bluuebunny/crossref_metadata_2025 huggingface dataset:
Positive Duties and Gender Equality
Authors: O'cinneide Colm
Published: October 2011

The imposition since 1998 of a variety of positive equality duties upon public authorities has attracted comparatively little academic attention. However, these duties are a central part of current government equality initiatives, increasingly constitute a major part of the work of the UK's equality commissions, and have been described as an essential part of a new ‘fourth generation’ of equality legislation. It now appears likely that a positive duty to promote gender equality will soon be imposed upon public authorities, which will complement similar race and disability duties. Will the introduction of this positive gender equality duty add to, detract or complement existing statutory provisions? Given the danger that ‘soft law’ initiatives may undermine existing anti-discrimination controls, will the duty provide a clear steer to public authorities, or will it lack teeth, substance and direction, and possibly even prove counter-productive?

Such positive duties are designed to compensate for the limitations of existing anti-discrimination law, by requiring the taking of positive steps to promote equality and eliminate discrimination, rather than just compelling a reactive compliance with the letter of the (equality) law. The justifications in principle for the introduction of such duties are strong: for the first time, the introduction of a positive gender duty will impose a clear legislative obligation upon public authorities to adopt a substantive equality approach and to take proactive action to redress patterns of disadvantage linked to gender discrimination. Serious concerns do however exist as to the extent to which such duties can be enforced, and the danger that they will simply encourage greater bureaucratic activity at the expense of real change. The proposed gender duty, as with the other duties that have been introduced, is no panacea. Nevertheless, it does constitute a good start, can serve a useful function by empowering public authorities to take positive action, and if effectively used will be a very valuable point of pressure to push for better things.
‘Modernising Discrimination Law’: Proposals for a Single Equality Act for Great Britain
Authors: Malik Maleiha
Published: October 2011

This article analyses the Discrimination Law Review, issued in June 2007, which proposes the introduction of a Single Equality Act for Great Britain. It argues that these proposals will lead to some valuable reforms especially through the harmonisation of legal definitions in areas such as disability discrimination and indirect discrimination. Yet, at the same time, the Discrimination Law Review has missed an opportunity to address some of the central problems that hinder the effectiveness of discrimination law. The analysis focuses on specific examples: the ‘comparator’ problem in equal pay and multiple discrimination cases; individual remedies; public sector duties; procurement; and positive action. The article concludes that although the proposals for a Single Equality Act will lead to greater protection for individuals they are unlikely to be an effective response to the problems of structural discrimination and social exclusion.
Banning Sexism: How Harassment Law may Threaten Freedom of Expression and Undermine Antidiscrimination Policies
Authors: Vrielink Jogchum , Sottiaux Stefan
Published: October 2011

On 26 September 2007, the Brussels’ Court of Commerce banned a sexist commercial and convicted its maker for violating several provisions of the federal Antidiscrimination Act. This contribution analyses the ruling and places it in a broader context. First, the facts of the case and the content of the judgment are presented. We then offer a closer inspection of the Court's reasoning and argue that the ruling is legally flawed and raises serious free speech concerns. To conclude, we consider some troubling implications the case may have for the fight against discrimination in Belgium.
Equality: A Fundamental Right in the European Union?
Authors: Howard Erica
Published: October 2011

This article analyses the development of a fundamental right to equal treatment or to non-discrimination within the EU legal order through a study of the general principles of Community law, the Charter of Fundamental Rights of the European Union and the Article 13 EC Equality Directives. It examines European Union legislation and case law of the European Court of Justice, including the opinions of the Advocates General and the Court of First Instance, in relation to the principle of equality or equal treatment to determine whether they support the existence of a fundamental right to equality before the law and to nondiscrimination. The equality clauses of international instruments are reviewed as aid in this analysis. Despite the fact that the sources discussed appear to establish a right to equality before the law or to non-discrimination, the limitations to the material and personal scope of these sources means that this right is, as yet, not a fundamental, universal right within the EU legal order.
Employers' Legal Liability for Sexual Harassment of Employees by Third Parties
Authors: Middlemiss Sam
Published: October 2011

The issue of whether or not an employer should be vicariously liable under statute for sexual harassment perpetrated against his employees by third parties is an important one that has been undecided until recently. Whether the issue has been decided by the legislative rules now covering it remains to be seen. Some commentators, including this writer, would disagree that the matter has been resolved sufficiently and argue the need for further change.

‘Thus an employer is not liable for third party harassment of which they had no knowledge, or for one off incidents of third-party harassment, or for conduct beyond their control.’ 1

This article will briefly outline the chequered history of this area of law and analyse how recent changes in UK law 2 (which were inspired by a EU Directive and a successful challenge to the legal rules in the UK raised by the Equal Opportunities Commission (EOC) in Equal Opportunities Commission v. Secretary of State for Trade and Industry) 3 and implemented by the Sex Discrimination Act 1975 (Amendment) Regulations have finally tried to resolve the issue.

