bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutation screening of interferon regulatory factor 1 gene (IRF‐1) as a candidate gene for atopy/asthma
Authors: Noguchi E. , Shibasaki M. , Arinami T. , Yamakawa‐Kobayashi K. , Yokouchi Y. , Takeda K. , Matsui A. , Hamaguchi H.
Published: March 2003

Background

IL‐4 gene cluster on chromosome 5 contains several candidate genes for atopy and asthma. Several independent studies have shown evidence for linkage between the markers flanking IL‐4 gene cluster and asthma and/or asthma‐related traits. Interferon regulatory factor 1 (IRF‐1) is located approximately 300 kb telomeric to IL‐4 and recent study reveals that IRF‐1 deficiency results in an elevated production of Th2‐related cytokines and a compensatory decrease in the expression of native cell‐ and Th1‐related cytokines.

Objective

To determine if there are any mutations associated with the development of atopy and asthma present in the coding exons and 5′ flanking region of the IRF‐1 gene.

Methods and results

We have screened the promoter and coding regions of the IRF‐1 gene in atopic asthmatics and controls by SSCP method. We found three novel nuclear variants (the −300G/T and 4396 A/G polymorphisms and the 6355G > A rare variant) in the IRF‐1 gene. No variants causing amino acid alterations of IRF‐1 were detected. The −300G/T polymorphism was in nearly complete linkage disequilibrium with the 4396 A/G polymorphism. An association between the 4396 A > G polymorphism and atopy/asthma was examined by transmission disequilibrium test in 81 asthmatic families. Either of 4396 A or 4396G alleles was not significantly preferentially transmitted to atopy‐ or asthma‐affected children.

Conclusion

The IRF‐1 gene is less likely to play a substantial role in the development of atopy and asthma in the Japanese population.
Natural rubber latex allergy in children: a follow‐up study
Authors: Ylitalo L. , Alenius H. , Turjanmaa K. , Palosuo T. , Reunala T.
Published: March 2003

Background

Natural rubber latex (NRL) allergy occurs frequently in children with spina bifida and other children with disorders requiring multiple operations. Also atopic children who have not undergone surgery can be sensitized to NRL, but the outcome of these children has not been studied.

Objective

To study how NRL‐allergic children manage at home and whether their skin prick test (SPT) reactivity, latex RAST or IgE antibody levels to NRL allergens change during the follow‐up.

Methods

Twenty‐four NRL‐allergic children who had not undergone surgery and eight children with histories of multiple operations were followed up for a mean of 2.8 years. Clinical symptoms were recorded and all children were re‐examined with SPT, latex RAST and ELISA for IgE antibodies to prohevein (Hev b 6.01), hevein (Hev b 6.02) and rubber elongation factor (REF, Hev b 1).

Results

Nineteen of the 24 NRL‐allergic children (79%) who had not undergone surgery had occasionally contacts to balloons and other NRL products at home, and 10 of them experienced symptoms ranging from contact urticaria to systemic reactions. Three of the eight NRL‐allergic children with a history of multiple operations had contacts to rubber balloons without any symptoms, and five children underwent 1–8 uneventful operations in a latex‐free environment. SPT reactivity to NRL allergens, latex‐RAST or IgE antibody levels to prohevein or hevein did not change in either group of NRL‐allergic children during the follow‐up.

Conclusions

Occurrence of clinical symptoms and no decrease in SPT reactivity or IgE levels to NRL allergens in the course of the present follow‐up study imply that more attention should be paid to the protection of NRL‐allergic children from rubber contacts in the home environment.
Combined effects of aerobiological pollutants, chemical pollutants and meteorological conditions on asthma admissions and A & E attendances in Derbyshire UK, 1993–96.
Authors: Lewis S. A. , Corden J. M. , Forster G. E. , Newlands M.
Published: March 2003

Background

The effect of outdoor aeroallergen exposure in asthma may be enhanced by air pollutants, including ozone, nitrogen dioxide and particulates, and by certain weather conditions. It is not yet established whether these interactions are important in determining asthma morbidity at the population level.

Objective

We have investigated the joint effects of aeroallergens, rainfall, thunderstorms and outdoor air pollutants on daily asthma admissions and Accident and Emergency (A & E) attendance using routinely collected data between 1993 and 1996 from Derby in central England.

Methods

Daily counts during the aeroallergen season of grass and birch pollen, basidiospores, Didymella, Alternaria and Cladosporium, maximum 1 hour ozone and nitrogen dioxide and daily average black smoke measurements, all made in the vicinity of the city centre, were categorized in tertiles. Rainfall was classified as dry, light (≤ 2 mm) or heavy (> 2 mm). The modifying effect of outdoor pollutant levels, and rainfall or the occurrence of a thunderstorm, upon the effects of individual aeroallergens on asthma admissions and A & E attendance were investigated by fitting appropriate interactions in log linear autoregression models with adjustment for potential confounders.

Results

We found a significant interaction between the effects of grass pollen and weather conditions upon A & E attendance, such that the increase with grass pollen count was most marked on days of light rainfall (adjusted rate ratio for ≥ 50 vs < 10 grains/m3 at lag 2 days = 2.1, 95% CI 1.4, 3.3). Asthma admissions increased with Cladosporium count. We found no statistically significant interactions between effects of any individual aeroallergen and outdoor air pollutant upon either measure of asthma morbidity.

