bluuebunny/crossref_metadata_2025 huggingface dataset:
'Husband's career first'
Authors: Cooke Fang Lee
Published: February 2007

An increasing number of professional Chinese have been coming to Britain for further education and employment in the last two decades. However, studies on the employment of Chinese migrants in Britain remain limited, particularly of women professionals from mainland China who enter Britain as the following spouse.This article compares the career experience of the ‘trailing’ wives of Chinese academic couples before and after their migration. It investigates what barriers migrant Chinese professional women may encounter in Britain; what familial strategy they adopt in advancing the family's economic and social position; how these Chinese women balance their work and family commitment; what support they receive from their husband to rebuild their career; how they adjust to their new life in Britain; and how they renegotiate their new social identity.
Work restructuring and changing craft identity
Authors: Sayce Susan , Ackers Peter , Greene Anne-Marie
Published: February 2007

This article explores the changes in worker identity that can occur during manufacturing restructuring – specifically those linked to the declining status of craft work – through an in-depth case study of Weaveco, a UK carpet manufacturer. An analysis of changes in the labour process is followed by employee reactions centred on the demise of the traditional craft identity of male carpet weavers. The voices of the weavers dramatize the tensions involved in reconstructing their masculine identity, and we consider the implications this has for understanding gendered work relations.
Empirical Studies in Action Selection with Reinforcement Learning
Authors: Whiteson Shimon , Taylor Matthew E. , Stone Peter
Published: February 2007

To excel in challenging tasks, intelligent agents need sophisticated mechanisms for action selection: they need policies that dictate what action to take in each situation. Reinforcement learning (RL) algorithms are designed to learn such policies given only positive and negative rewards. Two contrasting approaches to RL that are currently in popular use are temporal difference (TD) methods, which learn value functions, and evolutionary methods, which optimize populations of candidate policies. Both approaches have had practical successes but few studies have directly compared them. Hence, there are no general guidelines describing their relative strengths and weaknesses. In addition, there has been little cross-collaboration, with few attempts to make them work together or to apply ideas from one to the other. In this article we aim to address these shortcomings via three empirical studies that compare these methods and investigate new ways of making them work together.

First, we compare the two approaches in a benchmark task and identify variations of the task that isolate factors critical to the performance of each method. Second, we investigate ways to make evolutionary algorithms excel at on-line tasks by borrowing exploratory mechanisms traditionally used by TD methods. We present empirical results demonstrating a dramatic performance improvement. Third, we explore a novel way of making evolutionary and TD methods work together by using evolution to automatically discover good representations for TD function approximators. We present results demonstrating that this novel approach can outperform both TD and evolutionary methods alone.
An Action-Selection Calculus
Authors: Witkowski Mark
Published: February 2007

This article describes a unifying framework for five highly influential but disparate theories of natural learning and behavioral action selection. These theories are normally considered independently, with their own experimental procedures and results. The framework presented builds on a structure of connection types, propagation rules and learning rules, which are used in combination to integrate results from each theory into a whole. These connection types and rules form the action-selection calculus. The calculus will be used to discuss the areas of genuine difference between the factor theories and to identify areas where there is overlap and where apparently disparate findings have a common source. The discussion is illustrated with exemplar experimental procedures. The article focuses on predictive or anticipatory properties inherent in these action-selection and learning theories, and uses the dynamic expectancy model and its computer implementation SRS/E as a mechanism to conduct this discussion.
Localized Debates of Agricultural Biotechnology in Community Newspapers: A Quantitative Content Analysis of Media Frames and Sources
Authors: Crawley Catherine E.
Published: February 2007

This research is a quantitative content analysis of agricultural biotechnology coverage appearing in a collection of community newspapers in Northern California and Missouri between 1992 and 2004. It examines the similarities and differences in news media frames used to focus the debate at the local level, and evaluates the frequency and range of dominant political and social actors as news sources. Newspaper coverage in some community newspapers frames the story in more complex and diverse ways and includes a wider range of voices than has been reported in studies of coverage in the national, elite press. Oppositional viewpoints exist in some local newspapers, perhaps more so than in national news.
PEP/IS: A New Model for Communicative Effectiveness of Science
Authors: Kim Hak-Soo
Published: February 2007

Public engagement with a problem or an issue relative to science (PEP/IS) is suggested as an alternative and complementary model for understanding the communicative effectiveness of science. PEP/IS is conceptualized as the process of individual and collective problem solving in relation to science and exemplified with South Korean exploratory data. Finally, further steps for improving PEP/IS and related research capability are suggested with communicative effectiveness being anticipated.
Where is the pilot? The changing shapes of governance in the European hospital sector
Authors: Eeckloo Kristof , Delesie Luc , Vleugels Arthur
Published: February 2007

Hospital governance refers to the complex of checks and balances that determine how decisions are made within the top structures of hospitals. This article explores the essentials of the concept by analysing the root notion of governance and comparing it with applications in other sectors. Recent developments that put pressure on the decision-making system within hospitals are outlined. Examples from the UK, France and the Netherlands are presented.

