bluuebunny/crossref_metadata_2025 huggingface dataset:
Accuracy of eosinophils and eosinophil cationic protein to predict steroid improvement in asthma
Authors: Meijer R. J. , Postma D. S. , Kauffman H. F. , Arends L. R. , Koëter G. H. , Kerstjens H. A. M.
Published: March 2003

Background There is a large variability in clinical response to corticosteroid treatment in patients with asthma. Several markers of inflammation like eosinophils and eosinophil cationic protein (ECP), as well as exhaled nitric oxide (NO), are good candidates to predict clinical response.

Aim We wanted to determine whether we could actually predict a favourable response to inhaled corticosteroids in individual patients.

Methods One hundred and twenty patients with unstable asthma were treated with either prednisolone 30 mg/day, fluticasone propionate 1000 µg/day b.i.d. or fluticasone propionate 250 µg/day b.i.d., both via Diskhaler. They were treated during 2 weeks, in a double‐blind, parallel group, double dummy design. We measured eosinophils and ECP in blood and sputum, and exhaled nitric oxide as inflammatory parameters before and after 2 weeks in order to predict the changes in forced expiratory volume in 1 s (FEV1), provocative concentration of methacholine causing a 20% fall in FEV1 (PC20 Mch), and asthma quality of life (QOL). Secondly, to test whether these results were applicable in clinical practice we determined the individual prediction of corticosteroid response.

Results We found that changes in FEV1, PC20 Mch and QOL with corticosteroids were predominantly predicted by their respective baseline value and to a smaller extent by eosinophils in blood or sputum. ECP, measured in blood or sputum, was certainly not better than eosinophils in predicting clinical response to corticosteroids. Smoking status was an additional predictor for change in FEV1, but not for change in PC20 Mch or QOL. Prediction of a good clinical response was poor. For instance, high sputum eosinophils (≥ 3%) correctly predicted an improvement in PC20 Mch in only 65% of the patients.

Conclusion Our findings show that baseline values of the clinical parameters used as outcome parameters are the major predictors of clinical response to corticosteroids. Eosinophil percentage in blood or sputum adds to this, whereas ECP provides no additional information. Correct prediction of clinical response in an individual patient, however, remains poor with our currently used clinical and inflammatory parameters.
Extractable latex allergens in airborne glove powder and in cut glove pieces
Authors: Kujala V. , Alenius H. , Palosuo T. , Karvonen J. , Pfäffli P. , Reijula K.
Published: March 2003

Background Quantification of natural rubber latex (NRL) allergens of NRL glove extracts has been reported in several studies. Similarly, immunoassay studies reporting the level of NRL aeroallergens in air samples have been published. When studying the NRL allergens of gloves, however, little attention has been focused on identifying the relationship between extractable NRL allergens of medical gloves and NRL aeroallergens in indoor air.

Objective In an experimental study we analysed NRL aeroallergens of medical gloves in joint relation to total airborne dust concentration and NRL allergen concentration in gloves.

Methods NRL aeroallergen level was measured using a chamber setting with 18 lots of powdered medical gloves. In each setting 10 pairs of powdered NRL gloves were swinging in an unventilated chamber (9 m3). Air samples were collected using airflow through Millipore filters (pore size 0.8 µm). The filters were weighed before and after the experiment, and total airborne dust concentration in the chamber was calculated. The filter samples were then extracted and the NRL allergen level measured by IgE ELISA‐inhibition assay. Furthermore, cut NRL gloves were extracted and analysed by the same method. Finally, levels of two major NRL allergens, Hev b1 and Hev b 6.02, were measured in three selected NRL glove brands.

Results The NRL aeroallergen level in the chamber air ranged from < 0.9 to 2.9 allergen units (AU)/m3. The total airborne dust concentration in the chamber air remained low with all lots of gloves measured (range < 20 to 80 µg/m3). The NRL allergen level in cut glove extracts varied over 100‐fold (< 10 to 1050 AU/mL). Statistically significant correlation between aeroallergen concentration and airborne dust (r = 0.8, P = 0.0015) concentration was found. Moreover, significant correlation between aeroallergen levels and allergen content of cut glove pieces was observed (r = 0.59, P < 0.05). Hev b 1 levels varied from 9 to 25 ng/mL and the levels of Hev b 6.02 from 1720 to 14460 ng/mL in the glove extracts. In the extracts from airborne dust samples, Hev b 6.02 content varied from 61 to 183 ng/m3, whereas Hev b 1 levels were very low (0.4 to 3 ng/m3).

Conclusion An elevated NRL aeroallergen level is rather related to a high level of airborne glove powder than to a high concentration of extractable NRL allergen in medical gloves.
Montelukast for treating seasonal allergic rhinitis: a randomized, double‐blind, placebo‐controlled trial performed in the spring
Authors: Philip G. , Malmstrom K. , Hampel F. C. , Weinstein S. F. , LaForce C. F. , Ratner P. H. , Malice M.‐P. , Reiss T. F. ,   for the Montelukast Spring Rhinitis Study Group
Published: March 2003

Background Cysteinyl leukotrienes are important proinflammatory mediators believed to have a role in allergic rhinitis.

Objective This multicentre, randomized, double‐blind, placebo‐ and active‐controlled trial evaluated the effectiveness and tolerability of montelukast, a cysteinyl leukotriene receptor antagonist, for treating patients with seasonal allergic rhinitis.

