bluuebunny/crossref_metadata_2025 huggingface dataset:
Drainage demands of domestic washrooms in Hong Kong
Authors: Wong LT , Mui KW
Published: April 2009

Drainage demand estimation for an effective and healthy drainage stack design is examined in this study. Empirical expressions that incorporate building occupant load, simultaneous usage patterns and discharge flow attenuation along a horizontal pipe into the probable drainage load determination for a stack serving a number of domestic washrooms as installed in typical high-rise buildings in Hong Kong are proposed. Patterns of probable drainage demand and probable discharge flow in the stack are determined via Bayesian analysis and Monte Carlo simulations, respectively. The study outcome enables more effective sizing of a drainage stack for some residential buildings in a dense urban environment.

Practical application: Providing a mathematical model for drainage load calculations, this study is a useful tool to aid drainage stack sizing for some high-rise residential buildings.
The Relationship of Personality to Entrepreneurial Intentions and Performance: A Meta-Analytic Review
Authors: Hao Zhao  , Seibert Scott E. , Lumpkin G.T.
Published: April 2009

A set of meta-analyses were conducted to examine the relationship of personality to outcomes associated with two different stages of the entrepreneurial process: entrepreneurial intentions and entrepreneurial performance. A broad range of personality scales were categorized into a parsimonious set of constructs using the Five Factor model of personality. The results show that four of the Big Five personality dimensions were associated with both dependent variables, with agreeableness failing to be associated with either. Multivariate effect sizes were moderate for the full set of Big Five personality variables on entrepreneurial intentions (multiple R = .36) and entrepreneurial performance (multiple R = .31). Risk propensity, included as a separate dimension of personality, was positively associated with entrepreneurial intentions but was not related to entrepreneurial performance. These effects suggest that personality plays a role in the emergence and success of entrepreneurs.
Development of Nanohydroxyapatite/Polycarbonate Composite for Bone Repair
Authors: Liao Jianguo  , Zhang Li  , Zuo Yi  , Wang Huanan  , Li Jidong  , Zou Qin  , Li Yubao
Published: April 2009

In this study, nano-hydroxyapatite (n-HA) combined polycarbonate was synthesized by a novel method. The physical and chemical property of the composite was tested. The results indicated the n-HA a crystal has the similar grain size, phase composition and crystal structure as. TEM photos results show the n-HA crystals were uniformly distributed in the polymer matrix. Then, the chemical bond between inorganic n-HA and polycarbonate was investigated and discussed. Proliferation of MSCs/composite cultured for up to 11 days the adhesion were tested by MTT and SEM. The in vitro test confirmed that the n-HA/PC composite was biocompatible and no negative effect on MSCs has found. The composite is proved to be osteoconductive, and can stimulate the growth of new bone. These results indicated that the composite meet the basic requirement of bone substitute material, and be potentially applied for clinic.
Preparation and Evaluation of Nimesulide-loaded Ethylcellulose and Methylcellulose Nanoparticles and Microparticles for Oral Delivery
Authors: Ravikumara N.R. , Madhusudhan B. , Nagaraj T.S. , Hiremat Shobarani R. , Raina Gargi
Published: April 2009

The present study was designed to assess and compare with a range of surfactant-coated, nimesulide-free, and nimesulide-loaded ethylcellulose/methylcellulose (EC/MC) nanoparticles that were prepared by varying drug concentration (ED/MD), polymer concentration (EP/MP), and surfactant concentration (ES/MS). EC/MC nanoparticles prepared by desolvation method produced discrete particles and they were characterized by SEM, AFM, and FTIR studies. The particles mean size diameter (nm) ranged from 244 to 1056 nm and 1065 to 1710 nm for EC and MC nanoparticles, respectively. Studies on drug: polymer ratio showed a linear relationship between drug concentration and percentage of loading in nanoparticles. The encapsulation efficiency decreased with the increase of nimesulide concentration with respect to polymer concentration. Encapsulation efficiency of drug-loaded nanoparticles was varied between 32.8% and 64.9%. The in vitro release of drug-loaded nanoparticles was found to be a first order. This was significantly increased in EC nanoparticles (95.50%) in comparison with MC nanoparticles (95.12%) after 12 h in 24 h long study. Nimesulide release from EC nanoparticles was much slower at slightly alkaline pH 7.4. The in vitro hemolysis tests of nanoparticles were carried out to ascertain the hemocompatibility and shown to be insignificant for EC nanoparticles. In comparison, ES4 from EC formulations with nimesulide was found to be promising with slow and sustained drug release.
Advancing Towards a Tissue-engineered Tympanic Membrane: Silk Fibroin as a Substratum for Growing Human Eardrum Keratinocytes
Authors: Ghassemifar Reza , Redmond Sharon , Zainuddin  , Chirila Traian V.
Published: April 2009

