Chronic obstructive pulmonary disease in Welsh slate miners.

BACKGROUND: Exposure to respirable crystalline silica (RCS) causes emphysema, airflow limitation and chronic obstructive pulmonary disease (COPD). Slate miners are exposed to slate dust containing RCS but their COPD risk has not previously been studied. AIMS: To study the cumulative effect of mining on lung function and risk of COPD in a cohort of Welsh slate miners and whether these were independent of smoking and pneumoconiosis. METHODS: The study was based on a secondary analysis of Medical Research Council (MRC) survey data. COPD was defined as forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio <0.7. We created multivariable models to assess the association between mining and lung function after adjusting for age and smoking status. We used linear regression models for FEV1 and FVC and logistic regression for COPD. RESULTS: In the original MRC study, 1255 men participated (726 slate miners, 529 unexposed non-miners). COPD was significantly more common in miners (n = 213, 33%) than non-miners (n = 120, 26%), P < 0.05. There was no statistically significant difference in risk of COPD between miners and non-miners when analysis was limited to non-smokers or those without radiographic evidence of pneumoconiosis. After adjustment for smoking, slate mining was associated with a reduction in %predicted FEV1 [ß coefficient = -3.97, 95% confidence interval (CI) -6.65, -1.29] and FVC (ß coefficient = -2.32, 95% CI -4.31, -0.33) and increased risk of COPD (odds ratio: 1.38, 95% CI 1.06, 1.81). CONCLUSIONS: Slate mining may reduce lung function and increase the incidence of COPD independently of smoking and pneumoconiosis.

Immune mechanisms and the impact of the disrupted lung microbiome in chronic bacterial lung infection and bronchiectasis.

Recent studies analysing immunogenetics and immune mechanisms controlling susceptibility to chronic bacterial infection in bronchiectasis implicate dysregulated immunity in conjunction with chronic bacterial infection. Bronchiectasis is a structural pathological end-point with many causes and disease associations. In about half of cases it is termed idiopathic, because it is of unknown aetiology. Bronchiectasis is proposed to result from a 'vicious cycle' of chronic bacterial infection and dysregulated inflammation. Paradoxically, both immune deficiency and excess immunity, either in the form of autoimmunity or excessive inflammatory activation, can predispose to disease. It appears to be a part of the spectrum of inflammatory, autoimmune and atopic conditions that have increased in prevalence through the 20th century, attributed variously to the hygiene hypothesis or the 'missing microbiota'. Immunogenetic studies showing a strong association with human leucocyte antigen (HLA)-Cw*03 and HLA-C group 1 homozygosity and combinational analysis of HLA-C and killer immunoglobulin-like receptors (KIR) genes suggests a shift towards activation of natural killer (NK) cells leading to lung damage. The association with HLA-DR1, DQ5 implicates a role for CD4 T cells, possibly operating through influence on susceptibility to specific pathogens. We hypothesize that disruption of the lung microbial ecosystem, by infection, inflammation and/or antibiotic therapy, creates a disturbed, simplified, microbial community ('disrupted microbiota') with downstream consequences for immune function. These events, acting with excessive NK cell activation, create a highly inflammatory lung environment that, in turn, permits the further establishment and maintenance of chronic infection dominated by microbial pathogens. This review discusses the implication of these concepts for the development of therapeutic interventions.

Agreement between paper and pen visual analogue scales and a wristwatch-based electronic appetite rating system (PRO-Diary©), for continuous monitoring of free-living subjective appetite sensations in 7-10 year old children.

Electronic capture of free-living subjective appetite data can provide a more reliable alternative to traditional pen and paper visual analogue scales (P&P VAS), whilst reducing researcher workload. Consequently, the aim of this study was to explore the agreement between P&P VAS and a wristwatch-based electronic appetite rating system known as the PRO-Diary© technique, for monitoring free-living appetite sensations in 7-10 year old children. On one occasion, using a within-subject design, the 12 children (n=6 boys; n=6 girls) recorded their subjective appetite (hunger, prospective food consumption, and fullness), at two time points before lunch (11:30 and 12:00) and every 60 min thereafter until 21:00. The agreement between the P&P VAS and PRO-Diary© technique was explored using 95% limits of agreement and 95% confidence intervals (95% CI) calculated using the Bland and Altman (1986) technique. For hunger, prospective food consumption and fullness, the 95% limits of agreement were -1±25 mm (95% CI: lower limit -8mm; upper limit +6mm), 0±21 mm (95% CI: lower limit -6mm; upper limit +6mm) and -6±24 mm (95% CI: lower limit -14 mm; upper limit +1mm), respectively. Given the advantages associated with electronic data capture (inexpensive; integrated alarm; data easily downloaded), we conclude that the PRO-Diary© technique is an equivalent method to employ when continuously monitoring free-living appetite sensations in 7-10 year old children, but should not be used interchangeably with P&P VAS.

