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Biomedical subjects

D Stewart

Publications and source records attributed to D Stewart.

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

A phase I dose escalation study of the matrix metalloproteinase inhibitor BAY 12-9566 administered orally in patients with advanced solid tumours.

BACKGROUND: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced solid tumours, and to identify the maximum tolerated dose and dose for use in subsequent studies. PATIENTS AND METHODS: BAY 12-9566 was administered to 29 patients at doses ranging from 100 mg o.d. to 1600 mg (given either 400 mg q.i.d. or 800 mg b.i.d.). Blood samples for pharmacokinetic analyses were drawn on days 1-5, day 15 and days 29 and 30. Patients were continued on daily oral treatment of BAY 12-9566 until a dose limiting toxicity or tumour progression occurred. RESULTS: A maximum tolerated dose was not defined because plasma levels of BAY 12-9566 could not be sufficiently increased, even with escalating doses of drug. Pharmacokinetic analysis suggested that absorption was saturable at higher doses. The predominant toxicities related to drug were asymptomatic reversible effects on platelets and transaminases and mild anemia. There were no significant musculoskeletal toxicities. No objective responses were seen at the doses tested, but stable disease was observed in some patients based on tumour measurements. CONCLUSIONS: The recommended dose of BAY 12-9566 for further studies is 800 mg b.i.d. as this dose provides maximal plasma levels that can be achieved with a convenient dosing schedule for a chronically administered oral agent.

Administration, Oral↗
PubMed2000

A complex of N-WASP and WIP integrates signalling cascades that lead to actin polymerization.

Wiskott-Aldrich syndrome protein (WASP) and N-WASP have emerged as key proteins connecting signalling cascades to actin polymerization. Here we show that the amino-terminal WH1 domain, and not the polyproline-rich region, of N-WASP is responsible for its recruitment to sites of actin polymerization during Cdc42-independent, actin-based motility of vaccinia virus. Recruitment of N-WASP to vaccinia is mediated by WASP-interacting protein (WIP), whereas in Shigella WIP is recruited by N-WASP. Our observations show that vaccinia and Shigella activate the Arp2/3 complex to achieve actin-based motility, by mimicking either the SH2/SH3-containing adaptor or Cdc42 signalling pathways to recruit the N-WASP-WIP complex. We propose that the N-WASP-WIP complex has a pivotal function in integrating signalling cascades that lead to actin polymerization.

Actin Cytoskeleton↗
PubMed2000

High-dose therapy in breast cancer: out of favor but not out of promise.

The evidence for use of high-dose chemotherapy and autologous stem cell transplantation for breast cancer still remains inconclusive at best. A number of prospective randomized phase III studies have been either published or presented recently or are underway in North America and Europe. It will be crucial to complete the available prospective randomized phase III study and obtain the data when all studies reach a mature status. Only then will level I evidence become available to determine the efficacy and effectiveness of high-dose chemotherapy and autologous stem cell transplantation in breast cancer. Bone Marrow Transplantation (2000).

Antineoplastic Agents, Alkylating↗
PubMed2000

Estimation of body fat from anthropometry and bioelectrical impedance in Native American children.

OBJECTIVE: Obesity, as measured by body mass index, is highly prevalent in Native American children, yet there are no valid equations to estimate total body fatness for this population. This study was designed to develop equations to estimate percentage body fat from anthropometry and bioelectrical impedance as a critical part of Pathways, a multi-site study of primary prevention of obesity in Native American children. DESIGN: Percentage fat was estimated from deuterium oxide dilution in 98 Native American children (Pima/Maricopa, Tohono O'odham and White Mountain Apache tribes) between 8 and 11 y of age. The mean fat content (38.4%+/-8. 1%) was calculated assuming the water content of the fat-free body was 76%. Initial independent variables were height, weight, waist circumference, six skinfolds and whole-body resistance and reactance from bioelectrical impedance (BIA). RESULTS: Using all-possible-subsets regressions with the Mallows C (p) criterion, and with age and sex included in each regression model, waist circumference, calf and biceps skinfolds contributed least to the multiple regression analysis. The combination of weight, two skinfolds (any two out of the four best: triceps, suprailiac, subscapular and abdomen) and bioelectrical impedance variables provided excellent predictability. Equations without BIA variables yielded r2 almost as high as those with BIA variables. The recommended equation predicts percentage fat with a root mean square error=3.2% fat and an adjusted r2=0.840. CONCLUSION: The combination of anthropometry and BIA variables can be used to estimate total body fat in field studies of Native American children. The derived equation yields considerably higher percentage fat values than other skinfold equations in children.

