bluuebunny/crossref_metadata_2025 huggingface dataset:
Biological monitoring and questionnaire for assessing exposure to ethylenebisdithiocarbamates in a multicenter European field study
Authors: Fustinoni S , Campo L , Liesivuori J , Pennanen S , Vergieva T , van Amelsvoort LGPM , Bosetti C , Van Loveren H , Colosio C
Published: November 2008

This study deals with pesticide exposure profile in some European countries with a specific focus on ethylenebisdithiocarbamates (EBDC). In all, 55 Bulgarian greenhouse workers, 51 Finnish potato farmers, 48 Italian vineyard workers, 42 Dutch floriculture farmers, and 52 Bulgarian zineb producers entered the study. Each group was matched with a group of not occupationally exposed subjects. Exposure data were gained through self-administered questionnaires and measuring ethylenethiourea (ETU) in two spot urine samples collected, respectively, before the beginning of seasonal exposure (T0), and after 30 days, at the end of the exposure period (T30). Controls underwent a similar protocol. Study agriculture workers were involved in mixing and loading pesticides, application of pesticide mixture with mechanical or manual equipments, re-entry activities, and cleaning equipments. Chemical workers were involved in synthesis, quality controls, and packing activities. The number of pesticides to whom these subjects were exposed varied from one (zineb production) to eight (potato farmers). The use of personal protective devices was variegate and regarded both aerial and dermal penetration routes. EBDC exposure, assessed by T30 urinary ETU, was found to follow the order: greenhouse workers, zineb producers, vineyard workers, potato farmers, floriculture farmers with median levels of 49.6, 23.0, 11.8, 7.5, and 0.9 μg/g creatinine; the last group having ETU at the same level of controls (~0.5 μg/g creatinine). Among agriculture workers, pesticide application, especially using manual equipment, seems to be the major determinant in explaining internal dose. Although the analysis of self-administered questionnaires evidenced difficulties especially related to lack and/or poor quality of reported data, biological monitoring confirms to be a powerful tool in assessing pesticide exposure.
Anisotropic Damage-coupled Sheet Metal Forming Limit Analysis
Authors: Chow C.L. , Jie M.
Published: November 2008

This article presents a review of the sheet metal formability analysis based on the theory of damage mechanics. Specifically, the damage anisotropy is considered. Forming limit analyses based on the anisotropic damage are summarized, including the accumulative critical damage method, the damage-coupled vertex theory and the damage-coupled acoustic tensor method. The accumulative critical damage method postulates that the critical damage at the localized necking is strain-path or loading history independent. It can be applied to predict the forming limit diagrams under either proportional or nonproportional loading. The vertex theory considers that localized necking is associated with the vertex developed on yield surface. The theory is applicable to engineering materials exhibiting the strain-hardening and/or strain-rate dependent behaviors. The acoustic tensor method, on the other hand, can only be applied to the strain-softening materials, which are often observed in warm/hot sheet metal forming or hydroforming.
Multi-level Elastoplastic Damage Mechanics for Elliptical Fiber-reinforced Composites with Evolutionary Fiber Debonding
Authors: Ju J.W. , Ko Y.F. , Zhang X.D.
Published: November 2008

A micromechanical multi-level elastoplastic evolutionary damage framework is proposed to predict the overall mechanical behavior and interfacial damage evolutions of elliptical fiber-reinforced ductile composites. Progressively debonded fibers are replaced by equivalent microvoids. The effective elastic moduli of three phase composites, composed of a ductile matrix, randomly located yet monotonically aligned elliptical fibers and elliptical microvoids, are derived by using a micromechanical formulation. In order to characterize the homogenized elastoplastic behavior, an effective yield criterion is derived based on the ensemble-area averaging process and the first-order effects of eigenstrains. The resulting effective yield criterion, together with the overall associative plastic flow rule and the hardening law, constitutes the analytical framework for the estimation of effective elastoplastic damage responses of ductile composites containing both perfectly bonded and completely debonded fibers. An evolutionary interfacial fiber debonding process, governed by the internal stresses of fibers and the interfacial strength, is incorporated into the proposed work. The Weibull's probabilistic distribution is employed to describe the varying probability of fiber debonding. Further, systematic numerical simulations are presented to illustrate the potential of the proposed methodology.
Patterns of tobacco use: A 10-year follow-up study of smoking and snus habits in a middle-aged Swedish population
Authors: Lundqvist Gunnar , Sandström Herbert , Öhman Ann , Weinehall Lars
Published: November 2008

Aims: To study longitudinal patterns of tobacco use over a 10-year period among middle-aged men and women in Vaösterbotten County, Northern Sweden. Methods: The study is based on data from the 16,486 (8800 women and 7686 men) in the Vaösterbotten Intervention Programme (VIP) where people were invited to a health screening and counselling programme at 30, 40, 50 and 60 years of age. Results: Smoking decreased from 22.3% to 15.6% among women and from 18.5% to 12.7% among men. Use of snus (Swedish moist snuff) increased from 3.1% to 6.0% among women and from 24.6% to 26.3% among men. The number of people who used both snus and cigarettes was stable: 0.5% to 0.8% from baseline to follow-up for women, and 4.1% to 3.3% for men. The number of tobacco-free adults increased from 75.2% to 79.2% for women and from 61.1% to 64.3% for men. Of those who became smoke-free during the 10-year follow-up period, 80% of the women and 66% of the men quit smoking without transitioning to snus use. Conclusions: The majority of middle-aged Swedish men and women in this cohort that quit smoking did so without becoming snus dependent. In spite of an increasing use of snus, overall there was a decline in the number of people using tobacco products.
Habit and conscious control
Authors: Tarr Jen
Published: November 2008

