Il-1 beta breaks tolerance through inhibition of regulatory T cell function

IL-1 is a key proinflammatory driver of several autoimmune diseases including juvenile inflammatory arthritis, diseases with mutations in the NALP/cryopyrin complex and Crohn’s disease, and is genetically or clinically associated with many others. IL-1 is a pleiotropic proinflammatory cytokine; however the mechanisms by which increased IL-1 signaling promotes autoreactive T cell activity are not clear. Here we show that autoimmune-prone NOD and IL-1 receptor antagonist-deficient C57BL/6 mice both produce high levels of IL-1, which drives autoreactive effector cell expansion. IL-1beta drives proliferation and cytokine production by CD4+CD25+FoxP3– effector/memory T cells, attenuates CD4+CD25+FoxP3+ regulatory T cell function, and allows escape of CD4+CD25– autoreactive effectors from suppression. Thus, inflammation or constitutive overexpression of IL-1beta in a genetically predisposed host can promote autoreactive effector T cell expansion and function, which attenuates the ability of regulatory T cells to maintain tolerance to self.

IL-1 breaks tolerance through inhibition of regulatory T cell function

Diverse infectious and inflammatory environmental triggers, through unknown mechanisms, initiate autoimmune disease in genetically predisposed individuals. Here we show that IL-1b, a key cytokine mediator of the inflammatory response, suppresses CD25+CD4+ regulatory T cell function. Surprisingly, suppression by IL-1b occurs only where antigen is presented simultaneously to CD25+CD4+ T cells and to CD25CD4+ antigen-specific effector T cells. Further, NOD mice show an intrinsic over-production of IL-1 that contributes to reduced CD25+CD4+ regulatory T cell function. Thus, inflammation or constitutive over-expression of IL-1b in a genetically predisposed host can initiate a positive feedback loop licensing autoantigen-specific effector cells to inhibit the regulatory T cells maintaining tolerance to self.

Phonological sensitivity as a proximal contributor to phonological recoding skills in children's reading

Because it permits self-teaching, phonological recoding (the efficient translation of letters or letter groups into sound) is arguably the key skill acquired in learning to read an alphabetic writing system. Deficits in this skill are the most common source of children's reading difficulties. In addition, poor readers tend to perform at a lower level than good readers on a wide variety of phonological processing tasks. These findings have been widely interpreted as implying a latent phonological processing ability as a distal cause of variation in reading skill. Clearly, such an interpretation does not imply that all phonological processing skills contribute directly to the phonological recoding process. This paper outlines a series of studies conducted at the University of Queensland. This work consistently suggests that children's phonological sensitivity contributes more directly than other phonological processing abilities to the development of phonological recoding skills.

Systemic lupus erythematosus exhibits a dynamic and continuum spectrum of effector/regulatory T cells

Objective: The identification of regulatory T cells (Treg cells) as CD4(+)CD25(high) cells may be upset by the increased frequency of activated effector T cells (Teff cells) in inflammatory diseases such as systemic lupus erythematosus (SLE). This study aimed to evaluate the frequency of T-cell subsets according to the expression of CD25 and CD127 in active (A-SLE) and inactive SLE (I-SLE). Methods: Peripheral blood mononuclear cells (PBMCs) from 26 A-SLE patients (SLE Disease Activity Index (SLEDAI) = 10.17 +/- 3.7), 31 I-SLE patients (SLEDAI = 0), and 26 healthy controls (HC) were analysed by multicolour flow. cytometry. Results: CD25(high) cell frequency was increased in A-SLE (5.2 +/- 5.7%) compared to I-SLE (3.4 +/- 3.4%) and HC (1.73 +/- 0.8%) (p < 0.01). However, the percentage of FoxP3(+) cells in the CD25(high) subset was decreased in A-SLE (24.6 +/- 16.4%) compared to I-SLE (33.7 +/- 16) and HC (45 +/- 25.1%) (p < 0.01). This was partly due to the increased frequency of Teff cells (CD25(high)CD127(+)FoxP3(empty set)) in A-SLE (10.7 +/- 7.3%) compared to I-SLE (8.5 +/- 6.5) and HC (6.1 +/- 1.8%) (p = 0.02). Hence the frequency of Treg cells (CD25(+/high)CD127(low/empty set)FoxP3(+)) was equivalent in A-SLE (1.4 +/- 0.8%), I-SLE (1.37 +/- 1.0%), and HC (1.13 +/- 0.59%) (p = 0.42). A-SLE presented an increased frequency of CD25(+)CD127(+)FoxP3(+) and CD25(empty set)FoxP3(+)CD127(low/empty set) T cells, which may represent intermediate phenotypes between Treg and Teff cells. Conclusions: The present study has provided data supporting normal Treg cell frequency in A-SLE and I-SLE as well as increased frequency of Teff cells in A-SLE. This scenario reflects a Treg/Teff ratio imbalance that may favour the inflammatory phenotype of the disease. In addition, the increased frequency of T cells with putative intermediate phenotypes may be compatible with a highly dynamic immune system in SLE.

