bluuebunny/crossref_metadata_2025 huggingface dataset:
Mizolastine: antihistaminic activity from preclinical data to clinical evaluation
Authors: Simons F.E.R.
Published: March 2003

Mizolastine, a new H1‐receptor antagonist, is highly selective for histamine H1 receptors and has no anticholinergic, antiadrenergic, or antiserotonin activity. It is rapidly absorbed after oral ingestion, with peak plasma concentrations occurring at 1.5 h. The distribution and terminal elimination half‐life values are 2 and 13 h, respectively, in healthy young adult volunteers. Half‐life values are longer in the elderly and in subjects with chronic renal insufficiency; however, the differences are not large enough to be clinically relevant or to necessitate a dose adjustment in these populations.

 Mizolastine produces prompt, sustained, peripheral blockade of histamine H1 receptors in the skin. Suppression of the histamine‐induced wheal and flare begins 40–60 min after ingestion of a 10‐mg dose, peaks at 3–4 h, lasts for at least 24 h, and does not decrease during regular once‐daily dosing. The amount of wheal suppression is comparable to that produced by other leading new H1‐receptor antagonists.

 These pharmacokinetic and pharmacodynamic studies of mizolastine provide its clinical pharmacology ‘signature’. They also provide the scientific rationale for recommending a once‐daily 10‐mg dose and suggest that the efficacy and effectiveness of mizolastine will be widely confirmed in allergic disorders, especially rhinitis and urticaria.
Expression of histidine decarboxylase messenger RNA and histamine N‐methyltransferase messenger RNA in nasal allergy
Authors: HIRATA  , TAKEUCHI  , UKAI  , SAKAKURA
Published: March 2003

Background

Histamine is an important chemical mediator in allergic rhinitis. Histamine is synthesized by l‐histidine, catalysed by
l‐histidine decarboxylase (HDC) and metabolized mainly by histamine N‐methyltransferase (HMT). The patients with allergic rhinitis may have altered histamine metabolism in the nasal tissue.

Objective

The objective was to compare the expression of HDC mRNA and HMT mRNA in nasal mucosa with normal individuals and patients with allergic rhinitis.

Methods

We extracted RNA from scrapings of inferior turbinate mucosa of 11 patients with allergic rhinitis and from 11 normal subjects and from surgically dissected inferior turbinate mucosa of 11 patients. HDC, HMT and β‐actin mRNA were amplified by reverse transcription‐polymerase chain reaction (RT‐PCR).

Results

The mean ± sd of HDC/β‐actin ratios were 0.58 ± 0.28 for the scrapings of normal subjects, 0.93 ± 0.38 for the scrapings of the patients with allergic rhinitis and 1.41 ± 0.26 for the inferior turbinates of the patients with allergic rhinitis. The mean ± sd of HMT/β‐actin ratios were 1.66 ± 0.27 for the scrapings of normal subjects, 0.93 ± 0.20 for the scrapings of the patients with allergic rhinitis and 0.65 ± 0.28 for the inferior turbinates of the patients with allergic rhinitis. The differences among the three groups were statistically significant.

Conclusions

Increased HDC mRNA expression and decreased HMT mRNA expression may be playing some role in the hyperresponsiveness of patients with allergic rhinitis.
Candida albicans mannan‐ and protein‐induced humoral, cellular and cytokine responses in atopic dermatitis patients
Authors: SAVOLAINEN  , KOSONEN  , LINTU  , VIANDER  , PÈNE  , KALIMO  , TERHO  , BOUSQUET
Published: March 2003

Background

The cytokine observed most often in atopic dermatitis (AD) is IL‐4, but a role for IL‐5 and IFN‐γ in the late and delayed phase reactions has been suggested. In AD with head, neck and shoulder distribution, hypersensitivity to saprophytic yeasts is an important pathogenetic factor. The yeast allergens include both the mannan polysaccharides and the proteins. Mannans are major cross‐reacting allergens likely to be involved in the pathogenesis of AD.

Objective

To characterize the humoral, lymphoproliferative and cytokine (IL‐2, 4, 5 and IFN‐γ) responses of peripheral blood mononuclear cells (PBMCs) induced by Candida albicans mannan and protein antigens in AD.

Methods

Fifteen AD patients and seven healthy controls were included. Ficoll‐isolated PBMCs were stimulated by PHA and laboratory‐generated mannan and protein extracts of C. albicans. Lymphocyte proliferation was measured and cytokine production was studied by ELISA. The antigen‐specific IgG and IgE antibodies were analysed by ELISA and nitrocellulose RAST.

Results

In AD mannan (P < 0.005) and protein (P < 0.002), specific IgE levels were higher than in healthy controls. Both mannan and protein‐specific lymphoproliferations (both: P < 0.02) were higher in AD than in healthy controls. Mannan, but not protein, induced long lasting IL‐2 and IL‐4 productions from 24 h lasting up to 66–96 h and IL‐5 and IFN‐γ productions with elevated levels at 66 and 96 h. The mannan‐induced IL‐2 (P = 0.015) and IFN‐γ (P < 0.005) were increased in AD as compared with healthy controls. Significant correlations were seen between the protein‐induced proliferation responses and both serum total IgE (r = 0.59, P < 0.01) and protein‐specific IgE (r = 0.65, P < 0.005). The mannan‐induced IL‐2 responses correlated with the specific IgE (r = 0.62, P < 0.01) and proliferation (r = 0.51, P < 0.02) and S‐IgE level (r = 0.71, P < 0.002). Mannan‐induced IL‐4 and IFN‐γ productions also correlated (r = 0.43, P < 0.05).

