Biomedical subjects
Publications and source records attributed to R M Watson.
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BACKGROUND: Allergen inhalation challenge is a useful clinical model to investigate the effects of asthma therapies on allergen-induced airway responses; however, the repeatability of allergen-induced airway inflammation is not known. OBJECTIVE: The purpose of this study was to investigate the repeatability of allergen-induced increases in sputum eosinophils. This information will allow the prediction of the number of subjects required in studies evaluating asthma therapies. METHODS: Seventeen subjects completed 2 allergen challenges using the same dose of allergen, at least 3 weeks apart. Allergen-induced airway responses were measured for 7 hours after challenge. Differential cell counts from induced sputum were determined the day before and 7 and 24 hours after challenge; methacholine PC20 was measured the day before and 24 hours after challenge. RESULTS: The intraclass correlation coefficient for maximum percent late fall in FEV1 was 0.32 and for the area of the late response was 0.61. The sample size predicted to be necessary to observe 50% attenuation of the maximum percent late fall in FEV1 and the late area under the curve with a power of 0.95 was 9 subjects. The intraclass correlation coefficient for percent of allergen-induced sputum eosinophils was 0.60 at 7 hours and 0.53 at 24 hours after challenge. With a randomized cross-over study design, the sample size predicted to be necessary to observe 50% attenuation of allergen-induced percent of eosinophils with a power of 0.95 was 5 subjects. CONCLUSION: Allergen inhalation challenge with measurements of sputum eosinophils is a noninvasive and reliable method for evaluating the anti-inflammatory effects of asthma therapies.
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Inhalation of prostaglandin E2 (PGE2) had been reported to prevent allergen-induced bronchoconstrictor responses; however, the effects of inhaled PGE2 on allergen-induced airway inflammation or hyperresponsiveness after allergen are unknown. This study examined the effects of inhaled PGE2 on allergen-induced airway responses and inflammation. Eight mild asthmatics with a dual airway response to inhaled allergen were recruited into a double-blind randomized crossover study comparing the effects of inhaled PGE2 (100 microgram) or placebo, on allergen-induced changes in FEV1 measured for 7 h, induced sputum inflammatory cells, obtained at baseline, 7 and 24 h, and methacholine airway responsiveness measured at 24 h after challenge. Inhaled PGE2 attenuated the allergen-induced early fall in FEV1 from 24.4 +/- 3.6% after placebo to 10.3 +/- 2.5% after PGE2 (p = 0.002), the late fall in FEV1 from 21.2 +/- 2.7% after placebo to 12.6 +/- 3.6% after PGE2 (p = 0.03), allergen-induced methacholine airway hyperresponsiveness (p = 0.03) and allergen-induced increases in percent sputum eosinophils from 36.3 +/- 8.8% after placebo to 21.0 +/- 7.3% after PGE2 (p = 0.01), percentage of EG2+ cells (p = 0.02), and percentage of metachromatic cells (p = 0.02). These results indicate that inhaled PGE2 attenuates allergen-induced airway responses, hyperresponsiveness, and inflammation, when given immediately before inhaled allergen.
We have previously shown that allergen inhalation by asthmatics is associated with increases in bone marrow eosinophil/basophil colony-forming cells (Eo/B-CFU), and increases in CD34(+) hemopoietic progenitors expressing the alpha-subunit of the IL-5 receptor (IL-5Ralpha). This study investigated the effect of inhaled corticosteroid on baseline numbers and allergen-induced increases in these parameters. Nine subjects with mild, stable asthma inhaled budesonide (400 microgram/d) for 8 d in a placebo-controlled, double-blind, randomized crossover study. On Day 7, subjects inhaled allergen, with bone marrow sampling before and 24 h after challenge. Budesonide inhalation significantly attenuated the allergen-induced early and late asthmatic responses, degree of increase in sputum and blood eosinophils, as well as the baseline numbers of total bone marrow CD34(+) cells (p < 0.05), CD34(+)IL-3Ralpha+ cells (p < 0.01) and IL-5-responsive Eo/B-CFU (p < 0.05). Allergen inhalation significantly increased Eo/B-CFU grown in the presence of IL-3, GM-CSF, or IL-5 alone (p < 0.05) and in combination (p < 0.01), as well as the number of CD34(+)IL-5Ralpha+ cells (p < 0.01). However, these increases in Eo/B-CFU and CD34(+)IL-5Ralpha+ cells were not affected by budesonide treatment. These data demonstrate that short-term inhaled budesonide treatment has a systemic effect in inhibiting the turnover of a subpopulation of bone-marrow-derived progenitors, but that inhalation of allergen overcomes this inhibitory effect.
