bluuebunny/crossref_metadata_2025 huggingface dataset:
Biometrical modelling in genetics: are complex traits too complex?
Authors: Gjessing Håkon K. , Lie Rolv Terje
Published: September 2007

The field of traditional biometrical genetics uses mixed-effects models to quantify the influence of genetic and environmental factors on a biological trait, based essentially on estimating within-family trait correlations. Such analyses provide a useful preview of what may be discovered with the emerging full-scale genotyping strategies. However, biometrical analyses require unrealistically large sample sizes to obtain a reasonable precision, particularly for dichotomous traits. In addition, it may be very difficult to separate genetic and environmental effects because environmental correlations are poorly understood. We illustrate these and other difficulties using population-based cousins and nuclear family data for birth weight, collected from the Medical Birth Registry of Norway.
Bayesian latent variable modelling of multivariate spatio-temporal variation in cancer mortality
Authors: Tzala Evangelia , Best Nicky
Published: September 2007

In this article, three alternative Bayesian hierarchical latent factor models are described for spatially and temporally correlated multivariate health data. The fundamentals of factor analysis with ideas of space— time disease mapping to provide a flexible framework for the joint analysis of multiple-related diseases in space and time with a view to estimating common and disease-specific trends in cancer risk are combined. The models are applied to area-level mortality data on six diet-related cancers for Greece over the 20-year period from 1980 to 1999. The aim of this study is to uncover the spatial and temporal patterns of any latent factor(s) underlying the cancer data that could be interpreted as reflecting some aspects of the habitual diet of the Greek population.
Wall Street Reaction to Women in IPOs
Authors: Welbourne Theresa M. , Cycyota Cynthia S. , Ferrante Claudia J.
Published: September 2007

The authors examine the effect of having women on the top management teams of initial public offering (IPO) firms on the organizations' short- and long-term financial performance. Looking at three different samples, the authors found that trend data indicated IPO firms were gaining in the number of women they employ in their top management teams. Using data from 534 IPO firms, results suggest one reason why the trend is growing; women appear to have a positive association with the firms' short-term performance (Tobin's Q, which is market price to book value per share), 3-year stock price growth, and growth in earnings per share. Possible reasons for the positive effect of women on performance include better innovation and problem-solving processes in more diverse top management teams and the possibility that, on average, the women on these teams are higher performers than are the men on the same teams.
Mass mobilization and the struggle over the youth
Authors: Valentin Karen
Published: September 2007

Based on ethnographic fieldwork among young people in Hanoi, the article explores the role of Ho Chi Minh Communist Youth Union, the youth branch of the Communist Party of Vietnam, in the formal organization of youth in contemporary, urban Vietnam. The aim of the article is to examine the institutional paradox of the organization and the way in which inherent processes of social in– and exclusion are related to the nation–building project in which the youth is attributed a key role. I argue that while the practices and logics of the Youth Union imply a sorting out of young people at the individual level, youth as a social and generational category is a significant object of symbolic investment for political leaders.
Distribution channels for events: Supply and demand-side perspectives
Authors: Smith Karen A.
Published: September 2007

Distribution involves the dissemination of information, the means of booking and purchase, and product bundling or packaging. In an increasingly competitive market place, special events, like other tourism products, require an effective distribution strategy to reach their target tourist and local markets. This article systematically integrates data from interviews with events organizers and a survey of attendees at four events in Wellington, one of New Zealand's main event tourism destinations. The complexity of event distribution channels is influenced by the event's target market, capacity, partnership relationships, and other factors. Free events have simple distribution channels focused on disseminating information; channels for ticketed events are more complex. There is limited bundling of event tourism packages and a number of barriers exist to their further development in this destination.
A profile of the fall foliage tourism market
Authors: Spencer Daniel M. , Holecek Donald F.
Published: September 2007

Although fall color touring has long been pursued by the traveling public and promoted by destinations, it has been the subject of extraordinarily little research. This article helps fill this knowledge gap and assists destination marketers seeking to more effectively attract this market niche. Analyses of data from a telephone survey of households in the Great Lakes region indicate that marketers who wish to attract fall color tourists should promote a wide range of ancillary activities in addition to foliage viewing and target primarily older individuals in nearby markets.
Predictors of Homelessness among Older Adults in New York City
Authors: Shinn Marybeth , Gottlieb Jamie , Wett Jessica L. , Bahl Ajay , Cohen Arnold , Baron Ellis Deborah
Published: September 2007

We interviewed 61 housed and 79 homeless adults aged 55 and over about disability; economic, human and social capital; and stressful life events prior to becoming homeless. Over half of the homeless group had previously led conventional lives. Human capital, social capital and life events were more important than disability or economic capital in predicting homelessness. The homeless adults were younger, more likely to be male and better educated than housed adults, but had shorter job tenure and fewer social ties. Homeless adults faced multiple, cascading risks, including job loss and housing loss. Implications for prevention are discussed.
Just Thinking about It
Authors: Fitzpatrick Kevin M. , Irwin Jay A. , LaGory Mark , Ritchey Ferris
Published: September 2007

