Effectiveness of vertebroplasty using individual patient data from two randomised placebo controlled trials : meta-analysis

Objective To determine whether vertebroplasty is more effective than placebo for patients with pain of recent onset (≤6 weeks) or severe pain (score ≥8 on 0-10 numerical rating scale).

Design Meta-analysis of combined individual patient level data.

Setting Two multicentred randomised controlled trials of vertebroplasty; one based in Australia, the other in the United States.

Participants 209 participants (Australian trial n=78, US trial n=131) with at least one radiographically confirmed vertebral compression fracture. 57 (27%) participants had pain of recent onset (vertebroplasty n=25, placebo n=32) and 99 (47%) had severe pain at baseline (vertebroplasty n=50, placebo n=49).

Intervention Percutaneous vertebroplasty versus a placebo procedure.

Main outcome measure Scores for pain (0-10 scale) and function (modified, 23 item Roland-Morris disability questionnaire) at one month.

Results For participants with pain of recent onset, between group differences in mean change scores at one month for pain and disability were 0.1 (95% confidence interval −1.4 to 1.6) and 0.2 (−3.0 to 3.4), respectively. For participants with severe pain at baseline, between group differences for pain and disability scores at one month were 0.3 (−0.8 to 1.5) and 1.4 (−1.2 to 3.9), respectively. At one month those in the vertebroplasty group were more likely to be using opioids.

Conclusions Individual patient data meta-analysis from two blinded trials of vertebroplasty, powered for subgroup analyses, failed to show an advantage of vertebroplasty over placebo for participants with recent onset fracture or severe pain. These results do not support the hypothesis that selected subgroups would benefit from vertebroplasty.

Dimerization of retroviral RNA genomes : an inseparable pair

Many viruses carry more than one segment of nucleic acid into the virion particle, but retroviruses are the only known group of viruses that contain two identical (or nearly identical) copies of the RNA genome within the virion. These RNA genomes are non-covalently joined together through a process known as genomic RNA dimerization. Uniquely, the RNA dimerization of the retroviral genome is of crucial importance for efficient retroviral replication. In this article, our current understanding of the relationship between retroviral genome conformation, dimerization and replication is reviewed.

The A-rich RNA sequences of HIV-1 pol are important for the synthesis of viral cDNA

The bias of A-rich codons in HIV-1 pol is thought to be a record of hypermutations in viral genomes that lack biological functions. Bioinformatic analysis predicted that A-rich sequences are generally associated with minimal local RNA structures. Using codon modifications to reduce the amount of A-rich sequences within HIV-1 genomes, we have reduced the flexibility of RNA sequences in pol to analyze the functional significance of these A-rich ‘structurally poor’ RNA elements in HIV-1 pol. Our data showed that codon modification of HIV-1 sequences led to a suppression of virus infectivity by 5–100-fold, and this defect does not correlate with, viral entry, viral protein expression levels, viral protein profiles or virion packaging of genomic RNA. Codon modification of HIV-1 pol correlated with an enhanced dimer stability of the viral RNA genome, which was associated with a reduction of viral cDNA synthesis both during HIV-1 infection and in a cell free reverse transcription assay. Our data provided direct evidence that the HIV-1 A-rich pol sequence is not merely an evolutionary artifact of enzyme-induced hypermutations, and that HIV-1 has adapted to rely on A-rich RNA sequences to support the synthesis of viral cDNA during reverse transcription, highlighting the utility of using ‘structurally poor’ RNA domains in regulating biological process.

Labeling of multiple HIV-1 proteins with the biarsenical-tetracysteine system

Due to its small size and versatility, the biarsenical-tetracysteine system is an attractive way to label viral proteins for live cell imaging. This study describes the genetic labeling of the human immunodeficiency virus type 1 (HIV-1) structural proteins (matrix, capsid and nucleocapsid), enzymes (protease, reverse transcriptase, RNAse H and integrase) and envelope glycoprotein 120 with a tetracysteine tag in the context of a full-length virus. We measure the impact of these modifications on the natural virus infection and, most importantly, present the first infectious HIV-1 construct containing a fluorescently-labeled nucleocapsid protein. Furthermore, due to the high background levels normally associated with the labeling of tetracysteine-tagged proteins we have also optimized a metabolic labeling system that produces infectious virus containing the natural envelope glycoproteins and specifically labeled tetracysteine-tagged proteins that can easily be detected after virus infection of T-lymphocytes. This approach can be adapted to other viral systems for the visualization of the interplay between virus and host cell during infection.

8-modified-2'-deoxyadenosine analogues induce delayed polymerization arrest during HIV-1 reverse transcription

The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix αH in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2′-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2′-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication.

Learning to engage with human rights in heritage

Cultural heritage should not be seen merely as a technical matter or from a narrow visitor management point of view but rather as cultural practice—a form of cultural politics dominated by ruling regimes and social groups in which decisions are made about the future of and access to scarce resources. Several scholars have sought to push this approach further by arguing that heritage studies should take on the protection of human rights as a core consideration in the processes of identifying, inscribing, conserving and interpreting cultural heritage. This paper builds on these previous works to explore what the shift to a rights-based management approach in the World Heritage system might mean for various stakeholders in the heritage protection enterprise as they learn to meet this challenge and to find ways to support people’s right to access, enjoy and maintain cultural heritage. Reaffirming the need to maintain a strong relationship between theory and praxis, the paper draws into the discussion heritage practitioners, decision makers in governments and government agencies, scholars and educators. Of these, the principal emphasis in this paper is on educators who are seen to have a fundamentally important role in developing a critical understanding of the cultural heritage concept, how heritage is created, used and misused and how conservation approaches and programs sit within the broader context of community attitudes and aspirations and governmental responsibilities. A distinction is made between teachers in universities and trainers offering short courses more focused on specific employer needs. The paper focuses on World Heritage but refers to both tangible and intangible aspects. It shows how current moves to establish a rights-based approach to the management of World Heritage sites connects with moves elsewhere in global governance, most notably in the United Nations Permanent Forum on Indigenous Issues and the United Nations Human Rights Commission.

