bluuebunny/crossref_metadata_2025 huggingface dataset:
3 GOING NATIVE?
Authors: Scully Roger
Published: February 2006

This chapter reviews in detail existing knowledge about the subject matter of this study. Notions of pervasive socialization processes leading to attitudinal and behavioural changes for those serving within European institutions are shown to be widespread, appearing in much popular commentary academic literature on the EU, including that on the European Parliament. However, the discussion then goes on to demonstrate that strikingly little evidence has ever been presented to show that significant socialization effects operating among members of EU institutions lead to changes in attitudes and/or behaviour in an identifiably more pro-European direction. Virtually all empirical work in this area hitherto has produced indeterminate or null findings; furthermore, coherent theoretical foundations that might underpin the assumption of actors ‘going native’ in EU institutions have almost never been explicitly developed alongside the conduct of serious empirical research.
Evidence from Voting Behaviour
Authors: Scully Roger
Published: February 2006

This chapter examines empirical evidence on MEPs’ behaviour inside the European Parliament. Multivariate analysis of behaviour on several key votes in the chamber directly concerned with the advancement of European integration demonstrates there to be no consistent relationship between greater experience in the chamber (and thus longer exposure to the forces of socialization) and support for advancing European unity. A time-series analysis of the behaviour of new MEPs during the first months of the 1999-2004 parliament shows no tendency for them to become increasingly likely to side with their European rather than national party colleagues when these two forms of party loyalty come into conflict.
Conclusion—Becoming Europeans?
Authors: Scully Roger
Published: February 2006

This chapter concludes the study by summarising the major findings presented and addressing some potential counter-arguments to the conclusions drawn. Three broad implications of the study are then discussed. First, what does the study tell us about the European Parliament? The EP, it is suggested, fits much less well than other EU institutions into the ‘supra-national’ category, and MEPs largely remain nationally-based politicians. Second, the implications of the findings for European integration are assessed. Socialisation effects on political elites must, it is argued, play a much more limited role in explanations of European integration than many scholars have believed. Finally, the wider implications of this study for the analysis of institutional socialisation as a general phenomenon are considered.
Chapter 14 The Future of Retirement in Sweden
Authors: Sundén Annika
Published: February 2006

This chapter discusses the transformation of the Swedish retirement income system and comments on how it may change the future of retirement. It begins by outlining, and then comparing it to the system in place before the reform. The reform process is explored and future challenges are discussed. A final section offers some lessons for other countries.
I The Structuring of Social Citizenship: A Theoretical Framework
Authors: Ferrera Maurizio
Published: February 2006

The chapter surveys the “state-building” literature and discusses, in particular, the works of Stein Rokkan and of Albert Hirschman, highlighting their usefulness for studying welfare state developments. An original analytical framework is proposed for the exploration of spatial politics, based on a combination of “vocality” and “locality” options. The chapter then discusses the emergence and evolution of modern citizenship as a form of spatial closure, and proposes an interpretation of social rights as products of structuring processes.
4 Contested Social Sovereignty: Welfare States Meet the European Union
Authors: Ferrera Maurizio
Published: February 2006

This chapter reconstructs developments of EC law (including case law) relating to social protection, and traces the differential impact that free movement and competition rules have had on the various functional schemes and tiers or pillars of provision within national welfare states. It also identifies and illustrates the new strategies of spatial politics prompted by the boundary redefinitions operated by the EU, focussing on pensions (including pension funds), health care, and social assistance. Special attention is devoted to the position of third country nationals.
Mythical Objects (2002)
Authors: Salmon Nathan
Published: February 2006

Salmon’s account of error as accidental fiction is invoked to solve a notoriously difficult problem in philosophical logic, introduced by Peter Geach: How can it be correct to report that Hob and Nob have thoughts and beliefs concerning the same witch, when there are no such things as witches? Salmon’s answer is that Hob’s and Nob’s thoughts and beliefs concern the same mythical witch, which although not a real witch, is a real thing.
The Logic of What Might Have Been (1989)
Authors: Salmon Nathan
Published: February 2006

It is argued that some possible worlds are only contingently possible, and likewise that some impossible worlds are only contingently impossible. There are counterexamples to S5 modal logic and even to S4. What about B? Although there are no convincing grounds for supposing that even the actual world is only contingently possible, as far as the logic of modality is concerned (as opposed to the metaphysical reality), the actual world might instead have been impossible. The correct modal propositional logic is the simple system T.
The Limits of Human Mathematics (2001)
Authors: Salmon Nathan
Published: February 2006

Gödel’s claim is defended that his famous incompleteness theorems yield the result, as a mathematically established fact, that the mathematical problem-solving capacity of the human mind either exceeds that of any finite machine or is incapable of solving all of mathematics’ mysteries. The issue turns on the nature of mathematical proof by the human mind. Of particular relevance is the question of whether the deductive basis of human mathematics is decidable.
A Problem in the Frege–Church Theory of Sense and Denotation (1993)
Authors: Salmon Nathan
Published: February 2006

