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Biomedical subjects

J Stewart

Publications and source records attributed to J Stewart.

At least 91 records · Page 5Linked to original sources
PubMed2000

Social costs of untreated opioid dependence.

Using cost-of-illness methodology applied to a comprehensive survey of 114 daily opiate users not currently in or seeking treatment for their addiction, we estimated the 1996 social costs of untreated opioid dependence in Toronto (Ontario, Canada). The survey collected data on social and demographic characteristics, drug use history, physical and mental health status, the use of health care and substance treatment services, drug use modality and sex-related risks of infectious diseases, sources of income, as well as criminality and involvement with the law enforcement system. The annual social cost generated by this sample, calculated at Canadian $5.086 million, is explained mostly by crime victimization (44.6%) and law enforcement (42.4%), followed by productivity losses (7.0%) and the utilization of health care (6.1%). Applying the $13,100 cost to the estimated 8,000 to 13,000 users and 2.456 million residents living in Toronto yields a range of social cost between $43 and $69 per capita.

Cost of Illness↗
PubMed2000

Basic fibroblast growth factor as a mediator of the effects of glutamate in the development of long-lasting sensitization to stimulant drugs: studies in the rat.

RATIONALE: Repeated exposure to stimulant drugs, such as the indirect dopaminergic agonists amphetamine or cocaine, results in increased sensitivity to their effects on behavior and dopaminergic function. Neuroadaptations initiated in the ventral tegmental area (VTA), a cell body region of midbrain dopaminergic neurons, and dependent on glutamatergic transmission, underlie the development of this persistent drug-induced sensitization. How precisely drug actions in the VTA initiate long-lasting changes in dopaminergic function, and how glutamate participates in these events is not clear. OBJECTIVES: To discuss the idea that neurotrophic, neuroprotective factors are involved. RESULTS: We review the few studies that have been concerned with a role for neurotrophic factors in the changing response to stimulant drugs and present a summary of those conducted in our laboratory on basic fibroblast growth factor (bFGF), a neurotrophic factor produced by astrocytes. CONCLUSION: We argue that repeated exposure to stimulant drugs increases the demands on dopaminergic cell functioning, and, by stimulating glutamate release, recruits neurotrophic and neuroprotective substances such as bFGF. We propose that the actions of these factors, in turn, give rise to long-lasting neuronal adaptations that underlie sensitized responding to further drug exposure. Possible mechanisms whereby bFGF participates in the development of sensitization, including interactions with other neurotrophic factors, are discussed. In addition, we show how the evidence reviewed in this paper provides further support for the idea that repeated treatment with stimulant drugs induces synaptic plasticity.

Animals↗
PubMed2000

Stress-induced relapse to heroin and cocaine seeking in rats: a review.

Studies in humans suggest that exposure to stress increases the probability of relapse to drug use, but until recently there has been no animal model to study the mechanisms that mediate this effect. We have developed a reinstatement procedure that allows us to study the effect of stress on relapse to drug seeking in rats. Using this procedure, we have shown that exposure to intermittent footshock stress reliably reinstates heroin and cocaine seeking after prolonged drug-free periods. In the present paper, we summarize results from several studies on stress-induced reinstatement of heroin and cocaine seeking in rats. We first assess the degree to which the phenomenon of stress-induced relapse generalizes to other stressors, to behaviors controlled by other drugs of abuse, and to behaviors controlled by non-drug reinforcers. We then review evidence from studies concerned with the neurotransmitters, the brain sites, and the neural systems involved in stress-induced reinstatement of drug seeking. Finally, we consider the mechanisms that might underlie stress-induced relapse to drug seeking and the possible implications of the findings for the treatment of relapse to drug use in humans.

Animals↗
PubMed2000

Cocaine-induced conditioned place preference: reinstatement by priming injections of cocaine after extinction.

