bluuebunny/crossref_metadata_2025 huggingface dataset:
Child Factors Associated With Enrollment in Part C Early Intervention Among Children Adopted From China
Authors: Bruder Mary Beth , Dunst Carl J. , Mogro-Wilson Cristina
Published: January 2010

The provision of services under Part C of the Individuals With Disabilities Education Act is built on a premise that children benefit from early intervention. This article presents findings from a study of children adopted from China. Given information obtained from a survey, the researchers grouped children as (a) those who received early intervention, (b) those who did not receive early intervention and whose parents had concerns about their behavior and development, and (c) those who did not receive early intervention and whose parents had no concerns about their behavior and development. Results showed that parental judgments of their children’s behavior at the time of adoption best explained differences between the parents whose children received early intervention and parents who had no concerns about their children’s behavior and who did not receive early intervention. The behavioral markers that differentiated the groups from one another were as follows: child affect, poor attention, eating and feeding difficulties, problems communicating, poor physical health, and social interaction problems. Findings indicate that parents’ appraisals can be an important source of information for eligibility determination for this population of children.
Fuzzy Control for an Oceanic Structure: A Case Study in Time-delay TLP System
Authors: Chen Chen-Yuan , Lin Jeng-Wen , Lee Wan-I , Chen Cheng-Wu
Published: January 2010

In this paper, a Takagi-Sugeno (T-S) fuzzy model approach combined with a parallel distributed compensation (PDC) scheme is proposed for time-delay control of the response of a tension leg platform (TLP) system subjected to an external wave force. A global PDC-based fuzzy logic controller is constructed by blending all local state feedback controllers. A fuzzy-model-based control is thereby developed which can attenuate the influence of the external wave force. The controller is evaluated in terms of stability analysis, and the linear matrix inequality (LMI) conditions guaranteeing the stability of the TLP system derived via Lyapunov theory. A simulation example is given to show the feasibility of the proposed fuzzy control approach. The example shows the concept of half-circle fuzzy number can be used in fuzzy control and the proposed control method can be employed in practical engineering problems of oceanic structure.
Sport Performance in Four Acts: Players, Workers, Audience, and Immortality
Authors: Rinehart Robert E.
Published: January 2010

Using the “voices” of the “creators” of intertextualized sport, this article will demonstrate how sport is inextricably linked with performance. As well, an exegesis of the modernist and postmodernist frameworks of contemporary sport will show how many sports have evolved from grass roots to Goffman’s “framed” responses to the cult of celebrity and attempts to attain immortality and how these various responses to the need for human movement create dense archipelagoes of multifaceted cultural formations.
I Didn’t Have to Play Football to Be Hurt: An Inquiry Concerning the Disjunction Between Public and Private Self
Authors: Ryder Steve
Published: January 2010

This autoethnographic inquiry and resultant performative text examine individual choice in the formation of public and private identities. Central is the significant developmental role that socialization plays in the natural process by which biologically similar organisms establish unique perspectives: identity, specifically, the emergence of a gay identity. Revisiting poignant, liminal moments within the span of four decades of personal memory of a gay-identified male, I explore and prescribe meaning from the curious behaviours undertaken in the interest of trans-normative safety—physical, psychological, emotional, sociocultural, and so on.
“Keeping Up a Front”: Narratives About Intimate Partner Violence, Pregnancy, and Antenatal Care
Authors: Edin Kerstin E. , Dahlgren Lars , Lalos Ann , Högberg Ulf
Published: January 2010

Nine women who had been subjected to severe intimate partner violence during pregnancy narrated their ambiguous and contradictory feelings and the various balancing strategies they used to overcome their complex and difficult situations. Because allowing anyone to come close posed a threat, the women mostly denied the situation and kept up a front to hide the violence from others. Three women disclosed ongoing violence to the midwives, but only one said such disclosure was helpful. This article highlights the complexity of being pregnant when living with an abusive partner and challenges antenatal care policies from the perspective of pregnant women.
Carcass Traits and Fatty Acid Composition of Subcutaneous, Intramuscular and Liver Fat from Iberian Pigs Fed in Confinement only with Acorns or a Formulated Diet
Authors: Daza A. , Menoyo D. , López Bote C.J.
Published: January 2010

Twenty castrated male Iberian pigs were divided into two groups of 10 pigs each according to the experimental diet received daily during the fattening period in confinement (acorn fed ad libitum or 4 kg of a formulated diet rich in C18:1 n—9). Dietary effects on performance, carcass characteristics and backfat, intramuscular, and liver fatty acid composition were assessed. Pigs fed only with acorns ate less, leading to a lower growth performance and carcass quality than pigs fed the formulated diet. Pigs fed acorns had lower C16:0 proportions in outer, inner, and subinner subcutaneous backfat layers. The C18:1 n—9 proportions in the inner and subinner subcutaneous backfat layers were higher in pigs fed acorns than in those fed the formulated diet. Pigs fed acorns had higher C18:2 n—6 proportion than those fed the formulated diet in outer subcutaneous backfat layer. The diet did not affect outer, inner, and subinner subcutaneous backfat melting points. Except a higher C18:0 in intramuscular fat polar lipids and higher C16:1 n—9 in the liver polar lipid fraction in pigs fed acorns, the diet had no significant effect on intramuscular and liver fatty acid composition.
Hamas and the Israeli state: A ‘violent dialogue’
Authors: Ayyash Mark Muhannad
Published: January 2010