This article examines the process of learning the Alexander Technique, a method of body re-education, in relation to Bourdieu's observation that bodily knowledge is often subconscious and not easily translatable into words (1988). It argues that Alexander Technique is a useful case study for examining how the body learns because of the Technique's emphasis on conscious awareness and overcoming habitual reactions. Based on 18 months of fieldwork undertaking lessons in Alexander Technique and interviewing teachers and pupils, the Technique is examined as a `somatic mode of attention' (Csordas, 2002) and its effects on the habitus and bodily hexis are discussed. The relationship between habit and conscious control in the Technique has implications for our understanding of embodiment in the context of teaching and learning bodily practices.
The tail is wagging the dog
Authors: Howe P. David
Published: November 2008

The rules and regulations regarding the classification process through which athletes must be vetted to determine eligibility for Paralympic competition have been transformed drastically over the last two decades. A complex classification system initially developed by the International Organizations of Sport for the Disabled (IOSD) has been the distinctive feature of the Paralympic movement over this period. Key consideration must be given to the equitable nature of any classification system imposed by the International Paralympic Committee (IPC) in order to comply with the ideology of Paralympism. Paralympism is manifest in the dictum of the Paralympic movement: ` empower, inspire and achieve'. Using ethnographic data obtained by the author while a Paralympic athlete and journalist, this article explores recent debates within the sport of athletics surrounding classification. This is achieved by highlighting the process of classification and how, as a result of this process, some bodies are celebrated and others are not within a sporting culture established as a ghetto for imperfection.
Ethereal expression
Authors: Wulff Helena
Published: November 2008

Set in 19th-century Romanticism, classical ballets are still playing to full opera houses across the globe. This article explores paradoxes of time, cultural capital and gender in ballet as a global physical culture on- and off-stage. Drawing on ethnography of three national ballet companies in Stockholm, London and New York and a contemporary company in Frankfurt-am-Main, I suggest that classical ballet is preserved because it is not only a `high' culture, but also a physical culture which has been taught and cultivated between bodies for centuries. Scrutinizing the stories of the Romantic ballets that originated during an era in Europe when the supernatural was à la mode and class and cultural background had a greater impact on marriage choice than today, we note that ballets still have the ability to touch audiences through the archetypical themes of love in relation to social structure and norms, desire and morality. The most popular classical ballet productions such as Swan Lake, La Sylphide and Giselle have been challenged in radical contemporary versions which confirm the prominent position of classical ballet both in the ballet world and society at large. Comparative ethnographic work on ballet schools in different locations helps to uncover the global connections that point to the robust existence of ballet as a unitary form of physical culture.
Review: Managing TB in the 21st century: existing and novel drug therapies
Authors: Guy Elizabeth S. , Mallampalli Antara
Published: November 2008

With an estimated one-third of the world's population infected with Mycobacterium tuberculosis (MTB) and approximately 1.6 million deaths in 2006 attributed to tuberculosis (TB) world-wide, TB remains a major public health concern today. Considerable advances have been made in the effective treatment of TB, in particular with the adoption of directly observed therapy short course (DOTS), in national TB control programs, but in spite of this the currently available regimens are suboptimal. The long courses of therapy required, together with significant medication side-effects and resulting difficulties with adherence to therapy all contribute to increasing problems with emerging drug resistance. There is thus an urgent need for new antituberculous drug development, especially to enable effective shorter course therapy for drug-susceptible and resistant TB, to find effective drugs for treatment of drug-resistant TB, to shorten therapy for latent TB infection and to reduce drug interactions in combination with antiretroviral therapy, a major issue in the treatment of HIV co-infected patients. This review will attempt to summarize the current recommendations for treatment of TB and then describe the most promising new antimicrobials with activity against MTB, focusing on the ones currently undergoing clinical trials.
Review: Omalizumab in the treatment of severe asthma: efficacy and current problems
Authors: Pelaia Girolamo , Renda Teresa , Romeo Pasquale , Busceti Maria Teresa , Maselli Rosario
Published: November 2008

Omalizumab is a humanized monoclonal anti-IgE antibody recently approved for the treatment of severe allergic asthma. This drug inhibits allergic responses by binding to serum IgE, thus preventing their interactions with cellular IgE receptors. Omalizumab is also capable of downregulating the expression of high-affinity IgE receptors on inflammatory cells, as well as the numbers of eosinophils in both blood and induced sputum. The clinical effects of omalizumab include relevant improvements in respiratory symptoms and quality of life, paralleled by a marked reduction of asthma exacerbations, emergency room visits, and use of systemic corticosteroids and rescue bronchodilators. Omalizumab is relatively well tolerated, and only rarely induces anaphylactic reactions. Therefore, this drug represents a valid option as add-on therapy for patients with severe persistent allergic asthma, inadequately controlled by high doses of standard inhaled treatments.
Bronchial fistulae in ARDS patients: management with an extracorporeal lung assist device
Authors: Hommel M. , Deja M. , von Dossow V. , Diemel K. , Heidenhain C. , Spies C. , Weber-Carstens S.
Published: November 2008

Patients with bronchial tree lesions feature, in particular, a high risk for developing bronchial fistulae after surgical repair when the clinical situation is complicated by acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and mechanical ventilation is needed. The current authors hypothesised that extracorporeal carbon dioxide removal would significantly decrease inspiratory airway pressures, thus promoting the protection of surgical bronchial reconstruction.

