bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperfractionated cyclophosphamide in combination with pulsed dexamethasone and thalidomide (HyperCDT) in primary refractory or relapsed multiple myeloma
Authors: Kropff Martin H. , Lang Nicola , Bisping Guido , Dominé Nicole , Innig Georg , Hentrich Markus , Mitterer Manfred , Südhoff Thomas , Fenk Roland , Straka Christian , Heinecke Achim , Koch Olaf M. , Ostermann Helmut , Berdel Wolfgang E. , Kienast Joachim
Published: August 2003

Summary. Sixty patients with advanced multiple myeloma received 2–6 monthly treatment courses combining hyperfractionated cyclophosphamide (300 mg/m2 i.v. over 3 h q 12 h × 6, d 1–3) with pulsed dexamethasone (20 mg/m2/d p.o., d 1–4, 9–12, 17–20) and once daily thalidomide at individually escalating doses (100–400 mg/d) depending on tolerability (HyperCDT). Responding patients were maintained on daily thalidomide and monthly dexamethasone pulses. Complete, partial and minor response rates were 4%, 68% and 12% respectively; overall response rate was 84% (efficacy analysis). Median event‐free and overall survival was 11 and 19 months respectively. During at least one treatment cycle, 67% of patients experienced grade 4 neutropenia resulting in 17% grade 3 and 9% grade 4 infections. Side‐effects, presumably related to thalidomide, included neuropathy (40% grade 2, 16% grade 3), constipation (17%), oedema (5%), bradycardia (5%), skin reactions (3%), cerebrovascular events (5%) and deep vein thromboses (8%). Thromboses were not related to known thrombophilic risk factors. Four patients with prior myeloma therapy > 50 months developed myelodysplastic syndrome or secondary acute myeloid leukaemia 2–4 months after study entry. HyperCDT is a highly active and reasonably well‐tolerated salvage regimen in advanced or refractory multiple myeloma.
McLeod syndrome resulting from a novel XK mutation
Authors: Singleton Belinda K. , Green Carole A. , Renaud Susanne , Fuhr Peter , Poole Joyce , Daniels Geoff L.
Published: August 2003

Summary. McLeod Syndrome (MLS) is a rare X‐linked disorder characterized by haemopoietic abnormalities and late‐onset neurological and muscular defects. The McLeod blood group phenotype is typically associated with erythrocyte acanthocytosis, absence of the Kx antigen and reduced expression of Kell system antigens. MLS is caused by hemizygosity for mutations in the XK gene. We describe a patient with MLS who first showed symptoms in 1989 (aged 51 years). As the disease progressed, the patient developed a slight dementia, aggressive behaviour and choreatic movements. A cardiomyopathy was also diagnosed. An electroneuromyography showed neuropathic and myopathic changes. Liver enzymes were elevated and a blood smear showed acanthocytes. MLS was confirmed by serological analysis of the Kell antigens. Analysis of red blood cells by flow cytometry revealed the patient and his grandson to have reduced Kell antigen expression. The patient's daughters had two populations of red cells, consistent with them being heterozygous for an XK0 allele. The molecular basis of MLS in this family is a novel mutation consisting of a 7453‐bp deletion that includes exon 2 of the XK gene. This confirms that the patient's 7‐year‐old grandson, who is currently asymptomatic, also has the XK0 allele and is therefore likely to develop MLS.
Does sticky blood predict a sticky end? Associations of blood viscosity, haematocrit and fibrinogen with mortality in the West of Scotland
Authors: Woodward Mark , Rumley Ann , Tunstall‐Pedoe Hugh , Lowe Gordon D. O.
Published: August 2003

Summary. There is increasing evidence that blood viscosity and its major determinants (haematocrit, plasma viscosity and fibrinogen) are associated with an increased risk of incident cardiovascular events; however, their associations with mortality are not established. We therefore studied the associations of these variables with cardiovascular events and total mortality in 1238 men and women aged 25–64 years, followed for 13 years in the first North Glasgow MONICA (MONItoring CArdiovascular disease) survey and West of Scotland centres in the Scottish Heart Health Study. After adjustment for age and sex, increasing whole blood viscosity, plasma viscosity, haematocrit and fibrinogen (analysed by both von Clauss and heat precipitation assays) were significantly associated with mortality. Only the association for fibrinogen (von Clauss assay) remained significant after adjustment for major cardiovascular risk factors. We conclude that clottable fibrinogen may be independently associated with mortality. However, the significance of this association, and the extent to which viscosity is associated with mortality, remain to be established in larger studies and meta‐analyses.
Simultaneous (AC)n microsatellite polymorphism analysis and single‐stranded conformation polymorphism screening is an efficient strategy for detecting ankyrin‐1 mutations in dominant hereditary spherocytosis
Authors: Özcan Refik , Jarolim Petr , Lux Samuel E. , Ungewickell Ernst , Eber Stefan W.
Published: August 2003