Agreement between two methods of dietary data collection in female adolescent netball players.

The accuracy of a combined dietary data collection method (self-reported, weighed food diary and 24-h recall technique) in 13 female, adolescent netball players (14-16 years) was explored. The girls were observed for a 12 h period (08:00-20:00), during which food and drink items were available ad libitum throughout the day and for the period between 20:00 and 08:00 the following morning. All items were covertly weighed before and after consumption to calculate observed energy intake. To calculate participant reported energy intake, food and drink items were weighed and recorded in a food diary by the participants, which was then supplemented with information from the 24-h recall the following morning. Agreement between observed and participant reported energy intake was calculated using the Bland and Altman technique. The mean difference between observed and participant reported energy intake was 0.46 MJ d(-1) (change in mean of 4.2%) indicating a slight bias towards over-reporting using the combined dietary data collection method. There was good agreement at the group level with the confidence interval for bias ranging from 0.00 to 0.92 MJ d(-1). The combined dietary data collection method is an effective technique to employ in 14-16-year old, female adolescent netball players when quantifying energy intake.

Energy intake and appetite following netball exercise over 5 days in trained 13-15 year old girls.

Free-living energy intake and subjective appetite were monitored in a group of eleven 13-15-year old trained adolescent netball players. During preliminary visits, a FLEX heart rate calibration and resting metabolic test were conducted. Heart rate data were collected during a netball exercise session and sedentary period and during the waking hours of all study days, to enable exercise-induced and 24-h energy expenditure to be quantified. The girls completed two 5-day treatment weeks, interspersed with a 2-week 'wash out' period. A 47-min bout of netball exercise or an equivalent sedentary period was carried out on day 3 of each treatment week. Energy intake was measured over each 5-day period using a combined self-reported, weighed, food diary and 24-h recall interview technique. Subjective appetite (hunger, prospective food consumption, fullness) and mood were rated by subjects immediately before and after meals each day, and before and after the netball exercise and the sedentary period. Forty eight hour energy intake was significantly higher following the netball exercise compared to the sedentary period. The girls felt significantly more hungry immediately following the netball exercise compared to immediately before. In conclusion, a single intermittent exercise bout alters subsequent appetite and energy intake in trained 13-15-year old girls.

Where next for the design, delivery, and evaluation of community-based physical activity prescription? Emerging lessons from the United Kingdom.

Despite widespread use, community-based physical activity prescription is controversial. Data limitations have resulted in a lack of clarity about what works, under what circumstances, and for whom, reflected in conservative policy recommendations. In this commentary we challenge a predominantly negative discourse, using contemporary research to highlight promising findings and "lessons learnt" for design, delivery, and evaluation. In doing so, we argue for the importance of a more nuanced approach to future commissioning and evaluation. Novelty: Amalgamating learning from multiple research teams to create recommendations for advancing physical activity prescription.

T cell immunity to Zika virus targets immunodominant epitopes that show cross-reactivity with other Flaviviruses.

Zika virus (ZIKV) Infection has several outcomes from asymptomatic exposure to rash, conjunctivitis, Guillain-Barré syndrome or congenital Zika syndrome. Analysis of ZIKV immunity is confounded by the fact that several related Flaviviruses infect humans, including Dengue virus 1-4, West Nile virus and Yellow Fever virus. HLA class II restricted T cell cross-reactivity between ZIKV and other Flaviviruses infection(s) or vaccination may contribute to protection or to enhanced immunopathology. We mapped immunodominant, HLA class II restricted, CD4 epitopes from ZIKV Envelope (Env), and Non-structural (NS) NS1, NS3 and NS5 antigens in HLA class II transgenic mice. In several cases, ZIKV primed CD4 cells responded to homologous sequences from other viruses, including DENV1-4, WNV or YFV. However, cross-reactive responses could confer immune deviation - the response to the Env DENV4 p1 epitope in HLA-DR1 resulted in IL-17A immunity, often associated with exacerbated immunopathogenesis. This conservation of recognition across Flaviviruses, may encompass protective and/or pathogenic components and poses challenges to characterization of ZIKV protective immunity.