Through an analysis of Hamas’s suicide missions and Israel’s strategy of ‘shock and awe’, this article advances a concept of ‘violent dialogue.’ Drawing on Gadamer’s work, as well as some of the points that emerge out of the Gadamer—Derrida encounter, this concept is meant to explicate how acts of political violence create a certain type of communion between those engaged in violent conflict. It will suggest that the appearance of political violent acts does not represent the end of a dialogue between the violent actors, but rather the emergence of a specific form of dialogue under the subject matter of violence. It is argued that this communion takes place outside the intentions of the protagonists, and despite their attempts to separate from each other. This is significant for academic analysis of political violence in general, and for our perspective and outlook on the Israeli—Palestinian conflict in particular.
Is there an environmental version of the Kantian peace? Insights from water pollution in Europe
Authors: Bernauer Thomas , Kuhn Patrick M.
Published: January 2010

We examine whether there is an environmental version of the Kantian peace; that is, whether democracies that trade and are bound by international treaties are less likely to harm each other environmentally. Specifically, we study five factors that are likely to help in reducing beggar-thy-neighbour behaviour in terms of transboundary pollution: democracy, supranational institutions, trade relations, stringency of domestic environmental policy and international environmental commitment. The empirical focus is on upstream—downstream water pollution in Europe in 1970—2003. The observed effects of the five variables differ considerably across forms of pollution and definitions of beggar-thy-neighbour behaviour. Some of our explanatory variables contribute to reducing beggar-thy-neighbour behaviour. Hence there is some empirical support for the environmental Kantian argument. Nonetheless, state behaviour in this area remains characterized by free-riding incentives; the forces of democracy, trade and national and international regulation and institutions do not easily produce decent international behaviour.
Consuming European identity
Authors: Vidmar-Horvat Ksenija
Published: January 2010

• This article investigates consumerism in post-socialist Slovenia with respect to the formation of the shared European Union (EU) commodity market. It asks how, through forms of consumption, Europe is made present to the EU citizens in the post-socialist states and how political imaginaries of the ‘new Europe’ are being formed. It is argued that consumerism presents a cultural site on which the meaning of citizenship acquires its symbolic positioning. This positioning is then illuminated with respect to the emergence in post-socialist Slovenia of public discourses of ‘two Europes’, ‘two markets’, ‘first- and second-class’ EU citizens, which evolve around the perceptions that, after the two enlargement waves in 2004 and 2007, commodities in the EU differ in their origin of production and quality between the West and the East. The perceptions are linked to memories of socialism. However, this inconspicuous side of consumerism is also discussed as a selective mechanism by which the imagined community of the EU citizens is being constructed. •
Young Muslim women on the face veil (niqab)
Authors: Shirazi Faegheh , Mishra Smeeta
Published: January 2010

In order to understand Muslim women’s views on veiling in the West, one must take into account historical and socio-political factors such as a country’s colonial/national history, the nature of its immigration regime, the demographic composition of immigrant groups, and how the nation operationalizes concepts such as secularism and citizenship. While academic literature and media reports on young Muslim women in Europe indicate that wearing the niqab or face veil is often viewed as an act of rebellion or a form of personal/political/religious identity, our in-depth interviews of young Muslim women in the United States reveal a different story. While half the participants in this study wore a headscarf or hijab, not one of them said they were interested in wearing the niqab. Instead, they believed the niqab was unnecessary in the American context. However, an overwhelming majority upheld the right of a woman to wear a niqab if she wanted to do so. Two American Muslim women narrated why they gave up wearing the niqab after wearing it for a short time.
The linguistic market in Polish radio commercials
Authors: Haładewicz-Grzelak Małgorzata
Published: January 2010

Cultural and sociolinguistic studies on the pragmatics of radio have so far neglected the impact of radio advertising. Radio commercials are perceived as a marginal and unimportant outlet of consumerist values and I submit that the misrecognition of their ontological status is the gist of their hidden impact. The purpose of this study is thus to uncover some aspects in which radiocracy (a term coined by John Hartley) interrelates with culture through linguistic resources of a speech community. The discussion is theoretically anchored in Bourdieu’s work on symbolic capital, methodologically based in content analysis paradigm and empirically informed by an analysis of the linguistic market of Polish commercial radio as it was structured in the Christmas 2006 period.
A rules of thumb-based design sequence for diffuse daylight
Authors: Reinhart CF , LoVerso VRM
Published: January 2010

