bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Venous Thrombosis Caused by Congenital Malformation of the Inferior Vena Cava and Heterozygous Factor V Leiden Presenting as Venous Claudication
Authors: Fass Gary , Nasroolah Damry , Cavenaile Jean-Christophe
Published: November 2008

A case of an 18-year-old man with deep venous thrombosis of the lower limbs caused by hypoplasia of the inferior vena cava in combination with heterozygous factor V Leiden is presented. Both anomalies were found when the patient complained of venous claudication in both thighs. Inferior vena cava malformation is a rare condition and may predispose to the development of deep venous thrombosis. This patient was at an even higher risk for deep venous thrombosis as the inferior vena cava malformation was combined with a hypercoagulable state.
Negotiating the public secrecy of sex in a transnational tourist town in Caribbean Costa Rica
Authors: Frohlick Susan
Published: November 2008

My social positionality as an alleged sex tourist when I arrived as an `unaccompanied' woman traveling to a town in Caribbean Costa Rica to study women's adventure tourism, initiated a shift in ethnographic focus to female tourists' heterosexual sexual relations with locals. Using methodology that relies upon immersion I situated myself within the community and participated in everyday life in and beyond touristic events. I interacted with and interviewed female tourists predominantly, but also local men, local women and resident foreigners. This methodology was productive but presented a major dilemma for me: Where sex is both talked about and kept hidden, I had to negotiate the many layers and performances of the public secrecy about sex that pervade and play out in this transnational town, including how to transform `data' into representation. I conclude that the immersion of the anthropologist in the everyday lives of tourists in touristic settings reveals insights into the complexity of global sexual tourism, and presents problems too.
`An interplay at specific points'
Authors: Mathers Kathryn
Published: November 2008

Ethnographic research on the everyday lives of those who are privileged to travel as vacationers or on study abroad programs offers important insights into assumptions about global connections in the 21st century. This article tells the stories of two journeys between Cape Town and California. Through these narratives I explore the challenges and rewards of ethnographic work with travelers especially when this work takes seriously their lives when they are not tourists. Ethnographers of tourists face many challenges, some practical — tourists deliberately seek experiences that are independent of their everyday lives and ethnography is at its best focusing on the everyday. Others are due to the anthropologist's own uncertainty about her position as a tourist, making the anthropology of tourism a kind of native anthropology.
Picturing experience
Authors: Sather-Wagstaff Joy
Published: November 2008

While research on commemorative historical sites addresses the commodification of tragedy and the ethics of representing violent events for tourist consumption, the experiences of tourists who visit these sites are conspicuously absent. Because of this omission, our understanding of the individual and collective social significance of actual travel to commemorative places for a `heritage that hurts' is incomplete. As a means to address these concerns, this article presents how a visual and ethnographic methods-centered approach was utilized for engagement with tourists at the former site of the twin World Trade Center towers in Manhattan, both on-site and post-visit, during 2002—06. I focus specifically upon tourists' acts of `picturing experiences' at this site through both photographic activities during travel and also photo use for memory work in the post-tour everyday. In doing so, I discuss both the usefulness of and challenges with these methods as a means for working with highly mobile research participants such as tourists.
Doing ethnography of tourist enclaves
Authors: Schmid Karl Anthony
Published: November 2008

This article discusses the range of methodologies used to explore the making of tourism enclaves at Luxor, Egypt. Enclaving in tourism describes a process of segregating tourists from the local residents, to develop exclusive touristic spaces. This process has developed at Luxor since the beginning of elite tourism in the 19th century. It was apparent that both a historical and ethnographic approach would require the innovation of strategies to gather information about the contributions and resistance of key tourism actors (informal guides, tourists, tour operators, and government), to the production of enclaving. This article will examine the multifaceted approach used to gather information from and about these actors, including the benefits and drawbacks of integrating historical and ethnographic information. Investigating the production of exclusion also revealed ethical issues and other pitfalls to research.
Evidence-Based Policy
Authors: Hewison Alistair
Published: November 2008

Evidence-based policy making is espoused as a central feature of government in the United Kingdom. However, an expectation that this will improve the quality of policy produced and provide a path to increased involvement of nurses in the policy process is misplaced. The purpose of this article is to demonstrate that the emphasis on evidence-based policy is problematic and cannot be regarded as a “new model” of policy making. Also, it could deflect attention from more practical approaches to policy involvement on the part of nurses. Policy development activities, acquisition of skills in policy analysis, and other forms of involvement are needed if nurses are to move along the continuum from policy literacy, through policy acumen, to policy competence. This involves taking a critical stance on the notion of evidence-based policy.
Governing Masses
Authors: Gagnon Marilou , Holmes Dave
Published: November 2008