An inconsistent triad to which Fregean theory, as expounded by Church, seems committed is exposed: (i) Frege’s assertion that the sense that a sentence like ‘Holmes has an older brother’ expresses when it occurs within a propositional-attitude attribution — its indirect sense — is the customary sense of ‘the proposition that Holmes has an older brother’; (ii) a Fregean solution, suggested by Church, to the traditional Paradox of Analysis; and (iii) Church’s observation that ‘Holmes has an older brother’ and ‘Holmes has an older male sibling’, even when expressing their indirect senses, can both be correctly translated by means of a single sentence of another language (expressing its own indirect sense). It is argued that the solution to this problem threatens the very heart for the Frege-Church theory.
Proper Function and Convention in Speech Acts
Authors: Millikan Ruth Garret
Published: February 2006

A new analysis of the nature of illocutionary acts and of their relation to conventional acts and to the intentions of speakers is offered. The analysis pivots on a new description of the nature of linguistic convention, and on the claim that language devices themselves have purposes that are not derived as a function merely of speaker intentions or policies.
Historical Background to the Interpretation of Aristotle's Teleology
Authors: Johnson Monte Ransome
Published: February 2006

According to the standard history, Aristotelian teleology and final causes were discarded in the scientific revolution in favor of the mechanical philosophy. In fact, the term teleology was invented in the eighteenth century to designate the search for evidence of god in purposes, goals, intelligence, and design manifest in nature. The background natural theology is the adaptation of Aristotelian philosophy by Greek commentators and Neoplatonists (to bring it into line with the creation myth of Plato’s Timaeus), and by Arabic and Latin commentators (to being it into line with the creationism of Islam and Christianity). But already with the scholastics, there was a move to consider final causes applicable only to cases of intentional agency, or as a heuristic for material and moving causes (later, ‘mechanistic’ causes). Kant attempted to resolve the impasse between the natural theology and heuristic perspectives in his third Critique. Kant’s view of teleology has had a profound and arguably distorting influence on the later interpretation of Aristotle’s use of ends and goods in natural science. A better starting point for the examination of Aristotle’s teleology is a treatise by Aristotle’s associate and successor, Theophratus, who in his Metaphysics presents a critical view of teleological explanations.
Teleological Notions
Authors: Johnson Monte Ransome
Published: February 2006

The key term of Aristotle’s teleology is “the cause for the sake of which”. Aristotle discusses in several key texts (Physics, On the Soul, Metaphysics, Eudemian Ethics) the fact that this has two different senses: aim and beneficiary. The aim of a knife is cutting, but the beneficiary is the person who does, or orders, the cutting. Aristotle uses this distinction to show how natural things have both aims and are beneficiaries of their functions. He also shows how non-natural things, such as god, can operate as causes for the sake of which, but not as beneficiaries. Eternal things (like the unmoved mover, forms of living things, the universe itself, nature, and so forth) cannot be beneficiaries, because they cannot undergo change. Thus, the beneficiaries of Aristotle’s teleology are the elements, plants, and animals that can both undergo change and have functional aims. A survey of other terms of Aristotle’s teleology, such as “nature does nothing in vain”, the terms “complete” or “perfect”, as well as “end” and “entelechy” further show the specific orientation of Aristotle’s teleology, as do his use of axiological terms such as “better” and “fine”.
Teleological Dialectic
Authors: Johnson Monte Ransome
Published: February 2006

Aristotle articulates his natural teleology in the context of a dialectical engagement with his predecessors, identifying each of them with a salient causal factor: Empedocles (luck or chance), Democritus (necessity or spontaneity), Anaxagoras (intelligence or mind), and Plato (art and form). Aristotle tries to co-opt each of these factors into his naturalistic teleology by an a fortiori argument: to the extent that luck, necessity, intelligence, or art is a cause, nature must even more so be considered a cause. For luck is an incidental cause of that which nature is an intrinsic cause, necessity is a conjoint cause of that which nature is a leading cause, and art imitates nature.
Teleology and Organisms i: General Principles
Authors: Johnson Monte Ransome
Published: February 2006

Elements compose organic bodies, including tissues (homogenous bodies) and organs (heterogeneous bodies), and in so doing are for the sake of the whole organism of which they are the transformed parts. But the starting point for the explanation of living things is the identification of its functions: nutrition and reproduction for plants, perception and locomotion for animals, and virtue and intelligence for humans. Since the functions of plants are fundamental to all other living things, the vegetative functions are the primary ones in biological explanation. Thus, the survival and reproduction of each species is the basis for its explanation, and these are represented as goods for it. But although goods come first in the order of explanation, they come last in the order of development of the organism. Thus, intelligence is the last thing developed by a human, even though everything else has come to be for the sake of this. The reversal of explanatory and genetic order does not, however, imply some kind of mysterious “backwards causation”.
Teleology and the Cosmos
Authors: Johnson Monte Ransome
Published: February 2006