Conclusions

C. albicans mannan induced elevated IL‐2 and IFN‐γ responses in AD patients. The correlations of the cytokine responses with mannan‐induced IgE and proliferation responses suggest that C. albicans mannan induced TH1 type cytokine responses are involved in AD.
Effects of ONO‐1078 (pranlukast) on cytokine production in peripheral blood mononuclear cells of patients with bronchial asthma
Authors: Tohda  , Nakahara  , Kubo  , Haraguchi  , Fukuoka  , Nakajima
Published: March 2003

Background

ONO‐1078 (pranlukast) is a leukotriene receptor antagonist developed in Japan. This drug has been shown to be useful in oral treatment of bronchial asthma. The present study was undertaken to assess the effects of this drug on the production of cytokines in the peripheral blood mononuclear cells of patients with asthma under stimulation with specific antigens.

Methods

Peripheral blood mononuclear cells from mite antigen‐positive asthmatic patients (immunoglobulin E RAST score > 3) were incubated for 72 h in the presence of mite antigen (10 μg/mL). The supernatant of the culture was subjected to enzyme‐linked immunosorbent assay (ELISA) to quantify interleukin (IL) ‐4, IL‐3, IL‐5, and granulocyte macrophage‐colony stimulating factor (GM‐CSF). Other peripheral blood mononuclear cells from the same patients were incubated for 72 h in the presence of both mite antigen (10 μg/mL) and ONO‐1078 (0.5, 1, or 10 μg/mL), followed by ELISA of the supernatant to quantify the cytokines.

Results

Production of IL‐4, IL‐5, and GM‐CSF by mononuclear cells under stimulation with mite antigen was markedly suppressed when they were exposed to ONO‐1078 at a concentration of 10 μg/mL.

Conclusion

The results suggest that ONO‐1078 acts directly on peripheral blood mononuclear cells and that blockade of leukotriene receptors on blood mononuclear cells by the cysteinyl‐leukotriene receptor antagonist (LTRA) pranlukast (ONO‐1078) can dose‐dependently inhibit release of immunoreactive TH2‐type cytokines (IL‐3, IL‐4, GM‐CSF, and possibly IL‐5), but not of the TH1‐type cytokine IL‐2, when stimulated by mite allergen in vitro. The data may provide clues to the mechanism by which a number of LTRA including zafirulukast and montelukast can reduce airway, sputum and blood eosinophil counts in clinical asthma. It supports animal studies showing that anti‐IL‐5 antibodies partially block cys‐LT‐induced airway eosinophilia, suggesting that cys‐LTs may cause secondary release of IL‐5 from an unknown cell‐type.

These findings indicate that ONO‐1078 suppresses the production of IL‐4 (a cytokine that affects IgG antibody production), IL‐5, and GM‐CSF (cytokines that affect eosinophil activation) by peripheral blood mononuclear cells under stimulation with specific antigens in patients with bronchial asthma. Because of its anti‐inflammatory effects, ONO‐1078 should be useful in the treatment of bronchial asthma.
Circadian variation of urinary eosinophil protein X in asthmatic and healthy children
Authors: Storm Van'S Gravesande  , Mattes  , Grüntjens  , Kopp  , Seydewitz  , Moseler  , Kuehr
Published: March 2003

Background

It is suggested that urinary eosinophil protein X (EPX) is a noninvasive tool to monitor bronchial inflammation in asthmatic children. However, circadian variation of the number and activation of eosinophils might possibly influence urinary EPX excretion.

Objective

Measurements of urinary EPX (radioimmunoassay) were used to investigate circadian variation of eosinophilic activation and to monitor bronchial inflammation in children with asthma before and after treatment with corticosteroids.

Methods

Urinary EPX excretion (μg/mmol creatinine) was measured in the morning and afternoon in 22 stable asthmatics and in 16 nonatopic, nonasthmatic controls to investigate circadian variation. Additionally, EPX excretion in the afternoon was analysed in 21 children with chronic asthma before and after 6 weeks of treatment with inhaled corticosteroids, and in seven children within 24 h of admission due to an asthma exacerbation and again 3 months after discharge.

Results

EPX excretion in the first morning urine sample of the day compared with the afternoon urine sample was significantly higher both in children with asthma (n = 22; mean ± standard deviation: 179.7 ± 97.3 vs 60.9 ± 40.7 μg/mmol creatinine, P = 0.0001) and in nonatopic nonasthmatic controls (n = 16; 114.5 ± 57.1 vs 53.4 ± 29.0 μg/mmol creatinine, P = 0.0001). EPX excretion decreased significantly after 6 weeks of anti‐inflammatory treatment in the group of children with chronic asthma (n = 21; 124.7 ± 84.6 vs 87.5 ± 61.9 μg/mmol creatinine, P = 0.02) and in the group of children with an acute asthma exacerbation 3 months after discharge (n = 7; 233.2 ± 174.5 vs 75.8 ± 59.5 μg/mmol creatinine, P = 0.02).

Conclusion

This study suggests a circadian variation of EPX excretion in children with asthma and in nonatopic, nonasthmatic controls. Measurement of EPX excretion is helpful monitoring therapy in asthmatic children if circadian variation is considered.
Learning from vascular remodelling
Authors: Martin
Published: March 2003

