Centres for health promotion research in Canada.
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Academies and Institutes↗
Biomedical subjects
M Stewart
Publications and source records attributed to M Stewart.
The dental health status of five-year-old children in north and west Belfast.
OBJECTIVE: To investigate the influence of social deprivation upon the diet, dental health behaviours and dental health status of five-year-old children in Northern Ireland. DESIGN: Cross-sectional study. SETTING: Fifty-eight primary schools in North and West Belfast. SUBJECTS: A nine per cent (240) random sample of 2,666 five-year-old children resident and attending school in North and West Belfast. MAIN OUTCOME MEASURES: Dental health status measured by dmft index; parental assessments of the child's dental health behaviours: parental dental attendance patterns and attitudes towards dental health; parental assessments of the child's diet and snacking behaviours: parental attitudes towards snack foods; and demographic profile of child's family. RESULTS: One hundred and sixty-three children were examined, a 68 per cent response. The majority of the families were either in low income employment or unemployed. Sixty-eight per cent of children had experience of dental caries. Dental decay was unrelated to parental employment status but more children from unemployed families attended when in pain. The diet of the children was related to both employment status and parental attitude and was reflected in their caries experience. Caries experience was dependent upon parental dental attendance, the consumption of carbonated drinks and sugar containing bedtime drinks. CONCLUSIONS: The results suggest that unemployment and parental attitudes are important as determinants of dental caries in five-year-old children from North and West Belfast. These factors may influence the child's dental health care as well as type of diet.
Attitude to Health↗
Virus-encoded serine proteinase inhibitor SERP-1 inhibits atherosclerotic plaque development after balloon angioplasty.
BACKGROUND: Recurrent atherosclerotic plaque growth, restenosis, is a significant clinical problem after interventional procedures. Initiation of restenosis involves activation of inflammatory and thrombotic cascades, which are regulated by serine proteinase enzymes and inhibitors. We have investigated the use of a viral serine proteinase inhibitor, SERP-1, to reduce plaque development after primary balloon angioplasty. This is the first experimental report of the use of a viral anti-inflammatory protein for the prevention of atherosclerosis. METHODS AND RESULTS: Seventy-four cholesterol-fed rabbits were treated with either local or systemic infusions of SERP-1 protein (or control solutions) after balloon-mediated injury. Sites of SERP-1 infusion in rabbits had dramatically reduced plaque compared with control infusions at the 4-week follow-up. At low-dose infusions (30 to 300 pg), only the primary infusion site had a demonstrable decrease in plaque, whereas at higher-dose infusions (> 3000 pg), a generalized reduction in plaque development was detected. An associated decrease in mononuclear cell infiltration of the arterial wall was detected after SERP-1 infusion within the first 24 hours. Infusion of an active-site mutant of SERP-1 (P1-P1', ala-ala) lacking serine proteinase inhibitory activity failed to prevent plaque growth. CONCLUSIONS: Purified SERP-1, a virus-encoded secreted glycoprotein, reduces plaque growth after primary balloon-mediated injury. Plaque development is decreased by inhibition of serine proteinase activity and is associated with a focal reduction in macrophage infiltration immediately after injury. Investigation of serine proteinase inhibitors may provide new insight into the regulation of arterial responses to injury.
Angioplasty, Balloon↗
Separate binding sites on nuclear transport factor 2 (NTF2) for GDP-Ran and the phenylalanine-rich repeat regions of nucleoporins p62 and Nsp1p.
Nuclear transport factor 2 (NTF2) facilitates nuclear protein import through nuclear pore complexes (NPCs). Bacterially expressed rat NTF2 exists in solution as dimers and, when bound to Sepharose beads, is able to interact specifically with both the Ras-like GTPase Ran, and the xFxFG repeat containing domains of nucleoporins p62 (vertebrate) and Nsp1p (yeast). These interactions are sufficiently strong and specific to enable native Ran and p62 to be isolated from crude rat liver homogenates. Comparison of the sequences of the xFxFG repeat regions of p62 and Nsplp indicated that NTF2 was probably interacting with the phenylalanine-containing core of these repeats and not the intervening hydrophilic linkers. Ran and p62 do not compete with one another for binding to NTF2, indicating that they bind to different sites on NTF2. These interactions could help target Ran and NTF2 to a series of putative docking sites for the importin-substrate complex located along the central transport channel of the NPC and so facilitate the passage of import material being transported from the cytoplasm into the nucleus.