Aristotle’s cosmos consists of natural substances, each with its own proper functions, motions, and ends. To this extent, his cosmos is teleological. But there is no overall or cosmic teleology in a stronger sense, above and beyond the applicability of teleological explanations to each of the natural things. For the universe (or nature as a whole) does not have a proper function, or motions, goods or ends. The stars, elements, plants, animals and humans do, and nature is the principle of motion and the end for each of these. In the final chapter of Metaphysics XII (Lambda), Aristotle discusses an aporia about how the good exists in “the nature of the whole”. He ends not with a positive account, but with a criticism of his predecessors who have advanced an account of an extrinsic cause of the cosmos.
Conclusion
Authors: Johnson Monte Ransome
Published: February 2006

Aristotle’s teleological explanations are most successful in the domain of living things, and there is good reason to think that organisms are the objects of his most important teleological remarks. The attempts to apply teleological explanations to less complex entities (such as the elements) and more complex entities (such as cities) have been judged by history a failure. His explanations of organisms, on the other hand, have been celebrated by molecular biologists, embryologists and developmental biologists, and advocates of adaptationism in evolutionary biology. Teleology as a scientific proposition seems to require a sufficient level of complexity, but to break down at levels of too much complexity (at the level of human behavior, or of society, for example) or too little complexity (at the level of inanimate entities, for example). But whatever the scientific verdict on Aristotle’s teleology, it is clear that his conception of intrinsic ends has important implications for axiology (the theory of value). For he has shown how it is possible to identify objective goods, independent of human minds, and to avoid the dilemma between radical egalitarianism on the one hand and arbitrary or self-serving hierarchy on the other.
Zombies and Consciousness
Authors: Kirk Robert
Published: February 2006

By definition, zombies would be behaviourally and physically just like us, but not conscious. If a zombie world is possible, then physicalism is false. Just as importantly, the seductive conception of phenomenal consciousness embodied by the zombie idea is fundamentally misconceived. One of this book’s two main aims is to bring out the incoherence of the zombie idea with the help of an intuitively appealing argument (the ‘sole-pictures argument’). The other is to develop a fresh approach to understanding phenomenal consciousness by exploiting two key notions: that of a ‘basic package’ of capacities which is necessary and sufficient for perception in the full sense; and that of ‘direct activity’, which, when combined with the basic package, is necessary and sufficient for perceptual consciousness. These definitions may apply to quite humble creatures, and even to suitably constructed artefacts.
Introduction
Authors: Kirk Robert
Published: February 2006

A cook was charged with cruelty to animals for putting live prawns on a hot-plate, but the case was dropped for lack of expertise on whether prawns could suffer pain. What matters from the point of view of an interest in whether a creature is phenomenally conscious: whether there is ‘something it is like’ for it? Even if all the physical facts are known, might it still lack phenomenal consciousness, as ‘zombists’ (those who think zombies are conceivable) claim? The problem is not merely scientific: philosophical explanations are needed. This chapter introduces those and other central topics, and outlines the book.
Zombies and Minimal Physicalism
Authors: Kirk Robert
Published: February 2006

Epiphenomenalism accepts the causal closure of the physical, hence the possibility of zombies. But it is argued, via consideration of the ‘redescription thesis’, that physicalism involves commitment to the ‘strict implication thesis’, according to which the narrowly physical truths about the world strictly imply the significant mental truths. This is an empirical thesis but depends on logical or conceptual relations, although physicalists are not therefore compelled to subscribe to any strong doctrine of conceptual analysis. It follows that if zombies are even barely possible, physicalism is false. It also follows that bald assertions of psycho-physical identity do not dispense physicalists from commitment to this conclusion, nor does a thesis of a posteriori necessity.
What Has To Be Done
Authors: Kirk Robert
Published: February 2006

This chapter focuses on the nature of perceptual-phenomenal consciousness. This is the ‘what-is-it problem’, and contrasts strongly with the ‘what-is-it-like problem’. A solution to the latter cannot be found for Nagelian reasons, but that does not prevent an attempt to solve the what-is-it problem. Jackson’s Mary provides useful lessons: she could not get a priori from the physical and functional truths to a full knowledge-with-understanding of phenomenal truths, but she could get a priori from the physical truths to a knowledge of which phenomenal statements were true. The difference between Block’s ‘access consciousness’ and ‘phenomenal consciousness’ is no difficulty for the project; nor is a new science needed. In what follows, the moderate realism of everyday psychology will be useful.
Deciders
Authors: Kirk Robert
Published: February 2006

Considering humbler creatures than ourselves provides a better chance of uncovering what really matters for perceptual consciousness. This chapter discusses a series of broad classes of behaving systems, starting with ‘pure reflex systems’ and ending with ‘deciders’: systems with the ‘basic package’, capable of choosing between alternative courses of action, if only in a rudimentary sense. The idea of the basic package provides a framework for thinking about behaving systems, which advances the overall project of understanding perceptual consciousness. This framework helps to bridge the gap between descriptions in purely physical or biomechanical terms, and descriptions in psychological terms.
Direct Activity
Authors: Kirk Robert
Published: February 2006