Adipose Tissue↗
PubMed2000

Randomized trial of supervised injectable versus oral methadone maintenance: report of feasibility and 6-month outcome.

AIM: To assess the feasibility of a randomized clinical trial of supervised injectable versus oral methadone maintenance and to assess medium-term treatment outcomes. DESIGN: Randomized clinical trial of supervised injectable versus supervised oral methadone maintenance treatment (MMT). Trial participants were dependent illicit opiate injectors allocated at intake to supervised injectable or oral methadone maintenance treatment. SETTING: Specialist addictions treatment centre in South London. SUBJECTS: Forty dependent illicit opiate injectors seeking methadone maintenance treatment. INTERVENTIONS: Daily supervised injectable and oral methadone maintenance, delivered at the treatment centre. MAIN OUTCOME MEASURES: Frequency of illicit heroin use and frequency of illicit drug injecting during 30 days before intake to treatment and prior to 6-month follow-up. SECONDARY OUTCOME MEASURES: frequency of use of illicit methadone, crack cocaine, benzodiazepines and alcohol, physical and psychological health symptoms and acquisitive crime. RESULTS: Injectable and oral MMT were both generally acceptable to the study participants: there was a high level of agreement to enter the randomized trial, and subsequent retention in treatment was good. The average number of days of illicit heroin use reduced from 22.2 to 7.6 for the injectable MMT group and from 22.4 to 8.7 for the oral MMT group. The average number of days of illicit injecting reduced from 25.7 to 10.8 days for the injectable group and from 20.1 to 11.9 days for the oral group. Patients' physical and psychological health symptoms and involvement in acquisitive crime also reduced in both groups. Treatment satisfaction ratings at follow-up were higher among patients in the injectable MMT group. The ratio for the actual medication costs between injectable and oral MMT was 6.8:1, and for the direct operational costs was 4.7:1. There was some evidence of a differential patient response with greater reductions in heroin use occurring among patients who were daily illicit injectors and had poorer psychological and physical health (at entry) who were allocated to injectable MMT. CONCLUSIONS: Conduct of the trial has demonstrated that it is feasible to implement supervised injectable methadone maintenance treatment in the context of (although separate from) a specialist oral methadone maintenance service. Patients assigned to receive either supervised injectable or oral MMT had broadly equivalent, positive during-treatment outcomes at 6-month follow-up. Future studies should seek to identify patient characteristics which are linked to good outcome in injectable MMT. Practical evidence-based guidance to physicians about determining which patients are more suitable for injectable MMT is urgently needed.

Administration, Oral↗
PubMed2000

Routes of drug administration and multiple drug misuse: regional variations among clients seeking treatment at programmes throughout England.

AIMS: To investigate regional variations across England in routes of administration for heroin, non-prescribed methadone, non-prescribed benzodiazepines, cocaine powder, crack cocaine and amphetamines. DESIGN, SETTING, PARTICIPANTS: A survey of 1053 clients recruited to 54 residential and community drug misuse programmes. MEASUREMENTS: Structured face-to-face interviews conducted with clients at admission to treatment. FINDINGS: Routes of administration included injecting, smoking, snorting and oral use. For some drugs (methadone and benzodiazepines) one main route of administration was used. For other drugs (heroin, amphetamines and cocaine powder) there were marked variations in route. For all drugs except benzodiazepines, there were regional differences in routes of administration. Heroin injectors were more likely also to use other drugs by injection. CONCLUSIONS: The differences in routes of administration of different drugs, and the regional differences in routes of use, have implications for the provision of preventive and treatment services. Interventions to prevent transitions to injecting may be especially appropriate in areas where injecting is not prevalent. Hepatitis B vaccination continues to be advisable in both areas of high and low injecting prevalence. Needle exchange schemes and interventions targeted at drug overdose may be more suitable in areas of high injecting prevalence. Further research into regional differences in routes of drug use should be conducted with non-clinical samples.

