bluuebunny/crossref_metadata_2025 huggingface dataset:
The pharmacology of selective inhibition of COX-2
Authors: Grosser Tilo
Published: September 2006

Selective inhibitors of cyclooxygenase (COX)-2 were developed to improve the safety of anti-inflammatory therapy in patients at elevated risk for gastrointestinal complications which are thought to be caused primarily by depression of COX-1 derived mucosal prostanoids. They were not expected to be more efficacious analgesics than compounds acting on both cyclooxygenases, the traditional (t) non-steroidal antiinflammatory drugs (NSAIDs). While these predictions were generally supported by clinical evidence, an elevated rate of severe cardiovascular complications was observed in randomized controlled trials of three chemically distinct COX-2 selective compounds. The cardiovascular hazard is plausibly explained by the depression of COX-2 dependent prostanoids formed in vasculature and kidney; vascular prostacyclin (PGI2) constrains the effect of prothrombotic and atherogenic stimuli, and renal medullary prostacyclin and prostaglandin (PG) E2 formed by COX-2 contribute to arterial pressure homeostasis. A drug development strategy more closely linking research into the biology of the drug target with clinical drug development may have allowed earlier recognition of these mechanisms and the cardiovascular risk of COX-2 inhibition. Open questions are i) whether the gastrointestinal benefit of COX-2 selective compounds drugs can be conserved by identifying individuals at risk and excluding them from treatment; ii) whether the risk extends to tNSAIDs; iii) and whether alternative strategies to anti-inflammatory therapy with a more advantageous risk-benefit profile can be developed.
A Proinflammatory State Is Detectable in Obese Children and Is Accompanied by Functional and Morphological Vascular Changes
Authors: Kapiotis Stylianos , Holzer Gregor , Schaller Georg , Haumer Markus , Widhalm Harald , Weghuber Daniel , Jilma Bernd , Röggla Georg , Wolzt Michael , Widhalm Kurt , Wagner Oswald F.
Published: September 2006

Background—

Obesity is generally accepted as a risk factor for premature atherosclerosis. Subclinical inflammation as quantified by blood levels of C-reactive protein (CRP) contributes to the development and progression of atherosclerosis. We hypothesized that inflammation in obese children is related to functional and early morphological vascular changes.

Methods and Results—

Blood levels of high sensitivity (hs) CRP, hsIL-6, the soluble intercellular adhesion molecule1 (ICAM-1), vascular cell adhesion molecule (VCAM)-1, and E-selectin were measured in 145 severely obese (body mass index [BMI], 32.2±5.8 kg/m
2
) and 54 lean (BMI, 18.9±3.2 kg/m
2
) children 12±4 years old. Flow-mediated dilation (FMD) of the brachial artery and carotid intima-media thickness (IMT) measured by high-resolution ultrasound as markers of early vascular changes were assessed in 92 (77 obese and 15 lean) and 59 (50 obese and 9 lean) children, respectively. Obese children had significantly higher levels of hsCRP, hsIL-6, and E-selectin than healthy controls (4.1±4.8 versus 0.9±1.5 mg/L,
P
<0.001 for hsCRP; 1.99±1.30 versus 1.42±1.01 pg/mL,
P
=0.05 for hsIL-6; and 78±38 versus 59±29 ng/mL,
P
=0.01 for E-selectin). There were no differences in the levels of ICAM-1 and VCAM-1 between groups. Obese children had lower peak FMD response (7.70±6.14 versus 11.06±3.07%,
P
=0.006) and increased IMT (0.37±0.04 versus 0.34±0.03 mm,
P
=0.03) compared with controls. Morbidly obese children (n=14, BMI 44.1±3.9 kg/m
2
) had highest levels of hsCRP (8.7±0.7 mg/L), hsIL-6 (3.32±1.1 pg/mL), and E-selectin (83±40 ng/mL).

Conclusions—

A proinflammatory state is detectable in obese children, which is accompanied by impaired vascular endothelial function and early structural changes of arteries, even in young subjects at risk. It remains to be determined whether high hsCRP in obese children predicts cardiovascular events.
Negative Regulation of VEGF-Induced Vascular Leakage by Blockade of Angiotensin II Type 1 Receptor
Authors: Sano Hideto , Hosokawa Kohei , Kidoya Hiroyasu , Takakura Nobuyuki
Published: September 2006

Objective—Permeability of blood vessels is essential for tissue homeostasis. However, disorganized hyperpermeability leads to progression of diseases. Vascular endothelial growth factor-A (VEGF) is a key regulator for leakiness of blood vessels and it has been reported that VEGF-mediated hyperpermeability was suppressed by angiopoietin-1 (Ang1). We found that Angiotensin-converting enzyme (ACE) was downregulated in endothelial cells by Ang1. ACE converts angiotensin I to angiotensin II (AII). Here, we studied the relationship between VEGF and AII relative to vascular permeability.

Methods and Results—We showed that VEGF-mediated vascular hyperpermeability was suppressed in mice given AII type 1 receptor (AT1R) blocker (ARB); the effect was also seen in AT1R-deficient mice. In this system, we found that ARB inhibited VEGF-induced gap formation. Furthermore, we ascertained that angioedema induced by overexpression of VEGF decreased noticeably in ARB-treated ischemic mice.