The basic package is necessary for perceptual consciousness but seems not to be sufficient. What is also necessary is ‘direct activity’: a special feature of the way events constituting incoming perceptual information affect the system, explained partly with the help of the ‘rabbitoid’. This imagined creature is a decider, but is unlike a normal rabbit in that its perceptual information does not automatically give it the opportunity to modify its current goals if doing so would help it. Direct activity is further explained in terms of ‘instantaneity’ and ‘priority’. It is an integrated process, to be conceived of holistically, and contrasts sharply with what is often called the ‘availability’ or ‘poisedness’ of perceptual information.
Survival of the Fittest
Authors: Kirk Robert
Published: February 2006

The main alternative accounts of perceptual consciousness are briefly discussed, including scientific-psychological; neuroscientific; dualist; physicalist; Wittgensteinian; Sartrean; behaviourist; other kinds of functionalist; pure representationalist (Dretske, Tye); higher-order perception (Armstrong); higher-order thought (Rosenthal, Carruthers). The book concludes with a reminder of its core points.
The Connection between Old and New Approaches to Financial Satisfaction
Authors: Praag Bernard M. S. van
Published: February 2006

This chapter claims priority in the field of happiness and economics for the early researches on financial satisfaction by the Leyden School in Holland during the 1960s. Although the scope of the research exercise was more restricted compared to subsequent studies, the present-day significance of the Leyden School econometric approach is shown to provide new insights to the current debate.
6 Electoral Representation in Loosely Bounded Territories: Mass Politics in the EU?
Authors: Bartolini Stefano
Published: February 2006

This chapter investigates the electoral representation of the integration issues, assuming that the shift in the location of institutional power related to European integration may be accompanied by a corresponding change in the direction of the efforts of mass politics. It documents the extent to which European issues differentiate the attitudes of voters and parties alike. It argues that the attitudes of national and European parties, of political elites, and public opinion towards the constitutive issues of integration are hard to interpret, referring to historical cleavages or to a left-right dimension. It interprets the Europarties development as a top-down attempt by political elites to institutionalize an isomorphic party system at the EU level that tends to select those nation-like issues on which a structuring easier. It discusses the strong collusive push of both national and European parties towards constitutive EU issues in which their divisions appear insurmountable and would undermine their effective existence. The current situation witnesses an imbalance between the lack of party system structuring at the EU level and the growing potential for party system destructuring at the national level. If EU-related latent oppositions were to be politicized, the resulting alignments will not closely correspond with the political divisions on which domestic politics has traditionally been founded.
2 Mandate Theories: Government and Median
Authors: McDonald Michael D. , Budge Ian
Published: February 2006

The argument of Chapter One is spelled out in more detail in terms of propositional tables and accompanying discussion. These show the considerable overlap in the conditions for any mandate to exist, and the fact that the Government Mandate is a special case of the Median Mandate. The tables on voting and governments show that spontaneous majorities, essential to the Government Mandate, rarely form, while correspondences between median voter and median party in Parliament are quite common (three quarters of all governments).
7 Representing the Median Voter
Authors: McDonald Michael D. , Budge Ian
Published: February 2006

This chapter performs a static analysis of correspondences between median voter, Parliamentary median, and government preferences by individual government and election. Distortions are widespread but more evident under SMD than PR systems — which are of course designed to produce a ‘necessary’ correspondence between the median voter and the median party in Parliament. However, distortions at each stage (voter-Parliament, Parliament-government) and over time cancel each other out so long-term representational bias is limited.
Who Controls Short‐Term Policymaking?
Authors: McDonald Michael D. , Budge Ian
Published: February 2006

This chapter considers what happens after parties negotiate a government. How far do they succeed in carrying out their original intentions and thereby effectuating the preferences of the median voter? The analysis of government declarations gives mixed signals about who is in control of policy. On a general Left-Right orientation, the policy position marked by a country's median voter is the most reliably consistent indicator of what a government intends to do. If this effect is causal, it would have to be due to parliaments and governments looking over their shoulders at what the election communicated about the median voter Left–Right position and anticipating policy benefits at the next election, as opposed to the median voter effectively selecting a median parliamentary position that then takes control of the general tenor of policy. If the parliamentary median were the major influence, it would be the variable that withstood controls for the government and electorate. It does not come close to this however. And, while the government's Left–Right position nearly withstands statistical controls, the magnitude of its effect pales in comparison to that of the electorate's position.
10 Long‐Term Policy Regimes: Incrementalism Put in Context
Authors: McDonald Michael D. , Budge Ian
Published: February 2006

Policy outcomes are rather stable while politics in the short-term are in a state of flux — one which oscillates round long-term equilibrium point which is fairly stable within each country. Such well-established policy positions distinguish long-term policy regimes within each country. To change these, governments need popular support over fairly long periods of time, which usually is not forthcoming. Typically, actual policy outputs oscillate round a long-term equilibrium, which does not change very much over a four or five election period.
Functional bioinformatics for Arabidopsis thaliana
Authors: Clare A. , Karwath A. , Ougham H. , King R. D.
Published: February 2006

Motivation: The genome of Arabidopsis thaliana, which has the best understood plant genome, still has approximately one-third of its genes with no functional annotation at all from either MIPS or TAIR. We have applied our Data Mining Prediction (DMP) method to the problem of predicting the functional classes of these protein sequences. This method is based on using a hybrid machine-learning/data-mining method to identify patterns in the bioinformatic data about sequences that are predictive of function. We use data about sequence, predicted secondary structure, predicted structural domain, InterPro patterns, sequence similarity profile and expressions data.