The positioning of a hollow silicone collar around the carotid artery of a rabbit induces many changes of early atherosclerosis including intimal proliferation of smooth muscle cells. This occurs below an intact endothelium indicating that endothelial damage is not necessary for smooth muscle cell proliferation. The endothelium may in fact produce substances that control processes occurring in the intima. Vascular endothelial growth factor (VEGF) is an angiogenic agent that is produced by cultured vascular smooth muscle cells. The combination of hypoxia and factors such as platelet‐derived growth factor, tumour necrosis factor alpha, basic fibroblast growth factor, and interleukin‐1β lead to synergistic production of VEGF by cultured smooth muscle cells. VEGF receptors are present predominantly on the endothelium and may be an important target for modulating the response to damage, hypoxia and inflammation. Transfection of the gene for VEGF resulted in inhibition or regression of intimal hyperplasia induced by the silicone collar in the rabbit. Studies suggest that the two mediators responsible for this inhibition of smooth muscle cell proliferation are nitric oxide and prostacyclin, which are produced by cultured endothelial cells incubated with VEGF. Thus, VEGF produced by smooth muscle cells in response to hypoxia, damage or inflammation, acts on specific endothelial receptors to produce nitric oxide and prostacyclin, which inhibit smooth muscle cell proliferation. Failure of this process could give rise to intimal hyperplasia. Early clinical studies of VEGF transfection from the outside of human arteries using a biodegradable collar are in progress.
Activation of fibroblasts in collagen lattices by mast cell extract: a model of fibrosis
Authors: Berton  , Levi‐Schaffer  , Emonard  , Garbuzenko  , Gillery  , Maquart
Published: March 2003

Background

Mast cells are resident connective tissue cells able to secrete numerous inflammatory mediators in response to tissue aggression and might be implicated in the fibrotic processes.

Objectives

To study the effects of mast cell products on fibroblast activity in connective tissues.

Methods

Mast cell extract was prepared by sonication of pure mast cell preparations obtained by peritoneal lavage of rats and added to the culture medium of fibroblast‐populated collagen lattices.

Results

Mast cell extract was able to decrease the contraction of the collagen lattices, to stimulate total protein and collagen synthesis, and to increase the expression and activation of gelatinase A/MMP‐2.

Conclusion

These data are consistent with the hypothesis that mast cells in connective tissue may be responsible for fibroblast activation at the early phases of tissue repair and fibrosis.
Window pane condensation and high indoor vapour contribution − markers of an unhealthy indoor climate?
Authors: Emenius  , Korsgaard  , Wickman
Published: March 2003

Objective

The aim of this study was to investigate whether window pane condensation and indoor vapour contribution ≥ 3 g/m3 could be used as indicators of defective air change rate, high indoor humidity and high mite allergen concentration in mattress dust.

Methods

Actual ventilation rate, indoor temperature, air humidity (AIH/RH) and concentrations of mite allergen were measured in 59 houses and compared with received outdoor temperatures and air humidity. Indoor vapour contribution defined as the difference between the indoor and the outdoor vapour concentration was calculated. Sensitivity, specificity, predictive values and accuracy were calculated for window pane condensation and high vapour contribution (≥ 3 g/m3), as indicators of defective ventilation (< 0.5 ACH), high indoor humidity (≥ 7 g/kg and ≥ 45% RH) and high mite allergen concentration in mattress dust (≥ 2 μg/g).

Results

All houses with high humidity and high mite allergen concentrations were positive for the two indicators (high sensitivity), but with a specificity of only 50% so that half of the houses with reported condensation and high vapour contribution turned out to be low pollution houses with adequate high ventilation levels. Both indicators had high negative predictive values and absence of the two indicators almost certainly (97–100%) excluded high indoor pollution with high humidity and high mite concentrations. Overall more than 70% of the dwellings were correctly classified by the two indicators.

Conclusion

Absence of window pane condensation on double‐glazed windows and low indoor vapour contribution (< 3 g/m3) during the winter are true markers of a dwelling without high indoor air humidity and without high mite allergen concentrations in mattress dust in houses in a cold temperate climate with subzero outdoor temperatures. The presence of the two indicators is associated with a 18–45% risk of high humidity and mite allergen concentrations so in this latter group further measurements are needed for correct classification.
Austrian children living on a farm have less hay fever, asthma and allergic sensitization
Authors: Riedler  , Eder  , Oberfeld  , Schreuer
Published: March 2003

Background and objectives

In some studies, the prevalence of hay fever and asthma has been found to be lower in children from rural areas than in children from an urban environment. We hypothesized that living on a farm might be protective against development of allergic sensitization and allergic diseases.

Methods

In a cross‐sectional survey, parents of 2283 children aged 8–10 years from a mostly rural area in Austria answered a standardized questionnaire on allergic diseases and environmental factors. 1137 children performed a skin prick test to seven local allergens.

Results

The prevalence of hay fever (3.1 vs 10.3%, P = 0.0002), asthma (1.1 vs 3.9%, P = 0.017) and a positive skin prick reactivity to at least one of the common local allergens (18.8 vs 32.7%, P = 0.001) was significantly lower in children living on a farm than in children from a non‐farming environment. In a multivariate logistic regression model, adjusting for genetic background, parent education, living and housing conditions and dietary factors did not change the odds ratio for the association of farming and allergic sensitization. Only after including ‘regular contact with livestock and poultry’ into the model did the odds ratio change significantly (cOR 0.48 95% CI 0.30–0.75 to aOR 0.75 95% CI 0.37–1.52) indicating an association between regular contact with farm animals and reduced risk of atopic sensitization.

Conclusion

Possible explanations for the lower prevalence of hay fever, asthma and allergic sensitization in children living on a farm might be the development of immunotolerance or the stimulation of TH1 cells and suppression of TH2 cells by increased exposure of farm children to microbial antigens in the stables or farmhouses.
Selected recombinant Aspergillus fumigatus allergens bind specifically to IgE in ABPA
Authors: Kurup  , Banerjee  , Hemmann  , Greenberger  , Blaser  , Crameri
Published: March 2003

Background

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity lung disease resulting from exposure to Aspergillus fumigatus allergens. Patients with ABPA show elevated Aspergillus‐specific serum IgE, a major criterion used in the diagnosis of the disease. Crude culture filtrate and mycelial antigens have been used widely to demonstrate IgE antibody to Aspergillus in the sera of patients. While these antigens have been useful in the diagnosis of ABPA, occasionally they present inconsistency in their reactivity and lack of specificity. Although in recent years, a number of purified A. fumigatus allergens have been produced by molecular cloning, no attempt was made to evaluate them systematically.