Based on an evaluation of the current state of affairs, a research framework is developed, focusing on the determinants of governance configurations within the national healthcare systems and the wider legal and socio-economic context, as well as on the impact of governance configurations on the efficiency of the governing bodies and overall hospital performance.

The article concludes with a preview of the European Hospital Governance Project, which follows the outlines of the described research framework. New techniques of data mining that are used in this project are explained by means of a real data example.
Non-surgical management of stress urinary incontinence: ambulatory treatments for leakage associated with stress (ATLAS) trial
Authors: Richter Holly E , Burgio Kathryn L , Goode Patricia S , Borello-France Diane , Bradley Catherine S , Brubaker Linda , Handa Victoria L , Fine Paul M , Visco Anthony G , Zyczynski Halina M , Wei John T , Weber Anne M ,   for the Pelvic Floor Disorders Network
Published: February 2007

Background Non-surgical treatment for stress urinary incontinence (SUI) is recommended as first-line therapy, yet few prospective studies and no randomized trials compare the most common non-surgical treatments for SUI.

Purpose To present the design and methodology of the ambulatory treatments for leakage associated with stress (ATLAS) trial, a randomized clinical trial comparing three interventions for predominant SUI in women: intravaginal continence pessary; behavioral therapy (including pelvic floor muscle training and exercise and bladder control strategies); and a combination of the two treatments.

Methods Treatment outcome measures, collected at 12 weeks and six and 12 months post randomization, include the Patient Global Impression of Improvement (PGI-I), the Stress Incontinence Scale of the Pelvic Floor Distress Inventory (PFDI), seven-day bladder diaries, Pelvic Floor Impact Questionnaire (PFIQ), Pelvic Organ Prolapse-Urinary Incontinence Sexual Function Questionnaire (PISQ-12), Patient Satisfaction Questionnaire (PSQ) and the Medical Outcomes Study Short Form Health Survey (SF-36).

Limitations The study design reduces most common biases, but some degree of selection bias may remain.

Conclusion This trial will provide useful information to help counsel women with stress and mixed incontinence about the relative efficacy and satisfaction with pessary, behavioral therapy and both treatments combined.
The impact of helminths on the response to immunization and on the incidence of infection and disease in childhood in Uganda: design of a randomized, double-blind, placebo-controlled, factorial trial of deworming interventions delivered in pregnancy and early childhood [ISRCTN32849447]
Authors: Elliott Alison M , Kizza Moses , Quigley Maria A , Ndibazza Juliet , Nampijja Margaret , Muhangi Lawrence , Morison Linda , Namujju Proscovia B , Muwanga Moses , Kabatereine Narcis , Whitwortha James AG
Published: February 2007

Background Helminths have profound effects on the immune response, allowing long-term survival of parasites with minimal damage to the host. Some of these effects “spill-over”, altering responses to non-helminth antigens or allergens. It is suggested that this may lead to impaired responses to immunizations and infections, while conferring benefits against inflammatory responses in allergic and autoimmune disease. These effects might develop in utero, through exposure to maternal helminth infections, or through direct exposure in later life.

Purpose To determine the effects of helminths and their treatment in pregnancy and in young children on immunological and disease outcomes in childhood.

Methods The trial has three randomized, double-blind, placebo-controlled interventions at two times, in two people: a pregnant woman and her child. Pregnant women are randomized to albendazole or placebo and praziquantel or placebo. At age 15 months their children are randomized to three-monthly albendazole or placebo, to continue to age five years. The proposed designation for this sequence of interventions is a 2 × 2(×2) factorial design. Children are immunized with BCG and against polio, Diphtheria, tetanus, Pertussis, Haemophilus, hepatitis B and measles. Primary immunological outcomes are responses to BCG antigens and tetanus toxoid in whole blood cytokine assays and antibody assays at one, three and five years of age. Primary disease outcomes are incidence of malaria, pneumonia, diarrhoea, tuberculosis, measles, vertical HIV transmission, and atopic disease episodes, measured at clinic visits and twice-monthly home visits. Effects on anaemia, growth and intellectual development are also assessed.

Conclusion This trial, with a novel design comprising related interventions in pregnant women and their offspring, is the first to examine effects of helminths and their treatment in pregnancy and early childhood on immunological, infectious disease and allergic disease outcomes. The results will enhance understanding of both detrimental and beneficial effects of helminth infection and inform policy.
Sample-size calculations for trials that inform individual treatment decisions: a ‘true-choice’ approach
Authors: Girling Alan J , Lilford Richard J , Braunholtz David A , Gillett Wayne R
Published: February 2007

Background Sample size decisions for clinical trials should be taken in such a way as to maximize informed choice by reducing scientific uncertainty about the consequences of an intervention.

Purpose Recent approaches to trial design have focused on the potential decision impact of the trial when deciding whether the trial should be undertaken, and how large it ought to be. For the most part these approaches are concerned with the impact of trials either on clinical opinion or on collective reimbursement recommendations. Our purpose is to model the contribution of clinical trials to patient-level decision-making and to propose a way of assessing this contribution at the design stage.

Methods The model is developed within the framework of Bayesian decision theory. It is presumed that some patients make choices that they would not have made in the presence of perfect information about the likely consequences. These ‘false’ choices would be reversed in response to a fully informative (ie, very large) trial of the competing interventions. By contrast, choices that would not change in response to a fully informative trial are termed ‘true’ choices since they accurately reflect patient preferences.