Human tympanic membrane cells (hTMCs), harvested from tympanic membrane (TM) explants, were grown in culture and then seeded on membranes prepared from silkworm (Bombyx mori) silk fibroin (BMSF) and on tissue-culture plastic membranes (PET). Fibroin was isolated from silk cast into membranes with a thickness of 10—15 μm. The hTMCs were cultured on both materials for 15 days in a serum-containing culture medium. The cells grown on both substrata were subjected to nuclear staining (DAPI) and counted. Further, the cultures were immunostained for a number of protein markers related to the epithelial/keratinocyte phenotype and cell adhesion complexes. The BMSF membranes supported levels of hTMC growth higher than that observed on the PET membranes. The immunofluorochemical analysis indicated unequivocally that BMSF is a more suitable substratum than PET with respect to the growth patterns, proliferation, and cell—cell contact and adhesion. BMSF appear as a promising substratum in the tissue-engineered constructs for the replacement of TM in case of nonhealing perforations.
The Impact of Government Weekend Policy Changes and Foreign Institutional Holdings On Weekly Effect of Tourism Stock Performance
Authors: Chen Ming-Hsiang , Woo Gon Kim  , Liao Chao-Ning
Published: April 2009

Since the Taiwanese government implemented a 2-day weekend policy, traveling activities have become increasingly popular, and foreign institutional holdings (FIHs) on stocks of tourism firms have soared. This study investigates the influence of the weekend policy changes and increasing FIHs on the weekly effect of tourism stock returns over the period between 1994 and 2004. First, this study tests whether there is any weekly effect of tourism stock returns and whether weekly effects, if any, persist or diminish after the weekend policy changes. It is found that a significantly negative Tuesday effect on tourism stock returns existed. Second, the impact of the increasing FIHs on the negative Tuesday effect is examined. The increasing FIHs on tourism stocks not only weaken the negative Tuesday effect, but also decrease the risk of negative Tuesday returns. Policy implications based on the main findings are provided to guide tourism business managers, policy makers and investors.
Stakeholder Service Perspectives: a Triadic Analysis of Service Quality in South Mississippi Fine Dining Restaurants
Authors: Oubre Joshua J. , Brown Denise M.
Published: April 2009

The primary goal of this study was to replicate and extend earlier work by Fallon and Schofield that examined the relationship between customer, wait staff and manager perceptions in fine dining restaurants. Subjects included 266 participants from three fine-dining restaurants in Hattiesburg, Mississippi. Participants completed a survey instrument revised from the Fallon and Schofield instrument. Participants ranked the most important question in each section of the survey instrument to determine which factor in each quality dimension was most important. There were no significant differences among the participants by restaurant. Composite data were examined to identify differences in perception among participants using analysis of variance. A relationship between wait staff and customers confirmed the earlier work by Fallon and Schofield that managers ranked quality service dimensions higher than other participant groups. Customers ranked service higher as compared with wait staff, which is a new finding for this research.
Linking Marketing Efforts To Financial Outcome: an Exploratory Study in Tourism and Hospitality Contexts
Authors: Denizci Basak , Li Xiang (Robert)
Published: April 2009

The purpose of this article is to improve the understanding of the marketing-finance interface by developing a model to capture the relationship between marketing efforts and the creation of owners' firm-related wealth in tourism and hospitality industries. In addition, this study combines the balance sheet and income statement—driven measures (i.e., profit margin, Tobin's q ) and off-income-statement measures (i.e., customer satisfaction score) to assess the effect of marketing efforts on a firm's financial performance. The findings indicate that marketing efforts indeed affect the owner's firm-related wealth as measured by financial performance variables. Overall, this study provides a valuable benchmark for further research in the area of marketing productivity in the tourism and hospitality industries.
The Effects of Relational Benefits On Customers' Perception of Favorable Inequity, Affective Commitment, and Repurchase Intention in Full-Service Restaurants
Authors: Kim Wansoo , Ok Chihyung
Published: April 2009

The purpose of this study is to investigate how relational benefits (including confidence benefits, social benefits, and special treatment benefits) affect customers' perceptions of favorable inequity and affective commitment, and thus ultimately affect customer retention. The study first develops and presents a conceptual model of the relationships that exist between the constructs of “relational benefits,” “favorable inequity,” “affective commitment,” and “repurchase intention.” This model is then empirically tested using 411 sample long-term customers of full-service restaurants. The results indicate that relational benefits trigger customers' perceptions of being favorably treated and that these perceptions, in turn, induce customers to form an affective commitment and repurchase intention with respect to particular restaurants. The study confirms the strategic importance of relational benefits in fostering relationships with long-term customers in the context of full-service restaurants.
Molecular network of the comprehensive multiple sclerosis brain-lesion proteome
Authors: Satoh JI , Tabunoki H , Yamamura T
Published: April 2009

Background

A recent proteomics study of multiple sclerosis (MS) lesion-specific proteome profiling clearly revealed a pivotal role of coagulation cascade proteins in chronic active demyelination. However, among thousands of proteins examined, nearly all of remaining proteins are yet to be characterized in terms of their implications in MS brain-lesion development.

Methods

By the systems biology approach using four different pathway analysis tools of bioinformatics, we studied molecular networks and pathways of the proteome dataset of acute plaques, chronic active plaques (CAP), and chronic plaques (CP).