Administration, Inhalation↗
PubMed2000

A potato alpha-glucosidase gene encodes a glycoprotein-processing alpha-glucosidase II-like activity. Demonstration of enzyme activity and effects of down-regulation in transgenic plants.

In order to elucidate more fully the function of a potato gene (MAL1) encoding alpha-glucosidase activity, transgenic plants in which MAL1 expression was down-regulated were generated using antisense technology. In transgenic lines severely down-regulated in the expression of MAL1, total alpha-glucosidase activity was not decreased in leaves and tubers, and the contents of starch, glucose, fructose and sucrose remained unchanged in tubers. Phylogenetic analysis indicated that the MAL1 gene product was more similar to the glycoprotein-processing alpha-glucosidase II of mammalian and yeast origin than to other plant alpha-glucosidases. Using [14C-Glc]-labelled Glc2Man9GlcNAc2 as a substrate, it was demonstrated that glucosidase II activity was markedly down-regulated in microsomes isolated from tubers of four independent antisense lines studied in detail, strongly suggesting that MAL1 encodes glucosidase II activity. In field trials (but not in the glasshouse), MAL1 down-regulation produced an extremely stunted phenotype - the leaves were curled and tuber yield was decreased by 90% compared to control values. Microscopic analysis of leaves revealed significant differences between the antisense and control samples. Plants with down-regulated glucosidase II activity showed a greater degree of plasmolysis, and an increase in the size of mesophyll intracellular spaces. Analysis of cell walls also indicated changes in structure as a result of MAL1 down-regulation. In leaves from four antisense lines, the steady-state transcript level corresponding to the endoplasmic reticulum chaperone, BiP, was enhanced. This is diagnostic of stress in the endoplasmic reticulum.

Carbohydrate Metabolism↗
PubMed2000

Gender disparity in living renal transplant donation.

Numerous studies document that women constitute the majority of living kidney donors, but the reasons behind the disparity in donation rates between men and women remain obscure. We studied this issue by gathering data on family members of living donor allograft recipients at a single large center over a 5-year period (n = 144). By considering all potential donors (spouses and first-degree relatives) within each recipient's immediate family, we determined that men and women are excluded as donors at approximately similar rates on the basis of medical condition or known blood group type A, type B, type O incompatibility, and that a greater percentage of acceptable female donors (28.3%) compared with men (20.3%) go on to donate a kidney (P: = 0.027). However, when only first-degree relatives are considered, the difference in donation rate between men and women becomes nonsignificant (26.9% of women versus 22.2% of men; P = 0.229). Among spouses, the gender disparity in donation rate is greater (36% of wives versus 6.5% of husbands who are acceptable donors go on to donate a kidney; P = 0.003). Evidence that economic factors may contribute to the overall gender disparity is also presented. In conclusion, the gender disparity among living kidney donors observed in our population can be largely attributed to an overwhelming predominance of wives among spousal donors. Possible explanations and potential interventions to address underrepresentation of male donors are discussed.

Adult↗
PubMed2000

Information technology adoption in health care: when organisations and technology collide.

The implementation of advanced information systems is enabling great social and organisational changes. However, health care has been one of the slowest sectors to adopt and implement information technology (IT). This paper investigates why this is so, reviewing innovation diffusion theory and its application to both health organisations and information technology. Innovation diffusion theory identifies variables that influence the 'innovativeness' of organisations and the rate at which a technology diffuses. When analysed, these variables show why IT implementation has progressed at a slower rate in health compared with other industry sectors. The complexity of health organisations and their fragmented internal structure constrain their ability to adopt organisation wide IT. This is further impacted upon by the relative immaturity of strategic health IT which is complicated and unable to show quantifiable benefits. Both organisational and technological factors lead to the slow adoption of strategic IT. On the other hand, localised IT solutions and those providing measurable cost reductions have diffused well.

Diffusion of Innovation↗
PubMed2000

Treatment decision making in mature adults: gender differences.

