bluuebunny/crossref_metadata_2025 huggingface dataset:
Transnational Cooperation Dilemmas
Authors: Barrett Scott
Published: October 2005

This chapter develops a theoretical foundation for understanding international cooperation problems — why they arise, and why they are not easily addressed. Cooperation is cast as a game theoretic problem. In particular, full cooperation is shown not to be a Nash equilibrium, implying that full cooperation cannot be sustained by the anarchic international system. This framework is then examined from different perspectives, including experimental game theory, moral philosophy, and international relations. The theory is illustrated by the example of international whaling.
Games with Multiple Equilibria
Authors: Barrett Scott
Published: October 2005

This chapter explains that some international environmental problems are characterized by multiple equilibria, meaning that more than one outcome can be sustained by the anarchic international system. Some problems just happen to be chicken and coordination games. Others can sometimes be manipulated, by means of a treaty, to resemble games of these types. Case studies include the setting of aviation and automobile standards.
Customary Rights and Responsibilities
Authors: Barrett Scott
Published: October 2005

This chapter casts the challenge of international cooperation in the framework of customary international law. It explains how custom is developed and sustained, and why it cannot address all international cooperation problems on its own, i.e., why treaties are also needed. Custom has been particularly important in establishing property rights, such as the Exclusive Economic Zone. The chapter illustrates these ideas by explaining the role that custom played in addressing pollution of the Rhine.
International Environmental Agreements
Authors: Barrett Scott
Published: October 2005

This chapter explains why international agreements have increasingly been used to address international cooperation problems. It outlines the process of treaty making, and explains how process can shape outcomes. It then details the key features of treaties, such as the minimum participation level, basic obligations, withdrawal, and the use of trade restrictions. The appendix provides a comprehensive listing of multilateral environmental treaties currently in force, with information on date of adoption and entry into force, membership, and provisions for trade restrictions and administration.
The Treaty Participation Game
Authors: Barrett Scott
Published: October 2005

Building on the information developed in the previous six chapters, this chapter develops a theoretical model of international cooperation by means of the treaty instrument. The focus is on explaining why treaty participation is difficult to enforce. The theory shows that a treaty sustains cooperation by transforming the prisoners’ dilemma. It also shows that there is a limit to how far this approach can improve on non-cooperation. The theory is illustrated by the case study of conserving anadromous fish stocks.
The Montreal Protocol
Authors: Barrett Scott
Published: October 2005

This chapter develops the main case study of the book — the Montreal Protocol on Substances that Deplete the Ozone Layer. It explains how the treaty was negotiated, and describes its main features. The theory developed in the previous chapter explains that treaty outcomes are shaped in part by payoffs; this chapter provides estimates of the payoffs (net benefits) to participation in this treaty. The appendix includes the text of the original treaty.
Tipping Treaties
Authors: Barrett Scott
Published: October 2005

This chapter focuses on treaties that serve to coordinate international behavior. In this model, the minimum participation level is not the equilibrium participation level but the threshold participation level. When this minimum is reached, it pays all remaining non-participating countries to want to participate. This theory is applied to the case study of ocean dumping of oil by tankers.
Compliance and the Strategy of Reciprocity
Authors: Barrett Scott
Published: October 2005

The theory developed in Chapter eight assumes that treaty participants always comply with their obligations. In this chapter, compliance is enforced endogenously. The main conclusion is that a self-enforcing treaty must enforce both participation and compliance, but that treaty participation is the binding constraint on international cooperation. If the conditions allow participation to be enforced, then compliance can also be enforced. The theory is illustrated by reference to the Fur Seal and Montreal Protocol treaties.
The Depth and Breadth of International Cooperation
Authors: Barrett Scott
Published: October 2005

The focus of the theory developed to this stage has been on the credibility of punishments. This chapter weakens the demands on credibility so that the theory can embrace concerns for fairness. The theory shows that even when the demands on credibility are weakened, full cooperation cannot always be sustained. Instead, countries must choose between a treaty that is “broad but shallow” or “narrow but deep”. The theory explains why international negotiations will tend to favor broad but shallow treaties, but also why such treaties will typically fall far short of sustaining full cooperation.
Trade Leakage and Trade Linkage
Authors: Barrett Scott
Published: October 2005

The previous chapters developed a theory of environmental cooperation in isolation of other international affairs. This chapter considers the possibility of linking different issues, focusing on linkage to international trade. It explains that for many environmental problems, trade is automatically linked. One consequence of this is trade “leakage”. Cooperation to reduce pollution by some countries may, through the trade mechanism, cause other countries to increase their pollution. It explains how trade restrictions can more than neutralize this trade leakage; they can actually help in sustaining more cooperation without harming international trade. The theory is illustrated by reference to sea turtle protection, tuna conservation, and the Fur Seal and Montreal Protocol agreements.
Summary
Authors: Barrett Scott
Published: October 2005

This chapter briefly summarizes the book, by developing ten key points.
Global Climate Change and the Kyoto Protocol
Authors: Barrett Scott
Published: October 2005