Results An impact plot is proposed which maps how the expected numbers of ‘true’ and ‘false’ choices change in response to a trial of any given size. The approach is illustrated with reference to the choice of delivery mode for term breech presentation, using data obtained before the recent term breech trial. Applications in other contexts are indicated.

Limitations No account is taken of the magnitude of expressed patient preferences for one treatment over another. The upside is that the need for detailed utility-elicitation is obviated.

Conclusions The approach is a pragmatic aid to trial design in settings where patient preference drives the choice between alternative treatments.
A Practical Church Unity within Secular Hospitals
Authors: Balboni Michael
Published: February 2007

Ecclesial unity among Christian physicians is jeopardized by the culture of secular medicine. The medical context, rather than being a neutral sphere, has increasingly become a context that cuts loose and reshapes church members into a secular ecclesia. This thesis is demonstrated through focus groups composed of Christian physician-residents within Harvard Medical School residency programs. The interviews describe how many Christian physicians are psychologically isolated and spiritually endangered because of compliance to secular expectations within academic teaching hospitals. In contrast, the key to undoing secular atomization stems from the nature of the church as a people gathered in the presence of Christ. Thus, the essay develops an ecclesiology that focuses on the manifestation of unity in its local relationships and embodied practices. Despite severe time constraints, Christian physicians have the opportunity to reconstitute a unified church within the secular by pursuing one another in love and offering tangible signs of solidarity.
Aicardi Syndrome: An Unusual Case Associated With Pineal Gland Cyst and Ventricular Septal Defect
Authors: Mutlu Fatih Mehmet , Akin Ridvan , Uysal Yusuf , Unay Bulent , Altinsoy H. İbrahim , Bayraktar M. Zeki
Published: February 2007

Aicardi syndrome is a cerebroretinal disorder consisting of a heterogeneous spectrum of clinical findings that includes the triad of infantile spasms, agenesis of the corpus callosum, and chorioretinal lacunae. This report describes a 6-month-old girl who has all of the essential features suggestive of Aicardi syndrome, as well as a pineal gland cyst and ventricular septal defect. Although the characteristic features of Aicardi syndrome have been described, its association with pineal gland cyst and ventricular septal defect has not been reported in the literature.
Unusual Diagnosis in a Child Suffering From Juvenile Alexander Disease: Clinical and Imaging Report
Authors: Franzoni Emilio , Van der Knaap Marjo S. , Errani Alessandra , Colonnelli Maria Chiara , Bracceschi Roberta , Malaspina Elisabetta , Moscano Filomena Caterina , Garone Caterina , Sarajlija Jasenka , Zimmerman Robert A. , Salomons Gajja S. , Bernardi Bruno
Published: February 2007

Alexander disease is a rare, sporadic leukoencephalopathy characterized by white-matter abnormalities with frontal predominance and, as a rule, clinically associated with megalencephaly, seizures, spasticity, and psychomotor deterioration. We describe a boy who was diagnosed as affected by anorexia nervosa because of his refusal to eat, progressive weight loss, and psychologic disturbances. The observation of a hyperintense lesion on T2-weighed magnetic resonance images (MRIs) was initially explained as a pontine and extrapontine myelinolysis related to malnutrition. Following MRI and DNA analysis, we diagnosed a juvenile type of Alexander disease. Therefore, we can affirm the importance of the history and clinical examination to look for brainstem dysfunction in patients presenting with atypical anorexia nervosa.
Association Between Amygdala Volume and Anxiety Level: Magnetic Resonance Imaging (MRI) Study in Autistic Children
Authors: Juranek Jenifer , Filipek Pauline A. , Berenji Gholam R. , Modahl Charlotte , Osann Kathryn , Spence M. Anne
Published: February 2007

Our objective was to evaluate brain-behavior relationships between amygdala volume and anxious/depressed scores on the Child Behavior Checklist in a well-characterized population of autistic children. Volumes for the amygdala, hippocampus, and whole brain were obtained from three-dimensional magnetic resonance images (MRIs) captured from 42 children who met the criteria for autistic disorder. Anxious/depressed symptoms were assessed in these children by the Anxious/Depressed subscale of the Child Behavior Checklist. To investigate the association between anxious/depressed scores on the Child Behavior Checklist and amygdala volume, data were analyzed using linear regression methods with Pearson correlation coefficients. A multivariate model was used to adjust for potential covariates associated with amygdala volume, including age at MRI and total brain size. We found that anxious/depressed symptoms were significantly correlated with increased total amygdala volume (r = .386, P = .012) and right amygdala volume (r = .469, P = .002). The correlation between anxious/depressed symptoms and left amygdala volume did not reach statistical significance (r = .249, P = .112). Child Behavior Checklist anxious/depressed scores were found to be a significant predictor of amygdala total (P = .014) and right amygdala (P = .002) volumes. In conclusion, we have identified a significant brain-behavior relationship between amygdala volume and anxious/depressed scores on the Child Behavior Checklist in our autistic cohort. This specific relationship has not been reported in autism. However, the existing literature on human psychiatry and behavior supports our reported evidence for a neurobiologic relationship between symptoms of anxiety and depression with amygdala structure and function. Our results highlight the importance of characterizing comorbid psychiatric symptomatology in autism. The abundance of inconsistent findings in the published literature on autism might reflect differences between study populations regarding age at MRI, level of impairment within autistic subjects, and underlying anxiety level in the selected study groups.
Proton Magnetic Resonance Spectroscopy Findings and Clinical Effects of Montelukast Sodium in a Case With Sjögren-Larsson Syndrome
Authors: Pirgon Ozgur , Aydin Kursad , Atabek M. Emre
Published: February 2007