Results: We predicted the functional class of a high percentage of the Arabidopsis genes with currently unknown function. These predictions are interpretable and have good test accuracies. We describe in detail seven of the rules produced.

Availability: Rulesets are available at and predictions are available at

Contact:  afc@aber.ac.uk
Adapters, shims, and glue—service interoperability for in silico experiments
Authors: Radetzki U. , Leser U. , Schulze-Rauschenbach S. C. , Zimmermann J. , Lüssem J. , Bode T. , Cremers A. B.
Published: February 2006

Motivation: Computationally, in silico experiments in biology are workflows describing the collaboration of people, data and methods. The Grid and Web services are proposed to be the next generation infrastructure supporting the deployment of bioinformatics workflows. But the growing number of autonomous and heterogeneous services pose challenges to the used middleware w.r.t. composition, i.e. discovery and interoperability of services required within in silico experiments. In the IRIS project, we handle the problem of service interoperability by a semi-automatic procedure for identifying and placing customizable adapters into workflows built by service composition.

Results: We show the effectiveness and robustness of the software-aided composition procedure by a case study in the field of life science. In this study we combine different database services with different analysis services with the objective of discovering required adapters. Our experiments show that we can identify relevant adapters with high precision and recall.

Availability: The IRIS software and the profile language can be downloaded from

Contact:  ur@iai.uni-bonn.de
How Do English L1 Learners of Advanced Japanese Infer Unknown Kanji Words in Authentic Texts?
Authors: Kondo‐Brown Kimi
Published: February 2006

This study investigates advanced Japanese language learners’ abilities to infer unknown kanji(Chinese character) words while reading authentic Japanese texts. Data obtained from 42 English L1 students indicate that, first, although they can guess the meanings of unknown kanji words in context, they frequently make erroneous guesses or fail to guess at all. Second, the more proficient students can use context better than the less proficient students. Third, when reading comprehension ability is controlled, there is no difference in kanji inferencing ability between heritage language (HL) learners and non‐HL learners. Fourth, when the students can pronounce the given semantically unknown kanji words fully or partially while reading, such phonological knowledge proved to be related to successful inferencing.
The role of microorganisms in atopic dermatitis
Authors: Baker Barbara S
Published: February 2006

Atopic dermatitis (AD) is a common, fluctuating skin disease that is often associated with atopic conditions such as asthma and IgE-mediated food allergy and whose skin lesions are characterized by a Th-2 cell-mediated response to environmental antigens. The increasing prevalence and severity of atopic diseases including AD over the last three decades has been attributed to decreased exposure to microorganisms during early life, which may result in an altered Th-1/Th-2-balance and/or reduced T cell regulation of the immune response. Patients with AD exhibit defects in innate and acquired immune responses resulting in a heightened susceptibility to bacterial, fungal and viral infections, most notably colonization by S. aureus. Toxins produced by S. aureus exacerbate disease activity by both the induction of toxin-specific IgE and the activation of various cell types including Th-2 cells, eosinophils and keratinocytes. Allergens expressed by the yeast Malazessia furfur, a component of normal skin flora, have also been implicated in disease pathogenesis in a subset of AD patients.

Microorganisms play an influential role in AD pathogenesis, interacting with disease susceptibility genes to cause initiation and/or exacerbation of disease activity.
Development of serum IgM antibodies against superantigens ofStaphylococcus aureusandStreptococcus pyogenesin Kawasaki disease
Authors: Matsubara K , Fukaya T , Miwa K , Shibayama N , Nigami H , Harigaya H , Nozaki H , Hirata T , Baba K , Suzuki T , Ishiguro A
Published: February 2006

To serologically determine the association of microbial superantigens and the pathogenesis of Kawasaki disease (KD), we conducted a case-control study. Serum IgG and IgM antibodies against staphylococcal enterotoxin A (SEA), SEB, SEC, toxic shock syndrome toxin-1 (TSST-1), and streptococcal pyrogenic exotoxin A (SPEA) were measured by an enzyme-linked immunosorbent assay in 293 serum samples from 65 KD patients on clinical days 1–28 and 120 control samples. The administration of immunoglobulin products, which contain high concentrations of IgG antibodies against all the superantigens, directly elevated antitoxin IgG antibodies in KD patients. In contrast, antitoxin IgM antibodies were not detected in immunoglobulin products. Actually, we found a significant elevation of IgM antibodies against SEA in KD patients in the first (median titre: 0·020, P < 0·01 versus control), second (0·024, P < 0·001), third (0·030, P < 0·001) and fourth (0·038, P < 0·001) weeks, compared to the controls (0·015). Significant differences of IgM antibodies were also true for SEB, TSST-1, and SPEA throughout the first to fourth weeks, and for SEC throughout the second to fourth weeks. The prevalence of KD patients having high IgM titres (> mean + 2SD of control values) to the 5 superantigens was increased with the clinical weeks, and reached 29–43% of KD subjects at the fourth week. This is the first study that describes kinetics of IgM antibodies against superantigens and clarifies the serological significance throughout the clinical course of KD. Our results suggest that multiple superantigens involve in the pathogenesis of KD.
Suppressed cellular alloimmune responses in HIV-exposed seronegative female sex workers
Authors: Jennes W , Evertse D , Borget M-Y , Vuylsteke B , Maurice C , Nkengasong J N , Kestens L
Published: February 2006