The aim of this article is to critically discuss routine HIV testing policy in the United States by locating its origins within health promotion efforts to govern masses and the neoliberal construction of the individual as free, autonomous, responsible, and empowered. Basing our approach on the work of the late French philosopher Michel Foucault, we describe routine HIV testing as a bio-political intervention that redefines the norms and social practices pertaining to HIV testing with the goal of regulating the population's health. From a neoliberalist perspective, routine HIV testing is also introduced as a practice of self-care that should be undertaken by any rational person who performs good health practices around HIV/AIDS. The objective of this article is to situate routine HIV testing policy in relation to nursing practice and, most important, to demonstrate how this policy should not be considered in isolation from the political context in which it was created.
“Look Out New World, Here We Come”?
Authors: Lugo-Lugo Carmen R. , Bloodsworth-Lugo Mary K.
Published: November 2008

In this essay, the authors argue that, as suggested by Giroux, animated films offer children intricate teachings about race and sexuality, guiding children through the complexities of highly racialized and sexualized scenarios. Moreover, the authors explain how animated films for children teach children how to maneuver within the general terrain of “race” and “sexuality,” and they highlight quite specific differences. Thus, in their role as agents of socialization and “portable professors,” these films provide children with the necessary tools to reinforce expectations about normalized racial and sexual dynamics.
Unusual Anomaly Complicating Abdominal Aortic Aneurysm Repair: Anterior Inferior Vena Cava
Authors: Kleiner Daniel E. , Harthun Nancy L.
Published: November 2008

This case illustrates an unusual anomaly of the great veins. To our knowledge, these are the first published photographs of the vena cava traversing anterior to the distal aorta. This anatomic variant caused minor technical problems during open abdominal aortic aneurysm repair.
Increased Pinch Strength in Acute and Subacute Stroke Patients After Simultaneous Median and Ulnar Sensory Stimulation
Authors: Klaiput Akkarapol , Kitisomprayoonkul Wasuwat
Published: November 2008

Background. Peripheral nerve stimulation may induce cortical adaptations as it improves pinch strength in chronic stroke patients immediately after stimulation. Objective. Test the effects of peripheral sensory stimulation on pinch strength in patients with acute and subacute stroke. Methods. Stroke patients (N = 20) who had onset less than 6 months previously and could voluntarily pinch the thumb to the index finger participated in a randomized, single-blinded, controlled study. Ten patients received 2 hours of simultaneous electrical stimulation over the median and ulnar nerves at the wrist to the level of appreciating paresthesias (peripheral sensory stimulation group). Ten control patients received stimulation to the level of perception (sham-control group). Pinch strength of the thumb pad to tip and to lateral side of the index finger of the paretic hand and the Action Research Arm test were tested before and immediately after the stimulation. Results. Lateral and tip pinch strength were significantly increased in both groups ( P < .05). Mean ± SD of increased lateral pinch strength of peripheral sensory stimulation and sham-control groups were 1.24 ± 0.54 pounds and 0.20 ± 0.28 pounds, respectively. Mean ± SD of increased tip pinch strength of peripheral sensory stimulation and sham-control groups were 1.00 ± 0.72 pounds and 0.37 ± 0.36 pounds, respectively. Increase pinch strength of the peripheral sensory stimulation group was greater than the sham-control group, with significant difference ( P < .05). The Action Research Arm test was not significantly changed after stimulation in both groups ( P > .05). Conclusion. Peripheral sensory stimulation of the paretic hand may increase pinch strength of acute and subacute stroke patients immediately after stimulation.
Covenants and Anglicans
Authors: Quinn Frederick
Published: November 2008

Although there is a strong movement within Anglicanism to produce a Covenant, this article argues against such an approach. Postponing dealing with today's problems by leaving them for a vaguely worded future document, instead of trying to clarify and resolve them now, and live in peace with one another, is evasive action that solves nothing. Also, some covenant proposals represent a veiled attempt to limit the role of women and homosexuals in the church.

The article's core argument is that covenants were specifically rejected by Anglicans at a time when they swept the Continent in the sixteenth century. The Church of England had specifically rejected the powerful hierarchy of the Roman Catholic Church and the legalism of the Puritans in favor of what was later to become the Anglican via media, with its emphasis on an informal, prayerful unity of diverse participants at home and abroad. It further argues the Church contains sufficient doctrinal statements in the Creeds, Chicago-Lambeth Quadrilateral of 1886, 1888, and the Baptismal Covenant in the American Church's 1979 Book of Common Prayer.

Covenant proponents argue their proposed document follows in the tradition of classic Anglicanism, but Quinn demonstrates this is not the case. He presents Richard Hooker and Jeremy Taylor as major voices articulating a distinctly Anglican perspective on church governance, noting Hooker ‘tried to stake out parameters between positions without digging a ditch others could not cross. Hooker placed prudence ahead of doctrinal argument.’ Taylor cited the triadic scripture, tradition and reason so central to Anglicanism and added how religious reasoning differs from mathematical and philosophical reasoning. The author notes that the cherished Reformation gift of religious reasoning is totally unmentioned in the flurry of documents calling for a new Anglican Covenant.
Anglicanism in a Japanese Context
Authors: Kato John Hiromichi
Published: November 2008