Results

The database search on Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein analysis through evolutionary relationships (PANTHER) indicated the relevance of extracellular matrix (ECM)–mediated focal adhesion and integrin signaling to CAP and CP proteome. KeyMolnet disclosed a central role of the complex interaction among diverse cytokine signaling pathways in brain-lesion development at all disease stages, as well as a role of integrin signaling in CAP and CP. Ingenuity pathway analysis (IPA) identified the network constructed with a wide range of ECM components, such as collagen, type I α1, type I α2, type VI α2, type VI α3, fibronectin 1, fibulin 2, laminin α1, vitronectin, and heparan sulfate proteoglycan, as one of the networks highly relevant to CAP proteome.

Conclusions

Although four distinct platforms produced diverse results, they commonly suggested a role of ECM and integrin signaling in development of chronic lesions of MS. These in silico observations indicate that the selective blockade of the interaction between ECM and integrins in brain lesions in situ would be a target for therapeutic intervention in MS.
The relationship between handedness and risk of multiple sclerosis
Authors: Gardener H , Munger K , Chitnis T , Spiegelman D , Ascherio A
Published: April 2009

Background

Left-handedness has been studied as a marker for in-utero exposure to sex steroid hormones, and an increased risk of autoimmune and immune disorders among left-handed individuals has been suggested.

Objective

This study examines the relationship between hand preference and risk of multiple sclerosis, a presumed autoimmune disorder of unknown etiology.

Methods

The study population comprised participants in the Nurses’ Health Study, an ongoing prospective cohort study of 121,701 female nurses in the United States with followup from 1976 to 2002. The nurses were asked to report their natural hand preference (right, left, ambidextrous, forced to change).

Results

During followup 210 incident cases with multiple sclerosis were confirmed. A 62% increased risk of multiple sclerosis was observed among women who were naturally left handed as compared to those who were naturally right handed (95% CI: 1.04–2.53).

Conclusions

This study suggests a modest increase in risk of multiple sclerosis among left-handed women. Further investigation of this relationship is suggested in other populations including both males and females. While the current results suggest that prenatal exposure to sex hormones may play a role in multiple sclerosis risk, direct examination of the relationship between in-utero hormone exposure and hand preference is necessary before any conclusions can be drawn.
Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis
Authors: Liang J , Zhang H , Hua B , Wang H , Wang J , Han Z , Sun L
Published: April 2009

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system. Umbilical cord derived mesenchymal stem cells are immunosuppressive. We transplanted mesenchymal stem cells in a patient with refractory progressive MS, and the disease course was stabilized after the transplantation. We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.
Dialogic Absurdity
Authors: Druick Zoë
Published: April 2009

This article examines the popular phenomenon of news parodies using the concept of genre. While genre is often used as a category of industrial production and marketing, the author argues that Mikhail Bakhtin's notion of genre as a socially embedded aesthetic form allows us to understand the proliferation of news parodies as a commentary on the social authority of the news. Comparing examples from Canada, the UK, and the United States, the article argues that the political significance of intertextual social communication resides in the doubleness of texts that ask an audience to recognize the problems of official forms of culture while simultaneously possibly reinscribing their dominance. The article offers a comparison of shows that merely parody the news with those that actually satirize politics, and ends with a discussion of The Daily Show and The Colbert Report and their particular significance as daily news parodies.
Puppets, Slaves, and Sex Changes
Authors: Gournelos Ted
Published: April 2009

Disconnected neither from close textual analysis nor socially engaged theory, this article shows how what can be called “responsive” levels of political discourse are mobilized to react and propose alternatives to dominant ideology. Through an analysis of a character's changing sexuality in the television show South Park, it demonstrates how cultural texts can act discursively within the wider framework of contemporary politics. Over the course of eleven seasons, Mr. Garrison has functioned specifically to address and attack rhetoric surrounding queer identity, (hyper)masculinity, femininity, and heteronormative sexual identity. Engaging with contemporary queer theory, the essay attempts to formulate an understanding of identity based not in “difference,” “tolerance,” or “resistance” but as an assemblage of discourses and representations that are both reactions to and attempted critiques of dominant (binary) positions on sexuality that point us toward new, socially responsive locations and locutions within which one can conceive and interact with cultural politics.
Review: The Role of Grief in Dementia Caregiving
Authors: Noyes Brigg B. , Hill Robert D. , Hicken Bret L. , Luptak Marilyn , Rupper Randall , Dailey Nancy K. , Bair Byron D.
Published: April 2009

The literature examining issues of caregiver stress, burden, or depression has focused on the stress-process model of caregiving, which posits that there are characteristics inherent in dementia and in the course of caregiving for a person with dementia that can cause stress in the caregiver’s life. A more recent literature has emerged that argues that issues of loss and grief play a significant role in a caregiver’s ability to cope with the stressors of caregiving. This article reviews the caregiver stress and grief literatures, and proposes a conceptual model of dementia caregiving that outlines pathways of stress and grief in dementia caregiving. Issues specific to caregiver grief are proposed for future research and intervention design.
Dehydration and Thermal Strain in Junior Tennis
Authors: Bergeron Michael F.
Published: April 2009