This paper proposes and validates a daylighting design sequence for sidelit spaces. Since the design sequence uses the daylight factor as a performance metric, it is aimed towards spaces that primarily receive diffuse daylight. It should be complemented by a design analysis that looks at direct sunlight for glare and energy considerations. The sequence interconnects and refines earlier proposed rules of thumb and is intended to be used during the earliest design stages when concepts regarding programming, floor plans, massing and window areas are initially explored. All steps within the sequence were ‘validated’ using Radiance simulations of over 2300 sidelit spaces. During step one of the sequence the effective sky angles are calculated and target daylight factors are defined for all potential daylit zones within a building. In step two a refined version of the ‘daylight feasibility study’ is used to help the design team to identify building zones with high daylighting potential based on a target mean daylight factor criterion. During step three suitable interior room dimensions and surface reflectances are determined using a combination of the Lynes’ limiting depth, ‘no sky line’, and window-head-height rules of thumb. Step four provides a more accurate estimate of the required glazing area for each zone based on the Lynes daylight factor formula which is also validated as part of this work. The effect of external obstructions is considered throughout the process. The paper closes with a discussion of the merits of the design sequence compared to the glazing factor spreadsheet calculation method promoted by LEED-NC 2.2.
Office workers’ daily exposure to light and its influence on sleep quality and mood
Authors: Hubalek S. , Brink M. , Schierz C.
Published: January 2010

To study the amount of light entering the eye and its effects on office workers, measurements were taken from 23 office workers over a period of seven consecutive days. Two parameters of visible light were recorded: (i) illuminance and (ii) irradiance of the blue spectral component. Every evening before going to bed, a questionnaire had to be filled out, containing scales relating to the mood dimensions of pleasure and arousal, questions about the previous night’s sleep and a rough time table with information about the person’s whereabouts during the day. The exposure to light on workdays is regular but it varies strongly on days off. No evidence could be provided for the influence of age, sex or seasonal affective disorder (SAD) scores on the daily exposure to light of office workers. The amount of light entering the eye during the day appears to have a positive impact on sleep quality the following night. Pleasure and arousal were not significantly associated with daily light exposure.
Making art from evidence: Secret sex and police surveillance in the Tearoom
Authors: Biber Katherine , Dalton Derek
Published: January 2010

In 1962, police officers concealed themselves for two weeks in a men’s public toilet in Mansfield, Ohio, and filmed men performing illicit homosexual sex acts. The film footage was used to secure convictions for sodomy, and inaugurated a new form of police surveillance of homosexual public sex. In 2008, the visual artist William E. Jones screened the police footage in art galleries around the world, to both critical acclaim and public objection. This article examines the film, both as a prosecutorial artefact and an artwork, to explore what it says about public sex, police surveillance, the criminalization of homosexual practices, visual evidence, and contemporary art. It considers the validity of the public/private distinction as it applies to anonymous sex, it evaluates the probative value of images, the changing nature of surveillance, and the meanings of silence in both criminal procedure and artistic practice. This article argues that the act of transforming traumatic evidence into visual art requires deep ethical examination. Whatever artistic, political or historical contribution may be claimed for this work must be measured against the harm that it does to the film’s silent subjects.
Phosphatidylinositol 3-kinase isoforms as targets in respiratory disease
Authors: Marwick John A. , Kian Fan Chung  , Adcock Ian M.
Published: January 2010

Respiratory diseases such as chronic obstructive pulmonary disease [COPD], severe asthma, cystic fibrosis [CF] and idiopathic pulmonary fibrosis [IPF] are inadequately controlled by current therapies. The underlying molecular mechanisms and pathogenesis of these diseases remain unclear, making identification and validation of potential new therapeutic targets difficult. However, recent studies have identified the central signalling mediator PI3K as playing an integral role in the immune system including initiation and maintenance of inflammatory responses. Specifically, the relatively leukocyte-specific PI3Kγ and PI3Kδ isoforms are central to leukocyte function and can be targeted pharmacologically. Early to man studies using selective PI3K isoform inhibitors are required to determine whether they have a future in treating respiratory disease, particularly in controlling both innate and adaptive inflammatory responses as well as restoring glucocorticoid function and reducing tumorigenesis.
Quality of life in patients with chronic cough
Authors: Young Emma C. , Smith Jaclyn A.
Published: January 2010

Chronic cough is a relatively common symptom for which effective, acceptable treatments are lacking. Many patients suffer frequent coughing over several years without resolution and this has significant physical, social and psychological consequences. The recent development of cough-specific quality-of-life tools now allows quantification of the burden of coughing both in patients specifically presenting with chronic cough and also in common respiratory conditions.
Attenuation of isoproterenol-induced cardiac fibrosis in transgenic rats harboring an angiotensin-(1-7)-producing fusion protein in the heart
Authors: Ferreira Anderson J. , Castro Carlos H. , Guatimosim Silvia , Almeida Pedro W.M. , Gomes Enéas R.M. , Dias-Peixoto Marco Fabrício , Alves Márcia N.M. , Fagundes-Moura Cristiane R. , Rentzsch Brit , Gava Elisandra , Almeida Alvair P. , Guimarães Alexandre M. , Kitten Gregory T. , Reudelhuber Timothy , Bader Michael , Santos Robson A.S.
Published: January 2010

Objective: It has been shown that Ang-(1-7) has cardioprotective actions. To directly investigate the effects of Ang-(1-7) specifically in the heart, we generated and characterized transgenic (TG) rats which express an Ang-(1-7)-producing fusion protein driven by the α-MHC promoter.