Suicide ideation is a sensitive indicator of personal well-being. While ideation occurs in roughly 3 percent of the US population annually, in this study rates are 10 times higher. This article explores the role of social capital in mediating negative life circumstances on ideation for a sample of 161 homeless adults in a mid-sized Southern US metropolitan area. Our results imply that social capital does not function the same way for homeless persons as it does for the general population. This finding supports growing evidence that social capital's much touted benefits for personal well-being may not apply to disadvantaged populations.
Expert Knowledge, Cognitive Polyphasia and Health
Authors: Renedo Alicia , Jovchelovitch Sandra
Published: September 2007

This article develops a social representational approach to understanding expert knowledge and its relation to health. Research with homelessness professionals (HPs) working in the UK voluntary sector shows that expert definitions of homelessness can either undermine or enhance the health of the homeless. Guided by the concepts of social representations and cognitive polyphasia, the analysis reveals a contradictory field of knowledge, which reflects the struggle of professionals to sustain a humanizing approach and resist the pressures of statutory agendas. We conclude pointing to the need of recognizing the impact of professional's knowledge on the health and care policies for the homeless.
Evidence That Theory of Planned Behaviour Variables Mediate the Effects of Socio-demographic Variables on Homeless People's Participation in Service Programmes
Authors: Christian Julie , Armitage Christopher J. , Abrams Dominic
Published: September 2007

This article reports findings from two studies ( N = 88, N = 100) using Ajzen's theory of planned behaviour (TPB) to predict homeless people's uptake of service programmes. Study 1 was conducted with an opportunity sample whereas Study 2 employed a representative sample. Both studies provide support for the application of the TPB, and demonstrate that the effects of demographic characteristics on behaviour were mediated by TPB variables. The discussion focuses on the role of attitudinal and normative components in actual behaviour, and on the potential role of social normative processes and stigmatization in homeless people's uptake of services.
HIV Risk Reduction in a Nurse Case-managed TB and HIV Intervention among Homeless Adults
Authors: Schumann Anja , Nyamathi Adeline , Stein Judith A.
Published: September 2007

This study evaluated a six-month nurse case-managed intervention against a standard care control program among 295 sheltered homeless adults from Los Angeles, USA. The primary aim of the intervention was encouraging latent tuberculosis infection treatment completion. The secondary aim was reducing HIV risk, the focus of this report. A longitudinal path model revealed that the intervention impacted cognitive factors of AIDS Knowledge, Perceived AIDS Risk and Self-efficacy for Condom Use, but did not impact substance use and risky sexual behaviors. The dual intervention program for HIV and TB provided promising synergistic effects by targeting risk factors common to both infections.
Why modest geographic effects for asthma? Pharmaceutical treatment as neutralizing mechanism
Authors: Timmermans Stefan
Published: September 2007

Research on geographic health effects has been greatly advanced with the development of multilevel statistical techniques but less is known about the possible mechanisms by which social and geographical environments may affect physical health. In spite of well-established relationships between asthma etiology and the broader living environments, multilevel research on asthma shows at best marginal geographic effects. Based on in-depth, open-ended interviews with 50 caretakers of school-age children (6—12 years) diagnosed with asthma living in two different communities, this article elucidates mechanisms by which neighborhood effects may be neutralized. Caretakers of children with mild, controllable asthma attempt to create asthma-safe zones by administering long-term control and quick-relief medication, by removing indoor environmental triggers and by avoiding dangerous environments. At home, school and outdoors, the key strategy to control asthma was the use of relatively effective and accessible medications. Children with severe asthma did not benefit as much from medications but it was unclear that different communities made a difference in asthma care.
`That's just the cesspool where they dump all the trash': exploring working class men's perceptions and experiences of social capital and health
Authors: Dolan Alan
Published: September 2007

This article explores issues relating to the concept of social capital which has been become an important explanation for inequalities in health. It is based on an analysis of in-depth interviews with working class men living in two contrasting socio-economic areas — one relatively disadvantaged and one advantaged. It highlights the role of different community contexts in the nature and extent of local social capital. In particular, it demonstrates how de-industrialization and economic change as well as material deprivation and a perceived dis-investment in local communities impacted on the men's levels of social capital. Analysis also shows the ways in which gender mediates the processes through which social capital is developed and accessed as a personal and social resource, and how the norms and values associated with working class masculinities appeared to preclude the men from building supportive health-enhancing relationships with others in their community. The prominence of social capital has focused attention on the subjective dimensions of community life as potential determinants of health. This article has, therefore, sought to contribute to this field by widening our understanding about the relationship between social capital, gender and health.
A critical realist approach to understanding and evaluating heart health programmes
Authors: Clark Alexander M. , MacIntyre Paul D. , Cruickshank Justin
Published: September 2007