Role of regulatory T cells in long-term immune dysfunction associated with severe sepsis

Objective: To investigate the role of regulatory T cells in the modulation of long-term immune dysfunction during experimental sepsis. It is well established that sepsis predisposes to development of a pronounced immunosuppression. Nevertheless, the mechanisms underlying the immune dysfunction after sepsis are still not well understood. Design: Prospective experimental study. Setting: University research laboratory. Interventions: Wild-type mice underwent cecal ligation and puncture and were treated with antibiotic during 3 days after surgery. On days 1, 7, or 15 after cecal ligation and puncture, the frequency of regulatory T cells, proliferation of CD4(+) T cells and bacterial counts were evaluated. Fifteen days after cecal ligation and puncture, surviving mice underwent secondary pulmonary infection by intranasal inoculation of nonlethal dose of Legionella pneumophila. Some mice received agonistic glucocorticoid-induced tumor necrosis factor receptor antibody (DTA-1) before induction of secondary infection. Measurements and Main Results: Mice surviving cecal ligation and puncture showed a markedly increased frequency of regulatory T cells in thymus and spleen, which was associated with reduced proliferation of CD4(+) T cells. Fifteen days after cecal ligation and puncture, all sepsis-surviving mice succumbed to nonlethal injection of L. pneumophila. Treatment of mice with DTA-1 antibody reduced frequency of regulatory T cells, restored CD4(+) T cell proliferation, reduced the levels of bacteria in spleen, and markedly improved survival of L. pneumophila infection. Conclusion: These findings suggest that regulatory T cells play an important role in the progression and establishment of immune dysfunction observed in experimental sepsis. (Crit Care Med 2010; 38: 1718-1725)

Brief opportunistic intervention: The role of psychologists in initiating self-change amongst problem drinkers

Excessive consumption of alcohol is a serious public health problem. While intensive treatments are suitable for those who are physically dependent on alcohol, they are not cost-effective options for the vast majority of problem drinkers who are not dependent. There is good evidence that brief interventions are effective in reducing overall alcohol consumption, alcohol-related problems, and health-care utilisation among nondependent problem drinkers. Psychologists are in an ideal position to opportunistically detect people who drink excessively and to offer them brief advice to reduce their drinking. In this paper we outline the process involved in providing brief opportunistic screening and intervention for problem drinkers. We also discuss methods that psychologists can employ if a client is not ready to reduce drinking, or is ambivalent about change. Depending on the client's level of motivation to change, psychologists can engage in either an education-clarification approach, a commitment-enhancement approach, or a skills-training approach. Routine engagement in opportunistic intervention is an important public-health approach to reducing alcohol-related harm in the community.

Motor and functional skills of children with developmental coordination disorder: A pilot investigation of measurement issues

This paper reports on the motor and functional outcomes of 20 children with developmental coordination disorder (DCD) aged 4-8 years consecutively referred to a pediatric physiotherapy service. Children with a Movement ABC (M-ABC) score less than the 15th percentile, and with no concurrent medical, sensory, physical, intellectual or neurological impairments, were recruited. The Motor Assessment Outcomes Model (MAOM) [Coster and Haley, Infants and Young Children 4 (1992) 11] provided the theoretical base for measurement selection, and preliminary findings at the activities and participation levels of the model are reported in this article. Children with DCD performed at the lower end of the normal range on the Pea-body Developmental Motor Scales (fine motor total score) (M = 85.65, SD = 12.23). Performance on the Visual Motor Integration Test (VMI) standard scores was within the average range (M = 96.15, SD = 10.69). Videotaped observations of the children's writing and cutting indicated that 29% were left-handed and that a large proportion of all children (31%) utilized unusual pencil grasp patterns and immature prehension of scissors. Measurement at the participation level involved use of the Pictorial Scale of Perceived Competence and Social Acceptance (PCSA) and Pediatric Evaluation of Disability Inventory (PEDI). Overall, these young children rated themselves towards the more competent and accepted end of the PCSA over the dimensions of physical and cognitive competence and peer and maternal acceptance. The PEDI revealed generally average performance on social (M = 49.98, SD = 16.62) and mobility function (M = 54.71, SD = 3.99), however, self-care function was below the average range for age (M = 38.01, SD = 12.19). The utility of the MAOM as a framework for comprehensive measurement of functional and motor outcomes of DCD in young children is discussed. (C) 2003 Elsevier B.V. All rights reserved.