Amino Acid Sequence↗
2.5 A resolution crystal structure of the motile major sperm protein (MSP) of Ascaris suum.
We have determined the structure of the Ascaris major sperm protein (MSP) to 2.5 A resolution using X-ray crystallography. The MSP polypeptide chain has an immunoglobulin-like fold based on a seven-stranded beta sandwich. In two strands, cis-proline residues impart distinctive kinks, and overall the structure most closely resembles that of the N-terminal domain of the bacterial chaperonin, PapD. In the C2 crystal form which we have solved here, two MSP chains are tightly associated in the asymmetric unit and are related by a non-crystallographic 2-fold rotation axis. This arrangement almost certainly represents the MSP dimer that is present in solution. Additionally, the arrangement of two MSP dimers at one of the crystallographic 2-fold axes in the 215 A unit cell suggests a possible mode for the assembly of MSP into the filaments which promote cell movement. This dimer-dimer association is based on a beta sheet extension mechanism between adjoining MSP monomers which resembles the interaction between PapD and its protein substrate.
Amino Acid Sequence↗
The 1.6 angstroms resolution crystal structure of nuclear transport factor 2 (NTF2).
Nuclear transport factor 2 (NTF2) facilitates protein transport into the nucleus and interacts with both the small Ras-like GTPase Ran and nucleoporin p62. We have determined the structure of bacterially expressed rat NTF2 at 1.6 angstroms resolution using X-ray crystallography. The NTF2 polypeptide chain forms an alpha + beta barrel that opens at one end to form a distinctive hydrophobic cavity and its fold is homologous to that of scytalone dehydratase. The NTF2 hydrophobic cavity is a candidate for a potential binding site for other proteins involved in nuclear import such as Ran and nucleoporin p62. In addition, the hydrophobic cavity contains a putative catalytic Asp-His pair, which raises the possibility of an unanticipated enzymatic activity of the molecule that may have implications for the molecular mechanism of nuclear protein import.
Amino Acid Sequence↗
The motile major sperm protein (MSP) from Ascaris suum is a symmetric dimer in solution.
The major sperm protein (MSP) of Ascaris suum mediates amoeboid motility by forming an extensive intermeshed system of cytoskeletal filaments analogous to that formed by actin in many amoeboid cells. We have used a combination of biochemical and NMR methods to show that, in contrast to actin, MSP exist in solution as a symmetrical dimer. This result has important implications for the mechanism of both MSP filament assembly and the recognition of different MSP isoforms in vivo.
Actin Cytoskeleton↗
Regulation of leukocyte integrin function: affinity vs. avidity.
Leukocytes circulate freely in the bloodstream until receiving signals which activate adhesive mechanisms essential for immune responsiveness. Key mediators of these adhesion events are heterodimeric cell surface receptors called integrins. It is now apparent that several components may contribute to successful integrin-mediated adhesion: alterations in individual receptors lead to enhanced affinity for ligand; integrin clustering causes an increase in avidity; by spreading, the adhering cell is less susceptible to shear force. Model systems have allowed us to examine the contribution of each of these factors in generating adhesion. In more physiologically relevant situations, it can now be questioned whether integrin-mediated adhesion is regulated via alterations in receptor affinity or avidity, or whether both these mechanisms are involved.
Calcium↗
Macromolecular assemblages Atomic-resolution structural biology of the cell: a progress report.
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Journal Article↗
Linking microfilaments to intracellular membranes: the actin-binding and vesicle-associated protein comitin exhibits a mannose-specific lectin activity.
Comitin is a 24 kDa actin-binding protein from Dictyostelium discoideum that is located primarily on Golgi and vesicle membranes. We have probed the molecular basis of comitin's interaction with both actin and membranes using a series of truncation mutants obtained by expressing the appropriate cDNA in Escherichia coli. Comitin dimerizes in solution; its principle actin-binding activity is located between residues 90 and 135. The N-terminal 135 'core' residues of comitin contain a 3-fold sequence repeat that is homologous to several monocotyledon lectins and which retains key residues that determine these lectins' three-dimensional structure and mannose binding. These repeats of comitin appear to mediate its interaction with mannose residues in glycoproteins or glycolipids on the cytoplasmic surface of membrane vesicles from D.discoideum, and comitin can be released from membranes with mannose. Our data indicate that comitin binds to vesicle membranes via mannose residues and, by way of its interaction with actin, links these membranes to the cytoskeleton.
