bluuebunny/crossref_metadata_2025 huggingface dataset:
Drugs as allergens
Authors: Smal M. A. , Baldo B. A. , Harle D. G.
Published: August 2010

The combining site specificities of IgE antibodies that react with the oral antibacterial agent trimethoprim and found in the sera of two subjects who experienced anaphylaxis after taking the drug, were investigated. Hapten inhibition studies with some close analogues of trimethoprim and a range of other structurally related compounds showed that the allergenic determinant complementary to the IgE antibodies in the serum of one of the subjects was the 3,4‐dimethoxybenzyl group. The complementary allergenic structure recognized by the IgE antibodies in the serum from the second subject comprised both the trimethoxybenzyl and diaminopyrimidine rings of trimethoprim. Thus, as with thiopentone, but unlike the neuromuscular blocking drugs, the trimethoprim molecule has more than one determinant each with the capacity to provoke IgE formation, interact with the antibody combining site and provoke drug‐induced allergic reactions. The general approach set out here employing carefully selected structural analogues in hapten inhibition studies should be invaluable for confirming specificity and identifying allergenic determinants in IgE antibody‐mediated allergic drug reactions.
Leukotriene C4 and histamine in early allergic reaction in the nose
Authors: Bisgaard H. , Robinson C. , Rømeling F. , Mygind N. , Church M. , Holgate S. T.
Published: August 2010

We have examined the measurements of LTC4 and histamine in nasal lavage fluids and blown secretions as a possible model of the early mediator events during nasal allergy. A nasal challenge with grass pollen extract was undertaken on two separate occasions in 20 patients with a history of seasonal rhinitis and a positive immediate skin test to grass pollen. A 2 ml nasal lavage was performed before allergen challenge, and blown secretion collected separately 15 min after the provocation, followed by a final 2 ml nasal lavage. The dilution of nasal secretion by the lavage fluid was determined using 99mTc‐labelled albumin as an exogenous marker added to the fluid. The amounts of admixture in the nasal lavages did not correlate to the concentrations of LTC4 and histamine, indicating that the variable amounts of nasal secretion in nasal lavage do not constitute a confounding variable for measurements of LTC4 and histamine. In the pre‐challenge lavages, the median concentrations, of LTC4 and histamine were 1.7 and 52 nmol/1 respectively. Following allergen challenge neither LTC4 nor histamine measured in nasal lavage showed any significant change from pre‐challenge baseline values. However, measurements of both mediators in the blown secretion showed a significantly higher concentration than in the pre‐ or post‐challenge lavage samples, compatible with transitory release during the acute allergic reaction. However, it seems doubtful whether measurements of LTC4 or histamine can be compared between blown secretion and nasal lavage fluid, even if the dilution factor is disregarded. While allergen provocation of the nasal mucosa releases inflammatory mediators locally, uncontrolled variables confound their measurement in the nasal lavage fluids to an extent which limits the application of this model to study details of mediator release during nasal allergy.
Diagnosis and immunotherapy of mould allergy
Authors: Malling H.‐J. , Skov P. Stahl
Published: August 2010

The interrelation of in vitro IgE‐mediated parameters, i.e. serum‐specific IgE (RAST), basophil cell‐bound specific IgE, and histamine release from basophil leucocytes was investigated in a 1‐year placebo‐controlled, double‐blind Cladosporium immunotherapy study involving 22 adult asthmatics. The intense and early burst (within 6 weeks of immunotherapy) of serum‐specific IgE did not result in a corresponding increased binding of specific IgE molecules to basophils. Cell‐bound IgE increased in the Cladosporium season in both groups at the same time as serum levels of specific IgE declined in the Cladosporium group. In the placebo group histamine release from circulating basophils paralleled changes in basophil‐bound IgE. In Cladosporium‐treated patients, histamine release cell sensitivity after a lag phase (during immunotherapy dose‐increase) declined two log steps, i.e. the cells became less responding in spite of a significant increase in cell‐bound IgE. To further evaluate the sensitizing capacity of circulating specific IgE, passive sensitization studies were performed using basophils from a single donor. Although sera taken at the maximal IgE‐response showed an enhanced capacity of passive sensitization, the ratio between RAST and passive sensitization capacity increased significantly in Cladosporium‐treated patients, implying a less than expected sensitization capacity of immunotherapy‐induced specific IgE. The lack of active binding of IgE to basophils might be explained by a reduced Fc‐affinity of immunotherapy‐induced IgE in contrast to the Cladosporium seasonally induced IgE. Regarding the decrease in histamine release in Cladosporium‐treated patients in spite of an increased amount of cell‐bound specific IgE, immunotherapy may initiate a decrease in mediator releasibility which is not caused by a reduction in the number of Fc‐receptors but rather some yet unknown subcellular mechanisms regulating the histamine release. The described changes in IgE‐mediated parameters do not seem to be caused by interference with either specific IgG, or IgG4. Changes in histamine release in the Cladosporium, season were the only IgE‐mediated parameter significantly related to the graded clinical efficacy of immunotherapy.
The Lung
Authors: Bousquet Jean
Published: August 2010

•A positive food challenge doesn't imply that there is an IgE mediated allergy but implies the patient is intolerant to certain foods.

•If specific IgE and/or prick test to a specific food‐stuff is positive, an IgE‐mediated mechanism is likely to be involved but a proportion of patients with IgE to foods do not present any symptom when ingesting the food.
The Nose
Authors: Høst Arne
Published: August 2010

•Rhinitis is a common symptom in food allergic patients, but rhinitis is rarely the only symptom.

•Rhinitis due to adverse reactions to preservatives and colorants is very rare.