Sjögren-Larsson syndrome is a rare hereditary metabolic disorder characterized by congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. This genetic disease is caused by fatty acid aldehyde dehydrogenase deficiency, leading to an accumulation of long-chain alcohols. The role of enzyme in the degradation of leukotrienes paved the way to the development of a new therapeutic strategy for Sjögren-Larsson syndrome, leukotriene antagonists. We describe a 3-year-old boy with Sjögren-Larsson syndrome who had a lipid peak on proton magnetic resonance spectroscopy despite normal findings on cerebral magnetic resonance imaging. He benefited from treatment with montelukast sodium, especially with respect to the agonizing pruritus.
A complex splicing defect associated with homozygous ankyrin-deficient hereditary spherocytosis
Authors: Edelman E. Jennifer , Maksimova Yelena , Duru Feride , Altay Cigdem , Gallagher Patrick G.
Published: February 2007

Defects in erythrocyte ankyrin are the most common cause of typical, dominant hereditary spherocytosis (HS). Detection of ankyrin gene mutations has been complicated by allelic heterogeneity, large gene size, frequent de novo mutations, and associated mRNA instability. Using denaturing high-performance liquid chromatography (DHPLC)–based mutation detection, a mutation in the splice acceptor of exon 17 was discovered in a Turkish family. Reticulocyte RNA and functional minigene splicing assays in heterologous cells revealed that this mutation was associated with a complex pattern of aberrant splicing, suggesting that removal of intron 16 is important for ordered ankyrin mRNA splicing. As predicted by clinical, laboratory, and biochemical studies, the parents were heterozygous and the proband was homozygous for this mutation. These data indicate that DHPLC offers a highly sensitive, economic, and rapid method for mutation detection and, unlike previously suggested, homozygosity for a mutation associated with dominant ankyrin-linked HS may be compatible with life.
Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer
Authors: Venneri Mary Anna , Palma Michele De , Ponzoni Maurilio , Pucci Ferdinando , Scielzo Cristina , Zonari Erika , Mazzieri Roberta , Doglioni Claudio , Naldini Luigi
Published: February 2007

Tumor-infiltrating myeloid cells, including tumor-associated macrophages (TAMs), have been implicated in tumor progression. We recently described a lineage of mouse monocytes characterized by expression of the Tie2 angiopoietin receptor and required for the vascularization and growth of several tumor models. Here, we report that TIE2 expression in human blood identifies a subset of monocytes distinct from classical inflammatory monocytes and comprised within the less abundant “resident” population. These TIE2-expressing monocytes (TEMs) accounted for 2% to 7% of blood mononuclear cells in healthy donors and were distinct from rare circulating endothelial cells and progenitors. In human cancer patients, TEMs were observed in the blood and, intriguingly, within the tumors, where they represented the main monocyte population distinct from TAMs. Conversely, TEMs were hardly detected in nonneoplastic tissues. In vitro, TEMs migrated toward angiopoietin-2, a TIE2 ligand released by activated endothelial cells and angiogenic vessels, suggesting a homing mechanism for TEMs to tumors. Purified human TEMs, but not TEM-depleted monocytes, markedly promoted angiogenesis in xenotransplanted human tumors, suggesting a potentially critical role of TEMs in human cancer progression. Human TEMs may provide a novel, biologically relevant marker of angiogenesis and represent a previously unrecognized target of cancer therapy.
Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia
Authors: Fulci Valerio , Chiaretti Sabina , Goldoni Marina , Azzalin Gianluca , Carucci Nicoletta , Tavolaro Simona , Castellano Leandro , Magrelli Armando , Citarella Franca , Messina Monica , Maggio Roberta , Peragine Nadia , Santangelo Simona , Mauro Francesca Romana , Landgraf Pablo , Tuschl Thomas , Weir David B. , Chien Minchen , Russo James J. , Ju Jingyue , Sheridan Robert , Sander Chris , Zavolan Mihaela , Guarini Anna , Foà Robin , Macino Giuseppe
Published: February 2007