Summary. Nonsense/stop mutations in the ankyrin‐1 gene (ANK1) are a major cause of dominant HS (dHS) (frequency of 23% in German dHS patients). To date, no common mutation has been found and therefore a simple mutation screening is not feasible. The reduced expression of one cDNA allele in the (AC)n microsatellite polymorphism of the ankyrin‐1 gene, as seen in about 20% of Czech patients with dHS, may identify candidates with a possible frameshift/nonsense mutation. In order to verify the efficiency of this screening we screened the ankyrin‐1 gene of 22 Czech dHS patients for both the reduced cDNA allele expression in the frequent (AC)n and the common exonic 26/39 polymorphisms, as well as for polymerase chain reaction (PCR) single‐stranded conformation polymorphisms in any one of the 42 exons of ANK1. Anomalous PCR products were sequenced. We found seven new ANK1 frameshift/nonsense mutations in nine patients with, but in none of six patients without, a reduced cDNA allele expression (efficiency of 78%). We conclude that screening of dHS patients for such a reduced allele expression in common ANK1 polymorphisms is an efficient procedure for the identification of candidates for frameshift/nonsense mutations in the ankyrin‐1 gene.
Acute promyelocytic leukaemia in patients originating in Latin America is associated with an increased frequency of the bcr1 subtype of the PML/RARα fusion gene
Authors: Douer Dan , Santillana Sergio , Ramezani Laleh , Samanez Cesar , Slovak Marilyn L. , Lee Ming S. , Watkins Kristy , Williams Tony , Vallejos Carlos
Published: August 2003

Summary. The PML/RARα fusion gene in acute promyelocytic leukaemia (APL) has three subtypes based on the breakpoint site of the PML gene: long (bcr1), short (bcr3) and variable (bcr2) subtypes. The PML/RARα fusion protein is involved in the pathogenesis of APL and the breakpoint site of the PML gene might be associated with aetiological factor(s). Because APL is over‐represented in patients that originate in Latin America (Latinos), we evaluated whether the distribution of the PML/RARα fusion mRNA in this population is different to that reported in non‐Latinos. Among 52 APL patients (28 from Mexico and Central America diagnosed in Los Angeles and 24 from Peru, South America), bcr1, bcr2 and bcr3 expression was 75%, 10% and 15% respectively. However, bcr1 breakpoints were significantly higher compared with non‐Latino patients (340/654, 52%) reported in four studies. Often bcr1 and bcr2 are reported together; 862 (60%) of 1429 non‐Latino APL patients reported in nine studies were either bcr1 or bcr2, compared with 44 (85%) in our 52 Latino patients. This difference was also statistically significant when our patients were compared to each of the individual studies from USA and Europe, but not for a small series from China and Japan. These results suggest that the overrepresentation of APL among Latin American patients can be accounted for by an increase of a single subtype – bcr1, and the breakage sites in the PML gene may not be random but possibly influenced by genetic and/or environmental factor(s).
Disease activity and pretreatment, rather than hypogammaglobulinaemia, are major risk factors for infectious complications in patients with chronic lymphocytic leukaemia
Authors: Hensel Manfred , Kornacker Martin , Yammeni Sophie , Egerer Gerlinde , Ho Anthony D.
Published: August 2003

Summary. To identify patients at high risk of life‐threatening infections, we retrospectively analysed the prevalence of infectious complications in 187 chronic lymphocytic leukaemia patients treated in our institution since 1999 and correlated them with clinical features. A questionnaire with detailed questions regarding infectious complications was mailed to patients and their general practitioners. Major infections (requiring intravenous antibiotics or inpatient treatment) were reported in 37 patients (19·8%) and minor infections (requiring oral antibiotics and outpatient treatment) in 113 patients (60·4%). Univariate analysis identified advanced disease (P = 0·02), gender (P = 0·01), duration of disease (P = 0·007), number of previous chemotherapy regimens (P < 0·001), previous therapy with purine analogues and monoclonal antibodies (P < 0·001; P = 0·019), massive splenomegaly (P = 0·03), low granulocyte count (P < 0·001), low serum immunoglobulin concentration (P = 0·005), low haemoglobin concentration (P < 0·001) and high serum lactate dehydrogenase (LDH) concentration (P < 0·001) as risk factors for major infections. In multivariable logistic regression analysis, only the number of previous chemotherapy regimens (risk ratio [RR] = 1·8; 95% confidence interval [CI] 1·2–8·0) and haemoglobin concentration (RR = 0·6; CI 0·5–0·8) remained significant for major infections. The number of previous chemotherapy regimens was the only independent risk factor for minor (RR = 7·6; CI 2·2–25·7) and varicella‐zoster virus infections (RR = 2·1; CI 1·3–3·4). In untreated patients, the only risk factor for major infections was LDH concentration. Patients treated with purine analogues or autologous stem cell transplantation had a higher risk of developing viral infections. In conclusion, disease activity and pretreatment extent have a stronger impact on the risk of severe infectious complications than hypogammaglobulinaemia. Preferably, prophylactic strategies should be evaluated in patients defined by these parameters.
Anaphylaxis: risk factors for recurrence
Authors: Mullins R. J.
Published: August 2003

Background  There are few studies on the incidence or recurrence of anaphylaxis.

Objective  To examine the incidence of anaphylaxis and risk factors for recurrence.

Methods  A prospective study of 432 patients referred to a community‐based specialist practice in the Australian Capital Territory with anaphylaxis, followed by a survey to obtain information on recurrence.

Results  Of 432 patients (48% male, 73% atopic, mean 27.4 years, SD 19.5, median 26) with anaphylaxis, 260 patients were seen after their first episode; 172 experienced 584 previous reactions. fifty‐four percent of index episodes were treated in hospital. Aetiology was identified in 91.6% patients: food (61%), stinging insects (20.4%) or medication (8.3%). The minimum occurrence and incidence of new cases of anaphylaxis was estimated at 12.6 and 9.9 episodes/100,000 patient‐years, respectively. Follow‐up data were obtained from 304 patients (674 patient‐years). One hundred and thirty experienced further symptoms (45 serious), 35 required hospitalization and 19 administered adrenaline. Accidental ingestion of peanut/tree nut caused the largest number of relapses, but the highest risk of recurrence was associated with sensitivity to wheat and/or exercise. Rates of overall and serious recurrence were 57 and 10 episodes/100 patient‐years, respectively. Of those prescribed adrenaline, 3/4 carried it, 2/3 were in date, and only 1/2 patients faced with serious symptoms administered adrenaline. Five patients each developed new triggers for anaphylaxis, or re‐presented with significant psychiatric symptoms.