Playing tennis effectively and safely in the heat can be particularly challenging in junior tennis, especially during organized tournament competition when young players have to compete in demanding environmental conditions several times on the same day. With sweat rates ranging from 0.5 L to more than 2.0 L per hour, a young player can readily incur significant total body water and sodium deficits during a very long match or when participating in multiple matches on the same day over several days in a row. On-court thermal strain can be quite high, as tournament-level tennis can elicit appreciable metabolic heat production and storage, even during doubles; this can be exacerbated by poor hydration as well as carryover effects from previous same-day competition and heat exposure. Appropriate and effective safety and performance guidelines for young tennis players training and competing in the heat should focus on readily modifiable risk factors such as hydration management and scheduling of play versus any purported inherent thermoregulatory disadvantages in this specific age group.
Lifestyle Interventions in the Prevention and Treatment of Cancer
Authors: Brown Clarence H. , Baidas Said M. , Hajdenberg Julio J. , Kayaleh Omar R. , Pennock Gregory K. , Shah Nikita C. , Tseng Jennifer E.
Published: April 2009

Despite evidence that cancer death rates in the United States are declining, the absolute number of new cancers and cancer deaths continues to increase, and there is clear evidence that certain human behaviors are influencing these increases. The 4 major factors of lifestyle that continue to be causally related to certain cancers—tobacco use, an unhealthy diet, inadequate exercise, and excessive exposure to ultraviolet radiation—are each independently important in their effects on the genetic and molecular processes that result in the malignant transformation of human cells. There is both irrefutable and otherwise strong evidence that 4 common cancers that occur in the United States—lung cancer, colon/rectal cancer, breast cancer, and prostate cancer—and a less common cancer, malignant melanoma, have etiologic factors that are lifestyle based and therefore controllable through alterations in human behavior. These cancers and the evidence that lifestyle is important in the causation and/or prevention of the disease are the subjects of this review.
Community safety and economic crime
Authors: Croall Hazel
Published: April 2009

The contemporary focus of crime reduction and community safety policies on youth crime, anti-social behaviour and forms of conventionally defined property and violent crime excludes many hazards, in particular those associated with economic and corporate crime, which, despite their considerable impact, have a contested `criminal' status and have not generally been considered relevant to community safety. Drawing on work on the impact of economic crime, this article will map out the economic and physical harms associated with a selected range of economic and business offences. It will also argue that they pose a threat to citizens' quality of life and will explore their relevance to community safety. It will include activities that involve physical dangers and intrusions of privacy in the home and others that have an impact on consumers, the local neighbourhood and the quality of life. It will conclude with an analysis of the extent to which these crimes can and should be incorporated into a broader construction of community safety.
Does CCTV displace crime?
Authors: Waples Sam , Gill Martin , Fisher Peter
Published: April 2009

Crime displacement is a concern often raised regarding situational crime prevention measures. A national evaluation of closed circuit television cameras (CCTV) has provided an interesting test-bed for displacement research. A number of methods have been used to investigate displacement, in particular visualization techniques making use of geographical information systems (GIS) have been introduced to the identification of spatial displacement. Results concur with current literature in that spatial displacement of crime does occur, but it was only detected infrequently. Spatial displacement is found not to occur uniformly across offence type or space, notably the most evident spatial displacement was actually found to be occurring within target areas themselves. GIS and spatial analysis have been shown to complement more typical crime analysis methods and bring a much needed dimension to the investigation of displacement.
Helping offenders into employment
Authors: Vennard Julie , Hedderman Carol
Published: April 2009

The Probation Service has, for some years, worked with external service providers in partnership. One strand of this work has involved collaboration with voluntary sector organizations in helping offenders into education training and employment (ETE). Underlying this work is a slim but important evidence base, which shows that offending diminishes when offenders gain employment, and that being in work may trigger longer term desistance.

Drawing on an evaluation of a government-sponsored `Employment Pathfinder' and on other relevant research, the article argues that recent governmental pressure to contract out services, and to adhere to certain `what works in reducing re-offending' principles, has given rise to tension within this collaboration attributable to conflicting ideology and practice. Specifically, this has created a context in which there is limited scope to adopt practices which are informed by knowledge about `what works' in getting people into employment. A less prescriptive approach from the centre about what should be delivered, and how, would restore effective teamwork and might also open up probation practice to empirical and theoretical insights into the desistance process. Wider implications of these findings for the future involvement of organizations with expertise in the provision of services for offenders are discussed.
Invited review: Mesoscopic modelling: Materials at the appropriate scale
Authors: Stoneham A. M. , Harding J. H.
Published: April 2009

There are successful and standard ways to model materials for macroscopic engineering purposes. Likewise, there are many effective ways for atomic scale modelling, though only for relatively few atoms. But many materials properties of major importance depend on what happens at the mesoscale, where microstructures of ceramics or of teeth or bones, the dislocation engineering of metal alloys, and the spaghetti structures of polymers all have a major influence on performance. We discuss the main issues involved, and how such systems can be modelled effectively.
Ab initio exploration of layer slipping transformations in kaolinite up to 60 GPa
Authors: Mercier P. H. J. , Le Page Y.
Published: April 2009