To explore the way in which drugs act to reinstate drug-seeking behavior, we studied drug-induced reinstatement of a cocaine-induced conditioned place preference (CPP). In a series of experiments, we studied the establishment, maintenance, extinction and reinstatement of a cocaine-induced CPP in a three-chamber 'unbiased' apparatus. Groups of rats were given four 20-min pairings of one chamber with cocaine (10.0 mg/kg, i.p.) and four of the other with saline on alternate days. In 15-min tests for CPP, drug-free rats were placed in the center choice chamber with access to the entire apparatus. Experiments were designed to study the expression of the CPP, the maintenance of the CPP in tests given at 2, 4, and 6 weeks after training, and the reinstatement of the CPP by cocaine (5.0 mg/kg) after extinction by 12 repeated tests in the non-drugged state, and after extinction by pairing each chamber, on alternate days, with saline on four occasions. Robust CPPs were obtained that endured for 4 weeks and were maintained for up to 6 weeks when tests were given at 2-week intervals. Both extinction procedures led to the loss of the CPP that was in turn reinstated by priming injections of cocaine. These results indicate that a cocaine-induced CPP, once developed, endures for several weeks, and is maintained by occasional testing even in the absence of additional drug experience. The fact that the CPP is easily reinstated when testing is preceded by a priming injection of cocaine suggests that drugs may induce relapse by renewing the incentive value of drug-associated cues.

Animals↗
PubMed2000

Changes in astrocytic basic fibroblast growth factor expression during and after prolonged exposure to escalating doses of amphetamine.

We have shown that brief exposure to amphetamine leads to sustained glutamate-dependent increases in expression of the neurotrophic, neuroprotective factor, basic fibroblast growth factor, in astrocytes in dopaminergic cell body regions and that blockade of basic fibroblast growth factor in this region prevents the development of behavioral sensitization to amphetamine. Here we examine the effects of prolonged exposure to an escalating-dose regimen of amphetamine known to induce long-lasting sensitization to amphetamine and leading to increases in neuronal dendritic length and spine density in nucleus accumbens and prefrontal cortex and to decreases in spine density in occipital cortex. Astrocytic basic fibroblast growth factor immunoreactivity was increased in both dopaminergic cell body and terminal regions one week after termination of a two-week amphetamine treatment (1-4mg/kg). These effects were not evident one week after a five-week treatment (1-9mg/kg) and, in fact, one month later basic fibroblast growth factor levels in cell body regions were decreased. In the occipital cortex, basic fibroblast growth factor immunoreactivity was decreased one week after the two-week amphetamine treatment, but was not different from that seen in saline-treated animals after the five-week treatment. Increased astrocytic basic fibroblast growth factor expression appears to be an early, but relatively prolonged, response to amphetamine exposure and seems to parallel structural changes induced by repeated drug exposure.These findings suggest that basic fibroblast growth factor may participate in the development of structural changes brought about by amphetamine. The fact that the basic fibroblast growth factor response is not maintained after prolonged intense exposure to amphetamine suggests that the factors that initially induce basic fibroblast growth factor expression are self-regulating.

Amphetamine↗
PubMed2000

Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking.

The alpha-2 adrenergic receptor agonists, clonidine, lofexidine and guanabenz, blocked stress- but not cocaine-induced reinstatement of cocaine seeking at doses that suppressed footshock-induced release of noradrenaline in prefrontal cortex and amygdala. Rats were trained to self-administer cocaine (0.5 mg/kg/infusion, i.v; 10-12 days) and, after a drug-free period (7-13 days), were returned to the self-administration chambers for daily extinction and reinstatement test sessions. Both intermittent footshock (15 min, 0.6 mA) and cocaine priming (20 mg/kg, i.p.) reinstated extinguished drug seeking. Pretreatment with either clonidine (20, or 40 microg/kg, i.p.) or lofexidine (50, 100, 150, or 200 microg/kg, i.p.) attenuated footshock- but not cocaine-induced reinstatement of cocaine seeking. Guanabenz (640 microg/kg, i.p.), an alpha-2 agonist with low affinity for imidazoline type-1 receptors, also attenuated footshock- but not cocaine-induced reinstatement of cocaine seeking. The results point to an important role for NE systems in the effects of footshock on relapse to cocaine seeking.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2000

Carriage of N. lactamica in a population at high risk of meningococcal disease.

