Biomedical subjects
Publications and source records attributed to B Edwards.
Professor Brain Edwards, Professor of Health Care Development at the University of Sheffield, UK talks to Sarah Powell about changes in emphasis in health-care service management, inequalities of access to health care, the concept of mutuality, and the challenges of the future.
We have studied the in vitro effects of lead (Pb) as Pb-acetate (0. 1-1000 ppm) on the activation of rat spleen (SP) cells. At a concentration of 0.5 to 200 ppm, Pb augmented the uptake of [3H]thymidine, progression of SP cells through the cell cycle, and allogeneic and syngeneic mixed lymphocyte reactions. However, at concentrations above 200 ppm, Pb inhibited the proliferation of these cells. To understand the cellular and molecular basis of these responses, we examined the effects of Pb on the proliferation of isolated T and/or B cell populations. Pb failed to stimulate the proliferation of isolated T and B cells; however, the addition of gamma-irradiated B cells to T cell cultures or irradiated T cells to B cell cultures resulted in Pb-induced incorporation of [3H]thymidine. On the other hand, macrophages were unable to reconstitute this response. Pb also induced a significant rise in the intracellular concentration of inositol 1,4,5-trisphosphate in SP cells; however, unlike the activation of lymphocytes through the antigen receptors, Pb did not significantly stimulate protein tyrosine kinase activity. These observations suggest that Pb facilitates the T cell-B cell interaction-dependent proliferation of lymphocytes through a signaling pathway(s) independent of the antigen receptor.
PURPOSE: The 99mTc-labelled amine oxime 99mTc-HL91 (Prognox) is under investigation as a potential noninvasive clinical marker of tumour hypoxia whose uptake can be monitored by gamma camera imaging. The aim was to assess its retention in 3 tumours under control and enhanced oxygenation conditions. MATERIALS AND METHODS: The SaF murine sarcoma, grown subcutaneously in CBA mice, and human colon carcinoma HT29 and lung adenocarcinoma A549, grown as xenografts in SCID mice, were used at 6-8 mm diameter. Oxygenation status was enhanced by giving 500 mg/kg nicotinamide i.p. and breathing carbogen until the point of assay. Oxygenation/hypoxia was measured using the Eppendorf pO2 histograph (KIMOC 6650) with at least 5 tracks and at least 70 values, and expressing pO2 values as % < 2.5 mmHg. 99mTc-HL91 (0.8 or 8 MBq per mouse) was injected i.v. immediately before nicotinamide or saline, and animals were killed 2 h after injection. Tumour, skin, muscle, and blood samples were counted and isotope retention was expressed as % injected dose per gram. 14C-labelled uncomplexed HL91 was used similarly (0.2-0.4 MBq per mouse) and samples were solubilised and decolourised before counting. RESULTS: Nicotinamide and carbogen treatment reduced 99mTc-HL91 retention in all tumours to 54%-64% of control; it also reduced the proportion of pO2 values < 2.5 mmHg in all tumours. The mean proportion of pO2 values < 2.5 mmHg correlated very well with the mean ratio of tumour to blood retention at 2 h for all tumours, both unperturbed and oxygen-enhanced (r = 0.996, p < 0.001). Retention of 14C-HL91 in SaF tumour was unchanged by nicotinamide and carbogen, confirming that 99mTc complexation of the ligand is required for hypoxia specificity. CONCLUSION: There is excellent correlation between 99mTc-HL91 retention and hypoxia, as measured by the Eppendorf histograph, over the range of 50%-90% of values < 2.5 mmHg in 3 different tumour models, including 2 human xenografts. 99mTc complexation of the ligand is required for hypoxia specificity. 99mTc-HL91 (Prognox) shows good potential as a clinical marker for hypoxia and warrants further development.