Conclusion  In any 1 year, 1/12 patients who have suffered anaphylaxis will experience recurrence, and 1/50 will require hospital treatment or use adrenaline. Compliance with carrying and using adrenaline is poor. Occasional patients develop new triggers or suffer psychiatric morbidity.
Increased expression of surface activation markers on neutrophils following migration into the nasal lumen
Authors: Kinhult J. , Egesten A. , Benson M. , Uddman R. , Cardell L. O.
Published: August 2003

Background  The sequence of events following the recruitment of a free‐flowing neutrophil in the peripheral circulation, via adhesion, migration and release of mediators, to a neutrophil on the surface of the nasal epithelium is a co‐ordinated process. Little is known about the state of neutrophil activation following this course of events.

Objectives  To investigate the expression of surface activation markers on neutrophils, reflecting activation during their recruitment to the nose, and to see whether the inflammatory process during allergic rhinitis influences this process.

Method  Nine healthy controls and 12 patients with grass pollen‐induced intermittent allergic rhinitis were investigated during the peak of the pollen season. The expression of CD11b, CD66b and CD63 on the neutrophil cell surface, as a reflection of activation, was analysed using flow cytometry. Neutrophils were derived from peripheral blood and nasal lavage fluid. In addition, eosinophil cationic protein (ECP) and myeloperoxidase (MPO) as well as L‐, P‐ and E‐selectins in the nasal lavage fluid were analysed using RIA and ELISA, respectively.

Results  A marked increase in the expression of all three CD markers on the neutrophil cell surface was noticed following migration from the bloodstream to the surface of the nasal mucosa. At the peak of the grass pollen season, the MPO levels increased, reflecting an increase in the total number of nasal fluid neutrophils. In parallel, the expression of CD11b was further augmented. The expression of the CDb11b was reduced on neutrophils remaining in the circulation. In addition, the level of L‐selectin was reduced on neutrophils derived from the blood during allergic inflammation.

Conclusion  Neutrophils might become activated during their transfer from the blood to the surface of the nasal mucosa, but these changes may also be due to depletion of activated neutrophils in the blood via activated endothelial/epithelial adhesion and chemoattractant measures. The increased expression of surface activation markers during allergic rhinitis suggests roles for neutrophils in the inflammatory process.
Expression of CS‐1 fibronectin precedes monocyte chemoattractant protein‐1 production during elicitation of allergic contact dermatitis
Authors: Martín A. P. , Gagliardi J. , Baena‐Cagnani C. E. , Eberhard Y. , Uguccioni M. , Gallino N. , Mariani A. L. , Serra H. M.
Published: August 2003

Background
Leucocyte migration within inflammatory skin compartments in allergic contact dermatitis (ACD) is the result of a sophisticated multi‐step event where multiple molecules are involved.

Objective
Since non‐antigen‐specific mechanisms have been described as an early participant in elicitation of ACD, we investigated the kinetics of the expression of monocyte chemoattractant protein‐1 (MCP‐1/CCL2) and the type of infiltrating cells. We compared the time course production of MCP‐1/CCL2 with connecting segment‐1 (CS‐1) fibronectin and thymus and activation‐regulated chemokine (TARC/ CCL17) expression.

Methods
Biopsies from 10 individuals challenged in their back with the antigen responsible for their contact dermatitis and an irrelevant antigen were taken at different times and histology, immunohistochemistry for CS‐1 fibronectin, TARC/CCL17, CD3, CD68, CXCR3, CCR4 and in situ hybridization for MCP‐1/CCL2 were performed.

Results
At positive antigen stimulated sites expression of MCP‐1/CCL2 by basal keratinocytes and isolated cells in dermis started at 10 h. CS‐1 fibronectin and TARC/CCL17 expression by blood endothelial cells was found at 2 and 10 h, respectively. This was followed by dermal accumulation of mononuclear cells with a significant increase of CD3+ and CD68+cells. At 48 h, approximately 58% of infiltrating cells were CXCR3+, and 35% CCR4+.

Conclusions
We showed evidence of the fact that CS‐1 fibronectin expression precedes the production of MCP‐1/CCL2 and TARC/CCL17 in the skin of patients with ACD, suggesting that these molecules participate in the early complex process of migrating mononuclear cells during elicitation of ACD.
Proteolytic activity of the house dust mite allergen Der p 1 enhances allergenicity in a mouse inhalation model
Authors: Gough L. , Campbell E. , Bayley D. , Van Heeke G. , Shakib F.
Published: August 2003

Background
We have recently demonstrated that intraperitoneal immunization of mice with proteolytically active Der p 1, the major house dust mite allergen, results in a significant and selective enhancement of total and Der p 1‐specific IgE synthesis compared to mice immunized with proteolytically inactive Der p 1.

Objective
To investigate whether the proteolytic activity of Der p 1 would lead to enhanced inflammatory cellular infiltration of the lungs and systemic IgE production when administered through the respiratory system, which is the natural route of entry for this allergen.