Actin Cytoskeleton↗
Reconstitution in vitro of the motile apparatus from the amoeboid sperm of Ascaris shows that filament assembly and bundling move membranes.
We have developed an in vitro motility system from Ascaris sperm, unique amoeboid cells that use filament arrays composed of major sperm protein (MSP) instead of an actin-based apparatus for locomotion. Addition of ATP to sperm extracts induces formation of fibers approximately 2 microns in diameter. These fibers display the key features of the MSP cytoskeleton in vivo. Each fiber consists of a meshwork of MSP filaments and has at one end a vesicle derived from the plasma membrane at the leading edge of the cell. Fiber growth is due to filament assembly at the vesicle; thus, fiber elongation results in vesicle translocation. This in vitro system demonstrates directly that localized polymerization and bundling of filaments can move membranes and provides a powerful assay for evaluating the molecular mechanism of amoeboid cell motility.
Amoeba↗
Porcine model of stent thrombosis: platelets are the primary component of acute stent closure.
Acute stent thrombosis remains a major concern of coronary stent implantation. Animal studies using stents do not adequately mimic this clinical problem, since stent placement is rarely associated with acute closure. The purpose of this study was to develop and characterize a porcine model of stent thrombosis. Improved understanding through such a model may be useful toward preventing and treating acute stent closure. Whole blood was drawn from domestic crossbred swine one day before study. Platelets were isolated, labeled with 111-In tropolone, and reinjected within 18 hr of the study. Bilateral carotid arteries were exposed, and severe injury induced by a series of mechanical crushes. This method produced histologic injury similar to human coronary angioplasty, with medial disruption and large dissections protruding into the lumen. Stenting was performed in standard fashion with 3.5-mm JJIS stents. Local platelet deposition was measured and recorded as 111-In radioactivity using a miniaturized scintillation detector (Dosimeter Corp.) mounted directly at the artery injury site. This measurement was made in real time at 1-min intervals. Similarly, volumetric blood flow was measured in real time by Doppler flowmeter. Eighteen arteries of nine pigs were studied. In nine arteries from nine pigs, crush injury only was performed and monitored. In the contralateral artery, crush injury was followed immediately by placement of a 3.5-mm Palmaz-Schatz (coronary) stent. Blood flow decreased rapidly following injury in both groups and followed a cyclic pattern. Eight arteries of the crush alone and two arteries of the crush plus stent groups were totally occluded 1 hr after crush. 111-In counts normalized to baseline were significantly higher at 1 hr in both groups compared to baseline; in the stented group, counts were higher than in the unstented group. Blood flow was higher in the stented group than in unstented group for 1 hr. Histopathologic observation of the thrombi forming in both crush-only and crush-stent injuries showed severe medial dissections with obstructing medial flap formation. The thrombi forming in both groups were highly platelet rich. This model of stent and arterial thrombosis showed rapid formation of platelet-rich thrombus, cyclic blood flow variations, and acute occlusion in 20% of cases. Stent placement at arterial injury sites is associated with thrombus that is predominantly platelet rich. Stent placement at injury sites enhances platelet deposition over crush injury alone. Despite greater numbers of platelets, as shown by increased 111-In counts, stenting improved vessel patency. These were likely due to higher volumetric blood flow, continuous deposition, and embolization of labeled platelets.
Acute Disease↗
High insulin-like growth factor binding protein 1 levels in cirrhosis: link with insulin resistance.