BACKGROUND: 99mTc-HL91 is a new hypoxia imaging agent that demonstrates increased uptake and retention in globally hypoxic myocardium in vitro. The purpose of this study was to determine whether 99mTc-HL91 could detect regional ischemia in vivo by gamma camera imaging. METHODS AND RESULTS: Eight open-chest dogs with left circumflex (LCx) stenoses were studied. Injection of 5 mCi of 99mTc-HL91 and microspheres was followed by imaging over 4 hours. Heart slices were imaged, then stained with triphenyltetrazolium chloride (TTC), and tissues were well-counted. TTC staining demonstrated no injury. Mean LCx blood flow was 0.32+/-0.04 mL x min(-1) x g(-1), and mean left anterior descending coronary artery (LAD) flow was 0.96+/-0.02 mL x min(-1) x g(-1) (ratio, 0.33). "Hot spots" were detected in 8 of 8 experiments in vivo within 60 minutes and improved over 4 hours. Region of interest analysis of LCx/LAD activity ratios demonstrated significant increases within 30 minutes (final ratio, 3.0; P<0.05). LCx and LAD washout curves demonstrated significant differences within 15 minutes. Washout curves were biexponential over 1 hour, followed by linear retention from 1 to 4 hours. Four-hour fractional retention was 0.12 for LAD and 0.44 for LCx (P<0.01). Myocardial flow versus tracer uptake demonstrated 2 phases: phase 1 (flow, 0.05 to 0.7 mL x min(-1) x g(-1)) had an inverse linear correlation (r= -0.80); phase 2, (flow, >0.7 mL x min(-1) x g(-1)) had no correlation. Ischemic heart/liver ratios remained near 1.0 for 4 hours. CONCLUSIONS: 99mTc-HL91 positively identifies regional myocardial ischemia in a canine model using 99mTc imaging. Quantitative techniques allowed identification of ischemic myocardium within 15 minutes of tracer administration.
Cultured cells from Micropolyspora faeni-sensitized donors can adoptively transfer murine experimental hypersensitivity pneumonitis (EHP). We sought to determine the location of transferred cells in recipient animals, the influence of the origin of the cultured cells, and the effect of specific intratracheal challenge. We labeled cultured sensitized spleen or lung-associated lymph node (LALN) cells with CFDA-SE, a cytoplasmic stain, before transfer to naive recipients, which were sacrificed 1 h, 1 day, or 4 days thereafter. We also transferred labeled cultured spleen cells to recipients that were challenged with intratracheal M. faeni and sacrificed 4 days later (MF). Controls were recipients of M. faeni-sensitized and cultured cells challenged with intratracheal normal saline (NS) and recipients of ovalbumin (OVA)-sensitized cells cultured with M. faeni and challenged with intratracheal M. faeni (OVA). The number and proportion of cells that were stained were determined in dispersed spleen, peripheral and lung-associated lymph nodes, and lung parenchyma. The extent of the pulmonary inflammatory response was measured by determining the proportion of microscopic fields that were abnormal and the total number of dispersed pulmonary cells. CFDA-SE stained cells uniformly, and stained cells could be detected in recipients for up to 7 days after transfer. CFDA-SE treatment (0.5 microM) did not affect the ability of cells to transfer EHP adoptively. Transferred cells could be detected easily in lung, lung-associated and peripheral lymph nodes, blood, and spleen. Transferred cells localized to the lung at 1 h but then rapidly decreased with no difference between labeled cells from spleen and LALN. After intratracheal M. faeni challenge, there was no difference in the proportion of labeled cells in the lung among any of the groups (MF, NS, or OVA). There was an increase in the number of lung cells in the MF group compared with the control (NS and OVA) groups. We conclude that cells capable of transfer are transiently (1 h) trapped in the lung but are much decreased in the lung by four days after transfer. After intratracheal antigen challenge of recipients, there is a substantial increase in the number of pulmonary cells in animals exhibiting adoptive EHP but not in the control groups. Transferred cells responsible for EHP are increased in the lungs of animals with adoptive EHP.