MicroRNAs (miRNAs) are a novel class of small noncoding RNAs that modulate the expression of genes at the posttranscriptional level. These small molecules have been shown to be involved in cancer, apoptosis, and cell metabolism. In the present study we provide an informative profile of the expression of miRNAs in primary chronic lymphocytic leukemia (CLL) cells using 2 independent and quantitative methods: miRNA cloning and quantitative real-time–polymerase chain reaction (qRT-PCR) of mature miRNAs. Both approaches show that miR-21 and miR-155 are dramatically overexpressed in patients with CLL, although the corresponding genomic loci are not amplified. miR-150 and miR-92 are also significantly deregulated in patients with CLL. In addition, we detected a marked miR-15a and miR-16 decrease in about 11% of cases. Finally, we identified a set of miRNAs whose expression correlates with biologic parameters of prognostic relevance, particularly with the mutational status of the IgVH genes. In summary, the results of this study offer for the first time a comprehensive and quantitative profile of miRNA expression in CLL and their healthy counterpart, suggesting that miRNAs could play a primary role in the disease itself.
AGGRESCAN: a server for the prediction and evaluation of "hot spots" of aggregation in polypeptides
Authors: Conchillo-Solé Oscar , de Groot Natalia S , Avilés Francesc X , Vendrell Josep , Daura Xavier , Ventura Salvador
Published: February 2007

Background

Protein aggregation correlates with the development of several debilitating human disorders of growing incidence, such as Alzheimer's and Parkinson's diseases. On the biotechnological side, protein production is often hampered by the accumulation of recombinant proteins into aggregates. Thus, the development of methods to anticipate the aggregation properties of polypeptides is receiving increasing attention. AGGRESCAN is a web-based software for the prediction of aggregation-prone segments in protein sequences, the analysis of the effect of mutations on protein aggregation propensities and the comparison of the aggregation properties of different proteins or protein sets.

Results

AGGRESCAN is based on an aggregation-propensity scale for natural amino acids derived from in vivo experiments and on the assumption that short and specific sequence stretches modulate protein aggregation. The algorithm is shown to identify a series of protein fragments involved in the aggregation of disease-related proteins and to predict the effect of genetic mutations on their deposition propensities. It also provides new insights into the differential aggregation properties displayed by globular proteins, natively unfolded polypeptides, amyloidogenic proteins and proteins found in bacterial inclusion bodies.

Conclusion

By identifying aggregation-prone segments in proteins, AGGRESCAN http://bioinf.uab.es/aggrescan/ shall facilitate (i) the identification of possible therapeutic targets for anti-depositional strategies in conformational diseases and (ii) the anticipation of aggregation phenomena during storage or recombinant production of bioactive polypeptides or polypeptide sets.
Tissue and subcellular distribution of CLIC1
Authors: Ulmasov Barbara , Bruno Jonathan , Woost Philip G , Edwards John C
Published: February 2007

Background

CLIC1 is a chloride channel whose cellular role remains uncertain. The distribution of CLIC1 in normal tissues is largely unknown and conflicting data have been reported regarding the cellular membrane fraction in which CLIC1 resides.

Results

New antisera to CLIC1 were generated and were found to be sensitive and specific for detecting this protein. These antisera were used to investigate the distribution of CLIC1 in mouse tissue sections and three cultured cell lines. We find CLIC1 is expressed in the apical domains of several simple columnar epithelia including glandular stomach, small intestine, colon, bile ducts, pancreatic ducts, airway, and the tail of the epididymis, in addition to the previously reported renal proximal tubule. CLIC1 is expressed in a non-polarized distribution in the basal epithelial cell layer of the stratified squamous epithelium of the upper gastrointesitinal tract and the basal cells of the epididymis, and is present diffusely in skeletal muscle. Distribution of CLIC1 was examined in Panc1 cells, a relatively undifferentiated, non-polarized human cell line derived from pancreatic cancer, and T84 cells, a human colon cancer cell line which can form a polarized epithelium that is capable of regulated chloride transport. Digitonin extraction was used to distinguish membrane-inserted CLIC1 from the soluble cytoplasmic form of the protein. We find that digitonin-resistant CLIC1 is primarily present in the plasma membrane of Panc1 cells. In T84 cells, we find digitonin-resistant CLIC1 is present in an intracellular compartment which is concentrated immediately below the apical plasma membrane and the extent of apical polarization is enhanced with forskolin, which activates transepithelial chloride transport and apical membrane traffic in these cells. The sub-apical CLIC1 compartment was further characterized in a well-differentiated mouse renal proximal tubule cell line. The distribution of CLIC1 was found to overlap that of megalin and the sodium-phosphate cotransporter, NaPi-II, which are markers of the apical endocytic/recycling compartment in proximal tubule.

Conclusion

The cell and tissue specific patterns of CLIC1 expression suggest it may play distinct roles in different cell types. In certain polarized columnar epithelia, it may play a role in apical membrane recycling.
Temporal dynamics of gene expression in the lung in a baboon model of E. coli sepsis
Authors: Zhu Hua , Tang Yuhong , Ivanciu Lacramioara , Centola Michael , Lupu Cristina , Taylor Fletcher B , Lupu Florea
Published: February 2007

Background

Bacterial invasion during sepsis induces disregulated systemic responses that could lead to fatal lung failure. The purpose of this study was to relate the temporal dynamics of gene expression to the pathophysiological changes in the lung during the first and second stages of E. coli sepsis in baboons.