Particular human leucocyte antigen (HLA) polymorphisms have been associated with a reduced risk of HIV transmission. However, protective alloimmune responses expected to result from such a genetic predisposition have not been demonstrated. To this end, we analysed and compared cellular and humoral alloimmune responses in a cohort of female sex workers who remained human immunodeficiency virus (HIV)-seronegative despite more than 3 years of high-risk sexual activity (ESN FSWs) with those of low-risk HIV-seronegative female blood donors in Abidjan, Côte d’Ivoire. ESN FSWs showed significantly lower allostimulated CD69 expression and secretion of interferon-γ, macrophage inflammatory protein (MIP)-1β and RANTES (regulated upon activation, normal T-cell expressed and secreted) by lymphocytes than controls. In contrast, ESN FSWs showed significantly higher mitogen-stimulated CD69 expression and secretion of tumour necrosis factor-α and MIP-1β than controls. Suppression of cellular alloimmune responses among ESN FSWs was associated with a higher self-reported frequency of unprotected sex. Levels of anti-HLA class I alloantibodies in plasma were not significantly different between ESN FSWs and controls. These findings indicate that frequent sexual exposure to multiple partners results in suppression rather than activation of cellular alloimmune responses. Our data support the hypothesis that suppressed cellular alloimmune responses may play a role in protection against HIV infection.
Nickel-induced IL-10 down-regulates Th1- but not Th2-type cytokine responses to the contact allergen nickel
Authors: Minang J T , Areström I , Zuber B , Jönsson G , Troye-Blomberg M , Ahlborg N
Published: February 2006

Whereas the involvement of Th1- and Th2-type cytokines in contact allergy to nickel (Ni) is well documented, the role of the regulatory cytokine IL-10 is less clear. We therefore investigated the impact of IL-10 on Ni-induced Th1- (IFN-γ) and Th2-type (IL-4 and IL-13) cytokine responses in human peripheral blood mononuclear cells (PBMC). PBMC from 15 blood donors with reactivity to Ni (Ni-PBMC) and 8 control donors devoid of reactivity (control PBMC) were stimulated with Ni and the frequency of cytokine-producing cells and the levels of secreted cytokines were analysed by ELISpot (IL-4, IL-13 and IFN-γ) and ELISA (IL-10, IL-13 and IFN-γ), respectively. The Ni-induced response was further assessed in the presence of recombinant IL-10 (rIL-10) or neutralizing antibody to IL-10 and the phenotype of the Ni-specific cytokine-producing cells regulated by IL-10 was determined by cell depletion experiments. Ni induced IL-10 production in Ni-PBMC (mean, (range); 33·1 pg/ml (0–93·4 pg/ml)) but not control PBMC (2·2 pg/ml (0–14·9 pg/ml)) (P = 0·002). Ni also induced significant production of IL-4, IL-13 and IFN-γ that correlated with the IL-10 response. Addition of rIL-10 down-regulated the Ni-induced production of all cytokines but with a more pronounced effect on IFN-γ. However, neutralization of Ni-induced IL-10 enhanced the levels of IFN-γ induced by Ni (P = 0·004) but did not affect the number of IFN-γ-producing cells or the production of other cytokines. Cell depletion experiments suggested that the Ni-specific IFN-γ (and Th2-type cytokine) producing cells were CD4+ T cells. The impact of IL-10 on Ni-induced IFN-γ responses by CD4+ T cells suggests that an important role of IL-10 in vivo is to counteract the allergic reactions mediated by Th1-type cytokines.
The local immune response in ulcerative lesions of Buruli disease
Authors: Kiszewski A E , Becerril E , Aguilar L D , Kader I T A , Myers W , Portaels F , Hernàndez Pando R
Published: February 2006