Methods
Groups of mice were initially sensitized with proteolytically active Der p 1 through the intraperitoneal and the subcutaneous routes and subsequently exposed intranasally to either proteolytically active Der p 1, inactive Der p 1 or PBS. The extent of cellular infiltration of the lungs and systemic IgE production in the three animal groups were then compared.

Results
Here, we show for the first time that the administration of proteolytically active Der p 1 to mice through the intranasal route leads to significant inflammatory cellular infiltration of the lungs and systemic production of IgE.

Conclusions
These data underline the important role of the proteolytic activity of Der p 1 in driving the allergic response in the lungs.
In vitro and in vivo allergenicity of recombinant Bet v 1 compared to the reactivity of natural birch pollen extract
Authors: Tresch S. , Holzmann D. , Baumann S. , Blaser K. , Wüthrich B. , Crameri R. , Schmid‐Grendelmeier P.
Published: August 2003

Background
Diagnostic procedures using natural extracts show only limited quantitative correlation between in vivo and in vitro results. Highly pure recombinant allergens might show more predictive findings.

Objective
The aim of this study was to compare natural birch pollen extract (BPE) and recombinant Betula verrucosa (rBet v 1) for their diagnostic value comparing skin prick tests (SPTS) and nasal provocation tests (NPTS) with specific IgE in the serum.

Methods
Thirty‐four patients allergic to birch pollen and five healthy controls were investigated. SPT and NPT were performed with BPE and rBet v 1 at different concentrations. Specific serum IgE was measured by the Pharmacia CAP system.

Results

Commercial BPE and rBet v 1 (10 μg/mL) were able to elicit similar allergenic reactions in vivo and IgE binding in vitro. SPT reflects immediate‐type allergy as determined by NPT to a higher degree than specific IgE, for both reagents. To cause allergic reactions in NPT, higher amounts of rBet v 1 were needed than for skin tests and the sensitivity was lower than with BPE.

Conclusion

rBet v 1 alone is sufficient for a reliable diagnosis of birch pollen allergy in most patients and induces comparable skin test reactivity as BPE, but less allergic reactions in nasal provocations.
Epicutaneous exposure to protein antigen and food allergy
Authors: Hsieh K.‐Y. , Tsai C.‐C. , Herbert Wu C. H. , Lin R.‐H.
Published: August 2003

Background
The aetiology of food allergy remains unclear. Although failure to develop or breakdown in oral tolerance has been proposed, the existence of physiologic sensitization routes other than the gastrointestinal tract cannot be excluded.

Objective
The purpose of this study is to clarify whether or not exposure to allergen through the skin can promote food allergy.

Methods
BALB/c mice were shaved on the back, and a patch impregnated with 100 μg of ovalbumin (OVA) was applied to the dorsal skin for a 1‐week period and then removed. After three courses of sensitization, OVA‐specific antibodies in sera were measured, and then mice were orally challenged with 50 mg of OVA. Anaphylactic symptoms, plasma histamine levels, and histology of intestines and lungs after oral challenge were examined.

Results
Epicutaneous (EC) sensitization of mice to OVA induced a high level of OVA‐specific IgE. Subsequent oral challenge with OVA resulted in symptoms of systemic anaphylaxis with elevated levels of plasma histamine as well as histological changes in both intestines and lungs. In the presence of anti‐IL‐4 antibodies, EC sensitization failed to provoke an IgE response, but still induced a Th2‐predominant cellular immune response in lungs after oral challenge.

Conclusion
We demonstrated for the first time that food allergy can be induced by allergen exposure through the skin. Our results identify a novel role of EC sensitization in the pathogenesis of food allergy.
A kinetic study in adults with food hypersensitivity assessed as eosinophil activation in fecal samples
Authors: Magnusson J. , Gellerstedt M. , Ahlstedt S. , Andersson B. , Bengtsson U. , Telemo E. , Hansson T. , Peterson C. G. B.
Published: August 2003

Background
Immune‐mediated food hypersensitivity affecting the gut is difficult to evaluate, and objective tools to diagnose local gastrointestinal (GI) inflammatory reactions are lacking.

Objectives
To determine whether allergic manifestations in adults with a history of food‐related GI symptoms could be assessed in feces during symptomatic and non‐symptomatic periods, using the surrogate markers, eosinophil cationic protein (ECP), eosinophil protein X (EPX) and myeloperoxidase (MPO).

Methods
Thirteen subjects with food hypersensitivity‐related GI symptoms, confirmed by a positive double‐blind placebo‐controlled food challenge (DBPCFC), were subjected to an open kinetic food challenge design for 6 weeks. Symptoms were recorded and scored during the 3‐week study period and stool samples were obtained every day. The surrogate markers ECP, EPX and MPO were measured in the supernatants from feces samples.

Results
A significant increase in abdominal pain, distension and flatulence was observed during challenge, with a gradual decrease during elimination diet. Both between days and subjects, EPX levels were more frequently increased compared to ECP and MPO. Individuals with a history of a short duration of symptoms had significantly higher mean levels of EPX and MPO than those with a longer duration of symptoms.

Conclusions
An overall increase in levels of eosinophil markers, in particular EPX, was observed in feces from patients with food‐related GI symptoms. However, rather than being a tool to differentiate symptomatic from non‐symptomatic periods, EPX might be used for detecting an ongoing clinical or subclinical chronic inflammation, that may have an impact on the patient's clinical course of GI symptoms.
Regulation and kinetics of platelet‐activating factor and leukotriene C4 synthesis by activated human basophils
Authors: Lie W. J. , Homburg C. H. E. , Kuijpers T. W. , Knol E. F. , Mul F. P. J. , Roos D. , Tool A. T. J.
Published: August 2003

Background
Allergic disease is the result of an interplay of many different cell types, including basophils and mast cells, in combination with various inflammatory lipid mediators, such as platelet‐activating factor (PAF) and leukotrienes (LT). LTC4 synthesis by human basophils has been studied quite extensively. However, not much is known about the synthesis of PAF by human basophils.