•In anaphylactic systemic reactions to foods the rhinitis symptoms are caused by inflammatory mediators transported by the circulation.

•In non‐anaphylactic reactions, the nasal inflammation and symptoms are probably induced by interaction with food allergens transported to the nasal mucosa via the blood circulation.
The Ear
Authors: Høst Arne
Published: August 2010

•Otitis media with effusion is rarely caused by allergy to food.

•Allergic inflammation in the nasal mucosa, mainly due to IgE‐mediated reactions to foods, may cause eustachian tube dysfunction and subsequent otitis media with effusion.

•Inflammatory mediators from the nasal mucosa transported via the nasal mucociliary system may cause eustachian tube dysfunction.
The Joints and Muscles
Authors: Panush Richard S. , Veloso Mary Lind , Weiss Steven , Bielory Leonard
Published: August 2010

There are several reasons for considering the hypothesis that food hypersensitivity might relate to rheumatic diseases.

•Food can evoke immune responses.

•Food can cause immunologically mediated symptoms.

•Immunological mechanisms are important in the pathogenesis of rheumatic diseases.

•Antigens triggering rheumatic responses are unknown.

•Rheumatic diseases have been associated with foods in many reports.
Differences in the anti‐inflammatory effects of theophylline and pentoxifylline: important for the development of asthma therapy?
Authors: Entzian P. , Bitter‐Suermann S. , Burdon D. , Ernst M. , Schlaak M. , Zabel P.
Published: August 2010

Antiasthma drugs are now being re‐evaluated for their anti‐inflammatory effects. Theophylline is an immunomodulator; however, weak effects and the narrow therapeutic window make it a controversial drug. We compared the immunomodulatory potencies of theophylline with those of the xanthines pentoxifylline (POF) and A802715. Using a whole‐blood, cell‐culture system, we studied the effects on the release of tumor necrosis factor‐alpha (TNF‐a), interferon‐gamma (IFN‐γ), and interleukin‐6 (IL‐6) in six healthy subjects, and, in granulocyte suspensions, the effects on the release of reactive oxygen species (ROS). We also studied the influence of a 14‐day treatment with theophylline or POF on the release of the cytokines named above in 14 asthmatics. We found that equimolar concentrations of A802715 most effectively inhibit ROS generation, followed by POF; the effects of theophylline were weakest. A802715‐inhibited release of TNF‐a was four times as potent as that of theophylline, and POF two times as potent. Inhibition of IFN‐γ by A802715 was three times as potent, and by POF two times. Neither drug influenced IL‐6 release. After a 14‐day treatment of asthmatics, POF proved to inhibit TNF‐a release more effectively (by 44.3%) than theophylline (7.5%). It is concluded that study of xanthine derivatives in asthmatics might help the development of asthma therapy POF seems to be an especially promising candidate.
Effect of seasonal allergen exposure on mucosal IL‐16 and CD4+ cells in patients with allergic rhinitis
Authors: Pullerits T. , Lindén A. , Malmhäll C. , Lötvall J.
Published: August 2010

Background: CD4+ T cells constitute a major source of cytokines in allergic diseases such as allergic rhinitis. Interleukin (IL)‐16 selectively recruits CD4+ cells.

Methods: We evaluated the effect of natural allergen exposure during a grass‐pollen season on IL‐16 expression and number of CD4+ cells in nasal mucosa. Patients with allergic rhinitis (n=16) were treated with either a nasal glucocorticoid beclomethasone (BDP; 400 µg/day) or placebo, and gave nasal biopsies prior to and during the grass‐pollen season. The evaluated markers in allergic rhinitis patients were also compared to those in healthy control subjects (n=5).

Results: Prior to the pollen season, the expression of IL‐16, but not the number of CD4+ cells, was significantly higher in patients with allergic rhinitis than in healthy control subjects. The grass‐pollen season further increased IL‐16 expression and also increased the number of CD4+ cells in placebo‐treated, but not in BDP‐treated, allergic rhinitis patients. The pollen‐season‐induced change in IL‐16 expression and in CD4+ cells was significantly more pronounced in placebo‐ than in BDP‐treated patients. There was a significant correlation between the change in IL‐16 expression and the number of CD4+ cells.

Conclusions: These data suggest that local upregulation of IL‐16 expression contributes to the inflammation observed in seasonal allergic rhinitis. Hypothetically, inhibition of IL‐16 expression can be one of several mechanisms by which nasal glucocorticoids achieve their anti‐inflammatory effect in allergic rhinitis.
ALOX5 promoter genotype, asthma severity and LTC4 production by eosinophils
Authors: Kalayci O. , Birben E. , Sackesen C. , Keskin O. , Tahan F. , Wechsler M. E. , Civelek E. , Soyer O. U. , Adalioglu G. , Tuncer A. , Israel E. , Lilly C.
Published: August 2010

Background:  The number of Sp1–Egr1 binding tandem repeats at the ALOX5 promoter influences gene transcription and may modify the response to anti‐leukotriene treatment. The relationship of ALOX5 variants to asthma severity and leukotriene production by eosinophils is unknown.

Objective:  To characterize ALOX5 mRNA expression and cysteinyl‐leukotriene production by eosinophils from individuals bearing ALOX5 promoter deletional variants and their association with the severity of childhood asthma.

Methods:  Eosinophils from adult asthmatics bearing only variant alleles (with other than five tandem repeats on both chromosomes, non5/non5) or no variant alleles (5/5) were cultured in vitro and ALOX5 expression and leukotriene secretion were measured. A total of 621 children with mild or moderate‐severe asthma were genotyped at the ALOX5 core promoter.

