bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutant derivatives of the main respiratory allergen of cow are less allergenic than the intact molecule
Authors: KAUPPINEN  , ZEILER  , RAUTIAINEN  , RYTKÖNEN‐NISSINEN  , TAIVAINEN  , MÄNTYJÄRVI  , VIRTANEN  
Published: March 2003

BackgroundAllergen immunotherapy offers an alternative for drug treatment in the management of allergic diseases. Because immunotherapy often induces side‐effects, less allergenic preparations would be beneficial.ObjectiveThe purpose of this study was to examine whether the allergenicity of a cow‐derived lipocalin allergen, Bos d 2, could be diminished by substituting or deleting carboxy‐terminal amino acids including the cysteine which forms a disulphide bond with a cysteine inside the molecule.MethodsFour recombinant mutants of Bos d 2 were created by substituting or deleting the four most carboxy‐terminal amino acids. The immunological characteristics of the mutant preparations were compared with the unmodified rBos d 2 by Western blotting, ELISA inhibition, skin prick tests, and the proliferative responses of allergen‐specific T‐cell clones.ResultsIn Western blot, one of the two monoclonal antibodies showed reduced binding to the preparations without the terminal cysteine. In contrast, the other monoclonal antibody, human IgE and rabbit immune serum bound equally well to all the preparations. ELISA inhibition analyses revealed, however, that the preparations without the terminal cysteine bound antibody less efficiently. They were needed 15–38 times more than the unmodified rBos d 2 to cause the same level of inhibition. Surprisingly, one of the mutants with the terminal cysteine but a mutated adjacent amino acid turned out to be the weakest in inducing skin reactivity. All the preparations stimulated well allergen‐specific T‐cell clones.ConclusionsThe results show that the allergenicity of a lipocalin allergen, Bos d 2, can be diminished by modifying the carboxy‐terminal end of the molecule. Modifications in the area which encompasses a disulphide bond impaired the antibody binding without affecting the T‐cell stimulatory capacity. It was also shown that in vivo tests are necessary for determining the allergenicity of a modified allergen.
Immunohistochemical investigation of the cellular infiltrates at the sites of allergoid‐induced late‐phase cutaneous reactions associated with pollen allergen‐specific immunotherapy
Authors: Eberlein‐König B. , Jung C. , Rakoski J. , Ring J. 
Published: March 2003

BackgroundReduction in the size of the allergen‐induced late‐phase reaction (LPR) is seen as a consequence of successful allergen specific immunotherapy.ObjectiveIt was the aim of this study to characterize the cellular infiltrate at the sites of cutaneous LPR that may occur following injection of a depot pollen allergoid (Allergovit®) during immunotherapy and thereby determine the immunological nature of the response.MethodsPunch biopsies were taken 24 h after subcutaneous injection of a depot pollen allergoid from eight patients that showed LPR and a further five patients that did not. Additional biopsies taken 24 h after injection of allergoid‐free depot in the same patients served as controls. Immunoenzymatic labelling of the cryostat sections with different antibodies was performed with the APAAP technique. Results were expressed as cells/field (400 × magnification).ResultsSimilar dermal cellular infiltrations were seen following depot allergoid injections in patients both with and without LPR. Patients with LPR showed statistically significant increases in total cells, CD4+ cells, CD11c+ cells, CD45RO+ cells, CD45RB+ cells and activated eosinophils at the reactions sites as compared with control sites. In patients without LPR CD11c+ cells, HLA‐DR+ cells and CD45RA+ T cells increased significantly. CD8+, CD1a+, NP57+, CD23+ and CD25+ cells did not differ significantly in either group.ConclusionThese results indicate that activation of T cells, monocytes/macrophages and eosinophils at the sites of LPR following injection of depot allergoid are comparable with those following injection of allergen. Even in the absence of a cutaneous LPR, subsets of T cells and monocytes/macrophages increased. These cell activations may reflect events associated with the mechanisms of allergoid‐based specific immunotherapy, and suggest that at least part of the late‐phase reaction may be independent of IgE.
Electrophysiological effects of cetirizine, astemizole and d‐sotalol in a canine model of long QT syndrome
Authors: Weissenburger J. , Noyer M. , Cheymol G. , Jaillon P. 
Published: March 2003