Methods After a 3‐ to 5‐day, single‐blind placebo run‐in period, 1302 male and female patients (aged 15–81 years) with active allergic rhinitis symptoms were randomly assigned to receive montelukast 10 mg (n = 348), loratadine 10 mg (n = 602), or placebo (n = 352) administered once daily at bedtime for 2 weeks during the spring allergy season.

Results Mean patient characteristics and symptom scores at baseline were similar for the three treatment groups. The primary end‐point, daytime nasal symptoms score (mean of nasal congestion, rhinorrhea, nasal pruritus, and sneezing scores; 0–3 scale), improved from baseline during treatment by (least squares mean, 95% confidence interval) − 0.37 (− 0.43, − 0.31), − 0.47 (− 0.52, − 0.43), and − 0.24 (− 0.29, − 0.18) in the montelukast, loratadine, and placebo groups, respectively (P ≤ 0.001 comparing each active treatment with placebo). Mean changes from baseline in all other diary‐based scores, including night‐time and eye symptom scores, were significantly greater for each active treatment than for placebo. The rhinoconjunctivitis quality of life overall score improved significantly with montelukast and with loratadine as compared with placebo. Montelukast and loratadine showed a safety profile comparable to that of placebo.

Conclusion Montelukast is well tolerated and provides improvements in daytime and night‐time symptoms, as well as quality of life parameters, for patients with seasonal allergic rhinitis.
Oral tolerance induction to Dermatophagoides pteronyssinus and Blomia tropicalis in sensitized mice: occurrence of natural autoantibodies to immunoglobulin E
Authors: Sato M. N. , Oliveira C. R. , Futata E. A. , Victor J. R. , Maciel M. , Fusaro A. E. , Carvalho A. F. , Duarte A. J. S.
Published: March 2003

Background The dust mites Dermatophagoides pteronyssinus (Dp) and Blomia tropicalis (Bt) are important sources of indoor allergens in tropical and subtropical countries. Murine models allow the analysis of the immune response and regulation of IgE production to Dp and Bt allergens. Oral tolerance induces unresponsiveness in naive animals, but its application in sensitized animals can provide useful information to improve allergy therapy.

Objective To study the profile of IgE and IgG subclasses antibody upon oral administration with Bt and Dp extract in previously sensitized mice. Further, the occurrence of autoantibodies IgG anti‐IgE in the immunization and in the oral tolerance was investigated.

Methods A/Sn mice were immunized with Bt or Dp extract in alum, orally administrated with 0.25 mg of Bt or Dp extract or PBS at the 6th, 7th and 8th days after immunization and boosted twice with their respective allergens. To analyse the mice groups, specific IgE antibodies were measured by passive anaphylaxis reaction and specific IgG subclasses and anti‐IgE IgG autoantibody by ELISA assay.

Results IgE levels were markedly increased in Bt‐immunized mice compared with Dp‐immunized mice. A distinct profile of the specific isotypes was verified in Bt‐immunized mice with a preferential production of IgG3 and IgA antibodies, whereas Dp‐immunized mice developed high titres of anti‐Dp IgG1, IgG2a and IgG2b antibodies. The antigen feeding inhibited IgE response in both fed‐mice groups but only Dp‐fed mice presented decreased levels of IgG antibodies. Free anti‐IgE IgG autoantibodies were detected mainly in the Dp‐immunization and they correlated with the antibody isotypes found against the allergen.

Conclusions This is the first time that the murine‐type I hypersensitivity is employed to study Bt‐immunization, showing a marked IgE production, associated with IgG response, which is at least in part driven by T‐independent antigens. The oral tolerance protocol in previously sensitized animals was able to down‐modulate IgE response and points out this route as a strategy for allergy therapy.
A rapid test for detection of mite allergens in homes
Authors: Tsay A. , Williams L. , Mitchell E. B. , Chapman M. D.
Published: March 2003

Background International guidelines recommend allergen avoidance for asthma management, but do not include making assessments of allergen exposure. Mite allergen exposure cannot be assumed, especially in geographical regions where climatic conditions vary.

Objective To develop a rapid test that would enable consumers to detect mite allergen in the home.

Methods A lateral flow test using gold labelled antibody for mite group 2 allergen was developed as part of a detection kit incorporating the MITEST dust sampling device. Dust samples were assayed by ELISA for group 1 and group 2 allergens and by using the rapid test. The tests were compared as indices of mite allergen exposure.

Results There was a good correlation between group 1 and group 2 levels by ELISA (n = 349, r = 0.60, P < 0.001). In a multi‐centre study of 65 homes (263 dust samples) in five countries, there was a strong correlation between ELISA and the rapid test. Most samples with high scores in the test (43/48, 90%) contained > 1 µg/m2 group 2 allergen, whereas most low samples contained < 1 µg/m2 (50/64, 78%). Differences between mean group 2 levels of samples that scored low (0.28 µg/m2), medium (1.68 µg/m2) or high (3.18 µg/m2) on the test were highly significant (P 0.007 to < 0.001).