Carriage of Neisseria lactamica among household contacts of meningococcal disease (MCD) cases was investigated during an epidemic in Auckland, New Zealand. The overall carriage rate for N. lactamica was 10.5% (95% CI 7.4-13.5%) with a peak carriage rate in 2-year-olds of 61.5% (95% CI 26.6-88.1%). Factors associated with a significant (P < 0.05) increase in the likelihood of carriage included runny nose, the number of people per bedroom and youth. Genetic analysis of isolates revealed a striking correlation of strains within the same household but a high level of diversity between households, suggesting that household contact is an important factor in acquisition. For household contacts aged less than 5 years, there was a higher rate of carriage amongst those in contact with MCD cases under 8 years old than for contacts of cases aged 8 years and over. It is likely that development of MCD is a reflection of the nature and intensity of the exposure to a virulent strain of N. meningitidis, coupled with an absence of host resistance among those individuals not carrying N. lactamica.

Adolescent↗
PubMed2000

Long-term persistence of oligoclonal serum IgM repertoires in patients treated with allogeneic bone marrow transplantation (BMT).

Immunoglobulin gene rearrangements in patients treated with BMT have restricted repertoire diversity. Clonal variability remains low for 3 months and reconstitution of the humoral immune system appears to follow a wave-like pattern. In the present study we analysed serum IgM and IgG repertoires in 44 patients from 1 week to 3 years after transplantation. We applied a quantitative immunoblot technique in combination with a newly developed method for estimation of repertoire diversity in complex mixtures of antibodies. Our results demonstrate that 60% of BMT patients have severely reduced diversity in the IgM repertoire during and after the first year post-BMT, compared with healthy controls. In contrast, the majority of patients have a polyclonal IgG repertoire, similar to that of healthy controls. Serum IgM repertoires remain oligoclonal even though the serum concentration of total IgM is within normal range around 6 months post-BMT. During the first years after transplantation IgM as well as IgG repertoires are less diverse in patients receiving a BM graft from a sibling donor compared with those receiving a graft from an HLA-matched unrelated donor. Patients in the latter group show a higher incidence of infections and minor antigen mismatches which may promote the development of a diverse immunoglobulin repertoire post-BMT.

Adult↗
PubMed2000

Clarifying the concepts of confidence and competence to produce appropriate self-evaluation measurement scales.

INTRODUCTION: This paper reviews the literature on self-evaluation and discusses the findings of a small-scale qualitative study which explored the terms 'confidence' and 'competence' as useful measures in a self-evaluation scale. Four pre-registration house officers took part in interviews and completed a provisional instrument to assess their perceived competence. FINDINGS: Competence and confidence are useful terms for house officers expressing beliefs about their ability to perform their job but the terms should not be used synonymously. In our study, 'competent' represented what individuals knew about their ability and was based on the individual's previous experience of the task. 'Confident' described a judgement which influenced whether an individual was willing or not to undertake an activity. Confidence was not necessarily based on known levels of competence and therefore performance of tasks which were unfamiliar to the house officer also involved the assessment of risk. The authors give examples of task and skill scales which may be useful in the process of self-evaluation by pre-registration house officers. CONCLUSIONS: The authors suggest that the process of assessing oneself is complicated, and by its very nature can never be objective or free from the beliefs and values individuals hold about themselves. Therefore self-evaluation instruments are best used to help individuals analyse their work practices and to promote reflection on performance. They should not be used to judge the 'accuracy' of the individual's evaluation.

Attitude↗
PubMed2000

Involvement of the medial septum in stress-induced relapse to heroin seeking in rats.

