested decreased the %MPE for etonitazene or etorphine. These data suggest a rank order of relative efficacy of etonitazene > or = etorphine > morphine > or = GPA 1657 > or = buprenorphine. Similarly, numerical analysis of these data yielded the following apparent affinity and efficacy estimates: etonitazene (0.38 mg/kg, 128); etorphine (0.68 mg/kg, 125); morphine (50 mg/kg, 38), GPA 1657 (6.6, 39); and buprenorphine (0.042 mg/kg, 2.2). These data illustrate that in vivo affinity and efficacy estimates for a number of agonists are remarkably similar across different methods of analysis and are useful for drug classification.

Algorithms↗

PubMed1998

Increased extracellular dopamine in the nucleus accumbens of the rat during associative learning of neutral stimuli.

Brain microdialysis was used to study changes in dopamine in the nucleus accumbens and the dorsal striatum during associative learning between two neutral stimuli, flashing light and tone, presented on a paired schedule during stage 1 of a sensory preconditioning paradigm. The tone was subsequently paired with mild footshock using standard aversive conditioning procedures and the formation of a conditioned association between the flashing light and the tone in stage 1 was assessed by measuring the ability of the flashing light to elicit the same conditioned response as the tone when presented at test. The first experiment used behavioural monitoring only, to establish stimulus parameters for subsequent microdialysis experiments. Animals receiving paired presentation of the light and tone in stage 1 showed a conditioned suppression of licking to the light as well as to the tone, indicating that associative learning between the flashing light and the tone had occurred during stage 1, whilst in a separate group of animals given the same stimuli over the same time period but on an explicitly non-paired schedule, the conditioned emotional response was seen to the tone, but not to the light, showing that no association had been formed between the two stimuli during stage 1. In dialysis experiments using the same procedure, we measured a two-fold rise in dopamine in the nucleus accumbens during paired presentation of flashing light and tone, but not during non-paired presentation of the two stimuli. On subsequent test presentation of the two stimuli, we saw increases in accumbal dopamine on presentation of the tone in both groups, reflecting the formation of an association with the footshock in both. However the flashing light elicited an increase in dopamine only in the group which had received paired presentation at stage 1. Thus accumbal dopamine release at test is correlated to the ability of the stimulus to evoke a conditioned response measured behaviourally. Hypotheses of the behavioural function of the mesolimbic dopamine system centre on its role in mediating the effects of biological reinforcers, both rewarding and aversive, conditioned and unconditioned. The present results, showing increases in extracellular dopamine in the nucleus accumbens when an association is formed between two stimuli of which neither is a biological reinforcer nor, prior to formation of the association, affects dopamine levels, suggest a role for accumbal dopamine in the modulation of associative learning in general, not only that involving reinforcement.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1998

Establishing morphine and U-50,488H as discriminative stimuli in a three-choice assay with pigeons.

Pigeons were trained in a 3-choice assay to discriminate among injections of 5.6 mg/kg U-50,488H, 5.6 mg/kg morphine, and vehicle solution. In dose-response tests, subjects rarely responded on the U-50,488H-appropriate key when morphine was administered or on the morphine-appropriate key when they received U-50,488H. A high dose of naltrexone (1.0 mg/kg) completely blocked the morphine cue but failed to block completely the U-50,488H cue. In generalization tests, d-amphetamine primarily engendered saline-appropriate responding. Ethylketazocine produced mixed results, in that moderate doses produced responding on both the morphine- and U-50,488H-appropriate keys, but 3.2 mg/kg engendered primarily morphine-appropriate responding. These results demonstrate the feasibility, but not necessarily the value, of 3-choice discrimination procedures involving mu and kappa agonists and vehicle.

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

PubMed1997

Dopamine's role.

Explore the source record for details and available documents.

Animals↗

PubMed1997

Tolerance and cross-tolerance to morphine-like stimulus effects of mu opioids in rats.

The purpose of these experiments was to examine the relationship of agonist relative efficacy to the pattern of tolerance and cross-tolerance to the morphine-like stimulus effects of three opioid agonists. Rats were trained to discriminate 3.2 mg/kg morphine from saline under fixed-ratio 15 schedule of food reinforcement. Morphine, nalbuphine, and fentanyl produced dose-dependent increases in morphine-like stimulus effects and decreases in response rates. Repeated treatment with 20 mg/kg per day morphine increased the ED50 for stimulus control by fentanyl, morphine, or nalbuphine two-, four-, or 40-fold, respectively. Repeated treatment with 64 mg/kg per day nalbuphine increased the ED50 for stimulus control for morphine by two-fold, but lower or higher treatment doses had no significant effect. Treatment with 100 mg/kg per day nalbuphine increased the ED50 for nalbuphine by six-fold. Repeated treatment with 0.22 mg/kg per day fentanyl increased the ED50 for stimulus control by fentanyl or morphine by approximately two-fold. Comparisons among treatment conditions suggested that magnitude of tolerance to morphine-like stimulus effects did not vary as an inverse function of the relative efficacy of the agonist used for repeated treatment. Rather repeated morphine and fentanyl treatments produced comparable tolerance, whereas repeated nalbuphine treatment did not evoke substantial tolerance. Comparisons within treatment conditions, however, suggested that magnitude of tolerance may vary inversely with relative efficacy of the agonist tested for morphine-like stimulus effects. During treatment with morphine or fentanyl, greater tolerance was observed to the morphine-like stimulus effects of the lower efficacy agonist relative to the higher efficacy agonist.