Kaolinite transformation into other kaolin layer polytypes under pressure is of interest in many materials or industrial applications as well as in seismology. Assuming that this transformation would involve a layer slipping mechanism similar to that of the reversible dickite to HP dickite transformation observed at 2 GPa, the authors undertake here an exploratory study of corresponding transformations. Neglecting contributions from third neighbour layers and beyond to differences in total energy, it is concluded that 19 stacking models of kaolin layers are prime candidates for the lowest enthalpy under moderate pressure. Ab initio compression of those models up to 60 GPa shows that, although several of the above models come close to kaolinite in enthalpy, kaolinite probably survives compression up to ∼ 12 GPa. Beyond this pressure, a new family of kaolin polytypes with lower enthalpy than kaolinite, resulting from a different layer slipping mechanism, is spontaneously produced by ab initio compression. The silicon coordination transforms gradually from tetrahedra to triangular dipyramids with no drastic change to layer architecture. Corresponding distinguishable transformations between adjacent layers resulting from this new coordination are translations - a/3 and ( a+ b)/3, which are not possible translations at zero pressure. Numerous low enthalpy new polytypes based on those translations are possible. Compression to 20 GPa of two kaolin polytypes among the 19 models created above have spontaneously resulted, one into the repeated ( a+ b)/3 polytype with symmetry Cm, and the other one into the repeated - a/3 polytype with symmetry P1. As both models derive from kaolinite by a layer slipping mechanism and have very similar enthalpies, both considerably lower than that of kaolinite, those phases and the polytypes from the same family are prime candidates for post-kaolinite phases beyond ∼ 12 GPa.
Invited review: Modelling of thermodynamics and diffusion in multicomponent systems
Authors: Kattner U. R. , Campbell C. E.
Published: April 2009

The availability of reliable materials data is key to the successful design of materials and manufacturing processes. Commercial alloys seldom consist of only two or three elements, but rather may contain a large number of elements for which the needed data are rarely available. The CALPHAD (calculation of phase diagrams method), as implemented in a number of software tools, enables the development of thermodynamic and diffusion databases and the extrapolation of these property data from binary and ternary systems to higher order systems. The computational methods used to calculate thermodynamic and diffusion properties can be invaluable in the design of new materials. In addition, the databases and software tools provide an efficient method of storing a wealth of data and allow efficient retrieval of the needed information. The present paper reviews the development and application of multicomponent thermodynamic and diffusion mobility databases using the CALPHAD method.
Alloys by Design: Modelling next generation superalloys
Authors: Rae C.
Published: April 2009

The Alloys by Design project aims to develop and refine an integrated array of models to assist in the rapid development of nickel based superalloys. A viable alloy must be stable, creep resistant, castable and coatable. By incorporating the complex interactions between composition, microstructure and processing of the alloys into models, a wider range of compositions can be explored enabling more innovative design strategies. Each of these issues is addressed at a range of appropriate levels from the atomic scale to the continuum.
Air cooled bainitic steels for strong, seamless pipes Part 1 – alloy design, kinetics and microstructure
Authors: Gomez G. , Pérez T. , Bhadeshia H. K. D. H.
Published: April 2009

Seamless pipes are usually quenched and tempered after manufacture in order to obtain the desired properties. The possibility of avoiding this heat treatment is explored here, by designing steels which transform into an carbide free bainitic microstructure during cooling from the hot processing phase of the pipe. The cooling conditions studied are appropriate for the manufacturing process and care has been taken to ensure that the correct microstructure is generated for the range of cooling rates experienced in industrial practice. The alloy design has been validated by kinetic and microstructural studies.
Dissolution precipitation mechanism of TiC/Ti composite layer produced by laser cladding
Authors: Wu W. L.
Published: April 2009

TiC reinforced Ti matrix composite layer was fabricated by laser cladding of Ti and TiC powder mixture on Ti–6Al–4V alloy. Dissolution precipitation mechanism was speculated to illustrate the formation of TiC dendrite in the composite layer. Microstructure evolution of the composite layer has been explained by this mechanism. The composite incorporates the advantages of external particle composites and in situ synthesised particle composites. This mechanism offers an alternative novel idea for the design of bulk composites as well as composite layers. The composite layer exhibits high hardness and excellent wear resistance.
Invited review: Adaptive numerical modelling and hybrid physically based ANM approaches in materials engineering – a survey
Authors: Reed P. A. S. , Starink M. J. , Gunn S. R. , Sinclair I.
Published: April 2009