The legal effect of these changes will be considered as will their practical impact on employers in the UK. The deficiencies in the legislative rules which now apply will also be highlighted. Developments in other relevant areas of harassment law will also be considered.
Discrimination, Freedom, and the Limits of Contract
Authors: Demeyere Gillian
Published: October 2011

This article offers a challenge to the widely held view that legislative prohibitions against discrimination in employment represent a restriction on freedom of contract. Rather than engage in the political debate concerning the justifiability of such a restriction on an employer's contracting freedom, I instead argue how the apparent conflict between the individual's claim to equality and the employer's claim to freedom of contract might prove to be illusory. I argue that the freedom in freedom of contract is best understood, as it is defined in the republican tradition, in terms of immunity from interference on an arbitrary basis (freedom as “nondomination”). On this understanding of freedom, anti-discrimination law poses no threat to contracting freedom since discriminatory hiring and workplace practices fall outside the scope of the employer's freedom of contract. The article focuses mainly on Canadian law but the analysis and conclusions are generalizable to other common law jurisdictions where the employment relationship is subject to a prohibition against discrimination.
Retirement, Collective Agreement, and Age Discrimination: Implications for the Higher Education Sector in the UK
Authors: Manfredi Simonetta
Published: October 2011

This article explores the possible impact of the removal of the default retirement age of 65 on the Higher Education sector as an employer. It considers the findings from empirical research to highlight some of the management issues likely to be faced by the sector as a result of the removal of the default retirement age. One of these issues is the need to avoid job blockage and provide jobs and career opportunities for younger academics. Thus, it can be questioned whether the need to redistribute job opportunities among younger generations of employees would constitute a legitimate aim and objectively justify a contractual retirement age in the HE sector. In order to investigate this question, the CJEU emerging case law relating to retirement rules and objective justification under Article 6(1) of Council Directive 2000/78/EC, and the case of Seldon in the UK, are discussed. It is argued that the HE sector could draw on the experience of the CJEU case law and the use of the collective bargaining process to tackle the issues raised by the removal of the retirement age against a very challenging economic environment. This article also highlights that research findings indicate that in the absence of a contractual retirement age staff performance management is likely to come into focus in the management of human resources. It is suggested, however, that employers in the sector will need to give careful consideration to the way the performance of older workers is monitored and measured in order to avoid the risk of age bias that may lead to claims of age discrimination. Although this article focuses on the Higher Education sector, it is suggested that some of the research findings and the arguments presented here could apply to other employment sectors.
The Employment Equality Review And Fair Employment in Northern Ireland
Authors: Bell Christine
Published: October 2011

This article examines the process of the Employment Equality Review of the Northern Ireland Fair Employment legislation currently being undertaken by the Standing Advisory Commission on Human Rights. The article suggests key issues to be undertaken by the review both in terms of its processes and also in terms of the legislation's weaknesses. Specifically the article addresses affirmative action, contract compliance and several of the legislation's explicit and implicit exemptions. Finally the article considers the impact and limitations of two government policy initiatives which should address the issue of religious and political inequalities — the Policy Appraisal and Fair Treatment Guidelines and the Targeting Social Need spending priority. Throughout the article some suggestions for reform are made.
Stopping the Grog
Authors: Duff Catherine
Published: October 2011

Indigenous communities around Australia find themselves in the grip of chronic alcohol abuse and its related violence. For more than a decade Aboriginal and Torres Strait Islander peoples, especially Indigenous women, have been agitating for change. In many cases Indigenous communities have been calling for restrictions to limit or prohibit alcohol availability to their members. In the past, Australia's anti-discrimination regime has been used to justify official inactivity on the issue of alcohol availability in Indigenous communities. Indigenous drinkers and publicans have also appealed to the principle of non-discrimination in their opposition to grog restrictions.
Harassment at Work as Discrimination: The Current Debate in England and Wales
Authors: Roberts Pauline , Vickers Lucy
Published: October 2011

In 1996–97 there were a number of significant decisions which extended the scope of employers' liability for sexual and racial harassment at work, based upon the provisions of the Sex Discrimination Act 1975 and the Race Relations Act 1976. This article seeks to analyse the impact of these recent cases. It began by considering the relationship between the concepts of ‘harassment’ and ‘discrimination’ and the problems inherent in using the anti-discrimination legislation to deal with harassment and bullying at work; we then focus on the recently demonstrated ‘purposive’ approach of the Employment Appeal Tribunal and Court of Appeal in interpreting the statutes and consider how this combats the weaknesses identified. Alternative forms of relief will be briefly considered, in particular the recently enacted Protection from Harassment Act 1997. The authors, while welcoming the recent decisions, argue that there are some victims of bullying who remain outside the protection of the existing anti-discrimination legislation (as they do not fall within any of the groups identified for protection), notwithstanding the robust advances of the EAT. We suggest that the Protection from Harassment Act may not completely fill this gap.
Rethinking social support in women’s midlife years: Women’s experiences of social support in online environments
Authors: Dare Julie , Green Lelia
Published: October 2011