This chapter applies the theory developed in this book to a current challenge: global climate change. It provides an introduction to the issue, summarizes the history of negotiations, and provides estimates of the costs and benefits of mitigation. It then explains why the Kyoto Protocol will not succeed in sustaining cooperation because it fails to do what the book explains all good treaties must do — it fails to restructure incentives. In particular, it can only work if its obligations can be enforced, and yet Kyoto fails to provide the means for enforcement. The chapter then considers a range of alternative treaty designs, and explains why these will also fail. Finally, it uses the logic of the book to develop an alternative approach that is likely to prove more fruitful. This alternative approach focuses on the development and diffusion of new technologies rather than on emission targets and timetables.
Afterword to the Paperback Edition on Global Climate Change and the Kyoto Protocol
Authors: Barrett Scott
Published: October 2005

This chapter updates the previous chapter. It explains that while the Kyoto Protocol has entered into force, it is still unlikely to change behavior because the fundamental problems with this agreement have not been addressed. It illustrates the case for failure by the example of another, seemingly ingenious agreement — the Stability and Growth Pact that underpins European Monetary Union. This chapter also reconsiders the goals of the Framework Convention on Climate Change. It argues that the aim of avoiding “dangerous interference” with the climate system is unhelpful, since this level of atmospheric concentrations cannot be identified, and this approach focuses attention on quantitative limits when it would be better to focus efforts on taking “appropriate measures”.
Fordham, Jung and the self: a re‐examination of Fordham's contribution to Jung's conceptualization of the self
Authors: Urban Elizabeth
Published: October 2005

Abstract:  This paper is about Fordham's contribution to Jung's studies on the self. It opens with the epistemological dilemmas inherent in the subject, before moving on to an account of Fordham's research into the incompatible ways Jung used the term ‘self’. There is a description of Fordham's model, which covers his concepts of the primary self, deintegration, reintegration, self objects, self representations, and individuation in infancy. There is a section which discusses areas in which Fordham apparently diverged from Jung, including how these were reconciled by Fordham's developmental approach. These areas include the definition of the self as totality or archetype, the mind‐body relationship, the ‘ultimate’, the origins of the archetypes, and the primary self, the self and the sense of self. It concludes with an extension to Fordham's outline of a resolution to Jung's incompatible definitions. This draws upon the concept of the central archetype of order and how its unfolding is evidenced towards the end of the first year of infancy.
Individuation: finding oneself in analysis – taking risks and making sacrifices
Authors: Schmidt Martin
Published: October 2005

Abstract:  This paper looks at some of the processes that are at work in finding oneself in analysis. It explores Jung's unique contribution to our thinking about the self and its dynamic of individuation. The author attempts to show how the Self, in its quest for consciousness, requires the surrendering of ego inflation—the narcissistic delusion that the ego is the self. A case is made for seeing analysis as an individuation process which offers the opportunity for experiences of a more authentic sense of oneself. Jung stated that individuation requires the ego to enter into service of the Self. For this to happen, the author argues that both patient and analyst must be prepared to make sacrifices and take risks. Using clinical examples, he illustrates that, although purposive, the Self can be experienced as violent and destructive if the ego is unable to facilitate its expression. This may result in an individuation crisis for both analyst and patient. The paper demonstrates how impasse in analysis can evoke the transcendent function, which also requires sacrifices to be made and risks to be taken for analysis to proceed.
Sex, shame and the transcendent function: the function of fantasy in self development
Authors: Knox Jean
Published: October 2005

Abstract: This paper explores a developmental approach to the sense of self‐agency and to its influence on conscious and unconscious fantasy. I suggest that the emerging sense of self‐agency offers an over‐arching framework for our understanding of the nature and function of fantasy. In this context, intrusive and compulsive sexual fantasies which a person experiences as perverted and shameful, can be seen to serve differing psychic purposes, depending on the level of self‐agency which is predominant. The fantasies can serve both as warning signals of the dangers of relationship and as opportunities for the mind to reflect on its own processes. Differing psychodynamic theories of fantasy are examined in terms of the developmental sense of self‐agency that they represent.
Sexual metaphor and the language of unconscious phantasy
Authors: Colman Warren
Published: October 2005

Abstract:  This paper investigates the attempt to find a ‘bedrock’ for psychic life in the idea of unconscious phantasy. Through a detailed examination of the development of the concept of unconscious phantasy, especially in Kleinian discourse, it is argued that unconscious phantasies are inherently metaphorical and have no ‘concrete’ existence in the unconscious. The use of unconscious phantasy as metaphor enables a ‘two‐way’ form of interpretation that describes sexual behaviour and fantasy in terms of object relations (interpreting ‘away from sex’, while simultaneously describing object relations in terms of the sexual body (interpreting ‘towards sex’).
When does a dream begin to ‘have meaning’?   Linguistic constraints and significant moments  in the construction of the meaning of a dream
Authors: Marozza Maria Ilena
Published: October 2005

