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Biomedical subjects

M Stewart

Publications and source records attributed to M Stewart.

At least 55 records · Page 3Linked to original sources
PubMed2001

Molecular mechanism of translocation through nuclear pore complexes during nuclear protein import.

The trafficking of macromolecules between cytoplasm and nucleus through nuclear pore complexes is mediated by specific carrier molecules such as members of the importin-beta family. Nuclear pore proteins (nucleoporins) frequently contain sequence repeats based on FG cores and carriers appear to move their cargo through the pores by hopping between successive FG cores. A major question is why some macromolecules are transported while others are not. This selectivity may be generated by the ability to bind FG repeats, a local concentration of carrier-cargo complexes near the entrance to the pore channel, and steric hindrance produced by high concentrations of nucleoporins in the channel.

Active Transport, Cell Nucleus↗
PubMed2001

Propagation of synchronous epileptiform events from subiculum backward into area CA1 of rat brain slices.

The hippocampal trisynaptic pathway is comprised of superficial entorhinal afferents (part of the perforant path) to dentate granule cells, dentate mossy fiber inputs to CA3 pyramidal neurons, and CA3 cell projections to CA1 pyramidal neurons. This CA1 output is among others to the subiculum, and both CA1 and subiculum project to the entorhinal cortex to close the loop. Smaller circuits involving fewer hippocampal and parahippocampal regions have also been described. We present morphological and electrophysiological evidence from rat brain slices for a projection from subiculum back into area CA1. Axons of neurobiotin-labeled subicular pyramidal neurons were visualized in the apical dendritic region of CA1. Spontaneous activity in isolated subiculum--CA1 slices was produced by bathing slices in reduced magnesium media. Events in CA1 always followed events in proximal subiculum. Disruption of this subiculum--CA1 circuit with a radially oriented knife cut in the apical dendritic region between subiculum and CA1 eliminated afterdischarges in subicular and CA1 events, but did not de-synchronize the two regions. Full transections between CA1 and subiculum were necessary to functionally isolate the two regions. Only subiculum remained spontaneously active. We conclude that a subiculum--CA1 circuit supports afterdischarges in both regions and synchronizes their activity. This circuit may serve to maintain a level of depolarization in subicular and CA1 pyramidal neurons well beyond the duration of excitatory synaptic potentials resulting from activation of the trisynaptic circuitry.

Action Potentials↗
PubMed2001

5-fluorouracil steady state pharmacokinetics and outcome in patients receiving protracted venous infusion for advanced colorectal cancer.

PVI 5FU gives increased response rates and reduced toxicity when compared to bolus 5FU (J Clin Oncol 1989, 425-432). PVI 5FU administration was reported to give highly variable (>1000-fold) plasma 5FU concentrations at steady state (FU Css) which correlated with toxicity (Ann Oncol 1996, 47-53); but only 19 patients were studied. Therefore, we performed a study of PVI 5FU in 61 patients with advanced colorectal cancer to assess the variability (inter- and intra-subject) in 5FU Css associated with PVI 5FU (300 mg m(-2)day(-1)) and to attempt to correlate pharmacodynamic end-points (anti-tumour activity, toxicity) with 5FU Css as a prelude to 'exposure-guided' 5FU administration. All 5FU sampling was performed between 10 am and noon. PVI 5FU administration continued to 26 weeks in patients with disease improvement or stabilization. The response rate was 26% (33% stable disease) and median survival was 11 months. Hand-foot syndrome was the most common dose limiting toxicity. Variability in 5FU(300)Css was considerably less than previously reported; 94 +/- 25 ng ml(-1)(CV = 27%). No relationships were demonstrated between subject mean 5FU(300)Css and PD end-points such as response, mucositis, diarrhoea and hand-foot syndrome. The lack of correlation suggests that measurement of 5FU concentrations should not be used to individualize dosing in patients receiving PVI 5FU for advanced colorectal cancer.

Adult↗
PubMed2001

Runx2: a novel oncogenic effector revealed by in vivo complementation and retroviral tagging.

The Runx2 (Cbfa1, Pebp2alphaA, Aml3) gene was previously identified as a frequent target for transcriptional activation by proviral insertion in T-cell lymphomas of CD2-MYC transgenic mice. We have recently shown that over-expression of the full-length, most highly expressed Runx2 isoform in the thymus perturbs T-cell development, leads to development of spontaneous lymphomas at low frequency and is strongly synergistic with Myc. To gain further insight into the relationship of Runx2 to other lymphomagenic pathways, we tested the effect of combining the CD2-Runx2 transgene either with a Pim1 transgene (E(mu)-Pim1) or with the p53 null genotype, as each of these displays independent synergy with Myc. In both cases we observed synergistic tumour development. However, Runx2 appeared to have a dominant effect on the tumour phenotype in each case, with most tumours conforming to the CD3(+), CD8(+), CD4(+/-) phenotype seen in CD2-Runx2 mice. Neonatal infection of CD2-Runx2 mice with Moloney murine leukaemia virus (Moloney MLV) also led to a dramatic acceleration of tumour onset. Analysis of known Moloney MLV target genes in these lymphomas showed a high frequency of rearrangement at c-Myc or N-Myc (82%), and a significant number at Pim1 or Pim2 (23%), and at Pal1/Gfi1 (18%). These results indicate that Runx2 makes a distinct contribution to T-cell lymphoma development which does not coincide with any of the oncogene complementation groups previously identified by retroviral tagging.