The standpoint adopted here is that of a diocesan bishop serving in the Nippon SeiKoKai (NSKK, Anglican Church). The NSKK is a small church and has a long history in Japan. Its public stance has been relatively moderate and approaches Japanese society and other Christian churches in a modest way. Government agencies have tended to regard Christianity as peculiar and even dangerous. The moderate approach of the NSKK has meant that it has tended to yield its social work to the government. Liturgy and in particular the Eucharist has been the sustaining focus of the life of the NSKK. Monotheistic religions are regarded as not as suitable for peace as Buddhism and this creates special concerns for witness in a pseudo-religious and pseudo-communal society. The NSKK faces real challenges of enculturation and needs to find resources in the networks of the Anglican Communion for different experiences to be shared.
A New Perspective for Anglicanism
Authors: Hiroto Kayama
Published: November 2008

This article argues that Anglicans in North East Asia face a challenge to re-imagine their history in the light of the resources of the Anglican theological tradition. That history has been largely influenced by a narrative which has seen the Christian faith come from across the sea in the form of European missionaries in the Age of Discovery. But there is evidence of the presence of Christian faith long before this which came not through missionaries but through ordinary people who practised their faith. Anglicans can deploy a notion of via media which is not the assumption of a midpoint between contesting claims, but a method for sublating differing opinions by providing a new paradigm, integrating them into a new conceptual framework. Anglicans are thus called to aim for a church whose very mode of existence bears its message.
Anglicanism as Public Philosophy
Authors: Nishihara Renta
Published: November 2008

The contrast in social life between a messhi bōkō (sacrificing one's personal interest to the public good) and mekkō hōshi(sacrificing the public for the sake of the individual) cannot be settled in terms of a dualism. The Christian Church from its earliest times was without doubt a ‘public’ community. Setting up a hypothesis that the concept of ‘publicness’ presented by public philosophy is actually closely related to the ‘catholicity’ that has been a characteristic of Christianity since the time of the Early Church, the main object of this essay will be to demonstrate, by introducing concrete theological illustrations, that Anglicanism has the potential to be a ‘public philosophy’.
Problems with the Path of Phillips Brooks
Authors: Wells Christopher
Published: November 2008

This article takes the opportunity of Gillis Harp's recent biography of nineteenth-century American Episcopalian Phillips Brooks to engage Harp's theological situation of the Episcopal Church. Harp's revisionist historiographical argument, rejecting the Broad Church ‘myth of synthesis’ for a more agonized tale of trenchant party battles, is welcome for its perceptiveness and depth of analysis, not least as these historical difficulties remain at the centre of contemporary intra-Anglican and ecumenical conversations. Harp's commitment to a ‘Reformed’ and ‘evangelical’ Anglicanism, however, raises a series of questions – concerning the nature of orthodoxy and Christian doctrine, as well as ‘Protestant’ identity – that deserve greater investigation, and that historians and theologians would do well to pursue together.
Access and Allies
Authors: Notaker Hallvard
Published: November 2008

The article provides a detailed analysis of previously unresearched campaign management seminars for European Center-Right political parties within the European Democrat Union (EDU) in the 1980s. Original archival material shows how these seminars in several ways facilitated the spread of campaign techniques originating in the United States: (1) through the collective discussion and adaptation of U.S. innovations to a European context and (2) as a catalyst for bilateral relationships between otherwise unlikely partners. Members from small countries gained access to global leaders of campaign development in the shape of operatives from the U.K. Conservative Party, the German CDU, and the U.S. Republican Party. The campaign seminar group depended on the will of EDU members from these powerful countries to build and maintain a transnational organization within the frameworks of the cold war and European integration. In conclusion, the article argues that mediating instances such as the campaign seminars should be integrated in explanatory concepts such as “modernization” and “Americanization,” as should historical context.
Effect of TiC addition on semisolid isothermal heat treated microstructure of ZA84 magnesium alloy
Authors: Yang M. B. , Shen J. , Pan F. S.
Published: November 2008

The semisolid metal processing now is becoming an important forming process for the fabrication of magnesium alloys parts. Among the various methods of obtaining semisolid billet with non-dendritic microstructure, semisolid isothermal heat treatment is thought as a potential method. To provide a theoretical guide for the semisolid processing of ZA84 magnesium alloy, the semisolid isothermal heat treated microstructure of ZA84 magnesium alloy with and without TiC modifications is investigated. The results indicate that it is possible to produce a non-dendritic microstructure of ZA84 alloy by semisolid isothermal heat treatment, and that adding 0·5 wt-%TiC to ZA84 alloy benefits the non-dendritic microstructural evolution of the alloy. After treatment at 570°C for 120 min, the ZA84+0·5TiC alloy gives a non-dendritic microstructure with a higher liquid fraction (0·22 to 0·25) and finer unmelted primary solid particles (57 to 48 μm) than the ZA84 alloy. The formation of finer unmelted primary solid particles in the semisolid ZA84+0·5TiC alloy is possibly related to the refinement of the initial as cast microstructure and the higher liquid fraction of semisolid.
Endoplasmic reticulum stress is a target for therapy in Waldenstrom macroglobulinemia
Authors: Leleu Xavier , Xu Lian , Jia Xiaoying , Sacco Antonio , Farag Mena , Hunter Zachary R. , Moreau Anne-Sophie , Ngo Hai T. , Hatjiharissi Evdoxia , Ho Allen W. , Santos Daniel D. , Adamia Sofia , O'Connor Kelly , Ciccarelli Bryan , Soumerai Jacob , Manning Robert J. , Patterson Christopher J. , Roccaro Aldo M. , Ghobrial Irene M. , Treon Steven P.
Published: November 2008