Orthographic analogies and developmental dyslexia.

Goswami (1986, 1988) has demonstrated that children can use orthographic analogies (particularly at the onset-rime level) between the spelling patterns in words to help to decode new words (e.g. using 'beak' to read 'peak'). This strategy has been shown in children as young as six years old. Since it is known that children with developmental dyslexia find it particularly difficult to read words that they have not been specifically taught (Lovett, Warren-Chaplin, Ransby & Borden, 1990), the present study investigated whether dyslexic children might be unable to use analogies. Employing a design similar to that used by Goswami (1988), it was hypothesized that dyslexics would find it difficult to transfer spontaneously knowledge of a 'clue' word to decode new words that could be read by analogy with the clue word. The results of Expt 1 indicated that the dyslexic readers read significantly fewer of the analogous words than a reading age-matched comparison group of younger children. Furthermore, none of the nine dyslexic children read as many of the analogous words as the lowest scoring control child. In a second experiment, a design similar to that of Muter, Snowling & Taylor (1994) was used with a new and larger sample of dyslexic children. In this experiment, all the children were brought to criterion in reading the clue words before the analogous words were presented. Once again, the dyslexic children read significantly fewer words that were analogous with the clue words than did a reading age-matched comparison group. The number of analogous words that the dyslexic children read was significantly correlated with their performance on a test that is sensitive to the ability to detect rhyme. It is argued that a failure to make analogies may be one of the main causes of the reading impairment experienced by children with developmental dyslexia.

Individualizing the Good Behavior Game across type and frequency of behavior with emotionally disturbed adolescents.

The effects of the Good Behavior Game (GBG) individualized across type and frequency of behavior were examined in three classes of severely behaviorally disordered students using a reversal design. The findings showed that the individualized GBG was effective in simultaneously decreasing a variety of inappropriate behaviors exhibited by the three classes, including inappropriate verbalizations, touching, negative comments, cursing, and drumming. Teacher and student satisfaction data indicated that both groups had positive reactions to the individualized GBG. Reasons for the success of the technique are discussed.

The evolution of proteinase substrates with special reference to dipeptidylpeptidase IV.

The design and development of specific substrates for proteolytic enzymes is reviewed. Particular attention is given to substrates containing the leaving groups 4-methoxy-2-naphthylamide (MNA) and 7-amino-4-trifluoromethylcoumarin (AFC). The MNA substrates are used for histochemical and cytochemical purposes, and they yield a coloured final reaction product when azo-coupled with a diazonium salt, an osmiophilic product for electron microscopy when coupled with hexazotized Pararosaniline, or a fluorescent final reaction product when coupled with 5-nitrosalicylaldehyde. AFC substrates are considerably more sensitive, and they yield the fluorescent product AFC after enzymatic cleavage of the substrate. AFC is not sufficiently water-insoluble to allow (intra)cellular localization, but AFC substrates are successfully used for incubations in microwells (Immu-Probe technique) and for the demonstration of banding patterns after gel electrophoresis (enzyme-directed overlay membrane technique). The methods are discussed with the example of the elucidation of the role of dipeptidylpeptidase IV in autoimmune diseases.

Airways hyper-responsiveness to bradykinin and methacholine: effects of inhaled fluticasone.