Abstract:  The paper1 investigates the origin of the meaning of dreams starting with a discussion of psychotic dreams. The author distinguishes the dream as dream from the remembered and the narrated. A two‐step dream phenomenology is proposed that both acknowledges the objectivity of the dream and traces the origin of its meaning to its translation into language. Following a review of recent neurobiological theories of dreaming, the paper focuses on certain aspects of the psychoanalytical understanding of the dream phenomenon and in particular on the interpretation of dreams from the perspective of intersubjectivity and phantasy.
When Is More Better?
Authors: Hsee Christopher K. , Rottenstreich Yuval , Xiao Zhixing
Published: October 2005

We examine three determinants of the relationship between the magnitude of a stimulus and a person's subjective “value” of that stimulus: the process by which value is assessed (either by feeling or by calculation), the evaluability of the relevant magnitude variable (whether the desirability of a given level of that variable can be evaluated independently), and the mode of evaluation (whether stimuli are encountered and evaluated jointly or separately). Reliance on feeling, lack of evaluability, and separate evaluation lead to insensitivity to magnitude. An analysis invoking these factors provides a novel account for why people typically become less sensitive to changes in the magnitude of a stimulus as magnitude increases.
Connectionist Models of Word Reading
Authors: Seidenberg Mark S.
Published: October 2005

Connectionist models of word reading attempt to explain the computational mechanisms underlying this important skill. The goal of this research is an integrated theory of reading and its brain bases, with the computational model as the interface between the two. The models are governed by computational principles that differ considerably from naive intuitions but nonetheless account for many aspects of normal and impaired (dyslexic) reading.
Innovation Implementation
Authors: Klein Katherine J. , Knight Andrew P.
Published: October 2005

In changing work environments, innovation is imperative. Yet, many teams and organizations fail to realize the expected benefits of innovations that they adopt. A key reason is not innovation failure but implementation failure—the failure to gain targeted employees' skilled, consistent, and committed use of the innovation in question. We review research on the implementation process, outlining the reasons why implementation is so challenging for many teams and organizations. We then describe the organizational characteristics that together enhance the likelihood of successful implementation, including a strong, positive climate for implementation; management support for innovation implementation; financial resource availability; and a learning orientation.
Sequence Memory in Music Performance
Authors: Palmer Caroline
Published: October 2005

How do people remember and produce complex sequences like music or speech? Music provides an example of excellent sequence memory under fast performance conditions; novices as well as skilled musicians can perform memorized music rapidly, without making mistakes. In addition, musical pitches repeat often within a melodic sequence in different orders, yet people do not confuse the sequential ordering; temporal properties of musical pitches aid sequence memory. I describe a contextual model of sequence memory that is sensitive to the rate at which musical sequences are produced and to individual differences among performers. Age and musical experience differentiate adults' and children's memory for musical sequences during performance. Performers' memory for the sequential structure of one melody transfers or generalizes to other melodies in terms of the sequence of pitch events, their temporal properties, and their movements. Motion-analysis techniques provide further views of the time course of the cognitive processes that make sequence memory for music so accurate.
Development of Phonological Awareness
Authors: Anthony Jason L. , Francis David J.
Published: October 2005

Phonological awareness is critical for learning to read in alphabetic languages like English. This report summarizes normal development of phonological awareness as it has been revealed through recent multidisciplinary and cross-cultural research. We argue that a consensus on the definition of phonological awareness has emerged, that research has identified a general sequence of phonological awareness development that is universal across languages, and that certain characteristics of spoken and written languages influence the rate of normal development and levels of phonological awareness that are normally achieved.
Antecedents and Consequences of System-Justifying Ideologies
Authors: Jost John T. , Hunyady Orsolya
Published: October 2005

According to system justification theory, there is a psychological motive to defend and justify the status quo. There are both dispositional antecedents (e.g., need for closure, openness to experience) and situational antecedents (e.g., system threat, mortality salience) of the tendency to embrace system-justifying ideologies. Consequences of system justification sometimes differ for members of advantaged versus disadvantaged groups, with the former experiencing increased and the latter decreased self-esteem, well-being, and in-group favoritism. In accordance with the palliative function of system justification, endorsement of such ideologies is associated with reduced negative affect for everyone, as well as weakened support for social change and redistribution of resources.
New Methods for Comparing Groups
Authors: Wilcox Rand R.
Published: October 2005

A commonly used method for comparing groups of individuals is the analysis of variance (ANOVA) F test. When the assumptions underlying the derivation of this test are true, its power, meaning its probability of detecting true differences among the groups, competes well with all other methods that might be used. But when these assumptions are false, its power can be relatively low. Many new statistical methods have been proposed—ones that are aimed at achieving about the same amount of power when the assumptions of the F test are true but which have the potential of high power in situations where the F test performs poorly. A brief summary of some relevant issues and recent developments is provided. Some related issues are discussed and implications for future research are described.
Family members of relatives with alcohol, drug and gambling problems: a set of standardized questionnaires for assessing stress, coping and strain
Authors: Orford Jim , Templeton Lorna , Velleman Richard , Copello Alex
Published: October 2005

Aims To describe a set of standard questionnaire measures for the assessment of the needs of family members of relatives with alcohol, drug or gambling problems, and to present evidence of their reliability and validity from a series of related studies.

