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Biomedical subjects

K Donaldson

Publications and source records attributed to K Donaldson.

At least 91 records · Page 5Linked to original sources
PubMed1996

A prospective, randomized controlled trial of inpatient versus outpatient continence programs in the treatment of urinary incontinence in the female.

Seventy-four patients presenting with a mixed pattern of urinary symptoms were randomly allocated to undergo either inpatient or outpatient continence programs as initial treatment, without prior urodynamic investigation. Both programs consisted of physiotherapy, bladder retraining, fluid normalization, dietary advice and general support and advice. Nine out of 39 in the outpatient group and 8 out of the 35 of the inpatient group failed to complete the study. There was a significant decrease in frequency, nocturia, number of incontinent episodes and visual analog scores for both groups. In addition the outpatients had a significant reduction in loss on pad testing, and a significantly greater improvement in their visual analog score. In each group 63% were cured or improved to the extent that they did not require further treatment. Staff costs per outpatient were half those for an inpatient. We conclude that outpatient conservative treatment as detailed above is a successful first-line treatment of urinary incontinence in women. It is as successful and possibly better than inpatient treatment, and is significantly cheaper.

Adult↗
PubMed1996

Free radical activity associated with the surface of particles: a unifying factor in determining biological activity?

Using a sensitive phi X174 RF plasmid DNA assay, free radical activity was detected at the surface of normal and ultrafine titanium dioxide (TiO2), environmental particles (PM-10), asbestos and a range of man-made fibres. There were differences in the amount of free radical activity that was detected, with ultrafine TiO2 being much more active than normal-sized TiO2; PM-10 also had substantial free radical activity. Amphibole asbestos samples were highly active, whilst man-made fibres were much less active than asbestos. For all of the particles, the DNA damage could be ameliorated by mannitol, showing that hydroxyl radicals were involved. The ability of particles to generate free radicals at or near their surface, and thereby impose oxidant stress in key target cells, could be central to determining their pathogenicity.

Air Pollutants↗
PubMed1996

Evidence of overload, dissolution and breakage of MMVF10 fibres in the RCC chronic inhalation study.

This paper describes (i) the evidence revealing the biological mechanisms underlying data from inhalation experiments at the Research and Consulting Company (RCC) (HESTERBERG et al. 1993); and (ii) the quantitative evaluation of the kinetic rates of these mechanisms using a mathematical model developed at the Institute of Occupational Medicine (IOM) (TRAN et al. 1994).

Administration, Inhalation↗
PubMed1996

Adverse health effects of PM10 particles: involvement of iron in generation of hydroxyl radical.

OBJECTIVES: Environmental particles < 10 microns average aerodynamic diameter (PM10) are associated with mortality, exacerbation of airways diseases, and decrement in lung function. It is hypothesised that PM10 particles, along with other pathogenic particles, generate free radicals at their surface in reactions involving iron, and that this is a factor in the pathogenicity of PM10 particles. Identification of free radical activity in PM10 and examination of the content and role of iron in this process was undertaken. METHODS: Free radical activity was detected with a supercoiled plasmid, phi X174 RF1 DNA, and measured as scission of the supercoiled DNA (mediated by free radicals) by scanning laser densitometry. The role of the hydroxyl radical was confirmed by the use of the specific scavenger mannitol, and the role of iron investigated with the iron chelator desferrioxamine-B (DSF-B). Iron released from PM10 particles at pH 7.2 and pH 4.6 (to mimic conditions on the lung surface and in macrophage phagolysosomes, respectively) was assessed spectrophotometrically with the Fe++ chelator ferrozine and the Fe+ + + chelator DSF-B. RESULTS: PM10 particles showed significant free radical activity by their ability to degrade supercoiled DNA. A substantial part of this activity was due to the generation of hydroxyl radicals, as shown by partial protection with mannitol. Similarly, DSF-B also conferred protection against the damage caused to plasmid DNA indicating the role of iron in generation of hydroxyl radicals. Negligible Fe++ was released at either pH 7.2 or pH 4.6 by contrast with Fe+ + +, which was released in substantial quantities at both pHs, although twice as much was released at pH 4.6. CONCLUSIONS: PM10 particles generate the hydroxyl radical, a highly deleterious free radical, in aqueous solution. This occurs by an iron dependent process and hydroxyl radicals could play a part in the pathogenicity of PM10 particles. Iron release was greatest at the pH of the lysosome (pH 4.6) indicating that iron may be mobilised inside macrophages after phagocytosis, leading to oxidative stress in the macrophages.