The midlife years (45–55) often coincide with fundamental changes in women’s lives, as women experience transitions such as menopause, changes to family structure due to departure of children or divorce, and parents’ ageing and death. These circumstances tend to increase women’s reliance upon their social support networks. Evidence suggests that social support is critical in helping women manage transitions during the midlife period and develop a sense of self-efficacy; this article highlights that this support is being increasingly exchanged through mediated communication channels. The article presents a comparative investigation of mediated communication channels, primarily email and online chat, through which women give and receive social support, and addresses the factors underpinning women’s media choices. The findings indicate that in determining their media selection, women are judging their ‘audience’ and social context of their communication in order to select the most appropriate channel through which to exchange support.
Changing old habits? ‘New Age’ Catholicism, subjectivity and gender in BBC2’s The Monastery and its reception
Authors: Thomas Lyn
Published: October 2011

This article focuses on a recent BBC television programme, The Monastery, and its reception. The analysis demonstrates how religion becomes visible here through a hybrid televisual form merging ‘reality’ conventions with those of quality television. It argues that this ‘quality reality’ format both participates in, and nuances the making of class and gender in reality television. The analysis suggests that the religious culture represented here is also hybrid, combining elements of the alternative and subjectively focused spiritual practices researched by Heelas and Woodhead with Catholicism. The second part of the article discusses the responses to these representations of a small number of engaged viewers recruited at retreats at the filmed monastery, Worth Abbey in Sussex. It argues that the programme’s hybrid forms and representations, and particularly its representation of caring and spiritual masculinity, can explain its appeal to predominantly middle-class, white women viewers.
Inclusion as an instructional approach: Fostering inclusive writing communities in preschool classrooms
Authors: McCloskey Erin
Published: October 2011

Preschool students with disabilities engage in social interaction with peers less often than children developing typically in inclusive classrooms. This research explores how divergent theories of literacy learning, those inherent in the structure of special education and those promoted by scholars interested in emergent literacy learning, impact upon inclusive classrooms. This qualitative case study details how a writing community in an inclusive preschool classroom promoted social engagement and literacy learning of all students. The study highlights one preschooler with a disability to showcase one way in which these divergent theories of learning might be bridged.
Family literacy practices and home literacy resources: An Australian pilot study
Authors: Grieshaber Susan , Shield Paul , Luke Allan , Macdonald Shelly
Published: October 2011

The combined impact of social class, cultural background and experience upon early literacy achievement in the first year of schooling is among the most durable questions in educational research. Links have been established between social class and achievement but literacy involves complex social and cognitive practices that are not necessarily reflected in the connections that have been made. The complexity of relationships between social class, cultural background and experience, and their impact on early literacy achievement have received little research attention. Recent refinements of the broad terms of social class or socioeconomic status have questioned the established links between social class and achievement. Nevertheless, it remains difficult to move beyond deficit and mismatch models of explaining and understanding the underperformance of children from lower socioeconomic and cultural minority groups when conventional measures are used. The data from an Australian pilot study reported here add to the increasing evidence that income is not necessarily related directly to home literacy resources or to how those resources are used. Further, the data show that the level of print resources in the home may not be a good indicator of the level of use of those resources.
Ants, apples and the ABCs: The use of commercial phonics programmes in prior-to-school children’s services
Authors: Campbell Stacey , Torr Jane , Cologon Kathy
Published: October 2011

Commercial phonics programmes (e.g. Jolly Phonics and Letterland) are becoming widely used in the early years of school. These programmes claim to use a systematic explicit approach, considered as the preferred method of phonics instruction for teaching alphabetic code-breaking skills in Australia and the UK in the first years of school (Department of Education, Science and Training, 2005; Rose, 2006 ). However, little is known about the extent to which they are being used in prior-to-school settings, and the reasons behind decisions to use them. This study surveyed 283 early childhood staff in Sydney, Australia and found that commercial phonics programmes were being used in 36% of the early childhood settings surveyed. Staff with early childhood university qualifications and staff working in not-for-profit service types were less likely to use a commercial phonics programme than staff without university qualifications and staff working in for-profit services. Staff with less than 10 years’ experience were also more likely to use a commercial phonics programme. The rationale behind decisions determining whether or not staff used the programmes ranged from pragmatic reasons, such as parent pressure or higher management decisions, to pedagogical reasons, such as teacher beliefs about how children learn to read and write. The practices staff engage in to teach phonics are explored.
Persons with dementia become users of assistive technology: A study of the process
Authors: Rosenberg Lena , Nygård Louise
Published: October 2011

