bluuebunny/crossref_metadata_2025 huggingface dataset:
Convergent architecture of the transcriptome in human cancer
Authors: Zou Lihua
Published: October 2015

ABSTRACTS

Despite large-scale efforts to systematically map the cancer genome, little is known about how the interplay of genetic and epigenetic alternations shapes the architecture of the tumor’s transcriptome. With the goal of constructing a system-level view of the deregulated pathways in cancer cells, we systematically investigated the functional organization of the transcriptomes of 10 tumor types using data sets generated by The Cancer Genome Atlas project (TCGA). Our analysis indicates that the human cancer transcriptome is organized into well-conserved modules of co-expressed genes. In particular, our analysis identified a set of conserved gene modules with distinct cancer hallmark themes involving cell cycle regulation, angiogenesis, innate and adaptive immune response, differentiation, metabolism and regulation of protein phosphorylation. We applied a network inference approach to nominate candidate drivers of these conserved gene modules. The predicted drivers have consistent cancer-relevant functions related to the specific hallmarks and are enriched with cancer consensus genes and significantly mutated genes. We showed genetic alternations ofTP53and other cell cycle drivers have major downstream transcriptional impact on cell cycle regulation. Collectively, our analysis provided global views of convergent transcriptome architecture of human cancer. The result of our analysis can serve as a foundation to link diverse genomic alternations to common transcriptomic features in human cancer.
A majority of m6A residues are in the last exons, allowing the potential for 3′ UTR regulation
Authors: Ke Shengdong , Alemu Endalkachew A. , Mertens Claudia , Gantman Emily Conn , Fak John J. , Mele Aldo , Haripal Bhagwattie , Zucker-Scharff Ilana , Moore Michael J. , Park Christopher Y. , Vågbø Cathrine Broberg , Kusśnierczyk Anna , Klungland Arne , Darnell James E. , Darnell Robert B.
Published: October 2015

We adapted UV CLIP (cross-linking immunoprecipitation) to accurately locate tens of thousands of m6A residues in mammalian mRNA with single-nucleotide resolution. More than 70% of these residues are present in the 3′-most (last) exons, with a very sharp rise (sixfold) within 150–400 nucleotides of the start of the last exon. Two-thirds of last exon m6A and >40% of all m6A in mRNA are present in 3′ untranslated regions (UTRs); contrary to earlier suggestions, there is no preference for location of m6A sites around stop codons. Moreover, m6A is significantly higher in noncoding last exons than in next-to-last exons harboring stop codons. We found that m6A density peaks early in the 3′ UTR and that, among transcripts with alternative polyA (APA) usage in both the brain and the liver, brain transcripts preferentially use distal polyA sites, as reported, and also show higher proximal m6A density in the last exons. Furthermore, when we reduced m6A methylation by knocking down components of the methylase complex and then examined 661 transcripts with proximal m6A peaks in last exons, we identified a set of 111 transcripts with altered (approximately two-thirds increased proximal) APA use. Taken together, these observations suggest a role of m6A modification in regulating proximal alternative polyA choice.
Myeloid neoplasm demonstrating a STAT5B-RARA rearrangement and genetic alterations associated with all-trans retinoic acid resistance identified by a custom next-generation sequencing assay
Authors: Kluk Michael J. , Abo Ryan P. , Brown Ronald D. , Kuo Frank C. , Dal Cin Paola , Pozdnyakova Olga , Morgan Elizabeth A. , Lindeman Neal I. , DeAngelo Daniel J. , Aster Jon C.
Published: October 2015

We describe the case of a patient presenting with several weeks of symptoms related to pancytopenia associated with a maturation arrest at the late promyelocyte/early myelocyte stage of granulocyte differentiation. A diagnosis of acute promyelocytic leukemia was considered, but the morphologic features were atypical for this entity and conventional tests for the presence of a PML-RARA fusion gene were negative. Additional analysis using a custom next-generation sequencing assay revealed a rearrangement producing a STAT5B-RARA fusion gene, which was confirmed by reverse transcription polymerase chain reaction (RT-PCR) and supplementary cytogenetic studies, allowing the diagnosis of a morphologically atypical form of acute promyelocytic leukemia to be made. Analysis of the sequencing data permitted characterization of both chromosomal breakpoints and revealed two additional alterations, a small deletion in RARA exon 9 and a RARA R276W substitution, that have been linked to resistance to all-trans retinoic acid. This case highlights how next-generation sequencing can augment currently standard testing to establish diagnoses in difficult cases, and in doing so help guide selection of therapy.
Characterization of a novel fusion geneEML4-NTRK3in a case of recurrent congenital fibrosarcoma
Authors: Tannenbaum-Dvir Sarah , Glade Bender Julia L. , Church Alanna J. , Janeway Katherine A. , Harris Marian H. , Mansukhani Mahesh M. , Nagy Peter L. , Andrews Stuart J. , Murty Vundavalli V. , Kadenhe-Chiweshe Angela , Connolly Eileen P. , Kung Andrew L. , Dela Cruz Filemon S.
Published: October 2015