Objective
In this study, we have made a comprehensive comparison between the kinetics of PAF and LTC4 synthesis, in highly purified basophils, activated with different stimuli or with combinations of stimuli.

Methods
Synthesis of PAF and LTC4 by human basophils was determined with commercially available assay kits. The basophils were activated with C5a, fMLP, PMA, allergen or anti‐IgE, in the absence and presence of IL‐3 and/or in combination with elevation of cytosolic free Ca2+ by the sarcoplasmic reticulum Ca2+‐ATPase inhibitor thapsigargin.

Results
Most stimuli were found to induce both PAF and LTC4 synthesis. PAF synthesis and LTC4 release were enhanced by preincubation of the basophils with IL‐3 or by elevation of cytosolic free Ca2+ by thapsigargin. Incubation of human basophils with IL‐3 alone or thapsigargin alone did not result in detectable synthesis of PAF and LTC4, whereas the combination of the two resulted in high amounts of PAF and LTC4 synthesis. Depending on the stimulus used, LTC4 release was 5–100‐fold higher than PAF synthesis. In addition, PAF, but not LTC4, was transiently detected, probably due to PAF degradation.

LTC4 and PAF synthesis was strongly blocked by inhibitors of cytosolic phospholipase A2, indicating that this enzyme is involved in PAF and LTC4 synthesis by activated human basophils.

Conclusion
This study provides a first comprehensive comparison of PAF and LTC4 synthesis in highly purified human basophils, stimulated with a variety of stimuli.
Activation of mast cells by immunoglobulin E‐receptor cross‐linkage, but not through adenosine receptors, induces A1 expression and promotes survival
Authors: Möller C. , Xiang Z. , Nilsson G.
Published: August 2003

Background
Mast cells are a potent source of mediators that regulate the inflammatory response in allergy and asthma. Mast cells can be activated through different receptors, for example, via cross‐linkage of the high‐affinity IgE receptor (FcɛRI) and by adenosine acting on specific receptors. We have recently described mast cell survival of an IgE receptor activation by up‐regulation of the anti‐apoptotic gene A1.

Objective
To compare mast cell survival and expression of A1 after activation through the FcɛRI and by an adenosine agonist.

Methods
Bone marrow‐derived, cultured mouse mast cells (BMCMC) were activated either with IgE+antigen or with the adenosine receptor agonist 5′‐N‐ethylcarboxamido adenosine (NECA). Release of β‐hexosaminidase, cell viability, phosphorylation of Akt and IkB‐α, and expression of pro‐survival and pro‐apoptotic genes were measured after activation.

Results
Activation of BMCMC with NECA caused the release of β‐hexosaminidase, although to a lesser extent than after FcɛRI activation (33% and 98%, respectively). Activation by both NECA and FcɛRI stimulated phosphorylation of Akt (Ser473 and Thr308) and IkB‐α (Ser32), both of which are implicated in the regulation of cell survival. However, only cells that were activated through FcɛRI, but not by NECA, expressed A1 and exhibited an increased survival rate compared to the control.

Conclusion
These results show that adenosine receptor activation of BMCMC does not induce the same survival programme in mast cells as does activation through FcɛRI. These findings may be important for understanding the role that mast cells play in asthma provoked by different stimuli.
Polymorphisms in the interleukin‐4 and interleukin‐4 receptor α chain genes confer susceptibility to asthma and atopy in a Caucasian population
Authors: Beghé B. , Barton S. , Rorke S. , Peng Q. , Sayers I. , Gaunt T. , Keith T. P. , Clough J. B. , Holgate S. T. , Holloway J. W.
Published: August 2003

Background  IL‐4 by binding to its receptor (IL‐4R) is essential for the development of airway inflammation present in asthma, through the induction of IgE synthesis in B cells and differentiation of T cells to a Th2 phenotype.

Objective  To investigate the role of four common polymorphisms in the IL‐4 (IL4‐34CT and IL4‐589CT) and IL‐4Rα chain (IL4RAI50V and IL4RAQ576R) genes in conferring susceptibility to the development of atopy and/or asthma.

Methods  Two polymorphisms in the IL‐4 gene promoter, IL4‐34CT and IL4‐589CT, and two polymorphisms in the IL‐4Rα chain gene, IL4RAI50V and IL4RAQ576R, have been genotyped using PCR‐based methods in 341 asthmatic families and in 184 non‐asthmatic adults recruited from the south of England.

Results  Case–control analysis did not reveal differences in the distribution of the four polymorphisms between asthmatics and controls. However, the transmission disequilibrium test showed that the IL4‐589 T allele was preferentially transmitted to asthmatic children (P=0.036) and that the IL4RAQ576 was preferentially transmitted to children with atopic asthma (P=0.018). Haplotype analysis showed a strong association between the IL4‐34T/‐589T haplotype and asthma per se (P=0.041), and a strong association between the IL4RA I50/Q576 haplotype and atopic asthma (P=0.006).