Waldenstrom macroglobulinemia (WM) is an incurable low-grade lymphoma characterized by bone marrow (BM) involvement of IgM secreting lymphoplasmacytic cells. The induction of unfolded protein response (UPR) genes (“physiologic” UPR) enables cells to differentiate into professional secretory cells capable of production of high amounts of endoplasmic reticulum (ER)–processed proteins, such as immunoglobulins. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected, called proapoptotic/terminal UPR. We show that WM cells inherently express the physiologic UPR machinery compared with normal BM cells, and that increased ER stress leads to proapoptotic/terminal UPR in WM cells. We therefore examined tunicamycin, ER stress inducer, for potential antitumor effects in WM. Tunicamycin induced significant cytotoxicity, apoptosis and cell-cycle arrest, and inhibited DNA synthesis in WM cell lines and primary BM CD19+ cells from patients with WM with an inhibitory concentration (IC50) of 0.5 μg/mL to 1 μg/mL, but not in healthy donor cells. Importantly, coculture of WM cells in the context of the BM microenvironment did not inhibit tunicamycin-induced cytotoxicity. Finally, we demonstrate that ER stress inducer synergizes with other agents used in the treatment of WM. These preclinical studies provide a framework for further evaluation of ER stress inducing agents as therapeutic agents in WM.
Safety and efficacy of long-term treatment with romiplostim in thrombocytopenic patients with chronic ITP
Authors: Bussel James B. , Kuter David J. , Pullarkat Vinod , Lyons Roger M. , Guo Matthew , Nichol Janet L.
Published: November 2008

Chronic immune thrombocytopenic purpura (ITP) is characterized by low platelet counts and mucocutaneous bleeding. In previous studies romiplostim (AMG531), a thrombopoiesis-stimulating protein, increased platelet counts in most patients with chronic ITP. This ongoing, long-term open-label, single-arm study investigated safety and efficacy in patients who completed a previous romiplostim study and had platelet counts less than 5 × 109/L. One hundred forty-two patients were treated for up to 156 weeks (mean, 69 weeks). Platelet responses (platelet count ≥ 50 × 109/L and double baseline) were observed in 87% of all patients and occurred on average 67% of the time in responding patients. In 77% of patients, the romiplostim dose remained within 2 μg/kg of their most frequent dose at least 90% of the time. Ninety patients (63%) received treatment by self-administration. Treatment-related serious adverse events were reported in 13 patients (9%). Bone marrow reticulin was observed in 8 patients; marrows were not routinely performed in this study, so the true incidence of this event cannot be determined. Severe bleeding events were reported in 12 patients (9%). Thrombotic events occurred in 7 patients (5%). In conclusion, romiplostim increased platelet counts in most patients for up to 156 weeks without tachyphylaxis and had an acceptable safety profile. (ClinicalTrials.gov Identifier NCT00116688).
Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target
Authors: Young Ryan M. , Hardy Ian R. , Clarke Raedun L. , Lundy Nicolai , Pine Polly , Turner Brian C. , Potter Terry A. , Refaeli Yosef
Published: November 2008

We have generated mouse models of non-Hodgkin lymphoma (NHL) that rely on the cooperation between MYC overexpression and B-cell antigen receptor (BCR) signaling for the initiation and maintenance of B-cell lymphomas. Using these mouse models of NHL, we have focused on the identification of BCR-derived signal effectors that are important for the maintenance of NHL tumors. In the present study, we concentrate on Spleen tyrosine kinase (Syk), a nonreceptor tyrosine kinase required to transduce BCR-dependent signals. Using a genetic approach, we showed that Syk expression is required for the survival of murine NHL-like tumors in vitro and that tumor cells deficient in Syk fail to expand in vivo. In addition, a pharmacologic inhibitor of Syk was able to induce apoptosis of transformed B cells in vitro and led to tumor regression in vivo. Finally, we show that genetic or pharmacologic inhibition of Syk activity in human NHL cell lines are generally consistent with results found in the mouse models, suggesting that targeting Syk may be a viable therapeutic strategy.
The Raf-1 inhibitor GW5074 and dexamethasone suppress sidestream smoke-induced airway hyperresponsiveness in mice
Authors: Lei Ying , Cao Yong-Xiao , Xu Cang-Bao , Zhang Yaping
Published: November 2008

Background

Sidestream smoke is closely associated with airway inflammation and hyperreactivity. The present study was designed to investigate if the Raf-1 inhibitor GW5074 and the anti-inflammatory drug dexamethasone suppress airway hyperreactivity in a mouse model of sidestream smoke exposure.

