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Biomedical subjects

C Stewart

Publications and source records attributed to C Stewart.

At least 73 records · Page 4Linked to original sources
PubMed1998

Expression and function of the megakaryocyte growth and development factor receptor in acute myeloid leukemia blasts.

The receptor for megakaryocyte growth and development factor (MGDF), also known as thrombopoietin, has recently been cloned. MGDF stimulates platelet production and maturation both in vitro and in vivo. MGDF may thus have a role in attenuating the thrombocytopenia associated with acute myeloid leukemia (AML) and its therapy. However, there is concern that MGDF might induce AML blast proliferation and thereby increase the risk of treatment failure. To address this concern, we studied the expression of c-mpl mRNA and c-Mpl protein by blasts from AML patients. In addition we examined the in vitro effect of MGDF as well as the combined effect of MGDF and granulocyte colony-stimulating factor (G-CSF) or stem cell factor (SCF) on leukemic blast proliferation, recruitment into S-phase, induction of programmed cell death and activation of signal transducers and activators of transcription (STAT) proteins. Our results demonstrate that blasts from a substantial proportion of cases of AML express the receptor at either the mRNA or protein level. Moreover, the function of the MGDF receptor was demonstrated by activation of STAT proteins following exposure to MGDF. Nevertheless, blast proliferation in response to MGDF was rare, and the proliferative effect of MGDF was less than that of G-CSF or SCF. Furthermore, MGDF did not prevent programmed cell death induced by cytarabine. Finally, there appeared to be no correlation between receptor expression by AML blasts and functional response to MGDF. Based on these data, it would appear that clinical trials of MGDF may be undertaken safely in patients with AML.

Acute Disease↗
PubMed1998

Adolescents' knowledge of common foods and drinks and the importance of the pattern of consumption: a study undertaken in an area of high dental needs.

OBJECTIVE: To assess the knowledge of adolescents concerning the cariogenic status of a range of foods and drinks. To determine the associations between this knowledge and their awareness of the importance of the ways sugars may be consumed in order to reduce tooth decay. DESIGN: Self-complete questionnaires assessing the above factors in a cross sectional study. PARTICIPANTS: Four hundred and fifteen 14-15-year-old young people attending second level schools. SETTING: North and West Belfast area, Northern Ireland. OUTCOME MEASURES: Students rated the dental safety of common foods and drinks, and their views on the necessity of reducing all sugars, and avoiding them between meals were recorded. RESULTS: Correct assessment of harmful items ranged from 96.9% for chocolate and 92.8% for cola to 39.0% for orange squash and 17.8% for plain biscuits. For non-harmful products there were high levels for most items and somewhat lower levels for crisps (57.6%). Significant links were established between this knowledge and children's awareness of the role of eating patterns, although the items involved varied. A majority recognised the importance of eating patterns in relation to dental caries. CONCLUSION: Health educators should be aware that many adolescents have poor knowledge of the cariogenic status of some of the foods and drinks they consume and some are unsure of the importance of eating patterns.

Adolescent↗
PubMed1997

Isolation and characterization of basal cells from human upper respiratory epithelium.

Cellular pathways of normal and reparative differentiation of upper airway epithelium are not well understood. Of the three main cell types, basal and secretory cells are known to divide, while ciliated cells are considered terminally differentiated. Several investigations support the role of the basal cell as a progenitor cell type, but others suggest that the secretory cell can regenerate a complete mucocilliary epithelium. Thus, lineage relationships within renewing adult epithelia are still unclear. Understanding the pathways involved in upper airway epithelial cell differentiation is critical for studying injury and repair mechanisms and for developing clinical strategies for tracheal reconstruction. We undertook the current studies to determine the integrin profile of isolated human upper airway basal cells. Respiratory epithelial cells (REC) were isolated by elastase digestion, stained with FITC-labeled Griffonia simplicifolia isolectin B4 (GSI-B4), and sorted by flow cytometry. Approximately 80% of the lectin-positive cells were basal cells, as determined by morphology and cytokeratin staining. These cells expressed integrins alpha 1, alpha 2, alpha 3, alpha 5, alpha v beta 5, beta 1, beta 3, and alpha 6 beta 4, by immunohistochemistry. This is the first report to identify the integrin profile of isolated human upper airway basal cells. These basal cells could be maintained on type I collagen for at least 7 days, where they became partially confluent and retained expression of cytokeratins 5 and 14. Availability of pure populations of basal cells should permit investigations of their role in both normal and maladaptive repair of adult upper airway epithelium.