Results

Using human oligonucleotide microarrays, we have explored the temporal changes of gene expression in the lung of baboons challenged with sublethal doses of E. coli. Temporal expression pattern and biological significance of the differentially expressed genes were explored using clustering and pathway analysis software. Expression of selected genes was validated by real-time PCR. Cytokine levels in tissue and plasma were assayed by multiplex ELISA. Changes in lung ultrastructure were visualized by electron microscopy. We found that genes involved in primary inflammation, innate immune response, and apoptosis peaked at 2 hrs. Inflammatory and immune response genes that function in the stimulation of monocytes, natural killer and T-cells, and in the modulation of cell adhesion peaked at 8 hrs, while genes involved in wound healing and functional recovery were upregulated at 24 hrs.

Conclusion

The analysis of gene expression modulation in response to sepsis provides the baseline information that is crucial for the understanding of the pathophysiology of systemic inflammation and may facilitate the development of future approaches for sepsis therapy.
Effective quantitative real-time polymerase chain reaction analysis of the parkin gene (PARK2) exon 1–12 dosage
Authors: Shadrina Maria I , Semenova Elena V , Slominsky Petr A , Bagyeva Gulbahar H , Illarioshkin Sergei N , Ivanova-Smolenskaia Irina I , Limborska Svetlana A
Published: February 2007

Background

One of the causes of Parkinson's disease is mutations in the PARK2 gene. Deletions and duplications of single exons or exon groups account for a large proportion of the gene mutations. Direct detection of these mutations can be used for the diagnosis of Parkinson's disease.

Methods

To detect these mutations, we developed an effective technique based on the real-time TaqMan PCR system, which allows us to evaluate the copynumbers of the PARK2 gene exons by comparing the intensity of the amplification signals from some exon of this gene with that of the β-globin gene (the internal control).

Results

We analyzed rearrangements in exons 1–12 of the PARK2 gene in 64 patients from Russia with early-onset Parkinson's disease. The frequency of these mutations in our patients was 14%.

Conclusion

We have developed a simple, accurate, and reproducible method applicable to the rapid detection of exon rearrangements in the PARK2 gene. It is suitable for the analysis of large patient groups, and it may become the basis for a diagnostic test.
Growth regulation of simian and human AIDS-related non-Hodgkin's lymphoma cell lines by TGF-β1 and IL-6
Authors: Ruff Kristin R , Puetter Adriane , Levy Laura S
Published: February 2007

Background

AIDS-related non-Hodgkin's lymphoma (AIDS-NHL) is the second most frequent cancer associated with AIDS, and is a frequent cause of death in HIV-infected individuals. Experimental analysis of AIDS-NHL has been facilitated by the availability of an excellent animal model, i.e., simian Acquired Immunodeficiency Syndrome (SAIDS) in the rhesus macaque consequent to infection with simian immunodeficiency virus. A recent study of SAIDS-NHL demonstrated a lymphoma-derived cell line to be sensitive to the growth inhibitory effects of the ubiquitous cytokine, transforming growth factor-beta (TGF-beta). The authors concluded that TGF-beta acts as a negative growth regulator of the lymphoma-derived cell line and, potentially, as an inhibitory factor in the regulatory network of AIDS-related lymphomagenesis. The present study was conducted to assess whether other SAIDS-NHL and AIDS-NHL cell lines are similarly sensitive to the growth inhibitory effects of TGF-beta, and to test the hypothesis that interleukin-6 (IL-6) may represent a counteracting positive influence in their growth regulation.

Methods

Growth stimulation or inhibition in response to cytokine treatment was quantified using trypan blue exclusion or colorimetric MTT assay. Intracellular flow cytometry was used to analyze the activation of signaling pathways and to examine the expression of anti-apoptotic proteins and distinguishing hallmarks of AIDS-NHL subclass. Apoptosis was quantified by flow cytometric analysis of cell populations with sub-G1 DNA content and by measuring activated caspase-3.

Results

Results confirmed the sensitivity of LCL8664, an immunoblastic SAIDS-NHL cell line, to TGF-beta1-mediated growth inhibition, and further demonstrated the partial rescue by simultaneous treatment with IL-6. IL-6 was shown to activate STAT3, even in the presence of TGF-beta1, and thereby to activate proliferative and anti-apoptotic pathways. By comparison, human AIDS-NHL cell lines differed in their responsiveness to TGF-beta1 and IL-6. Analysis of a recently derived AIDS-NHL cell line, UMCL01-101, indicated that it represents immunoblastic AIDS-DLCBL. Like LCL-8664, UMCL01-101 was sensitive to TGF-beta1-mediated inhibition, rescued partially by IL-6, and demonstrated rapid STAT3 activation following IL-6 treatment even in the presence of TGF-beta1.

Conclusion

These studies indicate that the sensitivity of immunoblastic AIDS- or SAIDS-DLBCL to TGF-beta1-mediated growth inhibition may be overcome through the stimulation of proliferative and anti-apoptotic signals by IL-6, particularly through the rapid activation of STAT3.
Eruptive papules during efalizumab (anti-CD11a) therapy of psoriasis vulgaris: a case series
Authors: Lowes Michelle A , Chamian Francesca , Abello Maria V , Leonardi Craig , Dummer Wolfgang , Papp Kim , Krueger James G
Published: February 2007

Background

Newer biological therapies for moderate-to-severe psoriasis are being used more frequently, but unexpected effects may occur.