Conclusions

Rainfall and thunderstorms are important effect modifiers in the relation between grass pollen and measures of acute asthma morbidity. Interactions between ambient levels of aeroallergens and chemical pollutants in the Derby area do not play a major role in determining asthma admissions and A & E attendance.
Exposure to endotoxin or other bacterial components might protect against the development of atopy
Authors: Von Mutius  , Braun‐Fahrländer  , Schierl  , Riedler  , Ehlermann  , Maisch  , Waser  , Nowak
Published: March 2003

Background

Several recent studies have shown that growing up on a farm confers significant protection against the development of atopy. These findings point particularly towards the importance of exposure to stable dust and farm animals. It has furthermore been reported that endotoxin, an intrinsic part of the outer membrane of gram negative bacteria, is abundant in environments where livestock and poultry is kept.

The aim of this study was therefore to measure the level of environmental endotoxin exposure in homes of farmers' children, children with regular contact to livestock and control children with no contact to farm animals.

Methods

Eighty‐four farming and nonfarming families were identified in rural areas in Southern Germany and Switzerland. Samples of settled and airborne dust were collected in stables, and of settled dust indoors from kitchen floors and the children's mattresses. Endotoxin concentrations were determined by a kinetic Limulus assay.

Results

Endotoxin concentrations were highest in stables of farming families, but were also significantly higher indoors in dust from kitchen floors (143 EU/mg vs 39 EU/mg, P < 0.001) and children's mattresses (49479 EU/m2 vs 9383 EU/m2, P < 0.001) as compared to control children from nonfarming families. In addition, endotoxin levels were also significantly higher in mattresses and dust from kitchen floors in households where children had regular contact to farm animals (38.6 EU/mg and 23340 EU/m2, respectively) as compared to control subjects.

Conclusion

We propose that the level of environmental exposure to endotoxin and other bacterial wall components is an important protective determinant for the development of atopic diseases in childhood.
Personal exposure to allergenic pollen and mould spores in inland New South Wales, Australia
Authors: Mitakakis T. Z. , Tovey E. R. , Xuan W. , Marks G. B.
Published: March 2003

Background

In inland NSW, Australia, allergic sensitization to the fungi Alternaria and Cladosporium and to pollen is common and an important risk factor for asthma.

Objective

We report the results of a series of experiments designed to assess the nature of personal exposure to these airborne allergenic particles. We have tested the effect of exposure conditions and level of activity on measurements of the personal exposure.

Method

Personal Air Samplers (PAS) and Nasal Air Samplers (NAS) were employed. NAS are fitted just inside the nose and collect inhaled particles by impaction, while the PAS use a pump‐operated filter with constant air flow (2 L/min). Thirty‐three subjects (adults and children) used both NAS and PAS simultaneously for four one hour periods during which they performed activities or rested, both inside and outside their homes. Samples were analysed by light microscopy. Alternaria spores, Cladosporium spores, grass pollen and nongrass pollen were counted.

Results

Both samplers detected substantial variation in exposure between subjects. Between members of the same household, the intrahouse correlation coefficient ranged from < 0 − 0.38. Levels of pollen grains and fungal spores inhaled were higher during periods of activity than during rest, and higher while subjects were outdoors than indoors. During the active outdoor period, the number of Alternaria spores inhaled ranged from 4 to 794 (median 11) spores/hr, Cladosporium from 0 to 396 (median 4) spores/hr, grass pollen from 0 to 81 (median 1) grains/hr and nongrass pollen from 0 to 72 (median 5) grains/hr.

Conclusion

This is the first study to quantify individual inhaled levels of allergenic fungal spores and pollen under normal domestic circumstances. Exposure can be substantial and highly variable between individuals. The amount of particles inhaled relates both to location of the individual and activity being performed, independent of age group.
Clinical safety and tolerability of montelukast, a leukotriene receptor antagonist, in controlled clinical trials in patients aged ≥ 6 years
Authors: Storms W. , Michele T. M. , Knorr B. , Noonan G. , Shapiro G. , Zhang J. , Shingo S. , Reiss T. F.
Published: March 2003

Objective Montelukast is a leukotriene receptor antagonist administered orally once daily for treatment of chronic asthma in adults and children. A comprehensive analysis of safety data from double‐blind, randomized, placebo‐controlled trials with montelukast has not been previously reported.

Patients and methods A pooled analysis of safety data from 11 multicentre, randomized, controlled montelukast Phase IIb and III trials and five long‐term extension studies was performed. A total of 3386 adult patients (aged 15–85 years) and 336 paediatric patients (aged 6–14 years) were enrolled in the trials; 2031 adults received montelukast for up to 4.1 years, and 257 children received montelukast for up to 1.8 years. Summary statistics comparing incidences of adverse events among treatment groups were calculated.

Results The overall incidence of clinical and laboratory adverse events among montelukast‐treated patients, both adult and paediatric, was similar to that among patients receiving placebo. There were no clinically relevant differences in individual adverse events, including infectious upper respiratory conditions and transaminase elevations, between montelukast and placebo groups. Discontinuations due to adverse events occurred with similar frequencies during placebo, montelukast and inhaled beclomethasone therapy. No dose‐related adverse effects of montelukast were observed in adults treated with dosages as high as 200 mg per day (20 times the recommended dose) for 5 months. This tolerability profile montelukast observed in clinical trials has been generally reflected in the post‐marketing safety experience seen to date.

Conclusion These data indicate a tolerability profile for montelukast similar to placebo during both short‐term and long‐term administration, even at doses substantially higher than the recommended clinical dose of 10 mg once daily for adults and 5 mg once daily for children aged 6–14 years.
IL‐5 priming of the PMA‐induced oxidative metabolism of human eosinophils from allergic and normal subjects during a pollen season
Authors: Woschnagg C. , Garcia R. , Rak S. , Venge P.
Published: March 2003

AimTo study the effect of IL‐5 priming on the PMA‐induced oxidative metabolism of blood eosinophils from allergic patients and healthy controls, during pollen exposure.