Intermittent footshock stress has been shown to reinstate extinguished drug-taking behaviour in rats, but the brain areas involved in this effect are to a large degree unknown. Here we studied the role of the septum in stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin for 9-10 days (three 3-h sessions per day, 0.1 mg/kg per infusion). Following training, extinction sessions were given for 8-13 days by substituting saline for heroin, and then tests for reinstatement of heroin seeking were carried out. Reversible inactivation of the medial septum with tetrodotoxin (TTX; 1-5 ng, infused 25-40 min before the test sessions) reliably reinstated heroin seeking, mimicking the effect of 15 min of intermittent footshock. This effect of TTX was not observed after infusions made 1.5 mm dorsally into the lateral septum. In other experiments, it was found that infusions of a low, subthreshold dose of TTX (0.5 ng) into the medial septum, when combined with 2 min of footshock that in itself was ineffective, reinstated heroin seeking. Furthermore, electrical stimulation (400 microA pulses, 100 micros duration, 100 Hz frequency) of the medial septum during exposure to 10 min of intermittent footshock attenuated footshock-induced reinstatement of heroin seeking. These data suggest a role for the medial septum in stress-induced relapse to drug seeking. The septum is thought to be involved in neuronal processes underlying behavioural inhibition, thus we speculate that stressors provoke relapse by interfering with these processes.

Animals↗
PubMed2000

Clonidine blocks stress-induced reinstatement of heroin seeking in rats: an effect independent of locus coeruleus noradrenergic neurons.

Using a reinstatement procedure, it has been shown that intermittent footshock stress reliably reinstates extinguished drug-taking behaviour in rats. Here we studied the role of noradrenaline (NE), one of the main brain neurotransmitters involved in responses to stress, in reinstatement of heroin seeking. We first determined the effect of clonidine, an alpha-2 adrenergic receptor agonist that decreases NE cell firing and release, on stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin (0.1 mg/kg per infusion, IV, three 3-h sessions per day) for 9-10 days. Extinction sessions were given for up to 11 days during which saline was substituted for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30 min, 0.5 mA). During testing, clonidine was injected systemically (10-40 microgram/kg, i.p.) or directly into the lateral or fourth ventricles (1-3 microram). Clonidine (1-2 microgram per site) or its charged analogue, 2-[2, 6-diethylphenylamino]-2-imidazole (ST-91, 0.5-1 microgram per site), was also injected bilaterally into the locus coeruleus (LC), the main noradrenergic cell group in the brain. Clonidine blocked stress-induced reinstatement of drug seeking when injected systemically or into the cerebral ventricles. In contrast, neither clonidine nor ST-91 consistently altered stress-induced reinstatement when injected into the locus coeruleus. We therefore studied the effect of lesions of the lateral tegmental NE neurons on stress-induced reinstatement. 6-Hydroxydopamine (6-OHDA) lesions performed after training for heroin self-administration had no effect on extinction of heroin-taking behaviour, but significantly attenuated reinstatement induced by intermittent footshock. These data suggest that: (i) clonidine prevents stress-induced relapse to heroin seeking by its action on neurons other than those of the locus coeruleus; and (ii) activation of the lateral tegmental NE neurons contributes to stress-induced reinstatement of heroin seeking.

Animals↗
PubMed2000

Lectin binding characteristics of mouse placental cells.

The lectin binding characteristics of mouse placental cells were examined. Wax embedded tissue sections of placentae from d 14 pregnant mice were stained with 26 lectins, with a wide range of sugar specificities. Cell cultures prepared from d 14 mouse placentae and cultured for 24 h were stained with 7 of the lectins to determine if they could be used as markers for the different trophoblast cells in culture. In tissue sections all placental cell populations bound lectin but no lectin bound specifically to any single trophoblast population. All the lectins which bound to layer 1 cytotrophoblast lining the maternal blood spaces of the labyrinthine placenta also bound to the fetal endothelium of the labyrinthine placenta. Binding of lectin appeared strongest on the adluminal membrane of these cell populations suggesting a role for the carbohydrate moieties in nutrient transfer. Few lectins bound to junctional zone trophoblast. Overall, the binding of lectin to cultured cells did not correlate exactly with lectin binding to the cell populations in tissue sections. The value of lectins as markers for placental cells in culture was therefore found to be limited. Our findings indicate that carbohydrate expression by at least some placental cells may vary in culture from that expressed by the cells in vivo with obvious concerns for the validity of functional in vitro studies.

Animals↗
PubMed2000

The prevalence of thromboembolic events among women with extended bed rest prescribed as part of the treatment for premature labor or preterm premature rupture of membranes.