Conclusions A simple rapid test has been developed that detects mite allergen in the home within 10 min. The mite screening test should educate consumers about allergen exposure and encourage compliance with allergen‐avoidance procedures. This technology has applications for the detection of other common environmental allergens.
Allergen‐induced bronchial inflammation in house dust mite‐allergic patients with or without asthma
Authors: Lopuhaä C. E. , Out T. A. , Jansen H. M. , Aalberse R. C. , Van Der Zee J. S.
Published: March 2003

Background It is presently unknown which factors determine the occurrence and persistence of asthma in house dust mite‐allergic individuals. The level of allergen‐specific IgE antibodies does not seem to be decisive for asthmatic symptoms. Moreover, levels of exposure to mite allergens do not seem to differ significantly between asthmatic and non‐asthmatics individuals.

Aim It was hypothesized that the presence or absence of asthmatic symptoms in house dust mite‐allergic patients is associated with quantitative or qualitative differences in the cellular bronchial inflammatory response during the late phase of the allergic reaction. This hypothesis was tested in the bronchial allergen challenge model.

Material and methods Whole lung challenges with house dust mite extract were performed in 52 house dust mite‐allergic subjects, of whom 26 had asthma and 26 had perennial rhinitis without asthmatic symptoms. Primary outcomes were parameters for bronchial inflammation in serial samples of induced sputum (cell differentials, eosinophil cationic protein (ECP), interleukin‐8 (IL‐8), myeloperoxydase (MPO)). In addition, lung function, non‐specific bronchial hyper‐ responsiveness and serial blood samples (eosinophils and IL‐5) were analysed.

Results At baseline sputum eosinophils and ECP were similar in both groups but neutrophils and IL‐8 were higher in asthmatics. The early bronchoconstriction after allergen challenge was similar in asthma and non‐asthmatic rhinitis (median decrease in FEV1: asthma − 31.7% vs. non‐asthmatics − 29.1%, P > 0.1). The late phase bronchoconstriction was significantly greater in asthma (median decrease in FEV1: asthma − 27.6% vs. non‐asthmatics − 18.9%, P = 0.02). Induction of bronchial hyper‐responsiveness was similar in both groups. Bronchial allergen challenge elicited significant increases in sputum eosinophils and ECP, which were indistinguishable for both groups (P > 0.1 and P = 0.07, respectively). In contrast, higher numbers of neutrophils persisted in asthma 24 h after challenge and were accompanied by significant increases in IL‐8 and MPO, which were absent in non‐asthmatics (difference between groups P = 0.007 and P = 0.05, respectively).

Conclusion Allergen challenge induced very similar increases in eosinophils and ECP in induced sputum in allergic asthmatics and in allergic non‐asthmatic patients. The difference in bronchial inflammation between asthma and non‐asthmatic rhinitis appeared to be more closely related to indices for neutrophilic inflammation.
Safety of inhalant allergen immunotherapy with mass units‐standardized extracts
Authors: Nettis E. , Giordano D. , Pannofino A. , Ferrannini A. , Tursi A.
Published: March 2003

Background Allergen‐specific immunotherapy (SIT) is an effective treatment for patients with respiratory allergies. However, subcutaneous injection of allergens can provoke systemic side‐effects.

Objective This study was carried out to determine the incidence and risk factors of systemic reactions caused by SIT treatment, using extracts of different inhalant allergens, adsorbed in aluminium hydroxide and biologically standardized with the major allergens quantified in mass units.

Methods Five hundred and fifty‐five subjects with allergic rhinitis and/or asthma were evaluated on clinical history and skin prick test (SPT) reactions to common inhalant allergens. Subcutaneous SIT was administered to all patients, according to the suggested precautionary guidelines and administration schedule. Patients were treated with house dust mite, grass pollen, Parietaria judaica pollen and olive pollen extracts, each receiving one or two extracts.

Results A total of 36 359 injections were administered in the 555 patients. We observed 34 episodes of serious systemic side‐effects (0.093% of all injections), in 29 patients (5.2% of all patients), and no fatalities. About 55% of patients reported mild rhinitis and asthma. The majority (59%) of the serious systemic reactions (SSR), and all the anaphylactic reactions, were immediate (i.e. occurred within 30 min after the injection). Asthmatic subjects were at higher risk of SSR than patients with rhinitis (P = 0.01). Most of the side‐effects observed occurred during the dose‐increase phase (P < 0.05). There was no association of SSR with age, gender, SPT reactivity or allergen type.

Conclusion SIT performed in patients with respiratory allergies by specialized staff with the allergen extracts studied, standardized in mass units, provoked a low rate of SSR. The significant risk factors for systemic reactions were asthma and the build‐up period.
The range of minimum provoking doses in hazelnut‐allergic patients as determined by double‐blind, placebo‐controlled food challenges
Authors: Wensing M. , Penninks A. H. , Hefle S. L. , Akkerdaas J. H. , Van Ree R. , Koppelman S. J. , Bruijnzeel‐Koomen C. A. F. M. , Knulst A. C.
Published: March 2003

Background The risk for allergic reactions depends on the sensitivity of individuals and the quantities of offending food ingested. The sensitivity varies among allergic individuals, as does the threshold dose of a food allergen capable of inducing an allergic reaction.

Objective This study aimed at determining the distribution of minimum provoking doses of hazelnut in a hazelnut‐allergic population.

Methods Thirty‐one patients with a history of hazelnut‐related allergic symptoms, a positive skin prick test to hazelnut and/or an elevated specific IgE level, were included. Double‐blind, placebo‐controlled food challenges (DBPCFC) were performed with seven increasing doses of dried hazelnut (1 mg to 1 g hazelnut protein) randomly interspersed with seven placebo doses.