Programas de self-management em pacientes com DPOC: uma revisão sistemática

Introdução: Programas de self-management têm como objectivo habilitar os pacientes com estratégias necessárias para levar a cabo procedimentos específicos para a patologia. A última revisão sistemática sobre selfmanagament em DPOC foi realizada em 2007, concluindo-se que ainda não era possível fornecer dados claros e suficientes acerca de recomendações sobre a estrutura e conteúdo de programas de self-managament na DPOC. A presente revisão tem o intuito de complementar a análise da revisão anterior, numa tentativa de inferir a influência do ensino do self-management na DPOC. Objectivos: verificar a influência dos programas de self-management na DPOC, em diversos indicadores relacionados com o estado de saúde do paciente e na sua utilização dos serviços de saúde. Estratégia de busca: pesquisa efectuada nas bases de dados PubMed e Cochrane Collaboration (01/01/2007 – 31/08/2010). Palavras-chave: selfmanagement education, self-management program, COPD e pulmonary rehabilitation. Critérios de Selecção: estudos randomizados sobre programas de selfmanagement na DPOC. Extracção e Análise dos Dados: 2 investigadores realizaram, independentemente, a avaliação e extracção de dados de cada artigo. Resultados: foram considerados 4 estudos randomizados em selfmanagement na DPOC nos quais se verificaram benefícios destes programas em diversas variáveis: qualidade de vida a curto e médio prazo, utilização dos diferentes recursos de saúde, adesões a medicação de rotina, controle das exacerbações e diminuição da sintomatologia. Parece não ocorrer alteração na função pulmonar e no uso de medicação de emergência, sendo inconclusivo o seu efeito na capacidade de realização de exercício. Conclusões: programas de self-management aparentam ter impacto positivo na qualidade de vida, recurso a serviços de saúde, adesão à medicação, planos de acção e níveis de conhecimento da DPOC. Discrepâncias nos critérios de selecção das amostras utilizadas, períodos de seguimento desiguais, consistência das variáveis mensuradas, condicionam a informação disponibilizada sobre este assunto.

Prevalence of Asthma in a Portuguese Countryside Town:Repercussions on Absenteeism and Self-Concept

Background: Childhood asthma represents an increasing health problem and is the leading cause of hospital admission and absenteeism in children with chronic disease. It also compromises quality of life, eventually contributing to disturbances in self-concept. Self-concept is a recent and global perspective of “the self” and relates to skills, self-image and self-esteem. Little information is available on this topic and there are no data from Portuguese countryside towns. Objective: The aim of this study was to determine the prevalence of asthma among all school children in the 5th and 6th grades in a Portuguese countryside town and to establish its possible correlation with absenteeism and self-concept. Methods: In April 2002, two questionnaires were administered in the presence of the researcher to a group of 950 children attending different schools. The children completed the internationally renowned questionnaires: ISAAC and the Self-Concept Scale by Susan Harter. Results: Our sample (n = 818) had a mean age of 11 years (10-15 years) and a male-to-female ratio of 1/1. The cumulative prevalence of asthma was11.9% and that of active asthma was 8.8 %; 63.9% of asthmatics were male and 36.1 % were female. The mean age of asthmatics was 11.34 years and 74 % had active symptoms. Comparison of this group of 97 asthmatic children with the remaining children revealed a statistically significant correlation between the presence of asthma and school absenteeism (global: p = 0.04; gymnastics: 0.05). Regarding the Self-Concept Scale a statistically significant association was found between the presence of asthma and school achievement (p = 0.027), physical appearance (p = 0.015), behavior (p < 0.000) and self-esteem (p < 0.000). No statistically significant correlations were found in social acceptance (p = 0.289) or athletic competence (p = 0.085). Asthmatic boys had higher self-concept scores than girls, except in the domain of behavior. Conclusions: Twelve percent of the population studied was asthmatic. In asthmatic children, absenteeism was higher and self-concept was lower for almost all domains, except social acceptance and athletic achievement, probably due to overprotection.

T cell Maturation and Regulatory T Cell Differentiation:From the Thymus to the Periphery

Immunological tolerance, that is, the failure to mount an immune response to an otherwise immunogenic molecule, is one of the fundamental questions in immunology. The fact that lymphocytes express antigen receptors that are generated randomly and have the potential to recognize any conceivable antigen, adds another puzzle to the physiology of immunological tolerance. The other side of the coin, the general absence of immune responses to self antigens, is ensured by a tight regulation and several selection steps during T and B cell differentiation. One of these processes is the differentiation of regulatory T cells (Treg). While developing in the thymus, T cell clones bearing receptors with high affinity/avidity to antigens present at the time of differentiation may be eliminated by apoptosis or, alternatively, express Foxp3 and become Treg. Treg are key players in the regulation of immunological tolerance since humans and mice with complete loss of function variants of this gene develop fatal autoimmune conditions early in life.(...)