Observations of torsades de pointes during therapy with terfenadine and astemizole has raised concern about the cardiac safety of non‐sedating H1‐antagonist agents. We compared cetirizine, another compound of that class, to d‐sotalol and to astemizole in a model of acquired long QT syndrome.Open‐chest surgery was performed in adult beagle dogs anaesthetized with halothane and thiopental. Bradycardia was produced with β‐adrenergic blockade and sinus node crush. Four left ventricular intramyocardial unipolar monophasic action potentials (MAP) were recorded during atrial pacing at basic cycle lengths (BCL) 400–1500 msec, before and during three successive 1‐h drug infusions (0.14, 0.45 and 1.4 mg/kg/h for astemizole and cetirizine and 1.1, 2.2 and 4.5 mg/kg/h for d‐sotalol).Dose‐ and bradycardia‐dependent prolongations of MAP duration (MAPD) were produced by d‐sotalol (P < 0.001) and astemizole (P < 0.001) but not by cetirizine. At BCL 1500 ms, the three infusions of astemizole prolonged endocardial MAPD from 323 ± 8 msec (mean ± SE) at baseline to 343 ± 10, 379 ± 13 and 468 ± 26 msec, respectively (n = 9). Sotalol prolonged that MAPD from 339 ± 6 msec to 377 ± 7, 444 ± 15 and 485 ± 24 msec (n = 7). In contrast, cetirizine did not prolong MAPD: 341 ± 8 msec at baseline Vs 330 ± 8, 324 ± 9 and 323 ± 11 msec (n = 9). Drug‐induced increase in transmural dispersion reached +79 ± 19 msec after astemizole, +59 ± 21 msec after d‐sotalol and only +7 ± 11 msec after cetirizine. Runs of ventricular tachycardias and torsades de pointes occurred during dose three of astemizole (5/9 dogs) and d‐sotalol (4/7 dogs) but never during cetirizine.In the present model, astemizole and d‐sotalol but not cetirizine prolonged MAPD and transmural dispersions of repolarization and produced torsades de pointes. These results suggest that the halothane‐anaesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies.
Cardiovascular safety of fexofenadine HCl
Authors: Pratt C. , Brown A. M. , Rampe D. , Mason J. , Russell T. , Reynolds R. , Ahlbrandt R. 
Published: March 2003

BackgroundCertain first‐ and second‐generation H1‐receptor antagonists are associated with prolongation of the corrected QT interval (QTc) and, in rare instances, with ventricular dysrhythmias, including torsades de pointes ventricular tachycardia.ObjectiveTo assess the effect of fexofenadine HCl, a new non‐sedating antihistamine, on QTc.MethodsDose‐tolerance, safety, and drug‐interaction studies with healthy volunteers; and clinical efficacy studies with seasonal allergic rhinitis patients were conducted. Twelve‐lead ECG data were collected pre‐ and postdosing or serially throughout these studies. Outliers were defined as QTc >440 msec with a ≥10 msec increase from baseline.ResultsFexofenadine HCl at single doses up to 800 mg q.d. (once daily) and multiple doses up to 690 mg b.d. for 28 days in healthy volunteers resulted in no increases in QTc (recommended dose range is 120–180 mg daily); QTc changes were similar to placebo. Compared with placebo, there were no statistically significant QTc increases in patients receiving fexofenadine HCl 80 mg b.d. for 3 months, 60 mg b.d. for 6 months, or 240 mg q.d. for 12 months. No statistically significant increases in QTc were detected when fexofenadine HCl 120 mg b.d. was administered in combination with erythromycin (500 mg t.d.) or ketoconazole (400 mg q.d.) after dosing to steady‐state (6.5 days). In seasonal allergic rhinitis patients (n = 1160) treated with 40, 60, 120, or 240 mg b.d. fexofenadine HCl for 2 weeks, there were no dose‐related increases in QTc and no significant increases in mean QTc compared with placebo. Frequency and magnitude of QTc outliers with fexofenadine HCl and placebo were similar in all studies. No case of fexofenadine‐associated torsades de pointes has been observed in controlled trial experience with more than 6000 patients.ConclusionFexofenadine HCl has been investigated more extensively for possible electrophysiological effects than any other antihistamine. Fexofenadine HCl has no significant effect on QTc, even at doses much higher than those used in clinical practice.
Comparison of incremental and bolus dose inhaled allergen challenge in asthmatic patients
Authors: Taylor  , Harris  , O'Connor  
Published: March 2003

