bluuebunny/crossref_metadata_2025 huggingface dataset:
A Means and Measure of Civilisation: Colonial Authorities and Indigenous Law in Australasia
Authors: Ward Damen
Published: January 2006

British commentators on colonial policy in the early to mid‐nineteenth century often treated the existence of indigenous customary law and adjudicative forums as an indication of ‘civilisation’. However, not all customary laws were considered ‘civilised’ enough to be acknowledged by the British authorities. Furthermore, most British policy and debate was assimilationist. This article surveys two different assimilationist approaches. ‘Exceptionalist’ proposals favoured modifying the application of English law to indigenous peoples as a preliminary step towards assimilation. Such schemes can be contrasted with proposals for the ‘strict application’ of English law over indigenous peoples. In practice, however, the distinction between the two approaches was often blurred. Commentators and officials treated law as a means and measure of civilisation. The tension between these two roles often contributed to confused and ambiguous discussions of the application of English law to indigenous peoples. This article, therefore, suggests that Henry Reynolds’ views on British attitudes to indigenous customary law are overstated. The article concludes with a brief discussion of the distinction between legal and historical reasoning, and the limited implications of my historical arguments for the legal reasoning of cases such as Mabo and Wik.
Socialists in Nineteenth‐Century France
Authors: Pilbeam Pamela
Published: January 2006

French socialism was unique. It had a dual origin, the 1789 Revolution and the response to economic change. The competing traditions of the 1789 Revolution were of fundamental, but very divisive, importance to French socialists. Some honoured Robespierre and the Jacobins for their contribution to the centralisation and modernisation of the state (Blanc), while others denigrated the Terror and the failure to improve the lives of ordinary people (Fourier, Cabet, Buchez). A tiny number, inspired by the mythology of the Conspiracy of the Equals (Babeuf) as recollected by one of the conspirators in 1828 (Buonarroti) revered revolution as the means to social change (Blanqui).
Taking Private Life Seriously: Marriage and Nationhood
Authors: Brookes Barbara
Published: January 2006

In her path‐breaking book, Public Vows: A History of Marriage and the Nation, Nancy Cott notes how although marriage is commonly viewed as part of private life, assumptions about marriage have been an integral part of public policy and had implications for citizenship.1 A number of American colonies passed laws that aimed to prevent intermarriage between white and Negro or mulatto persons, in order to retain the dominance of the white race. Marriage and the nation are, therefore, intimately entwined, and histories which explore the intimate ties created by marriage are likely to throw new light on the evolution of nationhood.
Russia and the Origins of Twentieth‐century Antisemitism
Authors: Johnson Sam
Published: January 2006

In seeking explanations for the origins of modern antisemitism, historians have often dwelt extensively on the developments in anti‐Jewish discourse in nineteenth‐century Imperial Germany and the Hapsburg Empire. The role played by the Tsarist Empire – darkest, backward Russia – has frequently been overlooked or underplayed. Until the past decade or so, antisemitism in the dying days of Tsarism was often characterised as little different from its medieval predecessor. Recent interpretations have shed new light on changes in antisemitism in Russia in the late nineteenth century. Much like the apparently unchangeable Tsarist state, a multitude of internal and external influences gradually altered the nature of Russian antisemitic discourse, which – in the years after the 1917 Bolshevik Revolution – would have profound consequences for the rest of Europe.
Locating Male Sexualities in Latin American History: Two Anthropological Models
Authors: Rubenstein Anne
Published: January 2006

Anthropological models of how sexuality has worked in Latin America, especially in relation to masculinity and honor, have profoundly influenced studies of Latin American social history. New anthropological studies of male sexuality in Latin America, particularly Don Kulick's ethnography of cross‐dressing male sex workers in urban Brazil, offer new ways of thinking about gender, family, and power; historians of Latin America should consider Kulick's and related studies carefully.
The Islamic Origins Debate Goes Public
Authors: Von Sivers Peter
Published: January 2006

A central part of modern secularization has been the de‐theologization of the stories of religious origins. Islam is no different, even though this de‐theologization tends to be obscured by contemporary fundamentalism. In Islam, the story of origins centers on Mecca, Medina, the prophet Muhammad, the early Muslim community, and the expansion out of Arabia. A few scholars at the end of the nineteenth century and many at the end of the twentieth century raised the question of whether this story should be considered a theology – that is, an apologia or justification – of origins rather than a history as traditionally understood. This article provides a survey of the Islamic origins literature produced by Middle East scholars in the last century.
Intercolonial and Interimperial Relations in the Seventeenth Century
Authors: Hatfield April Lee
Published: January 2006

English, French, Dutch, and Spanish colonists and mariners in the seventeenth‐century understood their positions in the Atlantic world vis‐à‐vis one another. Colonies mirrored international rivalries and depended on their respective imperial countries. But they also depended on one another, cooperating across colonial and imperial borders to ensure their own survival or profit.
Atlantic Constraints and Global Opportunities
Authors: Games Alison
Published: January 2006