BACKGROUND: Although inhaled corticosteroids are the most effective anti-inflammatory agents available for the treatment of asthma, they have, at best, only modest effects on airways responsiveness to methacholine. Thus, hyper-responsiveness to methacholine is a relatively insensitive monitor of the effectiveness of glucocorticoids in asthmatic subjects. OBJECTIVE: The study aimed to determine if airways hyper-responsiveness to bradykinin provides a more sensitive index of glucocorticoid responsiveness in asthmatic subjects than does hyper-responsiveness to methacholine. METHODS: A double-blind, placebo-controlled, parallel group study comparing the effects of inhaled fluticasone (220 micro g twice daily) on responsiveness to the two stimuli in asthmatic subjects who had never previously received corticosteroid therapy. Drug (n = 13) or placebo (n = 12) were administered for 16 weeks. Responsiveness to bradykinin and methacholine was determined at baseline and at 4 week intervals. RESULTS: Placebo did not alter responsiveness to either stimulus compared to baseline. Fluticasone treatment significantly reduced responsiveness to bradykinin (P < 0.001 by Friedman anova) and methacholine (P = 0.02), but changes in responsiveness to bradykinin were significantly greater than those in methacholine responsiveness (P = 0.002). Bradykinin responsiveness was decreased at all treatment times compared to baseline, while methacholine responsiveness was not decreased until 8 weeks of therapy. When data were analyzed as changes from baseline (DeltaLog PD20), DeltaLog PD20 for methacholine was not different at any time-point between the two treatment groups. By contrast, DeltaLog PD20 for bradykinin was significantly greater in patients receiving fluticasone compared to those on placebo at all but the 16-week treatment time. Ten of 13 subjects receiving fluticasone failed, on at least one post-treatment visit, to show a 20% fall in forced expiratory volume (FEV1), even at the highest dose of bradykinin. CONCLUSIONS: Airways responsiveness to bradykinin is more profoundly, and more rapidly, reduced by inhaled glucocorticoids than is responsiveness to methacholine. Airways hyper-responsiveness to bradykinin provides a convenient and sensitive monitor of glucocorticoid responsiveness in asthma.

Airway neural responses to kinins: tachyphylaxis and role of receptor subtypes.

To further define the role of neural responses in the hyperreactivity of inflamed human upper airways to bradykinin (BK), we determined if repeated challenges with BK led to tachyphylaxis of neurally mediated responses in subjects with perennial allergic rhinitis. We also tested the hypothesis that enhanced reactivity to kinins in inflamed airways was caused by induction of B1-kinin receptors by comparing the effects of the selective B1-receptor agonist, des-Arg10-lysylbradykinin, and the B2 receptor agonist, BK, in the lower airways of asthmatics and in the upper airways of subjects with perennial allergic rhinitis. Repeated BK challenges led to tachyphylaxis of sneezing and of neurally mediated serous glandular secretion in subjects with perennial allergic rhinitis. Surprisingly, tachyphylaxis of increased local vascular permeability was also observed. By contrast, repeated challenges with BK in normal subjects led to reproducible increases in vascular permeability. Provocation with des-Arg10-lysylbradykinin did not cause bronchoconstriction in asthmatic subjects or increase glandular secretion or vascular permeability in the upper airways of subjects with rhinitis. We conclude that increased reactivity to kinins in inflamed human airways is mediated, at least in part, by neural reflexes, and is not caused by induction of B1-receptors.

Pharmacology of nasal provocation with bradykinin: studies of tachyphylaxis, cyclooxygenase inhibition, alpha-adrenergic stimulation, and receptor subtype.

We have evaluated mechanisms by which nasal provocation with bradykinin may induce symptoms of rhinitis. Repeated nasal challenges with 100 micrograms of bradykinin led to reproducible increases in symptoms and in vascular permeability. Premedication with aspirin did not alter bradykinin-induced responses. Topical application of the alpha-adrenergic agonist oxymetazoline significantly reduced bradykinin-induced subjective nasal congestion scores, but did not lead to a significant decrease in total symptoms or in vascular permeability. Finally, the B1 kinin receptor agonist des-Arg9-bradykinin (1 mg) was totally ineffective in inducing symptoms or increasing vascular permeability. Thus, nasal provocation with bradykinin leads to induction of symptoms and increased vascular permeability, presumably via stimulation of B2 kinin receptors, and is not dependent on prostanoid generation.

A competitive kinin receptor antagonist, [DArg0, Hyp3, DPhe7]-bradykinin, does not affect the response to nasal provocation with bradykinin.