Objective

To evaluate the recombinant proteins from A. fumigatus for their IgE antibody binding, we studied sera from ABPA patients and controls by antigen specific enzyme linked immunosorbent assay (ELISA).

Methods

Recombinant Aspergillus allergens Asp f 1, f 2, f 3, f 4, and f 6 were studied for their specific binding to IgE in the sera of ABPA patients, A. fumigatus skin prick test positive asthmatics, and normal controls from the USA and Switzerland. The sera were blinded and studied by ELISA in two different laboratories.

Results

All the recombinant allergens showed IgE antibody binding with sera from patients with ABPA, whereas only fewer asthmatics and normal sera showed significant binding. The three selected recombinant allergens together reacted with all the ABPA patients studied.

Conclusions

The results demonstrate that Asp f 2, f 4, and f 6 can be used in the serodiagnosis of ABPA, while IgE antibody binding to Asp f 1 and f 3 was not specific.
Effects of once daily dosing with inhaled budesonide on airway hyperresponsiveness and airway inflammation following repeated low‐dose allergen challenge in atopic asthmatics
Authors: Gauvreau  , Sulakvelidze  , Watson  , Inman  , Rerecich  , O'Byrne
Published: March 2003

Background

Repeated low‐dose allergen challenge increases airway hyperresponsiveness and sputum eosinophils in atopic asthmatics. Inhaled corticosteroids attenuate the airway responses to high‐dose allergen challenge, but have not been evaluated against repeated low dose challenge.

Objective

This study evaluates the effects of once daily treatments of two doses of inhaled budesonide on airway responses to repeated low‐dose allergen challenge.

Methods

Eight atopic asthmatics with a dual airway responses to inhaled allergen were recruited into a randomized, double‐blind crossover, placebo‐controlled study. In the mornings of four consecutive days (day 1‐day 4), subjects inhaled budesonide 100 μg, 400 μg, or placebo, 30 min before inhaling a concentration of allergen causing a 5% early fall in FEV1. Airway hyperresponsiveness to methacholine and sputum eosinophils were measured at baseline, on the afternoon of day 2, day 4, and 24 h after the last challenge. There was a 1‐week washout between each of the three treatment periods.

Results

The repeated low‐dose allergen challenge induced increases in the percentage sputum eosinophils from 2.0 ± 0.7% at baseline to 16.6 ± 7.1% on day 4 (P = 0.002), and this effect was reduced by once daily budesonide 100 μg to 5.6 ± 1.8% (P = 0.01) and by once daily budesonide 400 μg to 3.1 ± 0.9% (P = 0.004). Also, the allergen‐induced methacholine airway hyperresponsiveness which occurred by day 4 (P = 0.03) of the repeated low dose challenge was inhibited by budesonide 400 μg (P = 0.017).

Conclusion

Both budesonide 100 μg and 400 μg inhaled once daily significantly reduces allergen‐induced sputum eosinophilia after repeated low dose challenge; however, only the higher dose also attenuates the allergen‐induced airway hyperresponsiveness.
Comparison of the efficacy, safety and quality of life provided by fexofenadine hydrochloride 120 mg, loratadine 10 mg and placebo administered once daily for the treatment of seasonal allergic rhinitis
Authors: Van Cauwenberge  , Juniper  ,   THE STAR STUDY INVESTIGATING GROUP
Published: March 2003

Background

As there have been no previously published studies, this multinational, double‐blind, randomized, placebo‐controlled, parallel group study compared the efficacy, safety and impact on quality of life (QoL) in seasonal allergic rhinitis patients (SAR) of fexofenadine and loratadine (with placebo), when administered once daily.

Methods

Six hundred and eighty‐eight SAR patients were randomized to receive fexofenadine HCl 120 mg, loratadine 10 mg or placebo, once daily for 2 weeks. The key parameters were the change from baseline in: mean 24‐h reflective total symptom scores (TSS); sum of four individual symptom scores, excluding nasal congestion; instantaneous TSS; individual symptom scores including nasal congestion; and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ). Adverse events were recorded.

Results

Mean 24‐h reflective and instantaneous TSS were significantly reduced by both fexofenadine HCl (both P ≤ 0.0001) and loratadine (P ≤ 0.001 and P ≤ 0.005, respectively) compared with placebo (n = 639). Among individual symptom scores, fexofenadine HCl was significantly better than loratadine in improving 24‐h reflective itchy, watery, red eyes, as well as relieving nasal congestion (P ≤ 0.05 for both). Fexofenadine HCl was also significantly better than loratadine (P ≤ 0.03) and placebo (P ≤ 0.005) in improving QoL, and the differences were of a magnitude considered to be clinically relevant. Loratadine had no statistically significant effect on QoL compared with placebo. The incidence of adverse events was low and similar across all treatment groups.

Conclusion

Fexofenadine HCl and loratadine administered once daily are effective and well tolerated in SAR. In this study, fexofenadine HCl was significantly more effective than loratadine in relieving eye symptoms and nasal congestion. Furthermore, fexofenadine was significantly better than loratadine in improving QoL.
Probiotics in the management of atopic eczema
Authors: Isolauri E. , Arvola T. , SÜtas Y. , Moilanen E. , Salminen S.
Published: March 2003

Background

Over the last two decades the incidence of allergic diseases has increased in industrialized countries, and consequently new approaches have to be explored.

Objective

The potential of probiotics to control allergic inflammation at an early age was assessed in a randomized double‐blind placebo‐controlled study.