Methods

Mice were repeatedly exposed to smoke from four cigarettes each day for four weeks. After the first week of the smoke exposure, the mice received either dexamethasone intraperitoneally every other day or GW5074 intraperitoneally every day for three weeks. The tone of the tracheal ring segments was recorded with a myograph system and concentration-response curves were obtained by cumulative administration of agonists. Histopathology was examined by light microscopy.

Results

Four weeks of exposure to cigarette smoke significantly increased the mouse airway contractile response to carbachol, endothelin-1 and potassium. Intraperitoneal administration of GW5074 or dexamethasone significantly suppressed the enhanced airway contractile responses, while airway epithelium-dependent relaxation was not affected. In addition, the smoke-induced infiltration of inflammatory cells and mucous gland hypertrophy were attenuated by the administration of GW5074 or dexamethasone.

Conclusion

Sidestream smoke induces airway contractile hyperresponsiveness. Inhibition of Raf-1 activity and airway inflammation suppresses smoking-associated airway hyperresponsiveness.
Learning transcriptional regulatory networks from high throughput gene expression data using continuous three-way mutual information
Authors: Luo Weijun , Hankenson Kurt D , Woolf Peter J
Published: November 2008

Background

Probability based statistical learning methods such as mutual information and Bayesian networks have emerged as a major category of tools for reverse engineering mechanistic relationships from quantitative biological data. In this work we introduce a new statistical learning strategy, MI3 that addresses three common issues in previous methods simultaneously: (1) handling of continuous variables, (2) detection of more complex three-way relationships and (3) better differentiation of causal versus confounding relationships. With these improvements, we provide a more realistic representation of the underlying biological system.

Results

We test the MI3 algorithm using both synthetic and experimental data. In the synthetic data experiment, MI3 achieved an absolute sensitivity/precision of 0.77/0.83 and a relative sensitivity/precision both of 0.99. In addition, MI3 significantly outperformed the control methods, including Bayesian networks, classical two-way mutual information and a discrete version of MI3. We then used MI3 and control methods to infer a regulatory network centered at the MYC transcription factor from a published microarray dataset. Models selected by MI3 were numerically and biologically distinct from those selected by control methods. Unlike control methods, MI3 effectively differentiated true causal models from confounding models. MI3 recovered major MYC cofactors, and revealed major mechanisms involved in MYC dependent transcriptional regulation, which are strongly supported by literature. The MI3 network showed that limited sets of regulatory mechanisms are employed repeatedly to control the expression of large number of genes.

Conclusion

Overall, our work demonstrates that MI3 outperforms the frequently used control methods, and provides a powerful method for inferring mechanistic relationships underlying biological and other complex systems. The MI3 method is implemented in R in the "mi3" package, available under the GNU GPL fromhttp://sysbio.engin.umich.edu/~luow/downloads.phpand from the R package archive CRAN.
Silencing of directional migration in roundabout4 knockdown endothelial cells
Authors: Kaur Sukhbir , Samant Ganesh V , Pramanik Kallal , Loscombe Philip W , Pendrak Michael L , Roberts David D , Ramchandran Ramani
Published: November 2008

Background

Roundabouts are axon guidance molecules that have recently been identified to play a role in vascular guidance as well. In this study, we have investigated gene knockdown analysis of endothelial Robos, in particular roundabout 4 (robo4), the predominant Robo in endothelial cells using small interfering RNA technology in vitro.

Results

Robo1 and Robo4 knockdown cells display distinct activity in endothelial cell migration assay. The knockdown of robo4 abrogated the chemotactic response of endothelial cells to serum but enhanced a chemokinetic response to Slit2, while robo1 knockdown cells do not display chemotactic response to serum or VEGF. Robo4 knockdown endothelial cells unexpectedly show up regulation of Rho GTPases. Zebrafish Robo4 rescues both Rho GTPase homeostasis and serum reduced chemotaxis in robo4 knockdown cells. Robo1 and Robo4 interact and share molecules such as Slit2, Mena and Vilse, a Cdc42-GAP. In addition, this study mechanistically implicates IRSp53 in the signaling nexus between activated Cdc42 and Mena, both of which have previously been shown to be involved with Robo4 signaling in endothelial cells.

Conclusion

This study identifies specific components of the Robo signaling apparatus that work together to guide directional migration of endothelial cells.
Evolution of conserved secondary structures and their function in transcriptional regulation networks
Authors: Xie Hai-Bing , Irwin David M , Zhang Ya-Ping
Published: November 2008

Background

Many conserved secondary structures have been identified within conserved elements in the human genome, but only a small fraction of them are known to be functional RNAs. The evolutionary variations of these conserved secondary structures in human populations and their biological functions have not been fully studied.