Design Includes cross‐sectional and repeated‐measurement studies.

Setting and participants Family members affected by and concerned about the problem drinking or drug‐taking of close relatives in treatment and non‐treatment samples in the United Kingdom (white and Sikh) and Mexico City; family members of untreated heavy drinkers; and family members of problem gamblers.

Measurements Four measures derived from a stress–strain–coping–support model of alcohol, drugs and gambling problems and the family: Family Member Impact scale (FMI), Symptom Rating Test (SRT), Coping Questionnaire (CQ), and Hopefulness–Hopelessness scale (HOPE). FMI, SRT and CQ assess stress, strain and coping, respectively. The exact role of HOPE in the model remains to be determined. The support component remains unmeasured.

Findings Results from a number of studies support the internal reliability, discriminant and construct validity and sensitivity to change of the SRT and its two constituent scales (psychological and physical symptoms) and at least two subscales of the CQ (engaged and tolerant–inactive coping). Although showing evidence of satisfactory reliability and some evidence of discriminant validity, further work may be required on the CQ withdrawal coping subscale. Evidence suggests that the FMI is reliable and valid and may have a factor structure that will support future research (distinguishing worrying behaviour from active disturbance). HOPE is a new measure showing promising characteristics.

Conclusions A set of standard measures is available for helping to assess the needs of concerned and affected family members, derived from an explicit model of the family in relation to excessive drinking, drug taking or gambling. It may have a role to play in correcting the current neglect of the needs of such family members, estimated to be in the region of nearly a million adults in Britain alone.
Reasons for drinking less and their relationship to sustained remission from problem drinking
Authors: Matzger Helen , Kaskutas Lee Ann , Weisner Constance
Published: October 2005

Aims  To compare representative general population and treated samples on their reasons for drinking less and whether particular reasons were related to sustained remission from problem drinking for either group.

Participants and design  A total of 659 problem drinking adults in a Northern California county identified through a probability survey in the general population (n = 239) and a survey of consecutive admissions to public and private alcohol and drug programs (n = 420), who reported drinking less at the one‐year follow‐up and provided reasons for reducing their drinking, were assessed 1‐, 3‐, and 5‐years post‐baseline regarding their problem drinking status.

Measurements  Logistic regression models were used to predict sustained remission from problem drinking.

Results  While the treated sample endorsed a majority of reasons in significantly higher proportions than the general population sample, the same three reasons were significant for both groups in predicting sustained remission from problem drinking: hitting rock bottom, experiencing a traumatic event and undergoing a spiritual awakening. Interventions by medical personnel and family members were either non‐significant predictors or significantly negatively related to sustained improvement for both general population and treated problem drinkers.

Conclusions  General population and treatment samples have similar reasons for cutting down as they relate to sustained remission from problem drinking.
Correlates of regular cigarette smoking in a population‐based sample of Australian twins
Authors: Agrawal Arpana , Madden Pamela A. F. , Heath Andrew C. , Lynskey Michael T. , Bucholz Kathleen K. , Martin Nicholas G.
Published: October 2005

Aims  To investigate the role of measured risk factors and the influence of genetic and environmental factors on regular cigarette smoking.

Design  Members of monozygotic and dizygotic, including unlike‐sex twin pairs (n = 6257) from a young adult cohort from the Australian Twin Registry.

Methods  Cox proportional hazards models were used to determine whether putative risk factors were significantly associated with regular cigarette smoking. Risk factors were classified into four tiers: tier 1 (parental history, including parental education, alcoholism and cigarette smoking), tier 2 (early home and family influences), tier 3 (early life events, e.g. trauma) and tier 4 (psychiatric symptoms/disorders with onset prior to 14 years), after controlling for gender, zygosity and their interactions. Genetic models were fitted to examine the heritability of smoking behavior before and after controlling for significant covariates from the four tiers.

Findings  Parental history of cigarette smoking and alcoholism, parental closeness and home environment, as well as incidence of childhood sexual abuse or other trauma, a history of early onset panic attacks and conduct problems were associated with regular cigarette smoking. Important age interactions were found, particularly for family background risk factors. Regular cigarette smoking was moderately heritable, even after accounting for significant covariates.

Conclusions  Several measured risk factors are associated with regular smoking. While some of the genetic influences on regular smoking may be shared with these risk factors, a significant proportion of the genetic vulnerability to regular smoking is phenotype‐specific.
Drinking in the Commonwealth of Independent States—evidence from eight countries
Authors: Pomerleau Joceline , McKee Martin , Rose Richard , Haerpfer Christian W. , Rotman David , Tumanov Sergej
Published: October 2005

Aims To describe the frequency of alcohol consumption and beverage preferences in eight countries of the Commonwealth of Independent States (CIS).

Design Cross‐sectional.

Setting Populations of Armenia, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Republic of Moldova, Russian Federation and Ukraine.

Participants Representative samples of the adult population of each country (overall sample size 18,428; response rates: 71–88%).

Measurements A standardised questionnaire was administered by trained interviewers to examine alcohol consumption frequency and usual intakes of beer, wine and strong spirits.