Assessment of proximal outcomes of self-management programs : translation and psychometric evaluation of a German version of the Health Education Impact Questionnaire (heiQtm)

Purpose This paper describes the translation, cultural adaption, and psychometric evaluation of a German version of the Health Education Impact Questionnaire (heiQ™), a widely used generic instrument assessing a wide range of proximal outcomes of self-management programs.

Methods The translation was carried out according to international standards and included forward and backward translations. Comprehensibility and content validity were tested using cognitive interviews with 10 rehabilitation inpatients. Psychometric properties were examined in rehabilitation inpatients (n = 1,202) with a range of chronic conditions. Factorial validity was assessed using confirmatory factor analysis; concurrent validity was explored by correlations with comparator scales.

Results The items of the German heiQ™ were well understood by rehabilitation inpatients. The structure of the eight heiQ™ scales was replicated after minor adjustment. heiQ™ scales had higher correlations with comparator scales with similar constructs, particularly mental health concepts than with physical health. Moreover, all heiQ™ scales differentiated between individuals across different levels of depression.

Conclusion The German heiQ™ is comprehensible for German-speaking patients suffering from different types of chronic conditions; it assesses relevant outcomes of self-management programs in a reliable and valid manner. Further studies involving its practical application are warranted.

Spinoza/space/speed/sublime: Problems of philosophy and politics in the post-colonial fiction of Gerald Murnane

This article takes account of the ‘spontaneity’ of the post-colonial fiction of Gerald Murnane within the ‘dominating space’ of the philosophy of Spinoza. My use of Paul Carter’s terms here is strategic. The compact of fiction and philosophy in Murnane corresponds with the relationship of spontaneity to the dominating organization of desire in Carter’s rendering of an Aboriginal hunter. Carter’s phrase “‘a figure at once spontaneous and wholly dominated by the space of his desire’” worries Ken Gelder and Jane M. Jacobs, who suggest that it subjugates the formation of Aboriginal desire (incorporating spontaneity) to impulses of imperialism. The captivating immanence of Spinoza’s philosophy in Murnane’s fiction, which I will demonstrate with various examples, puts pressure on the fiction to occupy the same space as the space of the philosophy. Here is a clue to why Murnane’s post-colonial thematics have been little explored by critics with an interest in post-colonial politics. The desire of Spinoza’s philosophy creates a spatial textuality within which the spontaneity of Murnane’s fiction, to the degree that it maximizes or fills the philosophy, is minimized in its political effects. That is to say, the fiction shifts politics into an external space of what Roland Barthes calls “resistance or condemnation”. However, the different speeds (or timings) of Murnane and Spinoza, within the one space, mitigate this resistance of the outside, at least in respect of certain circumstances of post-coloniality. It is especially productive, I suggest, to engage Carter’s representation of an Aboriginal hunter through the compact of coincidental spaces and differential speeds created by Murnane’s fiction in Spinoza’s philosophy. This produces a ceaseless activation of desire and domination, evidenced in Murnane’s short story ‘Land Deal’, and indexed by a post-Romantic sublime. What limits the value of Murnane’s fiction in most contexts of post-colonial politics, is precisely what makes it useful in the matter of Carter’s Aboriginal hunter.

Pauline Kael and the Western genre as critical displacement of self & nation: metaphorics and affects of 'taste' in American film criticism

Pauline Kael (1919–2001) is one of the most influential American film critics of the second half of the twentieth century. Many people are writing on her presently, with at least half an eye to her future cultural, political and historical importance. Certainly the full impact of Kael’s work, both within and beyond the borders of cinema (however defined), has not yet been established. This article unpacks the mechanisms and operations of ‘taste’ in Kael’s writings by using two notions drawn from Roland Barthes’ observations about another key figure of current cultural critique: Julia Kristeva. The comparison of Kael with Kristeva is not dwelt upon; instead, the article focuses on how Kael used the concepts of ‘taste’ and ‘dis-taste’ to draw her readership into a field of what might be termed ‘permanent dissent’. This article concludes by sketching out why Jewish-American Kael’s taste might endure, through the dual transition she occupies from a Cold War to a post-Cold War period, and from an era when cinema was the supreme, undisputed, screen artform, to the rise of the myriad screen technologies of the networked, Internet age.

Copper : effects of deficiency and overload

Copper is an essential trace metal that is required for the catalysis of several important cellular enzymes. However, since an excess of copper can also harm cells due to its potential to catalyze the generation of toxic reactive oxygen species, transport of copper and the cellular copper content are tightly regulated. This chapter summarizes the current knowledge on the importance of copper for cellular processes and on the mechanisms involved in cellular copper uptake, storage and export. In addition, we will give an overview on disturbances of copper homeostasis that are characterized by copper overload or copper deficiency or have been connected with neurodegenerative disorders. © Springer Science+Business Media Dordrecht 2013.