Methods

A total of 27 infants, mean age 4.6 months, who manifested atopic eczema during exclusive breast‐feeding and who have had no exposure to any infant or substitute formula were weaned to probiotic‐supplemented, Bifidobacterium lactis Bb‐12 or Lactobacillus strain GG (ATCC 53103), extensively hydrolysed whey formulas or to the same formula without probiotics. The extent and severity of atopic eczema, the growth and nutrition of infants, and concentrations of circulating cytokines/chemokines and soluble cell surface adhesion molecules in serum and methyl‐histamine and eosinophilic protein X in urine were determined.

Results

The SCORAD score reflecting the extent and severity of atopic eczema was 16 (7–25) during breast‐feeding, median (interquartile range). After 2 months, a significant improvement in skin condition occurred in patients given probiotic‐supplemented formulas, as compared to the unsupplemented group; χ2 = 12.27, P = 0.002. SCORAD decreased in the Bifidobacterium lactis Bb‐12 group to 0 (0–3.8), and in the Lactobacillus GG group to 1 (0.1–8.7), vs unsupplemented 13.4 (4.5–18.2), median (interquartile range), in parallel with a reduction in the concentration of soluble CD4 in serum and eosinophilic protein X in urine.

Conclusion

The results provide the first clinical demonstration of specific probiotic strains modifying the changes related to allergic inflammation. The data further indicate that probiotics may counteract inflammatory responses beyond the intestinal milieu. The combined effects of these probiotic strains will guide infants through the weaning period, when sensitization to newly encountered antigens is initiated. The probiotic approach may thus offer a new direction in the search for future foods for allergy treatment and prevention strategies.
Is allergen skin test reactivity a predictor of mortality? Findings from a national cohort
Authors: Gergen Peter J. , Turkeltaub Paul C. , Sempos C. T.
Published: March 2003

Background

The importance of atopy on subsequent mortality is controversial. A clearer understanding is important as atopy is increasing worldwide.

Objective

To determine the influence of allergen skin test reactivity on observed mortality of a national cohort.

Methods

Baseline health status and atopic status (allergen skin testing) was measured as part of the second National Health and Nutrition Examination Survey (NHANES II), a representative sample of the US population, during the years 1976–80. Vital status and cause of death were assessed through December 31, 1992 for all examinees 30 years of age or older at baseline (n = 9252) as part of the NHANES II Mortality Study (NH2MS). The analytic sample contained 8179 men and women after excluding missing data. Allergen skin test reactivity was defined as weal ≥ 3 mm to one of eight 1 : 20 (w/v), 50% glycerinated (‘No US Standard of Potency’) allergens licensed by the FDA: house dust, cat, dog, Alternaria, mixed giant/short ragweed, oak, perennial rye grass, and Bermuda grass. Survival analyses were conducted using multivariate adjusted Cox regression models to evaluate the association between atopy and all‐cause, cardiovascular, and cancer mortality.

Results

There was no association between allergen skin test reactivity and all cause mortality: 30–44 years RR = 1.07 (95% CI 0.63–1.84); 45–59 years RR = 1.10 (0.78–1.55); 60–75 years RR = 1.07 (0.91–1.25). Results were unchanged when cancer or heart disease mortality were examined separately. The presence or absence of allergic symptoms, using the flare to define skin test reactivity, eliminating deaths in the first 5 years of follow‐up, or eliminating individuals with pre‐existing conditions did not alter the findings.

Conclusions

Atopy, defined by allergen skin test reactivity, with or without symptoms, is not a predictor of subsequent mortality.
Cytokine expression during allergen‐induced late nasal responses: IL‐4 and IL‐5 mRNA is expressed early (at 6 h) predominantly by eosinophils
Authors: Nouri‐Aria K. T. , O'brien F. , Noble W. , Jabcobson M. R. , Rajakulasingam K. , Durham S. R.
Published: March 2003

The production of TH2‐type cytokines [interleukin‐4 (IL‐4) and IL‐5] and tissue eosinophilia are characteristic features of allergic diseases. It was previously reported that at 24 h after allergen provocation, CD3+ T‐lymphocytes were the principal cell source of IL‐4 and IL‐5 mRNA transcripts in both atopic asthma and rhinitis.

To investigate whether IL‐4 and IL‐5 mRNA are expressed earlier during late nasal responses and if so, which cell(s) are responsible.

Nasal biopsies were obtained at 6 h after nasal allergen challenge and following a control challenge with the allergen diluent. Sections were immunostained for T‐lymphocytes (CD3+, CD4+) and eosinophils (EG2+). In situ hybridization was used to detect the number of cells expressing messenger RNA (mRNA) for IL‐4 and IL‐5.

In patients with allergic rhinitis, eosinophils (EG2+ cells P = 0.006) but not T‐ cells (CD3+ cells) increased in the nasal mucosa at 6 h after allergen challenge. The number of cells expressing IL‐4 mRNA (P = 0.01) and IL‐5 mRNA (P = 0.05) also increased at 6 h. Co‐localization studies showed that 76% of IL‐4 mRNA+ cells and 77% of IL‐5 mRNA+ cells were eosinophils, whereas at this time point, T‐cells and mast cells accounted for ≤5% of mRNA expression; the identity of the remaining 20% of IL‐4 and IL‐5 mRNA+ cells was not determined. By use of immunohistology, cytokine protein expression at 6 h was confirmed for IL‐4 but not for IL‐5. No increases in T‐cells, eosinophils or cytokine expression were detected in non‐atopic subjects.

Eosinophils represent an early source of IL‐4 which may contribute to TH2‐type responses during late nasal responses and ongoing allergic rhinitis.
Identification of vacuolar serine proteinase as a major allergen of Aspergillus fumigatus by immunoblotting and N‐terminal amino acid sequence analysis
Authors: Shen H.‐D. , Lin W.‐L. , Tam M. F. , Chou H. , Wang C.‐W. , Tsai J.‐J. , Wang S.‐R. , Han S.‐H.
Published: March 2003

Aspergillus species are common airborne fungi that have been identified as causative agents of extrinsic bronchial asthma. More than 10 allergens from A. fumigatus have been recently characterized by cDNA cloning.