Findings Between 11 and 34% of males and 26–71% of females reported never drinking alcohol. Abstention was lowest in the Russian Federation and Belarus, two traditional spirits‐drinking countries. It was particularly high in Kyrgyzstan and Georgia, two countries with a relatively low frequency of alcohol consumption but large amounts consumed per occasion (particularly Georgia). On the contrary, Moldovan respondents drank frequently, but consumed smaller amounts per occasion. As expected, spirits were consumed in largest amounts in traditional spirits‐drinking countries, as well as Armenia and wine in traditional wine‐drinking countries. Beer consumption was relatively high in Russia, Belarus, Ukraine and Kazakhstan (males), particularly in young respondents.

Conclusions Although cross‐country comparisons of alcohol intake should be interpreted cautiously, this study suggested that drinking patterns in the countries examined are not entirely typical of usual dry/wet drinking cultures, and confirms that the CIS is very diverse in terms of drinking patterns and beverage preferences. The study provides an important baseline for future comparisons as markets open to new products, as has been the case elsewhere in Europe.
Cirrhosis mortality in Ontario: effects of alcohol consumption and Alcoholics Anonymous participation
Authors: Mann Robert E. , Smart Reginald G. , Rush Brian R. , Zalcman Rosely Flam , Suurvali Helen
Published: October 2005

Aims We test the hypotheses that cirrhosis mortality rates are positively associated with per capita alcohol consumption and negatively associated with Alcoholics Anonymous (AA) membership rates.

Design The impact of alcohol consumption levels and AA membership rates on cirrhosis mortality rates in Ontario from 1968 to 1989 were examined. Time‐series analyses with ARIMA modelling were applied to male and female cirrhosis mortality rates in three age groups: 15–44, 45–64 and 65 + years. Missing AA membership data were interpolated using two methods: linear splines and cubic splines.

Findings In general, cirrhosis mortality rates were positively associated with alcohol consumption and negatively associated with AA membership. For some age and gender combinations, these effects were not statistically significant.

Conclusions The limits of this study include restrictions in the length of series available and in the ability to infer causality. Despite these limitations, these findings are consistent with previous research demonstrating that per capita consumption is a strong determinant of cirrhosis mortality rates, and also that higher levels of AA membership can reduce cirrhosis mortality rates.
Harm reduction interventions, behaviours and associated health outcomes in France, 1996–2003
Authors: Emmanuelli Julien , Desenclos Jean‐Claude
Published: October 2005

Aims  To track the effect of the French harm reduction programme targeted at intravenous drug users (IDUs) and associated health outcomes.

Material  Since 1996, we have collected monthly sales of sterile syringes and substitution treatments (buprenorphine high dosage and methadone) sold to IDUs in the 23 000 pharmacies in France and collated these figures in a single data base (SIAMOIS). To this data base we have also added the number of syringes distributed through community associations, as well as methadone treatments prescribed in public drug dependence clinics.

Methods  For the period 1996–2003 we analysed syringe sales and prescribed substitution treatments as indicators of access to harm reduction services. We compared variations of these figures over time with trends in health outcome indicators [annual number of fatal overdoses, hepatitis C virus (HCV) and human immunodeficiency virus (HIV) prevalence among intravenous drug users], risk behaviour indicators (rate of syringe sharing or rate of syringe re‐use) and legal indicators (heroin and cocaine use‐related arrests).

Findings  The number of sterile syringes sold or distributed to IDUs increased from 1996 to 1999 (+ 21%) and then decreased dramatically from 1999 to 2003 (−40%). In 2003, we estimated that more than 100 000 drug users used substitution treatments. Between 1996 and 2003, a decrease in syringe sharing and syringe re‐use was observed, HIV prevalence among IDUs decreased from 40% to 20% and HCV prevalence remained high (60–70%). From 1996 to 2003, arrests due to heroin use declined (from 17 328 to 4025) and deaths due to overdoses also decreased (from 465 to 89), whereas arrests for cocaine use increased from 1184 to 2511.

Conclusion  Our results indicate that, since 1996 in France, IDUs have had greatly improved access to sterile syringes and substitution treatments. The decrease in syringe sharing and re‐use practices and of HIV prevalence during the same time period indicates that the harm reduction policy implemented in France has had a positive impact. However, because of the persistent sharing and re‐use of syringes and a remaining high HCV prevalence in IDUs, efforts to facilitate access to sterile syringes must continue, and targeting of at‐risk groups must be improved. Behavioural surveys associated with HIV and HCV seroprevalence data are needed to further assess prevention of blood‐borne infections among IDUs in France.
Anisakis simplexallergy: a murine model of anaphylaxis induced by parasitic proteins displays a mixed Th1/Th2 pattern
Authors: Baeza M L , Conejero L , Higaki Y , Martín E , Pérez C , Infante S , Rubio M , Zubeldia J M
Published: October 2005