Results Twenty‐nine patients had a positive challenge. Itching of the oral cavity and/or lips was the first symptom in all cases. Additional gastrointestinal symptoms were reported in five patients and difficulty in swallowing in one patient. Lip swelling was observed in two patients, followed by generalized urticaria in one of these. Threshold doses for eliciting subjective reactions varied from a dose of 1 mg up to 100 mg hazelnut protein (equivalent to 6.4–640 mg hazelnut meal). Extrapolation of the dose–response curve showed that 50% of our hazelnut‐allergic population will suffer from an allergic reaction after ingestion of 6 mg (95% CI, 2–11 mg) of hazelnut protein. Objective symptoms were observed in two patients after 1 and 1000 mg, respectively.

Conclusion DBPCFCs demonstrated threshold doses in half of the hazelnut‐allergic patients similar to doses previously described to be hidden in consumer products. This stresses the need for careful labelling and strategies to prevent and detect contamination of food products with hazelnut residues.
Relationship between changes in interferon‐γ production by peripheral blood T cells and changes in peak expiratory flow rate in patients with chronic stable asthma
Authors: Koh Y. I. , Choi I. S. , Lee H.‐C.
Published: March 2003

Background Cytokines production by T helper lymphocytes (Th cells), which orchestrate the interplay of the different cells involved in airway inflammation of asthma, may be reflected in peripheral blood. Some studies have suggested that the Th cell cytokines by peripheral blood T cells correlate with asthma severity.

Objective To investigate the relationship between changes in IFN‐γ production by peripheral blood T cells and changes in lung function in chronic stable asthmatics.

Methods Sixteen patients with chronic stable moderate asthma aged 35–65 years (nine women) were recruited. Morning and evening peak expiratory flow rates (PEFR) monitoring and blood sampling for peripheral blood T cell culture, total IgE and blood eosinophils were performed at baseline and week 12. Levels of IFN‐γ, IL‐4 and IL‐5 in culture supernatants of peripheral blood T cell were determined by using enzyme‐linked immunosorbent assay (ELISA) kits.

Results Patients with increased IFN‐γ changes from baseline showed significantly increased changes in morning (P = 0.02) and evening (P < 0.05) PEFR compared with those with decreased IFN‐γ changes. The changes in IFN‐γ production and IFN‐γ: IL‐4 ratio significantly correlated with the changes in morning PEFR (Rs = 0.59, P < 0.02; Rs = 0.63, P < 0.01, respectively) and tended to correlate with the changes in evening PEFR (Rs = 0.45, P = 0.08; Rs = 0.5, P = 0.05, respectively). The changes in IL‐4 and IL‐5 did not correlate with the changes in IgE and blood eosinophils, respectively.

Conclusions These findings suggest that IFN‐γ may be associated with the alteration of lung function in asthmatics and play a role in the pathophysiology of chronic stable asthma.
Atopy and serum eosinophil cationic protein in 110 white children with vernal keratoconjunctivitis: differences between tarsal and limbal forms
Authors: Pucci N. , Novembre E. , Lombardi E. , Cianferoni A. , Bernardini R. , Massai C. , Caputo R. , Campa L. , Vierucci A.
Published: March 2003

Background A predominance of Th2 response has been suggested in vernal keratoconjunctivitis (VKC), and a high prevalence of IgE‐sensitized (IgE‐S) patients has been reported (positive skin prick test or serum‐specific‐IgE). Palpebral and bulbar VKC are considered to be expressions of the same disease and only occasional racial and histopathological differences are described between the two forms. Tear levels of eosinophil cationic proteins have been correlated with the severity of ocular symptoms; however, there is no published study that demonstrates the presence of serum markers of disease activity.

Objective This study was performed to evaluate the prevalence of IgE‐sensitization in palpebral, bulbar and mixed VKC and to determine possible useful markers of disease activity in peripheral circulation.

Methods A total of 110 white VKC patients (mean age 8.3 years, range 3.2–18 years) were evaluated for ocular score in the active phase of the disease. Skin prick tests and serum‐specific IgE for common allergens, serum‐total IgE, peripheral blood eosinophil counts (PBECs) and serum eosinophil cationic protein (s‐ECP) were determined. Fifteen age‐matched non‐IgE‐S control children underwent the same determinations.

Results s‐ECP, PBECs and s‐total IgE were significantly higher in IgE‐S than in non‐IgE‐S VKC patients and in non‐IgE‐S VKC patients than in controls. A lower prevalence of IgE‐S patients was found in bulbar vs. tarsal (P = 0. 050) or mixed forms (P = 0.002). The score of giant papillae was strongly correlated with s‐ECP levels (P < 0.001) and with PBECs (P = 0.001).