Studies have shown that women are less likely to receive several specific medical interventions, including organ transplantation, cardiac diagnostic studies, and coronary artery bypass surgery. This study investigates the hypothesis that this inequity may be explained by gender differences in treatment decisions made by older adults. A self-report questionnaire using hypothetical situations, treatment choices, and influencing factors was designed based on literature review and interviews with key informants. The questionnaire was administered to 250 nonpatient adults over the age of 50 in urban and rural settings in Ontario, Canada. Results revealed no significant gender differences in hypothetical treatment decisions made by patients nor in the factors affecting those decisions. In the absence of evidence that patient choice accounts for gender differences in utilization rates, physicians need to carefully examine their assumptions about patient preference and gender in the provision of specific interventions to male and female patients.

Adult↗
PubMed2000

Comparison of PCR detection of mecA with methicillin and oxacillin disc susceptibility testing in coagulase-negative staphylococci.

The provisional BSAC method for the detection of methicillin sensitivity in coagulase-negative staphylococci (CNS) requires incubation of isolates for 48 h and raises the problem of timely reporting of susceptibility data. The forthcoming withdrawal of methicillin raises another difficulty. We evaluated 42 clinically significant CNS blood culture isolates by PCR, methicillin and oxacillin disc testing and by using methicillin Etests. Our results suggest that, although oxacillin disc susceptibility testing is a reasonable first line step, optimal and timely detection of resistance or susceptibility may require a combination of phenotypic and genotypic methods.

Coagulase↗
PubMed2000

Myeloablative chemotherapy for recurrent aggressive oligodendroglioma.

The objective of this study was to ascertain the duration of tumor control and the toxicities of dose-intense myeloablative chemotherapy for patients with recurrent oligodendrogliomas. Patients with previously irradiated oligodendrogliomas, either pure or mixed, that were contrast enhancing, measurable, and behaving aggressively at recurrence were eligible for this study. Only complete responders or major partial responders (75 % reduction in tumor size) to induction chemotherapy--either intensive-dose procarbazine, lomustine, and vincristine or cisplatin plus etoposide-could receive high-dose thiotepa (300 mg/m2/day for 3 days) followed by hematopoietic reconstitution using either bone marrow or peripheral blood stem cells. Thirty-eight patients began induction chemotherapy and 20 (10 men, 10 women; median age 46 years; median Karnofsky score 80) received high-dose thiotepa. For the high-dose group, the median event-free, progression-free, and overall survival times from recurrence were 17, 20, and 49 months, respectively. Tumor control in excess of 2 years was observed in 6 patients (30%). Four patients (20%) are alive and tumor free 27 to 77 months (median, 42 months) from the start of induction therapy; however, fatal treatment-related toxicities also occurred in 4 patients (20%). Three patients died as a result of a progressive encephalopathy which, in 2 instances, was accompanied by a wasting syndrome; 1 patient died as a consequence of an intracerebral (intratumoral) hemorrhage. Fatal toxicities occurred in patients with pretreatment Karnofsky scores of 60 or 70. High-dose thiotepa to consolidate response was a disappointing treatment strategy for patients with recurrent aggressive oligodendroglial neoplasms, although several patients had durable responses. Moreover, as prescribed, high-dose thiotepa had significant toxic effects in previously irradiated patients, especially those with poorer performance status.

Adult↗
PubMed2000

Variation between and within drug treatment modalities: data from the National Treatment Outcome Research Study (UK).

This paper describes treatment practices in 54 drug treatment programmes taking part in the National Treatment Outcome Research Study (NTORS). Programmes were representative of the 4 main treatment modalities in the UK: in-patient, residential rehabilitation, methadone maintenance and methadone reduction. Distinguishing features of these forms of treatment were identified. Substantial variations in treatment practices were also observed within each modality, particularly for detoxification and prescribing arrangements, counselling and non-drug treatment services, and planned duration of treatment. Many programmes reported extensive waiting lists. These findings are discussed in the context of the growing international evidence of the association between patient outcome and the manner in which programme services are delivered.

Ambulatory Care↗
PubMed2000

New European instruments for treatment outcome research: reliability of the maudsley addiction profile and treatment perceptions questionnaire in Italy, Spain and Portugal.