Inhaled cysteinyl leukotrienes may cause recruitment of eosinophils into asthmatic airways. We compared the effects of inhaled leukotriene D4 (LTD4), methacholine, and allergen on airway eosinophils in 10 nonsmoking, atopic, mildly asthmatic subjects in a double-blind, diluent-controlled, randomized crossover study. Concentrations of LTD4, methacholine, and allergen resulting in a 30% decrease in FEV1, and diluent controls (ethanol and saline), were inhaled with at least 7 d between challenges. Spirometry was conducted for 4 h after inhalation challenge, and airway hyperresponsiveness (AHR) to methacholine was measured before and 24 h after challenge. Sputum was induced before and 4 h, 7 h, and 24 h after challenge. The maximum decrease in FEV1 was 31.4 +/- 1.8% with LTD4, 39.4 +/- 2.8% with methacholine, and 30.1 +/- 3.4% with allergen. AHR to methacholine, at the provocative concentration causing a 20% decrease in FEV1 (PC20), was enhanced 24 h after allergen challenge, but remained unchanged 24 h after LTD4 and methacholine (p > 0.05). The percentage of eosinophils in sputum was increased after inhalation of allergen at 7 h and 24 h (p = 0.003), but not after LTD4 or methacholine (p = 0.70). We demonstrated that neither inhalation of LTD4 nor of methacholine at concentrations causing submaximal bronchoconstriction increases the number of sputum eosinophils in the airways of mildly asthmatic subjects. However, LTD4 may still be an important cofactor for eosinophil recruitment in asthma.
Airway eosinophilia is the hallmark of asthma exacerbation. Coordination of cytokines such as interleukin (IL)-5, eotaxin and regulated on activation, normal T-cell expressed and secreted (RANTES) seem to be necessary for eosinophil extravasation including adhesion, chemotaxis, and activation. The purpose of this study was to characterize both the kinetics of allergen-induced inflammatory cell recruitment to the airways and cytokines selective for eosinophil chemotaxis, activation, or resolution. Eight atopic asthmatic individuals demonstrating a dual response to inhaled allergen completed a diluent-controlled crossover study. The subjects showed significant allergen-induced early and late airway asthmatic responses (p < 0.001), and an increase in the number of sputum eosinophils and metachromatic cells (p < 0.05). The number of eosinophils immunopositive for IL-5, eotaxin, and RANTES increased 7 h after allergen inhalation (p < 0.05), coincident with the peak number of activated eosinophils. Sputum cells immunopositive for IL-10 decreased significantly following allergen challenge (p = 0. 04), and correlated negatively with sputum eosinophils (r = -0.34, p = 0.02). This study shows that allergen-induced increases in sputum eosinophils are associated with the presence of cytokines specific for the activation and chemotaxis of eosinophils, and suggests that cooperation of eosinophilic cytokines may be important for the accumulation and regulation of activated eosinophils at the site of allergic inflammation.