We describe the clinical course of a recurrent case of congenital fibrosarcoma diagnosed in a 9-mo-old boy with a history of hemimelia. Following complete surgical resection of the primary tumor, the patient subsequently presented with bulky bilateral pulmonary metastases 6 mo following surgery. Molecular characterization of the tumor revealed the absence of the prototypicalETV6-NTRK3translocation. However, tumor characterization incorporating cytogenetic, array comparative genomic hybridization, and RNA sequencing analyses, revealed a somatic t(2;15)(2p21;15q25) translocation resulting in the novel fusion ofEML4withNTRK3. Cloning and expression ofEML4-NTRK3in murine fibroblast NIH 3T3 cells revealed a potent tumorigenic phenotype as assessed in vitro and in vivo. These results demonstrate that multiple fusion partners targetingNTRK3can contribute to the development of congenital fibrosarcoma.
Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers
Authors: Laskin Janessa , Jones Steven , Aparicio Samuel , Chia Stephen , Ch'ng Carolyn , Deyell Rebecca , Eirew Peter , Fok Alexandra , Gelmon Karen , Ho Cheryl , Huntsman David , Jones Martin , Kasaian Katayoon , Karsan Aly , Leelakumari Sreeja , Li Yvonne , Lim Howard , Ma Yussanne , Mar Colin , Martin Monty , Moore Richard , Mungall Andrew , Mungall Karen , Pleasance Erin , Rassekh S. Rod , Renouf Daniel , Shen Yaoqing , Schein Jacqueline , Schrader Kasmintan , Sun Sophie , Tinker Anna , Zhao Eric , Yip Stephen , Marra Marco A.
Published: October 2015

Given the success of targeted agents in specific populations it is expected that some degree of molecular biomarker testing will become standard of care for many, if not all, cancers. To facilitate this, cancer centers worldwide are experimenting with targeted “panel” sequencing of selected mutations. Recent advances in genomic technology enable the generation of genome-scale data sets for individual patients. Recognizing the risk, inherent in panel sequencing, of failing to detect meaningful somatic alterations, we sought to establish processes to integrate data from whole-genome analysis (WGA) into routine cancer care. Between June 2012 and August 2014, 100 adult patients with incurable cancers consented to participate in the Personalized OncoGenomics (POG) study. Fresh tumor and blood samples were obtained and used for whole-genome and RNA sequencing. Computational approaches were used to identify candidate driver mutations, genes, and pathways. Diagnostic and drug information were then sought based on these candidate “drivers.” Reports were generated and discussed weekly in a multidisciplinary team setting. Other multidisciplinary working groups were assembled to establish guidelines on the interpretation, communication, and integration of individual genomic findings into patient care. Of 78 patients for whom WGA was possible, results were considered actionable in 55 cases. In 23 of these 55 cases, the patients received treatments motivated by WGA. Our experience indicates that a multidisciplinary team of clinicians and scientists can implement a paradigm in which WGA is integrated into the care of late stage cancer patients to inform systemic therapy decisions.
Person-organization fit: bibliometric study and research agenda
Authors: Santos Leonardo Blanco dos , De Domenico Silvia Marcia Russi
Published: October 2015

Purpose

– The purpose of this paper is to propose a research agenda on person-organization fit (P-O fit).

Design/methodology/approach

– A systematic review of the literature from a bibliometric perspective is performed. All documents indexed in the Scopus database with the term “person-organization fit” in the title were mapped.

Findings

– An increasing interest in P-O fit since the 1990s is observed. Amy L. Kristof-Brown, affiliated to the University of Iowa, is the most productive author. All empirical studies from our sample used quantitative methodology and non-probabilistic sample, and 85.9 per cent of them were cross-sectional. The similarity conceptualization of P-O fit and the perceived fit perspective have been adopted more often. Job satisfaction, intention to leave and organizational commitment are the most studied outcomes of P-O fit.

Research limitations/implications

– By offering a general view of the production on P-O fit, the paper may be valuable not only for those who aim to start researching on the field, but also for practitioners who may benefit from an overview of the field to evaluate interventions to increase the fit between employees and organizations. Noticing the absence of publications from Latin America, and taking into account the positive outcomes of P-O fit to individuals and organizations, this paper aims to stimulate researchers from this region to develop research on P-O fit.