Methods and Results: After microinjection of the transgene into fertilized rat zygotes, we obtained four different transgenic lines. Homozygous animals were analyzed with regard to the expression profile of the transgene by ribonuclease protection assay. Transgene expression was detected mainly in the heart with weak or no expression in other organs. Heterozygous TG(hA-1-7)L7301 rats presented a significant increase in cardiac Ang-(1-7) concentration compared with control rats (17.1±2.1 versus 3.9±1.4 pg/mg protein in SD rats). Radiotelemetry analysis revealed that TG rats presented no significant changes in blood pressure and heart rate compared with normal rats. Overexpression of Ang-(1-7) in the heart produced slight improvement in resting cardiac function (+ dT/dt: 81530±1305.0 versus 77470±345.5 g/s bpm in SD rats, p < 0.05), which was in keeping with the enhanced [Ca2+] handling observed in cardiomyocytes of TG rats. TG(hA-1-7)L7301 rats also showed a greater capacity to withstand stress since TG rats showed a less pronounced deposition of collagen type III and fibronectin induced by isoproterenol treatment in the subendocardial area than in corresponding controls. In addition, hearts from TG rats showed reduced incidence and duration of reperfusion arrhythmias in comparison with SD rats.

Conclusion: These results indicate that Ang-(1-7) has blood pressure-independent, antifibrotic effects, acting directly in the heart.
Botulinum toxin therapy for osteoarticular pain: an evidence-based review
Authors: Singh Jasvinder A.
Published: January 2010

Botulinum (BoNT) toxin has been used for its muscle-paralyzing action in conditions such as treatment of wrinkles, cervical dystonia and blephrospasm. There is preclinical and emerging clinical evidence of another mechanism of action of BoNT, namely, an antinociceptive action. In this review, we provide an evidence-based review of clinical studies of BoNT in osteoarticular conditions, such as osteoarthritis, tennis elbow, low back pain, and hand pain. Many randomized controlled trials (RCTs) found evidence of short-term efficacy of an injection of BoNT in relief of pain, and in some cases, improvement of function and quality of life. However, more clinical trials are needed to better define the clinical use of BoNT for treatment of refractory osteoarticular pain.
Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34− fraction
Authors: Taussig David C. , Vargaftig Jacques , Miraki-Moud Farideh , Griessinger Emmanuel , Sharrock Kirsty , Luke Tina , Lillington Debra , Oakervee Heather , Cavenagh Jamie , Agrawal Samir G. , Lister T. Andrew , Gribben John G. , Bonnet Dominique
Published: January 2010

Leukemia-initiating cells (LICs) in acute myeloid leukemia (AML) are believed to be restricted to the CD34+ fraction. However, one of the most frequently mutated genes in AML is nucleophosmin (NPM), and this is associated with low CD34 expression. We, therefore, investigated whether NPM-mutated AMLs have LICs restricted to the CD34+ fraction. We transplanted sorted fractions of primary NPM-mutated AML into immunodeficient mice to establish which fractions initiate leukemia. Approximately one-half of cases had LICs exclusively within the CD34− fraction, whereas the CD34+ fraction contained normal multilineage hematopoietic repopulating cells. Most of the remaining cases had LICs in both CD34+ and CD34− fractions. When samples were sorted based on CD34 and CD38 expression, multiple fractions initiated leukemia in primary and secondary recipients. The data indicate that the phenotype of LICs is more heterogeneous than previously realized and can vary even within a single sample. This feature of LICs may make them particularly difficult to eradicate using therapies targeted against surface antigens.
Prediction of microRNAs affecting mRNA expression during retinal development
Authors: Arora Amit , Guduric-Fuchs Jasenka , Harwood Laura , Dellett Margaret , Cogliati Tiziana , Simpson David A
Published: January 2010

Background

MicroRNAs (miRNAs) are small RNA molecules (~22 nucleotides) which have been shown to play an important role both in development and in maintenance of adult tissue. Conditional inactivation of miRNAs in the eye causes loss of visual function and progressive retinal degeneration. In addition to inhibiting translation, miRNAs can mediate degradation of targeted mRNAs. We have previously shown that candidate miRNAs affecting transcript levels in a tissue can be deduced from mRNA microarray expression profiles. The purpose of this study was to predict miRNAs which affect mRNA levels in developing and adult retinal tissue and to confirm their expression.

Results

Microarray expression data from ciliary epithelial retinal stem cells (CE-RSCs), developing and adult mouse retina were generated or downloaded from public repositories. Analysis of gene expression profiles detected the effects of multiple miRNAs in CE-RSCs and retina. The expression of 20 selected miRNAs was confirmed by RT-PCR and the cellular distribution of representative candidates analyzed by in situ hybridization. The expression levels of miRNAs correlated with the significance of their predicted effects upon mRNA expression. Highly expressed miRNAs included miR-124, miR-125a, miR-125b, miR-204 and miR-9. Over-expression of three miRNAs with significant predicted effects upon global mRNA levels resulted in a decrease in mRNA expression of five out of six individual predicted target genes assayed.