What makes a geographic region a logical unit of historical analysis? Historians are products of disciplinary conventions that classify jobs and professional organizations first by place (generally a nation or a continental landmass) and then by historical period; thus place is often the starting point in historical research. For historians of the early modern period, anachronistic political boundaries can be confining because early borders (where they existed or were acknowledged) were porous, contested, and shifting; historians find themselves struggling to write non‐national histories within national paradigms. One strategy to escape this challenge can be seen in the growing field of Atlantic history, which takes as its unit of analysis not a single state but rather the four continents surrounding the Atlantic and the ocean itself. Atlantic approaches are greatly in vogue =among early modern historians. But might the Atlantic be too small a unit of analysis? To what extent should historians engage with questions about developments within the Atlantic by looking elsewhere around the globe and thereby integrating the Atlantic into a larger global history?
‘Heavy Hands and Light Touches’: Approaches to the Study of Cinematic Culture in the Third Reich
Authors: Fox Jo
Published: January 2006

In 1996, Eric Rentschler claimed that ‘cinema in the Third Reich involved a division of labour between heavy hands and light touches’. Such a description is a fitting comment on both the organisational processes of the propaganda machine under the Nazis and the sometimes inconsistent messages of their feature film productions. Issues surrounding the nature of cinematic culture in the Third Reich have prompted intense debates among film scholars. This article seeks to outline the key debates and issues, concluding with an analysis of Veit Harlan's Der große König, with reference to the diverse methodological approaches employed to study film under National Socialism. It argues that one needs to understand both the ‘heavy hands’ and the ‘light touches’ of NS film policy and production to enable a deeper understanding of feature films produced in the Third Reich.
Time, Space, and the History of Early Modern North America1
Authors: Mancke Elizabeth
Published: January 2006

This article analyzes some of the temporal and spatial categories we use to conceptualize and describe early modern North America. Some of our most significant spatial and temporal categories – in particular, “colonies” and “colonial”– are products of the historiography of the rise of the nation‐state and reflect those concerns and assumptions. The shift to Atlantic history, trans‐imperial histories, and the ethnic histories of non‐European peoples in the Americas, both indigenous and Africans, obliges us to scrutinize these categories, recognize their specificity and descriptive power, and use spatial and temporal descriptors that reflect the continent's historical complexity and the historiographic achievements of the past thirty years.
Life‐threatening interaction between antiretroviral therapy and vinblastine in HIV‐associated multicentric Castleman's disease
Authors: Kotb Rami , Vincent Isabelle , Dulioust Anne , Peretti Delphine , Taburet Anne‐Marie , Delfraissy Jean‐Francois , Goujard Cécile
Published: January 2006

Abstract:  Background: HIV‐infected patients still present a high risk of developing lymphoproliferative malignancies, despite the fact that their prognosis has been considerably improved by highly active antiretroviral therapy (HAART). Potential interactions exist between antiretroviral drugs, in particular protease inhibitors, and anti‐neoplastic ones, but their impact in terms of clinical and haematological adverse events remains unclear. Methods: We report a case of potentially life‐threatening interaction between vinblastine and antiretroviral therapy in a patient presenting with HIV‐associated multicentric Castleman's disease (MCD). Results: A 55‐year‐old HIV‐1 infected patient was diagnosed with MCD while being treated with a salvage HAART regimen consisting of zidovudine, lamivudine, abacavir, nevirapine and ritonavir‐boosted lopinavir. Vinblastine was prescribed as a monotherapy at the usual dose of 6 mg/m2 (i.e. 10 mg) every 3 weeks. The first vinblastine course was performed without HAART with no adverse event. Antiretroviral therapy was resumed for the two following courses which were associated with unexpected severe digestive and haematological toxicities, and moderate renal failure. Vinblastine was then administered alone at increasing doses without toxicity. HAART was finally resumed and we assessed that a decreased vinblastine dose of 2 mg/m2 was well tolerated, with a complete response of MCD. Conclusions: HAART regimen comprising protease inhibitors, which are potent inhibitors of cytochrome P450 and P‐gp, could interfere with anti‐neoplastic drugs, as demonstrated with vinblastine in our case report.
Cutaneous leucoclastic vasculitis (LV) following bortezomib therapy in a myeloma patient; association with pro‐inflammatory cytokines
Authors: Min Chang‐Ki , Lee Seok , Kim Yoo‐Jin , Eom Ki‐Seong , Lee Jong‐Wook , Min Woo‐Sung , Kim Chun‐Choo , Cho Chul‐Soo , Park Gyeongsin
Published: January 2006

Abstract:  The proteasome inhibitor, bortezomib, has anti‐myeloma activity even in myeloma cells refractory to multiple prior treatments. Bortezomib blocks the production of nuclear factor‐κB (NFκB)‐mediated pro‐inflammatory cytokines. We report a patient with myeloma who developed a cutaneous leucoclastic vasculitis (LV) after bortezomib treatment. The patient with LV exhibited a marked increase in serum levels of IL‐6, TNF‐α, and C‐reactive protein (CRP). Bortezomib administration may enhance the release of pro‐inflammatory cytokines, which might play a role in bortezomib‐induced cutaneous LV.
Nucleocytoplasmic transport of fluorescent mRNA in living mammalian cells: nuclear mRNA export is coupled to ongoing gene transcription
Authors: Tokunaga Kazuaki , Shibuya Toshiharu , Ishihama Yo , Tadakuma Hisashi , Ide Miyuki , Yoshida Minoru , Funatsu Takashi , Ohshima Yasumi , Tani Tokio
Published: January 2006