Results:  Asthmatics with non5/non5 genotype expressed less ALOX5 mRNA and produced less LTC4 into culture supernatants than 5/5 individuals (6.4 ± 2.0 and 20.0 ± 5.0 pg/ml, n = 5; P < 0.05). More asthmatic children bearing non5/non5 genotype had moderate‐severe asthma than children with the 5/5 genotype (5.3% vs. 1.4%, P = 0.008). Multivariate logistic regression identified ALOX5 promoter genotype as a significant predictor of disease severity (OR = 3.647, 95% CI: 1.146–11.608, P = 0.03). Consistent with these findings, children bearing the non5/non5 genotype had greater bronchomotor response to exercise as measured by the maximum fall after exercise and the area under the exercise curve (P < 0.05 for both).

Conclusion:  Our results suggest that children who express the asthma phenotype despite having a genetic variant that impairs their ability to express ALOX5 have more severe disease and thus are more likely to have asthma symptoms.
Cysteinyl‐leukotrienes contribute to sputum eosinophil chemotactic activity in asthmatics
Authors: Hemelaers L. , Henket M. , Sele J. , Bureau F. , Louis R.
Published: August 2010

Background:  Cysteinyl‐leukotrienes are lipid derived mediators involved in asthma. They are able to stimulate eosinophil chemotaxis in vitro. Induced sputum from asthmatics has been shown to contain eosinophil chemotactic activity. The purpose of our study was to evaluate the contribution of cysteinyl‐leukotrienes to sputum eosinophil chemotactic activity in asthmatics and to seek whether there might be differences between asthmatics free of inhaled corticosteroids vs those regularly receiving this treatment.

Methods:  Twenty‐two patients (11 corticosteroid free, mean FEV1 99% predicted, 11 corticosteroid‐treated, mean FEV1 77% predicted) recruited from our asthma clinic underwent a sputum induction. Sputum was processed according to standard procedure. Eosinophil chemotactic activity contained in the fluid phase was assessed using Boyden microchamber model and expressed as chemotaxis index (CI). Cysteinyl‐leukotrienes were measured in sputum supernatant by ELISA and their role in sputum eosionophil chemotactic activity was evaluated by using montelukast, a selective antagonist of a cys‐LT1 receptor.

Results:  Cysteinyl‐leukotrienes were well detectable in sputum supernatants from both steroid‐naive (247 ± 42 pg/ml) and steroid‐treated (228 ± 26 pg/ml) asthmatics. Sputum eosinophil chemotactic activity was indiscriminately present in both corticosteroid‐naive (CI: 2.61 ± 0.22) and corticosteroid‐treated (2.98 ± 0.35) asthmatics. Montelukast (100 μM) significantly inhibited the eosinophil chemotactic activity in both groups achieving a mean inhibition of 54.2 ± 9.2% (P < 0.001) and 64.7 ± 7.8% (P < 0.001) in steroid‐naive and steroid‐treated asthmatics respectively.

Conclusion:  Cysteinyl‐leukotrienes actively participate in sputum eosinophil chemotactic activity found in asthmatics irrespective of whether they are or not under treatment with inhaled corticoids.
3‐Nitrotyrosine, a marker of nitrosative stress, is increased in breath condensate of allergic asthmatic children
Authors: Baraldi E. , Giordano G. , Pasquale M. F. , Carraro S. , Mardegan A. , Bonetto G. , Bastardo C. , Zacchello F. , Zanconato S.
Published: August 2010

Background:  Asthmatic patients have high exhaled nitric oxide (NO) levels. NO‐mediated inflammatory actions are mainly due to NO conversion into reactive nitrogen species, which can lead to nitrotyrosine formation. The aim of this study was to assess 3‐nitrotyrosine (3‐NT) levels in exhaled breath condensate (EBC) of asthmatic and healthy children and to investigate whether there is any relationship with exhaled NO (FENO) and lung function.

Methods:  The study included 20 asthmatic children (10 steroid‐naive with intermittent asthma, 10 steroid‐treated with unstable persistent asthma) and 18 healthy controls. They underwent FENO measurement, EBC collection and spirometry. 3‐NT was measured by a new liquid chromatography–tandem mass spectrometry (LC‐MS/MS) method in isotopic dilution.

Results:  The median EBC concentration of 3‐NT (expressed as nitrotyrosine/tyrosine ratio × 100) in asthmatic children was fivefold higher than in healthy subjects [0.23% (0.12–0.32) vs 0.04% (0.02–0.06), P < 0.001] with no difference between steroid‐naive and unstable steroid‐treated asthmatic patients. FENO levels were higher in asthmatic [44.6 ppb (36.0–66.0)] than in healthy children [7.5 ppb (6.0–8.8), P < 0.001]. No correlation was found among 3‐NT, FENO and lung function parameters.

Conclusion:  Nitrotyrosine is high in EBC of asthmatic children and could be considered as a noninvasive marker of nitrosative events in the airways.
The socio‐economic burden of asthma is substantial in Europe
Authors: Accordini S. , Corsico A. , Cerveri I. , Gislason D. , Gulsvik A. , Janson C. , Jarvis D. , Marcon A. , Pin I. , Vermeire P. , Almar E. , Bugiani M. , Cazzoletti L. , Duran‐Tauleria E. , Jõgi R. , Marinoni A. , Martínez‐Moratalla J. , Leynaert B. , De Marco R. ,   Therapy and Health Economics Working Group of the European Community Respiratory Health Survey II
Published: August 2010

Background:  Few data are available on the asthma burden in the general population. We evaluated the level and the factors associated with the asthma burden in Europe.