Originality/value

– Original insights for future research are presented: The need for qualitative studies to understand the individual perception of fit; the study of complementary P-O fit from a needs–supplies perspective; and the need to consider the multi-dimensionality of constructs that are taken as content of fit, which may offer a possible answer to Van Vianen’s (2001) claim about the “value of fit”.
Impact of training on entrepreneurial intention: an interactive cognitive perspective
Authors: Boukamcha Fayçal
Published: October 2015

Purpose

– This paper aims to clarify the impact of the entrepreneurial training on a Tunisian trainee’s entrepreneurial cognitions and intention. An interactive cognitive perspective was adopted to test the interaction effect between the entrepreneurial cognitions: the perceived entrepreneurial self-efficacy, the perceived entrepreneurial feasibility and entrepreneurial desirability. A research model was built showing several relationships between entrepreneurial training, cognitions and intention.

Design/methodology/approach

– A survey was conducted on a convenience sample of 240 participants in four business incubators. The maximum-likelihood test was used as a structural equation modeling method to test the model.

Findings

– The results show the importance of the entrepreneurial training in the development of entrepreneurial cognitions. Further, the findings, to some extent, validate the interaction between the entrepreneurial cognitive patterns. However, entrepreneurial intention was only predicted through the entrepreneurial desirability. Several implications are discussed at the end of this paper.

Practical implications

– The findings seem interesting insofar, as they show the importance of entrepreneurial trainings in the entrepreneurial intention development through the enhancement of desirability. This process can be triggered by a training program that contains case studies, success stories and conferences to make the youth enthusiastic about self-employment.

Originality/value

– The significant impact of the entrepreneurial training on trainees’ cognitions should encourage governments and incubators to promote entrepreneurial training programs to enhance the youths’ willingness to create their own businesses. The findings in this paper seem interesting insofar as they show the importance of entrepreneurial trainings in the entrepreneurial intention development through the enhancement of desirability. This process can be triggered by a training program that contains case studies, success stories and conferences to make the youth enthusiastic about self-employment.
Modifying culture and identity: a deep gaze into tourists’ quotidian culture and identity modification processes
Authors: De Villiers Rouxelle
Published: October 2015

Purpose

– This paper aims to situate tourism within the wider context of temporary and permanent people movements and immigration as a form of permanent tourism with a deep gaze into tourists’ own national culture and even deeper gaze into the trappings of immigrants’ quotidian identity to define a modified identity. This paper offers, through auto-ethnography (AE) and confirmatory introspection (CI), a glimpse into the complex decision-making processes tourists, migrant workers and immigrants have to cope with to survive and thrive in a home “away” from their country of birth. The literature on the comparison between temporary mobility (tourism), nomadic migration (semi-permanent mobility) and permanent mobility (drifters, wanderers or denizen globe trotters) is sparse and unsystematic.

Design/methodology/approach

– The use of AE and CI allows the researcher with several years of cognitive and affective information and easy access to data on the private, lived experiences of the author and closely related family. Having lived and worked in several countries, supplemented by experiences of visiting over 35 countries for varying periods, the researcher has direct access to a wealth of rich data related to tourism (one- to five-week trips to Europe, USA, South America, the Middle East, Africa, Australia and the Pacific Islands), semi-permanent mobility (one-year exchange work placement in North America) and permanent mobility (more than ten years of being immigrants to New Zealand).

Findings

– The results show that tourists and immigrants are exposed to numerous decisions (varying in complexity and impact) before, during and after their travels that will impact on their acculturation, the genuineness of their experience and their willingness to modify their own identities, as well as the culture of the destinations they consume. Travelers have to overcome contextual and personal hurdles to achieve integration in a reasonable time. The way in which they tackle and overcome these hurdles will impact upon their modification of personal identity and acculturation.

Practical implications

– This paper offers practical advice to tourists, immigrants and employers on becoming adaptable consumers, highly resilient survivors and highly reliable organizations – able to thrive in today’s global marketplace. This study helps marketers, tourism professionals and employers of migrants to understand the processes consumers go through to modify identity to effectively and timely fit into new environments.

Originality/value

– AE- and CI-based research explores the tourist gaze and acculturation processes and discusses a two-directional model of modification of culture and identity. In addition, the paper highlights complex decision-making models tourists, nomads, globe trotters and immigrants use when considering alternative destinations and sought-after experiences.
Investigating the connections between health lean management and clinical risk management
Authors: Crema Maria , Verbano Chiara
Published: October 2015

Purpose

– The purpose of this paper is to investigate connections and overlaps between health lean management (HLM) and clinical risk management (CRM) understanding whether and how these two approaches can be combined together to pursue efficiency and patient safety improvements simultaneously.

Design/methodology/approach

– A systematic literature review has been carried out. Searching in academic databases, papers that focus not only on HLM, but also on clinical errors and risk reduction, were included. The general characteristics of the selected papers were analysed and a content analysis was conducted.

Findings

– In most of the papers, pursing objectives of HLM and CRM and adopting tools and practices of both approaches, results of quality and, particularly, of safety improvements were obtained. A two-way arrow between HLM and CRM emerged but so far, none of the studies has been focused on the relationship between HLM and CRM.