Conclusions

This study has detected the effect of miRNAs upon mRNA expression in immature and adult retinal tissue and cells. The validity of these observations is supported by the experimental confirmation of candidate miRNA expression and the regulation of predicted target genes following miRNA over-expression. Identified miRNAs are likely to be important in retinal development and function. Misregulation of these miRNAs might contribute to retinal degeneration and disease. Conversely, manipulation of their expression could potentially be used as a therapeutic tool in the future.
An integrated functional genomic study of acute phenobarbital exposure in the rat
Authors: Waterman Claire L , Currie Richard A , Cottrell Lisa A , Dow Jacky , Wright Jayne , Waterfield Catherine J , Griffin Julian L
Published: January 2010

Background

Non-genotoxic carcinogens are notoriously difficult to identify as they do not damage DNA directly and have diverse modes of action, necessitating long term in vivo studies. The early effects of the classic rodent non-genotoxic hepatocarcinogen phenobarbital have been investigated in the Fisher rat using a combination of metabolomics and transcriptomics, to investige early stage mechanistic changes that are predictive of longer term pathology.

Results

Liver and blood plasma were profiled across 14 days, and multivariate statistics used to identify perturbed pathways. Both metabolomics and transcriptomics detected changes in the liver which were dose dependent, even after one day of exposure. Integration of the two datasets associated perturbations with specific pathways. Hepatic glycogen was decreased due to a decrease in synthesis, and plasma triglycerides were decreased due to an increase in fatty acid uptake by the liver. Hepatic succinate was increased and this was associated with increased heme biosynthesis. Glutathione synthesis was also increased, presumably in response to oxidative stress. Liquid Chromatography Mass Spectrometry demonstrated a remodeling of lipid species, possibly resulting from proliferation of the smooth endoplasmic reticulum.

Conclusions

The data fusion of metabolomic and transcriptomic changes proved to be a highly sensitive approach for monitoring early stage changes in altered hepatic metabolism, oxidative stress and cytochrome P450 induction simultaneously. This approach is particularly useful in interpreting changes in metabolites such as succinate which are hubs of metabolism.
Virulence regulator AphB enhances toxR transcription in Vibrio cholerae
Authors: Xu Xiao , Stern Andrew M , Liu Zhi , Kan Biao , Zhu Jun
Published: January 2010

Background

Vibrio cholerae is the causative agent of cholera. Extensive studies reveal that complicated regulatory cascades regulate expression of virulence genes, the products of which are required for V. cholerae to colonize and cause disease. In this study, we investigated the expression of the key virulence regulator ToxR under different conditions.

Results

We found that compared to that of wild type grown to stationary phase, the toxR expression was lower in an aphB mutant strain. AphB has been previously shown to be a key virulence regulator that is required to activate the expression of tcpP. When expressed constitutively, AphB is able to activate the toxR promoter. Furthermore, gel shift analysis indicates that AphB binds toxR promoter region directly. We also characterize the effect of AphB on the levels of the outer membrane porins OmpT and OmpU, which are known to be regulated by ToxR.

Conclusions

Our data indicate that V. cholerae possesses an additional regulatory loop that use AphB to activate the expression of two virulence regulators, ToxR and TcpP, which together control the expression of the master virulence regulator ToxT.
A few strong connections: optimizing information retention in neuronal avalanches
Authors: Chen Wei , Hobbs Jon P , Tang Aonan , Beggs John M
Published: January 2010

Background

How living neural networks retain information is still incompletely understood. Two prominent ideas on this topic have developed in parallel, but have remained somewhat unconnected. The first of these, the "synaptic hypothesis," holds that information can be retained in synaptic connection strengths, or weights, between neurons. Recent work inspired by statistical mechanics has suggested that networks will retain the most information when their weights are distributed in a skewed manner, with many weak weights and only a few strong ones. The second of these ideas is that information can be represented by stable activity patterns. Multineuron recordings have shown that sequences of neural activity distributed over many neurons are repeated above chance levels when animals perform well-learned tasks. Although these two ideas are compelling, no one to our knowledge has yet linked the predicted optimum distribution of weights to stable activity patterns actually observed in living neural networks.

Results

Here, we explore this link by comparing stable activity patterns from cortical slice networks recorded with multielectrode arrays to stable patterns produced by a model with a tunable weight distribution. This model was previously shown to capture central features of the dynamics in these slice networks, including neuronal avalanche cascades. We find that when the model weight distribution is appropriately skewed, it correctly matches the distribution of repeating patterns observed in the data. In addition, this same distribution of weights maximizes the capacity of the network model to retain stable activity patterns. Thus, the distribution that best fits the data is also the distribution that maximizes the number of stable patterns.