Air Pollutants↗
PubMed1996

Wool and grain dusts stimulate TNF secretion by alveolar macrophages in vitro.

OBJECTIVE: The aim of the study was to investigate the ability of two organic dusts, wool and grain, and their soluble leachates to stimulate secretion of tumour necrosis factor (TNF) by rat alveolar macrophages with special reference to the role of lipopolysaccharide (LPS). METHODS: Rat alveolar macrophages were isolated by bronchoalveolar lavage (BAL) and treated in vitro with whole dust, dust leachates, and a standard LPS preparation. TNF production was measured in supernatants with the L929 cell line bioassay. RESULTS: Both wool and grain dust samples were capable of stimulating TNF release from rat alveolar macrophages in a dose-dependent manner. The standard LPS preparation caused a dose-dependent secretion of TNF. Leachates prepared from the dusts contained LPS and also caused TNF release but leachable LPS could not account for the TNF release and it was clear that non-LPS leachable activity was present in the grain dust and that wool dust particles themselves were capable of causing release of TNF. The role of LPS in wool dust leachates was further investigated by treating peritoneal macrophages from two strains of mice, LPS responders (C3H) and LPS non-responders (C3H/HEJ), with LPS. The non-responder mouse macrophages produced very low concentrations of TNF in response to the wool dust leachates compared with the responders. CONCLUSIONS: LPS and other unidentified leachable substances present on the surface of grain dust, and to a lesser extent on wool dust, are a trigger for TNF release by lung macrophages. Wool dust particles themselves stimulate TNF. TNF release from macrophages could contribute to enhancement of inflammatory responses and symptoms of bronchitis and breathlessness in workers exposed to organic dusts such as wool and grain.

Animals↗
PubMed1996

Binding of Aspergillus fumigatus spores to lung epithelial cells and basement membrane proteins: relevance to the asthmatic lung.

BACKGROUND: Aspergillus fumigatus is an opportunistic pathogen to which asthmatic subjects are particularly susceptible. The ability of spores of A fumigatus to bind to pulmonary cells and basement membrane proteins was investigated to determine the mechanisms involved in this susceptibility. METHODS: Cells of the A549 pulmonary epithelial cell line or purified basement membrane proteins were immobilised on the wells of microtitre plates. They were then exposed to spores of A fumigatus in suspension, with or without various pretreatments of the spores, cells, and proteins. Adherent spores were counted by light microscopy. RESULTS: Spores of A fumigatus bound in a concentration dependent manner to A549 epithelial cells and pretreatment of cells with interferon gamma (2500 units/ml) caused a significant doubling of spore binding. Binding of spores to A549 cells was inhibited by about a third by pre-incubation of the spores with fibrinogen (100 micrograms/ml). Spores bound specifically to extracellular matrix (ECM) components laid down by A549 cells, and pretreatment of the ECM components with hydrogen peroxide (25-80 microM) enhanced spore binding by approximately one third. They also bound specifically and in a saturable manner to purified fibrinogen, fibronectin, laminin, type I collagen, and type IV collagen. Pre-incubation of spores with Arg-Gly-Asp tripeptide (RGD; 50-200 micrograms/ ml) inhibited binding to fibronectin and type I collagen by 50%. CONCLUSIONS: This study suggests that the presence of activated epithelial cells and the exposure of basement membrane that occurs in asthma, together with oxidant stress, may facilitate the colonisation of the asthmatic lung by A fumigatus. The RGD sequence may be involved in spore binding to some ECM proteins. Free fibrinogen may protect against binding of A fumigatus spores to the pulmonary epithelium.