The study of the singular hypersensitivity reactions to Anisakis simplex (A.s) proteins, may help us to undestand many of the unknown immune interactions between helmiths infections and allergy. We have developed a murine model of allergy to A. simplex, that mimics human A. simplex allergy to study the specific aspects of anaphylaxis induced by parasites. Male C3H/HeJ mice were intraperitoneally sensitized to A. simplex. Mice were then intravenous or orally challenged with A. simplex. Antigen-specific immunoglobulins, polyclonal IgE, anaphylactic symptoms, plasma histamine levels and cytokine profiles were determined. Comparative IgE immunoblot analyses were also performed. Specific IgE, IgG1 and IgG2a were detected in sensitized mice since week 3. Polyclonal IgE raised and peaked with different kinetics. Intravenous A. simplex challenge produced anaphylaxis in mice, accompanied by plasma histamine release. Oral A. simplex challenge in similarly sensitized mice did not caused symptoms nor histamine release. Numerous A. simplex allergens were recognized by sensitized mouse sera, some of them similar to human serum. The A. simplex stimulated splenocytes released IL-10, IFN-γ, IL-4, IL-13 and IL-5. We describe a new animal model of anaphylaxis. It exhibits characteristics of type I hypersensitivity reactions to Anisakis simplex similar to those observed in allergic humans. Different responses to i.v. or oral A. simplex challenges emerged, which did not reflect a window tolerization period. The cytokine profile developed (mixed Th1/Th2 pattern) differed from the observed in classical models of anaphylaxis or allergy to food antigens. This model may permit to investigate the peculiar allergic reactions to parasitic proteins.
Immunoglobulin treatment reduces atherosclerosis in apolipoprotein E–/– low-density lipoprotein receptor –/– mice via the complement system
Authors: Persson L , Borén J , Nicoletti A , Hansson G K , Pekna M
Published: October 2005

Atherosclerosis is associated with activation of the immune system. Intravenously applied normal polyclonal immunoglobulins (IVIg) have broad therapeutic applications in the treatment of autoimmune and systemic inflammatory diseases. Recently, IVIg have been shown to inhibit atherogenesis in experimental animal models. To investigate the role of the complement system in this process, we used third complement component-deficient  (C3–/–) and control atherosclerosis-prone apolipoprotein E (ApoE) and low-density  lipoprotein  receptor  (LDLR)  double  knock-out  mice  fed  a normal diet. IVIg treatment reduced lesion fraction area in the aortic root of complement-sufficient mice whereas the lesion fraction area of C3–/– mice was not affected. Thus, complement activation plays a role in the anti-atherosclerotic effects of IVIg, possibly by C3-derived fragments generated through Fc-dependent complement activation.
Activation of c-Jun N-terminal kinase (JNK) signalling in experimentally induced gastric lesions in rats
Authors: Mitsuyama K , Tsuruta O , Matsui Y , Harada K , Tomiyasu N , Suzuki A , Takaki K , Masuda J , Handa K , Satoh Y , Bennett B L , Toyonaga A , Sata M
Published: October 2005

The c-Jun N-terminal kinase (JNK) participates in intracellular signalling cascades that mediate inflammatory responses. Therefore, the JNK signalling may be involved in gastric injury and inhibition of this pathway may form the basis of a new strategy for the treatment of gastric injury. The aim of this study was to determine whether JNK participates in the formation of gastric lesions in an experimental model. Acute gastric injury was induced in Sprague-Dawley rats by intragastric administration of 100% ethanol. The amount of phospho-JNK in the rat stomach was determined using immunohistochemistry and Western analysis. Animals received subcutaneous injections of a specific JNK inhibitor SP600125 or vehicle and the extent of mucosal damage in the stomach was determined. Western analysis revealed early phosphorylation of JNK and, to a lesser extent, p38 as well as late phosphorylation of the p42/44 extracellular signal-related kinases during the development of gastric lesions. JNK was phosphorylated in epithelial cells and in occasional mononuclear cells present at lesion sites. These cells were rarely found in samples from control specimens. Treatment with SP600125 significantly reduced the extent of gastric lesions. These findings indicate that experimental gastric injury is associated with activation of the JNK signalling pathway, and also suggest that JNK inhibitors may play a role in the treatment of gastric injury in humans.
O-glycosylatedversusnon-glycosylated MUC1-derived peptides as potential targets for cytotoxic immunotherapy of carcinoma
Authors: Stepensky D , Tzehoval E , Vadai E , Eisenbach L
Published: October 2005