Many adaptive numerical modelling (ANM) techniques such as artificial neural networks (including multilayer perceptrons), support vector machines and Gaussian processes have now been applied to a wide range of regression and classification problems in materials science. Materials science offers a wide range of industrial applications and hence problem complexity levels from well physically characterised systems (e.g. high value, low volume products) to high volume low cost applications with intrinsic scatter due to commercial manufacturing processes. The authors review a number of recent examples in the literature, with the aim of identifying best practice in the use of these techniques as part of a multistrand modelling approach. The importance of understanding the basic principles of these modelling techniques and how they can link with other modelling strategies is emphasised. In particular the authors wish to identify the importance of hybrid physically based ANM in taking the field forward, which can range from, at the most basic level, careful data selection and data preprocessing to a full integration of physically based models with advanced ANM. A number of case studies are presented to illustrate the main points of the paper.
Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms
Authors: Grand Francis H. , Hidalgo-Curtis Claire E. , Ernst Thomas , Zoi Katerina , Zoi Christine , McGuire Carolann , Kreil Sebastian , Jones Amy , Score Joannah , Metzgeroth Georgia , Oscier David , Hall Andrew , Brandts Christian , Serve Hubert , Reiter Andreas , Chase Andrew J. , Cross Nicholas C. P.
Published: April 2009

Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation–negative myelofibrosis (MF; n = 18), or JAK2 mutation–negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.
Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function
Authors: Schoenwaelder Simone M. , Yuan Yuping , Josefsson Emma C. , White Michael J. , Yao Yu , Mason Kylie D. , O'Reilly Lorraine A. , Henley Katya J. , Ono Akiko , Hsiao Sarah , Willcox Abbey , Roberts Andrew W. , Huang David C. S. , Salem Hatem H. , Kile Benjamin T. , Jackson Shaun P.
Published: April 2009

Procoagulant platelets exhibit hallmark features of apoptotic cells, including membrane blebbing, microvesiculation, and phosphatidylserine (PS) exposure. Although platelets possess many well-known apoptotic regulators, their role in regulating the procoagulant function of platelets is unclear. To clarify this, we investigated the consequence of removing the essential mediators of apoptosis, Bak and Bax, or directly inducing apoptosis with the BH3 mimetic compound ABT-737. Treatment of platelets with ABT-737 triggered PS exposure and a marked increase in thrombin generation in vitro. This increase in procoagulant function was Bak/Bax- and caspase-dependent, but it was unaffected by inhibitors of platelet activation or by chelating extracellular calcium. In contrast, agonist-induced platelet procoagulant function was unchanged in Bak−/−Bax−/− or caspase inhibitor–treated platelets, but it was completely eliminated by extracellular calcium chelators or inhibitors of platelet activation. These studies show the existence of 2 distinct pathways regulating the procoagulant function of platelets.
Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study
Authors: Landgren Ola , Kyle Robert A. , Hoppin Jane A. , Beane Freeman Laura E. , Cerhan James R. , Katzmann Jerry A. , Rajkumar S. Vincent , Alavanja Michael C.
Published: April 2009

Pesticides are associated with excess risk of multiple myeloma, albeit inconclusively. We included 678 men (30-94 years) from a well-characterized prospective cohort of restricted-use pesticide applicators to assess the risk of monoclonal gammopathy of undetermined significance (MGUS). Serum samples from all subjects were analyzed by electrophoresis performed on agarose gel; samples with a discrete or localized band were subjected to immunofixation. Age-adjusted prevalence estimates of MGUS were compared with MGUS prevalence in 9469 men from Minnesota. Associations between pesticide exposures and MGUS prevalence were assessed by logistic regression models adjusted for age and education level. Among study participants older than 50 years (n = 555), 38 were found to have MGUS, yielding a prevalence of 6.8% (95% CI, 5.0%-9.3%). Compared with men from Minnesota, the age-adjusted prevalence of MGUS was 1.9-fold (95% CI, 1.3- to 2.7-fold) higher among male pesticide applicators. Among applicators, a 5.6-fold (95% CI, 1.9- to 16.6-fold), 3.9-fold (95% CI, 1.5- to 10.0-fold), and 2.4-fold (95% CI, 1.1- to 5.3-fold) increased risk of MGUS prevalence was observed among users of the chlorinated insecticide dieldrin, the fumigant mixture carbon-tetrachloride/carbon disulfide, and the fungicide chlorothalonil, respectively. In summary, the prevalence of MGUS among pesticide applicators was twice that in a population-based sample of men from Minnesota, adding support to the hypothesis that specific pesticides are causatively linked to myelomagenesis.
Rescue of coagulation factor VII function by the U1+5A snRNA
Authors: Pinotti Mirko , Balestra Dario , Rizzotto Lara , Maestri Iva , Pagani Franco , Bernardi Francesco
Published: April 2009