The objective of this study is to identify A. fumigatus allergens through immunoblot analysis using sera from asthmatic patients.

IgE‐binding components of A. fumigatus and IgE cross‐reactivity among allergens of different prevalent airborne fungal species were analysed by immunoblot and immunoblot inhibition, respectively, using sera from asthmatic patients. The N‐terminal amino acid sequences of major allergens identified were determined by Edman degradation.

Among two batches (70 and 41 sera) of asthmatic sera tested, 19 (27%) and 14 (34%), respectively, have IgE immunoblot reactivity towards components of A. fumigatus. A 34‐kDa protein that reacts with IgE antibodies in 15 (79%) and 11 (79%) of the 19 and 14 positive samples, respectively, may be considered a major allergen of A. fumigatus. The N‐terminal amino acid sequences of the 34 kDa major allergen and the 30.5 and 30 kDa IgE‐binding components of A. fumigatus showed sequence identity to that of the vacuolar serine proteinase from A. fumigatus. The results from immunoblot inhibition show IgE cross‐reactivity among major allergens of A. fumigatus, P. notatum and P. oxalicum.

Results obtained suggest that the 34 kDa major allergen of A. fumigatus may be a vacuolar serine proteinase. There is IgE cross‐reactivity among serine proteinase allergens of A. fumigatus, P. notatum and P. oxalicum.
Asthma, smoking and chronic cough in rural and urban adult communities in The Gambia
Authors: Walraven G. E. L. , Nyan O. A. , Van Der Sande M. A. B. , Banya W. A. S. , Ceesay S. M. , Milligan P. J. M. , McAdam K. P. W. J.
Published: March 2003

Background Asthma is reported to be rare in traditional rural communities, but is thought to be increasing as lifestyles become more urbanized or ‘western’.

Objectives A community‐based survey of non‐communicable diseases was conducted from October 1996 to June 1997, and included comparison of the prevalence of asthma, smoking and chronic cough in rural and urban Gambia.

Methods A cluster sample survey was conducted in a random sample of rural and urban adults (≥ 15 years of age). Subjects were asked about respiratory symptoms using a locally adapted version based on the IULTD questionnaire. Spirometry (basal, methacholine provocation and reversibility with a bronchodilator) and skin prick tests were performed on a randomly selected subsample of all subjects and those who, when interviewed, said they wheezed or had been diagnosed as asthmatic by a doctor.

Results Out of 2166 participants in the urban population, 4.1% reported having had wheezing or whistling in the chest in the previous 12 months, 3.6% reported doctor‐diagnosed asthma, and 0.6% chronic cough. In the rural population with 3223 participants these figures were 3.3%, 0.7% and 1.2%, respectively. Wheeze was more common in women, cough for 3 months of the year was more common in the age‐groups 45+. Those who reported that they currently smoked accounted for 34% in urban and 42% in rural men. Figures were much lower for women (1.5% and 6.0%). Seven out of 574 randomly selected subjects (1.4%) exhibited bronchial hyper‐responsiveness to methacholine challenge. Four of 133 (3.0%) people with self‐reported wheeze and 3/69 (4.3%) participants with doctor‐diagnosed asthma reacted positively on bronchial provocation with methacholine. There was a remarkably high prevalence of positive skin prick tests to aeroallergens: 38% in participants with a history of wheeze and 27% in those without.

Conclusion The prevalence of wheeze (particularly in association with bronchial hyper‐responsiveness) was low in both rural and urban Gambia. This is in contrast to the relatively high prevalence of positive skin prick tests to aeroallergens (in both wheezers and non‐wheezers), questioning the mechanisms of interaction between allergy and asthma and the presence of protective factors against asthma in this West African population. The high smoking rates justify international concern about tobacco marketing in developing societies.
Age, sex, geographical and socio‐economic variations in admissions for anaphylaxis: analysis of four years of English hospital data.
Authors: Sheikh A. , Alves B.
Published: March 2003

Background Although the most severe of the allergic disorders, the epidemiology of anaphylaxis remains poorly described. Hospital admissions for anaphylaxis in England more than doubled during the 1990s.

Objective To provide baseline data for assessing future trends, and to assess whether there is sufficient regional variation in incidence to allow efficient testing of aetiological hypotheses, we sought to identify any age, sex, geographical and socio‐economic variations in hospital inpatient admissions for anaphylaxis.

Methods We studied all emergency admissions for anaphylaxis to English NHS hospitals between 1991 and 1995. Poisson regression modelling was used to calculate rates of anaphylaxis admission per 100 000 emergency admissions by age, sex, deprivation and by residence in urban/rural, North/South and East/West England.

Results Of the 13.5 million emergency inpatient admissions, 2323 patients had a primary diagnosis of anaphylaxis. Poisson regression analyses showed significant age, gender, geographical and socio‐economic variations in emergency admissions for anaphylaxis: adjusted Female rate ratio 1.19 (95% CI 1.09–1.29), South rate ratio 1.35 (95% CI 1.25–1.47), Rural rate ratio 1.35 (95% CI 1.17, 1.59), and Non‐deprived rate ratio 1.32 (95% CI 1.19, 1.46).