Conclusions Our data suggest that an overall eosinophilic response is present in VKC independently of IgE‐sensitization; bulbar forms, unlike tarsal and mixed forms, were associated with a low prevalence of IgE‐sensitization. Serum ECP was a useful marker of disease activity in tarsal and mixed forms.
Microarrayed recombinant allergens for diagnosis of allergy
Authors: Harwanegg C. , Laffer S. , Hiller R. , Mueller M. W. , Kraft D. , Spitzauer S. , Valenta R.
Published: March 2003

We suggest that the coapplication of recombinant allergens and microarray technology can lead to the development of new forms of multi‐allergen tests which allow the determining and monitoring of complex sensitization profiles of allergic patients in single assays. The allergen extracts which have so far been used for diagnosis only allowed the determining of whether an allergic patient is sensitized against a particular allergen source, but the disease‐eliciting allergens could not be identified. Through the application of recombinant DNA technology a rapidly growing panel of recombinant allergen molecules has become available which meanwhile comprises the epitope spectrum of most of the important allergen sources. We demonstrate that microarray technology can be used to establish multi‐allergen tests consisting of microarrayed recombinant allergen molecules. Microarrayed recombinant allergens can be used to determine and monitor the profile of disease‐eliciting allergens using single tests that require minute amounts of serum from allergic patients. The wealth of diagnostic information gained through microarray‐based allergy testing will likely improve diagnosis, prevention and treatment of allergy.
Clinical effects of air filters in homes of asthmatic adults sensitized and exposed to pet allergens
Authors: Francis H. , Fletcher G. , Anthony C. , Pickering C. , Oldham L. , Hadley E. , Custovic A. , Niven R.
Published: March 2003

Background Despite medical advice, many pet‐allergic asthma sufferers refuse to remove the pet to which they are sensitized from their home.

Objective We aimed to assess the clinical effects of air cleaners in the homes of adult asthma patients sensitized and exposed to cats and/or dogs.

Methods We performed a randomized, parallel‐group study of 30 asthmatic adults sensitized to and sharing a home with cats or dogs. The effects of placing air cleaners in the living room and bedroom for 12 months and using high efficiency particulate air filter vacuum cleaners (active group) were compared with using these vacuum cleaners alone (control group). Measures of airway responsiveness, treatment requirement, lung function, peak flow, reservoir and airborne allergen were recorded before, during and after the interventions. A beneficial clinical response was assessed in terms of a ‘combined asthma outcome’. This was defined as a two or more doubling dose improvement in bronchial hyper‐reactivity to histamine and/or a reduction in treatment requirement of at least one step change on the British Thoracic Society guidelines for asthma treatment.

Results A beneficial clinical response was observed in 10/15 subjects in the active group compared with 3/15 in the control group after 12 months intervention (P = 0.01). No significant differences between the active and control groups were detected for changes in measures of lung function, reservoir pet allergen and airborne pet allergen during the study.

Conclusion Whilst the study design has not allowed complete exclusion of a placebo effect, we believe that this pragmatic study of adult asthmatic patients sensitized and exposed to pets resulted in a small, but significant improvement in combined asthma outcome.
Th1/Th2 profile in peripheral blood in atopic cough and atopic asthma
Authors: Shirai T. , Suzuki K. , Inui N. , Suda T. , Chida K. , Nakamura H.
Published: March 2003

Background Eosinophilic tracheobronchitis with cough hypersensitivity, abbreviated as atopic cough, is an important cause of chronic cough. The reason for the absence of airway hyper‐responsiveness is unknown, differing from asthma, a Th2 cytokine‐mediated disorder.

Objective To compare the type 1 helper T cell (Th1)/Th2 balance in the peripheral blood from subjects with atopic cough and atopic asthma, we assessed the intracellular cytokine production at the single‐cell level.

Methods Thirty‐six subjects (10 patients with atopic cough, 18 with atopic asthma, and eight control subjects) were included. Intracellular IL‐4 and IFN‐γ were detected in CD4+ T cells by flow cytometry.

Results A significantly lower ratio of IFN‐γ‐/IL‐4‐producing CD4+ T cells after phorbol 12‐myristate acetate/ionomycin stimulation was found in patients with atopic cough and atopic asthma compared with normal subjects. In comparison between atopic patients, the ratio of IFN‐γ‐/IL‐4‐producing cells was significantly higher in atopic cough than in atopic asthma. However, the proportion of IL‐4‐producing CD4+ T cells was significantly higher in patients with atopic asthma than in normal control subjects and no significant difference was detected between patients with atopic cough and normal subjects. No significant difference in the proportion of IFN‐γ‐producing cells was found between the subjects. Overall, the total IgE levels were positively correlated to the IL‐4‐producing cells and inversely correlated to the ratio of IFN‐γ‐/IL‐4‐producing cells.

Conclusion These results show the lower degree of Th2 cytokine predominance in atopic cough compared with atopic asthma and suggest the relation between the Th1/Th2 balance and atopic status.
Sibling effect on atopy in children of patients with asthma
Authors: Koppelman G. H. , Jansen D. F. , Schouten J. P. , Van Der Heide S. , Bleecker E. R. , Meyers D. A. , Postma D. S.
Published: March 2003

Background Multiple population studies have shown the presence of a sibling effect on atopic disease. However, it is unclear if the sibling effect is also of importance in subjects who are genetically at high risk for the development of atopy.

Objective To study the presence of a sibling effect on markers of atopy (serum total IgE, specific IgE, skin tests) and asthma (bronchial hyper‐responsiveness to histamine) in families ascertained through a parent with asthma.

Methods First‐degree offspring in 200 asthma families were studied (n = 541). Mixed effects regression models were used to account for the dependence of the observations within a family, and to adjust for possible confounding variables.

Results Multiple regression analysis showed that having older siblings was inversely related to atopy, defined as ≥ 2, ≥ 3, ≥ 4, or ≥ 5 skin tests (P = 0.07–0.009). In addition, family size (number of siblings) had a significant protective effect on the presence of specific IgE to common aeroallergens (P = 0.03). Exposure to cigarette smoke in the first 3 years of life significantly increased the risk of having specific IgE to common aeroallergens (P = 0.04). No sibling effect was detected for serum total IgE or bronchial hyper‐responsiveness to histamine.