ATP-Binding Cassette Transporters↗
PubMed2001

Allogeneic chimerism with low-dose irradiation, antigen presensitization, and costimulator blockade in H-2 mismatched mice.

We have previously shown that the keys to high-level nontoxic chimerism in syngeneic models are stem cell toxic, nonmyelotoxic host treatment as provided by 100-cGy whole-body irradiation and relatively high levels of marrow stem cells. This approach was unsuccessful in H-2 mismatched B6.SJL to BALB/c marrow transplants, but with tolerization, stable multilineage chimerism was obtained. Ten million B6.SJL spleen cells were infused intravenously into BALB/c hosts on day -10 and (MR-1) anti-CD40 ligand monoclonal antibody (mAb) injected intraperitoneally at varying levels on days -10, -7, -3, 0, and +3 and the BALB/c mice irradiated (100 cGy) and infused with 40 million B6.SJL/H-2 mismatched marrow cells on day 0. Stable multilineage chimerism at levels between 30% to 40% was achieved in the great majority of mice at 1.6 mg anti-CD40 ligand mAb per injection out to 64 weeks after transplantation, without graft-versus-host disease. The transplanted mice were also tolerant of donor B6.SJL, but not third-party CBA/J skin grafts at 8 to 9 and 39 to 43 weeks after marrow transplantation. These data provide a unique model for obtaining stable partial chimerism in H-2 mismatched mice, which can be applied to various clinical diseases of man such as sickle cell anemia, thalassemia, and autoimmune disorders.

Animals↗
PubMed2001

Functional residual capacity and passive compliance measurements after antenatal steroid therapy in preterm infants.

Studies in preterm animal models have shown that antenatal corticosteroids enhance lung maturation by improving a variety of physiologic variables, including lung volumes. Changes in lung volume of preterm infants treated with a full course of antenatal steroids have not been investigated. We hypothesized that a full course of antenatal steroids would significantly increase functional residual capacity (FRC) in treated vs. untreated preterm infants. The objective of our study was to compare FRC and respiratory mechanics in steroid treated vs. untreated preterm infants. FRC and passive respiratory mechanics were prospectively studied within 36 hr of life in 20 infants (25-34 weeks of gestation) who had received a full course of antenatal steroids and in 20 matched untreated preterm infants. FRC was measured with the nitrogen washout method, and respiratory mechanics with the single-breath occlusion technique. Preterm infants who received steroids (n = 20; mean birth weight = 1,230 g; gestational age = 28.8 weeks) had a significantly higher FRC (29.5 vs. 19.3 mL/kg; P < 0.001) than untreated infants (n = 20; birth weight = 1,202 g; gestational age = 28.5 weeks). Passive respiratory system compliance was also increased in treated vs. untreated infants (P < 0.05). In conclusion, FRC and passive respiratory system compliance were significantly improved in preterm infants (25-34 weeks gestation) treated with a full course of antenatal steroids, compared to matched untreated infants. Although this study was not randomized, it confirms that antenatal steroids have important effects on pulmonary function that may contribute to a decreased risk of respiratory distress syndrome in treated preterm infants.

Female↗
PubMed2001

How the assembly dynamics of the nematode major sperm protein generate amoeboid cell motility.

Nematode sperm are amoeboid cells that use a major sperm protein (MSP) cytoskeleton in place of a conventional actin cytoskeleton to power their amoeboid motility. In these simple, specialized cells cytoskeletal dynamics is tightly coupled to locomotion. Studies have capitalized on this feature to explore the key structural properties of MSP and to reconstitute motility both in vivo and in vitro. This review discusses how the mechanistic properties shared by the MSP machinery and actin-based motility systems lead to a "push-pull" mechanism for amoeboid cell motility in which cytoskeletal assembly and disassembly at opposite ends of the lamellipodium are associated with independent forces for protrusion of the leading edge and retraction of the cell body.

Actins↗
PubMed2001

Lignans from Strophanthus gratus.

Three lignans, pinoresinol (1), 8-hydroxypinoresinol (2) and olivil (3) have been isolated from the leaves of Strophanthus gratus by reversed-phase HPLC.