Four patients were studied after surgical reconstruction of bronchial fistulae in whom ALI/ARDS developed and mechanical ventilation with positive end-expiratory pressure was required. Gas exchange, tidal volumes, airway pressures, respiratory frequency, vasopressor and sedation requirements were analysed before and after initiation of a pumpless extracorporeal lung assist device (pECLA; NovaLung®, Talheim, Germany). Initiation of pECLA treatment enabled a reduction of inspiratory plateau airway pressures from 32.4 to 28.6 cmH2O (3.2 to 2.8 kPa), effectively treated hypercapnia (from 73.6 to 53.4 mmHg (9.8 to 7.1 kPa)) and abolished respiratory acidosis (from pH 7.24 to 7.41). All patients survived and were discharged to rehabilitation clinics.

In patients after surgical bronchial reconstruction that was complicated by acute lung injury/acute respiratory distress syndrome, use of pumpless extracorporeal carbon dioxide removal was safe and efficient. Initiation of a pumpless extracorporeal lung assist device enabled a less invasive ventilator management, which may have contributed to healing of surgical bronchial repair.
Apoptosis in lung injury and fibrosis
Authors: Drakopanagiotakis F. , Xifteri A. , Polychronopoulos V. , Bouros D.
Published: November 2008

Pulmonary fibrosis is characterised by fibroblast accumulation and alveolar epithelium denudation. Increased apoptosis of alveolar epithelial cells and decreased apoptosis of fibroblasts may play an important role in the pathogenesis of disease. Inflammatory cells can modulate apoptosis of other cell types, both by removal of apoptotic debris and by cytokine production, thus preserving a pro-fibrotic environment. In the present review, some of the mechanisms by which apoptosis may contribute to the pathogenesis of idiopathic pulmonary fibrosis are described.
The classification, natural history and radiological/histological appearance of idiopathic pulmonary fibrosis and the other idiopathic interstitial pneumonias
Authors: Raghu G. , Nicholson A. G. , Lynch D.
Published: November 2008

The idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of rare interstitial lung diseases (ILDs) or diffuse parenchymal lung diseases, which, as their name implies, are of unknown aetiology. The past 10 yrs have seen important advances in the classification of the IIPs into idiopathic pulmonary fibrosis (IPF) and its corresponding histopathological pattern of usual interstitial pneumonia (UIP), plus six non-IPF IIP subtypes.

The present article will look at the current classification of IIPs, arising from the Consensus Statement of the American Thoracic Society and European Respiratory Society, and discusses the importance of differential diagnosis of IPF from the non-IPF IIP subtypes, especially nonspecific interstitial pneumonia. Diagnosis of IIPs is a dynamic process involving close collaboration between pulmonologists, radiologists and pathologists.

Increasingly accurate diagnosis of IPF has been made possible by the use of high-resolution computed tomography (HRCT) and refinements in surgical lung biopsy. In IPF, a lung HRCT will typically reveal irregular reticular opacities, traction bronchiestasis and, most importantly, peripheral honeycombing. In contrast, histological examination shows evidence of UIP manifesting as typically subpleural and paraseptal established fibrosis, often with honeycomb changes, associated with mild chronic inflammation and varying numbers of fibroblastic foci in continuity with the edges of areas of established fibrosis.

Despite these advances, obtaining a consistent and uniform diagnosis of idiopathic interstitial pneumonias is difficult, with studies showing significant disagreement in the diagnosis of interstitial lung diseases between academic centres of expertise and community-based clinicians. Greater interaction between academic and community clinicians, together with improved education, is needed to bridge this gap.
Recent clinical trials in idiopathic pulmonary fibrosis and the BUILD-1 study
Authors: Brown K. K. , Wells A. U.
Published: November 2008

Idiopathic pulmonary fibrosis (IPF), the most common of the interstitial pneumonias, is a progressive, life-limiting disease for which there are no truly effective therapies. In patients with biopsy-confirmed IPF, median survival is still <3 yrs. Although potent immunosuppressive therapy has underpinned the treatment of IPF in recent years and remains the standard of care, there is little quality evidence to support the efficacy and safety of traditional therapeutic strategies.

This has spurred the search for new treatments for IPF and has led to a series of clinical trials of new therapies, seven of which are reviewed herein. They include the Bosentan Use in Interstitial Lung Disease (BUILD)-1 trial, the results of which are discussed in detail, the European Idiopathic Pulmonary Fibrosis International Group Exploring N-acetylcysteine 1 Annual (IFIGENIA) trial, the interferon gamma (GIPF-001) trial and the INSPIRE trial, as well as trials of anticoagulant therapy, pirfenidone and etanercept.