Secondary prevention programmes for Coronary Heart Disease (CHD) aim to reduce cardiovascular risks and promote health in people with heart disease. Though programmes have been associated with health improvements in study populations, access to programmes remains low, and quality and effectiveness is highly variable. Current guidelines propose significant modifications to programmes, but existing research provides little insight into why programme effectiveness varies so much. Drawing on a critical realist approach, this article argues that current research has been based on an impoverished ontology, which has elements of positivism, does not explore the social determinants of health or the effects on outcomes of salient contextual factors, and thereby fails to account for programme variations. Alternative constructivist approaches are also weak and lacking in clinical credibility. An alternative critical realist approach is proposed that draws on the merits of subjectivist and objectivist approaches but also reflects the complex interplay between individual, programme-related, socio-cultural and organizational factors that influence health outcomes in open systems. This approach embraces measurement of objective effectiveness but also examines the mechanisms, organizational and contextual-related factors causing these outcomes. Finally, a practical example of how a critical realist approach can guide research into secondary prevention programmes is provided.
The implementation of youth imprisonment and constitutional law in Germany
Authors: Dünkel Frieder , van Zyl Smit Dirk
Published: September 2007

This article considers the impact that constitutional law can have on penal policy through an analysis of current developments in the law governing youth prisons in Germany. It sketches the emergence of constitutional guidelines for the development of German prison law generally and then pays close attention to a recent decision of the German Federal Constitutional Court on the constitutionality of current provisions on the implementation of youth imprisonment. The implications of the judgment of the Court for future German legislation in this area are outlined. Particular attention is paid to the emphasis that the legislator is expected to place on international minimum standards and to the role research on treatment plays in setting limits to legislative discretion. The conclusion considers the wider implications for penal policy of combining a formal rule that constitutionally guaranteed rights of prisoners can only be restricted by primary legislation, with substantive constitutional requirements for the objectives of penal legislation and for how these objectives should be met. It argues that such a rule is potentially applicable not only in Germany but also in other countries with similar constitutional traditions.
Youth sex offenders in court
Authors: Bouhours Brigitte , Daly Kathleen
Published: September 2007

Sexual offending by young people is increasingly viewed as a social problem that requires a strong response, but there is little research on the legal treatment of youthful sex offenders. On the one hand, these youths may be viewed as potential future sex offenders; on the other hand, because of their youth and immaturity they may be considered more reformable than adults and their behaviour more excusable. This article builds on an archival study of 385 sexual offence cases, which were disposed in court and by conference and formal caution, in South Australia from 1995 to 2001. Drawing on the transcripts of 55 cases sentenced by judges (i.e. the most legally serious offences), we analyse sentencing discourses and outcomes using both the explicit and latent content of the sentencing remarks. Specifically, we explore the judges' orientations and aims when sentencing adolescent sex offenders, how judges reconcile the seriousness of offending and the youthfulness of offenders and how they balance the competing interests of victims and offenders. Two major findings emerge. First, the cases fell in a three-way typology patterned by the victims' age, the context of the offence and the offender's criminal history. Second, our study suggests that while youth court judges consider sexual offending against children as very serious and are concerned by future offending, they do not adopt a punitive approach, but rather a therapeutic and rehabilitative perspective at sentencing.
Journalistic moral engagement
Authors: Aucoin James L.
Published: September 2007

The narrative strategies of mid-20th-century investigative journalists who published in leftist American magazines expanded the kinds of truths that could be told. Using specific cases of institutional failure, the journalists maneuvered the message through a variety of narrative techniques, including direct advocacy of alternatives, to the larger question of capitalism's morality. Their style offers an alternative model for American investigative journalists.
Multi-level assessments for better targeting of the poor
Authors: Fritzen Scott A. , Brassard Caroline
Published: September 2007

This paper examines how various poverty assessment modalities serve to strengthen the governance capacities necessary to target the poor. Large-scale surveys and qualitative, ‘bottom-up’ assessments both have shortcomings in this regard. A ‘multi-level’ synthesis would in theory link a unified indicator framework (such as the Millennium Development Goals) to localized situation assessments and facilitate multi-sectoral efforts to target the poor. Case studies of actual efforts to do this from Vietnam and Burma highlight the way in which the governance context of a country must be taken into account when designing such efforts.
An analytic approach to structuring co–management of community forests in Cameroon
Authors: Brown H. Carolyn Peach , Lassoie James P. , Wolf Steven A.
Published: September 2007

While decentralization is a prominent theme in contemporary natural resource policy and management discourse, questions have been raised concerning the sustainability of participatory approaches. Drawing on theoretical and empirical research on common pool resource management and participation, we develop a framework to evaluate community–level stakeholders’ potential suitability for engagement in co–management. Four criteria are assessed: stake in the resource, discount rate, social capital and capacity (leadership, organizational, enforcement of rules and knowledge). Inclusion of local actors who fit the framework in a governance arrangement could lead to more sustainable outcomes. We tested this screening strategy by assessing potential organizational partners for comanagement of non–wood forest products in community forests in Cameroon.
Zero-inflated generalized Poisson models with regression effects on the mean, dispersion and zero-inflation level applied to patent outsourcing rates
Authors: Czado Claudia , Erhardt Vinzenz , Min Aleksey , Wagner Stefan
Published: September 2007