Analysis of Variance↗
PubMed1996

Free radical activity and pro-inflammatory effects of particulate air pollution (PM10) in vivo and in vitro.

BACKGROUND: Epidemiological evidence has implicated fine particulate air pollution, particularly particles less than 10 microns in diameter (PM10), in the development of exacerbations of asthma and chronic obstructive pulmonary disease (COPD) although the mechanism is unknown. The hypothesis that PM10 particles induce oxidant stress, causing inflammation and injury to airway epithelium, was tested. METHODS: The effects of intratracheal instillation of PM10 was assessed in rat lungs (three per group). Inflammatory cell influx was measured by bronchoalveolar lavage (BAL) and air space epithelial permeability was assessed as the total protein in BAL fluid in vivo. The oxidant properties of PM10 particles were determined by their ability to cause damage to plasmid DNA and by changes in reduced (GSH) and oxidised (GSSG) glutathione. The effects of PM10 particles were compared in some experiments with those of fine (CB) and ultrafine (ufCB) carbon black particles. RESULTS: Six hours after intratracheal instillation of PM10 there was an influx of neutrophils (up to 15% of total cells in BAL fluid) into the alveolar space, increased epithelial permeability, the mean (SE) total protein in the BAL fluid increasing from 0.39 (0.01) to 0.62 (0.01) mg/ml, and increased lactate dehydrogenase (LDH) concentrations in the BAL fluid. An even greater inflammatory response was seen following intratracheal instillation of ufCB but not following CB instillation. PM10 particles had free radical activity in vivo, as shown by a decrease in GSH levels in the BAL fluid from 0.36 (0.05) to 0.25 (0.01) nmol/ml following instillation. The free radical activity of PM10 was confirmed in vitro by its ability to deplete supercoiled plasmid DNA, an effect which could be reversed by mannitol, a specific hydroxyl radical scavenger. BAL fluid leucocytes from rats treated with PM10 produced greater amounts of nitric oxide (NO), measured as nitrite (control 3.07 (0.33), treated 4.45 (0.23) microM/1 x 10(6) cells), and tumour necrosis factor alpha (control 21.0 (3.1), treated 179.2 (29.4) units/l x 10(6) cells) in culture than those obtained from control animals. Since the PM10 preparation was contaminated with small amounts of filter fibres due to the extraction process, the effects of instillation of filter fibres alone was assessed. These studies showed that filter fibres did not account for the proinflammatory and injurious effects of the PM10 suspension. CONCLUSIONS: These findings provide evidence that PM10 has free radical activity and causes lung inflammation and epithelial injury. These data support the proposed hypothesis for the mechanism by which particulate air pollution causes adverse effects in patients with airways diseases.

Air Pollutants↗
PubMed1996

Inhibition of the alveolar macrophage oxidative burst by a diffusible component from the surface of the spores of the fungus Aspergillus fumigatus.