Treatment trials in IPF are hindered by difficulties in achieving a secure diagnosis of IPF and the lack of validated outcome measures that represent either improvement or progression of disease. These and other limitations are discussed in the present article, as well as how some of these problems might be addressed in future trials.

Although few of the seven studies met their primary end-points, marginal trends either on primary end-points or statistically significant trends on exploratory end-points were a recurrent theme in most trials. In the BUILD-1 trial, for example, a trend in favour of bosentan was observed on time-to-disease progression or death.
Abnormal wound healing responses in pulmonary fibrosis: focus on coagulation signalling
Authors: Chambers R. C.
Published: November 2008

The normal response of tissue to injury involves a sequence of overlapping events, which need to occur in a timely and controlled manner for successful tissue repair and restoration of normal function. Failure to control the healing process can lead to considerable tissue remodelling and the replacement of functional tissue with permanent fibrous scar tissue.

It is proposed that pulmonary fibrosis arises from repetitive, widespread epithelial injury. However, the nature of the insult for the most common and most fatal form of pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), is currently unknown and the pathogenetic pathways leading to IPF remain to be fully elucidated. Increasing evidence suggests that abnormalities in a number of pathways involved in the wound healing response may play central roles.

The present article will briefly review the pathways involved in wound healing focusing on the control of fibroblast/myofibroblast function and the coagulation cascade actingviathe family of signalling receptors, the proteinase activated receptors, which influence a range of cellular responses implicated in the development of pulmonary fibrosis.

Understanding the involvement of these pathways in the aberrant wound repair-response in pulmonary fibrosis may lead to the identification of new targets and strategies for therapeutic intervention.
The role of apoptosis in pulmonary fibrosis
Authors: Uhal B. D.
Published: November 2008

Apoptosis has been defined as “gene-directed cellular self-destruction” and is an active process that is tightly regulated by a number of gene products, which promote or block cell death. Apoptotic death can be triggered by a wide variety of stimuli and, importantly, not all cells necessarily undergo apoptosis in response to the same stimulus. Abnormal regulation of apoptosis has been implicated in a wide range of diseases and approaches to modifying apoptosis represent important future therapeutic strategies.

Idiopathic pulmonary fibrosis (IPF) is a progressive and relentless disease involving scarring of the lung, which has been recognised as the most lethal interstitial lung disease. In the lungs of IPF patients, increased epithelial apoptosis, together with decreased apoptosis of myofibroblasts, represents persistent findings (particularly in areas of collagen deposition) supporting an interaction between altered apoptosis and the pathogenesis of the disease.

Data from human tissues and animal models are refining current knowledge of the processes involved in this pathogenesis. This has challenged the dogma that IPF is purely a disease of unresolved inflammation by emphasising the central roles played by the alveolar epithelial cell and myofibroblasts and, as part of that role, the importance of altered apoptosis.

Evidence suggests blockade of epithelial cell apoptosis can prevent subsequent collagen deposition, and induction of myofibroblast apoptosis, at least theoretically, would be expected to resolve ongoing fibrosis. These two concepts raise the prospect of therapeutic intervention aimed at modifying apoptosis and, thus, fibrosis in idiopathic pulmonary fibrosis.
Role of endothelin in lung fibrosis
Authors: Abraham D.
Published: November 2008

Accumulating evidence suggests that idiopathic pulmonary fibrosis (IPF) results from lung injury primarily following an abnormal wound healing response towards epithelial cell damage. Thus, rather than resulting from chronic inflammation, as thought previously, the inflammatory response acts as a modifier of the fibrogenic response, which can also be influenced by the host’s genetic background and environmental triggers. Several key mediators, including endothelin (ET)-1, have been implicated in the fibrosis and scarring associated with IPF.

Elevated levels of ET-1 have been detected in bronchoalveolar lavage fluid and serum from patients with IPF and increased expression of ET-1 has been detected in small pulmonary blood vessels and macrophages.In vitrodata show that ET-1 influences matrix production and degradation by promoting synthesis of collagen type I and III, inhibiting expression of matrix metalloproteinase-1 and promoting matrix remodelling. In addition, ET-1 promotes fibroblast differentiation to a myofibroblastic cell type, inducing the expression of proteins that contribute to a contractile phenotype including α-smooth muscle actin. Moreover, ET-1 has been shown to initiate alveolar epithelial cell transition into fibroblast-like cells, a process termed epithelial–mesenchymal transition, and thereby contribute to pulmonary fibrosis. Furthermore, recently reported data from the BUILD (Bosentan Use in Interstitial Lung Disease)-1 trial showed a trend towards a delay in time to disease progression or death following treatment with the endothelin receptor antagonist, bosentan, which was especially prominent in patients with biopsy-proven IPF. This adds to the evidence that ET-1 plays an important role in IPF.