This paper focuses on an extension of zero-inflated generalized Poisson (ZIGP) regression models for count data. We discuss generalized Poisson (GP) models where dispersion is modelled by an additional model parameter. Moreover, zero-inflated models, in which overdispersion is assumed to be caused by an excessive number of zeros, are discussed. In addition to ZIGP models considered by several authors, we now allow for regression on the overdispersion and zero-inflation parameters. Consequently, we propose tools for an exploratory data analysis on the dispersion and zero-inflation level. An application dealing with outsourcing of patent filing processes will be used to compare these nonnested models. The model parameters are fitted by maximum likelihood using our R package ‘ZIGP’ available on the Comprehensive RArchive Network (CRAN). Asymptotic normality of the Maximum Likelihood (ML) estimates in this non-exponential setting is proven. Standard errors are estimated using the asymptotic normality of the estimates. Appropriate exploratory data analysis tools are developed. Also, a model comparison using Akaike Information Criterion (AIC) statistics and Vuong tests is carried out. For the given data, our extended ZIGP regression model will prove to be superior over GP and zero-inflated Poisson (ZIP) models, and even over ZIGP models, with constant overall dispersion and zero-inflation parameters demonstrating the usefulness of our proposed extensions.
Modelling spatially correlated survival data for individuals with multiple cancers
Authors: Diva Ulysses , Banerjee Sudipto , Dey Dipak K
Published: September 2007

Epidemiologists and biostatisticians investigating spatial variation in diseases are often interested in estimating spatial effects in survival data, where patients are monitored until their time to failure (for example, death, relapse). Spatial variation in survival patterns often reveals underlying lurking factors that could assist public health professionals in their decision–making process to identify regions requiring attention. The Surveillance Epidemiology and End Results (SEER) database of the National Cancer Institute provides a fairly sophisticated platform for exploring novel approaches in modelling cancer survival, particularly with models accounting for spatial clustering and variation. Modelling survival data for patients with multiple cancers poses unique challenges in itself and in capturing the spatial associations of the different cancers. This paper develops the Bayesian hierarchical survival models for capturing spatial patterns within the framework of proportional hazard. Spatial variation is introduced in the form of county–cancer level frailties. The baseline hazard function is modelled semiparametrically using mixtures of beta distributions. We illustrate with data from the SEER database, perform model checking and comparison among competing models, and discuss implementation issues.
Personal Growth and Spirituality in Leadership Development
Authors: Luckcock Tim
Published: September 2007

This article is written from the perspective of a practising headteacher in the context of the Leadership Programme for Serving Headteachers and addresses the issue of how such training might be appropriated. It seeks to inquire analytically and critically into the bias of the programme, with a special interest in the topic of personal growth and spirituality in leadership development. First, it advocates deploying Hodgkinson's taxonomy of administrative process as a means of analysing the administrative bias of LPSH in relation to the official headteacher characteristics it legitimates. This leads into deeper investigation of the ideological bias of LPSH in relation to the construction of self. Finally, it takes an ambivalent stance on personal growth in professional development, situating it negatively in relation to the tendency of LPSH to promote the dominance of only one personality-type and positively in relation to appreciating spirituality in leadership.
Systemic Leadership for Schools and the Significance of Systemic Authorization
Authors: James Chris , Connolly Michael , Dunning Gerald , Elliott Tony
Published: September 2007

The purpose of this article is to make the case for a broader perspective on school leadership and school-environment interrelationships and to develop the concept of systemic leadership for schools and the related notion of systemic authorization. The article explores the background to the concept and relevant aspects of the conceptualization, which are: the primary task, leadership and task-related roles, and the system. We draw on research we have recently completed into the nature of primary schools where the level of student attainment in national test scores is high despite the students experiencing considerable socio-economic disadvantage. The schools we studied sought and received considerable support, validation and valuing from the wider system that provided leadership and authorization for the schools with beneficial outcomes. Importantly, this leadership and authorization was reciprocal in that the schools responded similarly to those in their system.
Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells
Authors: Duluc Dorothée , Delneste Yves , Tan Fang , Moles Marie-Pierre , Grimaud Linda , Lenoir Julien , Preisser Laurence , Anegon Ignacio , Catala Laurent , Ifrah Norbert , Descamps Philippe , Gamelin Erick , Gascan Hugues , Hebbar Mohamed , Jeannin Pascale
Published: September 2007

Tumor-associated macrophages (TAMs), the most abundant immunosuppressive cells in the tumor microenvironment, originate from blood monocytes and exhibit an IL-10highIL-12low M2 profile. The factors involved in TAM generation remain unidentified. We identify here leukemia inhibitory factor (LIF) and IL-6 as tumor microenvironmental factors that can promote TAM generation. Ovarian cancer ascites switched monocyte differentiation into TAM-like cells that exhibit most ovarian TAM functional and phenotypic characteristics. Ovarian cancer ascites contained high concentrations of LIF and IL-6. Recombinant LIF and IL-6 skew monocyte differentiation into TAM-like cells by enabling monocytes to consume monocyte–colony-stimulating factor (M-CSF). Depletion of LIF, IL-6, and M-CSF in ovarian cancer ascites suppressed TAM-like cell induction. We extended these observations to different tumor-cell line supernatants. In addition to revealing a new tumor-escape mechanism associated with TAM generation via LIF and IL-6, these findings offer novel therapeutic perspectives to subvert TAM-induced immunosuppression and hence improve T-cell–based antitumor immunotherapy efficacy.
Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease
Authors: Morris Claudia R. , Suh Jung H. , Hagar Ward , Larkin Sandra , Bland D. Anton , Steinberg Martin H. , Vichinsky Elliott P. , Shigenaga Mark , Ames Bruce , Kuypers Frans A. , Klings Elizabeth S.
Published: September 2007