1. In two double-blind, placebo controlled studies, we tested the effects of intranasal administration of 500 micrograms of a competitive kinin receptor antagonist, [DArg0, Hyp3, DPhe7]-bradykinin (NPC 567), on the response to nasal provocation with 20 micrograms of bradykinin. Nasal lavage was performed before and after provocation, and subjects recorded symptom scores. Lavages were assayed for albumin and TAME-esterase activity (indicators of vascular permeability). 2. In our initial study, 12 subjects received NPC 567 or placebo 5 min before bradykinin. After placebo, bradykinin challenge resulted in values (mean +/- s.e. mean) for albumin, TAME-esterase activity and total symptom scores of 275 +/- 51 micrograms ml-1, 32.1 +/- 7.2 counts min-1 x 10(-3), and 1.8 +/- 0.5, respectively. After NPC 567, bradykinin challenge resulted in values of 317 +/- 99 micrograms ml-1, 31.4 +/- 6.9 counts min-1 x 10(-3), and 2.6 +/- 0.4 for these parameters. No significant difference was observed between placebo and drug treatment for any parameter. 3. To evaluate if the lack of drug effect was due to its enzymatic degradation prior to bradykinin administration, a second study was performed in which NPC 567 was coadministered with bradykinin (n = 8). After placebo-bradykinin challenge, values of 168 +/- 42 micrograms ml-1, 11.3 +/- 4.0 counts min-1 x 10(-3), and 2.8 +/- 0.6 were recorded for albumin, TAME-esterase activity, and symptom scores, respectively, while following NPC 567-bradykinin challenge, these values were 174 +/- 51 micrograms ml-1, 12.3 +/- 4.1 counts min-1 x 10(-3), and 3.1 +/- 0.7.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of intranasal administration of endothelin-1 to allergic and nonallergic individuals.

Endothelin-1 (ET-1), a 21 amino acid peptide, and its receptors are distributed in the mammalian respiratory tract. To examine the responses of human upper airways to ET-1, we investigated the effects of intranasal administration of ET-1 to nine symptomatic allergic and nine nonallergic volunteers. Paper discs were used to administer ET-1 or diluent to one side of the nasal mucosa, and to collect secretions from the ipsilateral (challenged) and contralateral (opposite) nostrils. ET-1 (0.3-10 micrograms), but not diluent, induced dose-dependent bilateral increases in secretion weights, lysozyme secretion, symptoms of rhinorrhea and itch, and sneezing in both populations. ET-1 did not induce albumin secretion, histamine release, or symptoms of nasal congestion. Compared with the nonallergic subjects, allergic individuals sneezed more and had significantly higher bilateral secretion weights, contralateral lysozyme secretion, and symptoms of rhinorrhea following ET-1 provocation. In summary, ET-1 induced symptoms relevant to inflammatory upper airway diseases in allergic and nonallergic subjects. However, responses of allergic subjects were more pronounced, particularly with respect to symptoms associated with neural reflex responses, such as sneezing and contralateral secretion. Therefore, allergic inflammation enhances responsiveness of the nasal mucosa to ET-1.

Intranasal salmeterol inhibits allergen-induced vascular permeability but not mast cell activation or cellular infiltration.

BACKGROUND: Salmeterol is a long-acting beta2-adrenergic agonist that is widely used in the treatment of asthma. It has been suggested that non-bronchodilator actions of salmeterol may contribute to its efficacy. OBJECTIVE: To further evaluate the potential non-bronchodilator actions of salmeterol in vivo, using a model of nasal challenge with allergen. METHODS: Twelve asymptomatic subjects with seasonal allergic rhinitis participated in a randomized, double-blind, placebo-controlled crossover trial of the effects of a single dose of 100 microg of salmeterol on the response to allergen challenge. Sneezing and symptom scores, and levels of histamine and albumin in nasal lavages, were measured throughout the protocol. Concentrations of tryptase, prostaglandin D2 and lysozyme were measured during the acute allergic response, while levels of IL-3, IL-5 and IL-8 were measured at later time points. Numbers of eosinophils and of total white blood cells were also recorded. RESULTS: Salmeterol did not affect sneezing or symptom scores at any point. During the immediate response to allergen challenge, mast cell activation, reflected by concentrations of histamine, tryptase and prostaglandin D2, and serous glandular secretion, assessed by measurements of lysozyme, were unaffected by salmeterol treatment but vascular permeability, reflected by concentrations of albumin in nasal lavages, was significantly reduced. At later time points, salmeterol had no effect on levels of histamine or albumin and did not affect cellular infiltration. Concentrations of IL-3, IL-5 and IL-8 were not increased by allergen challenge in these subjects, so the effects of salmeterol could not be evaluated. CONCLUSIONS: Treatment with a single dose of salmeterol had no effect on activation of mast cells or cellular infiltration but inhibited vascular permeability. The ability of salmeterol to inhibit antigen-induced vascular permeability may contribute to its therapeutic efficacy in asthma.