Conclusion This study identifies striking national age, sex, geographical and socio‐economic variations in the incidence of inpatient admissions for anaphylaxis in England, affording important opportunities to generate and test aetiological hypotheses. Risk of anaphylaxis admission is considerably increased in females of child‐bearing age and those residing in southern, rural, and affluent areas are independent risk factors for anaphylaxis admission.
Characterization of ‘adult‐type’ mast cells derived from human bone marrow CD34+ cells cultured in the presence of stem cell factor and interleukin‐6. Interleukin‐4 is not required for constitutive expression of CD54, FcεRIα and chymase, and CD13 expression is reduced during differentiation
Authors: Shimizu Y. , Sakai K. , Miura T. , Narita T. , Tsukagoshi H. , Satoh Y. , Ishikawa S. , Morishita Y. , Takai S. , Miyazaki M. , Mori M. , Saito H. , Xia H. , Schwartz L. B.
Published: March 2003

Background In vitro‐derived human mast cells exhibit different properties, depending in part on the source of progenitor cells. Most investigations have used fetal liver, cord blood or peripheral blood. Few have used adult bone marrow.

Objective Human mast cells derived in vitro from the CD34+ progenitors in bone marrow and cord blood that had been cultured with recombinant human stem cell factor (rhSCF) and recombinant human interleukin‐6 (rhIL‐6) were compared.

Methods and results After 12 weeks of culture, nearly all of the cells were mast cells, and nearly all of these had cytoplasmic granules containing both tryptase and chymase (MCTC type), stained metachromatically with acidic toluidine blue, and expressed CD117 on the cell surface. Both tryptase protein and mRNA were detected by two weeks of culture. Chymase mRNA and protein were detected at 4 weeks but not at 2 weeks of culture. By 12 weeks, chymase content per cell, measured by ELISA, was significantly higher (P < 0.05) in human bone marrow‐derived mast cells (HBMMC) (5.6 ± 0.9 pg) than in cord blood‐derived mast cells (CBMC) (2.4 ± 0.9 pg), whereas histamine and tryptase levels were not significantly different. Of the cluster designations tested, CD29, CD49d, CD51 and CD61 were strongly expressed on HBMMC. CD54 and FcεRIα also were expressed constitutively. Approximately half of CD34‐sorted cells at day 0 were CD13+ and this diminished as mast cell maturation occurred. Electron microscopy revealed that 12‐week‐old HBMMC had many secretory granules that contained spherical electron dense cores surrounded by electron lucent space, consistent with previous reports of immature MCTC cells developing in vivo.

Conclusions CD34+ progenitors of human bone marrow are a rich source of mast cell progenitors capable of expressing granule and surface markers of mature mast cells in the presence of rhSCF and rhIL‐6.
Liposome‐entrapped D. pteronyssinus vaccination in mild asthma patients: effect of 1‐year double‐blind, placebo‐controlled trial on inflammation, bronchial hyper‐responsiveness and immediate and late bronchial responses to the allergen
Authors: Alvarez M. J. , Echechipía S. , García B. , Tabar A. I. , Martín S. , Rico P. , Olaguibel J. M.
Published: March 2003

Background Allergen vaccination is effective in mite‐allergic asthma. Liposomes are immunological adjuvants that can act as allergen carriers.

Objective To evaluate the immunological and functional effects of a liposome‐entrapped D. pteronyssinus vaccine on mite monosensitive, mild asthma patients.

Methods A double‐blind, placebo‐controlled trial was conducted on 26 asthma patients who randomly received vaccination or placebo for 1 year. The levels of exposure to Der p 1 allergen were constant during the study. Allergen bronchial challenge was made at the beginning (T0) and after 1 year of treatment (T12). The day before and 24 h after the allergen provocation, patients were challenged with methacholine (Mth) (until FEV1 fell by 40%) and blood and sputum samples were obtained. Dose–response curves to Mth were evaluated in terms of Mth‐PD20 (dose of Mth that induced 20% drop in FEV1), slope (Mth‐DRS) and level of plateau. Blood and sputum eosinophils and serum levels of eosinophil cationic protein (ECP) and intercellular adhesion molecule‐1 (ICAM‐1) were measured.

Results Groups were comparable at the start of the trial. At T12, previous to the allergen challenge, the active group showed higher values of both FEV1 and Mth‐PD20 and lower values of Mth‐DRS. The number of patients presenting a level of plateau increased in the active group (from two to four) and decreased in the placebo group (from two to one). At T12, before the allergen challenge, serum ECP levels increased in the placebo group and blood eosinophils showed a trend towards lower numbers in the active one. The immediate response and the changes in Mth‐DRS values, sputum eosinophils and serum ECP levels following the allergen challenge were attenuated in the active group.

Conclusion Liposome‐entrapped D. Pteronyssinus vaccination: (i)  protects mild asthma patients from the worsening of asthma due to sustained mite exposure; and (ii) reduces the functional and inflammatory changes induced by allergen bronchial provocation.
Blood basophil numbers in chronic ordinary urticaria and healthy controls: diurnal variation, influence of loratadine and prednisolone and relationship to disease activity
Authors: Grattan C. E. H. , Dawn G. , Gibbs S. , Francis D. M.
Published: March 2003

Background The basopenia of chronic urticaria relates to histamine releasing autoantibodies in the serum of patients with autoimmune urticaria. This reduction in circulating basophils may be due to active recruitment into weals. If so, it might be expected that numbers in blood would be reduced when urticaria is active and increased after treatment. The primary aim of this study was to look at diurnal variation of basophil numbers in patients with chronic ordinary urticaria (not physical or vasculitic) in relation to disease activity and the effect of treatment with antihistamines and corticosteroids, and to compare the results with healthy controls. A secondary aim was to compare a standard manual counting method with automated basophil counts and to look at numbers of other circulating leucocytes that might be relevant to urticaria pathogenesis.