Conclusions This study shows a protective sibling effect on the presence and severity of atopy but not on bronchial hyper‐responsiveness in children who are genetically at risk. The identification of the sibling effect in high‐risk families stresses the need to understand the basis of this effect, in order to design future prevention programmes.
Acquired crateriform hyperkeratotic papules of the lower limbs: an unusual variant of acrokeratoelastoidosis of Costa
Authors: Helbling I. , Tucker S. C. , Chalmers R. J. G.
Published: March 2003

We report a man with a 3-year-history of a striking eruption of small, 2–3 mm diameter keratotic, crateriform papules distributed symmetrically over the lower limbs. Morphologically the individual papules closely resembled those described in acrokeratoelastoidosis (AK) of Costa and in focal acral hyperkeratosis of Dowd (FAH). The case is unusual, however, in that there was dramatic involvement of the legs but the hands and feet were largely spared. Current terms used for these entities are unsatisfactory.
Oxidative stress in physical urticarias
Authors: Briganti S. , Cristaudo A. , D'Argento V. , Cassano N. , Turbino L. , Guarrera M. , Vena G. , Picardo M.
Published: March 2003

The pathogenesis of the physical urticarias has not been completely defined. Indeed, different stimuli can induce similar clinical manifestations, some of which are capable of generating reactive oxygen species. In order to evaluate whether the generation of an oxidative stress response could be a common pathogenetic mechanism of the disease, we have determined the profile of a number of chemical and enzymatic antioxidants in blood samples from a group of patients with physical urticarias. Compared with controls, a systemic imbalance of the antioxidants was detected in the patient group with a decrease of both plasma vitamin E and cellular catalase and glutathione peroxidase activities along with an increase of superoxide dismutase activity. Moreover, an increase in the percentage of plasma polyunsaturated fatty acids, as a target for peroxidative damage, was also observed. These alterations may lead to an increased percentage of peroxidable compounds in skin and to the intracellular generation of reactive oxygen species and could therefore provide one possible explanation for the patients' urticarial response to stimuli. Even if the alteration of the antioxidant status is secondary to changes in cytokine or complement activation, our results suggest a common biochemical profile in patients with different forms of physical urticaria.
Splenic T helper cell type 1 cytokine profile and extramedullary haematopoiesis in severe combined immunodeficient (scid) mice with inflammatory bowel disease (IBD)
Authors: Bregenholt S , Claesson M H
Published: March 2003

Scid mice develop a severe, chronic, and lethal IBD 3–6 months after engraftment of gut wall from immunocompetent congenic donors, induced by donor-derived CD4+ T cells migrating from the graft [7]. We have investigated intracellular T-helper type 1 (Th1) cytokines in the spleens of gut wall-transplanted scid mice with IBD. Increased fractions of interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and IL-2-positive CD4+ T cells were found in the spleens of diseased mice compared with control mice. Moreover, a small but significant population of CD4+ T cells which stained positive for granulocyte-macrophage colony-stimulating factor (GM-CSF) was found in scid mice with IBD but was virtually absent in congenic non-scid control mice. Cloning of granulocyte/macrophage colony-forming cells (G/M-CFC) revealed that both non-transplanted scid mice and scid mice with IBD had an 8–14-fold increase in splenic G/M-CFC compared with control mice. No significant difference in the number of G/M-CFC per total spleen was found between non-transplanted and disease scid mice, although both groups of mice showed a nearly two-fold increase compared with control mice. G/M-CFC were never found in the thymus, liver or lymph nodes of diseased mice. Immunohistochemistry revealed that the multinucleated giant cells observed in the gut wall of diseased mice did not represent haematopoietic foci, but were derived from macrophages. These observations point towards a dominant role for Th1-type CD4+ T cells in the immunopathogenesis of IBD, whereas haematopoiesis does not seem to be affected by the development of the disease.
Evaluation of IgA deficiency in Sardinians indicates a susceptibility gene is encoded within the HLA class III region
Authors: Cucca F , Zhu Z B , Khanna A , Cossu F , Congia M , Badiali M , Lampis R , Frau F , De Virgiliis S , Cao A , Arnone M , Piras P , Campbell R D , Cooper M D , Volanakis J E , Powis S H
Published: March 2003

IgA deficiency (IgA-D) has been associated with the HLA region, in particular with the North European haplotype HLA-A1, -B8, -DR3, but the exact location of the susceptibility gene(s) is unknown. Some reports suggest that a susceptibility gene is encoded in the class II region, while others implicate the class III region. We exploited differences between the common Sardinian and North European HLA-DR3 haplotypes to help localize the IgA-D susceptibility gene(s). With the knowledge that approximately 13% of HLA-DR3 homozygous individuals of North European origin are IgA-D, we examined 43 HLA-DR3 homozygous Sardinians to find that all had normal serum IgA, IgG and IgM levels. A detailed analysis of their MHC haplotypes indicated a common Sardinian HLA-DR3 haplotype TAP1A, TAP2A, HLA-DQB1*0201, -DQA1*0501, -DRB1*0301, LH1-(Z  +  2), D3A-(Z  +  2), C4B-0, C4A-L, G11-15, Bf-0.4, C2-a, HSP70-7.5, 9N3-(Z  +  10), 82I-(Z  −  2), TNFα-9, 62-(Z  −  20), HLA-B18, -Cw5, -A30 which diverges from the common North European HLA-DR3 haplotype telomeric to the HLA-DR region. In parallel studies of five Sardinians with IgA-D, two of the 10 HLA haplotypes (20%) contained HLA-DR3, a frequency similar to that observed in the background population. One of these was the HLA-DR3- B8 North European haplotype, which occurs rarely in Sardinia. Our data favour the hypothesis that a class III region allele, present on the common North European but not on the Sardinian HLA-DR3 haplotype, confers susceptibility to IgA-D.
Effect of annexin-1 on experimental autoimmune encephalomyelitis (EAE) in the rat
Authors: Huitinga I , Bauer J , Strijbos P J L M , Rothwell N J , Dijkstra C D , Tilders F J H
Published: March 2003