BACKGROUND: Aspergillus fumigatus is a fungus that grows on dead and decaying organic matter in the environment and whose spores are present ubiquitously in the air. The fungus causes a range of diseases in the human lung. A study was undertaken to demonstrate and partially characterise an inhibitor of the macrophage respiratory burst from the surface of A fumigatus spores that could be an important factor in allowing the fungus to colonise the lung. METHODS: The spore-derived inhibitor of the respiratory burst of rat alveolar macrophages, as measured by generation of superoxide anion, was demonstrated in Hank's balanced salt solution extracts of four clinical isolates and an environmental isolate of A fumigatus. The time course of the release of the inhibitor into aqueous solution was assessed and the cytotoxic potential of the spore-derived inhibitor towards macrophages was tested using the propidium iodide method. An oxygen electrode was used to confirm the superoxide anion measurements. Molecular weight cutoff filters were used to determine the size of the inhibitor as assessed in the respiratory burst assay and also by its ability to inhibit macrophage spreading on glass. The crude diffusate from the spore surface was fractionated by reversed phase high pressure liquid chromatography (HPLC) and the fractions analysed for inhibitory activity, protein, and carbohydrate content. RESULTS: A small molecular weight (< 10 kD) heat stable toxin was released from the spores of clinical and environmental isolates of A fumigatus within minutes of deposition in aqueous solution. The key effect of the toxin demonstrated here was its ability to inhibit the oxidative burst of macrophages as measured by superoxide anion release. The inhibition was not due to cell death or detectable loss of membrane integrity as measured by permeability to propidium iodide. The toxin was not a scavenger of superoxide anion. Oxygen electrode studies suggested indirectly that the inhibitor acted to inhibit the assembly of the macrophage NADPH-oxidase complex. Fractions of < 10 kD also inhibited the spreading of alveolar macrophages, confirming that the toxin had an additional effect on macrophages that leads to loss of adherence or impairment of cytoskeletal function. In reversed phase HPLC fractions the inhibitory activity eluted with an associated carbohydrate, although the exact chemical nature of the toxin remains to be elucidated. CONCLUSIONS: This spore toxin may, through its ability to diffuse rapidly into lung lining fluid, diminish the macrophage respiratory burst and play a part in allowing A fumigatus to persist in the lung and manifest its well known pathogenic effects. Future research will be focused on further molecular characterisation of the toxin and elaboration of the effect of the toxin on intracellular signalling pathways involved in the activation of alveolar macrophages.

Animals↗
PubMed1996

Mechanisms of cigarette smoke induced increased airspace permeability.

BACKGROUND: Increased epithelial permeability of the airspaces occurs commonly in the lungs of cigarette smokers. It is likely to be important in augmenting the inflammatory response in the airspaces and hence may have a role in the pathogenesis of emphysema. It has previously been shown that intratracheal instillation of cigarette smoke condensate induces increased epithelial permeability in vivo in rats and in vitro in epithelial cell monolayers, associated with a disturbance in the lung antioxidant, glutathione (GSH). The aim of this study was to assess the role of neutrophils, GSH, and tumour necrosis factor (TNF) in the increased epithelial permeability following intratracheal instillation of cigarette smoke condensate. METHODS: Epithelial permeability of the airspaces was measured in rat lungs as the passage of intratracheally instilled 125-iodine labelled bovine serum albumin (BSA) into the blood. The permeability of a monolayer of human type II alveolar epithelial cells to 125I-BSA was also measured. RESULTS: Cigarette smoke condensate produced a 59.7% increase in epithelial permeability over control values peaking six hours after instillation and returning to control values by 24 hours. Depletion of neutrophils and, to a lesser extent, macrophages by an intraperitoneal injection of antineutrophil antibody did not influence the increased epithelial permeability induced by cigarette smoke condensate. Although instillation of human recombinant TNF alpha produced an increase in epithelial permeability in the rat lung from 0.62 (0.61)% to 1.27 (0.08)%, only a trivial amount of TNF alpha was detected in bronchoalveolar lavage (BAL) fluid in vivo or in culture medium from BAL leucocytes obtained from animals treated with cigarette smoke condensate (94.9 (28.8) units/ml). Furthermore, antiTNF antibody did not abolish the increased epithelial permeability produced by cigarette smoke condensate. The role of GSH was assessed by measuring the changes in both the reduced (GSH) and oxidised form (GSSG) in lung tissue and in BAL fluid. One hour after instillation of cigarette smoke condensate there was a marked fall in the GSH content in the lung (from 809.8 (31.8) to 501.7 (40.5) nmol/g) in association with increased GSSG levels (from 89.8 (2.7) to 148.7 (48.8) nmol/g). This was followed by a return of GSH levels to control values, with a concomitant decrease in GSSG levels six hours after instillation. GSH levels in BAL fluid fell dramatically following cigarette smoke condensate (from 2.56 (0.30) to 0.31 (0.21) nmol/ml) and this fall was sustained up to six hours after instillation of cigarette smoke condensate. CONCLUSIONS: These studies suggest that neutrophils and TNF do not have a major role in the increased epithelial permeability induced by cigarette smoke condensate. However, the data support a role for the depletion of the antioxidant glutathione in the increased epithelial permeability caused by cigarette smoke condensate.