MethodsTwenty birch pollen allergic patients with seasonal symptoms of rhinitis or rhinitis plus asthma were studied during the birch pollen season of Sweden. Eosinophils were purified to > 95% by Percoll gradients followed by the MACS system. Oxidative metabolism was measured by a lucigenin enhanced chemiluminescence (CL) assay. Eosinophils were primed with IL‐5 and subsequently stimulated with PMA. The signal transduction mechanisms of IL‐5 priming were studied using the MEK inhibitor PD 98059, the PkC inhibitors Staurosporine, Ro 318220, Gö 6983 and the PI3kinase inhibitor Wortmannin.

ResultsDuring the season, the eosinophils from the allergic patients showed a reduced t½rise compared to the non‐allergic controls (P = 0.019) after stimulation. IL‐5 reduced the total PMA CL response both in control and patients’ cells (P = 0.012 and 0.0054 resp.), whereas it primed it in terms of the t½rise of the curves, in both groups (P = 0.012 and 0.0015 resp.). The PMA‐induced CL reactions were inhibited by PD 98059, all PkC‐inhibitors and Wortmannin. IL‐5 priming counteracted only the MEK inhibition significantly.

ConclusionsBlood eosinophils from allergic patients are primedin vivo,as compared to eosinophils from non‐allergic controls, during a pollen season. Interleukin‐5 primes equally the PMA‐induced oxidative metabolism of human eosinophils from healthy or allergic subjects.

The mechanism of IL‐5 priming after PMA stimulation of oxygen radical production is MEK independent.
IgE‐mediated occupational asthma induced by herbal medicine, Banha (Pinellia ternata)
Authors: Kim S.‐H. , Jeong H. , Kim Y.‐K. , Cho S.‐H. , Min K.‐U. , Kim Y.‐Y.
Published: March 2003

There have been few reported cases of occupational asthma induced by Pinellia ternata (Banha), and the mechanism responsible for this type of asthma is still undetermined. We report a case of Banha‐induced occupational asthma with IgE‐mediated mechanism. The patient had positive skin responses to Banha extract and Banha‐specific bronchial challenge elicited an early asthmatic response. The serum‐specific IgE binding to Banha extract was detectable and completely inhibited with the additions of 0.1 µg/mL of Banha extract on ELISA inhibition. Seven IgE binding components to Banha extract (6.5, 22, 24, 32, 34, and 48 kDa) were detected using SDS–PAGE and immunoblot analysis. In conclusion, the results of this study suggest that P. ternata (Banha)‐derived allergens are able to cause IgE‐mediated bronchoconstriction in exposed workers.
A3 receptors mediate rapid inflammatory cell influx into the lungs of sensitized guinea‐pigs
Authors: Spruntulis L. M. , Broadley K. J.
Published: March 2003

Background Inhaled adenosine causes bronchoconstriction in asthmatics and may modulate inflammatory cell activity. Elevated adenosine levels occur in the lungs after antigen challenge of asthmatics.

Objectives The aim of this study was to investigate whether the bronchoconstrictor effects of the adenosine derivative, 5′‐AMP, were associated with altered migration of inflammatory cells into the airways using a sensitized atopic guinea‐pig model previously shown to display a bronchoconstrictor response. Comparisons were made with the effects of inhaled antigen.

Methods Airway responses of conscious sensitized guinea‐pigs to inhalation exposures of 5′‐AMP were determined by whole body plethysmography as the change in specific airway conductance (sGaw). Influx of leucocytes into the airways was determined by bronchoalveolar lavage (BAL).

Results 5′‐AMP caused bronchoconstrictor airway responses in sensitized animals. Dose‐dependent infiltration of inflammatory cells into the lungs occurred 1 h after 5′‐AMP exposure. No bronchoconstriction or cell influx was seen in unsensitized guinea‐pigs. Exposure to ovalbumin (OA) also caused influx of inflammatory cells. Twenty‐four hours after an OA exposure, 5′‐AMP produced no bronchoconstriction. The P1‐receptor antagonists, 8‐PT and 8‐SPT, inhibited the 5′‐AMP‐induced bronchoconstriction, indicating that the bronchoconstriction seen in sensitized animals is mediated by A1 or A2 receptors. They had no effect on the cell influx, whereas the A3 antagonist, MRS‐1220, significantly inhibited cellular infiltration, suggesting mediation through A3 receptors. At 24 h after an OA challenge and accompanying the cellular influx, there was airway hyper‐responsiveness to the bronchoconstriction by histamine. In contrast, no hyper‐responsiveness to histamine was seen 1 h after 3 mm or 24 h after 300 mm 5′‐AMP.

Conclusions 5′‐AMP caused a rapid migration of eosinophils and macrophages into the airways only in sensitized guinea‐pigs, and this was blocked by the A3 antagonist MRS‐1220. This was not associated with bronchial hyper‐reactivity to histamine.
Allergenic proteins are fragmented in low concentrations of sodium hypochlorite
Authors: Chen P. , Eggleston P. A.
Published: March 2003

Background To facilitate allergen removal from indoor environments, it would be helpful to have household cleaning products that modified allergenic activity. Because NaOCl dissolves proteins in high concentrations and is both capable of killing bacteria and viruses and inactivating viral antigens at somewhat lower concentrations, we explored its effects on Mus m 1 and other indoor allergens.

Objective To examine the ability of NaOCl to reduce the allergenicity of Mus m 1 and other indoor allergens.