The present article examines recent evidence for the role of endothelin-1 in pulmonary fibrosis, and particularly, in the control of the function and differentiation of fibroblasts and myofibroblasts.
The role of chemokines and cytokines in lung fibrosis
Authors: Keane M. P.
Published: November 2008

Idiopathic pulmonary fibrosis (IPF) exhibits a complex and poorly understood pathogenesis. Overt inflammation in the lungs of patients with established IPF is absent, and classic anti-inflammatory therapies are inefficacious; however, inflammation may contribute to the disruption of the normal alveolar architecture, allowing interaction between fibroblasts and the epithelium. The polarisation of the inflammatory response toward a type-2 helper T-cell phenotype may also be important in the development of pulmonary fibrosis, as fibroproliferation could be favoured over repair. Furthermore, evidence has emerged regarding an imbalance between angiogenic and angiostatic chemokine levels, leading to an overall angiogenic pattern of expression in both animal models and tissue specimens from IPF patients. The precise role of vascular remodelling in IPF remains to be determined. Therefore, numerous questions exist regarding the role and importance of chemokines and cytokines in pulmonary fibrosis. Further investigation is required to facilitate the elucidation of IPF pathogenesis and identification of novel targets for treatment of this dismal disease.
The role of integrins in pulmonary fibrosis
Authors: Sheppard D.
Published: November 2008

Integrins are a large family of transmembrane glycoprotein receptors initially identified as mediators of cell adhesion and tissue integrity. However, it is now known that the primary function of integrins in mammals is to act as signalling proteins.

Signals from integrins are known to play critical roles in virtually every aspect of the behaviour of epithelial cells and in the development of certain pathological conditions, including pulmonary fibrosis. In this respect, the interaction between transforming growth factor-β, which is known to be pivotal in the development of pulmonary fibrosis, and the integrin αVβ6 is of particular interest.

Integrin αVβ6 is responsible for the activation of constitutively expressed latent transforming growth factor-β by a mechanism that allows for temporal and spatial activity control.

There is increasing evidence that this mechanism plays a critical role in the pathological activity of transforming growth factor-β. Although other activation mechanisms have been identified, studies suggest that αVβ6-mediated activation of transforming growth factor-β is necessary for the development of fibrosis in lung-disease models. The data from such studies imply that integrins may be attractive targets for intervention in pulmonary fibrotic diseases, such as idiopathic pulmonary fibrosis.
Neurotransmitter alterations in embryonic succinate semialdehyde dehydrogenase (SSADH) deficiency suggest a heightened excitatory state during development
Authors: Jansen Erwin EW , Struys Eduard , Jakobs Cornelis , Hager Elizabeth , Snead O Carter , Gibson K Michael
Published: November 2008

Background

SSADH (aldehyde dehydrogenase 5a1 (Aldh5a1); γ-hydroxybutyric (GHB) aciduria) deficiency is a defect of GABA degradation in which the neuromodulators GABA and GHB accumulate. The human phenotype is that of nonprogressive encephalopathy with prominent bilateral discoloration of the globi pallidi and variable seizures, the latter displayed prominently in Aldh5a1-/- mice with lethal convulsions. Metabolic studies in murine neural tissue have revealed elevated GABA [and its derivatives succinate semialdehyde (SSA), homocarnosine (HC), 4,5-dihydroxyhexanoic acid (DHHA) and guanidinobutyrate (GB)] and GHB [and its analogue D-2-hydroxyglutarate (D-2-HG)] at birth. Because of early onset seizures and the neurostructural anomalies observed in patients, we examined metabolite features during Aldh5a1-/- embryo development.

Methods

Embryos were obtained from pregnant dams sacrificed at E (embryo day of life) 10–13, 14–15, 16–17, 18–19 and newborn mice. Intact embryos were extracted and metabolites quantified by isotope dilution mass spectrometry (n = 5–15 subjects, Aldh5a1+/+ and Aldh5a1-/-) for each gestational age group. Data was evaluated using the t test and one-way ANOVA with Tukey post hoc analysis. Significance was set at the 95th centile.

Results

GABA and DHHA were significantly elevated at all gestational ages in Aldh5a1-/- mice, while GB was increased only late in gestation; SSA was not elevated at any time point. GHB and D-2-HG increased in an approximately linear fashion with gestational age. Correlative studies in human amniotic fluid from SSADH-deficient pregnancies (n = 5) also revealed significantly increased GABA.

Conclusion

Our findings indicate early GABAergic alterations in Aldh5a1-/- mice, possibly exacerbated by other metabolites, which likely induce a heightened excitatory state that may predispose neural networks to epilepsy in these animals.
Two sisters in the same dress: Heliconius cryptic species
Authors: Giraldo Nathalia , Salazar Camilo , Jiggins Chris D , Bermingham Eldredge , Linares Mauricio
Published: November 2008

Background

Sister species divergence and reproductive isolation commonly results from ecological adaptation. In mimeticHeliconiusbutterflies, shifts in colour pattern contribute to pre- and post-mating reproductive isolation and are commonly correlated with speciation. Closely related mimetic species are therefore not expected, as they should lack several important sources of reproductive isolation.

Results

Here we present phenotypic, behavioral and genetic evidence for the coexistence of two sympatric 'cryptic' species near Florencia in the eastern Andes of Colombia that share the same orange rayed colour pattern. These representH. melpomene malletiand a novel taxon in theH. cydnogroup, here designated as novel race ofHeliconius timareta,Heliconius timareta florencia. No-choice mating experiments show that these sympatric forms have strong assortative mating (≈96%) despite great similarity in colour pattern, implying enhanced divergence in pheromonal signals.