Animals↗
PubMed1996

Systemic oxidative stress in asthma, COPD, and smokers.

An imbalance between oxidants and antioxidants is proposed in smokers and in patients with airways diseases. We tested this hypothesis by measuring the Trolox equivalent antioxidant capacity (TEAC) of plasma and the levels of products of lipid peroxidation as indices of overall oxidative stress. The plasma TEAC was markedly reduced (0.66 +/- 0.07 mmol/L; mean +/- SEM; n = 11), with increased levels of lipid peroxidation products, in healthy chronic smokers as compared with healthy nonsmokers (1.31 +/- 0.10 mmol/L, n = 14, p < 0.001), an effect that was exaggerated in those who had smoked 1 h before the study. Plasma TEAC was also low in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (COPD) (0.46 +/- 0.10 mmol/L, n = 20, p < 0.001) or asthma (0.61 +/- 0.05 mmol/L, n = 9, p < 0.01) with increases in plasma lipid peroxidation products. There was a negative correlation between superoxide anion release by stimulated neutrophils and plasma antioxidant capacity (r = -0.73, p < 0.001) in patients with acute exacerbations of COPD. The profound decrease in TEAC was associated with a decreased plasma protein sulfhydryl concentrations in acute exacerbations of COPD but not in smokers or in asthmatic subjects. Therefore smoking, acute exacerbations of COPD, and asthma are associated with a marked oxidant/antioxidant imbalance in the blood, associated with evidence of increased oxidative stress. The decreased antioxidant capacity in plasma may result from different mechanisms in these conditions.

Adult↗
PubMed1996

Inhibition of the transcription factors NF-kappa B and AP-1 underlies loss of cytokine gene expression in rat alveolar macrophages treated with a diffusible product from the spores of Aspergillus fumigatus.

The spores of Aspergillus fumigatus have a survival advantage over other respirable fungal spores in the lung, leading to a number of lung diseases associated with this fungus. We have hypothesized that a component on the spore surface can inhibit the activation of alveolar macrophages, known to play an essential role in immune regulation in the lung. A diffusible product from the spores of A. fumigatus (AfD) inhibited the production of tumor necrosis factor alpha (TNF alpha) protein by alveolar macrophages in an enzyme-linked immunosorbent assay. Using a semiquantitative reverse transcription-polymerase chain reaction, we also demonstrated a potent inhibitory effect of AfD on the production of proinflammatory cytokine transcripts in rat alveolar macrophages. The inhibition occurred at the level of transcription, with AfD inhibiting the synthesis of TNF alpha-and interleukin 6 (IL-6)-specific mRNA transcripts. No effect was seen on the synthesis of interleukin 1 beta (IL-1 beta) cytokine transcripts or on the expression of the housekeeping gene beta-actin. Furthermore, AfD specifically inhibited the activation of nuclear transcription factors NF-kappa B and AP-1, both of which are required for the coordinate upregulation of transcription of the proinflammatory cytokines TNF alpha, IL-1 beta, and IL-6. We conclude that AfD can inhibit normal alveolar macrophage responses by selectively inhibiting the production of key inflammatory cytokines, and that the mechanism of inhibition is primarily at the level of transcriptional activation.

Animals↗
PubMed1996

Nystagmus reduction by horizontal rectus retroplacements.

Seven patients with nystagmus underwent large retroplacements of the four horizontal rectus muscles. Nystagmus was horizontal in all seven patients, but three had a vertical component. The horizontal nystagmus improved in all seven patients. All improved at least one line for distance and from three to five lines for near. Retroplacement of the four horizontal rectus muscles is a safe and effective procedure for the reduction of nystagmus and the improvement of vision, particularly for near vision, producing little or no induced strabismus or limitation of motility.

Adult↗
PubMed1995

Particulate air pollution and acute health effects.