Methods:  In 1999–2002, 1152 adult asthmatics were identified in the European Community Respiratory Health Survey (ECRHS)‐II and the socio‐economic burden (reduced activity days and hospital services utilization in the past 12 months) was assessed.

Results:  The asthmatics with a light burden (only a few reduced activity days) were 13.2% (95% CI: 11.4–15.3%), whereas those with a heavy burden (many reduced activity days and/or hospital services utilization) were 14.0% (95% CI: 12.1–16.1%). The burden was strongly associated with disease severity and a lower quality of life. Obese asthmatics had a significantly increased risk of a light [relative risk ratio (RRR) = 2.17; 95% CI: 1.18–4.00] or a heavy burden (RRR = 2.77; 95% CI: 1.52–5.05) compared with normal/underweight subjects. The asthmatics with frequent respiratory symptoms showed a threefold (RRR = 2.74; 95% CI: 1.63–4.61) and sixfold (RRR = 5.76; 95% CI: 3.25–10.20) increased risk of a light or a heavy burden compared with asymptomatic asthmatics, respectively. Moreover, the lower the forced expiratory volume in 1 s % predicted, the higher the risk of a heavy burden. The coexistence with chronic cough/phlegm only increased the risk of a heavy burden (RRR = 1.88; 95% CI: 1.16–3.06). An interaction was found between gender and IgE sensitization, with nonatopic asthmatic females showing the highest risk of a heavy burden (21.6%; 95% CI: 16.9–27.1%).

Conclusions:  The asthma burden is substantial in Europe. A heavy burden is more common in asthmatics with obesity, frequent respiratory symptoms, low lung function, chronic cough/phlegm and in nonatopic females.
Original article. Molecular and immunological characterization of cytochrome c: a potential cross‐reactive allergen in fungi and grasses
Authors: Sharma V. , Singh B. P. , Gaur S. N. , Arora N.
Published: August 2010

Background:  Recombinant allergens are required for component‐resolved diagnosis/therapy of allergic disorders. The study was aimed to express and characterize an allergenic protein from Curvularia lunata and study its cross‐reactivity.

Methods:  A clone encoding a 12‐kDa protein screened from the cDNA library of C. lunata was sequenced and expressed in pET22b+ vector. The purified protein was characterized by biophysical and immunological methods.

Results:  The sequence of gene encoding a 12‐kDa protein showed homology to cytochrome c. It was expressed in Escherichia coli yielding 0.5 mg protein/l culture and designated as Cur l 3. The absorption and circular dichroism spectrum of Cur l 3 were similar to horse cytochrome c and the protein reacted with cytochrome c antibody. ELISA with different fungal‐positive patients’ sera showed ≥ 3 times specific IgE to Cur l 3 compared with healthy controls. Mice anti‐Cur l 3 reacted with tropical and temperate grass extracts. Protein also reacted with grass‐positive patients’ sera. In vitro stimulation of peripheral blood mononuclear cells from C. lunata, fungi or grass‐positive patients with it released significant levels of Th2 cytokines. In vivo testing of this protein in allergic patients showed marked positive skin reactivity in 60% fungal and 43% grass‐positive cases. Cross inhibition assays (EC50) demonstrated allergenic cross‐reactivity of Cur l 3 with fungi and grasses.

Conclusions:  Cytochrome c, a major allergen from C. lunata was cloned, sequenced and expressed. It was identified as a cross‐reactive allergen among fungi and grasses and has potential for clinical application.
Role of symptoms and lung function in determining asthma control in smokers with asthma
Authors: Chaudhuri R. , McSharry C. , McCoard A. , Livingston E. , Hothersall E. , Spears M. , Lafferty J. , Thomson N. C.
Published: August 2010

Background:  Cigarette smoking in asthma increases the severity and accelerates the decline in lung function. The relative role of symptoms and lung function in determining asthma control in smokers with asthma is not known.

Aim of the study:  The aim of this study was to compare asthma control in smokers vs never‐smokers with asthma, using the validated Juniper asthma control questionnaire (ACQ), and assess if any difference was because of a particular symptom or the forced expiratory volume in one second (FEV1) value.

Methods:  This was a cross‐sectional study of 134 asthmatics (74 never‐smokers and 60 smokers) with ≥15% reversibility in FEV1 after salbutamol. All subjects completed the ACQ, recording FEV1 and asthma symptoms (night awakening, morning symptoms, dyspnoea, wheeze, activity limitation and use of reliever inhaler).

Results:  Compared with the never‐smokers, smokers with asthma had significantly worse median (IQR) total asthma control score [1.6 (1.1–2.3) vs 2.8 (1.7–3.4); (P < 0.0001)] and in each of the six individual symptom question scores (P < 0.001), but no difference in FEV1 levels (P = 0.908).

Conclusion:  Asthma control is significantly worse in asthmatics who smoke compared with never‐smokers, with all symptoms related to asthma control uniformly worse in smokers, independent of FEV1.
Identification of amino acids critical for IgE‐binding to sequential epitopes of bovine κ‐casein and the similarity of these epitopes to the corresponding human κ‐casein sequence
Authors: Han N. , Järvinen K. M. , Cocco R. R. , Busse P. J. , Sampson H. A. , Beyer K.
Published: August 2010

Background:  The delineation of allergenic (i.e. IgE‐binding) epitopes in cow’s milk proteins and the amino acids (AAs) critical for IgE‐binding is necessary to understand better the structural properties of an allergen and to develop more efficacious immunotherapeutic reagents. Furthermore, this information may enable us to understand better cross‐sensitivity between different allergens.