Conclusion

We hypothesize that these species might have resulted from recent convergence in colour pattern, perhaps facilitated by hybrid introgression of wing pattern genes.
Genome plasticity of Vibrio parahaemolyticus: microevolution of the 'pandemic group'
Authors: Han Haihong , Wong Hin-chung , Kan Biao , Guo Zhaobiao , Zeng Xiaotao , Yin Shengjun , Liu Xiumei , Yang Ruifu , Zhou Dongsheng
Published: November 2008

Background

Outbreak of V. parahaemolyticus infections occurred since 1996 was linked to a proposed clonal complex, the pandemic group. The whole genome sequence provides an unprecedented opportunity for dissecting genome plasticity and phylogeny of the populations of V. parahaemolyticus. In the present work, a whole-genome cDNA microarray was constructed to compare the genomic contents of a collection of 174 strains of V. parahaemolyticus.

Results

Genes that present variably in the genome accounted for about 22% of the whole gene pool on the genome. The phylogenetic analysis of microarray data generated a minimum spanning tree that depicted the phylogenetic structure of the 174 strains. Strains were assigned into five complexes (C1 to C5), and those in each complex were related genetically and phylogenetically. C3 and C4 represented highly virulent clinical clones. C2 and C3 constituted two different clonal complexes 'old-O3:K6 clone' and 'pandemic clone', respectively. C3 included all the 39 pandemic strains tested (trh
-, tdh
+ and GS-PCR+), while C2 contained 12 pre-1996 'old' O3:K6 strains (trh
+, tdh
- and GS-PCR-) tested herein. The pandemic clone (post-1996 'new' O3:K6 and its derivates O4:K68, O1:K25, O1:KUT and O6:K18) might be emerged from the old-O3:K6 clone, which was promoted by acquisition of toxRS/new sequence and genomic islands. A phylogenetic intermediate O3:K6 clade (trh
-, tdh
- and GS-PCR+) was identified between the pandemic and old-O3:K6 clones.

Conclusion

A comprehensive overview of genomic contents in a large collection of global isolates from the microarray-based comparative genomic hybridization data enabled us to construct a phylogenetic structure of V. parahaemolyticus and an evolutionary history of the pandemic group (clone) of this pathogen.
Dissecting an alternative splicing analysis workflow for GeneChip®Exon 1.0 ST Affymetrix arrays
Authors: Della Beffa Cristina , Cordero Francesca , Calogero Raffaele A
Published: November 2008

Background

A new microarray platform (GeneChip® Exon 1.0 ST) has recently been developed by Affymetrix http://www.affymetrix.com. This microarray platform changes the conventional view of transcript analysis since it allows the evaluation of the expression level of a transcript by querying each exon component. The Exon 1.0 ST platform does however raise some issues regarding the approaches to be used in identifying genome-wide alternative splicing events (ASEs). In this study an exon-level data analysis workflow is dissected in order to detect limit and strength of each step, thus modifying the overall workflow and thereby optimizing the detection of ASEs.

Results

This study was carried out using a semi-synthetic exon-skipping benchmark experiment embedding a total of 268 exon skipping events. Our results point out that summarization methods (RMA, PLIER) do not affect the efficacy of statistical tools in detecting ASEs. However, data pre-filtering is mandatory if the detected number of false ASEs are to be reduced. MiDAS and Rank Product methods efficiently detect true ASEs but they suffer from the lack of multiple test error correction. The intersection of MiDAS and Rank Product results efficiently moderates the detection of false ASEs.

Conclusion

To optimize the detection of ASEs we propose the following workflow: i) data pre-filtering, ii) statistical selection of ASEs using both MiDAS and Rank Product, iii) intersection of results derived from the two statistical analyses in order to moderate family-wise errors (FWER).
Functional characterization of a small heat shock protein from Mycobacterium leprae
Authors: Lini Nirmala , Rehna Elengikal Abdul Azeez , Shiburaj Sugathan , Maheshwari Jayapal Jeya , Shankernarayan Nallakandy Panagadan , Dharmalingam Kuppamuthu
Published: November 2008

Background

Small heat shock proteins are ubiquitous family of stress proteins, having a role in virulence and survival of the pathogen.M. leprae, the causative agent of leprosy is an uncultivable organism in defined media, hence the biology and function of proteins were examined by cloningM. lepraegenes in heterologous hosts. The study on sHsp18 was carried out as the knowledge about the functions of this major immunodominant antigen ofM. lepraeis scanty.

Results

The gene encodingMycobacterium lepraesmall heat shock protein (sHsp18) was amplified from biopsy material of leprosy patients, and cloned and expressed inE. coli. The localization andin vitrocharacterization of the protein are detailed in this report. Data show that major portion of the protein is localized in the outer membrane ofE. coli. The purified sHsp18 functions as an efficient chaperone as shown by their ability to prevent thermal inactivation of restriction enzymesSmaI andNdeI. Physical interaction of the chaperone with target protein is also demonstrated. Size exclusion chromatography of purified protein shows that the protein can form multimeric complexes underin vitroconditions as is demonstrated for several small heat shock proteins.