Methods Using purified mouse urinary allergen, we examined the effect on protein measured by Coomassie protein assay and on Mus m 1 measured by ELISA. We also examined the effects using SDS/PAGE and Western blots probed with sheep anti‐Mus m 1 and with allergic human serum.

Results When NaOCl and Mus m 1 were combined in a molar ratio of 100 : 1, IgE binding to Mus m 1 on Western blot was significantly reduced. At higher NaOCl concentrations the protein appeared to fragment and eventually became undetectable. Fragmentation appeared to be random in that peptides of a wide range of apparent molecular weight were produced. The reaction was complete within 1–2 min at OCl : pr ratios of greater than 200 : 1 and was optimal at pH 7.4. Immunological activity of other allergens (Fel d 1, Bla g 1, Der p 1) was decreased in vitro and dried allergen extracts were removed from surfaces. Adding an extraneous protein, BSA, to NaOCl:Mus m 1 solutions decreased the effect of NaOCl on the allergen.

Conclusions We concluded that NaOCl at concentrations commonly used in household products is capable of dramatically affecting allergenic protein.
IFN‐γ production in response to IL‐18 or IL‐12 stimulation by peripheral blood mononuclear cells of atopic patients
Authors: Shikano H. , Kato Z. , Kaneko H. , Watanabe M. , Inoue R. , Kasahara K. , Takemura M. , Kondo N.
Published: March 2003

Background Several studies have shown that interleukin (IL)‐4 and interferon‐gamma (IFN‐γ) are important for the regulation of immunoglobulin E (IgE) production and that IL‐18 and IL‐12 induce IFN‐γ.

Objective IFN‐γ production in response to IL‐18 or IL‐12 stimulation was investigated in peripheral blood mononuclear cells (PBMCs) of atopic patients with various levels of serum IgE.

Methods Cytokine production from PBMCs was measured following stimulation with a non‐specific stimulator (phytohemagglutinin: PHA), IL‐18 or IL‐12 in 12 healthy controls and 26 atopic patients with various serum IgE levels.

Results IFN‐γ production by IL‐18‐stimulated PBMCs was positively correlated with IFN‐γ production by IL‐12‐stimulated PBMCs (P < 0.05). However some atopic patients showed discrepancy between the levels of IFN‐γ production stimulated by IL‐12 and by IL‐18.

Conclusions The results shown here suggest the presence of abnormalities in the IL‐12 and/or IL‐18 signalling pathways, such as genetic defects in the atopic patients.
T cell involvement in cutaneous drug eruptions
Authors: Hari Y. , Frutig‐Schnyder K. , Hurni M. , Yawalkar N. , Zanni M. P. , Schnyder B. , Kappeler A. , Von Greyerz S. , Braathen L. R. , Pichler W. J.
Published: March 2003

Background The most frequent side‐effects of drug therapy are skin eruptions. Their pathomechanism is rather unclear.

Objective In this prospective study we investigated the T cell activation and drug specificity in different forms of drug‐induced exanthemas from 22 patients.

Methods During acute drug allergy, liver parameters and T cell subset activation in the circulation (up‐regulation of CD25 and HLA‐DR) were evaluated and skin biopsies of the acute lesion performed. After recovery, the causative drug was identified by lymphocyte transformation (LTT) and scratch‐patch tests.

Results Seventeen of 22 (17/22) patients had maculo‐papular exanthema, 4/22 bullous exanthema and 1/22 urticaria. The causative drugs were mainly antibiotics, anti‐epileptics and anti‐hypertensives. Up‐regulation of HLA‐DR on circulating CD4+ and/or CD8+ T cells was detected in 17 patients, being most marked in patients with bullous reactions or hepatic involvement. The LTT was positive in 14/21 analysed and the patch test in 7/15. All patients showed lymphocytic infiltration in the skin biopsy of the acute lesion. Generally CD4+ T cells dominated; a higher percentage of circulating CD8+ T cells was found in patients with bullous skin reactions or hepatic involvement.

Conclusion Our data demonstrate activation and drug specificity of T cells in drug‐induced skin eruptions. A predominant CD8+ T cell activation leads to more severe (bullous) skin symptoms or liver involvement, while predominant activation of CD4+ cells elicits mainly maculo‐papular reactions.
The relationship between low level nitrogen dioxide exposure and child lung function after cold air challenge
Authors: Ponsonby A.‐L. , Glasgow N. , Gatenby P. , Mullins R. , Mcdonald T. , Hurwitz M. , Pradith B. , Attewell R.
Published: March 2003

Background Nitrogen dioxide (NO2) or home gas appliance use has been inconsistently associated with adverse respiratory outcomes in childhood.

Objectives (i) To examine the contribution of home gas appliance type and personal NO2 exposure. (ii) To examine the relationship between NO2 exposure and child lung function and respiratory history. (iii) To assess whether these relationships vary by house dust mite sensitization status.

Methods A cross‐sectional survey of 344 children (71% of the eligible group) with a mean age of 9.1 years from four randomly selected schools in the Australian Capital Territory from July to September 1999. Study measurements included a parental questionnaire, NO2 exposure by passive gas samplers, skin prick testing for 10 aeroallergens and lung function at rest and after cold air challenge.

Results Total NO2 exposure was low with a mean concentration of 10.1 ppb. No associations were found between NO2 exposure or gas appliance use and asthma, wheeze or baseline lung function. Personal NO2 exposure was associated with a reduction in forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) after cold air challenge (adjusted difference − 0.12% (− 0.23% to − 0.01%) per 1 ppb increase). After exclusion of children who had home heating changed because of asthma, gas heater use was also significantly associated with a reduction in this measure (adjusted difference − 2.0% (− 3.7% to − 0.2%)). There was some evidence that these reductions were greater among the non‐mite‐sensitized children.