Due to the fact that many cellular proteins are extensively glycosylated, processing and presentation mechanisms are expected to produce a pool of major histocompatibility complex (MHC) class I-bound protein-derived peptides, part of which retain sugar moieties. The immunogenic properties of the presented glycosylated peptides in comparison to their non-glycosylated counterparts have not been determined clearly. We assessed the cellular immunogenicity of MUC1 (mucin)-derived peptides O-glycosylated with a Tn epitope (GalNAc) using HLA-A*0201 single chain (HHD)-transfected cell lines and transgenic mice. For part of the compounds Tn moiety did not interfere with the HLA-A*0201 binding. Moreover, part of the glycopeptides elicited effective cytotoxic responses, indicating recognition of the glycopeptide-HLA-A*0201 complex by the T cell receptor (TCR) and subsequent cytotoxic T lymphocyte (CTL) activation. The CTLs exhibited a substantial degree of cross-reactivity against target cells loaded with glycosylated and non-glycosylated forms of the same peptide. The studied (glyco)peptides showed cellular immunogenicity in both MUC1-HHD and HHD mice and induced effective lysis of (glyco)peptide-loaded target cells in CTL assays. However, the elicited CTLs did not induce selective lysis of human MUC1-expressing murine cell lines. Moreover, immunization with (glyco)peptide-loaded dendritic cells (DCs) did not induce significant immunotherapeutic effects. We conclude that Tn glycosylated MUC1-derived peptides can be presented by MHC class I molecules, and may be recognized by specific TCR molecules resulting in cytotoxic immune responses. However, the studied glycopeptides did not offer significant benefit as targets for cytotoxic immune response due apparently to (a) cross-reactivity of the elicited CTLs against the glycosylated and non-glycosylated forms of the same peptide and (b) low abundance of glycopeptides on tumour target cells.
Tolerosome‐induced oral tolerance is MHC dependent
Authors: Östman Sofia , Taube Maria , Telemo Esbjörn
Published: October 2005

Oral administration of a protein antigen generates a serum factor that induces tolerance when transferred into naïve recipients. This serum factor has been described in rats as consisting of exosome‐like structures or tolerosomes, which express major histocompatibility complex class II molecules (MHCII) and mediate antigen‐specific tolerance. In this study, we investigated the functions of serum‐derived tolerosomes both in vivo and in vitro. Tolerosomes were purified from the 100 000 g pellet fraction of serum from ovalbumin (OVA)‐fed mice. When transferred into naïve recipient mice, the tolerosomes mediated OVA‐specific tolerance. We also found that tolerosomes from OVA‐fed mice induced the activation of OVA‐specific T cells both in vivo and in vitro. The inoculation of severe combined immunodeficiency (SCID) mice with an interferon‐γ‐producing cell line normalized the expression of MHCII in the intestinal epithelial cells and restored their ability to generate tolerosomes. Syngeneic but not allogeneic transfer of tolerosomes from OVA‐fed donors induced tolerance in the recipients. Our results show that tolerosomes can be isolated from mouse serum, that tolerosome‐induced oral tolerance requires MHCII expression in intestinal epithelial cells, and that tolerosomes are functional only in syngeneic recipients.
Induction and recall of immune memory by mucosal immunization with a non‐toxic recombinant enterotoxin‐based chimeric protein
Authors: Gockel Christine M. , Russell Michael W.
Published: October 2005

Previous reports have suggested that peroral delivery of antigens chemically coupled to non‐toxic recombinant enterotoxin B subunits, such as the cholera toxin B subunit (CTB), induces tolerance to the antigen that may be abrogated by the toxic enzyme activity of intact enterotoxins, such as cholera toxin (CT). The aim of this study was to examine the immunogenicity of a genetically coupled protein composed of the saliva‐binding region (SBR) of the Streptococcus mutans surface antigen AgI/II and the non‐toxic A2 and B subunits of CT (SBR‐CTA2/B) compared with that of recombinant SBR admixed with CT (SBR + CT) and SBR chemically coupled to recombinant CTB (SBR‐CTB) following peroral delivery by intragastric (i.g.) immunization. The results showed that i.g. immunization with SBR‐CTA2/B, like SBR + CT, induced antigen‐specific serum immunoglobulin G (IgG) and salivary IgA antibodies, and sensitized splenic T cells. Comparison studies with SBR‐CTB produced serum IgG but not salivary IgA titres and failed to sensitize splenic cells. Immunization with SBR‐CTA2/B via the intranasal route also primed for the recall of antigen‐specific memory antibody responses 6 months later. These findings show that SBR‐CTA2/B is an immunogenic, not tolerogenic, chimeric protein that can induce and recall antigen‐specific memory responses upon mucosal immunization.
Cathepsin S is not crucial to TSHR processing and presentation in a murine model of Graves' disease
Authors: Kala Mrinalini , Chen Chun‐Rong , McLachlan Sandra M. , Rapoport Basil , Aliesky Holly , Chapman Harold A.
Published: October 2005

By regulating invariant (Ii) chain processing and MHC class II peptide loading, the endosomal protease cathepsin S (Cat S) has a potential role in autoimmune susceptibility. Indeed, Cat S null mice are resistant to I‐Ab‐restricted experimental myasthenia gravis due to inadequate peptide presentation. To explore the role of Cat S in a Graves' disease model, I‐Ad‐restricted wild‐type (WT) and Cat S–/– mice were immunized with adenovirus encoding the A subunit of thyroid stimulating hormone receptor (TSHR). TSHR adenovirus immunized mice develop Th1 T cells, TSHR antibodies, and a proportion become overtly hyperthyroid. Although TSHR presentation in vitro was initially impaired in Cat S–/– mice, subsequent TSHR presentation in vitro and disease development were similar in both groups but with higher antibody responses in Cat S null mice. WT and Cat S–/– mice recognized similar T cell epitopes from a panel of overlapping TSHR peptides. TSHR responses were found to be I‐Ad‐restricted and Cat S–/– I‐Ad B cells had marked defects in Ii processing. These data imply that loading of TSHR peptides critical to TSHR antibody responses becomes Ii‐independent. Contrasting findings among organ‐specific murine autoimmune models imply that potential uses of Cat S inhibitors to ameliorate autoimmunity must be determined empirically.
Putting the natural killer cell in its place
Authors: O'Connor Geraldine M. , Hart Orla M. , Gardiner Clair M.
Published: October 2005