Originality/value

– Results highlight an emerging research stream, with many useful theoretical and practical implications and opportunities for further research.
Assessing the structure and temporal dynamics of seabird communities: the challenge of capturing marine ecosystem complexity
Authors: Moreno Rocío , Stowasser Gabriele , McGill Rona A. R. , Bearhop Stuart , Phillips Richard A.
Published: October 2015

Understanding interspecific interactions, and the influences of anthropogenic disturbance and environmental change on communities, are key challenges in ecology. Despite the pressing need to understand these fundamental drivers of community structure and dynamics, only 17% of ecological studies conducted over the past three decades have been at the community level.

Here, we assess the trophic structure of the procellariiform community breeding at South Georgia, to identify the factors that determine foraging niches and possible temporal changes. We collected conventional diet data from 13 sympatric species between 1974 and 2002, and quantified intra‐ and inter‐guild, and annual variation in diet between and within foraging habits. In addition, we tested the reliability of stable isotope analysis (SIA) of seabird feathers collected over a 13‐year period, in relation to those of their potential prey, as a tool to assess community structure when diets are diverse and there is high spatial heterogeneity in environmental baselines.

Our results using conventional diet data identified a four‐guild community structure, distinguishing species that mainly feed on crustaceans; large fish and squid; a mixture of crustaceans, small fish and squid; or carrion. In total, Antarctic krill Euphausia superba represented 32%, and 14 other species a further 46% of the combined diet of all 13 predators, underlining the reliance of this community on relatively few types of prey. Annual variation in trophic segregation depended on relative prey availability; however, our data did not provide evidence of changes in guild structure associated with a suggested decline in Antarctic krill abundance over the past 40 years.

Reflecting the differences in δ15N of potential prey (crustaceans vs. squid vs. fish and carrion), analysis of δ15N in chick feathers identified a three‐guild community structure that was constant over a 13‐year period, but lacked the trophic cluster representing giant petrels which was identified using conventional diet data.

Our study is the first in recent decades to examine dietary changes in seabird communities over time. Conventional dietary analysis provided better resolution of community structure than SIA. However, δ15N in chick feathers, which reflected trophic (level) specialization, was nevertheless an effective and less time‐consuming means of monitoring temporal changes.
Functional responses of insectivorous bats to increasing housing density support ‘land‐sparing’ rather than ‘land‐sharing’ urban growth strategies
Authors: Caryl Fiona M. , Lumsden Linda F. , van der Ree Rodney , Wintle Brendan A.
Published: October 2015

Debates about ‘land‐sparing’ and ‘land‐sharing’ strategies for conserving biodiversity in cities provide an overly simplistic characterization of alternate planning options. Increased urbanization manifests in a number of ways and sophisticated analyses of how species respond to urban environments are required before generalizations about the relative merits of either planning strategy should be made.

We investigated how insectivorous bats respond to housing density (a measure of urbanization intensity) and a range of habitat variables by modelling the occupancy and activity of 12 species in Melbourne, Australia. In addition to species‐level analyses, species were grouped into guilds (‘matrix’, ‘patch’ or ‘edge’ species) depending on their ecomorphology and level of patch‐dependency.

Housing density (dwellings per hectare: dph) was the dominant explanatory variable of occupancy and activity of most species studied. Site occupancy probabilities of patch and edge species were reduced by half at housing densities of just 1·1–4·5 dph depending on species, while their activity was halved at housing densities of 2·6–10·3 dph. The activity of two matrix species also declined, but at higher housing densities (reducing by half at 4·5–7·9 dph). Patch and edge species responded nonlinearly to tree cover at low housing densities, with peaks in occupancy and activity at 20–60%. This response broke down at medium housing densities, however, as most species were no longer present.

Synthesis and applications. Occupancy probability and activity of almost all bat species studied were substantially reduced even at very low housing densities. Increasing tree cover had no positive effect on the occupancy and activity of patch and edge species once medium housing densities were reached. In order for land‐sharing strategies to provide good habitat for patch and edge bat species housing densities would need to be so low as to be impractical in most urban planning contexts. By contrast, land‐sparing with forested habitat remaining in 20% or more of the landscape could provide positive conservation outcomes for the species modelled here. We discuss the relevance of our findings in planning for conservation of bats and their habitats in other recently established and expanding cities.
Aid, Growth and Jobs
Authors: Fields Gary
Published: October 2015

Various development objectives are worthy, but one objective merits special attention: reducing the scourge of absolute economic misery in the world. This study focuses on an important but relatively underemphasized approach to poverty reduction: helping the poor earn more in the labour market for the work they do, so that they can buy the goods and services they need to move up out of poverty. The core of the study is divided into three sections: defining the global poverty challenge and the world's employment problem, presenting policy options for improving employment outcomes for the poor, and suggesting ways of choosing which policy interventions are most promising for poverty reduction.
Developing Management Practices to Support Joined‐Up Governance
Authors: Carey Gemma , Harris Patrick
Published: October 2015