HLT Hilotec: self-building manual for sustainable housing

The future of the construction industry will require changes at many levels. One is the ability of companies to adapt to new challenges, converting needs to opportunities and simultaneously contributing to the solving of social and environmental problems. In the coming decades we will see a change in attitude in the industry, with a strong tendency to adopt natural and recycled materials, as well as bet on green technology and social innovation oriented to emerging countries. On the other hand, emerging countries have a high demand for housing construction on a large scale, but the current techniques in the developed countries for building requires a large amount of natural resources and skilled labor. This contextualization brings sustainability problems for the construction sector in emerging countries, often with scarce natural resources and with the construction sector underdeveloped. Through a cooperative action between the construction company Mota-Engil Engineering and the University of Minho in Portugal, a construction technology was developed based on the use of Compressed Earth Blocks as part of a social concept for innovative small houses, favoring the adoption of local and natural materials and with the main premise of being dedicated to self-construction. The HiLoTec project - Development of a Sustainable Self-Construction System for Developing Countries was based on this idea. One of the several results of this project is this construction manual. To Mota-Engil the project was a platform for incubation of knowledge about earth construction and to obtain a constructive solution validated technically and scientifically, suitable to be implemented in the markets where it operates. For the University of Minho the project was an opportunity to strengthen skills in research, laboratory and scientific development, through the development of engineering studies, architecture and sustainability, as well as supporting the doctoral scholarships and dissemination of scientific publications. May the knowledge of this project be of benefit, in the future, for the welfare of those who build a HiLoTec house.

Development and psychometric properties of ECPICID-AVC to measure informal caregivers’ skills when caring for older stroke survivors at home

Introduction: Informal caregivers provide a significant part of the total care needed by dependent older people poststroke. Although informal care is often the preferred option of those who provide and those who receive informal care, informal caregivers often report lack of preparation to take care of older dependent people. This article outlines the development and psychometric testing of informal caregivers’ skills when providing care to older people after a stroke – ECPICID-AVC. Design: Prospective psychometric instrument validation study. Methods: Eleven experts participated in a focus group in order to delineate, develop and validate the instrument. Data were gathered among adult informal caregivers (n = 186) living in the community in Northern Portugal from August 2013 to January 2014. Results: The 32-item scale describes several aspects of informal caregiver’s skills. The scale has eight factors: skill to feed/hydrate by nasogastric feeding, skill to assist the person in personal hygiene, skill to assist the person for transferring, skill to assist the person for positioning, skill to provide technical aids, skill to assist the person to use the toilet, skill to feed/hydrate and skill to provide technical aids for dressing/undressing. Analysis demonstrated adequate internal consistency (Cronbach’s alpha = 0.83) and good temporal stability 0.988 (0.984–0.991). Conclusion: The psychometric properties of the measurement tool showed acceptable results allowing its implementation in clinical practice by the nursing community staff for evaluating practical skills in informal caregivers when providing care to older stroke survivors living at home.

Private Governance of Financial Markets: the US Regulatory Regime on Hedge Funds

The article investigates the private governance of financial markets by looking at the evolution of the regulatory debate on hedge funds in the US market. It starts from the premise that the privatization of regulation is always the result of a political decision and analyzes how this decision came about and was implemented in the case of hedge funds. The starting point is the failure of two initiatives on hedge funds that US regulators launched between 1999 an 2004, which the analysis explains by elaborating the concept of self-capture. Facing a trade off between the need to tackle publicly demonized issues and the difficulty of monitoring increasingly sophisticated and powerful private markets, regulators purposefully designed initiatives that were not meant to succeed, that is, they “self-captured” their own activity. By formulating initiatives that were inherently flawed, regulators saved their public role and at the same time paved the way for the privatization of hedge fund regulation. This explanation identifies a link between the failure of public initiatives and the success of private ones. It illustrates a specific case of formation of private authority in financial markets that points to a more general practice emerging in the regulation of finance.

Cultural competency of health-care providers in a Swiss University Hospital: self-assessed cross-cultural skillfulness in a cross-sectional study.