The concept of nursing expertise has been the focus of considerable debate since the early 1980s, yet an agreed definition of the concept and the precise criteria by which it can be evaluated remains elusive. This paper will describe an exploratory study into A & E nurses' constructs of the nature of nursing expertise. Seven first level Accident and Emergency (A & E) nurses were interviewed using Kelly's Repertory Grid Technique. Each was asked to provide examples of nurses with whom they are working or have worked, to match eight given examples designed to represent varying levels of clinical expertise. The informants were asked to consider in what way two of their chosen examples were alike and differed from a third in their clinical practice. A total of 55 bi-polar constructs emerged which were clustered under four main headings. These suggested that A & E nurses perceived expert practice to be characterized by a high level of empirical knowledge, supportive team building, assertive clinical leadership and patient-focused involvement.
This paper describes one part of a major study aimed at building a substantive theory of the triage process. The paper reports on some early findings of a major component of the reasoning strategy utilized by nurses when making triage decisions via the telephone. The study reveals that in telephone triage nurses compensate for the absence of face-to-face contact by creating a mental image of the caller and the situation being dealt with. This forms the basis of the nurses' assessment of the urgency of the problem. The properties that contribute to this process of 'visualization work' are presented and the linkages with current thought in relation to clinical reasoning are explored.
This investigation evaluated a possible source of reduced intelligibility in hypokinetic dysarthric speech, namely the mismatch between listeners' perceptual strategies and the acoustic information available in the dysarthric speech signal. A paradigm of error analysis was adopted in which listener transcriptions of phrases were coded for the presence and type of word boundary errors. Seventy listeners heard 60 phrases produced by speakers with hypokinetic dysarthria. The six-syllable phrases alternated strong and weak syllables and ranged in length from three to five words. Lexical boundary violations were defined as erroneous insertions or deletions of lexical boundaries that occurred either before strong or before weak syllables. A total of 1596 lexical boundary errors in the listeners' transcriptions was identified unanimously by three independent judges. The pattern of errors generally conformed with the predictions of the Metrical Segmentation Strategy hypothesis [Cutler and Norris, J. Exp. Psychol. 14, 113-121 (1988)] which posits that listeners attend to strong syllables to identify word onsets. However, the strength of adherence to this pattern varied across speakers. Comparison of acoustic evidence of syllabic strength to lexical boundary error patterns revealed a source of intelligibility deficit associated with this particular type of dysarthric speech pattern.
Cultured cells from Micropolyspora faeni-sensitized donors can adoptively transfer murine experimental hypersensitivity pneumonitis (EHP). To determine whether the CD4+ cells responsible for transfer have characteristics of Th1 or Th2 cells, we established cell lines from lung-associated lymph nodes of M. faeni-sensitized C3H/HeJ mice by culturing with antigen and either IFN-gamma, IL2, and anti-IL4, or IL4. Cell lines were stimulated regularly with antigen, fresh antigen-presenting cells, and the cytokine/anti-cytokine antibody cocktail. At various times after initiation of culture, cells were injected intravenously into recipients, which were then challenged intratracheally with M. faeni and sacrificed and the extent of pulmonary inflammatory response was determined. IFN-gamma, IL4, and IL10 levels were determined in supernatants of cell cultures stimulated with M. faeni to characterize the cell lines as Th1 (IFN-gamma, but low IL4 and IL10 secretion) or Th2 (IL4 and IL10, but low IFN-gamma secretion). Cell lines were differentiated into either Th1 (IFN-gamma = 310 +/- 45 U/ml, IL4 = 0.10 +/- 0.1 U/ml, IL10 = 1750 +/- 75 pg/ ml, >99% CD4+) cell lines by Day 16 of culture or Th2 cell lines (IFN-gamma = 1.8 +/- 1.0 U/ml, IL4 = 830 +/- 388 U/ml, IL10 = 51,700 +/- 10,900 pg/ml, >96% CD4+) by Day 30. Th1 cell lines were able to adoptively transfer EHP whereas Th2 cell lines were unable to adoptively transfer EHP. The ability to transfer EHP was directly related to the amount of IFN-gamma and inversely to the amount of IL4 secreted by antigen-stimulated cells. We conclude that it is possible to produce CD4+ cell lines with either Th1 or Th2 characteristics from lung-associated lymph nodes of mice exposed to M. faeni and that only Th1 CD4+ cell lines can adoptively transfer EHP.