In eukaryotic cells, export of mRNA from the nucleus to the cytoplasm is one of the essential steps in gene expression. To examine mechanisms involved in the nucleocytoplasmic transport of mRNA, we microinjected fluorescently labeled fushi tarazu (ftz) pre‐mRNA into the nuclei of HeLa cells. The injected intron‐containing ftz pre‐mRNA was distributed to the SC35 speckles and exported to the cytoplasm after splicing by an energy‐requiring active process. In contrast, the injected intron‐less ftz mRNA was diffusely distributed in the nucleus and then presumably degraded. Interestingly, export of the ftz pre‐mRNA was inhibited by treatment with transcriptional inhibitors (actinomycin D, α‐amanitin or DRB). Cells treated with transcriptional inhibitor showed foci enriched with the injected mRNA, which localize side by side with SC35 speckles. Those nuclear foci, referred to as TIDRs (transcriptional‐inactivation dependent RNA domain), do not overlap with paraspeckles. In addition, in situ hybridization analysis revealed that the export of endogenous poly(A)+ mRNA is also affected by transcriptional inactivation. These results suggest that nuclear mRNA export is coupled to ongoing gene transcription in mammalian cells.
Linking physiological processes with mangrove forest structure: phosphorus deficiency limits canopy development, hydraulic conductivity and photosynthetic carbon gain in dwarf Rhizophora mangle
Authors: LOVELOCK CATHERINE E. , BALL MARILYN C. , CHOAT BRENDAN , ENGELBRECHT BETTINA M. J. , HOLBROOK N. MICHELLE , FELLER ILKA C.
Published: January 2006

Spatial gradients in mangrove tree height in barrier islands of Belize are associated with nutrient deficiency and sustained flooding in the absence of a salinity gradient. While nutrient deficiency is likely to affect many parameters, here we show that addition of phosphorus (P) to dwarf mangroves stimulated increases in diameters of xylem vessels, area of conductive xylem tissue and leaf area index (LAI) of the canopy. These changes in structure were consistent with related changes in function, as addition of P also increased hydraulic conductivity (Ks), stomatal conductance and photosynthetic assimilation rates to the same levels measured in taller trees fringing the seaward margin of the mangrove. Increased xylem vessel size and corresponding enhancements in stem hydraulic conductivity in P fertilized dwarf trees came at the cost of enhanced midday loss of hydraulic conductivity and was associated with decreased assimilation rates in the afternoon. Analysis of trait plasticity identifies hydraulic properties of trees as more plastic than those of leaf structural and physiological characteristics, implying that hydraulic properties are key in controlling growth in mangroves. Alleviation of P deficiency, which released trees from hydraulic limitations, reduced the structural and functional distinctions between dwarf and taller fringing tree forms of Rhizophora mangle.
Water relations of baobab trees (Adansonia spp. L.) during the rainy season: does stem water buffer daily water deficits?
Authors: CHAPOTIN SAHARAH MOON , RAZANAMEHARIZAKA JUVET H. , HOLBROOK N. MICHELE
Published: January 2006

Baobab trees are often cited in the literature as water‐storing trees, yet few studies have examined this assumption. We assessed the role of stored water in buffering daily water deficits in two species of baobabs (Adansonia rubrostipa Jum. and H. Perrier and Adansonia za Baill.) in a tropical dry forest in Madagascar. We found no lag in the daily onset of sap flow between the base and the crown of the tree. Some night‐time sap flow occurred, but this was more consistent with a pattern of seasonal stem water replenishment than with diurnal usage. Intrinsic capacitance of both leaf and stem tissue (0.07–0.08 and 1.1–1.43 MPa−1, respectively) was high, yet the amount of water that could be withdrawn before turgor loss was small because midday leaf and stem water potentials (WPs) were near the turgor‐loss points. Stomatal conductance was high in the daytime but then declined rapidly, suggesting an embolism‐avoidance strategy. Although the xylem of distal branches was relatively vulnerable to cavitation (P50: 1.1–1.7 MPa), tight stomatal control and minimum WPs near −1.0 MPa maintained native embolism levels at 30–65%. Stem morphology and anatomy restrict water movement between storage tissues and the conductive pathway, making stored‐water usage more appropriate to longer‐term water deficits than as a buffer against daily water deficits.
Photoprotection mutants of Arabidopsis thaliana acclimate to high light by increasing photosynthesis and specific antioxidants
Authors: GOLAN TALILA , MÜLLER‐MOULÉ PATRICIA , NIYOGI KRISHNA K.
Published: January 2006

Biochemical and physiological acclimation to different light environments is crucial for plant growth and survival. In high light (HL), feedback de‐excitation (qE) is a well‐known photoprotective mechanism that dissipates excess excitation energy in the light‐harvesting antenna of photosystem II (PSII) and relieves excitation pressure in the photosynthetic electron transport chain. The xanthophylls zeaxanthin (Z) and lutein (L) function in qE, but also have roles as antioxidants. Although several studies have shown that qE is important during short‐term fluctuations in light intensity, here we show that it is not required for the growth of Arabidopsis thaliana in prolonged HL conditions in the laboratory. Mutants that are deficient in qE alone, qE and Z synthesis, or in qE, Z synthesis and also L synthesis were able to grow at 1800 µmol photons m−2 s−1 and exhibited no major symptoms of photooxidative stress. The mutants (and wild type) acclimated to HL by increasing photosynthetic capacity and decreasing light harvesting, which together rendered qE less important for photoprotection. At a metabolite level, the HL‐grown mutants appeared to compensate for their remaining qE deficit with increased α‐tocopherol and ascorbate levels compared to the wild type. The specificity of this response provides insight into the relationship between qE and the antioxidant network in plants.
Safety of a SQ‐standardised grass allergen tablet for sublingual immunotherapy: a randomized, placebo‐controlled trial
Authors: Kleine‐Tebbe J. , Ribel M. , Herold D. A.
Published: January 2006

Background:  Sublingual treatment of grass pollen induced rhinoconjunctivitis might provide easier access to specific immunotherapy (SIT) and minimize the risk of serious adverse events (AEs) compared to subcutaneous SIT.