This report describes the field testing of two recently developed instruments for treatment evaluation research - the Maudsley Addiction Profile (MAP) and the Treatment Perceptions Questionnaire (TPQ) - in Italy, Portugal and Spain. The MAP and TPQ have been developed in the United Kingdom as brief instruments which contain measures of high face validity for research applications with the adult psychoactive substance use disorder population. The present study assesses the application of these instruments in the continental European context and assesses the internal and test-retest reliabilities of the items. A total of 206 subjects participated in the study (124 subjects participated in the MAP test-retest study, and 95 clients completed the TPQ). Thirteen subjects completed both the MAP and the TPQ questionnaires. Results of the study indicated that the MAP can be administered to clients in 15 min or less. The internal and test-retest reliabilities of the MAP and TPQ are satisfactory. Both instruments are suitable for treatment evaluation and other relevant research purposes in the European Union.

Adult↗
PubMed2000

Organizational characteristics and issues affecting the longevity of self-help groups for parents of children with special needs.

In this article, the organizational characteristics and issues affecting the maintenance of nine self-help groups for parents of children with special needs are discussed. Qualitative data were collected through interviews with 20 parents and observation of six group meetings. For continued existence, groups must deal with the challenges of encouraging new leaders, attracting new members, obtaining funds or assistance to support their activities, and meeting the changing needs of members. Important organizational characteristics associated with longevity are committed and effective leadership, community connections that help provide needed funds or practical assistance, and the willingness of group members to change activities to meet changing needs. This information can be used by parents and service providers to plan new groups, recruit group members, and ensure the effective functioning of groups as they change over time.

Adult↗
PubMed2000

Psychiatric symptoms among clients seeking treatment for drug dependence. Intake data from the National Treatment Outcome Research Study.

BACKGROUND: Many people with substance use disorders are vulnerable to other psychiatric disorders and present to addiction treatment services with comorbid psychiatric symptoms. AIMS: To describe the prevalence of recent psychiatric treatment and current psychiatric symptoms and explore links between substance misuse, personal/social functioning and symptom severity. METHOD: Subjects were 1075 adults recruited to the National Treatment Outcome Research Study (NTORS), of whom 90% were opiate-dependent. Psychiatric symptoms at intake were recorded using sub-scales from the Brief Symptom Inventory. RESULTS: Recent psychiatric treatment was reported by one in five subjects. Psychiatric symptom levels were high and females had elevated scores on all scales. Symptoms were elevated among opiate users who were also frequent users of benzodiazepines, alcohol and, in particular, stimulants. Gender, physical health, drug dependence and personal relationship problems were more powerful predictors of psychiatric symptoms than substance use. CONCLUSIONS: Addictions service providers should be vigilant to psychiatric problems among their clients at intake to treatment. Psychiatric symptoms are more closely linked to polydrug use than to opiate use in this population.

Adolescent↗
PubMed2000

Psychosocial morbidity among women with nausea and vomiting of pregnancy: prevalence and association with anti-emetic therapy.

Unlike severe nausea and vomiting of pregnancy (NVP), it is not known whether milder forms of NVP have been associated with psychosocial morbidity. We undertook the study to explore the prevalence of psychosocial morbidity by severity of NVP, and determine whether, after correction for severity of nausea/vomiting, there is a relationship between psychosocial morbidity and women's decisions to take anti-emetics as a reflection of their distress due to NVP. From 1996-97, an NVP Healthline was advertised. Callers underwent semi-structured interviews about both their NVP and associated psychosocial morbidity in a previous pregnancy. Most of the 3201 callers resided in Canada, worked outside the home, reported on planned pregnancy (a median of) 4 years before, and described severe (> 5 episodes/day of) nausea and vomiting. More severe nausea/vomiting was associated with more frequent feelings of depression, consideration of termination of pregnancy, adverse effects on women's relationships with their partners or their partners' everyday lives, and the perceived likelihood that NVP would harm their baby (p < 0.0001). However, all psychosocial factors were reported by a clinically important proportion of women with mild nausea/vomiting (0-1 episodes/day). The severity of vomiting was most closely related to women's decisions to take anti-emetics, but other psychosocial factors were also independently associated with anti-emetic therapy. We conclude that psychosocial morbidity is evident across the spectrum of severity of nausea and vomiting among women with NVP. The severity of nausea or vomiting does not appear adequately to reflect the distress caused by NVP, as reflected by women's decisions to take anti-emetic therapy.

Adult↗