Conclusions The effect of low‐level NO2 exposure on these respiratory outcomes was not marked. The possible effect of low‐level NO2 exposure on non‐specific bronchial reactivity requires confirmation. Future studies on NO2 and respiratory health should include measures of house dust mite sensitization and bronchial hyper‐responsiveness.
Molecular cloning, expression and modelling of cat allergen, cystatin (Fel d 3), a cysteine protease inhibitor
Authors: Ichikawa K. , Vailes L. D. , Pomés A. , Chapman M. D.
Published: March 2003

Background Cats are an important source of indoor allergens. However, only two cat allergens, Fel d 1 and albumin, have been cloned and sequenced. IgE antibodies to Fel d 1 and albumin do not fully account for IgE responses to cat and there is good immunochemical evidence that cats produce other allergens.

Objective To identify and define the molecular structure of the other potential cat allergens.

Methods A cat skin cDNA library was screened using pooled serum obtained from five asthmatic patients which contained high levels of IgE antibody to cat dander. Selected cDNA clones were screened by plaque immunoassay and one cDNA clone, encoding cystatin, was expressed in E. coli. The three dimensional structure of cat cystatin was modelled using the SWISS‐MODEL computer program.

Results Three positive cDNA clones (A, B and C) were identified, two of which were fully sequenced. Clones A and C encoded the same 98 amino acid residue sequence which showed 79% and 75% homology with bovine and human cystatin A, respectively. The cat cystatin sequence contained the conserved cysteine protease inhibitor signature and two of three lipocalin motifs. By plaque immunoassay, 60–90% of cat allergic sera had IgE ab to the expressed cystatin clones. The cysteine protease inhibitor motif was also partially conserved in dog allergen sequences, Can f 1 and Can f 2, which are lipocalins. The recombinant protein was expressed in E. coli as an 11‐kDa protein, corresponding to the predicted MW of cat cystatin. The three‐dimensional structure of cat cystatin was modelled on human cystatin structures.

Conclusion A newly identified allergen, cystatin (Fel d 3), has been cloned from cat skin and is a member of the cysteine protease inhibitor family.
Selective development of a strong Th2 cytokine profile in high‐risk children who develop atopy: risk factors and regulatory role of IFN‐γ, IL‐4 and IL‐10
Authors: Van Der Velden V. H. J. , Laan M. P. , Baert M. R. M. , De Waal Malefyt R. , Neijens H. J. , Savelkoul H. F. J.
Published: March 2003

Background The immunological processes in early life and their relation to allergic sensitization leading to a Th2 cytokine profile are still not well understood.

Objective To analyse the environmental and genetic risk factors and immunological responses at birth in relation to the development of atopic disease at 12 months of age in a longitudinal study of high‐risk children.

Methods High‐risk children were followed from birth till 12 months of age. Mononuclear cells obtained at birth and 6 and 12 months thereafter were analysed for their proliferative and cytokine responses after polyclonal and allergen‐specific stimulation.

Results At 12 months of age 25% children had developed an atopic disease. Two atopic parents, parental smoking and atopic dermatitis of at least one of the parents were significant risk factors. In cord blood of newborns who developed atopy, an increased percentage of CD4+CD45RO+ cells and an increased polyclonal‐stimulated proliferation were observed. Furthermore, an impaired allergen‐induced, but not polyclonal‐stimulated IFN‐γ production was found, suggesting a regulatory defect. At 6 and 12 months of age, a strong Th2 profile (characterized by increased levels of IL‐4, IL‐5, and IL‐13) after both polyclonal and, to a lesser extent, allergen‐specific stimulation was found in the children developing atopy. Allergen‐induced IL‐10 production at 12 months of age was only observed in the non‐atopic children.

Conclusion Our data indicate that the first 6 months of life represent a critical time window for the initiation of immunological changes resulting in the development of atopy. The selective development of a Th2 cytokine profile in high‐risk children who develop atopy is due to increased production of Th2 cytokines, possibly caused by impaired allergen‐induced IFN‐γ production in the neonatal period. Furthermore, the decreased allergen‐induced IL‐10 levels observed in the atopic children at 12 months of age may result in a lack of down‐regulation of the inflammatory process.
Human mast cell progenitors in peripheral blood from atopic subjects with high IgE levels.
Authors: Nomura I. , Katsunuma T. , Matsumoto K. , Iida M. , Tomita H. , Tomikawa M. , Kawahara H. , Akasawa A. , Pawankar R. , Saito H.
Published: March 2003

Background It remains unclear whether the number of circulating mast cell progenitors is increased in patients with atopic diseases. Distinct genotypes are reported to affect mast cell/basophil activation.

Objective We compared the number and function of mast cell progenitors present in the peripheral blood from donors with normal IgE (IgE < 400 U/mL) and those with atopic dermatitis accompanied by high serum IgE (IgE > 5000 U/mL).

Methods Purified peripheral blood cells were cultured in serum‐free methylcellulose containing stem cell factor (SCF), IL‐6 plus IL‐3. Fresh methylcellulose containing the cytokines was layered over every 2 weeks. The cultured mast cells were retrieved from the methylcellulose and were functionally analysed.

Results Mast cell colonies were distinguished at 6 weeks of culture as other colony types had been degenerated. The number of mast cell colony‐forming cells varied depending on donors and was not significantly increased in peripheral blood from the hyper‐IgE atopic patients. A significant inversed correlation was found between the number of mast cells per one colony and the ages of donors. The cultured mast cells derived from atopic patients and those from normal IgE donors equally expressed FcεRI and released histamine through FcεRI, although IL‐4 priming in vitro markedly enhanced the function of mast cells regardless of donors.