The aim of this study was to explore actions and driving forces of the actors involved in the process of bringing assistive technology (AT) into the life of a person with dementia. Specific focus is placed on the unfolding transactions and what they led to, and how the AT intervention corresponded to the situation of the person with dementia. Three cases, i.e. three persons with dementia and their significant others ( n = 13), were followed using case methodology and grounded theory. The findings show how doing the right thing was the main driving force, although sometimes a source of conflict between actors. The actors’ views differed in many aspects, influencing the choice of problem and selected AT solution as well as the role of the AT and how it was placed and adjusted. A potential risk scenario was also identified, exemplifying how profoundly the view of the one who had decision power influenced the process.
A UK retrospective observational survey of vildagliptin as add-on antidiabetes therapy in elderly patients
Authors: Mistry Mukesh , Lister Nicola , Andrews Chris , Geransar Parnia , Sinclair Alan
Published: October 2011

In the UK, type 2 diabetes mellitus in patients aged ≥ 65 years is a significant healthcare burden, compounded by an increasing elderly population. Intensive therapies to control blood glucose can be hazardous for this patient group and information is limited about well-tolerated therapies. This retrospective, real-world survey recorded glycated haemoglobin A1c (HbA1C) levels and incidences of hypoglycaemic events in 72 elderly and very elderly patients (65–74 years and ≥ 75 years, respectively) receiving the dipeptidyl peptidase-4 inhibitor vildagliptin as part of combination therapy. After vildagliptin initiation, mean HbA1C levels decreased from 8.2% to 7.4% (p=0.0415), the mean change in the elderly and very elderly subgroups being similar (−0.8%, −0.9%, respectively); the mean incidence of hypoglycaemic events (1.4%) was unchanged. This observational survey provides real-life evidence that in patients aged ≥ 65 years with type 2 diabetes, vildagliptin is an effective, well-tolerated add-on therapy with low hypoglycaemic risk.
Wave reflection signatures: identifying early microvascular abnormalities in type 2 diabetes
Authors: Plumb Rick D , Hamilton Paul K , Rea Derrick J , Wright Stephen A , Hughes Sinead M , McGivern R Canice , McVeigh Gary E
Published: October 2011

Microvascular changes occur early in diabetes mellitus. Doppler ultrasound enables non-invasive identification of ocular microvascular haemodynamics through interrogation of blood flow velocity waveforms. Wave decomposition permits the spectrum of sinusoidal components comprising flow velocity waveforms to be quantified. We hypothesised that comprehensive interrogation of waveforms would be more sensitive in identifying microvascular abnormalities than traditional analysis employing the resistive index.

Thirty-four subjects with type 2 diabetes and 20 healthy controls between 30 and 70 years old were recruited. Doppler flow velocity waveform signals were captured from the ophthalmic and carotid arteries under standardised conditions. The signals were analysed using a wave decomposition algorithm and the sinusoidal components of average waveforms were compared between groups at both arterial sites.

The diabetes group displayed significant differences in the lower frequency sinusoidal components of both the ophthalmic artery (p<0.001) and, to a lesser extent, the carotid artery (p<0.05) waveforms compared with controls, with no difference noted in the resistive index at either site.

We conclude that wave decomposition analysis of Doppler flow velocity waveforms, recorded in proximity of the terminal vascular bed of interest, can identify subtle microvascular haemodynamic abnormalities not detected by traditional methods of analysis.
Developmental Leadership
Authors: Gilley Jerry W. , Shelton Paul M. , Gilley Ann
Published: October 2011

Research indicates that numerous variables influence an organization’s ability to change and innovate. There is a need to understand a leadership model that focuses on the aspects of human resource development (HRD). Furthermore, it is important for the HRD model of leadership to foster and support creativity and innovation in organizations. In response to this need, this article identifies and explains a developmental leadership model rooted within the HRD framework of organized learning, change, interventions, and development. The focus of this work is to discuss how a developmental leadership style can generate new perspectives in HRD that translate to innovation for the organization. Consequently, this article shares a theoretical model for different roles that make up developmental leadership in practice activities, while exploring the construct of development leadership, its purpose, roles, core values, characteristics, and impact on innovation and creativity. This article explores the potential of Developmental Leadership in HRD as a driver of organizational innovation. The stakeholders involved are organizations, leaders, and followers. A clear understanding of developmental leadership and innovation informs ways of doing business at many levels.
Baseball Salaries and Income Taxes
Authors: Alm James , Kaempfer William H. , Sennoga Edward Batte
Published: October 2011

In this article, the authors examine the impact on the salaries of free agents in Major League Baseball (MLB) of differences in state and local individual income taxes between major league cities, in an attempt to see if income taxes affect player salaries. This basic specification suggests that each percentage point of an income tax raises free agent salaries by $21,000 to $24,000; other estimates indicate even larger impacts. These findings suggest that the existence of this additional salary demand means that low-tax cities (e.g., Florida, Texas, and Washington) have a “home field advantage” in the baseball free agent market.
Feasibility of Endoscopic Transoral Surgical Lung Biopsy in a Live Canine Model
Authors: Liu Yun-Hen , Chu Yen , Wu Yi-Cheng , Chen Tzu-Ping , Lu Ming-Shian , Lu Hung-Yi , Yuan Hsu-Chia , Ko Po-Jen
Published: October 2011