Epidemiological studies have consistently shown an association between particulate air pollution and not only exacerbations of illness in people with respiratory disease but also rises in the numbers of deaths from cardiovascular and respiratory disease among older people. Meta-analyses of these studies indicate that the associations are unlikely to be explained by any confounder, and suggest that they represent cause and effect. We propose that the explanation lies in the nature of the urban particulate cloud, which may contain up to 100000 nanometer-sized particles per mL, in what may be a gravimetric concentration of only 100-200 micrograms/m3 of pollutant. We suggest that such ultra-fine particles are able to provoke alveolar inflammation, with release of mediators capable, in susceptible individuals, of causing exacerbations of lung disease and of increasing blood coagulability, thus also explaining the observed increases in cardiovascular deaths associated with urban pollution episodes. This hypothesis is testable both experimentally and epidemiologically.

Air Pollutants↗
PubMed1995

A novel model for human interstitial lung disease: hapten-driven lung fibrosis in rodents.

A novel model is described of chronic pulmonary fibrosis in rodents. The condition is induced by a single intratracheal instillation of a well-characterized fluorescent haptenic antigen, fluorescein isothiocyanate (FITC), into non-immune animals. This results in an acute inflammatory response involving a granulocytic infiltrate, which disappears over a week and is replaced by a chronic mononuclear infiltrate in which T lymphocytes predominate. Over several months, a chronic patchy fibrosis is accompanied by a sustained mononuclear interstitial infiltrate localized at sites of persistent FITC deposition. Where no FITC is present, the lung tissues are apparently normal. An immune response is mounted, as measured by the appearance of specific anti-FITC serum antibodies. This model has relevance to the pathogenesis of some forms of human interstitial lung disease.

Animals↗
PubMed1995

Cytogenetic and pathogenic effects of long and short amosite asbestos.

This study utilized two samples of amosite asbestos which differ in their length, but not in their diameter and which have been shown previously to have very different abilities to cause pathology in rats exposed by instillation or inhalation. The activity of these amosite samples in causing chromosomal aberrations in Chinese hamster ovary cells in culture was examined, along with the effect of the glutathione (GSH) synthesis-inhibiting agent buthionine sulphoximine. The incidence of chromosomal aberrations in cells treated with the short fibre sample was similar to control levels; the long amosite sample caused significantly more chromosomal aberrations than the short fibre sample. When cells were treated with buthionine sulphoximine to decrease the levels of intracellular glutathione, the incidence of chromosomal aberrations was increased in the control cells, but also on treatment with both short and long amosite, the long sample again being considerably more active than the short. The pathogenicity of the long amosite may result from the ability of the fibres to cause chromosome damage, while the enhancement of this damage caused by decreasing intracellular glutathione suggests that the asbestos fibres may impose an oxidant stress on the cells which contributes to these aberrations.

Animals↗
PubMed1995

Superoxide anion release by alveolar macrophages exposed to respirable industrial fibres: modifying effect of fibre opsonisation.

Phagocyte-derived free radicals are considered to play a role in fibre-related pathology and the components of the lung lining fluid could modify the surface of fibres. Therefore we examined the ability of long amosite asbestos and a range of man-made fibres to stimulate release of superoxide anion from rat alveolar macrophages when they were in their native form (unopsonised) and opsonised by incubation in rat Immunoglobulin G. We also assessed the specific amount of opsonin adsorbed to each fibre type. In the uncoated form all of the fibres produced modest amounts of superoxide release from macrophages. When they were opsonised however there was an effect on stimulation of release of superoxide that was fibre-specific. Both MMVF21 and RCF 1 were dramatically enhanced in their ability to stimulate release and this was related to a high affinity of their surface for IgG. Code 100/475 and SiC were not substantially affected by opsonisation and this was reflected in their low affinity for IgG. Long amosite had low affinity for IgG but showed dramatic enhancement of capacity to stimulate superoxide release. These fibre-specific differences in the effect of a coating of material that is found in the lung lining points out the problems of interpretation of in vitro data and more work on this important area is warranted.

Air Pollutants, Occupational↗