Conclusions These results indicate that the number of circulating mast cell progenitors may be regulated by unknown individual factors unrelated to IgE levels. Mast cell function may be regulated largely by environmental factors, such as IL‐4, but not determined by their progenitors' genotypes.
In utero priming of allergen‐specific helper T cells
Authors: Devereux Graham , Seaton Anthony , Barker Robert N.
Published: March 2003

Background Allergic diseases are major health problems in developed countries. Cord blood mononuclear cells (CBMC) at birth can proliferate after stimulation with allergen and this has led to the widespread view that the sensitization of the fetal immune system by allergens is a key determinant in establishing immunological bias towards allergy. However, the notion that the immune system can be primed by allergen in utero remains unproven. Determination of the CD45 isoform of responding T helper cells is an established method of determining the activation status of responding T helper cells because unsensitized cells express CD45RAhigh and previously sensitized cells CD45ROhigh.

Objective To determine if sensitization of allergen‐specific T helper cells can occur in utero by determining the CD45 isoform of CBMC proliferating in response to allergen.

Methods CBMC proliferative responses were measured after stimulation in culture with a panel of allergens, mitogen and control antigen. To ascertain whether any responding T helper cells had been primed in utero, depletion experiments established whether they carried the CD45ROhigh marker of previous activation or the CD45RAhigh marker of unstimulated T cells.

Results CBMC from a high proportion of 223 randomly selected neonates were stimulated to proliferate in vitro by allergens, with 76% responding to timothy grass pollen. In 50% of such responses to timothy grass, the CD45 isoform of the T cells that proliferate indicated that they had been previously activated. However, the remaining 50% of responses to timothy grass were mediated by previously unstimulated T cells. Proliferative responses mediated by CBMC sensitized in utero tended to be greater in magnitude than those mediated by unsensitized cells (P = 0.08). Seventy‐five per cent of CBMC samples proliferated after stimulation with mycobacterial PPD and, as in BCG‐vaccinated adults, all such CBMC proliferative responses at birth were predominately mediated by sensitized cells.

Conclusion Allergen‐ and antigen‐specific Th cells can be primed in utero.
Development of allergy and IgE antibodies during the first five years of life in Estonian children
Authors: Julge K. , Vasar M. , Björkstén B.
Published: March 2003

Background Epidemiological studies have demonstrated a low prevalence of allergic diseases and atopic sensitization among schoolchildren and young adults in the formerly socialist countries of Central and Eastern Europe as compared to Western Europe.

Objective The aim of our study was to prospectively investigate IgE responses to food and inhalant allergens and the development of allergy during early childhood in a population with a low prevalence of atopic disorders.

Methods In a population‐based prospective study, 273 children were followed from birth through the first 5 years of life, recording manifestations of allergy by questionnaires and clinical examinations at 0.5, 1, 2 and 5 years (n = 213). Skin prick tests (SPT) were performed using natural foods (cow's milk, egg white) and commercial extracts of inhaled allergens (cat, dog, D. pteronyssinus, birch, timothy). In addition, serum IgE levels and circulating IgE antibodies against the seven allergens were determined.

Results The prevalence of allergic diseases at 5 years of life was 19%. Atopic dermatitis was the most common allergic disease at all ages. The point prevalence of positive skin prick tests was 7% at 0.5, 1 and 2 years of age, and 3% at 5 years. Circulating IgE antibodies against food allergens were common at all ages, i.e. 13, 23, 36 and 36%, respectively, at 0.5, 1, 2 and 5 years. The prevalence of circulating IgE antibodies to inhalant allergens increased from 1.5% at 0.5 years to 11% at 1, 19% at 2 and 47% at 5 years. The antibody levels were generally low, however. The value of positive SPT and the presence of IgE antibodies in the diagnosis of clinical allergy were low.

Conclusion The results of this prospective study carried out in a previously socialist country with a low allergy prevalence among schoolchildren and young adults indicate that transient sensitization in early childhood is followed by a down‐regulation of skin reactivity.
Early, current and past pet ownership: associations with sensitization, bronchial responsiveness and allergic symptoms in school children
Authors: Anyo G. , Brunekreef B. , De Meer G. , Aarts F. , Janssen N. A. H. , Van Vliet P.
Published: March 2003

Background Studies have suggested that early contact with pets may prevent the development of allergy and asthma.

Objective To study the association between early, current and past pet ownership and sensitization, bronchial responsiveness and allergic symptoms in school children.

Methods A population of almost 3000 primary school children was investigated using protocols of the International Study on Asthma and Allergies in Childhood (ISAAC). Allergic symptoms were measured using the parent‐completed ISAAC questionnaire. Sensitization to common allergens was measured using skin prick tests (SPT)s and/or serum immunoglobulin (Ig)E determinations. Bronchial responsiveness was tested using a hypertonic saline challenge. Pet ownership was investigated by questionnaire. Current, past and early exposure to pets was documented separately for cats, dogs, rodents and birds. The data on current, past and early pet exposure were then related to allergic symptoms, sensitization and bronchial responsiveness.