Conclusions—Because ARB suppressed VEGF-induced vascular hyperpermeability, we propose that ARB may be used to minimize the risk of edema in therapeutic angiogenesis using VEGF.
T Cells in Atherogenesis
Authors: Robertson Anna-Karin L. , Hansson Göran K
Published: September 2006

The idea that atherosclerosis is an inflammatory disease is no longer controversial. Instead, much of the current research is now focused on understanding what drives this inflammation and how it is regulated. Adaptive immunity, in particular T cells, is highly involved in atherogenesis. It is well known that different subsets of T cells can drive or dampen inflammatory processes, but we still have much to learn about the regulation of this balance in the context of atherosclerosis. This review summarizes our knowledge of T cells in atherogenesis, their potential antigens, their contact-dependent activities, and their secretion of inflammatory and antiinflammatory mediators, aiming to illustrate how T cells can aggravate or attenuate this disease through cross-talk with other cells within or outside the atherosclerotic plaque.
Novel Mechanism of Endothelial Nitric Oxide Synthase Activation Mediated by Caveolae Internalization in Endothelial Cells
Authors: Maniatis Nikolaos A. , Brovkovych Viktor , Allen Scott E. , John Theresa A. , Shajahan Ayesha N. , Tiruppathi Chinnaswamy , Vogel Stephen M. , Skidgel Randal A. , Malik Asrar B. , Minshall Richard D.
Published: September 2006

Caveolin-1, the caveolae scaffolding protein, binds to and negatively regulates eNOS activity. As caveolin-1 also regulates caveolae-mediated endocytosis after activation of the 60-kDa albumin-binding glycoprotein gp60 in endothelial cells, we addressed the possibility that endothelial NO synthase (eNOS)-dependent NO production was functionally coupled to caveolae internalization. We observed that gp60-induced activation of endocytosis increased NO production within 2 minutes and up to 20 minutes. NOS inhibitor
N
G
-nitro-
l
-arginine (
l
-NNA) prevented the NO production. To determine the role of caveolae internalization in the mechanism of NO production, we expressed dominant-negative dynamin-2 mutant (K44A) or treated cells with methyl-β-cyclodextrin. Both interventions inhibited caveolae-mediated endocytosis and NO generation induced by gp60. We determined the role of signaling via Src kinase in the observed coupling of endocytosis to eNOS activation. Src activation induced the phosphorylation of caveolin-1, Akt and eNOS, and promoted dissociation of eNOS from caveolin-1. Inhibitors of Src kinase and Akt also prevented NO production. In isolated perfused mouse lungs, gp60 activation induced NO-dependent vasodilation, whereas the response was attenuated in eNOS
−/−
or caveolin-1
−/−
lungs. Together, these results demonstrate a critical role of caveolae-mediated endocytosis in regulating eNOS activation in endothelial cells and thereby the NO-dependent vasomotor tone.
Protein Kinase A–Mediated Acceleration of the Stretch Activation Response in Murine Skinned Myocardium Is Eliminated by Ablation of cMyBP-C
Authors: Stelzer Julian E. , Patel Jitandrakumar R. , Moss Richard L.
Published: September 2006

β-Adrenergic agonists induce protein kinase A (PKA) phosphorylation of the cardiac myofilament proteins myosin binding protein C (cMyBP-C) and troponin I (cTnI), resulting in enhanced systolic function, but the relative contributions of cMyBP-C and cTnI to augmented contractility are not known. To investigate possible roles of cMyBP-C in this response, we examined the effects of PKA treatment on the rate of force redevelopment and the stretch activation response in skinned ventricular myocardium from both wild-type (WT) and cMyBP-C null (cMyBP-C
−/−
) myocardium. In WT myocardium, PKA treatment accelerated the rate of force redevelopment and the stretch activation response, resulting in a shorter time to the peak of delayed force development when the muscle was stretched to a new isometric length. Ablation of cMyBP-C accelerated the rate of force redevelopment and stretch activation response to a degree similar to that observed in PKA treatment of WT myocardium; however, PKA treatment had no effect on the rate of force development and the stretch activation response in null myocardium. These results indicate that ablation of cMyBP-C and PKA treatment of WT myocardium have similar effects on cross-bridge cycling kinetics and suggest that PKA phosphorylation of cMyBP-C accelerates the rate of force generation and thereby contributes to the accelerated twitch kinetics observed in living myocardium during β-adrenergic stimulation.
Effective environments for knowledge and learning
Authors: Dove Angela
Published: September 2006

Physical space design is important for achieving excellence in learning and knowledge environments. Key influences on knowledge environments are outlined, drawn from theatre and television design, museums and learning, and writing. These influences have led to core design principles for the design of knowledge intensive spaces, including libraries. The use of metaphor has historically proved to be a rich source of inspiration for designers and architects, and this is a key principle for engaging all players in physical space design. Vertical space and lighting are discussed as currently underused resources in many business and learning environments. The vital importance is discussed of engaging front-line workers in a co-determinative design process. The concept is explored of informed and proactive clients, fully engaging with architects and space planners. Such a process is cost effective, and leads to innovative excellent knowledge space, though not always requiring extensive budgets. Business environments can learn much when planning knowledge and learning space from examples drawn from other areas, including libraries and universities which have actively used a process of innovation and experimentation in knowledge space design. A new paradigm of active learning is itself causing universities and other learning institutions to reevaluate the role of physical space in enhancing learning opportunities. Physical space design is one key to effective knowledge and learning environments, requiring a collaborative design process, and a methodology that is underpinned by core principles specific to knowledge work.
Britain as a container: immigration metaphors in the 2005 election campaign
Authors: Charteris-Black Jonathan
Published: September 2006