Aim of the study:  To identify a safe dose range for once‐daily administration of a grass allergen tablet in participants with grass pollen induced seasonal rhinoconjunctivitis.

Methods:  A randomized, double blind, placebo‐controlled Phase I trial was conducted outside the grass pollen season. Seven dosage groups [25 000, 75 000, 150 000, 300 000, 500 000, 750 000, or 1 000 000 standardized quality tablet (SQ‐T)], consisting of 12 participants randomized either to active treatment or placebo (3 : 1) daily for 28 days, commenced treatment in a staggered manner at intervals of approximately 1 week to allow for intermittent safety reviews.

Results:  The grass allergen tablet did not cause any serious, systemic or significant (leading to withdrawal) AEs. The overall incidence of AEs was 74% (1013 events); all of mild or moderate intensity and most considered treatment‐related. The most frequently reported treatment‐related AEs, including irritation of the throat, and itching sensations in the mouth and ears, increased with dose. These were primarily mild in intensity, started shortly after medication intake and lasted for minutes to a few hours maximum. Objective oral findings were also dose‐dependent. No clinically significant observations were found in safety laboratory, vital signs and 12‐lead ECG.

Conclusions:  A sublingual grass allergen tablet in doses up to 1 000 000 SQ‐T daily caused no serious or systemic AEs displaying a safety profile that allows further investigation as once‐daily self‐medication.
Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi‐centre, randomized, dose–response study
Authors: Werfel T. , Breuer K. , Ruéff F. , Przybilla B. , Worm M. , Grewe M. , Ruzicka T. , Brehler R. , Wolf H. , Schnitker J. , Kapp A.
Published: January 2006

Background:  The effect of specific immunotherapy (SIT) on eczema in atopic dermatitis is not known. Therefore, a multi‐centre, randomized dose–response trial, double‐blind with respect to the efficacy of a biologically standardized depot house dust mite preparation was performed.

Methods:  Eighty‐nine adults with a chronic course of atopic dermatitis, SCORAD ≥40 and allergic sensitization to house dust mites [CAP‐FEIA ≥3] were included, of whom 51 completed the study. Subcutaneous SIT with a house dust mite preparation (Dermatophagoides pteronyssinus/D. farinae) applying maintenance doses of 20, 2000 and 20 000 SQ‐U in weekly intervals for 1 year. The main outcome measures addressed the change of the SCORAD as average of the values after 9 and 12 months of SIT in comparison with the value at baseline.

Results:  The SCORAD declined in the three dose groups in a dose‐dependent manner (P = 0.0368, Jonckheere–Terpstra test) and was significantly lower in the two high‐dose groups (2000, 20000 SQ‐U) compared with the low‐dose group of 20 SQ‐U (P = 0.0379, U‐test) after 1 year of SIT. The use of topical corticosteroids was significantly reduced with higher doses (P = 0.0007, Mantel–Haenszel chi‐square test).

Conclusions:  Allergen‐SIT for 1 year with a house dust mite preparation is able to improve the eczema in patients with atopic dermatitis who are sensitized to house dust mite allergens and reduces the need for topical corticosteroids. SIT may be valuable in the treatment of this chronic skin disease.
IgE reactivity to latex allergens among sensitized healthcare workers before and after immunotherapy with latex
Authors: Sastre J. , Raulf‐Heimsoth M. , Rihs H.‐P. , Fernández‐Nieto M. , Barber D. , Lombardero M. , Martín S. , Quirce S.
Published: January 2006

Background:  New IgE sensitizations to proteins in allergen extracts have been shown to occur during allergen‐specific immunotherapy (IT).

Methods:  Twenty‐four healthcare workers (HCWs) – patients included in a latex IT study – were analysed, 16 in active treatment and eight in placebo. Sera were obtained at baseline and after 6 months of IT and analysed with immunoblotting and CAP System with eight single recombinant latex allergens (rHev b 1, 3, 5, 6.01, 8, 9, 10, 11, and a mix of rHev b1, 5, 6.01 and 8).

Results:  After IT with latex, three patients in the active treatment group had new IgE sensitizations, one to Hev b 5, one to Hev b 11 and another to Hev b 6.01. No other significant variation in mean of specific IgE to latex or recombinant allergens were observed in patients who received placebo or active treatment. A significant (P = 0.012) negative correlation (−0.72) was observed between maximal tolerated dose and specific IgE to Hev b 6.01 at baseline. After IT, immunoblot analysis demonstrated a significant increase in IgE binding in a band of approximately 22 kDa (P = 0.032) that may correspond to Hev b 6.01. New or more intense bands appeared in seven patients of the active group, while in three subjects a reduction was observed.