Background. The feasibility of using a transoral approach to the thoracic cavity has not yet been measured in humans or animals. The present study aimed to evaluate the feasibility of transoral surgical lung biopsy (TOLB) in 10 canines. Methods. Through an incision over the vestibulum oris, a homemade metal tube was introduced into the thoracic cavity under endoscopic guidance and used as a working channel of surgical lung biopsy. TOLB was performed on the predetermined lung lobe by using an electrocautery loop and endoscopic grasper. Results. Successful surgical lung biopsy was achieved in 8 of 10 animals in a mean time of 132 minutes (range 130-190 minutes). There were no major intraoperative or postoperative complications, and all animals survived for 2 weeks after surgery. Autopsy showed no evidence of vital structure injury, mediastinitis, or empyema. Conclusions. TOLB was demonstrated to be safe and feasible in a canine model.
Joint replacement in 131 painful osteoarthritic and post-traumatic distal interphalangeal joints
Authors: Sierakowski A. , Zweifel C. , Sirotakova M. , Sauerland S. , Elliot D.
Published: October 2011

This study reports the results of Swanson replacement of 131 DIP joints for painful osteoarthritis and two for ongoing pain after injury. Thirty-seven arthroplasties (28 patients) were carried out with extensor tendon division and repair, and postoperative immobilization for 8 weeks. Ninety-four (60 patients) were then carried out without tendon division, allowing immediate mobilization. At assessment after a mean period of 57 months, the mean postoperative range of movement was 39°, and the mean extensor lag was 11°, with significant improvement of both in both operative groups. The severity of pain improved significantly following surgery. All but one patient were satisfied with the cosmetic result of replacement. The overall complication rate was 7/131(5%). Three joints developed cellulitis and one developed osteomyelitis, requiring subsequent fusion. Two joints had subsequent fusions because of persistent lateral instability and marked ulnar deviation and one had a persistent mallet-type deformity, corrected by tendon shortening.
Endotoxin·albumin complexes transfer endotoxin monomers to MD-2 resulting in activation of TLR4
Authors: Esparza Gregory A , Teghanemt Athmane , Zhang DeSheng , Gioannini Theresa L , Weiss Jerrold P
Published: October 2011

Response to Gram-negative bacteria (GNB) is partially mediated by the recognition of GNB-derived endotoxin by host cells. Potent host response to endotoxin depends on the sequential interaction of endotoxin with lipopolysaccharide binding protein (LBP), CD14, MD-2 and TLR4. While CD14 facilitates the efficient transfer of endotoxin monomers to MD-2 and MD-2·TLR4, activation of MD-2·TLR4 can occur in the absence of CD14 through an unknown mechanism. Here, we show that incubation of purified endotoxin (E) aggregates (Eagg, M r ≥ 20 million) in PBS with ≥ 0.1% albumin in the absence of divalent cations Ca2+ and Mg2+, yields E·albumin complexes ( M r ∼70,000). E·albumin transfers E monomers to sMD-2 or sMD-2·TLR4 ectodomain (TLR4ecd) with a ‘ Kd’ of ∼4 nM and induces MD-2·TLR4-dependent, CD14-independent cell activation with a potency only 10-fold less than that of monomeric E·CD14 complexes. Our findings demonstrate, for the first time, a mechanistic basis for delivery of endotoxin monomers to MD-2 and for activation of TLR4 that is independent of CD14.
Goal-Directed Fluid Resuscitation
Authors: Choukalas Christopher G.
Published: October 2011

Fluid resuscitation and management are integral to critical care. Management strategies for common conditions in the intensive care unit are often in conflict. Evidence supports a goal-directed approach to fluid administration, and a number of goals have been evaluated. Concepts and evidence related to hemodynamic and metabolic goals are reviewed.
Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms
Authors: Malcovati Luca , Papaemmanuil Elli , Bowen David T. , Boultwood Jacqueline , Della Porta Matteo G. , Pascutto Cristiana , Travaglino Erica , Groves Michael J. , Godfrey Anna L. , Ambaglio Ilaria , Gallì Anna , Da Vià Matteo C. , Conte Simona , Tauro Sudhir , Keenan Norene , Hyslop Ann , Hinton Jonathan , Mudie Laura J. , Wainscoat James S. , Futreal P. Andrew , Stratton Michael R. , Campbell Peter J. , Hellström-Lindberg Eva , Cazzola Mario ,   on behalf of the Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium and of the Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative
Published: October 2011

In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.
IFN-γ-inducible protein of 10 kDa upregulates the effector functions of eosinophils through β2integrin and CXCR3
Authors: Takaku Yotaro , Nakagome Kazuyuki , Kobayashi Takehito , Hagiwara Koichi , Kanazawa Minoru , Nagata Makoto
Published: October 2011

Background

Eosinophils play an important role in the pathogenesis of bronchial asthma and its exacerbation. Recent reports suggest the involvement of IFN-γ-inducible protein of 10 kDa (IP-10) in virus-induced asthma exacerbation. The objective of this study was to examine whether CXCR3 ligands including IP-10 modify the effector functions of eosinophils.

