PrP gene dosage and long term potentiation.
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Animals↗
Biomedical subjects
C Black
Publications and source records attributed to C Black.
Manitoba's population-based databases and long-term planning: beyond the hospital databases.
The Manitoba Centre for Health Policy and Evaluation (MCHPE) conducts health services research focusing on Manitoba's administrative databases. Administrative databases contain information which is routinely and systematically collected for administrative purposes such as hospital and physician claims and funding requirements. This article describes the MCHPE's five major databases, their strengths and limitations, and the development of the Population Health Information System (PHIS). Four modules from PHIS illustrate how the data are used to provide useful information for health care planners, administrators and policy analysts. Finally, future projects and directions for using administrative databases are explored.
Data Collection↗
Malabsorption caused by coeliac disease in patients who have scleroderma.
Coeliac disease may account for malabsorption in scleroderma patients even when test suggest bacterial overgrowth. A small bowel biopsy is essential.
Adult↗
Expression of ectopeptidases in scleroderma.
OBJECTIVES: To examine the expression and concentrations of three ectopeptidases likely to be involved in regulating the functional levels of adhesion molecules and the turnover of connective tissue components, in patients with scleroderma (systemic sclerosis) (SSc) and in normal individuals. METHODS: Monoclonal antibodies against these antigens were used for immunoperoxidase staining of cryostat skin sections and for flow cytometric (fluorescence activated cell sorter) analysis of cultured dermal fibroblasts grown from SSc patients and normal controls. RESULTS: Although neutral endopeptidase-24.11 (NEP) (CD10) was not detected in either SSc or normal skin, aminopeptidase N (APN) (CD13) and dipeptidyl peptidase IV (DPPIV) (CD26) were both readily visualised. However, DPPIV appeared to be present in smaller concentrations in the SSc biopsy specimens. Moreover, while fibroblasts grown in vitro from both SSc and normal skin also had similar concentrations of APN, the expression of DPPIV in the cultured SSc cells was found to be very much less than that present in the normal fibroblasts. It is noteworthy that NEP, which was not detected in the tissue sections, was nevertheless readily detected in fibroblasts in culture. CONCLUSIONS: These results show that a number of cell surface proteases are expressed by dermal fibroblasts both in vivo and in vitro, and it is suggested that the marked downregulation of DPPIV in SSc could be at least partly responsible for the increased concentrations of adhesion molecules and matrix proteins associated with the molecular pathology of this disease.
Adolescent↗
Antiasthmatic effects of a leukotriene biosynthesis inhibitor (MK-0591) in allergic dogs.
Peptidoleukotrienes may be important mediators of human bronchial asthma. Accordingly, the effects of a selective leukotriene (LT) biosynthesis inhibitor (MK-0591) were assessed in allergic dogs characterized by acute bronchoconstriction and subsequent airway hyperresponsiveness induced by inhaled ragweed allergen. Peak acute increases in airway resistance (Rrs) induced by ragweed were associated with increased bronchoalveolar lavage histamine concentration, and neither parameter was inhibited by MK-0591 (8 micrograms.kg-1.min-1 i.v.). However, the duration of the bronchoconstriction was significantly decreased by MK-0591, with a reduction in the area under the curve of 40% (P < 0.05). Associated with the acute bronchoconstriction in placebo-treated animals was a fivefold increase in urinary LTE4 excretion (as seen with allergic asthmatic patients), which was reduced to < 10% of basal values by MK-0591. Similarly, whole blood LTB4 biosynthesis was abolished in the MK-0591-treated animals. Bronchial hyperresponsiveness preallergen (measured as the percent concentration of acetylecholine required to increase Rrs by 5 cmH2O.l-1.s) tended to improve with MK-0591 (0.41 +/- 0.15 vs. 0.23 +/- 0.05%). Five hours after allergen inhalation, the percent concentration declined substantially in the placebo group (0.07 +/- 0.02%; P < 0.01), revealing an increased airway responsiveness that was significantly blunted by MK-0591 (0.26 +/- 0.07%; P < 0.001). These data suggest that selective inhibition of LT biosynthesis by novel compounds such as MK-0591 may modify the airway changes associated with bronchial hyperresponsiveness, as well as offer symptomatic relief in asthma.