BACKGROUND: 99mTc-HL91 is a potential imaging agent that has demonstrated increased uptake in hypoxic tumor cells. The purpose of this study was to determine if 99mTc-HL91 demonstrates increased uptake and retention in ischemic and hypoxic myocardium. METHODS AND RESULTS: 99mTc-HL91 (11.1 MBq) was infused over 10 minutes, followed by a 60-minute clearance phase. Activity was monitored by using an NaI detector. Three groups were studied using Krebs-Henseleit buffer (KH): controls (12 mL/min, n = 6), low-flow ischemic (1 mL/min, n = 7), and hypoxic (12 mL/min, n = 8). Two groups were perfused with KH, red blood cells, and albumin: controls (6 mL/min, n = 6) and low-flow ischemic (0.5 mL/min, n = 6). For the KH hearts, the 99mTc-HL91 peak uptake progressively increased from control (6.3 +/- 0.5 microCi, mean +/- SEM) to hypoxic (9.1 +/- 1.0 microCi) to low flow (44.0 +/- 2.6 microCi; P < .01). The peak uptake low-flow/control ratio was 7:1. Final retention increased progressively from control (0.8 +/- 0.1 microCi) to hypoxic (2.9 +/- 0.5 muCi) to low flow (10.9 +/- 1.3 microCi; P < .01). The final low-flow/control activity ratio was 13.6:1. Similar results were observed in the red blood cell-perfused control and low-flow groups. CONCLUSIONS: This study introduces a new myocardial "hot spot" imaging agent, 99mTc-HL91. This agent demonstrates increased myocardial uptake and retention in hypoxic and low-flow ischemic models. Further in vivo imaging studies are warranted to determine the clinical potential of this agent.
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It would seem that time, tide and wind are favourably set for a shift in the organisation of cancer services. Let us test the hypotheses outlined in this brief paper and see if these changes will bring about demonstrable benefit.
We previously demonstrated that Thy1.2+, CD4+, Ia-T cells are responsible for transfer of murine adoptive experimental hypersensitivity pneumonitis (adoptive EHP). To characterize the culture conditions necessary for development of these cells, we depleted cell cultures of Thy1.2+, CD4+, CD8+, or Ia+ cells using MoAbs and complement or magnetic beads, prior to culture of sensitized C3H/HeJ murine spleen cells (SC) with Micropolyspora faeni. After culture, cells were transferred to recipients which were later challenged intratracheally with M. faeni. The extent of pulmonary inflammatory changes in these animals was determined 4 days after intratracheal (i.t.) challenge with M. faeni. Cultured M. faeni-sensitized SC which had been treated before culture with media, complement only, anti-CD8 plus complement or magnetic beads alone could transfer EHP to naive animals. SC treated with anti-Thy1.2 or anti-CD4 plus complement could not transfer EHP. Treatment of SC with anti-Iak plus magnetic beads diminished the ability of cultured cells to transfer EHP. We conclude that the ability to produce cells able to adoptively transfer EPH is dependent on the presence of Thy1.2+, CD4+, and Ia+ cells, but not CD8+ cells, at the onset of culture.
The utility of 5-hydroxy-2, 3-dihydrophthalazine-1, 4-dione (HDP) as a co-substrate for the chemiluminescent detection of horseradish peroxidase was assessed. Several substituted aryl boronic acid derivatives (4-phenyl, 4-iodo) acted as potent enhancers of the peroxidase catalyzed reaction. Addition of chelating agents (EDTA) and surfactants (Tween-20 and [poly (vinylbenzyl)tributylphosphonium chloride-poly (vinylbenzyl) trioctylphosphonium chloride copolymer]) modulated background light emission and the intensity and duration of the signal from both HDP and luminol. However, HDP was found to be inferior to luminol in the peroxidase assay. Comparative studies revealed that at 500 amol of peroxidase the S/B was ten-fold higher using a commercial luminol-based signal reagent as compared with an HDP-EDTA-Tween-20 reagent (S/B t = 0 min 21.8 vs 1.7, S/B t = 10 min 17.8 vs 2.0).