Methods

Eosinophils isolated from the blood of healthy donors were stimulated with CXCR3 ligands and their adhesion to rh-ICAM-1 was then measured using eosinophil peroxidase assays. The generation of eosinophil superoxide anion (O2-) was examined based on the superoxide dismutase-inhibitable reduction of cytochrome C. Eosinophil-derived neurotoxin (EDN) release was evaluated to determine whether CXCR3 ligands induced eosinophil degranulation. Cytokine and chemokine production by eosinophils was examined using a Bio-plex assay.

Results

Eosinophil adhesion to ICAM-1 was significantly enhanced by IP-10, which also significantly induced eosinophil O2-generation in the presence of ICAM-1. Both the enhanced adhesion and O2-generation were inhibited by an anti-β2integrin mAb or an anti-CXCR3 mAb. Other CXCR3 ligands, such as monokine induced by IFN-γ (Mig) and IFN-inducible T cell α chemoattractant (I-TAC), also induced eosinophil adhesion and O2-generation in the presence of ICAM-1. IP-10, but not Mig or I-TAC, increased the release of EDN. IP-10 increased the production of a number of cytokines and chemokines by eosinophils.

Conclusions

These findings suggest that CXCR3 ligands such as IP-10 can directly upregulate the effector functions of eosinophils. These effects might be involved in the activation and infiltration of eosinophils in the airway of asthma, especially in virus-induced asthma exacerbation.
Leveraging domain information to restructure biological prediction
Authors: Nan Xiaofei , Fu Gang , Zhao Zhengdong , Liu Sheng , Patel Ronak Y , Liu Haining , Daga Pankaj R , Doerksen Robert J , Dang Xin , Chen Yixin , Wilkins Dawn
Published: October 2011

Background

It is commonly believed that including domain knowledge in a prediction model is desirable. However, representing and incorporating domain information in the learning process is, in general, a challenging problem. In this research, we consider domain information encoded by discrete or categorical attributes. A discrete or categorical attribute provides a natural partition of the problem domain, and hence divides the original problem into several non-overlapping sub-problems. In this sense, the domain information is useful if the partition simplifies the learning task. The goal of this research is to develop an algorithm to identify discrete or categorical attributes that maximally simplify the learning task.

Results

We consider restructuring a supervised learning problem via a partition of the problem space using a discrete or categorical attribute. A naive approach exhaustively searches all the possible restructured problems. It is computationally prohibitive when the number of discrete or categorical attributes is large. We propose a metric to rank attributes according to their potential to reduce the uncertainty of a classification task. It is quantified as a conditional entropy achieved using a set of optimal classifiers, each of which is built for a sub-problem defined by the attribute under consideration. To avoid high computational cost, we approximate the solution by the expected minimum conditional entropy with respect to random projections. This approach is tested on three artificial data sets, three cheminformatics data sets, and two leukemia gene expression data sets. Empirical results demonstrate that our method is capable of selecting a proper discrete or categorical attribute to simplify the problem, i.e., the performance of the classifier built for the restructured problem always beats that of the original problem.

Conclusions

The proposed conditional entropy based metric is effective in identifying good partitions of a classification problem, hence enhancing the prediction performance.
Comparison of static immersion and intravenous injection systems for exposure of zebrafish embryos to the natural pathogen Edwardsiella tarda
Authors: van Soest Joost J , Stockhammer Oliver W , Ordas Anita , Bloemberg Guido V , Spaink Herman P , Meijer Annemarie H
Published: October 2011

Background

The zebrafish embryo is an important in vivo model to study the host innate immune response towards microbial infection. In most zebrafish infectious disease models, infection is achieved by micro-injection of bacteria into the embryo. Alternatively, Edwardsiella tarda, a natural fish pathogen, has been used to treat embryos by static immersion. In this study we used transcriptome profiling and quantitative RT-PCR to analyze the immune response induced by E. tarda immersion and injection.

Results

Mortality rates after static immersion of embryos in E. tarda suspension varied between 25-75%, while intravenous injection of bacteria resulted in 100% mortality. Quantitative RT-PCR analysis on the level of single embryos showed that expression of the proinflammatory marker genes il1b and mmp9 was induced only in some embryos that were exposed to E. tarda in the immersion system, whereas intravenous injection of E. tarda led to il1b and mmp9 induction in all embryos. In addition, microarray expression profiles of embryos subjected to immersion or injection showed little overlap. E. tarda-injected embryos displayed strong induction of inflammatory and defense genes and of regulatory genes of the immune response. E. tarda-immersed embryos showed transient induction of the cytochrome P450 gene cyp1a. This gene was also induced after immersion in Escherichia coli and Pseudomonas aeruginosa suspensions, but, in contrast, was not induced upon intravenous E. tarda injection. One of the rare common responses in the immersion and injection systems was induction of irg1l, a homolog of a murine immunoresponsive gene of unknown function.