Erythrocyte glutathione depletion has been linked to hemolysis and oxidative stress. Glutamine plays an additional antioxidant role through preservation of intracellular nicotinamide adenine dinucleotide phosphate (NADPH) levels, required for glutathione recycling. Decreased nitric oxide (NO) bioavailability, which occurs in the setting of increased hemolysis and oxidative stress, contributes to the pathogenesis of pulmonary hypertension (PH) in sickle cell disease (SCD). We hypothesized that altered glutathione and glutamine metabolism play a role in this process. Total glutathione (and its precursors) and glutamine were assayed in plasma and erythrocytes of 40 SCD patients and 9 healthy volunteers. Erythrocyte total glutathione and glutamine levels were significantly lower in SCD patients than in healthy volunteers. Glutamine depletion was independently associated with PH, defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. The ratio of erythrocyte glutamine:glutamate correlated inversely to TRV (r = −0.62, P < .001), plasma arginase concentration (r = −0.45, P = .002), and plasma-free hemoglobin level (r = −0.41, P = .01), linking erythrocyte glutamine depletion to dysregulation of the arginine-NO pathway and increased hemolytic rate. Decreased erythrocyte glutathione and glutamine levels contribute to alterations in the erythrocyte redox environment, which may compromise erythrocyte integrity, contribute to hemolysis, and play a role in the pathogenesis of PH of SCD.
Overexpression of CDX2 perturbs HOX gene expression in murine progenitors depending on its N-terminal domain and is closely correlated with deregulated HOX gene expression in human acute myeloid leukemia
Authors: Rawat Vijay P. S. , Thoene Silvia , Naidu Vegi M. , Arseni Natalia , Heilmeier Bernhard , Metzeler Klaus , Petropoulos Konstantin , Deshpande Aniruddha , Quintanilla-Martinez Leticia , Bohlander Stefan K. , Spiekermann Karsten , Hiddemann Wolfgang , Feuring-Buske Michaela , Buske Christian
Published: September 2007

The mechanisms underlying deregulation of HOX gene expression in AML are poorly understood. The ParaHox gene CDX2 was shown to act as positive upstream regulator of several HOX genes. In this study, constitutive expression of Cdx2 caused perturbation of leukemogenic Hox genes such as Hoxa10 and Hoxb8 in murine hematopoietic progenitors. Deletion of the N-terminal domain of Cdx2 abrogated its ability to perturb Hox gene expression and to cause acute myeloid leukemia (AML) in mice. In contrast inactivation of the putative Pbx interacting site of Cdx2 did not change the leukemogenic potential of the gene. In an analysis of 115 patients with AML, expression levels of CDX2 were closely correlated with deregulated HOX gene expression. Patients with normal karyotype showed a 14-fold higher expression of CDX2 and deregulated HOX gene expression compared with patients with chromosomal translocations such as t(8:21) or t(15;17). All patients with AML with normal karyotype tested were negative for CDX1 and CDX4 expression. These data link the leukemogenic potential of Cdx2 to its ability to dysregulate Hox genes. They furthermore correlate the level of CDX2 expression with HOX gene expression in human AML and support a potential role of CDX2 in the development of human AML with aberrant Hox gene expression.
Antihuman factor VIII C2 domain antibodies in hemophilia A mice recognize a functionally complex continuous spectrum of epitopes dominated by inhibitors of factor VIII activation
Authors: Meeks Shannon L. , Healey John F. , Parker Ernest T. , Barrow Rachel T. , Lollar Pete
Published: September 2007

The diversity of factor VIII (fVIII) C2 domain antibody epitopes was investigated by competition enzyme-linked immunosorbent assay (ELISA) using a panel of 56 antibodies. The overlap patterns produced 5 groups of monoclonal antibodies (MAbs), designated A, AB, B, BC, and C, and yielded a set of 18 distinct epitopes. Group-specific loss of antigenicity was associated with mutations at the Met2199/Phe2200 phospholipid binding β-hairpin (group AB MAbs) and at Lys2227 (group BC MAbs), which allowed orientation of the epitope structure as a continuum that covers one face of the C2 β-sandwich. MAbs from groups A, AB, and B inhibit the binding of fVIIIa to phospholipid membranes. Group BC was the most common group and displayed the highest specific fVIII inhibitor activities. MAbs in this group are type II inhibitors that inhibit the activation of fVIII by either thrombin or factor Xa and poorly inhibit the binding of fVIII to phospholipid membranes or von Willebrand factor (VWF). Group BC MAbs are epitopically and mechanistically distinct from the extensively studied group C MAb, ESH8. These results reveal the structural and functional complexity of the anti-C2 domain antibody response and indicate that interference with fVIII activation is a major attribute of the inhibitor landscape.
Determinants of PF4/heparin immunogenicity
Authors: Suvarna Shayela , Espinasse Benjamin , Qi Rui , Lubica Rauova , Poncz Mortimer , Cines Douglas B. , Wiesner Mark R. , Arepally Gowthami M.
Published: September 2007