Methods:  Eleven peptides, 10–14 AAs in length, representing the IgE‐binding epitopes of κ‐casein were synthesized on a derivatized cellulose membrane with single AA substitutions at each position. Membranes were incubated with pooled sera from 15 milk‐allergic patients and individual sera from 10 of the patients included in the pool.

Results:  For 10/11 allergenic peptides, one to five different single AA substitutions resulted in elimination of IgE‐binding of pooled patient sera. Overall at least one mutated peptide could be found for these 10 IgE‐binding sites that resulted in a reduction of IgE‐binding in at least 80% of the patients who recognized the native protein. Furthermore, the IgE‐binding region at AA104–112 on bovine κ‐casein showed a high degree of similarity with the human κ‐casein, respectively, including the AAs critical for IgE‐binding.

Conclusion:  This finding suggests that critical AAs should be assessed with both pooled and individual patient sera to account for the B‐cell epitope heterogeneity between patients, with cow’s milk allergy. In addition, we identified two potentially cross‐reactive peptides between bovine and human caseins of unknown clinical relevance.
Epicutaneous aeroallergen sensitization in atopic dermatitis infants – determining the role of epidermal barrier impairment
Authors: Boralevi F. , Hubiche T. , Léauté‐Labrèze C. , Saubusse E. , Fayon M. , Roul S. , Maurice‐Tison S. , Taïeb A.
Published: August 2010

Background:  Sensitization to atopens is an early phenomenon that overlaps with the onset of atopic dermatitis (AD) in infancy. Early epidermal barrier impairment may facilitate the epicutaneous penetration of atopens.

Objective:  To correlate transepidermal water loss (TEWL) and aeroallergen sensitization in infants with AD.

Methods:  In this cross‐sectional study we enrolled 59 AD children and 30 controls aged 3–12 months. Transepidermal water loss in uninvolved skin, specific immunoglobulin E, atopy patch test (APT) and skin prick tests were performed with respect to seven aeroallergens, i.e., Dermatophagoides pteronyssinus, D. farinae, cat, dog, birch pollen, ambrosia, and cockroach. Environmental conditions were assessed by a questionnaire, and the house dust mite (HDM) concentration was determined in dust samples.

Results:  Eighty‐nine percent of AD infants had a positive APT vs one out of eleven controls. AD infants had a significantly higher mean TEWL than controls (27.4 vs 11.1 g/m2/h, P < 0001). Children with two or more positive APT had higher TEWL than the others (31.1 vs 19.0 g/m2/h, P < 0.025). No correlation was found between indoor APT results and exposure to HDM, cats, and dogs at home.

Conclusions:  This study confirms the high prevalence of delayed sensitization to indoor and outdoor aeroallergens in AD infants, and shows that the higher the TEWL, the higher the prevalence of sensitization to aeroallergens. These data are in favor of a major role of a constitutive epidermal barrier impairment in determining early atopen sensitization in infants with AD.
The impact of food hypersensitivity reported in 9‐year‐old children by their parents on health‐related quality of life
Authors: Östblom E. , Egmar A.‐C. , Gardulf A. , Lilja G. , Wickman M.
Published: August 2010

Background:  There are only a few studies on the impact of food hypersensitivity (FHS) in children on health‐related quality of life (HRQL). The present study was designed to examine this impact in a population‐based birth cohort (BAMSE).

Methods:  A nested case–control study was performed within the cohort. The parents of 1378 nine‐year‐old children filled out a generic questionnaire with 13 subscales (Child Health Questionnaire Parental Form 28 – CHQ‐PF28) supplemented with disease‐specific questions concerning FHS. There were 212 children with report of FHS. Another 221 children with allergic diseases but not FHS were examined for comparison. Furthermore, the impact of pronounced symptoms of FHS and of increasing levels of food‐specific IgE antibodies on HRQL was also analysed.

Results:  The children with FHS exhibited significantly lower scores on the subscales physical functioning, role/social limitations – physical and general health in the generic instrument. Furthermore, children with food‐related symptoms from the lower airways were scored lower on Self Esteem, Parental Impact – time and Family Cohesion. Sensitization per se did not alter these patterns, but high levels of food‐specific IgE‐antibodies affected mental health and general health negatively. A physician’s diagnosis of food allergy did not affect any of the subscales negatively.

Conclusions:  Parents reported that FHS exerts a negative impact on the HRQL of 9‐year‐old children, in particular in children with symptoms from the lower airways or if the FHS is associated with high levels of food‐specific IgE‐antibodies. Healthcare‐givers must put major effort into improving and maintaining the HRQL of these children.
General considerations on rapid desensitization for drug hypersensitivity – a consensus statement
Authors: Cernadas J. R. , Brockow K. , Romano A. , Aberer W. , Torres M. J. , Bircher A. , Campi P. , Sanz M. L. , Castells M. , Demoly P. , Pichler W. J. ,   for the European Network of Drug Allergy and the EAACI interest group on drug hypersensitivity
Published: August 2010

To cite this article:Cernadas JR, Brockow K, Romano A, Aberer W, Torres MJ, Bircher A, Campi P, Sanz ML, Castells M, Demoly P, Pichler WJ, for the European Network of Drug Allergy and the EAACI interest group on drug hypersensitivity. General considerations on rapid desensitization for drug hypersensitivity – a consensus statement.Allergy2010;65: 1357–1366.