5-Lipoxygenase-Activating Proteins↗
Immunocytochemical localization and serologic detection of transforming growth factor beta 1. Association with type I procollagen and inflammatory cell markers in diffuse and limited systemic sclerosis, morphea, and Raynaud's phenomenon.
OBJECTIVE: To determine the presence of transforming growth factor beta 1 (TGF beta 1) and inflammatory cell markers (HLA-DR and Factor XIIIa) and to compare these with the presence of type I procollagen, in clinically uninvolved and involved skin from patients with different subsets of systemic sclerosis (SSc), and to analyze circulating levels of TGF beta 1 in SSc patients. METHODS: TGF beta 1, HLA-DR, Factor XIIIa, and type I procollagen were detected in skin biopsy sections using a biotin-streptavidin-peroxidase system. Levels of circulating TGF beta 1 were measured using a capture enzyme-linked immunosorbent assay technique. RESULTS: Patients with active diffuse cutaneous SSc (dcSSc) showed minimal TGF beta 1 but significant type I procollagen staining in involved skin, while the clinically uninvolved skin of these patients showed moderate extracellular and intra-epidermal TGF beta 1 immunoreactivity. Patients with limited cutaneous SSc (lcSSc) showed elevated TGF beta 1 staining in both involved and uninvolved skin, as well as procollagen staining. Significant TGF beta 1 reactivity, HLA-DR and Factor XIIIa immunoreactivity, numerous inflammatory cells, and procollagen staining were seen in specimens from patients with morphea. Sequential biopsies suggested the presence of cytokine activity at the earliest stages of disease, which was not maintained with progression of sclerosis. Among the disease groups studied, elevated levels of circulating TGF beta 1 were seen only in patients with morphea. CONCLUSION: The pattern of TGF beta 1 staining in dermal sections from patients with dcSSc, lcSSc, and morphea suggests that this cytokine is important in the pathogenesis of scleroderma. Furthermore, the presence of TGF beta 1 prior to the onset of fibrosis indicates an early involvement of this growth factor, possibly in the inflammatory stage of the disease.
Biomarkers↗
Expression and shedding of intercellular adhesion molecule 1 and lymphocyte function-associated antigen 3 by normal and scleroderma fibroblasts. Effects of interferon-gamma, tumor necrosis factor alpha, and estrogen.
OBJECTIVE: To examine intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 3 (LFA-3) in cultures of normal and systemic sclerosis (SSc) dermal fibroblasts. METHODS: The surface and soluble forms of ICAM-1 and LFA-3 were measured by flow cytometry and capture enzyme-linked immunosorbent assay, respectively. RESULTS: Surface ICAM-1 was significantly higher on SSc fibroblasts compared with normal controls. Beta-estradiol did not directly enhance ICAM-1 or LFA-3 expression in either normal or SSc cells, but significantly augmented the cytokine-induced increase in ICAM-1. Soluble ICAM-1 (sICAM-1) and sLFA-3 were detected in fibroblast cultures. While no difference was found in the level of sLFA-3, the shedding of sICAM-1 was significantly increased (P < 0.001) in cells from SSc patients. CONCLUSION: SSc fibroblasts express intrinsically elevated levels of surface ICAM-1 and release higher levels of sICAM-1 in vitro. Increased expression of ICAM-1 by interferon-gamma and tumor necrosis factor alpha alone, and the further induction in combination with beta-estradiol may underlie an aspect of fibroblast dysfunction in SSc and the female predisposition to the disease.
Antigens, CD↗
HLA-DQB1 associations with anti-topoisomerase-1 antibodies in patients with systemic sclerosis and their first degree relatives. United Kingdom Systemic Sclerosis Study Group.