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated disorder that occurs with variable frequency in patients exposed to heparin. HIT antibodies preferentially recognize large macromolecular complexes formed between PF4 and heparin over a narrow range of molar ratios, but the biophysical properties of complexes that initiate antibody production are unknown. To identify structural determinants underlying PF4/heparin immunogenicity, we characterized the in vitro interactions of murine PF4 (mPF4) and heparin with respect to light absorption, size, and surface charge (zeta potential). We show that PF4/heparin macromolecular assembly occurs through colloidal interactions, wherein heparin facilitates the growth of complexes through charge neutralization. The size of PF4/heparin macromolecules is governed by the molar ratios of the reactants. Maximal complex size occurs at molar ratios of PF4/heparin at which surface charge is neutral. When mice are immunized with complexes that differ in size and/or zeta potential, antibody formation varies inversely with heparin concentration and is most robust in animals immunized with complexes displaying a net positive zeta-potential. These studies suggest that the clinical heterogeneity in the HIT immune response may be due in part to requirements for specific biophysical parameters of the PF4/heparin complexes that occur in settings of intense platelet activation and PF4 release.
Tagging of MADS domain proteins for chromatin immunoprecipitation
Authors: de Folter Stefan , Urbanus Susan L , van Zuijlen Lisette GC , Kaufmann Kerstin , Angenent Gerco C
Published: September 2007

Background

Most transcription factors fulfill their role in complexes and regulate their target genes upon binding to DNA motifs located in upstream regions or introns. To date, knowledge about transcription factor target genes and their corresponding transcription factor binding sites are still very limited. Two related methods that allow in vivo identification of transcription factor binding sites are chromatin immunoprecipitation (ChIP) and chromatin affinity purification (ChAP). For ChAP, the protein of interest is tagged with a peptide or protein, which can be used for affinity purification of the protein-DNA complex and hence, the identification of the target gene.

Results

Here, we present the results of experiments aiming at the development of a generic tagging approach for the Arabidopsis MADS domain proteins AGAMOUS, SEPALLATA3, and FRUITFULL. For this, Arabidopsis wild type plants were transformed with constructs containing a MADS-box gene fused to either a double Strep-tag® II-FLAG-tag, a triple HA-tag, or an eGFP-tag, all under the control of the constitutive double 35S Cauliflower Mosaic Virus (CaMV) promoter. Strikingly, in all cases, the number of transformants with loss-of-function phenotypes was much larger than those with an overexpression phenotype. Using endogenous promoters in stead of the 35S CaMV resulted in a dramatic reduction in the frequency of loss-of-function phenotypes. Furthermore, pleiotropic defects occasionally caused by an overexpression strategy can be overcome by using the native promoter of the gene. Finally, a ChAP result is presented using GFP antibody on plants carrying a genomic fragment of a MADS-box gene fused to GFP.

Conclusion

This study revealed that MADS-box proteins are very sensitive to fusions with small peptide tags and GFP tags. Furthermore, for the expression of chimeric versions of MADS-box genes it is favorable to use the entire genomic region in frame to the tag of choice. Interestingly, though unexpected, it appears that the use of chimeric versions of MADS-box genes under the control of the strong 35S CaMV promoter is a very efficient method to obtain dominant-negative mutants, either caused by cosuppression or by alteration of the activity of the recombinant protein. Finally, we were able to demonstrate AGAMOUS binding to one of its targets by ChAP.
Chest wall syndrome among primary care patients: a cohort study
Authors: Verdon François , Burnand Bernard , Herzig Lilli , Junod Michel , Pécoud Alain , Favrat Bernard
Published: September 2007

Background

The epidemiology of chest pain differs strongly between outpatient and emergency settings. In general practice, the most frequent cause is the chest wall pain. However, there is a lack of information about the characteristics of this syndrome. The aims of the study are to describe the clinical aspects of chest wall syndrome (CWS).

Methods

Prospective, observational, cohort study of patients attending 58 private practices over a five-week period from March to May 2001 with undifferentiated chest pain. During a one-year follow-up, questionnaires including detailed history and physical exam, were filled out at initial consultation, 3 and 12 months. The outcomes were: clinical characteristics associated with the CWS diagnosis and clinical evolution of the syndrome.