This article explores how metaphors contribute to the formation of legitimacy in right-wing political communication on immigration policy in the 2005 British election campaign. It investigates the role played by metaphors in the formation of right-wing political legitimacy and the differences in how metaphor is used by the far and centre-right. The two main types identified are ‘natural disaster’ metaphors - predominantly relating to fluids - and ‘container’ metaphors concerning a build up of pressure within or outside a container. These two types are related through the notion of a bounded area protecting what is within from external danger. The container metaphor is persuasive in political communication because it merges a fourth dimension of time with spatially based concepts of two or three dimensions. It implies that controlling immigration through maintaining the security of borders (a spatially-based concept) will ensure control over the rate of social change in Britain (a time-based concept). It also heightens emotional fears associated with the penetration of a container.
Argumentation, dialogue and conflicting moral economies in post-1989 Romania: an argument against the trade union movement
Authors: Ieţcu Isabela
Published: September 2006

This article analyzes a representative newspaper article on transition to a market economy in Romania, in particular on the role of the trade union movement, by H.-R. Patapievici, a prominent public intellectual. The analytical framework combines critical discourse analysis (CDA), theories of argumentation, in particular pragma-dialectics, and a theory of modality in terms of distinct types of ‘conversational backgrounds’ of premises that arguers draw on in reasoning. I propose this integrated framework as an original contribution to the development of CDA as a method of textual analysis. I discuss a variety of argumentative fallacies and the way in which they prevent substantive dialogue with a range of relevant views. I relate the protagonist’s ‘strategic maneuvering’ to the pursuit of political strategies and to particular forms of recontextualization of liberal discourses in post-communism. I analyze the normative backgrounds that underlie argumentation in terms of conflicting moral economies and the way in which ‘strategic maneuvering’ functions to obscure ethical perspectives grounded in social justice and individual rights, and universalize and naturalize a particular ideological and moral perspective.
Deflecting responsibility in employer talk about race discrimination
Authors: Tilbury Farida , Colic-Peisker Val
Published: September 2006

This article explores a number of discursive devices used by employers when talking about employment market issues for migrants in Australia. Data come from a research project which sought to understand barriers to employment for ‘visibly different’ refugees and new migrants. Analysis reveals that employers use a number of rhetorical strategies, embedded within broader racist discourses, to deflect attention from their own possible culpability in discriminating against those from migrant and refugee backgrounds. The forms these ‘exoneration utterances’ take are examined in detail. Employers attribute inequitable employment outcomes to the market, their customers or clients, the community and to the applicants themselves, absolving themselves, and the companies they represent, of responsibility.
Genesis 1 and the Spirit: A Narrative-Rhetorical Ancient Near Eastern Reading in Light of Modern Science
Authors: Elbert Paul
Published: September 2006

The creation narrative in Genesis 1 has historically presented a number of interpretive difficulties to Torah and Old Testament scholars. That this ancient account might correlate in a harmonious manner with physical reality seemed difficult to believe. It has been considered to be a myth, while some have adopted it to ideology. But these interpretive perspectives have proved to be insufficient and premature. When confirmation of a cosmic beginning was found in 1963, Gen. 1.1 and the ensuing account of the Spirit's role in Earth history became a topic of serious investigation. With the ongoing discoveries of many anthropic-looking aspects of cosmic history, giving the cumulative and substantial impression that the universe had been designed for humankind, a divine role in optimizing Earth for life became an attractive consideration. The ensuing abrupt appearance of diverse life-forms, eventually including humankind, as sequentially described in this creation narrative, now appears to be heuristically compatible and consistent with experimental scientific findings. These findings are increasingly unharmonious with the speculation of the non-existence of God and with the impossibility of divine action, from the cosmic to life's biochemical realm. The present study argues, against the background of ancient Near Eastern literary texts, that the Genesis creation narrative was specifically designed by the Spirit and composed by a firmly guided littérateur so as to be understood from within its contextual literary setting, and that it is a unique written prophecy, originating in a distinctive Sabbath-keeping culture. On this hypothesis the text serves originally to remind attentive like-minded readers of the cultural significance of Sabbath observance, while detailing a series of unobservable creative events. However, the text appears also designed to be read, still within the original cultural perception of literary-minded Sabbath-keepers, from a perspective that is aware of the Spirit's intentional transparent design of the universe for the benefit of humankind. Using the narrative techniques of point of view, resumptive repetition, and rhetorical or communicative intention, techniques found in ancient literature, the present study suggests that previous interpretive difficulties yield to a literary solution, which offers an explanation for the potentially mysterious features of this prophetic composition. In divine foreknowledge the current modern witness of this remarkable narrative to the Spirit's past creative deeds now becomes more visible as a testimony to the invisible God.
Using Aesthetic Knowing to Teach Diversity of the Chronic Illness Experience to Nursing Students
Authors: Michael Susan , Candela Lori
Published: September 2006