OBJECTIVE: This study was undertaken to determine the prevalence of thromboembolic events among women with extended bed rest prescribed as part of the treatment of premature labor or preterm premature rupture of membranes. STUDY DESIGN: A retrospective chart review was undertaken of all women who had bed rest of >/=3 days' duration prescribed as part of the treatment of premature labor or preterm premature rupture of membranes in the Akron General Medical Center Perinatal Unit during the period January 1, 1997-December 31, 1998. The prevalence of thromboembolic events in this population was determined. The charts of all additional gravid women with antepartum or postpartum deep vein thrombosis or pulmonary embolism diagnosed during the study period were also reviewed. The prevalence of these disorders among the pregnant population for whom extended bed rest was not prescribed as part of the treatment of premature labor or preterm premature rupture of membranes was also calculated. Statistical comparison of the prevalences in the 2 populations was undertaken by means of the chi(2) analysis with the Fisher exact test. RESULTS: There were 192 patients admitted during the study period who had extended bed rest prescribed as part of the treatment of premature labor or preterm premature rupture of membranes. Three of these women had thromboembolic events, for a prevalence of 15.6 cases per 1000 women. Five additional gravid women were admitted for the treatment of deep vein thrombosis or pulmonary embolism. There were 6164 deliveries among women not treated with extended bed rest for premature labor or preterm premature rupture of membranes during this period. Thus the prevalence of these phenomena among the remaining pregnant women was 0.8 cases per 1000 women. The prevalences of these disorders in the 2 populations were highly significantly different. CONCLUSION: The prevalence of thromboembolic events among women for whom extended bed rest is prescribed as part of the treatment of premature labor or preterm premature rupture of membranes is significantly increased with respect to that among gravid women who do not receive this therapy and is substantially higher than previously reported. If this finding is confirmed in other populations, it may be prudent to undertake further studies to determine whether this prevalence can be reduced.

Bed Rest↗
PubMed2000

A dipstick immunoassay to rapidly measure serum oestrone sulfate concentrations in horses.

A dipstick, competitive immunoassay for rapidly measuring serum oestrone sulfate (OS) concentrations in horses was developed to distinguish mares 100 or more days pregnant from non-pregnant animals. 6-Ketoestrone 6-carboxymethyloxime conjugated to bovine serum albumin (oestrone CMO-BSA) was 'dotted' 25 mm from the bottom edge of 45 x 5 mm strips of polyester-film-supported cellulose nitrate membrane, pore size 3 microm. The strips were blocked, dried and a 15 x 5-mm cellulose absorbent sink attached 10 mm from the top of each strip. The manufactured dipsticks were stored with desiccant at room temperature until used. A monoclonal antibody recognizing OS was coated onto uniform, blue-dyed polystyrene microspheres (mean diameter, 0.31 microm) by adsorption. After blocking, several washes and resuspension by sonication, the antibody-coated microspheres were stored at 4 degrees C. The concentrations of oestrone CMO-BSA dotted onto the dipsticks and OS antibody coated onto the microspheres were optimized to produce a test that allowed maximum discrimination between the concentrations of OS found in serum of mares 100 or more days pregnant (i.e. >30 ng OS mL(-1)) relative to those found in non-pregnant mares (i.e. <10 ng OS mL(-1)). To perform the dipstick test, 30 microL of carrier buffer, 10 microL of OS antibody-coated microspheres and 10 microl of OS standard or serum sample were pipetted into a microwell and mixed. A dipstick was placed in the solution. All the liquid migrated up the dipstick into the absorbent sink within 15-20 min leaving a blue dot where the OCMO-BSA had been placed. The intensity of colour of the blue dot, which correlated inversely with the concentration of OS in the standard or serum sample, was assessed visually and by computer image analysis. An OS concentration less than 5 ng mL(-1) produced a deep blue dot, 20 ng/ml a light blue dot and a concentration greater than 50 ng mL(-1) a very faint blue dot, or none at all. Serum samples from 42 non-pregnant mares and 40 mares over 100 days pregnant were analysed by the dipstick test. All the serum samples from non-pregnant mares produced dipsticks with deep blue dots that ranged in intensity from 20 to 38 colour intensity units, equivalent to OS concentrations less than 7 ng mL(-1). Sera from all the pregnant mares generated dipsticks with either faint blue dots or none at all (i.e. < or =5 colour intensity units, equivalent to OS concentrations >40 ng mL(-1). It is concluded that this novel, rapid dipstick immunoassay offers a practical, alternative means of analysing serum OS concentrations in horses, and enables mares that are 100 or more days pregnant to be distinguished from those that are not pregnant.