Results

Among 24 620 consultations, we observed 672 cases of chest pain and 300 (44.6%) patients had a diagnosis of chest wall syndrome. It affected all ages with a sex ratio of 1:1. History and sensibility to palpation were the keys for diagnosis. Pain was generally moderate, well localised, continuous or intermittent over a number of hours to days or weeks, and amplified by position or movement. The pain however, may be acute. Eighty-eight patients were affected at several painful sites, and 210 patients at a single site, most frequently in the midline or a left-sided site. Pain was a cause of anxiety and cardiac concern, especially when acute. CWS coexisted with coronary disease in 19 and neoplasm in 6. Outcome at one year was favourable even though CWS recurred in half of patients.

Conclusion

CWS is common and benign, but leads to anxiety and recurred frequently. Because the majority of chest wall pain is left-sided, the possibility of coexistence with coronary disease needs careful consideration.
Intraoperative radiotherapy (IORT) is an option for patients with localized breast recurrences after previous external-beam radiotherapy
Authors: Kraus-Tiefenbacher Uta , Bauer Lelia , Scheda Antonella , Schoeber Carola , Schaefer Joerg , Steil Volker , Wenz Frederik
Published: September 2007

Background

For patients suffering of recurrent breast cancer within the irradiated breast, generally mastectomy is recommended. The normal tissue tolerance does not permit a second full-dose course of radiotherapy to the entire breast after a second breast-conserving surgery (BCS). A novel option is to treat these patients with partial breast irradiation (PBI). This approach is based on the hypothesis that re-irradiation of a limited volume will be effective and result in an acceptable frequency of side effects. The following report presents a single center experience with intraoperative radiotherapy (IORT) during excision of recurrent breast cancer in the previously irradiated breast.

Methods

Between 4/02 and 11/06, 15 patients were treated for in-breast recurrences at a median of 10 years (3–25) after previous EBRT (10 recurrences in the initial tumor bed, 3 elsewhere in-breast failures, 2 invasive recurrences after previous DCIS). Additional 2 patients were selected for IORT with new primary breast cancer after previous partial breast EBRT for treatment of Hodgkin's disease. IORT with a single dose of 14.7 – 20 Gy 50 kV X-rays at the applicator surface was delivered with the Intrabeam™-device (Carl Zeiss, Oberkochen, Germany).

Results

After a median follow-up of 26 months (1–60), no local recurrence occurred. 14 out of 17 patients are alive and free of disease progression. Two patients are alive with distant metastases. One patient died 26 months after BCS/IORT due to pulmonary metastases diagnosed 19 months after BCS/IORT. Acute toxicity after IORT was mild with no Grade 3/4 toxicities and cosmetic outcome showed excellent/good/fair results in 7/7/3 cases.

Conclusion

IORT for recurrent breast cancer using low energy X-rays is a valuable option for patients with recurrent breast cancer after previous radiotherapy.
Detection of the pediocin gene pedA in strains from human faeces by real-time PCR and characterization of Pediococcus acidilacticiUVA1
Authors: Mathys Sophie , von Ah Ueli , Lacroix Christophe , Staub Ernö , Mini Raffaella , Cereghetti Tania , Meile Leo
Published: September 2007

Background

Bacteriocin-producing lactic acid bacteria are commonly used as natural protective cultures. Among them, strains of the genus Pediococcus are particularly interesting for their ability to produce pediocin, a broad spectrum antimicrobial peptide with a strong antagonistic activity against the food-borne pathogen Listeria monocytogenes. Furthermore, there is increasing interest in isolating new bacteriocin-producing strains of human intestinal origin that could be developed for probiotic effects and inhibition of pathogenic bacteria in the gut. In this work, we typed a new strain, co-isolated from baby faeces together with a Bifidobacterium thermophilum strain, and characterized its proteinaceous compound with strong antilisterial activity.

Results

The newly isolated strain UVA1 was identified as a Pediococcus acidilactici by carbohydrate fermentation profile, growth at 50°C and 16S rDNA sequencing. The partially purified bacteriocin was heat resistant up to 100°C, active over a wide range of pH (2 to 9) and susceptible to proteolytic enzymes. The molecular weight, estimated by SDS-PAGE, was similar to that of pediocin AcH/PA-1 (4.5 kDa). P. acidilactici UVA1 harboured a 9.5-kb plasmid that could be cured easily, which resulted in the loss of the antimicrobial activity. Southern hybridization using the DIG-labelled pedA-probe established that the bacteriocin gene was plasmid-borne as for all pediocin described so far. Nucleotide sequence of the whole operon (3.5 kb) showed almost 100 % similarity to the pediocin AcH/PA-1 operon. The mRNA transcript for pedA could be detected in P. acidilactici UVA1 but not in the cured derivative, confirming the expression of the pedA-gene in UVA1. Using a new real-time PCR assay, eleven out of seventeen human faecal samples tested were found to contain pedA-DNA.

Conclusion

We identified and characterised the first pediocin produced by a human intestinal Pediococcus acidilactici isolate and successfully developed a new real-time PCR assay to show the large distribution of pedA-containing strains in baby faecal samples.
Expression of HPV-11 L1 protein in transgenic Arabidopsis thaliana and Nicotiana tabacum
Authors: Kohl Thomas O , Hitzeroth Inga I , Christensen Neil D , Rybicki Edward P
Published: September 2007

Background

We have investigated the possibility and feasibility of producing the HPV-11 L1 major capsid protein in transgenic Arabidopsis thaliana ecotype Columbia and Nicotiana tabacum cv. Xanthi as potential sources for an inexpensive subunit vaccine.