Results Among children currently exposed to pets, there was significantly less sensitization to cat (odds ratio (OR) = 0.69) and dog (OR = 0.63) allergens, indoor allergens in general (OR = 0.64), and outdoor allergens (OR = 0.60) compared to children who never had pets in the home. There was also less hayfever (OR = 0.66) and rhinitis (OR = 0.76). In contrast, wheeze, asthma and bronchial responsiveness were not associated with current pet ownership. Odds ratios associated with past pet ownership were generally above unity, and significant for asthma in the adjusted analysis (OR = 1.85), suggesting selective avoidance in families with sensitized and/or symptomatic children. Pet ownership in the first two years of life only showed an inverse association with sensitization to pollen: OR = 0.71 for having had furry or feathery pets in general in the first two years of life, and OR = 0.73 for having had cats and/or dogs in the first two years of life, compared to not having had pets in the first two years of life.

Conclusion These results suggest that the inverse association between current pet ownership and sensitization and hayfever symptoms was partly due to the removal of pets in families with sensitized and/or symptomatic children. Pet ownership in the first two years of life only seemed to offer some protection against sensitization to pollen.
Cytokine pattern in allergic and non‐allergic chronic rhinosinusitis in asthmatic children
Authors: Riccio A. M. , Tosca M. A. , Cosentino C. , Pallestrini E. , Ameli F. , Canonica G. W. , Ciprandi G.
Published: March 2003

Background Rhinosinusitis represents one of the most common chronic diseases. The association of rhinosinusitis with asthma has been frequently reported. Eosinophils and Th2 cells play a pathogenic mechanism in asthma.

Objective The aims of the study were to evaluate the cytokine pattern in chronic rhinosinusitis in asthmatic children and to compare the findings in allergic vs. non‐allergic asthmatics.

Methods Thirty‐five asthmatic children were evaluated, 19 males and 16 females, with an average age of 8.7 years. All children were asthmatic and suffered from chronic rhinosinusitis. Twenty were allergic and 15 were non‐allergic. Ten healthy children were studied as normal controls. Evaluated parameters were the levels of the following cytokines: IL‐1β, IL‐4, IL‐6, IL‐8, IL‐12, IFN‐γ and TNF‐α. Cytokines were recovered from rhinosinusal lavage and measured by immunoassays. Nasal cytology was also performed in all subjects and inflammatory cells were counted by conventional staining.

Results Allergic subjects showed a significant increase of IL‐4 (P < 0.01) and TNF‐α (P < 0.05) and a significant decrease of IL‐12 (P < 0.05) and of IFN‐γ (P < 0.0001), whereas IL‐1β, IL‐6 and IL‐8 were not significantly increased. Non‐allergic children showed a significant increase of IL‐4 (P < 0.05) and a significant decrease of IFN‐γ (P < 0.0001), IL‐12 was not significantly decreased, and IL‐1β, IL‐6 and IL‐8 were not significantly increased. A significant inflammatory infiltrate was present in all asthmatic children. Significant correlations were demonstrated between IL‐4 and IL‐12 (P < 0.001), IL‐12 and IFN‐γ (P < 0.001), IL‐8 and neutrophils (P < 0.01), and TNF‐α and monocytes/macrophages (P < 0.05), in allergic asthmatics. IL‐4 and IL‐12 were significantly correlated (P < 0.05) as well as IL‐8 and neutrophils (P < 0.01) in non‐allergic asthmatics.

Conclusion This study shows that allergic asthmatic children with chronic rhinosinusitis have a typical Th2 cytokine pattern, but also non‐allergic asthmatic children share a similar pattern. These findings would suggest the existence of a common pathophysiological mechanism shared by upper and lower airways and are consistent with the concept of united airways disease.
The protective role of country living on skin prick tests, immunoglobulin E and asthma in adults from the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyper‐responsiveness and atopy
Authors: Kauffmann F , Oryszczyn M. P , Maccario J
Published: March 2003

Background  Farming environment and traditional lifestyle seem to protect from childhood allergy.

Objective  The aim is to analyse the relationships of living in the country to asthma, positive skin prick tests and IgE among adults considering various windows of exposure over the life‐span.

Methods  The study concerns 805 adults drawn from the Epidemiological study on the Genetics and Environment of Asthma, bronchial hyper‐responsiveness and atopy (EGEA) (asthmatic cases, non‐asthmatic controls, and parents of cases with and without asthma). Ever living in the country concerned 55% of the subjects. Early (beginning < 1 years), childhood (beginning ≤ 16 years), prolonged (duration ≥ 10 years) and current life in the country were studied.

Results  The results based on the case control and family components of the study show that IgE levels were significantly lower in those who ever lived in the country and in particular in those who lived for ≥ 10 years. Positive skin prick tests (SPT) were significantly less prevalent in those who ever lived in the country and in particular in those with childhood (≤ 16 years) exposure. These associations remained independent of age, sex, smoking or asthma with IgE levels of 64 vs. 88 IU/mL; P = 0.004 for those ever living in the country vs. others and odds ratio for SPT positivity of 0.72 (95% CI [0.53–0.98]). In the more specific group with traditional mode of heating in childhood (use of wood) associations were stronger. The association with asthma, studied in parents of asthmatic probands showed that fathers, but not mothers, of asthmatics were significantly less often asthmatic themselves in relation to country living.

Conclusion  Country life protects from asthma and adulthood allergy. The protective effect is not restricted to exposure in early childhood.
Long‐term safety and efficacy of nevirapine tolerance induction
Authors: Messaad D. , Reynes J. , Fabre J. , Bousquet J. , Demoly P.
Published: March 2003

Background  The most frequent side‐effects due to nevirapine (Viramune®), the first non‐nucleoside HIV reverse transcriptase inhibitor introduced for clinical use, are cutaneous hypersensitivity reactions. In non‐serious cases, tolerance induction can be proposed.

Objective  Describe the long‐term safety and efficacy of tolerance induction to nevirapine.