Annexin-1, a calcium-dependent phospholipid binding protein, has been shown to act as an endogenous central neuroprotectant, notably against cerebral ischaemic damage. In the present study we extend these findings to an animal model of multiple sclerosis, EAE, and report that endogenous annexin-1 is expressed in ED1+ macrophages and resident astrocytes localized within the lesions in the central nervous system (CNS). Intracerebroventricular (icv) administration of an NH2-terminal fragment spanning amino acids 1–188 of annexin-1 after the onset of the clinical symptoms significantly reduced both the neurological severity as well as weight loss of mild EAE. Immunoneutralization of endogenous brain annexin-1 failed to exacerbate the clinical features of EAE. Thus, although the role of endogenous annexin-1 in the pathogenesis of EAE remains to be determined, our findings suggest that annexin-1 may be of therapeutic benefit to the treatment of multiple sclerosis.
Detection of complement C3 and factor B gene expression in normal colorectal mucosa, adenomas and carcinomas
Authors: Andoh A , Fujiyama Y , Sakumoto H , Uchihara H , Kimura T , Koyama S , Bamba T
Published: March 2003

Local secretion of complement components in the human intestine has been previously reported. However, the cellular source has not been identified. In this study, we demonstrate complement C3 and factor B mRNA expression in the normal colonic mucosa by in situ hybridization analysis. C3 and factor B genes were found to be expressed at high levels in the epithelial cells of the lower parts of the crypts in colonic mucosa, and this expression decreased gradually from the crypt base to the luminal surface. At the upper crypt and the luminal surface, these genes almost disappeared. C3 and factor B genes were expressed in all crypts at the same level. Furthermore, C3 and factor B gene expression was also identified in adenomas and carcinomas. In these neoplastic tissues, C3 and factor B genes were expressed uniformly, and the polarized distribution observed in the normal crypts was not detected. It is likely that complement components are locally synthesized in the intestine, and that these complement components may actively participate in normal immune and inflammatory responses over the enormous surface area of the intestinal mucosa.
Anti-mitochondrial antibodies in patients with dilated cardiomyopathy (anti-M7) are directed against flavoenzymes with covalently bound FAD
Authors: Otto A , Stähle I , Klein R , Berg P A , Pankuweit S , Brandsch R
Published: March 2003

Anti-mitochondrial antibodies (anti-M7) in sera from patients with dilated cardiomyopathy and myocarditis recognize, besides mitochondrial antigens, bacterial sarcosine dehydrogenase. The common target antigen was identified as the covalently bound FAD of mitochondrial and bacterial flavoenzymes. Thus, anti-M7-positive serum reacted on Western blots exclusively with covalently flavinylated enzymes. The antigenic specificity of anti-M7 sera was reproduced by an antiserum raised in rabbits with 6-hydroxy-d-nicotine oxidase. The heart mitochondrial membrane antigen recognized by anti-M7 serum was identified as the flavoprotein subunit of succinate dehydrogenase, the antigens in rat liver mitochondrial matrix as the flavoenzymes dimethylglycine dehydrogenase and sarcosine dehydrogenase. Anti-M7 serum contained a specific anti-flavoenzyme antibody fraction. Nanomolar concentrations of FAD and riboflavin inhibited the immune reaction on Western blots and in ELISA, and incubation with FAD-agarose depleted the anti-M7 activity of the serum. N-terminally deleted dimethylglycine dehydrogenase proteins were only immunoprecipitated by anti-M7 sera when the FAD was covalently incorporated. An affinity constant (KD) of 10−8 m was established for the anti-flavoenzyme antibodies by competitive ELISA. Of patients with cardiomyopathy and myocarditis, 36% and 25%, respectively, were anti-flavoenzyme-positive by Western blot and ELISA, but only two of 15 patients with other heart diseases and none of 50 healthy controls.
A tumour necrosis factor-alpha (TNF-α) promoter polymorphism is associated with chronic hepatitis B infection
Authors: Höhler T , Kruger A , Gerken G , Schneider P M , Meyer Zum Büschenfelde K-H , Rittner C
Published: March 2003