Results

We searched for polymorphisms within conserved secondary structures and identified a number of SNPs within these elements even though they are highly conserved among species. The density of SNPs in conserved secondary structures is about 65% of that of their flanking, non-conserved, sequences. Classification of sites as stems or as loops/bulges revealed that the density of SNPs in stems is about 62% of that found in loops/bulges. Analysis of derived allele frequency data indicates that sites in stems are under stronger evolutionary constraint than sites in loops/bulges. Intergenic conserved secondary structures tend to associate with transcription factor-encoding genes with genetic distance being the measure of regulator-gene associations. A substantial fraction of intergenic conserved secondary structures overlap characterized binding sites for multiple transcription factors.

Conclusion

Strong purifying selection implies that secondary structures are probably important carriers of biological functions for conserved sequences. The overlap between intergenic conserved secondary structures and transcription factor binding sites further suggests that intergenic conserved secondary structures have essential roles in directing gene expression in transcriptional regulation networks.
mtDNA depletion confers specific gene expression profiles in human cells grown in culture and in xenograft
Authors: Magda Darren , Lecane Philip , Prescott Julia , Thiemann Patricia , Ma Xuan , Dranchak Patricia K , Toleno Donna M , Ramaswamy Krishna , Siegmund Kimberly D , Hacia Joseph G
Published: November 2008

Background

Interactions between the gene products encoded by the mitochondrial and nuclear genomes play critical roles in eukaryotic cellular function. However, the effects mitochondrial DNA (mtDNA) levels have on the nuclear transcriptome have not been defined under physiological conditions. In order to address this issue, we characterized the gene expression profiles of A549 lung cancer cells and their mtDNA-depleted ρ0 counterparts grown in culture and as tumor xenografts in immune-deficient mice.

Results

Cultured A549 ρ0 cells were respiration-deficient and showed enhanced levels of transcripts relevant to metal homeostasis, initiation of the epithelial-mesenchymal transition, and glucuronidation pathways. Several well-established HIF-regulated transcripts showed increased or decreased abundance relative to the parental cell line. Furthermore, growth in culture versus xenograft has a significantly greater influence on expression profiles, including transcripts involved in mitochondrial structure and both aerobic and anaerobic energy metabolism. However, both in vitro and in vivo, mtDNA levels explained the majority of the variance observed in the expression of transcripts in glucuronidation, tRNA synthetase, and immune surveillance related pathways. mtDNA levels in A549 xenografts also affected the expression of genes, such as AMACR and PHYH, involved in peroxisomal lipid metabolic pathways.

Conclusion

We have identified mtDNA-dependent gene expression profiles that are shared in cultured cells and in xenografts. These profiles indicate that mtDNA-depleted cells could provide informative model systems for the testing the efficacy of select classes of therapeutics, such as anti-angiogenesis agents. Furthermore, mtDNA-depleted cells grown culture and in xenografts provide a powerful means to investigate possible relationships between mitochondrial activity and gene expression profiles in normal and pathological cells.
Isolation, characterization and comparison of Atlantic and Chinook salmon growth hormone 1 and 2
Authors: von Schalburg Kristian R , Yazawa Ryosuke , de Boer Johan , Lubieniecki Krzysztof P , Goh Benjamin , Straub Christopher A , Beetz-Sargent Marianne R , Robb Adrienne , Davidson William S , Devlin Robert H , Koop Ben F
Published: November 2008

Background

Growth hormone (GH) is an important regulator of skeletal growth, as well as other adapted processes in salmonids. The GH gene (gh) in salmonids is represented by duplicated, non-allelic isoforms designated as gh1 and gh2. We have isolated and characterized gh-containing bacterial artificial chromosomes (BACs) of both Atlantic and Chinook salmon (Salmo salar and Oncorhynchus tshawytscha) in order to further elucidate our understanding of the conservation and regulation of these loci.

Results

BACs containing gh1 and gh2 from both Atlantic and Chinook salmon were assembled, annotated, and compared to each other in their coding, intronic, regulatory, and flanking regions. These BACs also contain the genes for skeletal muscle sodium channel oriented in the same direction. The sequences of the genes for interferon alpha-1, myosin alkali light chain and microtubule associated protein Tau were also identified, and found in opposite orientations relative to gh1 and gh2. Viability of each of these genes was examined by PCR. We show that transposon insertions have occurred differently in the promoters of gh, within and between each species. Other differences within the promoters and intronic and 3'-flanking regions of the four gh genes provide evidence that they have distinct regulatory modes and possibly act to function differently and/or during different times of salmonid development.