Adult↗
PubMed1997

Thymocytes in Thy-1-/- mice show augmented TCR signaling and impaired differentiation.

Thy-1, a single variable-like immunoglobulin superfamily domain anchored in the plasma membrane by a glycosyl phosphaditylinositol tail [1], is a major surface glycoprotein in adult mammalian neurons and rodent thymocytes [2]; the function of Thy-1 has remained enigmatic since its discovery [3]. Studies in vitro have implicated Thy-1 in homotypic and heterotypic cell-cell interactions [2,4]. Ligation of Thy-1 initiates transmembrane signaling pathways that lead to diverse physiological outcomes in different cells [2,5-7]. In rodents, Thy-1 is highly expressed on the surface of CD4+CD8+ double-positive immature thymocytes and downregulated in mature T cells. Here, we report that thymocytes from Thy-1-/- mice [8] had altered cell-cell contacts, and hyperresponsiveness to T-cell receptor (TCR) triggering as demonstrated by the heightened activation of p56lck, phosphorylation of TCR subunits, Ca2+ fluxes and cell proliferation. Thy-1-/- thymocytes exhibited impaired maturation from the double positive to single positive stage of thymocyte development, possibly due to inappropriate negative selection, and were prone to T lymphomas in aged mice. These observations indicate that Thy-1 negatively regulates TCR-mediated signaling and controls activation thresholds during thymocyte differentiation.

Animals↗
PubMed1997

Characterization of a YAC contig containing the NBCCS locus and a novel Kruppel-type zinc finger sequence on chromosome segment 9q22.3.

Gorlin's syndrome or nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by a familial or hereditary predisposition to basal cell carcinomas (generally multiple and of early onset), odontogenic keratocysts (jaw cysts), palmar and plantar pits, a wide variety of developmental defects, as well as cancers such as medulloblastomas and ovarian fibromas. The gene for NBCCS has been mapped to human chromosome region 9q22.1-q31 by linkage analysis and by cytogenetic evidence of deletions in this region in patients with the syndrome. This is supported by loss of heterozygosity in tumors of polymorphic marker loci flanked by D9S197 and D9S180. We have utilized sequence tagged site (STS) mapping and somatic cell hybrid panel analysis to construct two overlapping yeast artificial chromosome (YAC) contigs spanning this region of the genome. We used the YAC contigs to identify a new zinc finger gene containing a highly informative microsatellite locus.

Amino Acid Sequence↗
PubMed1997

TWH regulates the development of subsets of spinal cord neurons.

Thymocyte winged helix (TWH) is a putative transcription factor expressed in the developing neural tube. At midgestation, TWH expression identifies subsets of spinal cord motor neurons and interneurons. TWH-expressing motor neurons were restricted to specific spinal cord levels, distinguishing motor neurons at lumbar from those at cervical levels. To understand the developmental role of TWH, we replaced the TWH gene with the lacZ reporter gene and generated mice with a homozygous disruption of the TWH gene. TWH(-/-) mutant mice had increased perinatal mortality, retarded postnatal growth, and motor weakness. The TWH(-/-) mutation resulted in alterations in the sizes and position of different neuronal populations. Our results demonstrate that TWH plays a critical role in neuronal development and suggest that TWH regulates the early differentiation of neural progenitors.

Animals↗
PubMed1997

In vitro and in vivo spectrofluorometry of a water-soluble meta-(tetrahydroxyphenyl)chlorin (m-THPC) derivative.

The pharmacokinetics of a water-soluble derivative obtained from meta-(tetrahydroxyphenyl)chlorin (m-THPC) was evaluated in in vitro and in vivo studies. Cytoplasm fluorescence was measured in two cell models (L1210 and HT29) using a flow cytometer and a confocal microspectrofluorometer. Cells were incubated with the compound at several doses (0-150 micrograms ml-1 for flow cytometry) and for several time periods (0-6 h for microspectrofluorometry). For in vivo studies, nude mice were grafted with human adenocarcinoma 15 days before intraperitoneal injection of polyethylene glycol-m-THPC (PEG-m-THPC). Fluorescence was recorded through an optical fibre spectrofluorometer using the 660 nm peak for detection. In in vitro studies, the fluorescence was found to be proportional to the dose. Maximum fluorescence was recorded in L1210 cells earlier and more intensely than in HT29 cells (3 h at 202 +/- 14 counts s-1 and 5 h at 43 +/- 2.15 counts s-1 respectively). Concerning in vivo studies, maximum tumour fluorescence was observed 24 h after injection (3568 +/- 178 counts s-1). Selectivity was expressed by the calculated tumour-to-skin and tumour-to-muscle ratios. The time taken to observe the maximum ratios (2.95 +/- 0.16 for tumour-to-skin and 6.61 +/- 0.3 for tumour-to-muscle) was almost the same as the time taken to observe the maximum fluorescence in the tumour. Studies are in progress to correlate these results with photodynamic effects.