Conclusions:  Hev b 6.01 seems to be the most relevant latex allergen in HCWs. New or more intense IgE binding to latex allergenic components occurs during latex immunotherapy. However, the levels of specific IgE against these new components are low and do not seem to have clinical relevance.
Haemodialysis‐associated anaphylactic and anaphylactoid reactions
Authors: Ebo D. G. , Bosmans J. L. , Couttenye M. M. , Stevens W. J.
Published: January 2006

Anaphylactic and anaphylactoid reactions related to haemodialysis have been increasingly described for almost 3 decades. The majority of these cases used to occur with ethylene oxide sterilized, and complement‐activating cellulose membranes. However, a considerable number of publications have focused on polyacrylonitrile AN69®high flux membranes, angiotensin converting enzyme inhibitors and iron as other important causes of potentially severe haemodialysis‐related anaphylactoid reactions. Clinical manifestations vary considerably and generally do not allow differentiation between IgE‐mediated anaphylaxis and anaphylactoid reactions (e.g. from nonspecific mediator release). Successful management of these patients requires multidisciplinary approach and involves prompt recognition and treatment by the attending physician, and identification of the offending agent(s) with subsequent avoidance of the incriminated compound(s). This review focuses on some major causes of anaphylactoid and anaphylactic reactions during haemodialysis. Special consideration is given to the therapeutic and diagnostic approach.
Association between interleukin‐1 receptor antagonist gene and asthma‐related traits in a German adult population
Authors: Pattaro C. , Heinrich J. , Werner M. , de Marco R. , Wjst M.
Published: January 2006

Background:  A recent study in German and Italian families associated variants in the interleukin‐1 receptor antagonist (IL1RA) gene with asthma. The aim of the present study was to further investigate the role of single nucleotide polymorphisms (SNPs) in the IL1RA gene in the development of atopy and lifelong asthma in a population‐based study.

Methods:  DNA samples from the German centres of the European Community Respiratory Health Survey were analysed for genetic variants in the IL1RA gene and the development of asthma, atopy and bronchial hyperreactivity.

Results:  Carriers of the rare G allele of SNP rs447713 had a significantly increased risk of developing asthma (P = 0.0013) and allergic sensitization (P = 0.0119). Carriers of the rare C allele of SNP rs3087271 had an increased risk of asthma (P = 0.0227) and high immunoglobulin E (IgE) levels (P = 0.0232). A haplotype built from eight SNPs in the IL1RA gene (A‐C‐A‐G‐A‐C‐G‐A) was associated with a higher prevalence of asthma (P = 0.007) and high total IgE (P = 0.02). Bronchial hyperreactivity was positively associated with the haplotype A‐C‐G‐G‐A‐C‐G‐C (P = 0.02) and negatively with the A‐C‐G‐G‐A‐C‐T‐C (P = 0.03).

Conclusion:  A previously described association between IL1RA and asthma in families could be reproduced in a population‐based sample. The genetic variants of IL1RA gene do not to seem to affect asthma alone, but to act as modulators of asthma‐related traits as well, where different haplotypes drive the development of different phenotypes.
European birth cohort studies on asthma and atopic diseases: I. Comparison of study designs – a GA2LEN initiative
Authors: Keil T. , Kulig M. , Simpson A. , Custovic A. , Wickman M. , Kull I. , Lødrup Carlsen K. C. , Carlsen K. H. , Smit H. A. , Wijga A. H. , Schmid S. , Von Berg A. , Bollrath C. , Eller E. , Bindslev‐Jensen C. , Halken S. , Høst A. , Heinrich J. , Porta D. , Forastiere F. , Brunekreef B. , Krämer U. , Willich S. N. , Wahn U. , Lau S. ,   the working group of GALEN‐WP 1.5 ’Birth Cohorts’
Published: January 2006

Background:  The reasons for the rise in asthma and allergies remain unclear. To identify risk or protective factors, it is essential to carry out longitudinal epidemiological studies, preferably birth cohort studies. In Europe, several birth cohort studies on asthma and atopic diseases have been initiated over the last two decades.

Aim:  One of the work packages within the Global Allergy and Asthma European Network (GA2LEN) project was designed to identify and compare European birth cohorts on asthma and atopic diseases. The present review (part I) describes their objectives, study settings, recruitment process and follow‐up rates. A subsequent review (part II) will compare outcome and exposure parameters.

Methods:  For each birth cohort, we collected detailed information regarding recruitment process, study setting, baseline data (pregnancy, birth, parents/siblings) as well as follow‐up rates, outcome and exposure parameters at each time point.

Results:  We identified and assessed 18 European birth cohorts on asthma, allergic rhinitis and eczema. Six of these studies also focused on food allergies. The birth cohorts were mostly initiated in the 1990s with predominantly urban/metropolitan settings. Many studies were able to maintain high follow‐up rates, even after five or more years.

Conclusions:  Due to the unique cooperation within the GA2LEN project a common database was established containing study characteristics of European birth cohorts on asthma and atopic diseases. This can be used as a basis for evaluating the possibility to pool data and perform meta‐analyses, as well as to recommend criteria for conducting future birth cohorts.
Polymorphisms of the GSTM1 and GSTT1 genes in patients with allergic diseases in the Czech population
Authors: Holla L. I. , Stejskalova A. , Vasku A.
Published: January 2006

Background:  Allergic diseases belong to the most common chronic disorders affecting mankind and their prevalence in population is increasing. Several studies have indicated that oxidative stress impairs pulmonary function and makes existing asthma worse. Members of the glutathione‐S‐transferase (GST) superfamily of genes are important in protection of cells from reactive oxygen species.