BackgroundAttenuation of airway responses to inhaled allergen is increasingly used to evaluate anti‐asthma drugs. Many studies use different allergen challenge methods and the presence of the late asthmatic response can be identified by a screening challenge with inhalation of incremental doses of allergen. Once defined, subsequent challenges are often administered as a constant dose based on the dose from the screening challenge. Previously, constant dose challenges have been employed but never validated.ObjectiveA comparative study of two methods of delivering inhaled allergen by evaluating the responses of an incremental dose allergen challenge and the same cumulative dose administered as a bolus over a single inhalation.MethodsThirty‐five male patients with mild allergic asthma underwent incremental dose challenge followed 3–6 weeks later by a bolus dose challenge. Bronchoconstrictor responses were expressed as the maximum percentage fall in FEV1 from baseline during the early (0–2 h) and late (4–10 h) asthmatic responses and area under the percentage change in FEV1‐time curve (AUC).ResultsThere were no significant differences between the challenges. The mean ± sem fall in FEV1 following incremental and bolus dose challenge was 33.1 ± 1.8% and 29.9 ± 2.2% during the early response, and 36.9 ± 2.4% and 34.0 ± 3.1% during the late response, respectively. The mean ± sem AUC following incremental and bolus dose challenge was 35 ± 3 and 33 ± 3 Δ%FEV1/h for the AUC0–2 h, 147 ± 12 and 139 ± 16 Δ%FEV1/h for the AUC4–10 h, and 204 ± 14 and 190 ± 19 Δ%FEV1/h for the AUC0–10 h, respectively.ConclusionBolus dose allergen challenge is a safe method to administer inhaled allergen in clinical trials with a valid response when compared with incremental dose allergen challenge.
Tear levels of interferon‐γ, interleukin (IL) ‐2, IL‐4 and IL‐5 in patients with vernal keratoconjunctivitis, atopic keratoconjunctivitis and allergic conjunctivitis
Authors: Uchio  , Ono  , Ikezawa  , Ohno  
Published: March 2003

BackgroundA predominance of TH2 activity in chronic allergic diseases, such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC), has been suggested recently. However, there is no published study on tear levels of cytokines of the two different subgroups, TH1 and TH2, in patients with ocular allergy.ObjectivesWe measured interferon (IFN)‐γ, interleukin (IL)‐2, IL‐4 and IL‐5 levels in tears by ELISA, to determine whether the levels of these cytokines are elevated in allergic ocular diseases when compared among patient groups and normal controls.MethodsTear levels of IL‐2, IFNγ, IL‐4 and IL‐5 were measured by ELISA using samples from patients with VKC, AKC (AKC‐NP, without proliferative lesions; and AKC‐P, with proliferative lesions), allergic conjunctivitis (AC) and normal subjects. The levels of these cytokines in tears and the clinical severity of AD were also compared.ResultsTear IL‐4 level in patients with AKC was significantly higher than those in VKC, AC and controls, and tear IL‐4 levels in patients with AKC‐P vs VKC differed significantly. Tear IL‐5 levels in patients with diseases associated with proliferative lesions, VKC and AKC‐P, were higher than those in AC and normal controls. However, tear level of IL‐5 in patients with AKC‐P was significantly higher than that in AKC‐NP. Although the dermatological severity of AD correlated significantly with tear IL‐4 level, IFNγ, IL‐2 and IL‐5 levels did not correlate with dermatological severity of AD.ConclusionThese results indicate that the TH2‐like cytokines play an important pathophysiological role in severe ocular allergic conditions such as AKC and VKC and that tear level of IL‐5 may be a candidate marker to evaluate the clinical status of ocular allergy. The different patterns of tear levels of IL‐4 and IL‐5 among ocular allergic diseases may reflect the origin and immunological basis of these cytokines.
The search of latex sensitization in spina bifida: diagnostic approach
Authors: Nieto  , Mazón  , Estornell  , Nieto  , Reig  , García‐Ibarra  
Published: March 2003