Drug hypersensitivity reactions can occur with most drugs, are unpredictable, may affect any organ or system, and range widely in clinical severity from mild pruritus to anaphylaxis. In most cases, the suspected drug is avoided in the future. However, for certain patients, the particular drug may be essential for optimal therapy. Under these circumstances, desensitization may be performed. Drug desensitization is defined as the induction of a temporary state of tolerance of a compound responsible for a hypersensitivity reaction. It is performed by administering increasing doses of the medication concerned over a short period of time (from several hours to a few days) until the total cumulative therapeutic dose is achieved and tolerated. It is a high‐risk procedure used only in patients in whom alternatives are less effective or not available after a positive risk/benefit analysis. Desensitization protocols have been developed and are used in patients with allergic reactions to antibiotics (mainly penicillin), insulins, sulfonamides, chemotherapeutic and biologic agents, and many other drugs. Desensitization is mainly performed in IgE‐mediated reactions, but also in reactions where drug‐specific IgE have not been demonstrated. Desensitization induces a temporary tolerant state, which can only be maintained by continuous administration of the medication. Thus, for treatments like chemotherapy, which have an average interval of 4 weeks between cycles, the procedure must be repeated for every new course. In this paper, some background information on rapid desensitization procedures is provided. We define the drugs and drug reactions indicated for such procedures, describe the possible mechanism of action, and discuss the indications and contraindications. The data should serve as background information for a database (accessible via the EAACI‐homepage) with standardized protocols for rapid desensitization for antibiotics, chemotherapeutic agents, monoclonal antibodies/fusion proteins, and other drugs.
Natural killer–dendritic cell interaction in lymphocyte responses in hypersensitivity reactions to betalactams
Authors: Chaves P. , Torres M. J. , Aranda A. , Lopez S. , Canto G. , Blanca M. , Mayorga C.
Published: August 2010

To cite this article: Chaves P, Torres MJ, Aranda A, Lopez S, Canto G, Blanca M, Mayorga C. Natural killer–dendritic cell interaction in lymphocyte responses in hypersensitivity reactions to betalactams. Allergy 2010; 65: 1600–1608.

Background:  Betalactams are the commonest cause of allergic reactions mediated by either IgE or T lymphocytes in which innate and adaptive immune systems mediate the earlier stages of immunological responses. One of the links between these systems is related to the interaction between natural killer (NK) and dendritic cells (DC). We have evaluated the role of NK cells and NK‐DC interaction in the immunopathological mechanisms of nonimmediate reactions to betalactams.

Methods:  Patients allergic to amoxicillin (AX) (N = 17) and tolerant controls (N = 13) were included. Changes in phenotype (CD69, IFNγ, perforin, and granzyme B) in AX‐stimulated NK cells, the cytotoxic activity on mature or immature DC (imDC), and the proliferation and phenotype of NK lymphocytes after culture with AX and DC were determined by flow cytometry.

Results:  Amoxicillin induced activation and increases of perforin and granzyme B (P = 0.007 and P = 0.041 respectively) but not IFNγ production in NK cells from patients. In NK subpopulations, AX induced a significant enhancement of perforin and granzyme B in CD56dim (P = 0.005 and P = 0.002 respectively) and of IFNγ in CD56bright (P = 0.001). The cytotoxic phenotype was demonstrated by an increase of annexin V only in imDC (P < 0.001). Amoxicillin also induced an increased NK proliferation with different patterns, cytotoxic or proinflammatory, depending on the presence of imDC or mature DC, respectively. No differences were observed in NK cells from tolerant controls.

Conclusion:  These data could demonstrate the involvement of NK cells in the immunopathological mechanisms of nonimmediate allergic reactions to AX, showing that both the innate and adaptive immune systems are involved and crosstalk, producing amplification of the harmful effects observed in these drug reactions.
Combining capture–recapture data and pedigree information to assess heritability of demographic parameters in the wild
Authors: PAPAÏX J. , CUBAYNES S. , BUORO M. , CHARMANTIER A. , PERRET P. , GIMENEZ O.
Published: August 2010

Quantitative genetic analyses have been increasingly used to estimate the genetic basis of life‐history traits in natural populations. Imperfect detection of individuals is inherent to studies that monitor populations in the wild, yet it is seldom accounted for by quantitative genetic studies, perhaps leading to flawed inference. To facilitate the inclusion of imperfect detection of individuals in such studies, we develop a method to estimate additive genetic variance and assess heritability for binary traits such as survival, using capture–recapture (CR) data. Our approach combines mixed‐effects CR models with a threshold model to incorporate discrete data in a standard ‘animal model’ approach. We employ Markov chain Monte Carlo sampling in a Bayesian framework to estimate model parameters. We illustrate our approach using data from a wild population of blue tits (Cyanistes caeruleus) and present the first estimate of heritability of adult survival in the wild. In agreement with the prediction that selection should deplete additive genetic variance in fitness, we found that survival had low heritability. Because the detection process is incorporated, capture–recapture animal models (CRAM) provide unbiased quantitative genetics analyses of longitudinal data collected in the wild.
The role of genotype‐by‐environment interactions in sexual selection
Authors: INGLEBY F. C. , HUNT J. , HOSKEN D. J.
Published: August 2010

Genotype‐by‐environment interactions (GxEs) in naturally selected traits have been extensively studied, but the impact of GxEs on sexual selection has only recently begun to receive attention. Here, we review recent models and consider how GxEs might affect the evolution of sexual traits through influencing sexual signal reliability and also how GxEs may influence variation in sexually selected traits and the process of reproductive isolation. We then assess the current empirical literature on GxEs in sexual selection and conclude by highlighting areas that need additional work. Research on GxEs and sexual selection is an important new area of study for the discipline, which has largely focused on relatively simple mate choice/competition scenarios to date. Investigators now need to apply this knowledge to more complex, but realistic, situations, to more fully explore the evolution of sexual traits, and in this review we suggest potentially useful directions for future research.
Development of a convenient in vitro fertilization method using interspecific hybrids between Oryzias latipes and Oryzias curvinotus
Authors: Kamei Yasuhiro , Itou Junji , Oda Shoji , Masui Mami , Kim Jin‐Hyeong , Ishikawa Tomoko , Yuba Shunsuke , Kinoshita Masato , Mitani Hiroshi , Todo Takeshi
Published: August 2010