BACKGROUND: As the diversity of the European population evolves, measuring providers' skillfulness in cross-cultural care and understanding what contextual factors may influence this is increasingly necessary. Given limited information about differences in cultural competency by provider role, we compared cross-cultural skillfulness between physicians and nurses working at a Swiss university hospital. METHODS: A survey on cross-cultural care was mailed in November 2010 to front-line providers in Lausanne, Switzerland. This questionnaire included some questions from the previously validated Cross-Cultural Care Survey. We compared physicians' and nurses' mean composite scores and proportion of "3-good/4-very good" responses, for nine perceived skillfulness items (4-point Likert-scale) using the validated tool. We used linear regression to examine how provider role (physician vs. nurse) was associated with composite skillfulness scores, adjusting for demographics (gender, non-French dominant language), workplace (time at institution, work-unit "sensitized" to cultural-care), reported cultural-competence training, and cross-cultural care problem-awareness. RESULTS: Of 885 questionnaires, 368 (41.2%) returned the survey: 124 (33.6%) physicians and 244 (66.4%) nurses, reflecting institutional distribution of providers. Physicians had better mean composite scores for perceived skillfulness than nurses (2.7 vs. 2.5, p < 0.005), and significantly higher proportion of "good/very good" responses for 4/9 items. After adjusting for explanatory variables, physicians remained more likely to have higher skillfulness (β = 0.13, p = 0.05). Among all, higher skillfulness was associated with perception/awareness of problems in the following areas: inadequate cross-cultural training (β = 0.14, p = 0.01) and lack of practical experience caring for diverse populations (β = 0.11, p = 0.04). In stratified analyses among physicians alone, having French as a dominant language (β = -0.34, p < 0.005) was negatively correlated with skillfulness. CONCLUSIONS: Overall, there is much room for cultural competency improvement among providers. These results support the need for cross-cultural skills training with an inter-professional focus on nurses, education that attunes provider awareness to the local issues in cross-cultural care, and increased diversity efforts in the work force, particularly among physicians.

The de facto independence of regulatory agencies and its consequences for policy making and regulatory outcomes

This dissertation focuses on the practice of regulatory governance, throughout the study of the functioning of formally independent regulatory agencies (IRAs), with special attention to their de facto independence. The research goals are grounded on a "neo-positivist" (or "reconstructed positivist") position (Hawkesworth 1992; Radaelli 2000b; Sabatier 2000). This perspective starts from the ontological assumption that even if subjective perceptions are constitutive elements of political phenomena, a real world exists beyond any social construction and can, however imperfectly, become the object of scientific inquiry. Epistemologically, it follows that hypothetical-deductive theories with explanatory aims can be tested by employing a proper methodology and set of analytical techniques. It is thus possible to make scientific inferences and general conclusions to a certain extent, according to a Bayesian conception of knowledge, in order to update the prior scientific beliefs in the truth of the related hypotheses (Howson 1998), while acknowledging the fact that the conditions of truth are at least partially subjective and historically determined (Foucault 1988; Kuhn 1970). At the same time, a sceptical position is adopted towards the supposed disjunction between facts and values and the possibility of discovering abstract universal laws in social science. It has been observed that the current version of capitalism corresponds to the golden age of regulation, and that since the 1980s no government activity in OECD countries has grown faster than regulatory functions (Jacobs 1999). Following an apparent paradox, the ongoing dynamics of liberalisation, privatisation, decartelisation, internationalisation, and regional integration hardly led to the crumbling of the state, but instead promoted a wave of regulatory growth in the face of new risks and new opportunities (Vogel 1996). Accordingly, a new order of regulatory capitalism is rising, implying a new division of labour between state and society and entailing the expansion and intensification of regulation (Levi-Faur 2005). The previous order, relying on public ownership and public intervention and/or on sectoral self-regulation by private actors, is being replaced by a more formalised, expert-based, open, and independently regulated model of governance. Independent regulation agencies (IRAs), that is, formally independent administrative agencies with regulatory powers that benefit from public authority delegated from political decision makers, represent the main institutional feature of regulatory governance (Gilardi 2008). IRAs constitute a relatively new technology of regulation in western Europe, at least for certain domains, but they are increasingly widespread across countries and sectors. For instance, independent regulators have been set up for regulating very diverse issues, such as general competition, banking and finance, telecommunications, civil aviation, railway services, food safety, the pharmaceutical industry, electricity, environmental protection, and personal data privacy. Two attributes of IRAs deserve a special mention. On the one hand, they are formally separated from democratic institutions and elected politicians, thus raising normative and empirical concerns about their accountability and legitimacy. On the other hand, some hard questions about their role as political actors are still unaddressed, though, together with regulatory competencies, IRAs often accumulate executive, (quasi-)legislative, and adjudicatory functions, as well as about their performance.