Natural killer (NK) cells were originally described as ‘null’ lymphocytes, but we have increasing evidence of their role in recognizing pathogen, and our knowledge of NK cell receptors continues to expand exponentially. Human NK cells have many receptors for human leucoctye antigen (HLA) class I. These killer immunoglobulin‐like receptors (KIRs) and CD94/NKG2 receptors can signal in both positive and negative ways to regulate NK cell functions. The inhibitory receptors are the best characterized, but even in these cases much of their functional biology remains elusive. In this review, some recent advances in terms of the three‐immunoglobulin (3Ig)‐domain KIRs are discussed. Natural cytotoxicity receptors (NCRs) are among the activatory receptors found on NK cells. While pathogen ligands for these receptors have been described, endogenous ligands remain elusive. NCRs and NKG2D, a receptor for stress‐induced antigens, appear to play complementary functional roles in terms of NK cell activation. More recently described on NK cells are the Toll‐like receptors. In particular, these receptors of the innate immune system allow NK cells to directly sense pathogen, and their ligation on accessory cells indirectly activates NK cells through cytokine production. It is becoming clear that none of these receptor systems functions in isolation and that it is the sum of the signals (which will reflect the pathogenic situation), in addition to the cytokine milieu, that will direct NK cell activation. The resulting cytotoxicity, cytokine production and direct cell–cell regulatory interactions with other cells of the immune system, for example dendritic cells, ultimately determine the role of the NK cell in the context of an overall immune response.
Characterization of a novel PMA‐inducible pathway of interleukin‐13 gene expression in T cells
Authors: Keen Judith C. , Cianferoni Antonella , Florio Giovanni , Guo Jia , Chen Rongbing , Roman Jessica , Wills‐Karp Marsha , Casolaro Vincenzo , Georas Steve N.
Published: October 2005

Although interleukin 13 (IL‐13) is an important mediator of asthma and allergic diseases, the molecular mechanisms regulating IL‐13 gene expression are not well understood. This study was designed to define the molecular mechanisms governing IL‐13 gene expression in T cells. IL‐13 expression was examined in human peripheral blood T cells and in the EL‐4 T‐cell line by enzyme‐linked immunosorbent assay and reverse‐transcription polymerase chain reaction. An IL‐13 promoter deletion analysis was performed using luciferase‐based reporter plasmids transiently transfected into EL‐4 cells by electroporation. DNA binding factors were investigated using electrophoretic mobility shift assays. In contrast to IL‐4 expression, which required concomitant activation of calcium‐ and protein kinase C‐ (PKC‐) dependent signalling pathways, PKC activation alone was sufficient for IL‐13 protein secretion in mitogen‐primed (but not resting) peripheral blood T cells, and for IL‐13 mRNA expression and promoter activity in EL‐4 T cells. Promoter deletion analysis localized a phorbol 12‐myristate 13‐acetate (PMA) ‐sensitive element to a proximal promoter region between − 109 and − 79 base pairs upstream from the IL‐13 transcription start site. This promoter region supported the binding of both constitutive and PMA‐inducible nuclear factors in gel shift assays.
CD2 activation of human lamina propria lymphocytes reduces CD3 responsiveness
Authors: Ebert Ellen C.
Published: October 2005

Lamina propria lymphocytes (LPLs) are thought to be antigen‐activated memory T cells. Yet, they respond better to ligation of the CD2 receptor than the CD3 receptor by mitogenic antibodies. This study defines their constitutive state of activation and relates it to their CD3 hyporesponsiveness. The activated state of LPLs was demonstrated by their heightened display of the activated CD2 epitope, T113. Constitutive CD2 activation was shown by the reduction in spontaneous proliferation when the CD2–CD58 interaction was blocked. LPLs preferentially recognized CD58 rather than the major histocompatibility complex molecules on monocytes, triggering proliferation and interferon‐γ (IFN‐γ) secretion that was inhibited by blocking the CD2–CD58 interaction. To determine whether CD2 activation of LPLs contributes to their CD3 hyporesponsiveness, they were first stimulated with mitogenic CD2 antibodies and then tested for CD3‐induced proliferation. The responses were greatly reduced by prior CD2 stimulation compared with LPLs cultured in medium alone. This effect was not caused by apoptosis or by changes in CD3 expression induced by CD2 triggering. This study shows that LPLs are constitutively activated through CD2, that they preferentially recognize CD58 on monocytes and that CD2 stimulation leads to CD3 hyporesponsiveness.