The homotypic aggregation of neutrophils requires the participation of L-selectin and the beta 2-integrins, but it has not been clear whether the two receptors recognize one another as counter-structures or whether other adhesion molecules are involved. We have examined aggregation of live neutrophils with target populations, manipulated to alter expression of adhesive epitopes, using flow cytometry. A target population depleted of both L-selectin and activatable beta 2-integrin displayed an ability to aggregate with live neutrophils, suggesting that these two molecules are not counter-structures. We also found that an O-sialoglycoprotease (GCP) from Pasteurella haemolytica is capable of inhibiting homotypic aggregation. Neutrophils treated with GCP lose O-glycosylated proteins but retain L-selectin and activatable beta 2-integrin. One or more of the GCP substrates appears to function in L-selectin-dependent binding but not in beta 2-integrin-dependent binding. Together the data suggest a mechanism of aggregation that is analogous to leukocyte-endothelial cell adhesion in which a low-affinity carbohydrate-dependent interaction precedes a high-affinity integrin-dependent adhesion.
OBJECTIVE: To assess the efficacy of the subureteric Teflon injection (STING) procedure in the refluxing duplex ureter. PATIENTS AND METHODS: The STING procedure was performed in 23 patients (five boys and 18 girls, mean age 6.5 years, [range 1.5-14]) with six refluxing upper and 31 refluxing lower moieties. Teflon was injected separately into each moiety of the duplex. All patients were assessed by a micturating cystourethrogram and ultrasonography at least 3 months after treatment and the results were analysed retrospectively for the success rate of each refluxing unit and the overall cure rate of patients. RESULTS: No patient suffered ureteric obstruction. After the first STING the unit cure rate was 57% but only nine of 23 patients were completely cured. This improved to a unit cure rate of 68% and 11 patients cured after a second STING. CONCLUSION: Because the patient cure rate was poor we do not advocate using the STING to treat vesicoureteric reflux in the duplex kidney.
We previously demonstrated that recipient CD4+ cells are necessary for expression of adoptive murine experimental hypersensitivity pneumonitis (EHP). In contrast, the acute inflammatory response to intratracheal (i.t.) administration of Micropolyspora faeni (direct EHP) is not CD4+ cell dependent (Am. J. Respir. Crit. Care Med. 1994;149:1286-1294). To further characterize the cells responsible for development of pulmonary inflammation in recipient animals, we depleted recipients of either Thy1.2+ or CD8+ cells before transfer of M. faeni-sensitized cultured C3H/HeJ spleen cells and i.t. challenge with M. faeni. We used the same depletion technique to determine the contribution of these cells to the pulmonary response to i.t. M. faeni in animals that did not receive cultured cells (direct EHP). The nature and extent of pulmonary inflammatory changes in these animals were assayed either 4 d after i.t. challenge with M. faeni in adoptive EHP or 2 d after i.t. challenge with M. faeni in direct EHP. We also tested the hypothesis that our previously demonstrated ablation of adoptive EHP caused by administration of anti-CD4 antibody was due to depletion of recipient CD4+ cells by allowing recovery of recipient CD4+ cells of anti-CD4-treated animals before i.t. challenge. In addition, we allowed Thy1.2+ cell recovery of anti-Thy1.2-treated animals before i.t. challenge. Cultured M. faeni-sensitized spleen cells could adoptively transfer EHP to animals treated with an irrelevant antibody or PBS. Depletion of Thy1.2+ but not CD8+ cells ablated the ability of recipient animals to express adoptive EHP. Direct EHP was not affected by depletion of Thy1.2+ or CD8+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)