Medaka is a small Asian freshwater teleost and has been an excellent model for fertilization studies for more than 50 years. Therefore, experimental procedures for in vitro fertilization (IVF) and cryopreservation of sperm are well established. In contrast, since the eggs or early embryos can not be cryopreserved, many females are killed to obtain unfertilized eggs for IVF. Recent progress in genomics is establishing medaka as a new model animal in functional genomics, and numerous mutant and transgenic strains have been established and stored as frozen sperm. Accumulated preserved resources require a simple and reliable recovery method for IVF. In this paper, we describe a method for obtaining a large number of unfertilized eggs without killing females, using sterile interspecific hybrids between Oryzias latipes and O. curvinotus. However, there is no report about the normality of offspring that were obtained by IVF using unfertilized eggs spawned in mating with the sterile hybrid male. In this paper, we have confirmed the reliability of the method regarding the influences on the next generation and also assessed conditions for efficient collection of unfertilized eggs. The method would be useful not only for fertilization studies but also for keeping transgenics and mutants, including a mutant library for a reverse genetic approach.
Developmentally regulated expression of matrix metalloproteinases during fetal rat colon morphogenesis
Authors: Kurakata Hidenori , Oka Masashi , Matsubara Yasuo , Niwa Tohru , Utsunomiya Hirotoshi , Fujishiro Mitsuhiro , Miki Kazumasa , Fukamachi Hiroshi , Kubota Syunichiro , Ichinose Masao
Published: August 2010

To investigate the role of matrix metalloproteinases (MMPs) during gastrointestinal tract development, the expression of gelatinases (MMP‐2 and MMP‐9) was investigated during fetal rat colon morphogenesis. Fetal rat colons were separated into epithelial and mesenchymal fractions without cross contamination using a chelating agent and a dissecting microscope. Gelatinase activity measured using fluorescently labeled gelatin was higher in the mesenchymal than in the epithelial fraction; the developmental profile revealed that, in both fractions, gelatinase activity was enhanced during colon morphogenesis. During colonic gland formation, there was prominent MMP‐2 activity, elevated MMP‐2 mRNA expression, and an increase in the level of the active form of MMP‐2 in the mesenchymal fraction. The mRNA expression of the tissue inhibitor of metalloproteinase 2 corresponded with an elevation in the level of the active form of MMP‐2; the mRNA expression of the cell surface activator of MMP‐2, membrane type matrix metalloproteinase 1, did not increase significantly. MMP‐9 activity was low; only the pro‐form was observed in the epithelial fraction at the end of fetal life. These results suggest that, during colon morphogenesis, MMP activity is under strict spatio‐temporal control, and that the activity of MMP‐2, which is regulated at both the transcriptional and proteolytic activation levels, is very much involved in rat colon morphogenesis.
Cell‐autonomous and inductive processes among three embryonic domains control dorsal‐ventral and anterior‐posterior development of Xenopus laevis
Authors: Sakai Masao
Published: August 2010

This review aims to propose an integrated model for dorsal‐ventral and anterior‐posterior development of Xenopus. Fertilized Xenopus eggs contain two determinants, a vegetal half endomesodermal determinant and a vegetal pole dorsal determinant (DD). The organizer forms in the specific intersection of the determinants, in a cell‐autonomous manner. At late blastula, different combinations of the determinants form three embryonic domains, the competent animal domain, the organizer domain, and the entire vegetal half domain. These three domains cooperatively form dorsal‐ventral and anterior‐posterior axes: the organizer domain secrets dorsal inducing signals which induce or ‘activate’ the competent animal domain to form anterior‐most neural tissues. The vegetal non‐dorsal‐marginal domain secrets posteriorizing signals, which ‘transform’ the anterior properties of the neural tissue to posterior properties.
Cryptic fragment α4 LG4‐5 derived from laminin α4 chain inhibits de novo adipogenesis by modulating the effect of fibroblast growth factor‐2
Authors: Yamashita Hironobu , Goto Chie , Tajima Rie , Koparal Ayse Tansu , Kobori Masato , Ohki Yuji , Shitara Kenya , Narita Ryo , Toriyama Kazuhiro , Torii Shuhei , Niimi Tomoaki , Kitagawa Yasuo
Published: August 2010

Cleavage of the extracellular matrix (ECM) by proteolysis unmasks cryptic sites and generates novel fragments with biological activities functionally distinct from those of the intact ECM molecule. The laminin G‐like (LG)4‐5 fragment has been shown to be excised from the laminin α4 chain in various tissues. However, the functional role of this fragment has remained unknown to date. To investigate this, we prepared α4 LG1‐3 and α4 LG4‐5 fragments by elastase digestion of recombinant α4 LG1‐5, and examined their effects on de novo adipogenesis in mice at the site of injection of basement membrane extract (Matrigel) and fibroblast growth factor (FGF)‐2. Although the addition of whole α4 LG1‐5 suppressed adipogenesis to some extent, the α4 LG4‐5 fragment could strongly suppress adipogenesis at a concentration of less than 20 nm. Addition of the α4 LG4 module, which contains a heparin‐binding region, had a suppressive effect, but this was lost in mutants with reduced heparin‐binding activity. In addition, antibodies against the extracellular domain of syndecan‐2 and ‐4, which are known receptors for the α4 LG4 module, suppressed adipogenesis. Thus, these results suggest that the cryptic α4 LG4‐5 fragment derived from the laminin α4 chain inhibits de novo adipogenesis by modulating the effect of FGF‐2 through syndecans.
Molecular mechanism of transforming growth factor‐β‐mediated inhibition of growth arrest and differentiation in a myoblast cell line
Authors: Murakami Masanori , Ohkuma Mizue , Nakamura Masataka
Published: August 2010