Aims of the study:  Relationships among allergic diseases including asthma and variations in the GST mu (GSTM1) and GST theta (GSTT1) genes were investigated in 1006 Caucasian subjects.

Methods:  The multiplex polymerase chain reaction protocol was used for simultaneous amplification of both genes for molecular analysis. Genotype frequencies among patients and controls were assessed and the associations of the genotypes with intermediary phenotypes of allergy were statistically determined.

Results:  The frequencies of GST null genotypes did not differ significantly between patients with allergic diseases (or asthma alone) and healthy controls. However, when compared with patients homozygous or heterozygous for GSTM1 functional allele, asthmatics carrying both GSTM1 null alleles displayed significantly worse lung function, assessed by forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio (Tiffenau index), (P < 0.01).

Conclusions:  Genetic polymorphisms of the GSTM1 and GSTT1 genes, both individually and in combination, were not associated with the development of allergic diseases including asthma in the Czech population, the GSTM1 gene variability, however, may influence lung functions in our asthmatics.
The effect of β2‐adrenoceptor haplotypes on bronchial hyper‐responsiveness in patients with asthma
Authors: Wilson A. M. , Gray R. D. , Hall I. P. , Lipworth B. J.
Published: January 2006

Background:  The β2‐adrenoceptor exhibits genetic polymorphism which may be clinically relevant in terms of treatment response or bronchial hyper‐responsiveness (BHR). The combined effect of these genotypes, or the haplotype, has not been fully characterized in terms of BHR.

Methods:  We performed a retrospective analysis of the effects of haplotypes of amino acid substitution at position 16 (Gly/Arg) and position 27 (Gln/Glu) on spirometry and BHR to methacholine and adenosine monophosphate (AMP) in 594 asthmatic patients.

Results:  There was a significant (P < 0.05) overall effect for forced expiratory volume (FEV1) but not after correction for steroid dose and atopic status. There were no significant differences for BHR to methacholine or AMP between the different haplotypes and no difference between the numbers of patients with or without clinically relevant BHR. Methacholine PD20 geometric mean‐fold difference was 1.63 (95% CI: 0.95–2.80) between Arg–Arg/Gln–Gln and Gly–Gly/Gln–Gln and 1.26 (95% CI: 0.75–2.11) between Gly–Gly/Gln–Gln and Gly–Gly/Glu–Glu.

Conclusions:  The degree of BHR to indirect and direct stimuli does not differ between β2‐adrenoceptor haplotypes, and haplotypes cannot be used to predict BHR in patients presenting with asthma. Although β2‐adrenoceptor haplotypes do not predict BHR they may be important in predicting response to bronchodilator therapy.
Immune mechanisms of allergen‐specific sublingual immunotherapy
Authors: Moingeon P. , Batard T. , Fadel R. , Frati F. , Sieber J. , Van Overtvelt L.
Published: January 2006

Sublingual immunotherapy has been shown in some clinical studies to modulate allergen‐specific antibody responses [with a decrease in the immunoglobulin E/immunoglobulin G4 (IgE/IgG4) ratio] and to reduce the recruitment and activation of proinflammatory cells in target mucosa. Whereas a central paradigm for successful immunotherapy has been to reorient the pattern of allergen‐specific T‐cell responses in atopic patients from a T helper (Th)2 to Th1 profile, there is currently a growing interest in eliciting regulatory T cells, capable of downregulating both Th1 and Th2 responses through the production of interleukin (IL)‐10 and/or transforming growth factor (TGF)‐β. We discuss herein immune mechanisms involved during allergen‐specific sublingual immunotherapy (SLIT), in comparison with subcutaneous immunotherapy. During SLIT, the allergen is captured within the oral mucosa by Langerhans‐like dendritic cells expressing high‐affinity IgE receptors, producing IL‐10 and TGF‐β, and upregulating indoleamine dioxygenase (IDO), suggesting that such cells are prone to induce tolerance. The oral mucosa contains limited number of proinflammatory cells, such as mast cells, thereby explaining the well‐established safety profile of SLIT. In this context, second‐generation vaccines based on recombinant allergens in a native conformation formulated with adjuvants are designed to target Langerhans‐like cells in the sublingual mucosa, with the aim to induce allergen‐specific regulatory T cells. Importantly, such recombinant vaccines should facilitate the identification of biological markers of SLIT efficacy in humans.
Risk factors for asthma in young adults: a co‐twin control study
Authors: Thomsen S. F. , Ulrik C. S. , Kyvik K. O. , Larsen K. , Skadhauge L. R. , Steffensen I. E. , Duffy D. L. , Backer V.
Published: January 2006

Background:  The liability to asthma is influenced both by genetic and environmental factors. The objective of this study was to identify risk factors for asthma in young adult twin pairs during an 8‐year period.

Methods:  From the birth cohorts 1953–1982 of the Danish Twin Registry, 6090 twin pairs who were initially unaffected with respect to asthma at a nationwide questionnaire‐based study in 1994 participated in a similar follow‐up study in 2002. Subjects were regarded incident asthma cases when responding affirmatively to the question ‘Do you have, or have you ever had asthma'? in 2002. Pairs in which only one twin developed asthma – discordant pairs – were identified and conditional logistic regression was applied to detect effects of risk factors.