Results

Transformation of plants was only achieved with the HPV-11 L1 gene with the C-terminal nuclear localization signal (NLS-) encoding region removed, and not with the full-length gene. The HPV-11 L1 NLS
- gene was stably integrated and inherited through several generations of transgenic plants. Plant-derived HPV-11 L1 protein was capable of assembling into virus-like particles (VLPs), although resulting particles displayed a pleomorphic phenotype. Neutralising monoclonal antibodies binding both surface-linear and conformation-specific epitopes bound the A. thaliana-derived particles and – to a lesser degree – the N. tabacum-derived particles, suggesting that plant-derived and insect cell-derived VLPs displayed similar antigenic properties. Yields of up to 12 μg/g of HPV-11 L1 NLS- protein were harvested from transgenic A. thaliana plants, and 2 μg/g from N. tabacum plants – a significant increase over previous efforts. Immunization of New Zealand white rabbits with ~50 μg of plant-derived HPV-11 L1 NLS- protein induced an antibody response that predominantly recognized insect cell-produced HPV-11 L1 NLS- and not NLS+ VLPs. Evaluation of the same sera concluded that none of them were able to neutralise pseudovirion in vitro.

Conclusion

We expressed the wild-type HPV-11 L1 NLS
- gene in two different plant species and increased yields of HPV-11 L1 protein by between 500 and 1000-fold compared to previous reports. Inoculation of rabbits with extracts from both plant types resulted in a weak immune response, and antisera neither reacted with native HPV-11 L1 VLPs, nor did they neutralise HPV-11 pseudovirion infectivity. This has important and potentially negative implications for the production of HPV-11 vaccines in plants.
Knowledge and use of emergency contraception among women in the Western Cape province of South Africa: a cross-sectional study
Authors: Myer Landon , Mlobeli Regina , Cooper Di , Smit Jennifer , Morroni Chelsea
Published: September 2007

Background

Emergency contraception (EC) is widely available free of charge at public sector clinics in South Africa. At the same time, rates of teenage and unintended pregnancy in South Africa remain high, and there are few data on knowledge of EC in the general population in South Africa, as in other resource-limited settings.

Methods

We conducted a cross-sectional, interviewer-administered survey among 831 sexually active women at 26 randomly selected public sector clinics in the Western Cape province.

Results

Overall, 30% of the women had ever heard of EC when asked directly, after the method was described to them. Only 15% mentioned EC by name or description spontaneously. Knowledge of EC was independently associated with higher education, being married, and living in an urban setting. Four percent of women had ever used EC.

Discussion

These data suggest that knowledge of EC in this setting is more common among women of higher socioeconomic status living in urban areas. For EC to play a role in decreasing unintended pregnancy in South Africa, specific interventions are necessary to increase knowledge of the method, where to get it, and the appropriate time interval for its use before the need for EC arises. Future health promotion campaigns should target rural and low socioeconomic status communities.
An action research protocol to strengthen system-wide inter-professional learning and practice [LP0775514]
Authors: Braithwaite Jeffrey , Westbrook Johanna I , Foxwell A Ruth , Boyce Rosalie , Devinney Timothy , Budge Marc , Murphy Karen , Ryall Mary-Ann , Beutel Jenny , Vanderheide Rebecca , Renton Elizabeth , Travaglia Joanne , Stone Judy , Barnard Amanda , Greenfield David , Corbett Angus , Nugus Peter , Clay-Williams Robyn
Published: September 2007

Background

Inter-professional learning (IPL) and inter-professional practice (IPP) are thought to be critical determinants of effective care, improved quality and safety and enhanced provider morale, yet few empirical studies have demonstrated this. Whole-of-system research is even less prevalent. We aim to provide a four year, multi-method, multi-collaborator action research program of IPL and IPP in defined, bounded health and education systems located in the Australian Capital Territory (ACT). The project is funded by the Australian Research Council under its industry Linkage Program.

Methods/Design

The program of research will examine in four inter-related, prospective studies, progress with IPL and IPP across tertiary education providers, professional education, regulatory and registration bodies, the ACT health system's streams of care activities and teams, units and wards of the provider facilities of the ACT health system. One key focus will be on push-pull mechanisms, ie, how the education sector creates student-enabled IPP and the health sector demands IPL-oriented practitioners. The studies will examine four research aims and meet 20 research project objectives in a comprehensive evaluation of ongoing progress with IPL and IPP.

Discussion

IPP and IPL are said to be cornerstones of health system reforms. We will measure progress across an entire health system and the clinical and professional education systems that feed into it. The value of multi-methods, partnership research and a bi-directional push-pull model of IPL and IPP will be tested. Widespread dissemination of results to practitioners, policymakers, managers and researchers will be a key project goal.