This article determines the effectiveness of incorporating an aesthetic project into a nursing course in facilitating nursing students' understanding of patients'experiences with chronic illness. From fall 1999 through spring 2002, the authors collected data from 136 final-semester nursing students who were providing case management to chronically ill patients as part of their course work. Students engaged their patients in sharing the meaning of living with a chronic illness through any method the patient chose (poetry, song, drawing, etc). All students presented results in class and completed an evaluation questionnaire about the project. Of the students, 72.4% indicated that the project benefited their patients in some way and 55.6% stated that their nursing care changed because of what they discovered through the project; 68% also reported that the project changed them in some way. Nurses' holistic understanding of chronic illness can make their care more effective and satisfying.
The making of health:: a reflection on the first 10 years in the life of a journal
Authors: Radley Alan , Cheek Julianne , Ritter Christian
Published: September 2006

This introduction to the Tenth Anniversary Issue surveys articles that have been published in health: since its launch. Reviewing the original aims of the journal, the editors discuss some of the main issues that authors have raised, both about health and illness. Focusing upon articles that have been published in this particular journal, we discuss the way that new medical technologies - particularly global ones - have shaped ideas about disease and its treatment, and in consequence about what ‘good health’ should be. Related to the growth in medical and other technology - not least the rise of the Internet during the life of this journal - is the number of articles that discuss the rights of patients and the establishment of what might be termed an ‘illness culture’. We conclude that there continues to be more to health than it being the background to illness or disease, and ask the question: should the ‘taken for grantedness’ of health be taken for granted any longer?
Health stories as connectors and subjectifiers
Authors: Frank Arthur W.
Published: September 2006

Health circulates inside bodies, as a condition of cells, tissues and organs, and outside bodies as signs. Health stories offer people bits of a subjectivity of health: an awareness of what is interior, expressed in signs that are exterior. Three genres of health stories are described: technoluxe stories, unbearable health stories and strategic health stories. These stories call out to people, bidding to be subjectifiers of health. Stories connect people who may become patients, providers of health services, health products, images, fears and desires. Following Latour, health stories are understood as a form of plug-in: resources that provide people with an ability to recognize and connect what was disparate.
An archaeology of the instant?
Authors: Haslam Michael
Published: September 2006

The discovery and interpretation of microscopic residues on stone artefacts is an expanding front within archaeological science, allowing reconstructions of the past use of specific tools. With notable exceptions, however, the field has seen little theoretical development, relying largely on a rationale in which either individual findings are widely generalized or the age of the site determines the importance of the results. Here an approach to residue interpretation is proposed that draws on notions of narrative, scale, action and agency as one means of expanding the theoretical scope and application of residue studies. It is suggested that the individual resonance of the findings of residue analyses with people in the present day can be used to provide a more nuanced understanding of past actions, which in turn allows both better integration and communication of those findings within and outside the archaeological community, and begins to overcome the problems associated with the typically small sample sizes analysed in stone-tool residue studies.
The aestheticization of suffering on television
Authors: Chouliaraki Lilie
Published: September 2006

This article analyses an example of war footage in order to trace the ways in which the tension between presenting airwar as an `objective' piece of news and as an instance of intense human suffering is resolved in television's strategies of mediation. The bombardment of Baghdad in 2003 during the Iraq war was filmed in long-shot and presented in a quasi-literary narrative that capitalized on an aesthetics of horror, on sublime spectacle (Boltanski). The aestheticization of suffering on television is thus produced by a visual and linguistic complex that eliminates the human pain aspect of suffering, whilst retaining the phantasmagoric effects of a tableau vivant. The argument of this article is that such aestheticization of suffering manages simultaneously to preserve an aura of objectivity and impartiality, and to take a pro-war side in the war footage. The conclusion is that television's participation in the legitimation of war is more open to political and ethical criticism when seen in the light of the semiotic aestheticization of suffering than when it is confined to the general denunciation of `news bias' and the search for abstract objectivity.
University Challenge
Authors: Green Andrew
Published: September 2006

This article addresses the complex issue of lecturers’ subject knowledge and teaching. It explores the subject knowledge models of Banks, Leach and Moon (expressed in their chapter ‘New understandings of teachers’ pedagogic knowledge’, in J. Leach and B. Moon’s edited work Learners and Pedagogy, 1999) and of Grossman, Wilson and Shulman (see their ‘Teachers of substance: Subject matter knowledge for teaching’, in Knowledge Base for the Beginning Teacher edited by M.C. Reynolds, 1989). The article then delineates how these can be used in the development of robust teaching models of the subject. It also suggests how these models can be used to develop a scholarly view of teaching and how this may impact on student transition and development. The article emerges from a study of teaching and learning in English Literature departments within the UK higher education sector, but it draws conclusions and offers recommendations applicable to teaching across the Arts and Humanities in and beyond the UK context.
Student Perceptions of Internationalization of the Curriculum
Authors: Absalom Matthew , Vadura Katharine
Published: September 2006