Various forms of ‘boundary‐crossing’ practices continue to proliferate in public management and public service provision (i.e. activities that require engagement and collaboration across sectors, institutions, and organisations). Yet the dynamic nature of this type of joined‐up working is proving to be a major management challenge. In this paper, we bring a number of concepts to bear on the management of joined‐up and cross‐boundary working in public management of complex social issues. Firstly, we present the concept of ‘adaptive management’, which we draw from field of environmental policy and planning (and human ecology). Secondly, we introduce a rethinking of the role of ‘policy targets’ using a complexity lens. These concepts are integrated into a practice heuristic (or framework) designed to assist cross‐boundary policy implementation in real‐world settings. We argue that adaptive management approaches may have significant utility for ensuring effective governance in uncertain environments.
Is Populism an Ideology? A Refutation and a New Perspective
Authors: Aslanidis Paris
Published: October 2015

The dominant theoretical paradigm originating in the work of Cas Mudde conceives of populism as a thin-centered ideology that focuses on the antagonism between people and elites against the backdrop of popular sovereignty. While this framework has contributed signiﬁcantly to an improved scientiﬁc analysis of populism, it is argued in this article that its ideological connotations are ill-conceived both conceptually and methodologically, and that its normative implications and failure to acknowledge the graded nature of populist behavior hinder the further evolution of the ﬁeld of populism studies. Combining insights from the work of Ernesto Laclau and the proponents of frame theory, the article suggests dropping the ideological clause and simply conceiving populism as a discursive frame. The article contends that frame analysis reveals a strong ﬁt between discursive elements and cognitive features of populism, furnishing solid methodological foundations to conduct empirical research and encouraging cooperation with neighboring ﬁelds of social science.
A comparison of recommendations for pharmacologic thromboembolism prophylaxis after caesarean delivery from three major guidelines
Authors: Palmerola KL , D'Alton ME , Brock CO , Friedman AM
Published: October 2015

Objective

Guidelines for pharmacologic obstetric venous thromboembolism (VTE) prophylaxis from the American Congress of Obstetricians (ACOG), the Royal College of Obstetricians and Gynaecologists (RCOG), and the American College of Chest Physicians (Chest) vary significantly. The objective of this study was to determine the practical implications of these recommendations in terms of prophylaxis rates for a tertiary obstetric population.

Study design

Cross‐sectional.

Setting

Tertiary referral hospital.

Population

Patients post‐operative day 1 after caesarean delivery.

Methods

This cross‐sectional study evaluated rates of pharmacologic prophylaxis for women based on RCOG, ACOG, and Chest recommendations. Medical, obstetric, and demographic risk factors for thromboembolism were reviewed for individual patients. Rates of prophylaxis based on each of the guidelines with 95% confidence intervals were calculated.

Outcome measure

Recommended pharmacologic prophylaxis.

Results

About 293 patients were included in the analysis. Under RCOG guidelines, 85.0% of patients would receive post‐caesarean pharmacologic prophylaxis [95% confidence interval (CI) 80.5–88.6%] compared with 1.0% of patients under ACOG guidelines (95% CI 0.3–3.0%) and 34.8% of patients under Chest guidelines (95% CI 29.6–40.4%). Caesarean during labour, obesity, advanced maternal age, pre‐eclampsia, and multiple gestation were among the most commonrisk factors.

Conclusion

Recommended prophylaxis differed significantly. Under ACOG recommendations a small minority of patients would receive prophylaxis, whereas under RCOG recommendations a large majority of patients would receive low‐molecular‐weight heparin. Given the large differences in prophylaxis rates for post‐caesarean thromboprophylaxis based on different guidelines, further research is urgently needed to compare the risks and benefits of recommendations.

Tweetable Abstract

Recommendations from major society guidelines for post‐caesarean thromboprophylaxis differ greatly.
Scottish Shire Elections: Preliminary Findings in Sheriff Court Books
Authors: MacDonald Alan
Published: October 2015

Historians of the Scottish parliament have paid little attention to shire elections because of an apparent lack of local source material. This article explores some of the reasons for this perception and argues that sheriff court records contain considerably more evidence than has been appreciated hitherto. It demonstrates that these records provide details of the electoral process, the regularity of elections, the numbers of electors, external interference in elections and internal divisions within the electorate, local responses to national political events, and attitudes to representation through such things as levying taxes locally to reimburse representatives’ expenses. It challenges the once widely‐held view that the lesser nobility, who comprised the electorate, were uninterested in parliamentary participation, suggesting instead that the statute of 1587, by which shire representation was established, was reasonably successful. Finally, it considers the potential for further research in these and other records which, it is argued, will provide a much deeper understanding of 17th‐century Scotland's parliamentary history in particular and political history in general.
Enacting a Local Reform in the Age of Reform: A Salary for the Chairman of Middlesex Sessions
Authors: Landau Norma
Published: October 2015