Case presentations

We present a group of 15 patients who developed inflammatory papules while on efalizumab therapy (Raptiva, Genentech Inc, anti-CD11a). Immunohistochemistry showed that there were increased CD11b+, CD11c+ and iNOS+ cells (myeloid leukocytes) in the papules, with relatively few CD3+ T cells. While efalizumab caused a decreased expression of CD11a on T cells, other circulating leukocytes from patients receiving this therapy often showed increased CD11b and CD11c. In the setting of an additional stimulus such as skin trauma, this may predispose to increased trafficking into the skin using these alternative β2 integrins. In addition, there may be impaired immune synapse formation, limiting the development of these lesions to small papules. There is little evidence for these papular lesions being "allergic" in nature as there are few eosinophils on biopsy, and they respond to minimal or no therapy even if efalizumab is continued.

Conclusion

We hypothesize that these papules may represent a unique type of "mechanistic" inflammatory reaction, seen only in the context of drug-induced CD11a blockade, and not during the natural disease process.
Expression, intracellular targeting and purification of HIV Nef variants in tobacco cells
Authors: Marusic Carla , Nuttall James , Buriani Giampaolo , Lico Chiara , Lombardi Raffaele , Baschieri Selene , Benvenuto Eugenio , Frigerio Lorenzo
Published: February 2007

Background

Plants may represent excellent alternatives to classical heterologous protein expression systems, especially for the production of biopharmaceuticals and vaccine components. Modern vaccines are becoming increasingly complex, with the incorporation of multiple antigens. Approaches towards developing an HIV vaccine appear to confirm this, with a combination of candidate antigens. Among these, HIV-Nef is considered a promising target for vaccine development because immune responses directed against this viral protein could help to control the initial steps of viral infection and to reduce viral loads and spreading. Two isoforms of Nef protein can be found in cells: a full-length N-terminal myristoylated form (p27, 27 kDa) and a truncated form (p25, 25 kDa). Here we report the expression and purification of HIV Nef from transgenic tobacco.

Results

We designed constructs to direct the expression of p25 and p27 Nef to either the cytosol or the secretory pathway. We tested these constructs by transient expression in tobacco protoplasts. Cytosolic Nef polypeptides are correctly synthesised and are stable. The same is not true for Nef polypeptides targeted to the secretory pathway by virtue of a signal peptide. We therefore generated transgenic plants expressing cytosolic, full length or truncated Nef. Expression levels were variable, but in some lines they averaged 0.7% of total soluble proteins. Hexahistidine-tagged Nef was easily purified from transgenic tissue in a one-step procedure.

Conclusion

We have shown that transient expression can help to rapidly determine the best cellular compartment for accumulation of a recombinant protein. We have successfully expressed HIV Nef polypeptides in the cytosol of transgenic tobacco plants. The proteins can easily be purified from transgenic tissue.
Design of a retrospective patient record study on the occurrence of adverse events among patients in Dutch hospitals
Authors: Zegers Marieke , de Bruijne Martine C , Wagner Cordula , Groenewegen Peter P , Waaijman Roelof , van der Wal Gerrit
Published: February 2007

Background

Various international studies have shown that a substantial number of patients suffer from injuries or even die as a result of care delivered in hospitals. The occurrence of injuries among patients caused by health care management in Dutch hospitals has never been studied systematically. Therefore, an epidemiological study was initiated to determine the incidence, type and impact of adverse events among discharged and deceased patients in Dutch hospitals.

Methods/Design

Three stage retrospective patient record review study in 21 hospitals of 8400 patient records of discharged or deceased patients in 2004. The records were reviewed by trained nurses and physicians between August 2005 and October 2006. In addition to the determination of presence, the degree of preventability, and causes of adverse events, also location, timing, classification, and most responsible specialty of the adverse events were measured. Moreover, patient and admission characteristics and the quality of the patient records were recorded.

Discussion

In this paper we report on the design of the retrospective patient record study on the occurrence of adverse events in Dutch hospitals. Attention is paid to the strengths and limitations of the study design. Furthermore, alterations made in the original research protocol in comparison with former international studies are described in detail.
Randomised controlled trial of a psychiatric consultation model for treatment of common mental disorder in the occupational health setting
Authors: van der Feltz-Cornelis Christina M , Meeuwissen Jolanda AC , de Jong Fransina J , Hoedeman Rob , Elfeddali Iman
Published: February 2007

Background

Common mental disorders are the most prevalent of all mental disorders, with the highest burden in terms of work absenteeism and utilization of health care services. Evidence-based treatments are available, but recognition and treatment could be improved, especially in the occupational health setting. The situation in this setting has recently changed in the Netherlands because of new legislation, which has resulted in reduced sickness absence. Severe mental disorder has now become one of the main causes of work absenteeism. Occupational physicians (OPs) are expected to take an active role in diagnosis and treatment, and seem to be in need of support for a new approach to handle cases of more complex mental disorders. Psychiatric consultation can be a collaborative care model to achieve this.