Methods  Six HIV‐infected patients started a tolerance 1 to 2 months after an episode of nevirapine hypersensitivity. Increasing doses of nevirapine (2.5, 10, 25, 100, 250 and 750 μg and 2.5, 5, 10, 25, 50 and 100 mg) were given orally at half‐hour intervals under strict medical surveillance and patients were followed up regularly.

Results  All but two of the patients tolerated this induction well. One had a mild and transient reaction on day 1; nevirapine was not stopped. One had a moderate to severe reaction one month later; nevirapine was stopped and he recovered fully. All other patients have been taking nevirapine for more than 3 months without any adverse reaction.

Conclusion  Therefore, when no alternatives are available in severely ill and hypersensitive HIV‐infected patients, tolerance induction is a possible therapeutic option.
Cystic fibrosis transmembrane conductance regulator gene mutations: do they play a role in the aetiology of allergic bronchopulmonary aspergillosis?
Authors: Eaton T. E. , Weiner Miller P. , Garrett J. E. , Cutting G. R.
Published: March 2003

Background  Previous work suggests that cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations may be implicated in the aetiology of allergic bronchopulmonary aspergilosis (ABPA).

Objective  To compare the frequency of CF gene mutations in asthmatics with ABPA of varying severity with asthmatics who were skin prick test (SPT)‐positive to Aspergillus fumigatus (Af) without evidence of ABPA and asthmatics SPT‐negative to Af.

Methods  Thirty‐one Caucasian patients with ABPA were identified, together with asthmatics SPT positive to Af without evidence of ABPA (n = 23) and SPT negative to Af (n = 28). Genomic DNA was tested for 16 CF mutations accounting for approximately 85% of CF alleles in Caucasian New Zealanders.

Results  Four (12.9%) ABPA patients were found to be carriers of a CF mutation (ΔF508 n = 3, R117H n = 1), one (4.3%) asthmatic SPT positive to Af without ABPA (ΔF508), and one (3.6%) asthmatic SPT negative to Af (R117H). All patients with a CF mutation had normal sweat chloride (< 40 mM). There was no significant difference between the frequency of CF mutations in the ABPA patients and asthmatics without ABPA. However, the frequency of CF mutations in the ABPA patients was significantly different (P = 0.0125) to the expected carrier rate in the general population.

Conclusion  These results lend further support to a possible link between CF mutations and ABPA.
Prevention of sensitization to house dust mite by allergen avoidance in school age children: a randomized controlled study
Authors: Arshad S. H. , Bojarskas J. , Tsitoura S. , Matthews S. , Mealy B. , Dean T. , Karmaus W. , Frischer T. , Kuehr J. , Forster J. ,   the SPACE study group
Published: March 2003

Background Sensitization to dust mites predisposes to asthma and allergic rhinitis, and prevention of this sensitization might reduce the rising prevalence of these disorders.

Objective To test the effectiveness of dust mite avoidance measures on the development of sensitization to dust mites in children.

Methods As part of a multicentre study (Study of Prevention of Allergy in Children of Europe), 242 children, aged 5–7 years, in three European countries (United Kingdom, Greece and Lithuania), were randomized to prophylactic group (n = 127) and control group (n = 115). At randomization these children were required to have a family history of atopy and positive skin test to an aeroallergen but not to house dust mite. Children in the prophylactic group were provided with dust mite impermeable mattress covers and advice on environmental measures to reduce exposure to dust‐mite allergen. Control group children were given non‐specific advice. After 12 months a standardized questionnaire was completed and skin prick tests were performed.

Results Ten children in the prophylactic group and 19 in the control group were lost to follow‐up. Three of 117 (2.56%) children in the prophylactic group and nine of 96 (9.38%) in the control group developed sensitization to dust mites. Logistic regression analysis confirmed an independent effect of prophylactic measures (adjusted odds ratio (OR): 0.14, 95% confidence interval (CI): 0.03–0.79, P = 0.03). Fifteen children need to be treated to prevent sensitization in one child.

Conclusion Dust mite sensitization can be reduced in school age children with simple mite avoidance measures.
Immunotherapy with keyhole lampet hemocyanin‐conjugated decapeptide vaccine in cypress pollen allergy
Authors: Demoly P. , Persi L. , Dhivert H. , Delire M. , Bousquet J.
Published: March 2003

Background Cupressaceae pollen allergy is a world‐wide pollinosis but immunotherapy has rarely been tested. Immunotherapy is usually allergen‐specific but new forms may be targeted towards IgE.

Objectives A randomized, double‐blind, placebo‐controlled trial was carried out to assess the efficacy of a vaccine made of keyhole lampet hemocyanin (KLH)‐conjugated decapeptide from the Fcε4 domain of the IgE in cypress pollinosis.

Methods Sixty patients with cypress pollen allergy were studied. They were included on a suggestive clinical history, positive skin tests and nasal challenge to cypress pollen extract. Three intramuscular injections of the vaccine (250 µg) or placebo were administered monthly with a booster injection 5 to 8 weeks later. The primary end‐point criterion was the threshold dose inducing a positive nasal challenge. The secondary end‐point was the symptom‐medication scores measured when cypress pollen grains were over 50 grains/m3.

Results Nasal challenge before treatment was non‐significantly different between the placebo and vaccine groups. After treatment there was no significant difference between the two groups. Pollen counts were over 50 grains/m3 for 8 weeks during the trial. There was no significant difference in total symptom scores between the placebo and vaccine groups. The vaccine was safe.

Conclusions The KLH‐conjugated decapeptide vaccine was not effective in cypress pollen allergy.