Conclusion

A core proximal promoter for transcription of both gh1 and gh2 is conserved between the two species of salmon. Nevertheless, transposon integration and regulatory element differences do exist between the promoters of gh1 and gh2. Additionally, organization of transposon families into the BACs containing gh1 and for the BACs containing gh2, are very similar within orthologous regions, but much less clear conservation is apparent in comparisons between the gh1- and gh2-containing paralogous BACs for the two fish species. This is consistent with the hypothesis that a burst of transposition activity occurred during the speciation events which led to Atlantic and Pacific salmon. The Chinook and other Oncorhynchus GH1s are strikingly different in comparison to the other GHs and this change is not apparent in the surrounding non-coding sequences.
Erratum to: PAIS: paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN74418480]
Authors: den Hertog Heleen M , Worp H Bart van der , van Gemert H Maarten A , Algra Ale , Kappelle L Jaap , van Gijn Jan , Koudstaal Peter J , Dippel Diederik WJ ,   the PAIS investigators
Published: November 2008

Background

The Paracetamol (Acetaminophen) In Stroke (PAIS) study is a phase III multicenter, double blind, randomized, placebo-controlled clinical trial of high-dose acetaminophen in patients with acute stroke. The trial compares treatment with a daily dose of 6 g acetaminophen, started within 12 hours after the onset of symptoms, with matched placebo. The purpose of this study is to assess whether treatment with acetaminophen for 3 days will result in improved functional outcome through a modest reduction in body temperature and prevention of fever.

The previously planned statistical analysis based on a dichotomization of the scores on the modified Rankin Scale (mRS) may not make the most efficient use of the available baseline information. Therefore, the planned primary analysis of the PAIS study has been changed from fixed dichotomization of the mRS to a sliding dichotomy analysis.

Methods

Instead of taking a single definition of good outcome for all patients, the definition is tailored to each individual patient's baseline prognosis on entry into the trial.

Conclusion

The protocol change was initiated because of both advances in statistical approaches and to increase the efficiency of the trial by improving statistical power.

Trial Registration

Current Controlled Trials [ISCRTN74418480]
The clinicopathologic characteristics and prognostic significance of triple-negativity in node-negative breast cancer
Authors: Rhee Jiyoung , Han Sae-Won , Oh Do-Youn , Kim Jee Hyun , Im Seock-Ah , Han Wonshik , Ae Park In , Noh Dong-Young , Bang Yung-Jue , Kim Tae-You
Published: November 2008

Background

Triple-negative (TN) breast cancer, which is defined as being negative for the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), represents a subset of breast cancer with different biologic behaviour. We investigated the clinicopathologic characteristics and prognostic indicators of lymph node-negative TN breast cancer.

Methods

Medical records were reviewed from patients with node-negative breast cancer who underwent curative surgery at Seoul National University Hospital between Jan. 2000 and Jun. 2003. Clinicopathologic variables and clinical outcomes were evaluated.

Results

Among 683 patients included, 136 had TN breast cancer and 529 had non-TN breast cancer. TN breast cancer correlated with younger age (< 35 y, p = 0.003), and higher histologic and nuclear grade (p < 0.001). It also correlated with a molecular profile associated with biological aggressiveness: negative for bcl-2 expression (p < 0.001), positive for the epidermal growth factor receptor (p = 0.003), and a high level of p53 (p < 0.001) and Ki67 expression (p < 0.00). The relapse rates during the follow-up period (median, 56.8 months) were 14.7% for TN breast cancer and 6.6% for non-TN breast cancer (p = 0.004). Relapse free survival (RFS) was significantly shorter among patients with TN breast cancer compared with those with non-TN breast cancer (4-year RFS rate 85.5% vs. 94.2%, respectively; p = 0.001). On multivariate analysis, young age, close resection margin, and triple-negativity were independent predictors of shorter RFS.

Conclusion

TN breast cancer had higher relapse rate and more aggressive clinicopathologic characteristics than non-TN in node-negative breast cancer. Thus, TN breast cancer should be integrated into the risk factor analysis for node-negative breast cancer.
Voluntary exercise inhibits intestinal tumorigenesis in Apc
Min/+mice and azoxymethane/dextran sulfate sodium-treated mice
Authors: Ju Jihyeung , Nolan Bonnie , Cheh Michelle , Bose Mousumi , Lin Yong , Wagner George C , Yang Chung S
Published: November 2008

Background

Epidemiological studies suggest that physical activity reduces the risk of colon cancer in humans. Results from animal studies, however, are inconclusive. The present study investigated the effects of voluntary exercise on intestinal tumor formation in two different animal models, Apc
Min/+ mice and azoxymethane (AOM)/dextran sulfate sodium (DSS)-treated mice.

Methods

In Experiments 1 and 2, five-week old female Apc
Min/+ mice were either housed in regular cages or cages equipped with a running wheel for 6 weeks (for mice maintained on the AIN93G diet; Experiment 1) or 9 weeks (for mice on a high-fat diet; Experiment 2). In Experiment 3, male CF-1 mice at 6 weeks of age were given a dose of AOM (10 mg/kg body weight, i.p.) and, 12 days later, 1.5% DSS in drinking fluid for 1 week. The mice were then maintained on a high-fat diet and housed in regular cages or cages equipped with a running wheel for 16 weeks.