Conclusions

We conclude that local cortical networks are very likely to use a highly skewed weight distribution to optimize information retention, as predicted by theory. Fixed distributions impose constraints on learning, however. The network must have mechanisms for preserving the overall weight distribution while allowing individual connection strengths to change with learning.
A tutorial on pilot studies: the what, why and how
Authors: Thabane Lehana , Ma Jinhui , Chu Rong , Cheng Ji , Ismaila Afisi , Rios Lorena P , Robson Reid , Thabane Marroon , Giangregorio Lora , Goldsmith Charles H
Published: January 2010

Pilot studies for phase III trials - which are comparative randomized trials designed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as "feasibility" or "vanguard" studies, they are designed to assess the safety of treatment or interventions; to assess recruitment potential; to assess the feasibility of international collaboration or coordination for multicentre trials; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including: 1) the general reasons for conducting a pilot study; 2) the relationships between pilot studies, proof-of-concept studies, and adaptive designs; 3) the challenges of and misconceptions about pilot studies; 4) the criteria for evaluating the success of a pilot study; 5) frequently asked questions about pilot studies; 7) some ethical aspects related to pilot studies; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format.
Variable viral clearance despite adequate ganciclovir plasma levels during valganciclovir treatment for cytomegalovirus disease in D+/R- transplant recipients
Authors: Perrottet Nancy , Manuel Oriol , Lamoth Frédéric , Venetz Jean-Pierre , Sahli Roland , Decosterd Laurent A , Buclin Thierry , Pascual Manuel , Meylan Pascal
Published: January 2010

Background

Valganciclovir, the oral prodrug of ganciclovir, has been demonstrated equivalent to iv ganciclovir for CMV disease treatment in solid organ transplant recipients. Variability in ganciclovir exposure achieved with valganciclovir could be implicated as a contributing factor for explaining variations in the therapeutic response. This prospective observational study aimed to correlate clinical and cytomegalovirus (CMV) viral load response (DNAemia) with ganciclovir plasma concentrations in patients treated with valganciclovir for CMV infection/disease.

Methods

Seven CMV D+/R- transplant recipients (4 kidney, 2 liver and 1 heart) were treated with valganciclovir (initial dose was 900-1800 mg/day for 3-6.5 weeks, followed by 450-900 mg/day for 2-9 weeks). DNAemia was monitored by real time quantitative PCR and ganciclovir plasma concentration was measured at trough (Ctrough) and 3 h after drug administration (C3h) by HPLC.

Results

Four patients presented with CMV syndrome, two had CMV tissue-invasive disease after prophylaxis discontinuation, and one liver recipient was treated pre-emptively for asymptomatic rising CMV viral load 5 weeks post-transplantation in the absence of prophylaxis. CMV DNAemia decreased during the first week of treatment in all recipients except in one patient (median decrease: -1.2 log copies/mL, range: -1.8 to 0) despite satisfactory ganciclovir exposure (AUC0-12 = 48 mg·h/L, range for the 7 patients: 40-118 mg·h/L). Viral clearance was obtained in five patients after a median of time of 34 days (range: 28-82 days). Two patients had recurrent CMV disease despite adequate ganciclovir exposure (65 mg·h/L, range: 44-118 mg·h/L).

Conclusions

Valganciclovir treatment for CMV infection/disease in D+/R- transplant recipients can thus result in variable viral clearance despite adequate ganciclovir plasma concentrations, probably correlating inversely with anti-CMV immune responses after primary infection.
Tocotrienols are good adjuvants for developing cancer vaccines
Authors: Abdul Hafid Sitti Rahma , Radhakrishnan Ammu Kutty , Nesaretnam Kalanithi
Published: January 2010

Background

Dendritic cells (DCs) have the potential for cancer immunotherapy due to their ability to process and present antigens to T-cells and also in stimulating immune responses. However, DC-based vaccines have only exhibited minimal effectiveness against established tumours in mice and humans. The use of appropriate adjuvant enhances the efficacy of DC based cancer vaccines in treating tumours.

Methods

In this study we have used tocotrienol-rich fraction (TRF), a non-toxic natural compound, as an adjuvant to enhance the effectiveness of DC vaccines in treating mouse mammary cancers. In the mouse model, six-week-old female BALB/c mice were injected subcutaneously with DC and supplemented with oral TRF daily (DC+TRF) and DC pulsed with tumour lysate from 4T1 cells (DC+TL). Experimental mice were also injected with DC pulsed with tumour lysate and supplemented daily with oral TRF (DC+TL+TRF) while two groups of animal which were supplemented daily with carrier oil (control) and with TRF (TRF). After three times vaccination, mice were inoculated with 4T1 cells in the mammary breast pad to induce tumour.

Results

Our study showed that TRF in combination with DC pulsed with tumour lysate (DC+TL+TRF) injected subcutaneously significantly inhibited the growth of 4T1 mammary tumour cells as compared to control group. Analysis of cytokines production from murine splenocytes showed significant increased productions of IFN-γ and IL-12 in experimental mice (DC+TL+TRF) compared to control, mice injected with DC without TRF, mice injected with DC pulsed with tumour lysate and mice supplemented with TRF alone. Higher numbers of cytotoxic T cells (CD8) and natural killer cells (NK) were observed in the peripheral blood of TRF adjuvanted DC pulsed tumour lysate mice.

Conclusion

Our study show that TRF has the potential to be an adjuvant to augment DC based immunotherapy.
Impact of clinical urgency, physician supply and procedural capacity on regional variations in wait times for coronary angiography
Authors: Wijeysundera Harindra C , Stukel Therese A , Chong Alice , Natarajan Madhu K , Alter David A
Published: January 2010

Background

Despite universal health care, there continues to be regional access disparities to coronary angiography in Canada. Our objective was to evaluate the extent to which demand-side factors such as clinical urgency/need, and supply-side factors, as reflected by differences in physician and procedural supply account for these inequalities.