Results:  A total of 126 monozygotic (MZ) and 273 dizygotic (DZ) discordant twin pairs were identified. In MZ twins hay fever (OR = 3.16, 95% CI: 1.29–7.73, P = 0.007) and exercise (OR for inactivity = 0.35, 95% CI: 0.13–0.91, P = 0.023) were significantly associated with asthma, whereas in DZ twins, hay fever (OR = 2.44, 95% CI: 1.44–4.13, P = 0.001), eczema (OR = 1.96, 95% CI: 1.02–3.78, P = 0.040), female sex (OR between males and females = 0.54, 95% CI: 0.36–0.80, P = 0.002), and increasing levels of body mass index (BMI; OR per unit = 1.11, 95% CI: 1.02–1.20, P = 0.009) were significant predictors of asthma.

Conclusions:  Hay fever, eczema, female sex, exercise and increasing levels of BMI were risk factors for asthma in young adults. The different risk profile observed in MZ twins compared with DZ twins may reflect an underlying genetic vulnerability shared between those risk factors and asthma.
Twelve‐year follow‐up after discontinuation of preseasonal grass pollen immunotherapy in childhood
Authors: Eng P. A. , Borer‐Reinhold M. , Heijnen I. A. F. M. , Gnehm H. P. E.
Published: January 2006

Background:  In a previous controlled study, we demonstrated that preseasonal grass pollen immunotherapy for 3 years was effective in children. Moreover, a significant clinical benefit could still be observed 6 years after discontinuation of specific immunotherapy (SIT). In the current study, we examined the same group of patients again to investigate whether there is a prolonged benefit 12 years after SIT is stopped.

Methods:  Twenty‐two patients with previous SIT (from 1989 through 1991) or standardized seasonal pharmacotherapy only were prospectively followed during the grass pollen season of 2003. Primary end points were symptom score, medication use, and combined symptom and medication score. In addition, skin prick test reactivity, development of new sensitizations, and prevalence of seasonal asthma were evaluated.

Results:  Total hay fever symptom score (P < 0.03), use of medication (P < 0.05), and combined symptom and medication score (P < 0.03) remained lower in patients with previous SIT when compared with the control group. Decreased immediate skin response to grass pollen returned 12 years after cessation of SIT. The percentage of new sensitization, however, continued to be significantly smaller in patients with previous SIT (58%) compared with the controls (100%, P < 0.05). There was a tendency for lower prevalence of seasonal asthma in the post‐SIT group (P = 0.08).

Conclusion:  This prospective controlled prolonged follow‐up study demonstrates the ongoing clinical benefit 12 years after discontinuation of SIT. Furthermore, the reduction in onset of new sensitization, which was found 6 years after discontinuation of SIT, is sustained 6 years later.
The role of Foxp3+ T cells in long‐term efficacy of prophylactic and therapeutic mucosal tolerance induction in mice
Authors: Winkler B. , Hufnagl K. , Spittler A. , Ploder M. , Kállay E. , Vrtala S. , Valenta R. , Kundi M. , Renz H. , Wiedermann U.
Published: January 2006

Background:  Mucosal tolerance induction is suggested as treatment strategy for allergic diseases. Using a murine model of birch pollen (BP) allergy we investigated the long‐term efficacy and the underlying mechanisms of mucosal tolerance induction with two structurally different molecules in a prophylactic and in a therapeutic set‐up.

Methods:  The three‐dimensional major BP allergen Bet v 1 or a nonconformational hypoallergenic fragment thereof was intranasally applied before (prophylaxis) or after sensitization (therapy).

Results:  In the prophylactic application both the Bet v 1 allergen and the fragment prevented allergic sensitization, and this effect lasted for 1 year. In the therapeutic approach established allergic immune responses were also suppressed after treatment with either of the molecules. However, a long‐lasting curative effect (6 months) was only achieved with the Bet v 1 allergen but not with the Bet v 1 fragment.

Real‐time reverse transcriptase polymerase chain reaction (RT‐PCR) analysis of splenocytes revealed that tolerance induction with the Bet v 1 allergen was associated with enhanced expression of transforming growth factor (TGF)‐β, interleukin (IL)‐10, and Foxp3 mRNA in CD4+ T cells, whereas treatment with the fragment led to the induction of either Foxp3 (prophylaxis) or IL‐10 (therapy) alone.

Conclusion:  From these data we concluded (i) that the mechanisms underlying peripheral tolerance are linked to the conformation of the antigen, (ii) that mucosal tolerance is mediated by separate regulatory cell subsets, and (iii) that the long‐term efficacy of immunosuppression is associated with the presence of Foxp3+ T cells.
Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome
Authors: Shashi V , Keshavan MS , Howard TD , Berry MN , Basehore MJ , Lewandowski E , Kwapil TR
Published: January 2006

Chromosome 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a markedly elevated risk of schizophrenia in adulthood. Cognitive impairments such as a low IQ and deficits in attention and executive function are common in childhood. The catechol O‐methyltransferase (COMT) gene maps within the deleted region and is involved in the degradation of dopamine, a neurotransmitter thought to be important in cognition and the development of schizophrenia. Thus, we examined the correlation between neurocognitive deficits and a common polymorphism Val158Met in the COMT gene in a cohort of children with 22q11DS. Our results show that children with 22q11DS who have the Met allele have higher IQ and achievement scores and perform better on measures of prefrontal cognition, such as the Continuous Performance Task, as compared with those with the Val allele. These results confirm that the hemizygous COMT Val158Met genotype impacts upon cognition in children with 22q11DS.
A questionnaire study for 128 patients with Gaucher disease
Authors: Mankin HJ , Trahan CA , Barnett NA , Laughead J , Bove CM , Pastores GM
Published: January 2006