Analgesics, Opioid↗

PubMed1997

Latent inhibition: the nucleus accumbens connection revisited.

It has been proposed that dopaminergic transmission in the nucleus accumbens plays a key role in regulating latent inhibition (LI), i.e. the retardation of conditioning that occurs if a to-be-conditioned stimulus is first presented a number of times ('preexposure') without other consequence. New evidence in support of this hypothesis is presented or reviewed here, showing that: (1) intra-accumbens injection of haloperidol at the time of conditioning potentiates LI; (2) destruction of dopaminergic terminals in the nucleus accumbens potentiates LI; (3) intra-accumbens haloperidol reverses the blockade of LI caused by systemic nicotine; (4) intra-accumbens haloperidol reverses the blockade of LI caused by systemic amphetamine; (5) after a single systemic injection of amphetamine (insufficient on its own to block LI), a subsequent intra-accumbens injection of amphetamine at the time of conditioning blocks LI; and (6) intra-accumbens (like systemic) amphetamine administered 15 min before conditioning, without prior systemic amphetamine, failed to block LI. The difference between the effects on LI of one and two administrations of amphetamine, respectively, is interpreted in terms of the need for sensitisation of the response to amphetamine, with the result that the response to the second administration includes a component of impulse-dependent dopamine release in the nucleus accumbens that is otherwise lacking. Data from dialysis experiments suggest that such impulse-dependent accumbens dopamine release also occurs at relatively long delays after a single systemic administration of amphetamine. It was accordingly predicted, and found, that, although LI is intact 15 min after an i.p. injection (confirming previous results), it is abolished at 90 min after the injection of amphetamine. This finding is consistent with the effects of amphetamine in human subjects, in whom LI is blocked 90 min after a single oral administration. Overall, these results strengthen the case that the blockade of LI by elevated, and potentiation of LI by decreased, dopaminergic transmission are both due specifically to actions in the nucleus accumbens; and also add to the similarities between LI studied in animal and human subjects, respectively.

Animals↗

PubMed1997

Determining priorities for change in primary care: the value of practice-based needs assessment.

BACKGROUND: Primary care is being expected to expand the range of services it provides, and to take on many of the tasks traditionally provided in secondary care. At the same time, general practitioners (GPs) will become increasingly responsible for assessing their patients' health care needs and commissioning care from other providers. This article describes an approach taken in one general practice to meet these difficult challenges. AIM: To examine whether information on health and health care needs, when used as the basis for a priority setting exercise, can provide a useful first step in planning primary care provision within a practice. METHOD: A three-stage process of information-gathering from a number of sources, including continuous data recording of patient contacts and a postal survey of all adults registered with the practice, identification of key findings and discussion of associated issues, and priority setting of proposals for practice development using the nominal group technique. RESULTS: Continuous data recording of patient contacts with GPs and the practice nurse provided data on 4489 GP contacts with 2027 patients, 1000 district nurse contacts with 101 patients, and 361 health visitor contacts with 172 clients. More than 70% of patient records had been computerized, with 600 diagnostic READ codes identified and 11,500 separate entries made. The socioeconomic and health survey questionnaire achieved an 84% response rate. Following the priority-setting exercise, 28 proposed practice developments were identified. These were reduced to a final list of eight. CONCLUSION: A comprehensive method of practice-based needs assessment, when used as the basis for some form of priority setting, has great potential in helping to plan primary care services within a practice. The success of such initiatives will require a substantial investment of resources in primary care and fundamental changes to the way in which primary care is funded.

Health Priorities↗

PubMed1996

Behavioral contingencies modulate tolerance to discriminative stimulus effects of morphine.

Experiments examined how learning processes modulate tolerance to discriminative stimulus effects of morphine. Rats were trained to discriminate saline and 3.2 mg/kg morphine, and the doses of morphine required to mimic the training dose were determined before, during and after repeated treatment with saline or high doses of morphine (10 mg/kg, b.i.d.). In one set of experiments, training was either suspended or continued with saline and the original training dose during a 2-week treatment regimen. When training was suspended, high-dose morphine treatment increased the dose of morphine required for stimulus effects approximately 3-fold. Tolerance persisted 2 days after treatment ended, but disappeared within 7 days. In contrast, continued training with saline and 3.2 mg/kg morphine during high-dose treatment both attenuated development of tolerance and transferred control to lower doses. Transfer of control to lower doses appeared conditional upon recent termination of high-dose treatment, as it disappeared within 7 days. Treatment with saline did not change the doses of morphine required for stimulus effects under either training condition. A final experiment examined whether high-dose treatment could transfer control to higher doses of morphine. The treatment dose of 10 mg/kg morphine itself was used as the training dose during a 2-week treatment regimen. The dose of morphine required for stimulus effects increased 2- to 4-fold during treatment, but quickly returned to control values when treatment ended. These results extend previous findings that conditioning and pharmacodynamic processes jointly regulate development of tolerance to discriminative effects of morphine.