Methods/design

This is a two-armed cluster-randomized clinical trial, with randomization among OPs. Forty OPs in two big companies providing medical care for multiple companies will be randomized to either the intervention group, i.e. psychiatric consultation embedded in a training programme, or the control group, i.e. only training aimed at recognition and providing Care As Usual. 60 patients will be included who have been absent from work for 6–52 weeks and who, after screening and a MINI interview, are diagnosed with depressive disorder, anxiety disorder or somatoform disorder based on DSM-IV criteria. Baseline measurements and follow up measurements (at 3 months and 6 months) will be assessed with questionnaires and an interview. The primary outcome measure is level of general functioning according to the SF-20. Secondary measures are severity of the mental disorder according to the PHQ and the SCL-90, quality of life (EQ-D5), measures of Return To Work and cost-effectiveness of the treatment assessed with the TiC-P. Process measures will be adherence to the treatment plan and assessment of the treatment provided by the Psychiatric Consultant (PC) in both groups.

Discussion

In the current study, a psychiatric consultation model that has already proved to be effective in the primary care setting, and aimed to enhance evidence-based care for patients with work absenteeism and common mental disorder will be evaluated for its efficacy and cost-effectiveness in the occupational health setting.
The role of regulation in influencing income-generating activities among public sector doctors in Peru
Authors: Jumpa Manuel , Jan Stephen , Mills Anne
Published: February 2007

Objective

To examine in Peru the nature of dual practice (doctors holding two jobs at once – usually public sector doctors with private practices), the factors that influence individuals' decisions to undertake dual practice, the conditions faced when doing so and the potential role of regulatory intervention in this area.

Methods

The study entailed qualitative interviews with a sample of twenty medical practitioners based in metropolitan Lima, representing a cross-section of those primarily employed in either the private or public sectors and engaged in clinical practice or policy making. The interviews focused on:

individuals' experience with dual practice;

the general underlying pressures that influence the nature and extent of such activities; and

attitudes toward, and the influence of, regulation on such activities.

Results

Dual practice is an activity that is widespread and well-accepted, and the prime personal motivation is financial. However, there are also a number of important broad macroeconomic influences on dual practice particularly the oversupply of medical services, the deregulated nature of this market, and the economic crisis throughout the country, which combine to create major hardships for those attempting to make a living through medical practice. There is some support among doctors for tighter regulation.

Conclusion

Research findings suggest appropriate policy responses to dual practice involve tighter controls on the supply of medical practitioners; alleviation of financial pressures brought by macro-economic conditions; and closer regulation of such activities to ensure some degree of collective action over quality and the maintenance of professional reputations. Further research into this issue in rural areas is needed to ascertain the geographical generalizability of these policy responses.
FBXW7/hCDC4 controls glioma cell proliferation in vitro and is a prognostic marker for survival in glioblastoma patients
Authors: Hagedorn Martin , Delugin Maylis , Abraldes Isabelle , Allain Nathalie , Belaud-Rotureau Marc-Antoine , Turmo Michelle , Prigent Claude , Loiseau Hugues , Bikfalvi Andréas , Javerzat Sophie
Published: February 2007

Background

In the quest for novel molecular mediators of glioma progression, we studied the regulation of FBXW 7 (hCDC 4/hAGO/SEL 10), its association with survival of patients with glioblastoma and its potential role as a tumor suppressor gene in glioma cells. The F-box protein Fbxw7 is a component of SCFFbxw7, a Skp1-Cul1-F-box E3 ubiquitin ligase complex that tags specific proteins for proteasome degradation. FBXW 7 is mutated in several human cancers and functions as a haploinsufficient tumor suppressor in mice. Any of the identified targets, Cyclin E, c-Myc, c-Jun, Notch1/4 and Aurora-A may have oncogenic properties when accumulated in tumors with FBXW 7 loss.

Results

We tested the expression of FBXW 7 in human glioma biopsies by quantitative PCR and compared the transcript levels of grade IV glioma (glioblastoma, G-IV) with those of grade II tumors (G-II). In more than 80% G-IV, expression of FBXW 7 was significantly reduced. In addition, levels of FBXW 7 were correlated with survival indicating a possible implication in tumor aggressiveness. Locus 4q31.3 which carries FBXW 7 was investigated by in situ hybridization on biopsy touchprints. This excluded allelic loss as the principal cause for low expression of FBXW 7 in G-IV tumors. Two targets of Fbxw7, Aurora-A and Notch4 were preferentially immunodetected in G-IV biopsies. Next, we investigated the effects of FBXW 7 misregulation in glioma cells. U87 cells overexpressing nuclear isoforms of Fbxw7 lose the expression of the proliferation markers PCNA and Ki-67, and get counterselected in vitro. This observation fits well with the hypothesis that Fbxw7 functions as a tumor suppressor in astroglial cells. Finally, FBXW 7 knockdown in U87 cells leads to defects in mitosis that may promote aneuploidy in progressing glioma.

Conclusion

Our results show that FBXW 7 expression is a prognostic marker for patients with glioblastoma. We suggest that loss of FBXW 7 plays an important role in glioma malignancy by allowing the accumulation of multiple oncoproteins and that interfering with Fbxw7 or its downstream targets would constitute a new therapeutic advance.