One of the recent imperatives in higher education worldwide has been internationalization of the curriculum. The object of this article is to explore student perceptions of internationalization across diverse course offerings within one school of the University of South Australia (UniSA). UniSA is notable in the Australian context as a university which from very early in its development enshrined internationalization among its seven ‘graduate qualities’. In this preliminary study, we explore the notions of internationalization of the curriculum as represented in the literature, describing the context for internationalization at UniSA before exploring student perceptions. Our data reveal that on the whole students appear to have a deep and integrated sense of internationalization of the curriculum which at times clashes with a less developed conceptualization defined by their course of study. From our study we are able to begin to define certain principles which foster internationalization of the curriculum and draw some challenging conclusions about its future in higher education.
Rce1 deficiency accelerates the development of K-RAS–induced myeloproliferative disease
Authors: Wahlstrom Annika M. , Cutts Briony A. , Karlsson Christin , Andersson Karin M. E. , Liu Meng , Sjogren Anna-Karin M. , Swolin Birgitta , Young Stephen G. , Bergo Martin O.
Published: September 2006

The RAS proteins undergo farnesylation of a carboxyl-terminal cysteine (the “C” of the carboxyl-terminal CaaX motif). After farnesylation, the 3 amino acids downstream from the farnesyl cysteine (the -aaX of the CaaX motif) are released by RAS-converting enzyme 1 (RCE1). We previously showed that inactivation of Rce1 in mouse fibroblasts mislocalizes RAS proteins away from the plasma membrane and inhibits RAS transformation. Therefore, we hypothesized that the inactivation of Rce1 might inhibit RAS transformation in vivo. To test this hypothesis, we used Cre/loxP recombination techniques to simultaneously inactivate Rce1 and activate a latent oncogenic K-RAS allele in hematopoietic cells in mice. Normally, activation of the oncogenic K-RAS allele in hematopoietic cells leads to rapidly progressing and lethal myeloproliferative disease. Contrary to our hypothesis, the inactivation of Rce1 actually increased peripheral leukocytosis, increased the release of immature hematopoietic cells into the circulation and the infiltration of cells into liver and spleen, and caused mice to die more rapidly. Moreover, in the absence of Rce1, splenocytes and bone marrow cells expressing oncogenic K-RAS yielded more and larger colonies when grown in methylcellulose. We conclude that the inactivation of Rce1 worsens the myeloproliferative disease caused by oncogenic K-RAS.
BAFF and APRIL support chronic lymphocytic leukemia B-cell survival through activation of the canonical NF-κB pathway
Authors: Endo Tomoyuki , Nishio Mitsufumi , Enzler Thomas , Cottam Howard B. , Fukuda Tetsuya , James Danelle F. , Karin Michael , Kipps Thomas J.
Published: September 2006

Chronic lymphocytic leukemia (CLL) B cells express BR3, the specific receptor for the B cell–activating factor of tumor necrosis factor family (BAFF). CLL cells also express 2 other receptors for BAFF, namely B-cell maturation antigen (BCMA) and the transmembrane activator and calcium modulator and cyclophilin ligand-interactor (TACI), which also bind a proliferation-inducing ligand (APRIL). We found that signaling through BR3, but not BCMA or TACI, activated the alternative nuclear factor of κ B (NF-κB) pathway in CLL cells, whereas signaling through BCMA/TACI induced activation of the canonical NF-κB pathway. Blocking BR3 did not inhibit the capacity of BAFF to support CLL cell survival in vitro. On the other hand, specifically blocking the canonical NF-κB pathway with UTC, an inhibitor of IκB kinase β (IKKβ), or transfection of CLL cells with the IκBα super-repressor, blocked the capacity of BAFF and APRIL to promote CLL cell survival in vitro. This contrasts what is found with normal blood B cells, which apparently depend on activation of the alternative NF-κB pathway for BAFF-enhanced survival. These findings suggest that inhibitors of protein kinase IKKβ, which is required for activation of the canonical NF-κB pathway, might have a therapeutic role in this disease.
Prolonged pancytopenia in a gene therapy patient with ADA-deficient SCID and trisomy 8 mosaicism: a case report
Authors: Engel Barbara C. , Podsakoff Greg M. , Ireland Joanna L. , Smogorzewska E. Monika , Carbonaro Denise A. , Wilson Kathy , Shah Ami , Kapoor Neena , Sweeney Mirna , Borchert Mark , Crooks Gay M. , Weinberg Kenneth I. , Parkman Robertson , Rosenblatt Howard M. , Wu Shi-Qi , Hershfield Michael S. , Candotti Fabio , Kohn Donald B.
Published: September 2006

A patient with adenosine deaminase–deficient severe combined immune deficiency (ADA-SCID) was enrolled in a study of retroviral-mediated ADA gene transfer to bone marrow hematopoietic stem cells. After the discontinuation of ADA enzyme replacement, busulfan (75 mg/m2) was administered for bone marrow cytoreduction, followed by infusion of autologous, gene-modified CD34+ cells. The expected myelosuppression developed after busulfan but then persisted, necessitating the administration of untransduced autologous bone marrow back-up at day 40. Because of sustained pancytopenia and negligible gene marking, diagnostic bone marrow biopsy and aspirate were performed at day 88. Analyses revealed hypocellular marrow and, unexpectedly, evidence of trisomy 8 in 21.6% of cells. Trisomy 8 mosaicism (T8M) was subsequently diagnosed by retrospective analysis of a pretreatment marrow sample that might have caused the lack of hematopoietic reconstitution. The confounding effects of this preexisting marrow cytogenetic abnormality on the response to gene transfer highlights another challenge of gene therapy with the use of autologous hematopoietic stem cells.
Putative cross-kingdom horizontal gene transfer in sponge (Porifera) mitochondria
Authors: Rot Chagai , Goldfarb Itay , Ilan Micha , Huchon Dorothée
Published: September 2006

Background

The mitochondrial genome of Metazoa is usually a compact molecule without introns. Exceptions to this rule have been reported only in corals and sea anemones (Cnidaria), in which group I introns have been discovered in the cox1 and nad5 genes. Here we show several lines of evidence demonstrating that introns can also be found in the mitochondria of sponges (Porifera).