Hyperinsulinemic euglycemic clamps were performed on six patients with compensated alcoholic cirrhosis and on six normal comparison subjects. As in previous studies, glucose uptake in the cirrhotic patients was only 21% of the comparison value. The cirrhotic patients had high growth hormone (GH) and low insulin-like growth factor-I (IGF-I) levels, with low insulin-like growth factor-binding protein (IGFBP)-3 levels, but surprisingly high IGFBP-I levels (26.8 +/- 8.4 microgH vs. 3.2 +/- 0.2 microm/L, P < .001). The log IGFBP-1 level was inversely correlated with the log insulin sensitivity (r = -.95). The clamps were repeated with a somatostatin infusion to suppress GH secretion. IGFBP-1 increased in both groups, especially in the cirrhotic subjects. Insulin sensitivity increased in the normal subjects but was unchanged in the cirrhotic patients. Following GH treatment (0.13 U/kg/d for 5 days), the clamps were repeated. GH, IGF-1, and IGFBP-3 levels were now similar in the two groups; IGFBP-1 levels decreased in the cirrhotic patients but remained fivefold higher than the comparison value (10.6 +/- 3.7 vs. 2.1 +/- 0.4, P < .05). Glucose uptake in the cirrhotic patients remained only 29% of the comparison value, but the change in their insulin sensitivity was inversely correlated with the change in their IGFB-1 levels (r = -.84). These results suggests an important role for IGFBP-1 in modulating insulin sensitivity in cirrhosis.
Adult↗
Neuropsychometric evaluation of long-term survivors of adult brain tumours: relationship with tumour and treatment parameters.
BACKGROUND: Cognitive deficits are the hallmark of dose limiting late radiation morbidity in the CNS. Little is known about the neuropsychometric morbidity of treatment in adults with primary brain tumours. We set out to evaluate systematically the neuropsychometric function of all long-term survivors in order to document the frequency and severity of impairment and study its relationship with tumour and treatment related parameters. MATERIALS AND METHODS: 30 patients surviving in clinical and radiological remission for > 4 years following irradiation were recalled for clinical examination, CT/MRI scan and neuropsychometric testing. The 14 males, 16 females, (mean age 42.5 years), represented all but one long term survivors treated with radiotherapy in the Department of Clinical Oncology between 1971 and 1990. Twenty-five patients had a histological diagnosis of glioma. Patients treated before 1987 (n = 16) received whole brain irradiation (WBI); focused irradiation (FI) has been used since (n = 14). RESULTS: The two groups were similar were in age, initial tumour type and surgical treatment, but the WBI group showed more evidence of neuropsychometric impairment than the FI group with significantly lower group median scores in tests of visuospatial organisation (WAIS Block Design, P = 0.01), visual memory (Rey Complex figure, P = 0.003) and complex information processing (Trails A, P = 0.003; Trails B, P = 0.002). Pre-morbid IQ estimated from sociodemographic variables, was comparable in the 2 groups which were not significantly different in their emotional state as assessed by the HADS. On univariate analysis radiation volume (P = 0.05) and time from treatment (P = 0.02) were the main factors associated with neuropsychometric deficit. Multivariate analysis by logistic regression confirmed WBI as the only independent predictor of neuropsychometric impairment (WBI vs. FI, odds ratio = 7.1, 95% C.I. 1.2-42.3, P = 0.03). CONCLUSIONS: Neuropsychometric deficits are common and can be related to time from treatment and radiation technique. Neuropsychometric testing can be a useful tool in the evaluation of different treatment strategies.
Adult↗
Autologous bone marrow harvesting in outpatients.