Animals↗
PubMed2000

21-day oral etoposide for metastatic breast cancer: a phase II study and review of the literature.

Previous studies of etoposide for metastatic breast cancer commonly used bolus regimens given over a short period of time and included heavily pretreated patients. Results were poor. Chronic oral regimens would be expected to be superior to bolus doses based on pharmacologic studies and patients with less previous chemotherapy would be expected to have higher response rates. We studied the efficacy of oral etoposide at a dose of 50 mg/m2/day for 21 days of a 28-day cycle in good-risk patients with metastatic breast cancer. Healthy patients (Eastern Cooperative Oncology Group performance status 0, 1, or 2) who had not received chemotherapy for at least 1 year before study entry were selected for therapy. Thirty-four patients were entered; three patients were ineligible and one was cancelled. Thirty patients were available for analysis of response. One complete response and eight partial responses were documented (response rate, 30%; 95% confidence interval, 15-49%). A higher response rate was observed in those patients who never received chemotherapy compared with those who had received prior chemotherapy (57 vs. 6%, p = 0.004). There were two treatment-related deaths, both owing to myelosuppression and infection. We found long-term administration of oral etoposide to have a reasonable response rate for metastatic breast cancer (30%). Our response rate was comparable to those of other published studies of long-term oral etoposide regimens for metastatic breast cancer. Response rates in single-arm studies have generally been higher for long-term oral regimens than those for bolus regimens. We also found the regimen to be significantly toxic, an observation that may be underemphasized in the earlier literature.

Administration, Oral↗
PubMed2000

Household crowding a major risk factor for epidemic meningococcal disease in Auckland children.

BACKGROUND: New Zealand is in its ninth year of a serogroup B meningococcal disease epidemic with annual rates of up to 16.9 cases per 100,000. The highest incidence is in Maori and Pacific Island children in the Auckland region. We conducted a case-control study to identify potentially modifiable risk factors for this disease. METHODS: A case-control study of 202 cases of confirmed and probable meningococcal disease in Auckland children younger than 8 years of age recruited from May, 1997, to March, 1999, was undertaken. Controls (313) were recruited door-to-door by a cluster sampling method based on starting points randomly distributed in the Auckland region. They were frequency matched with the expected distribution of age and ethnicity in the meningococcal disease cases. RESULTS: With the use of a multivariate model and controlling for age, ethnicity, season and socioeconomic factors, risk of disease was strongly associated with overcrowding as measured by the number of adolescent and adult (10 years or older) household members per room [odds ratio (OR), 10.7; 95% confidence interval (CI), 3.9 to 29.5]. This would result in a doubling of risk with the addition of 2 adolescents or adults to a 6-room house. Risk of disease was also associated with analgesic use by the child, which was thought to be a marker of recent illness (OR 2.4, CI 1.5 to 4.0); number of days at substantial social gatherings (10 or more people for > 4 h; OR 1.8, CI 1.2 to 2.6); number of smokers in the household (OR 1.4, CI 1.0 to 1.8); sharing an item of food, drink or a pacifier (OR 1.6, CI 1.0 to 2.7); and preceding symptoms of a respiratory infection (cough, "cold or flu," runny nose, sneezing) in a household member (OR 1.5, CI 1.0 to 2.5). CONCLUSION: Some of these identified risk factors for meningococcal disease are modifiable. Measures to reduce overcrowding could have a marked effect on reducing the incidence of this disease in Auckland children.

Adolescent↗