Our previous studies with genomic minigenes have demonstrated that an engineered small nuclear RNA-U1 (U1+5a) partially rescued coagulation factor VII (FVII) mRNA processing impaired by the 9726+5G>A mutation. Here, to evaluate the U1+5a effects on FVII function, we devised a full-length FVII splicing-competent construct (pSCFVII-wt). This construct drove in COS-1 cells the synthesis of properly processed FVII transcripts and of secreted functional FVII (23 ± 4 ng/mL), which were virtually undetectable upon introduction of the 9726+5G>A mutation (pSCFVII-9726+5a). Cotransfection of pSCFVII-9726+5a with pU1+5a resulted in a partial rescue of FVII splicing and protein biosynthesis. The level increase in medium was dose dependent and, with a molar excess (1.5×) of pU1+5a, reached 9.5% plus or minus 3.2% (5.0 ± 2.8 ng/mL) of FVII-wt coagulant activity. These data provide the first insights into the U1-snRNA–mediated rescue of donor splice sites at protein level, thus further highlighting its therapeutic implications in bleeding disorders, which would benefit even from tiny increase of functional levels.
Pralatrexate-induced tumor cell apoptosis in the epidermis of a patient with HTLV-1 adult T-cell lymphoma/leukemia causing skin erosions
Authors: Marneros Alexander G. , Grossman Marc E. , Silvers David N. , Husain Sameera , Nuovo Gerard J. , MacGregor-Cortelli Barbara , Neylon Ellen , Patterson Molly , O'Connor Owen A. , Zain Jasmine M.
Published: April 2009

Pralatrexate is a novel antifolate, which shows increased antitumor activity in human tumor xenograft studies in mice compared with methotrexate. We investigated the effects of pralatrexate in a patient with adult T-cell lymphoma/leukemia with significant skin involvement. Atypical lymphocytes in epidermal Pautrier microabscesses were positive for HTLV-1. After the patient presented with leukemic conversion and with worsening of an erythematous generalized papular rash, he received one dose of pralatrexate. Within one week, his skin developed innumerable small erosions limited to the areas of the papular rash, sparing unaffected skin. Here we present in vivo evidence that pralatrexate-induced erosions in skin affected by adult T-cell lymphoma/leukemia are a manifestation of apoptosis of tumor cells infiltrating the epidermis and are not the result of cytotoxicity by pralatrexate on keratinocytes. This distinction is critical and may profoundly influence the clinical decision to continue pralatrexate treatment. Pralatrexate-induced skin erosions may indicate response to treatment.
Pseudomonas aeruginosain patients hospitalised for COPD exacerbation: a prospective study
Authors: Garcia-Vidal C. , Almagro P. , Romaní V. , Rodríguez-Carballeira M. , Cuchi E. , Canales L. , Blasco D. , Heredia J. L. , Garau J.
Published: April 2009

Risk factors forPseudomonas aeruginosa(PA) isolation in patients hospitalised for chronic obstructive pulmonary disease (COPD) exacerbation remain controversial. The aim of our study was to determine the incidence and risk factors for PA isolation in sputum at hospital admission in a prospective cohort of patients with acute exacerbation of COPD.

We prospectively studied all patients with COPD exacerbation admitted to our hospital between June 2003 and September 2004. Suspected predictors of PA isolation were studied. Spirometry tests and 6-min walking tests were performed 1 month after the patients were discharged. High-resolution computed tomography (HRCT) was performed in a randomised manner in one out of every two patients to quantify the presence and extent of bronchiectasis. Patients were followed up during the following year for hospital re-admissions.

A total of 188 patients were included, of whom 31 (16.5%) had PA in sputum at initial admission. The BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index (OR 2.18, CI 95% 1.26–3.78; p = 0.005), admissions in the previous year (OR 1.65, CI 95% 1.13–2.43; p = 0.005), systemic steroid treatment (OR 14.7, CI 95% 2.28–94.8; p = 0.01), and previous isolation of PA (OR 23.1, CI 95% 5.7–94.3; p<0.001) were associated with PA isolation. No relationship was seen between bronchiectasis in HRCT and antibiotic use in the previous 3 months.

PA in sputum at hospital admission is more frequent in patients with poorer scoring on the BODE index, previous hospital admissions, oral corticosteroids and prior isolation of PA.
Utility of quantitative T-cell responsesversusunstimulated interferon-γ for the diagnosis of pleural tuberculosis
Authors: Dheda K. , van Zyl-Smit R. N. , Sechi L. A. , Badri M. , Meldau R. , Meldau S. , Symons G. , Semple P. L. , Maredza A. , Dawson R. , Wainwright H. , Whitelaw A. , Vallie Y. , Raubenheimer P. , Bateman E. D. , Zumla A.
Published: April 2009

The clinical utility of antigen-specific interferon (IFN)-γ release assays (IGRAs) using pleural mononuclear cells, for the diagnosis of tuberculosis (TB), requires clarification.

We compared the diagnostic utility of unstimulated pleural IFN-γ levels with several pleural antigen-specific T-cell IGRAs (early secretory antigenic target-6 and culture filtrate protein-10 (T-SPOT.®TB, QuantiFERON®-TB Gold In-tube), purified protein derivative (PPD) and heparin-binding haemagglutinin (HBHA)) in 78 South African TB suspects. Test results were compared against a clinical score and a reference standard.

Out of 74 evaluable subjects 48, seven and 19 had definite, probable and no TB, respectively. 11 (15%) out of 74 pleural samples (nine (19%) out of 48 of the definite TB cases) had total cell counts that were inadequate for T-cell processing. In the remaining 63 samples, the sensitivity, specificity, positive predictive value and negative predictive value of different diagnostic methods were as follows. Maximal bioclinical score: 54, 89, 92 and 43%, respectively; T-SPOT.®TB: 86, 60, 84 and 64%, respectively; QuantiFERON®-TB Gold In-tube: 57, 80, 87 and 44%, respectively; HBHA-specific IGRA: 59, 31, 64 and 27%, respectively; PPD-specific IGRA: 81, 40, 76 and 46%, respectively; and pleural fluid unstimulated IFN-γ: 97, 100, 100 and 94%, respectively.