STUDY OBJECTIVE: To assess the experience with autologous bone marrow harvesting in outpatients. DESIGN: Retrospective analysis of outpatients who underwent autologous bone marrow harvesting from 1990 to 1992. SETTING: University-affiliated surgical day hospital. SUBJECTS: 235 outpatients who underwent 264 autologous bone marrow harvests. Patients are candidates for autologous bone marrow harvesting on an outpatient basis if they are Karnofsky performance status of 80-100 and ASA status I, II or III. MEASUREMENTS AND MAIN RESULTS: The incidence of perioperative complications and hospital admission from the Surgical Day Hospital, the duration of the harvesting procedure and postanesthesia care unit (PACU) stay, details of the postoperative pain management, and costs and charges of the outpatient procedure compared with the same procedure performed on inpatients were assessed. Mean age was 37.7 years +/- 10.5 SD; + 7.7% patients were male and 52.3% were female. The disease process included non-Hodgkin's lymph/ma (30.3%), leukemia (24.3%), metastatic breast cancer (18.4%), Hodgkin's disease (17.3%), testicular carcinoma (6.5%) and other (1.6%). The patients were ASA status II (54.5%) or ASA III (45.5%) and received general endotracheal anesthesia. Each patient had 10.7 ml/kg +/- 2.8 SD of marrow harvested over a period of 110.7 minutes + 30.4 SD and total recovery room time of 233.7 minutes +/- 85.5 SD. Of 251 harvest, only three (1.1%) required hospital admission. PACU complaints included transient hypotension and dizziness (5.3%), nausea (3.8%), vomiting (3.4%), and (1.9%) temperature elevation. 83.7% of patients were reached at home the following day and 4.1% complained of nausea and/or vomiting at home. 6.8% of patients experienced temperature elevation at home. Only 27.1% of patients took the acetaminophen with codeine that was prescribed. The reminder required no opioid at home. Outpatient charge/ inpatient charge was 51.1%, and outpatient cost/inpatient was 74.4%. CONCLUSION: Autologous bone marrow harvesting is an acceptable ambulatory surgical procedure that results in a very law postanesthesia complication rate. Postoperative pain is easily controlled. The outpatient setting offers cost and time advantages to the patient.
Adult↗
Nuclear pores and macromolecular assemblies involved in nucleocytoplasmic transport.
Transport in and out of the nucleus is mediated by nuclear pore complexes (NPCs). Information has recently been emerging both on the structure of many of the proteins involved in this transport and on the complexes formed between them. In addition to NPC-based complexes, such as those based on nucleoporins Nsp1p and p62, cytoplasmic protein macromolecular assemblies are also important for nucleocytoplasmic transport.
Animals↗
The prognostic value of epidermal growth factor receptor mRNA expression in primary ovarian cancer.
The expression of mRNA for the epidermal growth factor (EGF) receptor, EGF and transforming growth factor alpha (TGF-alpha) was determined in 76 malignant, six borderline and 15 benign primary ovarian tumours using the reverse transcriptase-polymerase chain reaction and related to clinical and pathological parameters. Of the malignant tumours, 70% (53/76) expressed EGF receptor mRNA, 31% (23/75) expressed EGF mRNA and 35% (26/75) expressed TGF-alpha mRNA. For the borderline tumours, four of six (67%) expressed EGF receptor mRNA, 1/6 (17%) expressed TGF-alpha mRNA and none expressed EGF mRNA. Finally, 33% (5/15) of the benign tumours expressed EGF receptor mRNA, whereas 40% (6/15) expressed EGF mRNA and 7% (1/15) expressed TGF-alpha mRNA. The presence of the EGF receptor in malignant tumours was associated with that of TGF-alpha (P = 0.0015) but not with EGF (P = 1.00), whereas there was no relationship between the presence of EGF and TGF-alpha (P = 1.00). EGF receptor mRNA expression was significantly and positively associated with serous histology (P = 0.006) but not with stage or grade. Neither EGF nor TGF-alpha showed any link with histological subtype or stage. The survival of patients with malignant tumours possessing EGF receptor mRNA was significantly reduced compared with that of patients whose tumours were negative (P = 0.030 for all malignant tumours; P = 0.007 for malignant epithelial tumours only). In contrast, neither the expression of TGF-alpha nor EGF was related to survival. These data suggest that the presence of EGF receptor mRNA is associated with poor prognosis in primary ovarian cancer.
Base Sequence↗
What do cancer patients mean when they complain of concentration and memory problems?
Cognitive function items are increasingly included in quality of life measures, and complaints of concentration and memory difficulties are often reported by cancer patients. The aim of this study was to examine the factors influencing patients' level of complaint by comparing subjective reports with objective test performance of a sample of adult lymphoma patients, disease-free and > or = 6 months after treatment. There was no significant difference between complainers and non-complainers in sociodemographic or clinical characteristics or in their performance on standard neuropsychometric tests of concentration and memory. Those reporting concentration and memory difficulties had significantly higher scores on measures of anxiety, depression and fatigue. This calls into question the validity of including cognitive function items in self-report quality of life measures. Patients who report concentration and memory difficulties should be screened for clinically significant and potentially remediable mood disorder. Objective testing remains the method of choice for assessing higher mental function.
Adult↗