Animals↗
PubMed1997

Thyroid hormones and selenium status in breast cancer.

Within a case-control study of postmenopausal breast cancer patients (n = 99) and matched healthy controls (n = 105), thyroid hormone levels were compared and correlated with toenail selenium concentrations. Plasma triiodothyronine (T3) was significantly lower in cases (1.4 +/- 0.4 nmol/l) than in controls (1.6 +/- 0.4 nmol/l), and a strong inverse relationship with breast cancer was observed with an odds ratio of 0.17 (95% CI = 0.08-0.36) in the highest compared with the lowest tertile of T3. Plasma thyroxine and thyroid-stimulating hormone concentrations were similar between cases and controls. Plasma T3 concentration was positively associated with toenail selenium in cases (age-adjusted regression coefficient = 0.049) and controls (age-adjusted regression coefficient = 0.036). Toenail selenium concentrations tended to be lower in cases than in controls, but the differences did not reach statistical significance. Although the disease process per se may explain the lower plasma T3 concentrations, it is also possible, inasmuch as these patients were in early-stage breast cancer, that selenium status may be influencing T3 levels via changes in the activity of the selenoenzyme type 1 iodothyronine deiodinase.

Aged↗
PubMed1997

Expression of c-mpl mRNA, the receptor for thrombopoietin, in acute myeloid leukemia blasts identifies a group of patients with poor response to intensive chemotherapy.

PURPOSE: c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS: We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS: Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION: These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

Adult↗
PubMed1997

Validation study of a computerized version of the Western Ontario and McMaster Universities VA3.0 Osteoarthritis Index.

OBJECTIVE: To study the validity and feasibility of a computerized version of the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index. METHODS: Thirty patients with osteoarthritis (OA) of the knee completed both a paper and a computerized version of WOMAC in random order. The visual analog scaled version of WOMAC, VA3.0, was used. We studied criterion validity by comparing the paper and computerized versions. RESULTS: All patients completed the computerized version without undue difficulty. Criterion validity, based on aggregated subscale scores, was excellent: Pain, ICC = 0.89, Stiffness, ICC = 0.87, Physical Function, ICC = 0.95. CONCLUSION: The computerized version of WOMAC VA3.0 is a valid alternative to the paper version.

Aged↗
PubMed1997

Dental caries treatment pattern in 14-15-year-old school pupils attending high caries schools in north & west Belfast and their ability to recognise untreated disease.

The study examined the dental caries treatment profile of 186 14-15-year-old children in schools known previously to have a high overall caries experience, the schools being located in a high caries area of Northern Ireland. The children had a high mean number of decayed and untreated teeth. The majority of children who had untreated decay were unaware of this status and had a mean D value of 3.85. There was a significantly higher number of untreated carious teeth for children who had not attended a dentist within the past year when compared with those who had attended (mean values 4.08 and 2.54 respectively). While there were high levels of unmet needs overall it is concluded that children who had not attended the dentist for the past year had very high levels of untreated decay.

Adolescent↗
PubMed1996

IL-12-deficient mice are defective but not devoid of type 1 cytokine responses.

Interleukin-12 (IL-12) has been described as a pivotal molecule in the immune response based in part on its ability to influence the differentiation of T helper (Th) cells into a type 1 (Th1) phenotype. This event is crucial in that appropriate differentiation of naive T cells can determine susceptibility or resistance to given pathogens by influencing the balance between cellular and humoral immunity. In order to further delineate the role of IL-12 in the immune response, we generated mice deficient for this cytokine. IL-12 knockout mice were viable, fully fertile, and displayed no obvious developmental abnormalities. Upon immunological analysis, these mice demonstrated an impaired ability to effect a Th1 response as well as an impaired ability to produce interferon-gamma in response to endotoxin in vivo. These data establish an essential role for IL-12 in the generation of optimal Th1 responses in vivo, but weak responses can occur independently of IL-12.