BACKGROUND: The cysteinyl leukotrienes (cysLTs) have been implicated in the pathogenesis of allergen-induced airway responses. The purpose of this study was to evaluate the effects of pretreatment with the cysLT receptor antagonist pranlukast on allergen-induced early asthmatic responses (EARs) and late asthmatic responses (LARs) and on allergen-induced airway hyperresponsiveness (AHR). METHODS: Ten atopic, nonsmoking patients with mild asthma and previously demonstrated early- and late-phase allergen-induced asthmatic responses participated in a double-blind, placebo-controlled, cross-over study, comparing treatment with either 450 mg pranlukast given twice daily or placebo for 5.5 days. A methacholine challenge was performed before administration of medication, and the result was expressed as the PC20. An allergen inhalation challenge was performed on the morning of the fifth day of treatment 2 hours after administration of medication. Methacholine challenges were also performed 2 hours after medication on days 4 and 6 (24 hours before and 24 hours after allergen administration) to examine allergen-induced AHR. RESULTS: Pranlukast attenuated allergen-induced early responses, late responses, and AHR. The mean (SEM) maximal percent fall in FEV1 from baseline during the early response was 30.0% (5.1%) during placebo treatment and 15.5% (3.5%) during pranlukast treatment (mean difference, 14.5%; 95% confidence interval [CI], 5.3 to 23.7; P = .007), with a mean protection afforded by pranlukast of 48.3%. The mean maximal percent fall in FEV1 during the late response was 34.7% (5.3%) during placebo treatment and 24.0% (4.4%) during pranlukast treatment (mean difference, 10.7%; 95% CI, 4.1 to 17.3; P = .006), with a mean protection afforded by pranlukast of 30.8%. The mean allergen-induced shift in PC20 was -1.76 (0.32) doubling doses during placebo treatment and -0.38 (0.31) doubling doses during pranlukast treatment (mean difference, -1.38 doubling doses; 95% CI, 0.44 to 2.32; P = .012), with a mean protection afforded by pranlukast of 78.4%. CONCLUSION: These results demonstrate that pranlukast can attenuate allergen-induced early and late airways responses and AHR and adds further support for an important role for the cysLTs in mediating allergen-induced asthmatic responses.
BACKGROUND: Measurements of airway responsiveness are frequently used to evaluate anti-asthma drugs. OBJECTIVE: This study investigated the utility of methacholine airway responsiveness measurements in evaluating anti-asthma medications, both in terms of a bronchoprotective effect and the ability to attenuate allergen-induced methacholine airway hyperresponsiveness. METHODS: Methacholine airway responsiveness was measured as PC20 on two occasions (separated by 35+/-17 days, mean +/- SD) in 40 subjects with mild, stable asthma. Additional subjects had PC20 measurements made before and after administration of either inhaled salbutamol (200 microg) (n = 20) or allergen inhalation challenge (n = 31). RESULTS: The reproducibility of the methacholine PC20 with this method was high (intraclass correlation coefficient = 0.94). The average shift in PC20 after salbutamol was 4.11 doubling concentrations (SD = 1.08). On the basis of these results, a sample size of 12 subjects would be required to demonstrate a 1 doubling concentration difference in the bronchoprotective effect of two drugs with a 90% power. The average shift in PC20 after allergen was 1.29 doubling concentrations. On the basis of these results and an estimated SD of 0.96, a sample size of 24 subjects would be required to demonstrate that a drug is effective in attenuating 50% of allergen-induced airway hyperresponsiveness with a 90% power. CONCLUSION: These results confirm the high reproducibility of methacholine PC20 measurements in subjects with mild, stable asthma and demonstrate its utility in evaluating the effects of anti-asthma drugs.
Increases in inflammatory cell progenitors, particularly eosinophil/basophil colony-forming cells (Eo/B-CFU), occur in peripheral blood after allergen provocation. The role of bone marrow (BM) in these reactions is unclear. We examined the effect of allergen challenge on human bone marrow progenitor cell growth. Fifteen asthmatic subjects, eight dual responders (DR) and seven isolated early responders (IER), were challenged with inhaled allergen. BM aspirates were taken before and 24 h after challenge and progenitors were enumerated by a colony-forming assay. Eo/B-CFU numbers increased in both groups after allergen challenge (p < 0.0001). For DR, the increases were significant for BM incubated with optimal GMCSF and IL-5, but not with IL-3. For IER, the increases were significant for all three cytokines tested. At a suboptimal concentration of IL-5, there was a significant increase in the number of Eo/B-CFU after allergen in the DR, from 5.25 +/- 1.2 to 9.68 +/- 2.1 per 2.5 x 10(5) cells plated (p < 0.01), which was not demonstrated in the IER (p = 0.94). The responses at this concentration of IL-5 were different between groups (p < 0.05). These results demonstrate that inhaled allergen increases BM Eo/B-CFU, and that the bone marrow of dual responders is more responsive to IL-5 after allergen.