Bradykinin effects in guinea pig tracheal epithelial cells are mediated through a B2 kinin receptor and can be inhibited by the selective antagonist Hoe 140.

Attempts to evaluate the role of kinins in airway inflammation in humans using the bradykinin receptor antagonist [DArg0-Hyp3-DPhe7]-bradykinin (NPC 567) were unsuccessful, possibly because of the low potency and poor stability of this compound. Recently, [DArg0-Hyp3-Thi5-DTic7-Oic8]-bradykinin (Hoe 140), a novel antagonist that seems to overcome these weaknesses, has been developed. The present study was performed to compare the potency and efficacy of Hoe 140 to those of NPC 567 and another antagonist, [DArg0-Hyp3-DPhe7-Ile8]-bradykinin (B7418), on kinin receptors on guinea pig tracheal epithelial cells. Radioligand binding studies showed the presence of two types of B2 kinin receptors on guinea pig tracheal epithelial cells: a high-affinity site with a Kd of 0.44 nM and Bmax of 12.1 fmol/10(6) cells (4000 sites/cell), and a lower affinity site with a Kd of 10 nM and Bmax of 16 fmol/10(6) cells (9600 sites/cell). Bradykinin-induced prostaglandin E2 production seemed to be associated primarily with the lower affinity site. All three B2 receptor antagonists displaced labeled bradykinin from both classes of binding sites and inhibited bradykinin-induced prostaglandin E2 production, but Hoe 140 was up to 40-fold more potent than NPC 567 and showed an affinity comparable to that of bradykinin for both binding sites. This higher potency of Hoe 140, and its stability against peptidases, suggests that this compound will be useful in evaluating the role of bradykinin in inflammatory diseases of the airways.

Nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat.

Kinins are generated in nasal secretions during allergic reactions and during induced rhinovirus colds. To determine if kinins may contribute to the symptomatology of these inflammatory reactions, 8 subjects were challenged with increasing doses of bradykinin or with placebo. Levels of albumin, histamine, and N-alpha-tosyl-L-arginine methyl ester (TAME)-esterase were measured in nasal lavages, and symptom scores were noted. No symptoms or increases in mediators or protein were observed after placebo challenge. Symptom scores increased in a dose-dependent manner, however, in response to bradykinin challenge. Increased symptoms were associated with significant increases in albumin and TAME-esterase activity, but no increases in histamine were observed. Nasal conductance measurements confirmed that bradykinin induces dose-dependent unilateral obstruction in the challenged nostril. Other common symptoms were rhinorrhea and, of particular relevance to rhinovirus infections, a persistent sore throat. We conclude that bradykinin causes increased vascular permeability and rhinitis, which are independent of mast cell mediator release. Kinins may, therefore, contribute to the symptomatology of inflammatory reactions of the upper airways, including the common cold.

Tryptase and histamine as markers to evaluate mast cell activation during the responses to nasal challenge with allergen, cold, dry air, and hyperosmolar solutions.

We have used assays for histamine and for the specific mast cell enzyme, tryptase, to examine the response of the nasal mucosa to provocation with several different stimuli and to evaluate the reliability of histamine as a marker of mast cell activation. High levels of histamine detected in baseline lavages of some subjects are not associated with any detectable tryptase, suggesting they are not mast cell derived. During pronounced immediate allergic responses, however, mast cell degranulation clearly occurs, and a striking correlation between histamine and tryptase is observed. This correlation is weaker when a more modest allergic response is induced, possibly reflecting differential diffusion of the two mediators across the epithelium. Provocation of susceptible individuals with cold, dry air leads to increased recoveries of both histamine and tryptase, confirming that mast cell degranulation occurs during this reaction. Although hyperosmolarity of the nasal mucosa may contribute to mast cell degranulation induced by cold, dry air, a brief exposure of the nasal cavity to hyperosmolar mannitol was not associated with measurable production of tryptase. The combined use of histamine and tryptase measurements can therefore provide useful evidence regarding the role of mast cell activation in the pathogenesis of inflammatory responses.