Conclusion  Our data suggest that polymorphisms in the IL‐4 and IL‐4Rα chain genes might play a role both conferring susceptibility to and modulating severity of atopy and asthma.
Thresholds of clinical reactivity to milk, egg, peanut and sesame in immunoglobulin E‐dependent allergies: evaluation by double‐blind or single‐blind placebo‐controlled oral challenges
Authors: Morisset M. , Moneret‐Vautrin D. A. , Kanny G. , Guénard L. , Beaudouin E. , Flabbée J. , Hatahet R.
Published: August 2003

Background
The prevalence of food anaphylaxis due to masked allergens has increased within the last 10 years. Contamination of manufactured products by food allergens is a key concern for food industries.

Objective
To determine quantities eliciting reactions in patients who have an IgE‐dependent food allergy, thanks to standardized oral provocation tests. To evaluate the subsequent levels of sensitivity required for the detection tests of allergens for egg, peanut, milk and sesame.

Methods
Prick‐in‐prick tests, Cap system RAST, and single or double‐blind placebo‐controlled food challenges (SBPCFC or DBPCFC) were performed. The doses of natural food were gradually increased from 5 to 5000 mg for solid food and from 1 to 30 mL for peanut oil, sunflower oil, soy oil and sesame oil.

Results
Data from 125 positive oral challenges to egg, 103 to peanut, 59 to milk and 12 to sesame seeds were analysed. Haemodynamic modifications were observed in 2%, 3%, 1.7%, and 8% of the oral challenges (OCs) to egg, peanut, milk and sesame, respectively. Respiratory symptoms were observed in 12%, 20%, 10% and 42% of egg, peanut milk and sesame allergies, respectively. A cumulative reactive dose inferior or equal to 65 mg of solid food or 0.8 mL of milk characterized 16%, 18%, 5% and 8% of egg, peanut, milk and sesame allergies, respectively. 0.8% of egg allergies, 3.9% of peanut allergies, and 1.7% of milk allergies reacted to 10 mg or less of solid food or to 0.1 mL for milk. The lowest reactive threshold has been observed at less than 2 mg of egg; 5 mg of peanut, 0.1 mL of milk and 30 mg of sesame seed. Ten out of 29 OC with peanut oil, two out of two OC with soy oil and three out of six OC with sunflower oil were positive. Five out six OC with sesame oil were positive: 1 and 5 mL induced an anaphylactic shock.

Conclusion
The risk of asthma and anaphylactic shock to sesame and peanut is confirmed. Minimal reactive quantities show that, in order to guarantee a 95% safety for patients who are allergic to egg, peanut and milk, and on the basis of consumption of 100 g of food, the detection tests should ensure a sensitivity of 10 p.p.m. for egg, 24 p.p.m. for peanut and 30 p.p.m. for milk proteins. Oil allergies being considered, the limit of sensitivity should fall to 5 p.p.m.
Usefulness of specific immunotherapy in patients with severe perennial allergic rhinitis induced by house dust mite: a double‐blind, randomized, placebo‐controlled trial
Authors: Varney V. A. , Tabbah K. , Mavroleon G. , Frew A. J.
Published: August 2003

Objectives
To evaluate the effectiveness of specific immunotherapy (SIT) in patients with severe house dust mite (HDM)‐induced perennial allergic rhinitis using diary cards and objective endpoints.

Patients and Methods
Thirty‐six adult patients were selected with moderate to severe allergic rhinitis due to HDM allergy uncontrolled by regular anti‐allergic drugs. Twenty‐eight patients completed the study, 22 of these patients also had mild asthma. Subjects were stratified for HDM sensitivity on the basis of their 4‐week diary card score and the size of their immediate and late‐phase skin reaction to HDM. The groups were well matched for all relevant parameters. Patients were randomized to receive active preparation (Alutard®‐SQ, ALK, Dermatophagoides pteronyssinus extract) or an identical placebo preparation. Increasing doses were administered until the maintenance dose was reached. This dose was then given once a month for 12 months.

Results
Clinical efficacy was evaluated by symptom medication diary cards recorded for 4 weeks after 12 months of continuous treatment and compared with pre‐treatment scores. Skin test reactivity was re‐measured after 12 months of treatment to HDM, cat dander and codeine phosphate. After 1 year of treatment, the actively treated group showed a 58% reduction in diary card symptom scores (P<0.002) and a 20% reduction in the use of rescue medication. The placebo group had a 32% reduction in symptom scores (P=NS), but no reduction in rescue medication requirements. The active group showed 36% reduction in skin prick test sensitivity to D. pteronyssinus (P=0.006), while the placebo group values were unchanged. Skin reactivity to codeine was unchanged in both groups. No significant adverse reactions to SIT were encountered.

Conclusions
One year of SIT for D. pteronyssinus in patients with poorly controlled rhinitis (±mild asthma) produced clinically useful improvement as shown by symptom–medication diary cards and reductions in immediate skin reactions compared with placebo treatment.
In vitro stability and immunoreactivity of the native and recombinant plant food 2S albumins Ber e 1 and SFA‐8
Authors: Murtagh G. J. , Archer D. B. , Dumoulin M. , Ridout S. , Matthews S. , Arshad S. H. , Alcocer M. J. C.
Published: August 2003

Background
The ability of an intact protein to reach the circulatory system may be a prerequisite to allergenicity and many allergens, particularly those from plant foods, have been found to be consistently more resistant to digestion by pepsin than other proteins.

Objective
This study assessed the pepsinolytic stability of native 2S albumins from Brazil nut and sunflower seed and their recombinant versions produced in Pichia pastoris. The physicochemical stability of native and recombinant Brazil nut 2S albumins and recombinant sunflower seed 2S albumin was also assessed. The immunoreactivity of native Brazil nut 2S albumin and recombinant 2S albumins was compared using serum from patients allergic to Brazil nuts and animals immunized with native 2S albumins.