Conclusion

The small heat shock protein sHsp18 ofM. lepraeis a chaperone and shows several properties associated with other small heat shock proteins. Membrane association andin vitrochaperone function of sHsp18 shows that the protein may play a role in the virulence and survival ofM. lepraein infected host.
A randomized controlled trial of tea tree oil (5%) body wash versus standard body wash to prevent colonization with methicillin-resistant Staphylococcus aureus (MRSA) in critically ill adults: research protocol
Authors: Thompson Gillian , Blackwood Bronagh , McMullan Ronan , Alderdice Fiona A , Trinder T John , Lavery Gavin G , McAuley Danny F
Published: November 2008

Background

Over the past ten years MRSA has become endemic in hospitals and is associated with increased healthcare costs. Critically ill patients are most at risk, in part because of the number of invasive therapies that they require in the intensive care unit (ICU). Washing with 5% tea tree oil (TTO) has been shown to be effective in removing MRSA on the skin. However, to date, no trials have evaluated the potential of TTO body wash to prevent MRSA colonization or infection. In addition, detecting MRSA by usual culture methods is slow. A faster method using a PCR assay has been developed in the laboratory, but requires evaluation in a large number of patients.

Methods/Design

This study protocol describes the design of a multicentre, phase II/III prospective open-label randomized controlled clinical trial to evaluate whether a concentration of 5% TTO is effective in preventing MRSA colonization in comparison with a standard body wash (Johnsons Baby Softwash) in the ICU. In addition we will evaluate the cost-effectiveness of TTO body wash and assess the effectiveness of the PCR assay in detecting MRSA in critically ill patients. On admission to intensive care, swabs from the nose and groin will be taken to screen for MRSA as per current practice. Patients will be randomly assigned to be washed with the standard body wash or TTO body wash. On discharge from the unit, swabs will be taken again to identify whether there is a difference in MRSA colonization between the two groups.

Discussion

If TTO body wash is found to be effective, widespread implementation of such a simple colonization prevention tool has the potential to impact on patient outcomes, healthcare resource use and patient confidence both nationally and internationally.

Trial Registration

[ISRCTN65190967]
The Adnectin CT-322 is a novel VEGF receptor 2 inhibitor that decreases tumor burden in an orthotopic mouse model of pancreatic cancer
Authors: Dineen Sean P , Sullivan Laura A , Beck Adam W , Miller Andrew F , Carbon Juliet G , Mamluk Roni , Wong Henry , Brekken Rolf A
Published: November 2008

Background

Pancreatic cancer continues to have a 5-year survival of less than 5%. Therefore, more effective therapies are necessary to improve prognosis in this disease. Angiogenesis is required for tumor growth, and subsequently, mediators of angiogenesis are attractive targets for therapy. Vascular endothelial growth factor (VEGF) is a well-characterized mediator of tumor angiogenesis that functions primarily by binding and activating VEGF receptor 2 (VEGFR2). In this study, we evaluate the use of CT-322, a novel biologic (Adnectin). This small protein is based on a human fibronectin domain and has beneficial properties in that it is fully human, stable, and is produced in bacteria. CT-322 binds to and inhibits activation of VEGFR2.

Methods

The efficacy of CT-322 was evaluated in vivo using two orthotopic pancreatic tumor models. The first model was a human tumor xenograft where MiaPaCa-2 cells were injected into the tail of the pancreas of nude mice. The second model was a syngeneic tumor using Pan02 cells injected into pancreas of C57BL/6J mice. In both models, therapy was initiated once primary tumors were established. Mice bearing MiaPaCa-2 tumors were treated with vehicle or CT-322 alone. Gemcitabine alone or in combination with CT-322 was added to the treatment regimen of mice bearing Pan02 tumors. Therapy was given twice a week for six weeks, after which the animals were sacrificed and evaluated (grossly and histologically) for primary and metastatic tumor burden. Primary tumors were also evaluated by immunohistochemistry for the level of apoptosis (TUNEL), microvessel density (MECA-32), and VEGF-activated blood vessels (Gv39M).

Results

Treatment with CT-322 was effective at preventing pancreatic tumor growth and metastasis in orthotopic xenograft and syngeneic models of pancreatic cancer. Additionally, CT-322 treatment increased apoptosis, reduced microvessel density and reduced the number of VEGF-activated blood vessels in tumors. Finally, CT-322, in combination with gemcitabine was safe and effective at controlling the growth of syngeneic pancreatic tumors in immunocompetent mice.

Conclusion

We conclude that CT-322 is an effective anti-VEGFR2 agent and that further investigation of CT-322 for the treatment of pancreatic cancer is warranted.
Derivation and internal validation of an equation for albumin-adjusted calcium
Authors: James Matthew T , Zhang Jianguo , Lyon Andrew W , Hemmelgarn Brenda R
Published: November 2008

Background

Previously published equations to adjust calcium for albumin concentration may vary depending on factors such as the type of reagents used. Albumin-adjusted calcium equations derived from laboratories using the bromocresol purple (BCP) albumin binding reagent have not been described.