This article examines the unsuccessful attempts made from 1833 to 1842 by Middlesex's justices of the peace to obtain a local statute allowing them to pay a salary to their chairman. Instead of securing such an act, they had to settle for a statute enacted by the government, a statute authorising the government to appoint their chairman for judicial proceedings. The article uses the story of Middlesex's attempt to obtain a salary for the chairman to examine: justices' attempts to reform the office of chairman of county Sessions; the limited powers of justices in their county Sessions; and the centralising aspirations of central government.

The statute that the government produced in 1844 originated as a public bill. In contrast, the statute that Middlesex had attempted to obtain originated as private bills. The statute enacted by the government contained defects that probably would not have marred a statute enacted under the rules governing private bills. So, this article uses the legislative misadventures of the government's bill to compare the procedures for enactment of public and private bills. The article therefore provides a case study of mid‐19th‐century legislative procedures governing enactment of local legislation, while arguing that, as of the mid 19th century, parliament had not developed procedures appropriate to both representative government and a centralising central government using public bills for local matters.
Gouty arthropathy: Review of clinico‐pathologic and imaging features
Authors: Parathithasan Nishanthinie , Lee Wai‐Kit , Pianta Marcus , Oon Shereen , Perera Warren
Published: October 2015

Gout is a common inflammatory arthropathy in adults, with the prevalence increasing in males of older age. It occurs when monosodium urate (MSU) crystals are deposited in joints and connective tissue causing inflammation. The gold standard for the diagnosis of gout is the demonstration of negatively birefringent, needle‐shaped MSU crystals through synovial fluid aspiration. However, this is an invasive technique and may not always be conclusive or feasible. Imaging techniques have been developed to aid in diagnosis of gout non‐invasively. Radiography has a low utility in the early diagnosis of gout and demonstrates erosions in late stages. Ultrasound (US) has a high overall sensitivity in diagnosing gout with the ‘double contour’ sign having a high specificity. Magnetic resonance imaging is good at detecting tophi, bone marrow oedema and erosions, but has a limited role in diagnosis because of its high cost and limited availability. Conventional computed tomography (CT) has no role in the routine diagnosis of gout before development of erosions and tophi. A newer technology, dual‐energy CT (DECT) has been shown to be able to detect MSU crystals burden with high accuracy. It has a higher specificity and lower sensitivity that US in gout diagnosis. However, because of radiation exposure and cost, it has a better utility in diagnosing clinically suspected gout complicated by other concurrent rheumatologic conditions or if radiography, US and synovial aspiration are inconclusive or not feasible. This paper will review the clinico‐pathologic and imaging features of gouty arthropathy.
Role of radiation in the treatment of non‐metastatic osseous Ewing sarcoma
Authors: Ning Matthew S , Perkins Stephanie M , Borinstein Scott C , Holt Ginger E , Stavas Mark J , Shinohara Eric T
Published: October 2015

Introduction

Local control, either with surgery, radiation (RT) or both, is essential in the management of localised Ewing sarcoma; however, the relative role of RT remains controversial.

Methods

Using the Surveillance, Epidemiology, and End Results database, 612 patients treated for non‐metastatic skeletal Ewing sarcoma between the years 1988 and 2010 were identified.

Results

Median age and follow‐up were 13 years (range: 0–21) and 56 months (range: 0–287), respectively. Five‐year overall survival (OS) for the cohort was 74.4 ± 2.0%. Patients received surgery alone (51.3%), RT alone (21.6%) or both (27.1%). Patients with skeletal Ewing sarcoma had improved OS with surgery alone compared with other treatments. However, in subset analyses, RT was not inferior to surgery alone for appendicular (5‐year OS: 80.0% vs. 79.3%), non‐pelvic (84.3% vs. 79.9%) or localised disease (confined to cortex or periosteum; 79.7% vs. 80.6%). After controlling for stage and site, no increase in mortality was observed with RT versus surgery alone (hazard ratio = 0.77 (95% confidence interval: 0.49–1.19)).

Conclusions

In regard to survival, RT did not appear to be inferior to surgery alone for most patients, particularly those with disease at favourable sites (localised, appendicular, non‐pelvic). In select patients with Ewing sarcoma, RT may be an appropriate strategy for local control that does not necessarily compromise survival outcomes.
The impact of altering filling pressures in diagnostic outpatient hysteroscopy on the procedure completion rates and associated pain: a randomised double‐blind controlled trial
Authors: Haggag Hisham M. , Hassan AbdelGany M.A.
Published: October 2015

Background

Several studies have compared different distension media and analgesics to optimise the efficiency of outpatient hysteroscopy. However, studies comparing different uterine filling pressures are scarce.