Animals↗
PubMed1996

In vivo trapping of nitric oxide in the brain of neonatal rats treated with the HIV-1 envelope protein gp 120: protective effects of alpha-phenyl-tert-butylnitrone.

AIDS dementia complex is a neurological syndrome characterized by cognitive deficits and motor and behavioral dysfunction. The HIV-1 envelope glycoprotein gp 120 has been implicated in the development of AIDS dementia. This protein has been shown to be neurotoxic and to cause learning impairment and retardation of the development of complex motor behavior in rat neonates. Nitric oxide has been implicated in gp 120-induced neurotoxicity. In the present study, we report for the first time in vivo evidence for the formation of nitric oxide in the CNS as a result of multiple subcutaneous injections of gp 120 to neonatal rats. Nitric oxide was trapped in the brain of neonatal rats by N-methyl-D-glucamine dithiocarbamate-Fe and the nitric oxide content measured by electron paramagnetic resonance spectroscopy. The nitrone-based spin trap alpha-phenyl-tert-butylnitrone at 50 mg/kg was found to prevent gp 120-mediated nitric oxide formation and to also protect against gp 120-induced behavioral impairment.

Animals↗
PubMed1996

Functional MRI of lateral occipitotemporal cortex during pursuit and motion perception.

We performed functional imaging with a conventional 1.5-T magnetic resonance scanner in 9 normal subjects. We used a gradient-echo technique to examine changes in signal between periods when subjects viewed a stationary black-and-white grating, a moving grating, and when they followed a moving spot. We located image pixels with significant differences between the viewing conditions. In 7 subjects, these occurred in the lateral occipitotemporal cortex, a region previously identified as a putative human homologue of the motion-sensitive middle temporal area (MT, or V5) of monkeys. Signal intensity was greater during pursuit of the moving dot than during viewing of the moving grating with the eyes still, despite the fact that the moving grating generated more retinal image motion. In contrast, signal intensity in striate cortex was least during pursuit of the moving dot. These findings suggest that the lateral occipitotemporal cortex has extraretinal signals during pursuit. Such signals may include attentional input, corollary eye movement information, or even a pursuit command. Extraretinal signals suggest that the lateral occipitotemporal cortex may contain a human homologue not only of MT but also of other components of the monkey V5 complex, such as the medial superior temporal area.

Adult↗
PubMed1996

Health care utilization as a marker for suicidal behavior on an American Indian Reservation.

OBJECTIVE: Overall suicide mortality rates are higher among American Indians than in the general population and are particularly high among Indians residing in the upper Midwest. The identification, during encounters with health care providers, of individuals at high risk of suicide is a potential intervention strategy. The purpose of this study was to examine whether increased health care utilization and symptom patterns were associated with suicide and suicide attempts among American Indian patients in an Indian Health Service facility. DESIGN: A case-control study design was used. SETTING/PATIENTS: Cases of completed suicides over a 6-year period and cases of suicide attempts over a 15-month period were identified on a Plains Indian Reservation. The pattern of utilization of health services by these subjects prior to their suicide or attempt was compared with that of control subjects matched for age and gender. MAIN RESULTS: Only 24% of subjects who died of suicide used the reservation clinic or hospital for services in the 6 months prior to their suicide, compared with 54% of controls (odds ratio [OR] 0.28; 95% confidence interval [CI], 0.09, 0.87). The patterns of symptom complaints and diagnoses for these visits did not differ significantly between case and control subjects. Case subjects who attempted suicide were more likely to be seen during the 6 months prior to their attempt than control subjects (57% vs 40%, OR 1.72; 95% CI 0.75, 3.93). Persons who attempted suicide were more likely to have documentation of psychological and interpersonal problems than were control subjects. Only 14% of subjects completing suicide had a previous history of suicide attempts. CONCLUSIONS: In this region, American Indians who committed suicide were less likely to use clinical services provided by the Indian Health Service prior to their death. However, there was a relatively strong association between suicide attempts and the prior use of health services, particularly the use of mental health services. In this American Indian population, clinic-based methods for early detection and intervention to prevent imminent suicide would reach fewer than one fourth of suicide victims. Further research is needed to identify the usefulness of community outreach efforts to identify and intervene among individuals at high risk of death by suicide.

Adult↗