Methods

Our cohort consisted of 74,254 consecutive patients referred for coronary angiography in Ontario, Canada between April 1st 2005 and March 31st 2006, divided into three urgency strata based on a clinical urgency scale. Cox-proportional hazard models were developed, adjusting for age, gender, socioeconomic status (SES), region, and urgency score, with greater hazard ratios (HR) indicating shorter wait times. To evaluate mediators of any residual wait-time differences, we examined the influence of the regional supply of cath lab facilities, invasive cardiologists and general practitioners (GP).

Results

We found that the urgency score was a significant predictor of wait time in all three strata (urgent patients: HR 1.61 for each unit increase in patient urgency (95% Confidence interval (CI) 1.55-1.67); semi-urgent patients: HR 1.55 (95% CI 1.44-1.68); elective patients: HR 1.13 (95% CI 1.08-1.18)). After accounting for clinical need/urgency, regional wait time differences persisted; these were most consistently associated with variation in cath lab supply. The impact of invasive cardiologist supply was restricted to urgent patients while that of GP supply was confined to semi-urgent and elective patients.

Conclusion

We found that there remained significant regional disparities in access to coronary angiography after accounting for clinical need. These disparities are partially explained by variations in supply of both procedural capacity and physician services, most notably in elective and semi-urgent patients.
The Nuclear Receptor Corepressor Has Organizational Effects within the Developing Amygdala on Juvenile Social Play and Anxiety-Like Behavior
Authors: Jessen Heather M. , Kolodkin Mira H. , Bychowski Meaghan E. , Auger Catherine J. , Auger Anthony P.
Published: January 2010

Nuclear receptor function on DNA is regulated by the balanced recruitment of coregulatory complexes. Recruited proteins that increase gene expression are called coactivators, and those that decrease gene expression are called corepressors. Little is known about the role of corepressors, such as nuclear receptor corepressor (NCoR), on the organization of behavior. We used real-time PCR to show that NCoR mRNA levels are sexually dimorphic, that females express higher levels of NCoR mRNA within the developing amygdala and hypothalamus, and that NCoR mRNA levels are reduced by estradiol treatment. To investigate the functional role of NCoR on juvenile social behavior, we infused small interfering RNA targeted against NCoR within the developing rat amygdala and assessed the enduring impact on juvenile social play behavior, sociability, and anxiety-like behavior. As expected, control males exhibited higher levels of juvenile social play than control females. Reducing NCoR expression during development further increased juvenile play in males only. Interestingly, decreased NCoR expression within the developing amygdala had lasting effects on increasing juvenile anxiety-like behavior in males and females. These data suggest that the corepressor NCoR functions to blunt sex differences in juvenile play behavior, a sexually dimorphic and hormone-dependent behavior, and appears critical for appropriate anxiety-like behavior in juvenile males and females.
Gonadotropin-Releasing Hormone-I-Mediated Activation of Progesterone Receptor Contributes to Gonadotropin α-Subunit Expression in Mouse Gonadotrophs
Authors: Chen Junling , An Beum-Soo , So Wai-Kin , Cheng Linan , Hammond Geoffrey L. , Leung Peter C. K.
Published: January 2010

In pituitary cells, cross talk between GnRH-I and the progesterone receptor accentuates gonadotropin production. We show that GnRH-I activates a progesterone response element (PRE)-driven luciferase reporter gene at 8 h and gonadotropin α-subunit (gsuα) gene expression at 24 h in two mouse gonadotrope cell lines, αT3-1 and LβT2. In αT3-1 cells, progesterone had an additive effect on GnRH-I-induced PRE-luciferase reporter gene activity but not on GSUα mRNA levels. However, progesterone had no synergistic effect on the GnRH-I-induced expression of these genes in LβT2 cells. Up-regulation of the PRE-luciferase reporter gene by GnRH-I was attenuated by pretreatment with protein kinase A (H89) and protein kinase C (GF109203X) inhibitors in both cell lines, whereas only GF109203X inhibited GnRH-I-induced GSUα mRNA levels. Most important, in both cell lines within the same time frame, knockdown of progesterone receptor levels by small interfering RNA reduced GnRH-I activation of GSUα mRNA levels by approximately 40%. We conclude that the effect of GnRH-I on gsuα expression in both αT3-1 and LβT2 cells is mediated by ligand-independent activation of progesterone receptor and that this contributes to the self-priming effect of GnRH-I in the pituitary.
Bronchial Fistula Associated with Sunitinib in a Patient Previously Treated with Radiation Therapy
Authors: Basille Damien , Andrejak Michel , Bentayeb Houcine , Kanaan Marc , Fournier Clément , Lecuyer Emmanuelle , Boutemy Marie , Garidi Réda , Douadi Youcef , Dayen Charles
Published: January 2010

Objective:

To report a case of bronchial fistula associated with sunitinib in a patient previously treated with radiation therapy.