Aim

The objective of this study was to evaluate and compare different uterine filling pressures during diagnostic outpatient hysteroscopy in an attempt to find the optimal pressure allowing adequate visualisation while minimising pain and increasing patient satisfaction.

Materials and Methods

This was a double‐blind randomised controlled trial. A total of 240 women who had diagnostic outpatient hysteroscopy were randomly divided into three equal groups: the uterine filling pressure was 30 mm Hg in group 1, 50 mm Hg in group 2 and 80 mm Hg in group 3. The primary outcome was adequate visualisation, and secondary outcomes were the proportion of completed procedures, pain perceived during the procedure, immediately after the procedure and 30 min later.

Results

Adequate visualisation was lower in group 1 (88.7% vs 97.5% and 98.7%; P = 0.009), but was not different between groups 2 and 3 (P > 0.999). The proportion of completed procedures was not different among the groups. There was a progressive increase in pain scores from the lower to the higher pressure groups during the procedure, immediately after the procedure and 30 min after completing the procedure.

Conclusion

Uterine filling pressure of 50 mm Hg was associated with better visualisation than 30 mm Hg and lower pain scores than that of 80 mmHg with no difference in the proportion of completed procedures.
A brief review of the application and pharmacology of ethnomedicines of Indigenous Australians
Authors: Tucci Joseph , Wilkens Sabine
Published: October 2015

Objective

Indigenous Australians suffer higher mortality and have statistically worse outcomes for many chronic disease states than the non‐Indigenous population. Although many of these people are prescribed pharmaceutical drugs for their illnesses, some still use medicines that were traditional to their culture. This report reviews some of the traditional medicines used for ailments seen in Indigenous Australian communities.

Design

A literature search was conducted, with the period between the publication of an ‘Aboriginal Pharmacopoeia’ in 1988 and ‘current’ our target interval for searching. The ethics of publishing knowledge belonging to Aboriginal people is briefly discussed in this context.

Results

Ailments were grouped into communicable diseases, pain and inflammation, skin disorders and gastrointestinal disorders. Although cancer is regarded as a disease of the ‘white man’, it is briefly discussed in the context that several traditional medicines and foods may have provided some protective effects. Where known, the ethnopharmacology of these medicines is discussed, as well as a brief description of their preparation and application.

Conclusion

Some Indigenous Australians continue to use traditional medicines. We have tabulated these according to ailment, and have listed pharmacological actions where known. What is not known, however, is their potential to interact with pharmaceutical drugs. Further study in this area is needed to optimise health outcomes for Indigenous Australians, especially those in remote communities.
Micronutrient status and neurodevelopment in internationally adopted children
Authors: Fuglestad Anita J. , Kroupina Maria G. , Johnson Dana E. , Georgieff Michael K.
Published: October 2015

Aim

To assess the status of nutrients relevant for brain development in internationally adoptees from disparate global regions and determine whether identified deficiencies are associated with neurodevelopment.

Methods

Participants included children adopted from Post‐Soviet States (n = 15), Ethiopia (n = 26) or China (n = 17), ages 8–18 months. A comprehensive nutritional battery and a neurodevelopmental assessment were completed at baseline (within one month of arrival) and follow‐up (six months later).

Results

At baseline, 35% were stunted, and 68% had at least one abnormal nutritional biochemical marker. The most common were low retinol‐binding protein (33%), zinc deficiency (29%), vitamin D insufficiency/deficiency (21%), and iron deficiency (15%). There was significant catch‐up growth in height and weight at follow‐up, but little improvement in micronutrient deficiencies. Iron deficiency was associated with lower cognitive scores on the Bayley Scales of Infant Development‐III, p = 0.027, and slower speed of processing, p = 0.012. Zinc deficiency was associated with compromised memory functioning, p = 0.001.

Conclusion

Nutrient deficiencies were common during the early adoption period in internationally adoptees from three global regions, and iron and zinc deficiencies were associated with poorer neurodevelopmental outcomes. Results emphasise the importance of monitoring micronutrient status at arrival and during the early adoption period, irrespective of country of origin.
The Relationship Between Development of Neuronal and Astrocytic Tau Pathologies in Subcortical Nuclei and Progression of Argyrophilic Grain Disease
Authors: Ikeda Chikako , Yokota Osamu , Nagao Shigeto , Ishizu Hideki , Oshima Etsuko , Hasegawa Masato , Okahisa Yuko , Terada Seishi , Yamada Norihito
Published: October 2015