Higher numbers of eosinophil/basophil colony-forming units (Eo/B CFU) are observed in blood of atopic individuals, and can be enhanced in atopic asthmatics by allergen-inhalation challenge. It is known that mature basophils and eosinophils synthesize cytokines relevant to allergic inflammation. To investigate the potential role of growth factors in allergic disease we examined the expression of the hemopoietic cytokines, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-5, in differentiating Eo/B colony cells from normal and atopic individuals, and from atopic asthmatics before and after allergen-inhalation challenge. Peripheral blood was collected from two normal and 12 atopic individuals, and also from 25 atopic asthmatics before and 24 h after allergen challenge. Nonadherent mononuclear cells were isolated and grown in semisolid growth medium. Eo/B colonies were selected and cytospins were prepared for immunocytochemical analysis of colony cells. Eo/B colonies, especially carbol chromotrope 2R+ cells, selected at Days 10, 14, and 18 from atopic donors contained messenger RNA for GM-CSF by combined in situ reverse transcription-polymerase chain reaction and cytochemistry, and demonstrated time-dependent expression of GM-CSF by immunocytochemistry (P = 0.007). Atopic individuals demonstrated a higher percentage of cells expressing GM-CSF than did normal subjects under all growth conditions when examined at Day 14 (P = 0. 04). Atopic asthmatics challenged with inhaled allergen who demonstrated a dual airway response, an increase in the number of blood eosinophils (P = 0.0001), and an increase in the number of Eo/B CFU (P = 0.02) also demonstrated a significant increase in the percentage of colony cells expressing immunostainable GM-CSF (P = 0. 0009), but only a variable effect on those expressing IL-5, 24 h after allergen. These results suggest that GM-CSF expression by differentiating Eo/Bs may provide an additional stimulus in vivo to enhance Eo/B progenitor differentiation in atopic and asthmatic individuals, especially after allergen challenge. The concept of microenvironmental differentiation, where blood progenitor cells may aid in their own differentiation, is supported by these ex vivo findings.
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OBJECTIVE: To determine whether or not landmarks of the ears and face could be reliably identified using a laser scaning system. DESIGN: A single centre study with two assessors jointly agreeing the siting of the landmarks on the ear on two separate occasions from an original laser scanned image. SETTING: University based research study in London, UK. SUBJECTS: 20 subjects, 11 males, 9 females, aged 16-24 years with normal facial development. MAIN OUTCOME MEASURES: Differences were determined between the locations of landmarks on the two occasions studied. Differences were assessed for the x, y and z co-ordinates of each point. RESULTS: The mean difference between the two sitings of 21 landmarks ranged between 0 and 0.85 mm in the x, y and z axes. With a small number of exceptions, the differences were not statistically significant. The three-dimensional mean differences between the two sitings of each landmark ranged between 1 and 2.5 mm. Coefficients of repeatability ranged between 1.6 and 7.0 mm. CONCLUSIONS: Landmarks of the ears and face from a laser scanned image can be sited consistently by two assessors. Since the landmarks can be located it should be possible to evaluate dimensional measurements of the ear and its position on the face.