Transforming growth factor‐β (TGF‐β) has been demonstrated to inhibit myogenesis in myoblasts. Here we report that transcriptional upregulation of p21WAF1/Cip1 and muscle creatinine kinase (MCK) genes in C2C12 cells, which are associated with growth arrest at the G1 phase and representative cell‐lineage‐specific expression during myogenesis, was inhibited by TGF‐β treatment. C2C12 cells expressed TWIST2, but not TWIST1, which was downregulated in myogenic differentiation in response to low‐serum cultures. We further found that TGF‐β prevented differentiation‐associated downregulation of TWIST2 transcription, resulting in maintaining TWIST2 mRNA expression as high as that in growing C2C12 cells. Ectopic TWIST2 suppressed the p21 and MCK promoters activated by the exogenous addition of E2A and MyoD and this inhibitory effect of TWIST2 was cancelled by the introduction of short hairpin RNA (shRNA) against TWIST2. On the other hand, TWIST2 shRNA failed to recover endogenous promoter activities from TGF‐β‐mediated repression. The results clearly indicate that TGF‐β inhibits G1 arrest and maintains TWIST2 expression in C2C12 cells. Our data however suggest that the TGF‐β signaling pathway may not involve TWIST2 to inhibit p21 and MCK expression.
Molecular analysis of endoderm regionalization
Authors: Yasugi Sadao , Mizuno Takeo
Published: August 2010

We have engaged in a number of studies in our laboratory that have focused on the molecular mechanisms underlying gut formation, with particular attention being paid to the establishment of regional differences found in the entire gut and within each digestive organ. We have found from our analyses that the presumptive fate of the endoderm in the embryos of vertebrates is determined quite early during development, but the realization of this fate often requires molecular cues from the neighboring tissues such as the lateral plate mesoderm and the mesenchyme derived from it. The mesenchyme seems often to exert instructive or supportive induction effects and, in some cases, a completely inhibitory role during the differentiation of the endodermal epithelium. In addition, many reports on the formation of the stomach, intestine, liver and salivary gland in vertebrates, and of Drosophila gut, all indicate that the morphogenesis and cytodifferentiation of these organs are regulated by the regulated expression of genes encoding growth factors and transcription factors. We have further shown that the epithelium can regulate the differentiation of the mesenchyme into the connective tissue and the smooth muscle layers, thus demonstrating the occurrence of literally interactive processes in the development of the digestive organs.
Evolutionary developmental studies of cyclostomes and the origin of the vertebrate neck
Authors: Kuratani Shigeru
Published: August 2010

Because they lack some gnathostome‐specific traits, cyclostomes have often been regarded as representing an intermediate state linking non‐vertebrate chordates and gnathostomes. To understand the evolutionary origins of the jaw and paired fins, lamprey embryos and larvae have been used as comparative models. The lack of the jaw–neck region is a conspicuous feature specific to cyclostomes; however, the absence of these features has been largely neglected both in evolutionary developmental studies and in the field of classical comparative embryology. This review seeks to develop a possible evolutionary scenario of the vertebrate neck muscles by taking the cucullaris (trapezius) muscle as the focus. By combining the comparative embryology of lampreys and gnathostomes, and considering the molecular‐level developmental mechanism of skeletal muscle differentiation, this review argues that the establishment of the vertebrate neck deserves to be called an evolutionary novelty based on the remodeling of mesenchymal components between the cranium and the shoulder girdle, which involves both mesodermal and neural crest cell lineages.
Draft genome of the medaka fish: A comprehensive resource for medaka developmental genetics and vertebrate evolutionary biology
Authors: Takeda Hiroyuki
Published: August 2010

The medaka Oryzias latipes is a small egg‐laying freshwater teleost, and has become an excellent model system for developmental genetics and evolutionary biology. The medaka genome is relatively small in size, ∼800 Mb, and the genome sequencing project was recently completed by Japanese research groups, providing a high‐quality draft genome sequence of the inbred Hd‐rR strain of medaka. In this review, I present an overview of the medaka genome project including genome resources, followed by specific findings obtained with the medaka draft genome. In particular, I focus on the analysis that was done by taking advantage of the medaka system, such as the sex chromosome differentiation and the regional history of medaka species using single nucleotide polymorphisms as genomic markers.
Isthmus organizer for mesencephalon and metencephalon
Authors: Nakamura Harukazu , Sato Tatsuya , Suzuki‐Hirano Asuka
Published: August 2010

The vertebrate central nervous system is elaborated from a simple neural tube. Brain vesicles formation is the first sign of regionalization. Classical transplantation using quail and chick embryos revealed that the mesencephalon–metencephalon boundary (isthmus) functions as an organizer of the mesencephalon and metencephalon. Fgf8 is accepted as a main organizing molecule of the isthmus. Strong Fgf8 signal activates the Ras‐ERK signaling pathway to differentiate the cerebellum. In this review, the historical background of the means of identifying the isthmus organizer and the molecular mechanisms of signal transduction for tectum and cerebellum differentiation is reviewed.