Methods
Digestibility was measured in simulated gastric fluid followed by SDS‐PAGE. Circular dichroism spectra were used to analyse unfolding, as proteins were denatured by temperature, pH and guanidinium chloride. Immunoreactivity was assessed by immunoblot, RAST and ELISA.

Results
Brazil nut 2S albumin was significantly more resistant to proteolytic digestion than other Brazil nut proteins. It was also resistant to thermally and chemically induced denaturation. Equally high resistance to proteolytic digestion was observed with sunflower seed 2S albumin. The recombinant albumins mirrored their native counterparts in stability and immunoreactivity.

Conclusion
The important food allergen Brazil nut 2S albumin is as stable to digestion as is sunflower seed 2S albumin, whose allergenicity has yet to be determined. The 2S albumins and their recombinant counterparts could not be easily denatured by physicochemical treatments. The results suggest that 2S albumin is the only Brazil nut protein to reach the gut immune system intact. The production of properly folded recombinant proteins will facilitate mechanistic studies as well as diagnostic testing and antigen‐based therapies.
Association between interleukin‐18 gene polymorphism 105A/C and asthma
Authors: Higa S. , Hirano T. , Mayumi M. , Hiraoka M. , Ohshima Y. , Nambu M. , Yamaguchi E. , Hizawa N. , Kondo N. , Matsui E. , Katada Y. , Miyatake A. , Kawase I. , Tanaka T.
Published: August 2003

Background
IL‐18 has been shown to exert anti‐allergic or allergy‐promoting activities, but the existence of genetic polymorphisms in the coding regions of IL‐18 gene has not been demonstrated.

Objective
The aim of this study was to investigate whether polymorphism is present in the coding regions of the IL‐18 gene and, if so, to further analyse the association between polymorphism and asthma in a case–control study.

Methods
We screened the coding regions of the IL‐18 gene for polymorphisms by using PCRsingle‐stranded conformation polymorphism and direct sequencing of PCR products, followed by analysis of the association between polymorphism and asthma.

Results
We identified one polymorphism (105A/C) in the coding regions. The frequency of the 105A allele was significantly higher in asthmatic patients than in controls (P<0.01; odds ratio (OR)=1.83 (1.37–2.26)). Significant linkage disequilibrium was observed between the 105A/C and −137G/C polymorphisms in the 5′ flanking region of the IL‐18 gene (D=0.58, P<0.0001). However, in asthmatic patients the 105A allele was not associated with either total serum IgE or IL‐18 levels.

Conclusion
The 105A/C polymorphism of the IL‐18 gene may be associated with the pathogenesis of asthma.
Seasonal adaptation of ex‐ephippio and parthenogenetic offspring of Daphnia magna: differences in life history and physiology
Authors: Arbačiauskas Kȩstutis , Lampert Winfried
Published: August 2003

Physiology and life history of ex‐ephippial and parthenogenetic offspring of Daphnia magna Straus were compared to test the hypothesis that females hatching from resting eggs are well adapted to the predictable high‐food conditions of the spring algal bloom.

Although ex‐ephippial neonates were smaller than parthenogenetic neonates, they showed higher juvenile growth rates that compensated for the size difference by the time of maturation.

At high food concentration, ex‐ephippial females were even larger at maturation than parthenogenetic females, produced more eggs, and reached a higher rate of population increase.

The high activity of the ex‐ephippial females was accompanied by higher metabolic rates, which in combination with the low initial mass resulted in reduced survival times under starvation.

Thus, the two phenotypic types of offspring produced by Daphnia are adapted to differing conditions. Ex‐ephippial females are superior to parthenogenetic offspring under high food conditions, but inferior when food is limiting.

This pattern selects for synchronous hatching of resting eggs in spring when the spring algal bloom is to be expected.
Concentration‐dependent sugar preferences in nectar‐feeding birds: mechanisms and consequences
Authors: Schondube Jorge E. , Del Rio Carlos Martínez
Published: August 2003

Specialised nectar‐feeding birds tend to prefer sucrose over glucose‐fructose mixtures or to be indifferent when tested at concentrations close to 584 mmol L−1 sucrose equivalents. The role of the potential interaction between sugar composition and concentration on the sugar preferences of these birds, however, has not been explored.

We tested the hypothesis that sugar preferences in nectar‐feeding birds are concentration‐dependent. We predicted that at high concentrations they would prefer sucrose over hexoses, whereas at low sugar concentrations they would prefer hexoses. We expected birds to show differences in food intake that matched their sugar preferences when they fed on equicaloric solutions of sucrose and 1 : 1 mixture of glucose and fructose. Consequently, the curves describing the relationship between food intake and sugar concentration for these two sugar solutions should cross. We tested these hypotheses in two species of nectar‐feeding birds: the Cinnamon‐bellied Flowerpiercer, Diglossa baritula (Wagler) and the Magnificent Hummingbird, Eugenes fulgens (Swainson).

The sugar preferences of both species were concentration dependent. At lower concentrations they preferred hexoses, whereas at higher concentrations they shifted their preference to sucrose. However, these concentration‐dependent preferences were not matched by parallel differences in intake.