The frequency and functional properties of anti-topoisomerase-1 antibodies (ATA) have been studied in 58 systemic sclerosis (SSc) probands, 218 first degree relatives and 22 spouses. The dependence of ATA on the presence of certain HLA-DRB1 and HLA-DQB1 alleles was examined. ATA were detected by immunodiffusion, by absorption or inhibition of topoisomerase-1 enzymic activity, by immunoblotting of a K562 cell extract and by immunoprecipitation of 35S radiolabelled cell lines. HLA class II typing for HLA-DRB1 and HLA-DQB1 was performed by oligonucleotide typing in 49 families. Six probands and two relatives had ATA. The relatives with ATA had SSc. All eight individuals with ATA directly inhibited topoisomerase-1 function. Four of the eight had limited skin disease and four had diffuse skin involvement. The seven who were genotyped had at least one HLA-DQB1 allele encoding for tyrosine at position 30 of the first domain. Therefore, ATA are not widely dispersed within families, but rather are only present in those with SSc, and certain genetic requirements appear necessary for their generation.
Alleles↗
Excess matrix accumulation in scleroderma is caused partly by differential regulation of stromelysin and TIMP-1 synthesis.
Scleroderma (systemic sclerosis: SSc) is an autoimmune disorder in which excessive extracellular matrix is deposited in skin and internal organs. Because of the importance of metalloproteinases in the turnover of connective tissue, in this study we have developed a novel procedure which utilises flow cytometry (FACS) to measure the production of stromelysin (MMP-3), gelatinase A (MMP-2), and the proteinase inhibitor TIMP-1, by SSc skin fibroblasts. In the presence of monensin, which prevents the secretion of these matrix proteins, there was a similar intracellular accumulation of gelatinase A in normal and SSc cells. However, whereas stromelysin levels also increased in the normal cells, no net synthesis could be detected in the SSc fibroblasts. In marked contrast, the synthesis of TIMP-1 was 50% greater in the SSc cells than in the normal fibroblasts. Our results thus show unequivocally, for the first time, that cells from SSc patients simultaneously produce less stromelysin but substantially higher amounts of TIMP-1 than do normal dermal fibroblasts, suggesting that abnormalities in the regulation of the matrix enzymes and their inhibitors play an important part in the molecular pathology of SSc.
Adolescent↗
Measurement of canine urinary thromboxanes by GC-MS and HPLC-RIA.
Immunoaffinity extraction/gas chromatography-mass spectrometry (IA/GC-MS) and high-performance liquid chromatography-radioimmunoassay (HPLC-RIA) methods were developed to analyse a major human urinary thromboxane metabolite, 2,3-dinor thromboxane B2, in the urine of dogs, a species commonly used for functional studies of thromboxane pharmacology. The beta-metabolite 2,3-dinor TXB2 was unequivocally identified in pooled normal canine urine by IA/GC-MS, and its excretion measured in 6 anesthetized dogs over a 7h period as 2001 +/- 132 pg 2,3-dinor TXB2/mg creatinine (range 624-4493 pg/mg). Thromboxane immunoreactivity co-eluting with synthetic 2,3-dinor TXB2 was also identified by HPLC-RIA and similarly determined (2585 +/- 276 pg/mg creatinine). Exogenous 2,3-dinor TXB2 could be quantitatively recovered by both methodologies over a wide range of concentrations (50-5000 pg/mL), although with better precision by IA/GC-MS (added vs recovered; m = 1.05, r = 0.99) compared with HPLC-RIA (added vs recovered; m = 0.89, r = 0.89). The cyclooxygenase inhibitor indomethacin given by infusion in anaesthetized dogs (2.5, 8 and 25 micrograms/kg/min) dose-dependently inhibited 2,3-dinor TXB2 excretion measured by IA/GC-MS, with maximal inhibition (83.0 +/- 4.2%) being achieved after 6h (25 micrograms/kg/min). Similar results were obtained by HPLC-RIA, with a correlation of 0.88 (slope = 0.9) between the methodologies in samples after drug treatment. These data suggest that the profile of metabolism and excretion of thromboxanes in dogs resembles that of man, and provide a useful animal model for the non-invasive in vivo assessment of inhibitors of thromboxane biosynthesis.
Animals↗
ED security: a national telephone survey.