BACKGROUND: The cysteinyl leukotrienes (LTC4, LTD4 and LTE4) have been implicated in the pathogenesis of allergen-induced airway responses. The effects of pretreatment with BAYx 1005, an inhibitor of leukotriene biosynthesis via antagonism of 5-lipoxygenase activating protein, on allergen-induced early and late asthmatic responses has been evaluated. METHODS: Eight atopic subjects with mild asthma participated in a two period, double blind, placebo controlled, cross-over trial. Subjects were selected on the basis of a forced expiratory volume in one second (FEV1) of > 70% predicted, a methacholine provocative concentration causing a 20% fall in FEV1 (PC20) of < 32 mg/ ml, a documented allergen-induced early response (EAR, > 15% fall in FEV1 0-1 hour after allergen inhalation) and late response (LAR, > 15% fall in FEV1 3-7 hours after allergen inhalation), and allergen-induced airway hyperresponsiveness (at least a doubling dose reduction in the methacholine PC20 30 hours after allergen inhalation). During the treatment periods subjects received BAYx 1005 (500 mg twice daily) or placebo for 3.5 days; treatment periods were separated by at least two weeks. On the third day of treatment, two hours after administration of medication, subjects performed an allergen inhalation challenge and FEV1 was measured for seven hours. RESULTS: Treatment with BAYx 1005 attenuated the magnitude of both the allergen-induced early and late asthmatic responses. The mean (SE) maximal fall in FEV1 during the EAR was 26.6 (3.3)% during placebo treatment and 11.4 (3.3)% during treatment with BAYx 1005 (mean difference 15.2 (95% confidence interval (CI) 9.4 to 21.00) with a mean protection afforded by BAYx 1005 of 57.1%. The mean (SE) maximal fall in FEV1 during the LAR was 19.8 (5.7)% during placebo treatment and 10.7 (4.4)% during BAYx 1005 treatment (mean difference 9.2 (95% CI 1.4 to 17.0) with a mean protection afforded by BAYx 1005 of 46.0%. The area under the time response curve (AUC0-3) was also reduced after treatment with BAYx 1005 compared with placebo by 86.5%.h (mean difference 26.3 (95% CI 17.1 to 38.5)) and the AUC3-7 by 59.6%.h (mean difference 26.9 (95% CI-3.8 to 57.6)). CONCLUSIONS: These results show that antagonism of 5-lipoxygenase activating protein can attenuate allergen-induced bronchoconstrictor responses and support an important role for the cysteinyl leukotrienes in mediating these asthmatic responses.
Treatment with inhaled beta(2)-agonists immediately before allergen inhalation inhibits allergen-induced early, but not late asthmatic responses (LAR). By contrast, 2 wk treatment with inhaled albuterol increases airway responses to inhaled allergen. We examined the effects of regular albuterol treatment on allergen-induced increases in inflammatory cells in blood and induced sputum. Ten mild, stable allergic asthmatics inhaled albuterol (800 micrograms/day) or placebo for 7 d in a controlled, randomized, double-blind, crossover study. Allergen inhalation was performed 12 h after the final dose. Methacholine airway responsiveness and blood samples were analyzed before and 24 h after, and induced sputum was obtained before, 7 h and 24 h after allergen. Allergen significantly reduced methacholine PC20, increased blood eosinophil numbers, and numbers of sputum neutrophils, EG2 positive and metachromatic cells (p < 0.05), without significant differences between treatments. Albuterol treatment significantly increased the LAR compared to placebo treatment (p = 0.003) and significantly enhanced the number of sputum eosinophils (p = 0.009) and sputum ECP (p = 0.04) at 7 h but not 24 h post-allergen (p > 0.05). We conclude that regular use of inhaled albuterol significantly increases the LAR to inhaled allergen, in association with an increase in the number of sputum eosinophils and the release of ECP, suggesting albuterol increases the late response by increasing eosinophil influx into the airways.
Disability-related outlays are increasing at a rate well above the medical inflation rate. This article discusses the experience of one company in its attempt to manage these skyrocketing costs, by developing a new program that integrates health and related benefits by combining the medical and human resources interventions into a unified program. The authors discuss the initiation, development and progress of the program, concluding with measured results revealing reduced lost work time, improved employee health and productivity, and reduced disability costs.
A variety of removable prostheses is available to restore the dentition which exhibits wear and extensive loss of teeth from the arch. Such treatment may be either interceptive or transitional in order to stabilise the occlusion or definitive as part of rehabilitation. Tooth surface loss may necessitate crowning with the provision of conventional removable partial dentures or decoronation and the use of overdentures. Extensive loading generated by parafunction is often considered to risk the failure of restorations stabilised by implants and so may contra-indicate treatment. Screening out unsuitable cases appears to result in few incidents of implant failure and new designs may further reduce the risk.
Two independently selected groups of 20 patients who were edentulous in te mandible, were followed up on a regular basis over a 5-year period following restoration with a lower implant stabilised prosthesis and conventional upper denture. Significantly more treatment was required by those who received complete mandibular overdentures than those provided with complete fixed mandibular prostheses. In addition to adjustment for the relief of denture trauma to the mucosa, more mechanical problems arose with overdenture implant prostheses.