Although nectar composition and concentration are often discussed as two different floral traits, our results show that they have a synergistic effect on the sugar preferences of nectar‐feeding birds.
The fly that came in from the cold: geographic variation of recovery time from low‐temperature exposure in Drosophila subobscura
Authors: David J. R. , Gibert P. , Moreteau B. , Gilchrist G. W. , Huey R. B.
Published: August 2003

The time required for an ectotherm to recover from cold exposure is a useful, non‐lethal index of cold tolerance. We explore how recovery times are affected by exposure to low temperatures, develop statistical methodologies, and study geographic variation in recovery time in four populations of Drosophila subobscura, a cold‐tolerant species.

We exposed flies to a low temperature (−7 °C to 1 °C) for 16 h, returned them to ambient temperature, and recorded the elapsed time (‘recovery time’) until they stood. Other flies were exposed to even colder temperatures (−11 °C to −7 °C), but for shorter times.

Recovery times were inversely related to exposure temperature, but had a plateau between −6 °C and −4 °C.

Populations had similar recovery times at ‘warm’ temperatures, but two subtropical populations had relatively long recovery times at colder temperatures.

Inter‐population differences were also evident in a regression analysis, and recovery times were inversely related to latitude (ordered‐factor analysis). Populations differed slightly in the slopes of regressions but differed strongly in their intercepts.

The physiological mechanisms underlying the non‐linear responses are unknown, but the plateau region suggests that recovery time is governed by the interplay of two temperature‐dependent processes. Two models are proposed for the interaction of these processes.
Physiological and morphological responses to simultaneous cold exposure and parasite infection by wild‐derived house mice
Authors: Kristan Deborah M. , Hammond Kimberly A.
Published: August 2003

Many animals respond to environmental demands with phenotypic plasticity of morphology and physiology. We examined the effects of ambient temperature and parasitism on morphology and physiology of wild‐derived house mice (Mus musculus) that were exposed to cold and/or experimentally infected with a naturally occurring intestinal nematode (Heligmosomoides polygyrus).

Parasitized mice had changes in some organ masses, decreased ability to digest food, and lower rates of glucose transport but similar total glucose transport capacity as unparasitized mice. Wild‐derived house mice did not use fat stores to respond to parasitism but did increase mucosal mass in the small intestine enough to maintain glucose acquisition at a similar level to unparasitized mice.

Cold‐exposed mice showed increased masses of some organs, lower rates of glucose transport but similar total capacity to transport glucose as warm acclimated mice.

The effects of cold exposure and parasite infection were largely independent of each other for the morphological and physiological parameters we measured.

The more recent exposure of wild‐derived house mice to fluctuating temperatures and to parasite infection may help to explain the subtle differences that we observed in how wild‐derived mice respond to environmental demands compared to their laboratory mouse counterparts.
The effect of variation in dietary intake on maternal deposition of antioxidants in zebra finch eggs
Authors: Royle Nick J. , Surai Peter F. , Hartley Ian R.
Published: August 2003

Maternal diet can significantly influence the quality and size of eggs, and this may, in turn, influence the fitness of offspring. In this study, we show how antioxidants (vitamin E compounds and carotenoids) in the diet of female zebra finches influence the concentrations of antioxidants in their eggs. Antioxidants are biochemicals derived from the diet, which reduce damage to cell membranes caused by the free radicals produced during normal metabolism and growth.

Females were given either a seed‐only or a seed + rearing food diet prior to egg laying. The seed + rearing food diet was more enriched with carotenoids, but had lower amounts of less effective antioxidants, such as γ‐tocopherol. Eggs were collected as they were laid, then analysed to determine the concentrations of antioxidants using high‐performance liquid chromatography.

Females in the two food groups had similar rates of food consumption and laid similar sized clutches. Females on the seed‐only diet produced eggs of similar mass to that of females on the seed + rearing food diet.

The concentrations of the most effective antioxidant (α‐tocopherol) were higher in the eggs of females from the seed‐only group and, for both food groups, concentrations decreased with successively laid eggs within clutches. The concentration of carotenoids in egg yolks did not differ between food treatments, but also decreased with successive eggs. Less effective antioxidants were relatively under‐represented in eggs in relation to their availability in food, and were deposited in similar overall amounts between the two food treatments, and independently of laying sequence.

Our results indicate that egg size is not necessarily an accurate guide to egg quality, especially when comparing between clutches of different females or across species. Females may be able to adjust egg composition to influence offspring quality variation within broods, possibly traded‐off against their personal use of antioxidants, their future reproductive success, control over sibling competition within their brood and/or brood reduction.
Circannual control of the life cycle in the Varied Carpet Beetle Anthrenus verbasci
Authors: Nisimura T. , Numata H.
Published: August 2003

Anthrenus verbasci shows a circannual pupation rhythm, and a transfer from long‐day to short‐day conditions caused a phase shift. Short‐day conditions produced synchronous pupation, and the critical day‐length was between 13 and 14 h, which corresponded to the natural day‐length in September.

A decrease in temperature does not seem to act as a zeitgeber under natural conditions, because a change from 25 to 20 °C caused no or little phase shift.

Under conditions of natural photoperiod and temperature, larvae pupated synchronously in April, although under natural day‐length at 20 °C larvae pupated in February. Therefore, a decrease in day‐length crossing the critical value in September probably shifts the phase of the circannual rhythm so that the gate to pupation opens in February, and probably low temperatures in winter suppress pupation until April.

Newly hatching larvae transferred outdoors pupated successfully only when transferred between late April and mid‐September, although larvae transferred after mid‐July developed into smaller pupae than those transferred earlier. Therefore, synchronous pupation and emergence in spring are needed to allow larvae of the next generation to grow sufficiently before winter.