Conclusions

Based on the differences in mortality rates between experiments and gene expression profiles of individual embryos we conclude that zebrafish embryos cannot be reproducibly infected by exposure to E. tarda in the immersion system. Induction of il1b and mmp9 was consistently observed in embryos that had been systemically infected by intravenous injection, while the early transcriptional induction of cyp1a and irg1l in the immersion system may reflect an epithelial or other tissue response towards cell membrane or other molecules that are shed or released by bacteria. Our microarray expression data provide a useful reference for future analysis of signal transduction pathways underlying the systemic innate immune response versus those underlying responses to external bacteria and secreted virulence factors and toxins.
Co-production of GroELS discriminates between intrinsic and thermally-induced recombinant protein aggregation during substrate quality control
Authors: Platas Gemma , Rodríguez-Carmona Escarlata , García-Fruitós Elena , Cano-Garrido Olivia , Villaverde Antonio
Published: October 2011

Background

The effects and effectiveness of the chaperone pair GroELS on the yield and quality of recombinant polypeptides produced in Escherichia coli are matter of controversy, as the reported activities of this complex are not always consistent and eventually indicate undesired side effects. The divergence in the reported data could be due, at least partially, to different experimental conditions in independent research approaches.

Results

We have then selected two structurally different model proteins (namely GFP and E. coli β-galactosidase) and two derived aggregation-prone fusions to explore, in a systematic way, the eventual effects of GroELS co-production on yield, solubility and conformational quality. Host cells were cultured at two alternative temperatures below the threshold at which thermal stress is expected to be triggered, to minimize the involvement of independent stress factors.

Conclusions

From the analysis of protein yield, solubility and biological activity of the four model proteins produced alone or along the chaperones, we conclude that GroELS impacts on yield and quality of aggregation-prone proteins with intrinsic determinants but not on thermally induced protein aggregation. No effective modifications of protein solubility have been observed, but significant stabilization of small (encapsulable) substrates and moderate chaperone-induced degradation of larger (excluded) polypeptides. These findings indicate that the activities of this chaperone pair in the context of actively producing recombinant bacteria discriminate between intrinsic and thermally-induced protein aggregation, and that the side effects of GroELS overproduction might be determined by substrate size.
Randomized Phase II Study of Dulanermin in Combination With Paclitaxel, Carboplatin, and Bevacizumab in Advanced Non–Small-Cell Lung Cancer
Authors: Soria Jean-Charles , Márk Zsuzsanna , Zatloukal Petr , Szima Barna , Albert István , Juhász Erzsébet , Pujol Jean-Louis , Kozielski Jerzy , Baker Nigel , Smethurst Dominic , Hei Yong-jiang , Ashkenazi Avi , Stern Howard , Amler Lukas , Pan Yang , Blackhall Fiona
Published: October 2011

Purpose

To evaluate the efficacy and safety of dulanermin combined with paclitaxel and carboplatin (PC) and bevacizumab (PCB) as first-line treatment for advanced or recurrent non–small-cell lung cancer (NSCLC).

Patients and Methods

Patients with squamous NSCLC and/or CNS metastases received PC every 3 weeks alone (arm 1) or with dulanermin 8 mg/kg for 5 days (arm 2). Patients with nonsquamous NSCLC received PCB alone (arm 3) or with dulanermin 8 mg/kg for 5 days (arm 4) or 20 mg/kg for 2 days (arm 5). The primary end point was the objective response rate (ORR).

Results

Overall, 213 patients were randomly assigned (arm 1, n = 41; arm 2, n = 39; arm 3, n = 42; arm 4, n = 40; arm 5, n = 41). The ORR in arms 1 to 5 was 39% (95% CI, 24% to 56%), 38% (95% CI, 24% to 54%), 50% (95% CI, 35% to 65%), 40% (95% CI, 25% to 56%), and 40% (95% CI, 25% to 56%), respectively. The odds ratio for ORR was 1.04 (P = 1.000) for arm 1 versus arm 2, 1.53 (P = .391) for arm 3 and versus arm 4, and 1.53 (P = .391) for arm 3 versus arm 5. The most common grade ≥ 3 adverse events were neutropenia, asthenia, anemia, thrombocytopenia, and hemoptysis. Of 161 available serum samples, a trend toward increased caspase-cleaved cytokeratin-18 was observed after dulanermin treatment in cycles 1 and 2. Among 84 patients evaluated for GalNT14 expression, there was a trend toward favorable progression-free survival and overall survival with dulanermin treatment in those with high GalNT14 expression.