Results

In the Apc
Min/+ mice maintained on either the AIN93G or the high-fat diet, voluntary exercise decreased the number of small intestinal tumors. In the AOM/DSS-treated mice maintained on a high-fat diet, voluntary exercise also decreased the number of colon tumors. In Apc
Min/+ mice, voluntary exercise decreased the ratio of serum insulin like growth factor (IGF)-1 to IGF binding protein (BP)-3 levels. It also decreased prostaglandin E2 and nuclear β-catenin levels, but increased E-cadherin levels in the tumors.

Conclusion

These results indicate hat voluntary exercise inhibited intestinal tumorigenesis in Apc
Min/+ mice and AOM/DSS-treated mice, and the inhibitory effect is associated with decreased IGF-1/IGFBP-3 ratio, aberrant β-catenin signaling, and arachidonic acid metabolism.
Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance
Authors: Hembruff Stacey L , Laberge Monique L , Villeneuve David J , Guo Baoqing , Veitch Zachary , Cecchetto Melanie , Parissenti Amadeo M
Published: November 2008

Background

Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7DOX-2), epirubicin (MCF-7EPI), paclitaxel (MCF-7TAX-2), or docetaxel (MCF-7TXT). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters.

Results

In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance.

Conclusion

This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of resistance cannot be attributed solely to changes in drug accumulation or the activity of drug transporters. The identities of these additional drug-transporter-independent mechanisms are discussed, including their likely clinical relevance.
Spontaneous transformation of human granulosa cell tumours into an aggressive phenotype: a metastasis model cell line
Authors: Imai Misa , Muraki Miho , Takamatsu Kiyoshi , Saito Hidekazu , Seiki Motoharu , Takahashi Yuji
Published: November 2008

Background

Granulosa cell tumours (GCTs) are frequently seen in menopausal women and are relatively indolent. Although the physiological properties of normal granulosa cells have been studied extensively, little is known about the molecular mechanism of GCT progression. Here, we characterise the unique behavioural properties of a granulosa tumour cell line, KGN cells, for the molecular analysis of GCT progression.

Methods

Population doubling was carried out to examine the proliferation capacity of KGN cells. Moreover, the invasive capacity of these cells was determined using the in vitro invasion assay. The expression level of tumour markers in KGN cells at different passages was then determined by Western blot analysis. Finally, the growth and metastasis of KGN cells injected subcutaneously (s.c.) into nude mice was observed 3 months after injection.

Results

During in vitro culture, the advanced passage KGN cells grew 2-fold faster than the early passage cells, as determined by the population doubling assay. Moreover, we found that the advanced passage cells were 2-fold more invasive than the early passage cells. The expression pattern of tumour markers, such as p53, osteopontin, BAX and BAG-1, supported the notion that with passage, KGN cells became more aggressive. Strikingly, KGN cells at both early and advanced passages metastasized to the bowel when injected s.c. into nude mice. In addition, more tumour nodules were formed when the advanced passage cells were implanted.

Conclusion

KGN cells cultured in vitro acquire an aggressive phenotype, which was confirmed by the analysis of cellular activities and the expression of biomarkers. Interestingly, KGN cells injected s.c. are metastatic with nodule formation occurring mostly in the bowel. Thus, this cell line is a good model for analysing GCT progression and the mechanism of metastasis in vivo.
The association between C-reactive protein and the likelihood of progression to joint replacement in people with rheumatoid arthritis: a retrospective observational study
Authors: Poole Chris D , Conway Pete , Reynolds Alan , Currie Craig J
Published: November 2008

Background

This study sought to evaluate the association between systemic inflammation as measured by C-reactive protein and total joint replacement and the association between change in CRP status (low, ≤ 10 mg/L and high, >10 mg/L) measured over one year and total joint replacement in patients diagnosed with rheumatoid arthritis.

Methods

A cohort of patients was selected from The Health Improvement Network (THIN) dataset of anonymised patient-level data from UK general practice with a confirmed chronic rheumatic diagnosis. Surgery-free survival was evaluated using Cox proportional hazards regression models (CPHM).

Results

2,421 cases had at least one CRP measurement of which 125 cases (5.2%) had at least one major joint replacement. In CPHM, each additional unit increase in log mean CRP (range 1 to 6) was associated with a hazard ratio (HR) for major orthopaedic surgery of 1.36 (95% CI 1.10 to 1.67; p = 0.004), after controlling for age at first rheumatoid presentation and average body mass index over the same observation period. Repeated CRP observations around one year apart were recorded in 1,314 subjects. After controlling for confounding factors, in cases whose CRP remained high (>10 mg/L), the HR for joint replacement increased more than two-fold (p = 0.040) relative to cases whose CRP remained low. In patients whose CRP increased from low to high, the HR was 1.86 compared to those who remained in a low state (p = 0.217). By comparison, among those subjects whose CRP was reduced from a high to low state, the hazard ratio was more than halved (1.46) from to those who remained high (p = 0.441). Although underpowered, the trend evident from CRP change corroborates the association of TJR progression with mean CRP.

Conclusion

CRP level predicts progression to major joint replacement after standardisation for relevant risk factors as did change in CRP status between low and high states observed over one year.