Gaucher disease is an uncommon autosomal recessive disorder characterized by lysosomal storage of glucosyl ceramide, a material released during cell degradation. Patients with Gaucher disease often have significant hematologic, bone structural, and visceral problems which sometimes greatly affect their health and life style. Based on some extraordinary scientific discoveries over the past 45 years, a treatment system has evolved which consists of administration of an enzyme, which destroys the lysosome‐stored material and to some extent restores the patients to good health. There are still some problems for these patients; however, and the purpose of the study is to define some of the clinical, sociologic, and psychologic problems with a specially designed questionnaire. Questionnaire data was collected for 128 patients from two institutions with complete anonymity, and the information compared against data from a National Health Inteview Survey. The results show that many of the patients still have fairly extensive problems, which could possibly be helped by some alterations in treatment protocols.
Mutation analysis in hereditary haemorrhagic telangiectasia in Germany reveals 11 novel ENG and 12 novel ACVRL1/ALK1 mutations
Authors: Wehner L‐E , Folz BJ , Argyriou L , Twelkemeyer S , Teske U , Geisthoff UW , Werner JA , Engel W , Nayernia K
Published: January 2006

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal‐dominant disease characterized by recurrent epistaxis, mucocutaneous telangiectasias and visceral arteriovenous malformations. Mutations in endoglin (ENG) and activin A receptor type II‐like kinase 1 (ACVRL1 or ALK1) have been found in patients with HHT. We have screened a total of 51 unselected German index cases with the suspected diagnosis of HHT. We identified 30 different mutations in 32 cases (62.7%) by direct sequencing. Among these mutations, 11 of 13 ENG mutations and 12 of 17 ACVRL1 mutations were not previously reported in the literature. Two of the ACVRL1 mutations were each shared by two families. An analysis of the genotype–phenotype correlation is consistent with a more common frequency of pulmonary arteriovenous malformations in patients with ENG mutations than in patients with ACVRL1 mutations in our collective.
Common variants of multiple genes that control reverse cholesterol transport together explain only a minor part of the variation of HDL cholesterol levels
Authors: Boekholdt SM , Souverein OW , Tanck MWT , Hovingh GK , Kuivenhoven JA , Peters RIG , Jansen H , Schiffers PMH , Van Der Wall EE , Doevendans PA , Reitsma PH , Zwinderman AH , Kastelein JJP , Jukema JW
Published: January 2006

It is assumed that the combined effects of multiple common genetic variants explain a large part of variation of high‐density lipoprotein cholesterol (HDL‐C) plasma levels, but little evidence exists to corroborate this assumption. It was our objective to study the contribution of multiple common genetic variants of HDL‐C‐related genes to variation of HDL‐C plasma levels. A well‐characterized cohort of 546 Caucasian men with documented coronary artery disease was genotyped for common functional variants in genes that control reverse cholesterol transport: ATP‐binding cassette transporter A1, apolipoprotein A‐I and apolipoprotein‐E, cholesteryl ester transfer protein, hepatic lipase, lecithin : cholesterol‐acyl transferase, lipoprotein lipase, and scavenger receptor class B type 1. Multivariate linear regression showed that these variants, in conjunction, explain 12.4% (95% confidence interval: 6.9–17.9%) of variation in HDL‐C plasma levels. When the covariates smoking and body mass index were taken into account, the explained variation increased to 15.3% (9.4–21.2%), and when 10 two‐way interactions were incorporated, this percentage rose to 25.2% (18.9–31.5%). This study supports the hypothesis that multiple, mildly penetrant, but highly prevalent genetic variants explain part of the variation of HDL‐C plasma levels, albeit to a very modest extent. Multiple environmental and genetic influences on HDL‐C plasma levels still have to be elucidated.
Cytokinin affects circadian‐clock oscillation in a phytochrome B‐ and Arabidopsis response regulator 4‐dependent manner
Authors: Zheng Binglian , Deng Yan , Mu Jinye , Ji Zhendong , Xiang Tingting , Niu Qi‐Wen , Chua Nam‐Hai , Zuo Jianru
Published: January 2006

In higher plants, many developmental processes, such as photomorphogenesis and flowering, are coregulated by light and the phytohormone cytokinin. Interactions between light and cytokinin pathways are presumably mediated by common signaling intermediates. However, the molecular mechanism of these interactions remains unclear. Here, we report that cytokinin specifically induces the expression of the Arabidopsis circadian oscillator genes LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK‐ASSOCIATED 1 (CCA1) but represses the expression of TIMING OF CAB EXPRESSION 1 in a light‐dependent manner. Consistent with these observations, cytokinin causes a shifted phase of the circadian clock. Mutant studies showed that the altered clock oscillation modulated by cytokinin is dependent on phytochrome B (PHYB) and ArabidopsisRESPONSE REGULATOR 4 (ARR4). Whereas overexpression of LHY or CCA1 renders plants slightly more sensitive to cytokinin, phyB and a lhy/cca1 double mutant are less sensitive to the hormone. These results suggest that cytokinin affects the circadian clock oscillation in a PHYB‐ and ARR4‐dependent manner and that cytokinin signaling is also regulated by light‐signaling components, including PHYB, LHY and CCA1. Therefore, phyB, ARR4 and the circadian oscillator may function as signaling intermediates to integrate light and cytokinin pathways.