Case Summary:

A 40-year-old man with renal cell cancer diagnosed in 2005 and initially treated by radical nephrectomy presented in March 2007 with a recurrence with cerebral, mediastinal, and lung metastases. A thoracic computed tomography (CT) scan showed a subcarinal tumor obstructing the bronchus intermedius. The patient was initially treated with cerebral and thoracic radiotherapy and then with sunitinib 50 mg/day (4 weeks on, 2 weeks off). Two months after the beginning of treatment, a CT scan revealed a dramatic reduction in the size of the tumor, associated with a bronchial fistula. This was confirmed by flexible bronchoscopy, which showed complete necrosis of the tumor and a large perforation of the bronchus intermedius. Sunitinib was immediately withdrawn and antibiotic prophylaxis was instituted. It was not possible to place an endobronchial stent. Two weeks later, flexible bronchoscopy revealed the reappearance of a yellowish mass protruding into the bronchus intermedius (40% obstruction). A few months later, the obstruction of the bronchus intermedius progressed to 90% and was associated with a contralateral obstruction of the left mainstem bronchus (20%). A rigid bronchoscopy was then performed to clear the obstruction and an endobronchial stent was placed, with satisfactory initial results. In February 2008, the patient presented with new bronchial obstruction under the endobronchial stent but refused a rigid bronchoscopy and died in March 2008.

Discussion:

Sunitinib, a multitarget tyrosine kinase inhibitor with antiangiogenic and antitumoral activities, has been approved for the treatment of advanced renal cell carcinoma. This treatment is generally well tolerated. Serious complications may occur, however. According to the Naranjo probability scale, the bronchial fistula was possibly related to sunitinib treatment.

Conclusions:

This is a rare case of a bronchial perforation leading to a fistula associated with sunitinib treatment after mediastinal radiation therapy. Clinicians may consider strict follow-up of patients with proximal lung metastases treated with sunitinib (CT scan and, if appropriate, placement of an endobronchial stent).
Capturing autonomy, competence, and relatedness at work: Construction and initial validation of the Work‐related Basic Need Satisfaction scale
Authors: Van den Broeck Anja , Vansteenkiste Maarten , De Witte Hans , Soenens Bart , Lens Willy
Published: January 2010

The satisfaction of the basic psychological needs for autonomy, competence, and relatedness, as defined in Self‐Determination Theory, has been identified as an important predictor of individuals' optimal functioning in various life domains. The study of work‐related need satisfaction seems, however, hampered by the lack of a validated measure. To assist future research, the present study aimed to develop and validate a Work‐related Basic Need Satisfaction scale (W‐BNS). Using four Dutch‐speaking samples, evidence was found for the three‐factor structure of the scale, the discriminant validity, and the reliability of the three need satisfaction subscales as well as their criterion‐related and predictive validity. The W‐BNS may therefore be considered as a promising tool for future research and practice.
Two-color Fluorescence Labeling in Acrolein-fixed Brain Tissue
Authors: Luquin Esther , Pérez-Lorenzo Eva , Aymerich María S. , Mengual Elisa
Published: January 2010

Acrolein is a potent fixative that provides both excellent preservation of ultra-structural morphology and retention of antigenicity, thus it is frequently used for immunocytochemical detection of antigens at the electron microscopic level. However, acrolein is not commonly used for fluorescence microscopy because of concerns about possible autofluorescence and destruction of the luminosity of fluorescent dyes. Here we describe a simple protocol that allows fine visualization of two fluorescent markers in 40-μm sections from acrolein-perfused rat brain. Autofluorescence was removed by pretreatment with 1% sodium borohydride for 30 min, and subsequent incubation in a 50% ethanol solution containing 0.3% hydrogen peroxide enhanced fluorescence labeling. Thus, fluorescence labeling can be used for high-quality detection of markers in tissue perfused with acrolein. Furthermore, adjacent acrolein-fixed sections from a single experiment can be processed to produce high-quality results for electron microscopy or fluorescence labeling.
Identification of Markers for Newly Formed β-Cells in the Perinatal Period: A Time of Recognized β-Cell Immaturity
Authors: Aye Tandy , Toschi Elena , Sharma Arun , Sgroi Dennis , Bonner-Weir Susan
Published: January 2010

Markers of β-cell maturity would be useful in staging the differentiation of stem/progenitor cells to β-cells whether in vivo or in vitro. We previously identified markers for newly formed β-cells in regenerating rat pancreases after 90% partial pancreatectomy. To test the generality of these markers of newly formed β-cells, we examined their expression during the perinatal period, a time of recognized β-cell immaturity. We show by semiquantitative RT-PCR and immunostaining over the time course from embryonic day 18/20 to birth, 1 day, 2 days, 3 days, 7 days, and adult that MMP-2, CK-19, and SPD are truly markers of new and immature β-cells and that their expression transiently peaks in the perinatal period and is not entirely synchronous. The shared expression of these markers among fetal, newborn, and newly regenerated β-cells, but not adult, strongly supports their use as potential markers for new β-cells in the assessment of both the maturity of stem cell–derived insulin-producing cells and the presence of newly formed islets (neogenesis) in the adult pancreas.