Methods Manual basophil counts using a toluidine blue stain and automated 5‐part differentials (Coulter® Gen. S™) were performed at 4‐hourly intervals from 08.00 to 20.00 in 10 healthy controls (six women, age 24 to 63 years) and seven chronic urticaria patients (five women, 24 to 50 years). All chronic urticaria patients had severe daily or almost daily urticaria. Only one of six chronic urticaria sera showed in vitro basophil histamine releasing activity. Counts were performed without treatment, after a week of taking loratadine 10 mg daily and after 3 days of adding prednisolone at 0.6 mg/kg/day (maximum 40 mg). Daily urticarial activity scores (UAS) were derived from weal numbers and itch, maximum 7.

Results There was no significant overall diurnal variation of basophil numbers in healthy controls or chronic urticaria patients. Mean (SE) manually counted basophil were higher in healthy controls than chronic urticaria (43.4/µL (2.1) vs. 4.4 (0.8), P < 0.001). Basophil counts were reduced in healthy controls on steroids (19.2 (1.9), P < 0.001) but increased in chronic urticaria (8.9 (1.9), P < 0.001). Loratadine did not influence them. UAS fell on treatment (3.3 (0.4) baseline, 1.4 (0.5) on loratadine and 0.5 (0.2) on prednisolone with loratadine, P < 0.001). There was a negative linear correlation between basophil numbers and UAS in untreated chronic urticaria patients (P = 0.001, Spearman rank correlation). Manual and automated basophil counts showed poor agreement. Lymphocyte numbers were lower in chronic urticaria than healthy controls. Neutrophils increased whereas lymphocytes and eosinophils decreased in all subjects on prednisolone. They were unaffected by loratadine.

Conclusion The results are consistent with the hypothesis that circulating basophils may be recruited from blood into urticarial weals during disease activity. Automated counts are not suitable for assessing basophil numbers in chronic urticaria. The relevance of reduced lymphocyte numbers in chronic urticaria needs to be explored.
The relationship between exhaled nitric oxide and allergic sensitization in a random sample of school children
Authors: Van Amsterdam J. G. C. , Janssen N. A. H. , De Meer G. , Fischer P. H. , Nierkens S. , Van Loveren H. , Opperhuizen A. , Steerenberg P. A. , Brunekreef B.
Published: March 2003

Background Exhaled nitric oxide (NO) has been proposed as novel a non‐invasive marker of airway inflammation.

Objective The level of exhaled NO was determined in a random sample of school children (7–12 years old) with the aim of investigating the relationship between exhaled NO and sensitization to common allergens.

Results In the 450 children tested by skin prick tests (SPT), the prevalence of sensitization was 29.5% (overall), 21.9% (sensitization to indoor allergens), and 15.0% (sensitization to outdoor allergens). Regression analysis showed that levels of exhaled nitric oxide were closely associated with various measures of sensitization to aeroallergens. Sensitization to indoor allergens was associated with higher levels of exhaled NO (eNO) than sensitization to outdoor allergens when assessed by IgE but not when assessed by SPT. Children with reported wheeze in the past 12 months had much stronger associations between sensitization and eNO than children without wheeze.

Conclusion We conclude that allergic sensitization is strongly associated with increased levels of exhaled NO, especially in children with wheeze.
Fetal exposure to intact immunoglobulin E occurs via the gastrointestinal tract
Authors: Thornton C. A. , Holloway J. A. , Popplewell E. J. , Shute J. K. , Boughton J. , Warner J. O.
Published: March 2003

Background Consideration of the evolutionary significance of IgE might provide insight into the immunological interactions occurring in utero and during early post‐natal life that regulate later atopic disease.

Objective We postulated that the fetal gut is exposed to intact amniotic fluid IgE that might interact with local IgE receptors.

Methods IgE levels in matched maternal blood and amniotic fluid (n = 47) or breast milk (n = 15) collected from pregnant women in the UK (Southampton) and Brazil (Sao Paulo) were studied. Expression of IgE receptors, FcɛRI and FcɛRII (CD23), in fetal gastrointestinal tract (n = 19) and skin (n = 11) was examined immunohistochemically.

Results Human amniotic fluid at 16–18 weeks' gestation contained intact IgE at levels that increased as maternal circulating levels increased (Spearman's ρ = 0.897; P < 0.001). Circulating IgE levels from women in Sao Paulo, Brazil, associated positively not only with term (> 37 weeks' gestation) amniotic fluid (ρ = 0.993; P < 0.001) but also breast milk IgE levels (ρ = 0.785; P = 0.001). Maternal levels of IgE did not change significantly over pregnancy and fetal circulating levels of IgE were very low (< 0.6 IU/mL). Low‐affinity IgE receptors (CD23) were expressed in lymphoid follicles of the fetal gut from 16 weeks of gestation (6/8), but not from 11 to 16 weeks (0/11) or in the skin.

Conclusion Amniotic fluid contains intact IgE that might bind to CD23+ cells within the lymphoid follicles of the fetal gastrointestinal tract. The evolutionary significance of these interactions might be to prepare the immune system for helminthic parasite exposure at birth via IgE‐mediated antigen focusing, or ‘education’ of the developing immune system about the prevailing extrauterine environment. However, at present in societies where helminthosis is not a significant health issue, this pathway may still be operational and associated with the development of atopic disease.
Rifampicin-induced lupus erythematosus
Authors: Patel G. K. , Anstey A. V.
Published: March 2003

Rifampicin has been prescribed throughout the world for over 20 years, yet only four cases of rifampicin-induced lupus erythematosus (LE) have been reported. Rifampicin-induced LE is associated with combination therapy with clarithromycin or ciprofloxacin. These drugs are all metabolized through the cytochrome P450 liver enzyme system and combined usage may lead to higher rifampicin blood levels. Drug-induced LE differs from systemic LE; cutaneous manifestations, although uncommon, are an important clue to the diagnosis. We report a case of rifampicin-induced LE presenting with florid cutaneous features.