Results

A 2,349 bp fragment of the mitochondrial cox1 gene was sequenced from the sponge Tetilla sp. (Spirophorida). This fragment suggests the presence of a 1143 bp intron. Similar to all the cnidarian mitochondrial introns, the putative intron has group I intron characteristics. The intron is present in the cox1 gene and encodes a putative homing endonuclease. In order to establish the distribution of this intron in sponges, the cox1 gene was sequenced from several representatives of the demosponge diversity. The intron was found only in the sponge order Spirophorida. A phylogenetic analysis of the COI protein sequence and of the intron open reading frame suggests that the intron may have been transmitted horizontally from a fungus donor.

Conclusion

Little is known about sponge-associated fungi, although in the last few years the latter have been frequently isolated from sponges. We suggest that the horizontal gene transfer of a mitochondrial intron was facilitated by a symbiotic relationship between fungus and sponge. Ecological relationships are known to have implications at the genomic level. Here, an ecological relationship between sponge and fungus is suggested based on the genomic analysis.
Expression of P2 receptors in human B cells and Epstein-Barr virus-transformed lymphoblastoid cell lines
Authors: Lee Dong Hyeon , Park Kyu Sang , Kong In Deok , Kim Jun Woo , Han Bok Ghee
Published: September 2006

Background

Epstein-Barr virus (EBV) infection immortalizes primary B cells in vitro and generates lymphoblastoid cell lines (LCLs), which are used for several purposes in immunological and genetic studies. Purinergic receptors, consisting of P2X and P2Y, are activated by extracellular nucleotides in most tissues and exert various physiological effects. In B cells, especially EBV-induced LCLs, their expression and function have not been well studied. We investigated the expression of P2 receptors on primary human B cells and LCLs using the quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method for revealing the gene expression profile of the P2 receptor subtypes and their changes during transformation.

Results

The mRNA transcripts of most P2 receptors were detected in primary B cells; the expression of P2X3and P2X7receptors was the lowest of all the P2 receptors. By contrast, LCLs expressed several dominant P2 receptors – P2X4, P2X5, and P2Y11– in amounts similar to those seen in B cells infected with EBV for 2 weeks. The amount of most P2 subtypes in LCLs or EBV-infected B cells was lower than in normal B cells. However, the amount of P2X7receptor expressed in LCLs was higher. Protein expression was studied using Western blotting to confirm the mRNA findings for P2X1, P2X4, P2X7, P2Y1, and P2Y11receptors. ATP increased the intracellular free Ca2+concentration ([Ca2+]i) by enhancing the Ca2+influx in both B cells and LCLs in a dose-dependent manner.

Conclusion

These findings describe P2 receptor expression profiles and the effects of purinergic stimuli on B cells and suggest some plasticity in the expression of the P2 receptor phenotype. This may help explain the nature and effect of P2 receptors on B cells and their role in altering the characteristics of LCLs.
Histone deacetylase inhibitors strongly sensitise neuroblastoma cells to TRAIL-induced apoptosis by a caspases-dependent increase of the pro- to anti-apoptotic proteins ratio
Authors: Mühlethaler-Mottet Annick , Flahaut Marjorie , Bourloud Katia Balmas , Auderset Katya , Meier Roland , Joseph Jean-Marc , Gross Nicole
Published: September 2006

Background

Neuroblastoma (NB) is the second most common solid childhood tumour, an aggressive disease for which new therapeutic strategies are strongly needed. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in most tumour cells, but not in normal tissues and therefore represents a valuable candidate in apoptosis-inducing therapies. Caspase-8 is silenced in a subset of highly malignant NB cells, which results in full TRAIL resistance. In addition, despite constitutive caspase-8 expression, or its possible restoration by different strategies, NB cells remain weakly sensitive to TRAIL indicating a need to develop strategies to sensitise NB cells to TRAIL. Histone deacetylase inhibitors (HDACIs) are a new class of anti-cancer agent inducing apoptosis or cell cycle arrest in tumour cells with very low toxicity toward normal cells. Although HDACIs were recently shown to increase death induced by TRAIL in weakly TRAIL-sensitive tumour cells, the precise involved sensitisation mechanisms have not been fully identified.

Methods

NB cell lines were treated with various doses of HDACIs and TRAIL, then cytotoxicity was analysed by MTS/PMS proliferation assays, apoptosis was measured by the Propidium staining method, caspases activity by colorimetric protease assays, and (in)activation of apoptotic proteins by immunoblotting.