BackgroundSensitization to latex has become a major problem in children with spina bifida. Life‐threatening reactions may occur in these patients, therefore the search of latex sensitization must be an active task in all of these children.ObjectiveTo design an approach for the diagnosis of latex sensitization in children with spina bifida.MethodsWe studied 100 consecutive unselected patients. Skin prick tests with a commercial latex extract were performed, latex‐specific serum immunoglobulin (Ig) E was determined by CAP test, and risk factors were studied. Originally, patients with an area of latex skin test > 50% of the area of histamine and/or CAP class ≥ 3 were considered sensitized to latex. Diagnostic tests were also performed in a control group of 51 atopic and nonatopic children.ResultsAfter performing a receiver‐operating characteristics curve for both tests we recommend skin tests > 25% of the area of histamine (sensitivity − SEN = 79%, specificity − SPE = 100%, positive predictive value − PPV = 100%, negative predictive value − NPV = 90%), or CAP class ≥ 2 (SEN = 88%, SPE = 100%, PPV = 100%, NPV = 94%) as diagnostic cut‐off points. The anamnesis had a SEN of 44% for diagnosis, and a SPE of 100%. Latex sensitization was associated with more than 5 operations (OR = 8, 95% CI = 3–21.3), a personal history of atopy (OR = 11.5, 95% CI = 2.3–57.1), and serum total IgE ≥ 2 z‐units (OR = 4, 95% CI = 1.6–10).ConclusionFor the routine evaluation of children with spina bifida, we propose a diagnostic algorithm with skin prick tests as a first step and CAP second.
Possible mechanism of bronchoprotection by SIN‐1 in anaesthetized guinea pigs: roles of nitric oxide and peroxynitrite
Authors: Kanazawa  , Hirata  , Yoshikawa  
Published: March 2003

BackgroundS‐morpholinosydnonimine (SIN‐1) is thought to generate peroxynitrite. Recent reports suggested that peroxynitrite possessed a potent vascular relaxant activity via guanylate cyclase activation. However, no previous studies have examined the relaxant effect of peroxynitrite on airway smooth muscle.ObjectiveTo determine the mechanism of bronchoprotection by SIN‐1, considering in particular the involvement of nitric oxide (NO) and peroxynitrite.MethodsPeroxynitrite formation was assayed by monitoring the oxidizing activity of dihydrorhodamine 123, and NO was measured polarographically as a redox current in vitro. We examined the effect of SIN‐1 delivered to the airway by ultrasonic nebulization against bronchoconstriction induced by acetylcholine in anaesthetized guinea pigs.ResultsSIN‐1 produced peroxynitrite in a time‐ and concentration‐dependent manner, but did not produce NO in vitro. However, when mixed with glutathione (GSH) and bronchoalveolar lavage fluid (BALF), peroxynitrite formation by SIN‐1 was inhibited and SIN‐1 induced the release of NO. SNAP (S‐nitroso‐N‐acetyl‐penicillamine) and SIN‐1 each inhibited acetylcholine‐induced bronchoconstriction in a dose‐dependent manner in vivo. Though GSH alone did not have any effect on baseline airway resistance and acetylcholine‐induced bronchoconstriction, pretreatment with GSH significantly enhanced SNAP‐ and SIN‐1‐induced bronchoprotection. In addition, pretreatment with carboxy‐PTIO, a NO scavenger, completely inhibited bronchoprotective effect of SNAP on acetylcholine‐induced bronchoconstriction, but partially inhibited SIN‐1‐induced bronchoprotection.ConclusionThese findings demonstrated that SIN‐1 is a potent peroxynitrite‐releasing compound and caused significant bronchoprotection against acetylcholine. The mechanism of bronchoprotection by SIN‐1 appears to be mediated by peroxynitrite but also at least in part through NO regeneration, which may involve GSH and airway thiols as a consequence of exposure to peroxynitrite.
Clinical relevance of food additives in adult patients with atopic dermatitis
Authors: Worm  , Ehlers  , Sterry  , Zuberbier  
Published: March 2003