Unstimulated IFN-γ was the most accurate test for distinguishing TB from non-TB effusions in a high-burden setting. The antigen-specific T-cell IGRAs were limited by suboptimal accuracy and the inability to isolate sufficient mononuclear cells to perform the assay.
Impaired detection ofMycobacterium tuberculosisimmunity in patients using high levels of immunosuppressive drugs
Authors: Sester U. , Wilkens H. , van Bentum K. , Singh M. , Sybrecht G. W. , Schäfers H-J. , Sester M.
Published: April 2009

We have previously shown, in renal transplant recipients on maintenance immunosuppression, that a whole-blood assay was superior in detecting immunity towards purified protein derivative (PPD) compared with skin testing. As blood tests may have limitations during high-dose immunosuppression therapy, the present study was aimed at characterising the effect of high immunosuppressive drug levels on PPD-specific T-cell immunity.

PPD-reactive CD4 T-cells from 13 renal transplant recipients were longitudinally quantified by the induction of cytokines using flow cytometry. To further address the effect of high and low maintenance immunosuppression, drug effects were studiedin vitroand in 49 age-matched lung transplant recipients and 49 renal transplant recipients.

Maintenance immunosuppression after renal transplantation did not affect PPD-specific T-cell detection (median T-cell frequencies 0.55% before and 0.46% >12 months after transplantation), whereas specific T-cell frequencies were significantly lower 3 months after transplantation (0.15%; p = 0.0002). Likewise, high-level maintenance immunosuppression after lung transplantation was associated with a significantly lower prevalence in PPD-specific T-cell reactivity compared with renal transplant recipients (16.7%versus52.1%; p = 0.0005). In line with the observations madein vivo, calcineurin inhibitors analysedin vitroled to a dose-dependent decrease in antigen-specific T-cell reactivity.

The flow cytometric assay is not adversely affected by low drug doses. In contrast, decreased levels of PPD-specific T-cells early after transplantation and low prevalence of PPD-reactivity in lung transplant recipients suggest a reduced sensitivity ofin vitrotesting during high-level immunosuppression.
Seasonality of tuberculosis in an Eastern-Asian country with an extreme continental climate
Authors: Naranbat N. , Nymadawa P. , Schopfer K. , Rieder H. L.
Published: April 2009

Aggregate monthly notifications of incident sputum smear-positive tuberculosis (TB) in Mongolia, stratified by sex and age groups, were analysed separately for Ulaanbaatar, Mongolia, and the rest of the country for the 9-yr period from 1998 to 2006. TB notifications were compared with ambient surface temperature.

More than twice as many TB cases were notified in the peak month (April) compared with the trough months (October–December), paralleling the temperature curve. The fluctuations recurred consistently over the entire observation period, were identical in the capital compared with the rest of the country, and were independent of age and sex.

TB notifications parallel the temperature amplitudes and have a magnitude not reported elsewhere. We hypothesise that the influence of temperature on life either indoors or outdoors is consistent with the transmission probability ofMycobacterium tuberculosisand the subsequent delay to disease recognition and notification with the incubation period, possibly co-determined by other factors, rather than accessibility to services.
Clinical relevance ofMycobacterium malmoenseisolation in the Netherlands
Authors: Hoefsloot W. , van Ingen J. , de Lange W. C. M. , Dekhuijzen P. N. R. , Boeree M. J. , van Soolingen D.
Published: April 2009

Uncertainty exists about the clinical relevance ofMycobacterium malmoenseisolation, especially in pulmonary samples. We therefore determined clinical relevance, treatment and outcome ofM. malmoenseisolation in the Netherlands.

A retrospective medical file study was conducted for all patients in the Netherlands from whomMycobacterium malmoensehad been isolated between January 2002 and January 2006. Diagnostic criteria for nontuberculous mycobacterial (NTM) disease published by the American Thoracic Society (ATS) were used to determine clinical relevance. Treatment was compared with guidelines published by the British Thoracic Society.

In total, 51 patients were found from whomM. malmoensewas isolated. Of these, 40 (78%) patients had pulmonary isolates and 32 (80%) of them met the ATS diagnostic criteria. Cavitary disease was most common (n = 28; 88%). Patients with pulmonary disease were mostly males, with an average age of 56 yrs and pre-existing chronic obstructive pulmonary disease. Cervical lymphadenitis was the most common extrapulmonary disease type. Adherence to treatment guidelines was poor. A good clinical response to treatment was observed in 70% and 73% of patients treated for pulmonary and extrapulmonary disease, respectively.

In conclusion,M. malmoenseis a clinically highly relevant NTM in the Netherlands causing serious pulmonary morbidity. Adherence to treatment guidelines is not satisfactory.