Results

Sub-toxic doses of HDACIs strongly sensitised caspase-8 positive NB cell lines to TRAIL induced apoptosis in a caspases dependent manner. Combined treatments increased the activation of caspases and Bid, and the inactivation of the anti-apoptotic proteins XIAP, Bcl-x, RIP, and survivin, thereby increasing the pro- to anti-apoptotic protein ratio. It also enhanced the activation of the mitochondrial pathway. Interestingly, the kinetics of caspases activation and inactivation of anti-apoptotic proteins is accelerated by combined treatment with TRAIL and HDACIs compared to TRAIL alone. In contrast, cell surface expression of TRAIL-receptors or TRAIL is not affected by sub-toxic doses of HDACIs.

Conclusion

HDACIs were shown to activate the mitochondrial pathway and to sensitise NB cells to TRAIL by enhancing the amplitude of the apoptotic cascade and by restoring an apoptosis-prone ratio of pro- to anti-apoptotic proteins. Combining HDACIs and TRAIL could therefore represent a weakly toxic and promising strategy to target TRAIL-resistant tumours such as neuroblastomas.
Diagnostic accuracy of an integrated respiratory guideline in identifying patients with respiratory symptoms requiring screening for pulmonary tuberculosis: a cross-sectional study
Authors: English René G , Bachmann Max O , Bateman Eric D , Zwarenstein Merrick F , Fairall Lara R , Bheekie Angeni , Majara Bosielo P , Lombard Carl , Scherpbier Robert , Ottomani Salah Eddine
Published: September 2006

Background

To evaluate the diagnostic accuracy of the integrated Practical Approach to Lung Health in South Africa (PALSA) guideline in identifying patients requiring bacteriological screening for tuberculosis (TB), and to determine which clinical features best predict suspected and bacteriologically-confirmed tuberculosis among patients with respiratory symptoms.

Methods

A prospective, cross-sectional study in which 1392 adult patients with cough and/or difficult breathing, attending a primary care facility in Cape Town, South Africa, were evaluated by a nurse using the guideline. The accuracy of a nurse using the guideline to identify TB suspects was compared to that of primary care physicians' diagnoses of (1) suspected TB, and (2) proven TB supported by clinical information and chest radiographs.

Results

The nurse using the guideline identified 516 patients as TB suspects compared with 365 by the primary care physicians, representing a sensitivity of 76% (95% confidence interval (CI) 71%–79%), specificity of 77% (95% CI 74%–79%), positive predictive value of 53% (95% CI 49%–58%), negative predictive value of 90% (95% CI 88%–92%), and area under the receiver operating characteristic curve (ARUC) of 0.76 (95% CI 0.74–0.79). Sputum results were obtained in 320 of the 365 primary care physicians TB suspects (88%); 40 (13%) of these were positive for TB. Only 4 cases were not identified by the nurse using the guideline. The primary care physicians diagnostic accuracy in diagnosing bacteriologically-confirmed TB (n = 320) was as follows: sensitivity 90% (95% CI 76%–97%), specificity 65% (95% CI 63%–68%), negative predictive value 7% (95% CI 5%–10%), positive predictive value 99.5% (95% CI 98.8%–99.8%), and ARUC 0.78 (95% CI 0.73–0.82). Weight loss, pleuritic pain, and night sweats were independently associated with the diagnosis of bacteriologically-confirmed tuberculosis (positive likelihood ratio if all three present = 16.7, 95% CI 5.9–29.4).

Conclusion

The PALSA guideline is an effective screening tool for identifying patients requiring bacteriological screening for pulmonary tuberculosis in this primary care setting. This supports the randomized trial finding that use of the guideline increased TB case detection.
Analysis of patient flows for orthopedic procedures using small area analysis in Switzerland
Authors: Matter-Walstra Klazien , Widmer Marcel , Busato André
Published: September 2006

Background

In general cantons regulate and control the Swiss health service system; patient flows within and between cantons are thereby partially disregarded. This paper develops an alternative spatial model, based upon the construction of orthopedic hospital service areas (HSAOs), and introduces indices for the analysis of patient streams in order to identify areas, irrespective of canton, with diverse characteristics, importance, needs, or demands.

Methods

HSAOs were constructed using orthopedic discharge data. Patient streams between the HSAOs were analysed by calculating three indices: the localization index (% local residents discharged locally), the netindex (the ratio of discharges of nonlocal incoming residents to outgoing local residents), and the market share index (% of local resident discharges of all discharges in local hospitals).

Results

The 85 orthopedic HSAOs show a median localization index of 60.8%, a market share index of 75.1%, and 30% of HSAOs have a positive netindex. Insurance class of bed, admission type, and patient age are partially but significantly associated with those indicators. A trend to more centrally provided health services can be observed not only in large urban HSAOs such as Geneva, Bern, Basel, and Zurich, but also in HSAOs in mountain sport areas such as Sion, Davos, or St.Moritz. Furthermore, elderly and emergency patients are more frequently treated locally than younger people or those having elective procedures.

Conclusion

The division of Switzerland into HSAOs provides an alternative spatial model for analysing and describing patient streams for health service utilization. Because this small area model allows more in-depth analysis of patient streams both within and between cantons, it may improve support and planning of resource allocation of in-patient care in the Swiss healthcare system.
Structure, (governance) and health: an unsolicited response
Authors: Reidpath Daniel D , Allotey Pascale
Published: September 2006

Background

In a recently published article, it was suggested that governance wasthesignificant structural factor affecting the epidemiology of HIV. This suggestion was made notwithstanding the observed weak correlation between governance and HIV prevalence (r= .2). Unfortunately, the paper raised but left unexamined the potentially more important questions about the relationship between the broader health of populations and structural factors such as the national economy and physical infrastructure.