To determine current practices regarding security measures in the emergency department (ED), a random sample of 250 hospitals with EDs was surveyed by telephone. Security issues addressed included personnel (in-house security, contract guards, or police), hours of staffing in the ED, how security is armed, whether ED doors are locked at off-hours, and whether alarm buttons, direct phone lines, a paging code, closed circuit surveillance, metal detectors, and seclusion rooms are used. This information was stratified according to hospital size, ED census, rural/suburban/urban setting, teaching/nonteaching status, and region. Generally, on-site security presence increases with increasing hospital size and ED census, suburban and urban locations, and teaching status. Small, rural hospitals are more likely to lock the ED doors at off-hours, whereas the use of security codes does not clearly follow demographic trends. Larger hospitals in suburban and urban settings and having a teaching status are more likely to have secure/detention rooms and closed circuit surveillance. The use of alarm buttons and/or direct telephone lines varies widely, but is generally more common in larger, teaching hospitals, located in urban and suburban settings.
Bed Occupancy↗
Magnetic resonance imaging of osteitis condensans ilii.
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Adult↗
Analyzing health outcomes through international comparisons.
There is increasing interest in the conduct of international studies that compare health care outcomes. This paper draws from the literature in sociology, anthropology, and psychology to examine the problems that can be encountered when collecting primary data for comparative purposes. Issues of study design, selection, development, and adaptation of instruments, problems encountered in collecting primary data, and techniques for analyzing comparative data are discussed. The paper is intended as a primer for health services researchers conducting comparative outcomes research in international settings.
Data Collection↗
Fibroblastic rheumatism.
The first British case of fibroblastic rheumatism is reported. Treatment with apha-interferon in combination with a reducing course of steroids resulted in some regression of the cutaneous nodules, and initial improvement in the skin fibrosis and digital contractures.
Adult↗
Image analysis derived ploidy and proliferation indices in soft tissue sarcomas: comparison with clinical outcome.
AIMS: To compare prognostic information obtained by image analysis cytometry of paraffin wax embedded soft tissue sarcomas with conventional assessment. METHODS: A CAS 200 image analyser was used to determine DNA content of Feulgen stained cytology preparations and tissue sections and to quantify immunostaining by Ki67 and PC10 antibodies. A mitotic count in 50 high power fields was undertaken and histological grade assigned by the Trojani system. Clinical details including follow up and outcome were obtained by case note review. The Kruskal-Wallis one way analysis test, Spearman rho significance test, Kaplan-Meier method, and log-rank test were applied in statistical analysis. RESULTS: Ploidy status, DNA index, 2.5c exceeding rate, 5c exceeding rate, mitotic count and Trojani grade all correlated significantly with clinical outcome. The relation between Ki67 index and outcome did not reach significance. The PC10 index and outcome were not related. Only 2.5c exceeding rate, 5c exceeding rate, and mitotic count correlated significantly with Trojani grade. CONCLUSIONS: DNA content determination of soft tissue sarcomas by image analysis provides quantifiable information of benefit in prediction of outcome. Larger series are required to determine the independent value of ploidy. In this study quantification of anti-Ki67 and anti-PC10 immunostaining was not of prognostic benefit) by contrast with mitotic count and Trojani grade.
Cell Division↗
Effect of FLAP antagonist MK-0591 on leukotriene production and ozone-induced airway responses in dogs.
We used the 5-lipoxygenase-activating protein (FLAP) antagonist MK-0591 to investigate the importance of leukotrienes (LT) in causing ozone-induced bronchoconstriction, airway inflammation, and airway hyperresponsiveness in dogs. Six random source dogs were studied. On one day, dogs were treated with MK-0591 (2 mg/kg iv) followed by a continuous intravenous infusion of 8 micrograms.kg-1.min-1. On the other day, the diluent was infused. Acetylcholine airway responsiveness was measured before and 1 h after ozone inhalation (3 ppm for 30 min). On each day, whole blood and bronchoalveolar lavage (BAL) cells were challenged with calcium ionophore to stimulate LTB4 production. Urinary LTE4 levels were measured before and after ozone. MK-0591 inhibited LTB4 production in whole blood by 96% (P = 0.001) and that from BAL cells by 91% (P = 0.001). By contrast, MK-0591 had no effect on ozone-induced bronchoconstriction, airway hyperresponsiveness, or influx of neutrophils into BAL. The mean log difference of the pre- to post-acetylcholine provocative concentration was 0.64 +/- 0.40 during MK-0591 treatment and 0.68 +/- 0.40 during diluent treatment (P = 0.71). These results indicate that peptidoleukotrienes are produced during ozone inhalation and that MK-0591 inhibits LT production in dogs. However, LTs do not play a role in ozone-induced bronchoconstriction, airway inflammation, or airway hyperresponsiveness in dogs.
5-Lipoxygenase-Activating Proteins↗
Localization of endothelin-1 and its binding sites in scleroderma skin.
OBJECTIVE: Endothelin-1 (ET-1) has been implicated in the pathogenesis of systemic sclerosis (SSc) as it is both a potent vasoconstrictor and fibroblast mitogen and is raised in the circulation of patients with SSc and primary Raynaud's phenomenon. METHODS: We examined the localization and level of expression of ET-1 and its putative receptors in clinically "uninvolved" (i.e., prescleroderma skin) and involved skin from patients with diffuse cutaneous systemic sclerosis (dcSSc), using the alkaline phosphatase antialkaline phosphatase technique while ET-1 binding sites were examined using in vitro autoradiography. RESULTS: There was an increase in dermal ET-1 staining in clinically uninvolved and involved skin from patients with early active dcSSc compared with late stage fibrotic SSc skin and normal skin from healthy volunteers. Increased ET-1 staining was associated predominantly with the superficial vessels in the SSc skin sections. In addition, there was a significant increase in [125I]ET-1 binding to superficial vessels and the dermal/epidermal junction in SSc skin compared with the binding to similar structures in normal tissue. There was no change in [125I]ET-1 binding to the deep dermal vessels in both SSc and normal skin. This increase in [125I]ET-1 binding in SSc skin was not maintained with increasing tissue fibrosis. CONCLUSION: The presence of increased ET-1 levels as well as its binding sites in both the prescleroderma and involved skin of patients with dcSSc compared to controls suggests that ET-1 may play a role in the pathology of dermal fibrosis and vasoconstriction in SSc.
Adult↗
Collagen type I is not under autocrine control by transforming growth factor-beta 1 in normal and scleroderma fibroblasts.
BACKGROUND: The ability of transforming growth factor-beta (TGF-beta) to induce synthesis of extracellular matrix proteins stimulated this study in which we address the hypothesis that TGF-beta can induce, in normal fibroblasts, the sustained, elevated collagen synthesis characteristic of the scleroderma fibroblast. EXPERIMENTAL DESIGN: Fibroblasts were studied for synthesis of and responsiveness to TGF-beta. Secreted TGF-beta levels were determined in a bioassay and at the transcriptional level in a series of scleroderma (SSc) and normal fibroblasts. The ability of cells to interact functionally with a 3-dimensional collagen matrix after TGF-beta treatment was examined. The kinetics of TGF-beta-induced fibrosis in fibroblasts was studied. RESULTS: SSc fibroblasts were not characterized by elevated TGF-beta synthesis. There was no evidence of coordinate regulation of TGF-beta and collagen over passage number. Repeated pulses of 200 pM of TGF-beta did not significantly induce sustained procollagen alpha 1(I) mRNA synthesis in normal fibroblasts, and this treatment did not significantly alter the characteristics of normal fibroblasts in a collagen gel. mRNA for both collagen and TGF-beta type II receptor was induced by TGF-beta in both SSc and control cells. SSc fibroblasts were found to have an impaired ability to activate the small latent complex of TGF-beta. CONCLUSIONS: Our data give no support to the hypothesis that TGF-beta can maintain the SSc phenotype in vitro or that it is able to induce this phenotype. The inducibility of TGF-beta receptor mRNA in SSc fibroblasts after exposure to TGF-beta suggests that the lack of sustained elevation in collagen synthesis is not due to lack of responsiveness by the fibroblasts but is rather a reflection of the transient nature of TGF-beta-induced fibrosis.
Cell Division↗