Buruli disease (BU) is a progressive necrotic and ulcerative disease of the skin and subcutaneous tissue caused by Mycobacterium ulcerans. BU is considered the third most common mycobacterial disease after tuberculosis and leprosy. Three clinical stages of the cutaneous lesions have been described in BU: pre-ulcerative, ulcerative and healed lesions. In this study we used immunohistochemistry and automated morphometry to determine the percentage of macrophages and of CD4/CD8 lymphocytes and their expression of interferon (IFN)-γ, interleukin (IL)-10, tumour necrosis factor (TNF)-α and transforming growth factor (TGF)-β. Expression of these cytokines was correlated with the inflammatory response evaluated by histopathology. All the studied BU ulcerative cases showed extensive necrosis and chronic inflammation. The most important feature was the presence or absence of granulomas co-existing with a mixed pro-inflammatory/anti-inflammatory cytokine balance. When granulomas were present significantly higher expression of IFN-γ was seen, whereas in ulcerative lesions without granulomas there was increased expression of IL-10 and significantly higher bacillary counts. These features correlated with the chronicity of the lesions; longer-lasting lesions showed granulomas. Thus, granulomas were absent from relatively early ulcerative lesions, which contained more bacilli and little IFN-γ, suggesting that at this stage of the disease strong suppression of the protective cellular immune response facilitates proliferation of bacilli.
Human autoantibodies to diacyl-phosphatidylethanolamine recognize a specific set of discrete cytoplasmic domains
Authors: Laurino C C F C , Fritzler M J , Mortara R A , Silva N P , Almeida I C , Andrade L E C
Published: February 2006

The aim of this study was to characterize a novel human autoantibody–autoantigen system represented as cytoplasmic discrete speckles (CDS) in indirect immunofluorescence (IIF). A distinct CDS IIF pattern represented by 3–20 discrete speckles dispersed throughout the cytoplasm was identified among other cytoplasmic speckled IIF patterns. The cytoplasmic domains labelled by human anti-CDS-1 antibodies did not co-localize with endosome/lysosome markers EEA1 and LAMP-2, but showed partial co-localization with glycine–tryptophan bodies (GWB). CDS-1 sera did not react with several cellular extracts in immunoblotting and did not immunoprecipitate recombinant GW182 or EEA1 proteins. The typical CDS-1 IIF labelling pattern was abolished after delipidation of HEp-2 cells. Moreover, CDS-1 sera reacted strongly with a lipid component co-migrating with phosphatidylethanolamine (PE) in high performance thin-layer chromatography (HPTLC)-immunostaining of HEp-2 cell total lipid extracts. The CDS-1 major molecular targets were established by electrospray ionization–mass spectrometry (ESI-MS), HPTLC-immunostaining and chemiluminescent enzyme-linked immunosorbent assay as diacyl-PE species, containing preferentially a cis-C18 : 1 fatty acid chain at C-2 of the glycerol moiety, namely 1,2-cis-C18 : 1-PE and 1-C16 : 0-2-cis-C18 : 1-PE. The clinical association of CDS-1 sera included a variety of systemic and organ-specific autoimmune diseases but they were also observed in patients with no evidence of autoimmune disease.
Leptin, soluble interleukin-6 receptor, C-reactive protein and soluble vascular cell adhesion molecule-1 levels in human coronary atherosclerotic plaque
Authors: Karaduman M , Oktenli C , Musabak U , Sengul A , Yesilova Z , Cingoz F , Olgun A , Sanisoglu S Y , Baysan O , Yildiz O , Taslipinar A , Tatar H , Kutlu M , Ozata M
Published: February 2006

The aim of the present study was to explore the relationship between tissue levels of leptin, soluble interleukin-6 receptor (sIL-6R), high-sensitive-C-reactive protein (hs-CRP) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in atherosclerotic plaques, and traditional risk factors. Coronary artery specimens were obtained from 35 consecutive patients (26 men and nine women) who underwent coronary artery bypass grafting procedure. The mean tissue levels of leptin, hs-CRP and sIL-6R were significantly higher in patients with diabetes mellitus than without diabetes mellitus. When patients were classified according to the smoking status, the mean tissue levels of leptin, hs-CRP and sIL-6R were significantly higher in current smokers than both former smokers and non-smokers. In addition, the mean tissue levels of leptin and sIL-6R were significantly higher in former smokers than non-smokers. There was a positive association between leptin and hs-CRP, sIL-6R and plasma glucose in all patients. Plasma HDL levels were associated negatively with atherosclerotic tissue levels of leptin. Tissue levels of sIL-6R were associated significantly in a positive manner with leptin, hs-CRP and plasma glucose, while tissue levels of hs-CRP were associated with both leptin and sIL-6R. In conclusion, it is attractive to speculate that hs-CRP, sIL-6R and leptin could act synergistically in course of local inflammatory activity and those molecules may not be just markers of inflammation and cardiovascular risk but are also likely to play a pathogenic role in atheromatous plaque. In addition, atherosclerotic tissue levels of CRP, sIL-6R and leptin were significantly higher in current smokers and patients with diabetes.
Cancer immunotherapy using dendritic/tumour-fusion vaccine induces elevation of serum anti-nuclear antibody with better clinical responses
Authors: Homma S , Sagawa Y , Ito M , Ohno T , Toda G
Published: February 2006