Methods

Utilizing substantially the same data sources as the original article, the relationship between population health (healthy life expectancy) and three structural factors (access to improved water, GDP per capita, and governance) were examined in each of 176 countries.

Results

Governance was found to be significantly correlated with population health, as were GDP per capita, and access to improved water. They were also found to be significantly correlated with each other.

Conclusion

The findings are discussed with reference to the growing interest in structural factors as an explanation for population health outcomes, and the relatively weak relationship between governance and HIV prevalence.
Girls' perception of physical environmental factors and transportation: reliability and association with physical activity and active transport to school
Authors: Evenson Kelly R , Birnbaum Amanda S , Bedimo-Rung Ariane L , Sallis James F , Voorhees Carolyn C , Ring Kimberly , Elder John P
Published: September 2006

Background

Preliminary evidence suggests that the physical environment and transportation are associated with youth physical activity levels. Only a few studies have examined the association of physical environmental factors on walking and bicycling to school. Therefore, the purpose of this study was (1) to examine the test-retest reliability of a survey designed for youth to assess perceptions of physical environmental factors (e.g. safety, aesthetics, facilities near the home) and transportation, and (2) to describe the associations of these perceptions with both physical activity and active transport to school.

Methods

Test and retest surveys, administered a median of 12 days later, were conducted with 480 sixth- and eighth-grade girls in or near six U.S. communities. The instrument consisted of 24 questions on safety and aesthetics of the perceived environment and transportation and related facilities. Additionally, girls were asked if they were aware of 14 different recreational facilities offering structured and unstructured activities, and if so, whether they would visit these facilities and the ease with which they could access them. Test-retest reliability was determined using kappa coefficients, overall and separately by grade. Associations with physical activity and active transport to school were examined using mixed model logistic regression (n = 610), adjusting for grade, race/ethnicity, and site.

Results

Item-specific reliabilities for questions assessing perceived safety and aesthetics of the neighborhood ranged from 0.31 to 0.52. Reliabilities of items assessing awareness of and interest in going to the 14 recreational facilities ranged from 0.47 to 0.64. Reliabilities of items assessing transportation ranged from 0.34 to 0.58. Some items on girls' perceptions of perceived safety, aesthetics of the environment, facilities, and transportation were important correlates of physical activity and, in some cases, active transport to school.

Conclusion

This study provides some psychometric support for the use of the questionnaire on physical environmental factors and transportation for studying physical activity and active transport to school among adolescent girls. Further work can continue to improve reliability of these self-report items and examine their association of these factors with objectively measured physical activity.
Decreased metalloproteinase production as a response to mechanical pressure in human cartilage: a mechanism for homeostatic regulation
Authors: Monfort Jordi , Garcia-Giralt Natalia , López-Armada María J , Monllau Joan C , Bonilla Angeles , Benito Pere , Blanco Francisco J
Published: September 2006

Articular cartilage is optimised for bearing mechanical loads. Chondrocytes are the only cells present in mature cartilage and are responsible for the synthesis and integrity of the extracellular matrix. Appropriate joint loads stimulate chondrocytes to maintain healthy cartilage with a concrete protein composition according to loading demands. In contrast, inappropriate loads alter the composition of cartilage, leading to osteoarthritis (OA). Matrix metalloproteinases (MMPs) are involved in degradation of cartilage matrix components and have been implicated in OA, but their role in loading response is unclear. With this study, we aimed to elucidate the role of MMP-1 and MMP-3 in cartilage composition in response to mechanical load and to analyse the differences in aggrecan and type II collagen content in articular cartilage from maximum- and minimum-weight-bearing regions of human healthy and OA hips. In parallel, we analyse the apoptosis of chondrocytes in maximal and minimal load areas. Because human femoral heads are subjected to different loads at defined sites, both areas were obtained from the same hip and subsequently evaluated for differences in aggrecan, type II collagen, MMP-1, and MMP-3 content (enzyme-linked immunosorbent assay) and gene expression (real-time polymerase chain reaction) and for chondrocyte apoptosis (flow cytometry, bcl-2 Western blot, and mitochondrial membrane potential analysis). The results showed that the load reduced the MMP-1 and MMP-3 synthesis (p < 0.05) in healthy but not in OA cartilage. No significant differences between pressure areas were found for aggrecan and type II collagen gene expression levels. However, a trend toward significance, in the aggrecan/collagen II ratio, was found for healthy hips (p = 0.057) upon comparison of pressure areas (loaded areas > non-loaded areas). Moreover, compared with normal cartilage, OA cartilage showed a 10- to 20-fold lower ratio of aggrecan to type II collagen, suggesting that the balance between the major structural proteins is crucial to the integrity and function of the tissue. Alternatively, no differences in apoptosis levels between loading areas were found – evidence that mechanical load regulates cartilage matrix composition but does not affect chondrocyte viability. The results suggest that MMPs play a key role in regulating the balance of structural proteins of the articular cartilage matrix according to local mechanical demands.