BackgroundAdverse reactions to food play an important role in the pathogenesis of atopic dermatitis (AD). In infancy and childhood, food allergies are observed in up to 30%, whereas nonallergic hypersensitivity reactions (pseudoallergic reactions) towards food additives have been reported to occur between 2 and 7%. By contrast, sensitizations towards food allergens are rarely of clinical relevance in adults and little data is available on nonallergic hypersensitivity reactions. To date the role of pseudoallergic reactions as an aggravating factor in AD of adult patients remains controversial. However, many adult patients report on food‐related aggravation of the disease and nonallergic hypersensitivity reactions have been incriminated repeatedly.ObjectiveTo elucidate the relevance of food additives in adult patients suffering from AD.MethodsFifty patients were monitored over 4 weeks under regular diet followed by 6 weeks of a diet omitting known pseudoallergens. Skin status of patients was assessed every 2 weeks by a standardized scoring, and serum eosinophilic cationic protein (ECP) was determined before and after diet.ResultsNine of fifty patients dropped out, 26 showed a significant improvement of the Costa‐score by 57%. In 23/26 patients a corresponding reduction of serum ECP level by 52% on average was determined. Responder patients (24/26) were orally challenged with food rich in pseudoallergens followed by double‐blind exposure to food additives (n = 15). A worsening of the eczema was seen in 19/24 patients after intake of pseudoallergen‐rich food and in 6/15 patients after exposure to food additives.ConclusionThese results indicate that a subgroup of adult patients with AD clinically improve on low‐pseudoallergen diet but only a small subgroup respond to oral provocation with food additives.
The challenge procedure influences the extent of allergen‐induced urinary excretion of leukotriene E4
Authors: Kumlin  , Dahlén  
Published: March 2003

BackgroundCysteinyl‐leukotrienes are central mediators in asthma and urinary leukotriene E4 (LTE4) is a reliable marker of their endogenous formation.ObjectiveThis study tested the hypothesis that the procedure used for allergen bronchoprovocation influences the bronchoconstrictor response and the amount of LTE4 excreted following allergen challenge.MethodsSeven atopic asthmatic men underwent two allergen bronchoprovocations 4 weeks apart. The same total dose of allergen was given at both sessions, cumulatively on one occasion and as a single dose at the other session. Urine was collected in hourly samples before and after challenge and LTE4 was measured with previously validated methodology.ResultsThe mean (± se) drop in FEV1 was not significantly different between the cumulative (29 ± 2.4%) and the single dose challenge (25 ± 2.8%). There was a significant increase in post‐challenge levels of urinary LTE4 after both sessions. The peak excretion of LTE4 occurred 1 h following the maximal drop in FEV1 for both challenges. However, the post‐challenge increase in urinary LTE4 was significantly larger at the cumulative session. In fact, the net increase (post‐challenge minus prechallenge) of urinary LTE4 was more than twofold higher after the cumulative session (AUC 0–3 h post‐challenge: 46.7 ± 8.2 vs 22.1 ± 9.8, P < 0.05).ConclusionThe peak excretion of urinary LTE4 occurred within 2 h after the termination of either challenge but the magnitude of urinary excretion of LTE4 was larger when cumulative challenge was performed. The findings are important to consider when designing studies where allergen‐induced urinary excretion of LTE4 is an outcome variable.
Identification and characterization of a group 2 conifer pollen allergen from Chamaecyparis obtusa, a homologue of Cry j 2 from Cryptomeria japonica
Authors: Yasueda  , Saito  , Sakaguchi  , Ide  , Saito  , Taniguchi  , Akiyama  , Inouye  
Published: March 2003

BackgroundNot only Cryptomeria japonica (Japanese cedar) pollen but also that of Chamaecyparis obtusa (Japanese cypress) induces the allergic symptoms of Japanese cedar pollinosis. However, allergens from C. obtusa pollen have not been as well characterized as those from C. japonica pollen.ObjectiveWe sought to identify and characterize a homologue of the second major allergen of C. japonica pollen, Cry j 2, from the pollen of C. obtusa.MethodsAn allergen homologous to Cry j 2 was identified in C. obtusa pollen extract by immunoblot analysis, probed with anti‐Cry j 2 monoclonal antibodies and purified by a series of column chromatographic steps.ResultsThe allergen isolated from the extract showed a slightly diffuse band of 45 kDa and closely spaced double‐bands of 42 and 45 kDa on SDS‐PAGE, under reducing and non‐reducing conditions, respectively; the bands were approximately 5–7 kDa larger than those of Cry j 2. In 24 of 30 residues, the N‐terminal amino acid sequence of the allergen was identical with corresponding sequence in Cry j 2. Most patients with pollinosis who were IgE antibody‐positive to Cry j 2 were shown to be IgE antibody‐positive to this allergen, and the IgE antibody levels to both allergens were highly correlated.ConclusionThe results indicate that the allergen isolated from C. obtusa pollen in this study is a homologue of Cry j 2. The allergen was designated as Cha o 2 according to the WHO/IUIS Allergen Nomenclature Subcommittee recommendation.