Dendritic cell (DC) vaccines might induce both anti-tumour immunity and autoimmunity. In this report, we demonstrate elevated levels of anti-nuclear antibody (ANA) in the sera of patients with cancer who had received immunotherapy with a dendritic/tumour-fusion vaccine. Twenty-two patients were treated with DC vaccine of fusion cells composed of autologous DCs and tumour cells (DC/tumour-fusion vaccine), which was generated by treating each cell type with polyethylene glycol. Nine of the 22 patients were treated with both the DC/tumour-fusion vaccine and systemic administration of recombinant human interleukin (rhIL)-12. Serum levels of ANA were examined with an enzyme-linked immunosorbent assay kit. One patient with gastric carcinoma (patient 1, DC/tumour-fusion vaccine alone), one patient with breast cancer (patient 2, DC/tumour-fusion vaccine alone) and one patient with ovarian cancer (patient 3, DC/tumour-fusion vaccine + rhIL-12) showed significant elevations of serum ANA levels during treatment. In patient 1 malignant ascitic effusion resolved and serum levels of tumour markers decreased. Patients 2 and 3 remained in good physical condition during treatment for 24 and 9 months, respectively. Immunoblot analysis indicated antibody responses to autologous tumour cells after vaccination in patient 2. None of the treated patients showed clinical symptoms suggesting autoimmune disease. Patients with elevated serum levels of ANA had significantly longer treatment periods than those without it. Elevated serum levels of ANA after DC/tumour-fusion cell vaccine might be associated with anti-tumour immune response induced by the vaccination.
Reduction of tissue transglutaminase autoantibody levels by gluten-free diet is associated with changes in subsets of peripheral blood lymphocytes in children with newly diagnosed coeliac disease
Authors: Agardh D , Lynch K , Brundin C , Ivarsson S-A , Lernmark Å , Cilio C M
Published: February 2006

Tissue transglutaminase (tTG) autoantibodies decline after gluten-free diet in patients with coeliac disease. We tested the hypothesis that gluten-free diet-induced change in tTG autoantibody levels affects subsets of peripheral blood lymphocytes. Peripheral blood was obtained from 20 children with biopsy-proven active coeliac disease. Gluten-free diet was initiated and the children examined again after three and six months. tTG autoantibodies were measured in radioligand binding assays and lymphocyte subsets by flow cytometry. IgA-tTG levels at diagnosis, 2204 U/ml (median, range 113–24990), were reduced over six months to 76 U/ml (median, range 1–1261) (P < 0·001). At six months, 12/20 (60%) children had reduced their IgA-tTG levels to < 100 U/ml and these children showed a decrease in B cells (mean change −3·8%, P = 0·014), CD4+ T cells (mean −4·32%, P = 0·011) and CD4+ T cells expressing CD25high (mean change −0·62%, P = 0·036). In contrast, the CD4+CD25highCCR4+ T cell population increased during the same period (mean change 11·5%, P = 0·0036). The decline in IgA-tTG levels correlated to the decrease in B cells (r = 0·56, P = 0·01), CD4+ T cells (r = 0·66, P = 0·004) as well as CD4+CD25high T cells (r = 0·59, P = 0·01). A negative correlation was found between the decline in IgA-tTG and CD4+CD25high T cells expressing CD45RO (r = –0·49, P = 0·03) and CCR4 (r = –0·54, P = 0·01). This is the first observational study on the effect of gluten-free diet on concurrent changes of tTG autoantibodies and specific peripheral blood lymphocyte subsets. Our data suggest that flow cytometry may be a useful complement to tTG autoantibodies when studying the effects of gluten-free diet in children with coeliac disease.
Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements
Authors: Arlt Wiebke , Rosenthal Carmen , Hahner Stefanie , Allolio Bruno
Published: February 2006

Objective  Evaluation of glucocorticoid replacement quality in adrenal insufficiency (AI) relies primarily on clinical judgement and thus largely depends on the physician's expertise. It is a matter of debate whether cortisol day curves are of value in assessing glucocorticoid replacement quality. Here we compared the results of a structured clinical assessment to the outcome of repeated, timed serum cortisol measurements.

Design  Cross‐sectional study in the outpatient department of a university teaching hospital.

Patients  Forty‐six patients (19 men, 27 women, age range 16–76 years) with primary (n = 23) and secondary (n = 23) AI on stable replacement with a median dose of 37·5 mg cortisone acetate (range 25–50 mg) since 10 ± 7 years (range 1–31 years).

Measurements  Clinical performance was scored by structured assessment of signs and symptoms, physical examination and routine biochemical tests. Serum cortisol was measured on two to three separate occasions in three timed samples after the morning glucocorticoid dose. Bone mineral density was measured in 15 patients with long‐standing glucocorticoid replacement.

Results  Thirty‐seven patients were considered well replaced, whereas clinical scores suggested over‐ or under‐replacement in five and four, respectively. There was no correlation of the clinical score with total or body weight‐adjusted glucocorticoid dose. The mean z score of serum cortisol differed significantly between under‐ and over‐replaced patients (P < 0·05) but neither group differed significantly from well‐replaced patients. Bone mineral density was normal in all patients studied.

Conclusions  Our results suggest that serum cortisol day curves are of limited value in the monitoring of glucocorticoid replacement. Bone mineral density in AI is generally normal and does not require routine follow‐up.