Cytokines such as TNF-α and interferon gamma (IFN-γ) are important for the elimination of infected hepatocytes during acute hepatitis B virus (HBV) infection. Two G versus A transitions in the TNF-α promoter region at positions −308 and −238 possibly influence TNF-α expression. We investigated these TNF-α polymorphisms in 71 patients with chronic HBV infection, in 32 subjects that had spontaneously recovered from acute HBV infection, and in 99 healthy controls. The −238 A promoter variant was present in 18 (25%) of 71 patients with chronic HBV infection compared with two (6%) of 32 subjects with acute infection (P < 0.04), and seven (7%) of 99 controls (P < 0.003). By contrast, the prevalence of the variant at position −308 was similar in all investigated groups. The observed differences could not be explained by linkage disequilibrium to HLA-B or -DRB1* alleles. These findings suggest an association between the TNF-α promoter polymorphism at position −238 and the development of chronic HBV infection. This promoter variant appears to be linked to defective viral clearance.
Effects of granulocyte colony-stimulating factor (G-CSF) treatment on granulocyte function and receptor expression in patients with ventilator-dependent pneumonia
Authors: Hustinx W N M , Van Kessel C P M , Heezius E , Burgers S , Lammers J-W , Hoepelman I M
Published: March 2003

Considerable experimental evidence in animals suggests that treatment with G-CSF may have a beneficial effect in the management of severe infections in non-neutropenic hosts. This beneficial effect is attributed to an enhancement of granulopoiesis and neutrophil function, the latter possibly involving up-regulation of receptors on neutrophils that are involved in antibody-mediated cytotoxicity and killing of microorganisms. We compared neutrophil function and phenotype in blood and bronchoalveolar lavage fluid (BALF) of 10 patients with severe ventilator-dependent pneumonia, at baseline and following initiation of G-CSF treatment as adjunct to standard therapy. G-CSF treatment was associated with three-fold increased blood neutrophil counts at day 3 of treatment compared with baseline counts. Mean serum G-CSF concentration increased from 313 to 2007 pg/ml. After correction for lavage dilution effects, BALF G-CSF levels did not differ significantly from baseline, nor did neutrophil receptor expression (FcγRI, FcγRII, FcγRIII, CR3, and l-selectin) or indicators of neutrophil function such as respiratory burst activity, phagocytosis and killing of Candida albicans in BALF or blood. The mortality in this group of patients was 30% and compared favourably to the APACHE II-derived predicted mortality of 60%. We conclude that the possible therapeutic benefit of G-CSF administration in the early phase of severe bacterial pneumonia is not readily explained by its effect on baseline indicators of neutrophil function or receptor expression.
Induction of unresponsiveness against IgA in IgA-deficient patients on subcutaneous immunoglobulin infusion therapy
Authors: Sundin U , Nava s , Hammarström L
Published: March 2003

Patients with IgA deficiency often demonstrate circulating antibodies against IgA, which have been suggested to be associated with transfusion reactions. Sera from three patients with common variable immunodeficiency (CVID) and one with a selective IgA deficiency with anti-IgA antibodies receiving subcutaneous gammaglobulin replacement therapy were analysed for serum levels of IgG, IgA and anti-IgA before and during a treatment period of 4–7 years. Treatment with gammaglobulin preparations containing significant amounts of IgA (< 5 mg/ml) resulted in a decrease or disappearance of the anti-IgA antibodies. Analysis of serum fractions, however, revealed anti-IgA activity in the complex-containing fractions. In vitro experiments gave similar results with a shift of anti-IgA activity from the monomeric to the complex-containing fractions (that could not be detected in whole serum). When the patients were subsequently switched to treatment with a preparation containing less IgA (< 80 μg/ml) or made an interruption in the treatment schedule, the anti-IgA antibodies reappeared. Importantly, however, one of the patients lost his anti-IgA activity during a 3-month period on the preparation containing the higher IgA levels, and these antibodies did not reappear after switching to the low IgA-containing preparation. After 5 years on this preparation, anti-IgA can still not be detected, suggesting induction of unresponsiveness.
Immunity to type IX collagen in rodents: a study of type IX collagen for autoimmune and arthritogenic activities
Authors: Cremer M A , YE X J , Terato K , Griffiths M M , Watson W C , Kang A H
Published: March 2003

Type IX collagen (CIX), a cartilage-specific glycoprotein, constitutes ≤ 10% of cartilage collagen. To ascertain whether CIX can induce arthritis as shown for type II and XI collagen (CII and CXI), outbred rats were sensitized with bovine, chick and human CIX; inbred rats, mice, and guinea pigs were sensitized with bovine CIX. Mice and guinea pigs proved resistant to arthritis, as did rats sensitized with CIX/Freund's incomplete adjuvant (FIA). Arthritis was seen in rats when 100 μg of Mycobacterium tuberculosis (Mtb) were added to FIA, but seldom with smaller doses of Mtb, suggesting the arthritis was adjuvant-induced. High levels of antibodies to rat CIX, containing complement-fixing subclasses, were detected in rat sera in addition to DTH and lymphocyte proliferation responses to rat CIX. Given the potential for CIX-induced disease, CIX-sensitized rats were injected intraperitoneally with lipopolysaccharide (LPS) to stimulate proinflammatory cytokine release, and intra-articularly with rat CIX to stimulate arthritis. LPS stimulation was ineffective; however, intra-articularly injected CIX produced transient synovitis. When rats with stable adjuvant arthritis were sensitized with CIX/FIA, significant increases in paw volume were measured compared with controls given CI/FIA. Immunohistochemical studies of actively and passively sensitized rats revealed deposits of CIX antibody, but not C3, at the joint margins where proteoglycan staining was weak. Together, these findings suggest that autoimmunity to CIX, in contrast to CII and CXI, is not directly pathogenic but may contribute to joint injury provided arthritis is initiated by an independent disease process.