Methods

The linear regression equation for the binding of calcium and BCP-albumin was derived in a cohort of 4613 outpatients, and the albumin-adjusted calcium equation was internally validated in a separate cohort of 1538 subjects. The performance of this equation was compared with a previously published equation (adjusted [Ca](mmol/L) = total [Ca](mmol/L) + 0.02 (40 - [albumin] (g/L)) in 343 subjects with albumin < 33 g/L (below reference range).

Results

The local adjustment equation was expressed by the relationship; adjusted [Ca](mmol/L) = total [Ca](mmol/L) + 0.012 (39.9 - [albumin](g/L)). The equation showed evidence of good internal validity (shrinkage value of adjusted r2 = -0.0059). Classification of calcium status differed between the two equations in 47 of 343 subjects with low serum albumin (weighted κ = 0.46; moderate agreement).

Conclusion

A locally derived and internally validated albumin-adjusted calcium equation differed from previously published equations and resulted in important differences in classification of calcium status in hypoalbuminemia patients. Individual laboratories should determine their own linear regression equation for calcium on albumin rather than relying on published formulas.
Pyrethroid resistance in the major malaria vector Anopheles arabiensis from Gwave, a malaria-endemic area in Zimbabwe
Authors: Munhenga Givemore , Masendu Hieronymo T , Brooke Basil D , Hunt Richard H , Koekemoer Lizette K
Published: November 2008

Background

Insecticide resistance can present a major obstacle to malaria control programmes. Following the recent detection of DDT resistance in Anopheles arabiensis in Gokwe, Zimbabwe, the underlying resistance mechanisms in this population were studied.

Methods

Standard WHO bioassays, using 0.75% permethrin, 4% DDT, 5% malathion, 0.1% bendiocarb and 4% dieldrin were performed on wild-collected adult anopheline mosquitoes and F1 progeny of An. arabiensis reared from wild-caught females. Molecular techniques were used for species identification as well as to identify knockdown resistance (kdr) and ace-1 mutations in individual mosquitoes. Biochemical assays were used to determine the relative levels of detoxifying enzyme systems including non-specific esterases, monooxygenases and glutathione-S-transferases as well as to detect the presence of an altered acetylcholine esterase (AChE).

Results

Anopheles arabiensis was the predominant member of the Anopheles gambiae complex. Of the 436 An. arabiensis females, 0.5% were positive for Plasmodium falciparum infection. WHO diagnostic tests on wild populations showed resistance to the pyrethroid insecticide permethrin at a mean mortality of 47% during February 2006 and a mean mortality of 68.2% in January 2008. DDT resistance (68.4% mean mortality) was present in February 2006; however, two years later the mean mortality was 96%. Insecticide susceptibility tests on F1
An. arabiensis families reared from material from two separate collections showed an average mean mortality of 87% (n = 758) after exposure to 4% DDT and 65% (n = 587) after exposure to 0.75% permethrin. Eight families were resistant to both DDT and permethrin. Biochemical analysis of F1 families reared from collections done in 2006 revealed high activity levels of monooxygenase (48.5% of families tested, n = 33, p < 0.05), glutathione S-transferase (25.8% of families tested, n = 31, p < 0.05) and general esterase activity compared to a reference susceptible An. arabiensis colony. Knockdown resistance (kdr) and ace-I

R
mutations were not detected.

Conclusion

This study confirmed the presence of permethrin resistance in An. arabiensis populations from Gwave and emphasizes the importance of periodic and ongoing insecticide susceptibility testing of malaria vector populations whose responses to insecticide exposure may undergo rapid change over time.
Impact of schizophrenia and schizophrenia treatment-related adverse events on quality of life: direct utility elicitation
Authors: Briggs Andrew , Wild Diane , Lees Michael , Reaney Matthew , Dursun Serdar , Parry David , Mukherjee Jayanti
Published: November 2008

Objective

To examine the impact of schizophrenia, its treatment and treatment-related adverse events related to antipsychotics, on quality of life from the perspective of schizophrenia patients and laypersons.

Methods

Health state descriptions for stable schizophrenia, extra pyramidal symptoms (EPS), hyperprolactinemia, diabetes, weight gain and relapse were developed based on a review of the literature and expert opinion. The quality of life impact of each health state was elicited using a time trade-off instrument administered by interview to 49 stable schizophrenia patients and 75 laypersons. Regression techniques were employed to examine the importance of subject characteristics on health-related utility scores.

Results

Patients and laypersons completed the interview in similar times. Stable schizophrenia had the highest mean utility (0.87 and 0.92 for laypersons and patients respectively), while relapse (0.48 and 0.60) had the lowest mean utility. Of the treatment-related adverse events, EPS had the lowest mean utility (0.57 and 0.72, respectively). Age, gender and PANSS score did not influence the utility results independently of health state. On average, patient utilities are 0.077 points higher than utilities derived from laypersons, although the ranking was similar between the two groups.

Conclusion

Events associated with schizophrenia and treatment of schizophrenia can bring about a significant detriment in patient quality of life, with relapse having the largest negative impact. Results indicate that patients with stable schizophrenia are less willing to trade years of life to avoid schizophrenia-related symptoms compared to laypersons. Both sets of respondents showed equal ability to complete the questionnaire.