Conclusion

The addition of dulanermin to PC and PCB did not improve outcomes in unselected patients with previously untreated advanced or recurrent NSCLC.
The Effect of Hypoxia and Work Intensity on Insulin Resistance in Type 2 Diabetes
Authors: Mackenzie R. , Elliott B. , Maxwell N. , Brickley G. , Watt P.
Published: October 2011

Context:

Hypoxia and muscle contraction stimulate glucose transport in vitro. We have previously demonstrated that exercise and hypoxia have an additive effect on insulin sensitivity in type 2 diabetics.

Objectives:

Our objective was to examine the effects of three different hypoxic/exercise (Hy Ex) trials on glucose metabolism and insulin resistance in the 48 h after acute hypoxia in type 2 diabetics.

Design, Participants, and Interventions:

Eight male type 2 diabetics completed 60 min of hypoxic [mean (sem) O2 = ∼14.7 (0.2)%] exercise at 90% of lactate threshold [Hy Ex60; 49 (1) W]. Patients completed an additional two hypoxic trials of equal work, lasting 40 min [Hy Ex40; 70 (1) W] and 20 min [Hy Ex20; 140 (12) W].

Main Outcome Measures:

Glucose rate of appearance and rate of disappearance were determined using the one-compartment minimal model. Homeostasis models of insulin resistance (HOMAIR), fasting insulin resistance index and β-cell function (HOMAβ-cell) were calculated at 24 and 48 h after trials.

Results:

Peak glucose rate of appearance was highest during Hy Ex20 [8.89 (0.56) mg/kg · min, P < 0.05]. HOMAIR and fasting insulin resistance index were improved in the 24 and 48 h after Hy Ex60 and Hy Ex40 (P < 0.05). HOMAIR decreased 24 h after Hy Ex20 (P < 0.05) and returned to baseline values at 48 h.

Conclusions:

Moderate-intensity exercise in hypoxia (Hy Ex60 and Hy Ex40) stimulates acute- and moderate-term improvements in insulin sensitivity that were less apparent in Hy Ex20. Results suggest that exercise duration and not total work completed has a greater influence on acute and moderate-term glucose control in type 2 diabetics.
The impact of facial lipoatrophy treatment with polymethyl methacrylate in AIDS patients as measured by four quality-of-life questionnaires
Authors: Warde M , Gragnani A , Gomes H , Hochman B , Ferreira L M
Published: October 2011

Life-expectancy increased in patients infected with HIV/AIDS with the advent of highly active antiretroviral therapy (ART). Facial lipoatrophy is a common complication in these patients, eventually leading to stigma, segregation and a negative impact in quality of life (QOL). We measured the impact of the treatment of facial lipoatrophy with polymethyl methacrylate (PMMA) in the QOL of patients with HIV/AIDS by using four questionnaires that address QOL. Forty consecutive patients on ART referred for facial lipoatrophy treatment were enrolled in this study. The first 20 were allocated to the intervention group and were treated with tissue augmentation with PMMA. The other 20 were allocated to the control group, which received treatment only after six months. At baseline, four questionnaires were applied to all patients in both groups and again after six months. The variation in scores within the control group for all domains of all four instruments was significantly better when compared with that within the control group. We detected improvement in the QOL of patients with HIV/AIDS and facial lipoatrophy when they were treated with PMMA.
Assessing effectiveness and cost-effectiveness of concurrency reduction for HIV prevention
Authors: Enns E A , Brandeau M L , Igeme T K , Bendavid E
Published: October 2011

We estimated the effectiveness and cost-effectiveness of changes in concurrent sexual partnerships in reducing the spread of HIV in sub-Saharan Africa. Using data from Swaziland, Tanzania, Uganda and Zambia, we estimated country-specific concurrency behaviour from sexual behaviour survey data on the number of partners in the past 12 months, and we developed a network model to compare the impact of three behaviour changes on the HIV epidemic: (1) changes in concurrent partnership patterns to strict monogamy; (2) partnership reduction among those with the greatest number of partners; and (3) partnership reduction among all individuals. We estimated the number of new HIV infections over 10 years and the cost per infection averted. Given our assumptions and model structure, we find that reducing concurrency among high-risk individuals averts the most infections and increasing monogamy the least (11.7% versus 8.7% reduction in new infections, on average, for a 10% reduction in concurrent partnerships). A campaign that costs US$1 per person annually is likely cost-saving if it reduces concurrency by 9% on average, given our baseline estimates of concurrency. In sensitivity analysis, the rank ordering of behaviour change scenarios was unaffected by potential over-estimation of concurrency, though the number of infections averted decreased and the cost per HIV infection averted increased. Concurrency reduction programmes may be effective and cost-effective in reducing HIV incidence in sub-Saharan Africa if they can achieve even modest impacts at similar costs to past mass media campaigns in the region. Reduced concurrency among high-risk individuals appears to be most effective in reducing HIV incidence, but concurrency reduction in other risk groups may yield nearly as much benefit.