Progressive supranuclear palsy (PSP) cases frequently have argyrophilic grain disease (AGD). However, the PSP‐like tau pathology in AGD cases has not been fully clarified. To address this, we examined tau pathologies in the subcortical nuclei and frontal cortex in 19 AGD cases that did not meet the pathological criteria of PSP or corticobasal degeneration, nine PSP cases and 20 Braak NFT stage‐matched controls. Of the 19 AGD cases, five (26.3%) had a few Gallyas‐positive tau‐positive tufted astrocytes (TAs) and Gallyas‐negative tau‐positive TA‐like astrocytic inclusions (TAIs), and six (31.6%) had only TAIs in the striatum and/or frontal cortex. Subcortical tau pathology was sequentially and significantly greater in AGD cases lacking these tau‐positive astrocytic lesions, AGD cases having them, and PSP cases than in controls. There was a significant correlation between three histologic factors, including the AGD stage and the quantities of subcortical neuronal and astrocytic tau pathologies. Tau immunoblotting demonstrated 68‐ and 64‐kDa bands and 33‐kDa low‐molecular mass tau fragments in PSP cases, and although with lesser intensity, in AGD cases with and without TAs and TAIs also. Given these findings, the progression of AGD may be associated with development of the neuronal and astrocytic tau pathologies characteristic of PSP.
GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis
Authors: Kargl J , Andersen L , Hasenöhrl C , Feuersinger D , Stančić A , Fauland A , Magnes C , El‐Heliebi A , Lax S , Uranitsch S , Haybaeck J , Heinemann A , Schicho R
Published: October 2015

Background and Purpose

Tumour cell migration and adhesion constitute essential features of metastasis. G‐protein coupled receptor 55 (GPR55), a lysophospholipid receptor, has been shown to play an important role in carcinogenesis. Here, we investigated the involvement of GPR55 in migration and metastasis of colon cancer cells.

Experimental Approach

Adhesion and migration assays using the highly metastatic colon cancer cell line HCT116 and an in vivo assay of liver metastasis were performed. The GPR55 antagonist CID16020046, cannabidiol, a putative GPR55 antagonist and GPR55 siRNA were used to block GPR55 activity in HCT116 colon cancer cells.

Key Results

HCT116 cells showed a significant decrease in adhesion to endothelial cells and in migration after blockade with CID16020046 or cannabidiol. The inhibitory effects of CID16020046 or cannabidiol were averted by GPR55 siRNA knock down in cancer cells. The integrity of endothelial cell monolayers was increased after pretreatment of HCT116 cells with the antagonists or after GPR55 siRNA knockdown while pretreatment with lysophosphatidylinositol (LPI), the endogenous ligand of GPR55, decreased integrity of the monolayers. LPI also induced migration in GPR55 overexpressing HCT116 cells that was blocked by GPR55 antagonists. In a mouse model of metastasis, the arrest of HCT116 cancer cells in the liver was reduced after treatment with CID16020046 or cannabidiol. Increased levels of LPI (18:0) were found in colon cancer patients when compared with healthy individuals.

Conclusions and Implications

GPR55 is involved in the migratory behaviour of colon carcinoma cells and may serve as a pharmacological target for the prevention of metastasis. © 2015 The British Pharmacological Society
Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models
Authors: Cross A J , Widzowski D , Maciag C , Zacco A , Hudzik T , Liu J , Nyberg S , Wood M W
Published: October 2015

Background and Purpose

Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine.

Experimental Approach

We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant‐like and anxiolytic‐like drug action.

Key Results

Norquetiapine had equivalent activity to established antidepressants at the noradrenaline transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5‐HT1A receptors, and the anxiolytic‐like activity of norquetiapine in rat punished responding was blocked by the 5‐HT1A antagonist, WAY100635.

Conclusions and Implications

Quetiapine and norquetiapine have multiple in vitro pharmacological actions, and results from preclinical studies suggest that activity at NET and 5‐HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine.
Orienting Toward Face‐Like Stimuli in Early Childhood
Authors: Shah Punit , Happé Francesca , Sowden Sophie , Cook Richard , Bird Geoffrey
Published: October 2015

Newborn infants orient preferentially toward face‐like or “protoface” stimuli and recent studies suggest similar reflexive orienting responses in adults. Little is known, however, about the operation of this mechanism in childhood. An attentional‐cueing procedure was therefore developed to investigate protoface orienting in early childhood. Consistent with the extant literature, 5‐ to 6‐year‐old children (n = 25) exhibited orienting toward face‐like stimuli; they responded faster when target location was cued by the appearance of a protoface stimulus than when location was cued by matched control patterns. The potential of this procedure to investigate the development of typical and atypical social perception is discussed.
Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency
Authors: Elgizouli M , Lowe D M , Speckmann C , Schubert D , Hülsdünker J , Eskandarian Z , Dudek A , Schmitt-Graeff A , Wanders J , Jørgensen S F , Fevang B , Salzer U , Nieters A , Burns S , Grimbacher B
Published: October 2015

The gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), and is expressed solely in leucocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain-of-function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kδ syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naive T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID, but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype.