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Biomedical subjects

E Kyle

Publications and source records attributed to E Kyle.

17 recordsLinked to original sources
PubMed2001

How accurate are pulse oximeters in patients with acute exacerbations of chronic obstructive airways disease?

The aim of this study was to determine the extent of correlation and agreement between arterial oxygen saturation and oxygen saturation as recorded by transcutaneous pulse oximetry, with a view to identifying whether pulse oximetry can be used as an alternative to arterial values in the clinical management of patients with acute exacerbations of chronic obstructive airways disease (COAD) in the emergency department. It also aims to determine whether there is a cut-off level of oxygen saturation by pulse oximetry that can screen for significant systemic hypoxia in this group. This prospective study of patients with acute exacerbations of COAD who were deemed by their treating doctor to require an arterial blood gas analysis to determine their ventilatory status, compared arterial oxygen saturation with simultaneously recorded oxygen saturation measured by transcutaneous pulse oximetry. Data were analysed using Pearson correlation, bias plot (Bland-Altman) methods for agreement and the receiver operator characteristic (ROC) curve method for determination of a screening cut-off. Sixty-four sample-pairs were analysed for this study. Nine (14%) had significant hypoxia (arterial PO2 less than 60 mmHg). The correlation coefficient was 0.91. The bias (Bland-Altman) plot shows a constant bias of -0.758% and only fair agreement, with 95% limits for agreement of -8.2 to + 6.7%. With respect to the ROC curve analysis, the 'best' cut-off for detection of hypoxia was at oxygen saturation by pulse oximetry of 92% (sensitivity 100%, specificity 86%). In conclusion, there is not sufficient agreement for oxygen saturation measured by pulse oximetry to replace analysis of an arterial blood gas sample in the clinical evaluation of oxygenation in emergency patients with COAD. However, oxygen saturation by pulse oximetry may be an effective screening test for systemic hypoxia, with the screening cut-off of 92% having sensitivity for the detection of systemic hypoxia of 100% with specificity of 86%.

Acute Disease↗
PubMed2001

Venous pH can safely replace arterial pH in the initial evaluation of patients in the emergency department.

OBJECTIVE: This study aims to determine the extent of correlation of arterial and venous pH with a view to identifying whether venous samples can be used as an alternative to arterial values in the clinical management of selected patients in the emergency department. METHODS: This prospective study of patients who were deemed by their treating doctor to require an arterial blood gas analysis to determine their ventilatory or acid-base status, compared pH on an arterial and a venous sample taken as close to simultaneously as possible. Data were analysed using Pearson correlation and bias (Bland-Altman) methods. RESULTS: Two hundred and forty six patients were entered into the study; 196 with acute respiratory disease and 50 with suspected metabolic derangement. The values of pH on arterial and venous samples were highly correlated (r=0.92) with an average difference between the samples of -0.4 units. There was also a high level of agreement between the methods with the 95% limits of agreement being -0.11 to +0.04 units. CONCLUSION: Venous pH estimation shows a high degree of correlation and agreement with the arterial value, with acceptably narrow 95% limits of agreement. Venous pH estimation is an acceptable substitute for arterial measurement and may reduce risks of complications both for patients and health care workers.

Acid-Base Imbalance↗
PubMed2000

Focal adhesion kinase (FAK) phosphorylation is not required for genistein-induced FAK-beta-1-integrin complex formation.

It has previously been shown that changes in the activity of focal adhesion kinase (FAK), and its binding to beta-1-integrin, accompany genistein-induced adhesion of prostate cells. Consumption of genistein world wide is associated with a lower incidence of metastatic prostate cancer. Early human clinical trials of genistein are under way to evaluate genistein's potential causal role in this regard. Though an important cell adhesion-associated signaling molecule, FAK's role in regulating prostate cell adhesion was not clear. Elucidation of this process would provide important information relating to both biology and potential clinical endpoints. It was hypothesized that FAK activation and complex formation are temporally related in prostate cells, and can thus be separated. Significant activation of FAK was demonstrated when cells adhered to fibronectin, as compared to poly-L-lysine, thus demonstrating that beta-1-integrin plays a significant role in activating FAK. Neither FAK activation, nor FAK-integrin complex formation, required beta-1-integrin ligand. However, disruption of the cellular cytoskeleton by cytochalasin D prevented FAK activation, but did not block genistein-induced complex formation. In the face of a disrupted cytoskeleton, signaling through FAK could not be restored through either integrin cross linking, or re-establishment of tensile forces via attachment to solid matrix. These studies demonstrate that FAK-beta-1-integrin complex formation does not require FAK activation, suggesting that it is an early event in prostate cell adhesion. An intact cytoskeleton is necessary for FAK activation. The functional importance of beta-1-integrin in prostate cells is demonstrated. Current findings support plans to test genistein in prostate cancer.

Cell Adhesion↗
PubMed1998

Prostate cancer cell growth inhibition by tamoxifen is associated with inhibition of protein kinase C and induction of p21(waf1/cip1).

BACKGROUND: Inhibition of protein kinase C (PKC) and modulation of transforming growth factor-beta (TGF-beta) are both associated with tamoxifen treatment, and both appear to be important in the regulation of prostate cancer cell growth. Investigations were performed which sought to measure the efficacy, and to elucidate the mechanism of growth inhibition by tamoxifen, in hormone-refractory prostate cancer. METHODS: Growth assays were performed on PC3, PC3-M, and DU145 prostate cancer cells. TGF-beta was measured by ELISA; p21(waf1/cip1) and retinoblastoma (Rb) protein levels were measured by Western blot; PKC activity was measured by kinase assay; and effects upon cell cycle were measured by flow cytometric analysis. RESULTS: IC50s for growth inhibition ranged from 5.5-10 microM, and were not affected by estrogen. Tamoxifen-mediated growth inhibition was not associated with induction of TGF-beta. However, tamoxifen treatment was associated with inhibition of PKC, which was followed by induction of p21(waf1/cip1), Rb dephosphorylation, and G1/S phase cell cycle arrest. Similar effects were observed with the known PKC inhibitor, Ro31-8220. CONCLUSIONS: These data suggest that micromolar concentrations of tamoxifen inhibit prostate cancer cell growth by inhibition of PKC, resulting in induction of the p21(waf1/cip1) protein.

Antineoplastic Agents, Hormonal↗
PubMed1997

Genistein-induced apoptosis of prostate cancer cells is preceded by a specific decrease in focal adhesion kinase activity.

Genistein (5,7,4'-trihydroxyisoflavone), an isoflavinoid found in soy beans, has been identified as potentially causal for the low incidence of metastatic prostate cancer (PCa) in certain countries. Although genistein-induced PCa cell adhesion has been identified as a possible causative mechanism, direct growth inhibition by genistein has been reported and also could be causal. If in vivo growth inhibition was significant, then growth inhibition should occur at concentrations attained with dietary consumption, the mechanism of growth inhibition should be relevant to PCa, and genistein (a broad-spectrum in vitro protein-tyrosine kinase inhibitor) should have relatively specific kinase inhibitory effects in vivo. These considerations were investigated by measuring growth inhibitory activity in a variety of PCa cell lines. Growth inhibitory effects were shown not to occur with concentrations below the low micromolar range (i.e., 3 logs above that attained in serum). In-depth mechanistic studies with the PC3-M metastatic variant cell line demonstrated that growth inhibition was independent of genistein's estrogenic effects. Genistein was shown to decrease the viability of nonadherent cells, suggesting a lack of dependence on cell adhesion for growth inhibition. However, important molecular and kinetic differences between genistein's effects on growth in adherent versus nonadherent cells were identified. Specific suppression of focal adhesion kinase activity (without global decreases in phosphotyrosine) was shown to precede induction of apoptosis, which was responsible for growth inhibition in adherent cells. These findings do not support an in vivo growth inhibitory role by genistein consumed in quantities associated with a soy-based diet. They do, however, identify genistein as a potential therapeutic agent for PCa and as a tool with which to study the control of apoptosis in PCa.

Apoptosis↗
PubMed1996

Electroporation of synthetic oligodeoxynucleotides: a novel technique for ex vivo bone marrow purging.

Recent data suggest that tumor cells contaminating reinfused bone marrow may contribute to relapse in patients undergoing autologous bone marrow transplantation. Purging strategies that are able to remove these contaminating tumor cells need to be developed. This study describes how electroporation (EP) can be used to improve intracellular delivery of synthetic antisense oligodeoxynucleotides (ODNs), thereby enhancing their ability to suppress a target protein. Antisense ODNs that were introduced into cells by EP led to immediate suppression of targeted c-myc protein; this was associated with rapid cell death in the diffuse histiocytic lymphoma, U937; Burkitt's lymphoma, ST486; breast carcinoma, MCF-7; and Ewing's sarcoma, CHP-100, cell lines. Electroporation was found to have little or no detrimental effect on cells responsible for murine hematopoietic long-term reconstitution as determined from in vivo competitive repopulation studies. Using human c-myc-directed antisense ODNs as a model for the application of this approach to bone marrow purging, selective killing of human lymphoma U937 cells relative to normal human bone marrow cells was shown in cell mixing studies. In vivo studies were performed in which a survival advantage was shown for athymic mice that were inoculated with antisense-treated U937 cells as opposed to control cells. These studies suggest that EP of bone marrow may be of use in enhancing intracellular delivery of a variety of molecular/pharmaceutical agents. Taken together, these data suggest that the use of electroporation to enhance delivery of antisense ODNs is a promising new approach towards ex vivo bone marrow purging.

Adenocarcinoma↗
PubMed1996

Genistein-stimulated adherence of prostate cancer cells is associated with the binding of focal adhesion kinase to beta-1-integrin.

The isoflavinoid genistein is a protein-tyrosine kinase inhibitor which has been identified as a putative cancer prevention agent. Its consumption is associated with a low incidence of clinical metastatic prostate cancer in the face of a sustained high incidence of organ-confined prostate cancer. We therefore undertook studies to examine genistein's effect upon cell adhesion as one possible mechanism by which it could be acting as an antimetastatic agent. A morphogenic analysis revealed that genistein caused cell flattening in a variety of cell lines: PC3-M, PC3, and DU-145 prostate carcinoma cells, as well as MCF-7 breast carcinoma cells. Mechanistic studies focused on the highly metastatic PC3-M cell line, and revealed that cell flattening was accompanied by an increase in cell adhesion. Further investigations demonstrated that focal adhesion kinase (FAK) accumulated in areas of focal cell attachment, and that this accumulation occurred only when cells were actively undergoing genistein-mediated morphologic change. Concurrent formation of a complex between the cell attachment molecule, beta-1-integrin, and FAK was shown to occur, and to correlate with transient activation of FAK activity. Genistein is presented as a novel investigative tool for use in the study of molecular events involved in the process of cell adhesion.

Antineoplastic Agents↗
PubMed1995

Inhibition of protein-tyrosine kinase activity in intact cells by the aptameric action of oligodeoxynucleotides.

Direct interaction of oligodeoxynucleotides (ODNs) with proteins represents one of the nonantisense-mediated effects of ODNs. Phosphorothioate-capped ODNs have been shown to inhibit directly the in vitro kinase activity of the chronic myelogenous leukemia-associated protein-tyrosine kinase p210bcr-abl. In this study we have determined the efficacy of this aptameric ODN in a cellular system using the K562 chronic myelogenous leukemia-derived cell line. Significant effects upon cellular phosphotyrosine content, as well as cellular growth in soft agar, are observed. These effects are sequence specific and are not mediated through changes in p210bcr-abl protein levels. Additional ODNs are described that also reduce cellular phosphotyrosine levels and inhibit growth in soft agar but do not inhibit p210bcr-abl kinase activity in vitro.

Base Sequence↗
PubMed1994

Aptameric inhibition of p210bcr-abl tyrosine kinase autophosphorylation by oligodeoxynucleotides of defined sequence and backbone structure.

Protein tyrosine kinases play key roles in cellular physiology. Specific inhibitors of these enzymes are important laboratory tools and may prove to be novel therapeutic agents. In this report we describe a new class of tyrosine kinase inhibitor, synthetic oligodeoxynucleotides (ODNs). An ODN is described which specifically inhibits p210bcr-abl tyrosine kinase autophosphorylation in vitro with a Ki of 0.5 microM. Inhibition is non-competitive with respect to ATP. The effects upon inhibitory activity of ODN structure modifications are described. The inhibition described is not mediated by classical antisense mechanisms and represents an example of the recently recognized aptameric properties of ODNs.

3T3 Cells↗
PubMed1994

Filgrastim fails to improve haemopoietic reconstitution following myeloablative chemotherapy and peripheral blood stem cell rescue.

The morbidity of high-dose chemotherapy has been considerably reduced by the use of autologous peripheral blood progenitor cell reinfusion. Most studies have used myeloid colony-stimulating factors after stem cell reinfusion, making it difficult to determine the relative contribution of each of these variables to the early recovery of blood cells. The financial implications of colony-stimulating factor use are an area of concern as dose intensification in chemosensitive malignancies is increasingly employed. We have studied 19 consecutive patients receiving high-dose chemotherapy with and without filgrastim (Amgen, granulocyte colony-stimulating factor, G-CSF) after stem cell infusion to examine its effect on the kinetics of blood cell recovery, the complications of myelosuppression and the associated costs. Analysis of the two treatment groups reveals that administration of filgrastim 10 micrograms kg-1 day-1 following stem cell reinfusion does not further accelerate haemopoietic recovery, fails to reduce the incidence of neutropenic fever or antibiotic usage and significantly increases the cost of the procedure. The results of this study do not support the routine use of filgrastim after high-dose chemotherapy and peripheral blood stem cell reinfusion.

Adolescent↗
PubMed1993

Effect of over-expression of bacterial ribonuclease H on the utility of antisense MYC oligodeoxynucleotides in the monocytic leukemia cell line U937.

RNase H has been clearly implicated in vitro in mediating some antisense effects. In vivo evidence is limited to experiments performed in Xenopus oocytes in which antisense oligonucleotides are microinjected. In other mammalian cell systems scant data have been obtained to support or deny a role for RNase H as an antisense mediator in vivo. These experiments were designed to test the hypothesis that RNase H mediates the MYC antisense-induced reduction in MYC protein observed in the human monocytic leukemia cell line U937. A bacterial RNase H-containing episomal replicon was constructed and stable transfectants were obtained which expressed E coli RNase H in their cytoplasm at a 10-fold higher level than endogenous RNase H. These cells failed to demonstrate heightened sensitivity to MYC antisense (phosphorothioate, end capped and phosphodiester) compared with untransfected or E coli RNase H antisense transfected cells. PCR analysis of each transfectant treated and untreated with MYC antisense failed to demonstrate the appearance of truncated MYC mRNA. These results do not support a role for RNase H in the mediation of MYC antisense-induced MYC protein reduction and growth inhibition in U937 cells.

Base Sequence↗
PubMed1979

Obligatory urinary and fecal nitrogen losses in young women, older men, and young men and the factorial estimation of adult human protein requirements.

Obligatory urinary and fecal nitrogen losses and urinary urea nitrogen and creatinine excretion levels were determined in 11 young women (four of whom used oral contraceptives), eight older men, and five young men. Values for obligatory nitrogen losses in the young women who did not use oral contraceptives were similar to those observed previously in young women and lower than those reported for young men. Our values for older men were lower than previously reported values for obligatory losses observed in young and elderly men, but similar to previously reported values for young women and to values for our women who did not use oral contraceptives. The four oral contraceptive users had significantly higher levels of total urinary and fecal obligatory nitrogen losses than the nonusers in our study. When values from our study and values from other recent studies are considered, variations in obligatory nitrogen losses appear to be larger among individuals within an age-sex group than the observed differences between groups. When the intakes of protein recommended as safe by the Food aculated from obligatory nitrogen losses per se, the recommended levels appear to be only marginally adequate.

Adult↗
PubMed1976

Case-note abstraction: a methodological substudy as cautionary tale.

A sample of 42 case notes of alcoholic patients were abstracted for 17 items by three different raters. Interrater agreement was generally rather low. Research based on case-note abstraction which does not report on abstraction reliabilities must therefore be viewed with some suspicion. It would be helpful if clinical material could more often be collected in a standardized manner.

Abstracting and Indexing↗