Chromatography, High Pressure Liquid↗
PubMed2001

Study sampling in the Canadian Study of Health and Aging.

The Canadian Study of Health and Aging drew representative samples of people aged 65 or over from the community and institutions across Canada. The sample was designed to provide regional and national prevalence estimates for dementia by age and sex. Thirty-six sampling areas were used in a stratified cluster design with optimal allocation; sampling weights were developed to provide population estimates. The sample included 9,008 people aged 65 or over from the community, and 1,255 from institutions. This report describes the sampling procedures, the methods used to recruit people to the study and participation rates, the characteristics of the resulting sample, and the way in which sample weights should be used.

Aged↗
PubMed2001

Data collected in the Canadian Study of Health and Aging.

The Canadian Study of Health and Aging collected data focusing on the epidemiology of dementia, using interviews and questionnaires, clinical and neuropsychological examinations, physical measurements and blood collection, and access to public records such as death certificates, from people 65 and over in community (N = 9,008) institutional settings (N = 1,255). The study produced 12 data sets, including community health interviews, clinical and neuropsychological assessments, risk factor questionnaires, and caregiver interviews. This report describes the data collection and processing procedures, summarizes the content of each data set, and outlines the information collected in sufficient detail to permit its suitability for secondary analyses to be scrutinized.

Aged↗
PubMed2001

Estimating antemortem cognitive status of deceased subjects in a longitudinal study of dementia.

There was a five-year delay between the two waves of the Canadian Study of Health and Aging during which 2,982 participants died. Their cognitive status before death should be taken into account in estimating the incidence of dementia in the cohort. Information concerning antemortem cognitive status was available from death certificates and from an interview with a close relative of the decedent at the CSHA-2 follow-up. The interview included a direct question on whether the person had been diagnosed with dementia and questions covering cognitive signs and symptoms from which we formed an algorithm to predict probability of dementia. These sources of information were validated using a small sample of study participants who died within five months of undergoing the CSHA clinical examination. Sensitivity of the death certificate and the question regarding diagnosis of dementia was low (33% and 44%), although their specificity was very high. Accordingly, we combined these with the predictive algorithm to form an overall estimate of the probability of antemortem dementia. This raised the sensitivity to 82% (specificity 93%).

Aged↗
PubMed2001

Group support for couples coping with a cardiac condition.

BACKGROUND/RATIONALE: Support groups of peers were designed to convey support specific to stressful situations encountered by persons with a first-time myocardial infarction and by their spouse or partners. There were no previous published support intervention studies focused on the couple. Survivors and spouses (n=28) participated in a pilot study which tested the effect of a 12-week support group intervention. DESIGN: The support groups for couples were cofacilitated by a peer and professional. The facilitators recorded field notes, while participants completed weekly diaries about the intervention activities. Following the intervention, participants were interviewed individually and facilitators were interviewed jointly about the perceived effect of the intervention and influencing factors. This article focuses on the facilitators' and participants' perceptions of intervention processes and outcomes. FINDINGS: Support processes in the group included social comparison, social learning, and social exchange. Three types of support--emotional, information, and affirmation--were provided. All participants were satisfied with the support intervention and referred to the positive effect on their coping, confidence, outlook, and spousal relationship. Factors that influenced the intervention effect were participant input, cofacilitation, similarity of group members, and the provision of information and support. CONCLUSIONS: Future interventions could consider similarity of peers, leadership, and optimum timing and duration.

Adaptation, Psychological↗
PubMed2001

Whose evidence counts? An exploration of health professionals' perceptions of evidence-based practice, focusing on the maternity services.

OBJECTIVES: to gain an insight into how health professionals in the maternity services define evidence and how they perceive different types of evidence are valued in maternity care. DESIGN: using a qualitative approach data were collected by semi-structured interviews: the content of each was analysed thematically. SETTING: England. PARTICIPANTS: a purposeful sample of ten midwives, two obstetricians and one research nurse. FINDINGS: definitions of evidence vary widely among health practitioners. These definitions are affected by individuals' own beliefs and give rise to a hierarchy in which some types of evidence are valued above others. All the participants made direct or indirect reference to cultural beliefs inherent within the health service, and indicated that these beliefs determine the extent to which different types of evidence are seen as legitimate. IMPLICATIONS FOR PRACTICE: the concept of evidence-based practice is not value-free. Evidence that reinforces notions of authoritative knowledge may be transposed into clinical practice quickly and easily. Conversely, health practitioners may have difficulty putting evidence into practice that challenges the cultural norms of the profession. There is a need for further work to make explicit the values that underpin different sources of knowledge and expose the hierarchies of evidence that exist.

Anecdotes as Topic↗