Animals↗

PubMed1996

In vivo apparent pA2 analysis in rats treated with either clocinnamox or morphine.

Experiments tested the hypothesis that loss of agonist potency or effectiveness following irreversible antagonist or chronic agonist treatment may result from affinity changes at mu opioid receptors. Apparent affinity of naltrexone or nalbuphine for mu opioid receptors was measured in vivo in rats treated with either a single dose of the irreversible antagonist clocinnamox or repeated doses of morphine. Apparent affinity of each antagonist was estimated from its potency as an antagonist of discriminative stimulus or rate-decreasing effects of morphine in rats trained to discriminate 3.2 mg/kg morphine and saline. In control rats, apparent pA2 values for naltrexone and nalbuphine were 7.5-7.6 and 5.3, respectively. In clocinnamox-treated rats, apparent pA2 values for naltrexone were 7.2-7.7, suggesting that clocinnamox treatment did not alter affinity of naltrexone for sites through which morphine exerts behavioral effects. In rats treated repeatedly with morphine, apparent pA2 values for nalbuphine were 5.1-5.3, suggesting that repeated morphine treatment did not alter affinity of nalbuphine for these sites. The observation that neither clocinnamox nor repeated morphine treatment altered in vivo affinity estimates for naltrexone or nalbuphine, respectively, suggests that the reductions in agonist potency produced by these treatments do not result from changes in affinity at mu opioid receptors.

Animals↗

PubMed1996

Prolonged intraperitoneal infusion of 5-fluorouracil using a novel carrier solution.

A novel peritoneal carrier solution, Icodextrin 20 (7.5%), has allowed exploration of prolonged, intraperitoneal (i.p.) infusion of the cytotoxic drug 5-fluorouracil (5-FU). A phase I and pharmacokinetic study was performed to determine the toxicities and maximum tolerated dose of prolonged and continuous intraperitoneal 5-FU in patients with peritoneal carcinomatosis. Seventeen patients were entered into this study. Each patient had a Tenckhoff catheter placed into the peritoneal cavity under general anaesthetic. After initial flushing and gradual increase in exchange volumes with Icodextrin 20, 5-FU was administered daily from Monday to Friday, 50% as a bolus in the exchange bag and 50% in an elastomeric infusor device delivering continuous 5-FU to the peritoneal cavity at 2 ml h-1. Treatment was continued for 12 weeks or until intolerable toxicity developed. Abdominal pain and infective peritonitis proved to be the main dose-limiting toxicities. Initial problems with infective peritonitis were overcome by redesign of the delivery system, and it proved possible to deliver 300 mg m-2 5-FU daily (5 days per week) for 12 weeks. Pharmacokinetic studies showed i.p. steady-state 5-FU concentrations (mean 47 500 ng ml-1) that were > 1000-fold higher than systemic venous levels (mean 30 ng ml-1).

Adult↗

PubMed1996

Photolysis of retinol in liposomes and its protection with tocopherol and oxybenzone.

In this work the stabilities of retinol in methanolic solutions and liposomal suspensions exposed to UV light were compared using absorbance spectroscopy and the ability of alpha-tocopherol and the sunscreen additive, oxybenzone, to reduce the rate of retinol decomposition assessed. Retinol in methanol decolorized almost completely within a few minutes of exposure to a 6 W 350 nm wavelength lamp. From the concentration dependence of the reaction rates it appears that retinol activated by light can decomposed either directly or after collision with a second retinol molecule. Several reaction products are formed. alpha-Tocopherol solutions were unaffected by 350 nm light but they did darken when irradiated with 250 nm wavelength light. Addition of alpha-tocopherol or removal of oxygen from the retinol in methanol solutions reduced only slightly the rates of retinol photolysis. When dispersed in water within liposomes made of equimolar egg phosphatidylcholine (PC) and cholesterol, up to six-fold increases in the decomposition rate of the retinol were observed. The reaction rate could be reduced but only slightly by increasing the ratio of PC to retinol. A mechanism that explains the concentration dependence of the retinol photolysis is that the reduction in reaction rate on diluting the retinol concentration within a given liposome was due to the prevention of the reaction between one light-activated retinol molecule with another within the same liposome. Incorporation of oxybenzone into the liposomes reduced the reaction rates. The results suggested that most of the protection in this case arises through the oxybenzone closet to the light source absorbing the light, thereby preventing it reaching retinol much further into the sample. Incorporation of alpha-tocopherol into the liposomes could also reduce substantially the photolysis rate of co-entrapped retinol. The mechanism of protection in this case appears to be via the tocopherol quenching activated retinol molecules. The close proximity of the tocopherol to the retinol within a single liposome has shown to be important in this case. Only slight protection of retinol in one liposome by tocopherol in another was observed under the conditions studied. This means that the protection by tocopherol will still be observed if the liposome dispersions are diluted considerably or if only thin samples are exposed to light.

Benzophenones↗