Drug repositioning for Alzheimer's disease

Existing drugs for Alzheimer's disease provide symptomatic benefit for up to 12 months, but there are no approved disease-modifying therapies. Given the recent failures of various novel disease-modifying therapies in clinical trials, a complementary strategy based on repositioning drugs that are approved for other indications could be attractive. Indeed, a substantial body of preclinical work indicates that several classes of such drugs have potentially beneficial effects on Alzheimer's-like brain pathology, and for some drugs the evidence is also supported by epidemiological data or preliminary clinical trials. Here, we present a formal consensus evaluation of these opportunities, based on a systematic review of published literature. We highlight several compounds for which sufficient evidence is available to encourage further investigation to clarify an optimal dose and consider progression to clinical trials in patients with Alzheimer's disease.

Donepezil and memantine for moderate-to-severe Alzheimer's disease

Background: Clinical trials have shown the benefits of cholinesterase inhibitors for the treatment of mild-to-moderate Alzheimer's disease. It is not known whether treatment benefits continue after the progression to moderate-to-severe disease. Methods: We assigned 295 community-dwelling patients who had been treated with donepezil for at least 3 months and who had moderate or severe Alzheimer's disease (a score of 5 to 13 on the Standardized Mini-Mental State Examination [SMMSE, on which scores range from 0 to 30, with higher scores indicating better cognitive function]) to continue donepezil, discontinue donepezil, discontinue donepezil and start memantine, or continue donepezil and start memantine. Patients received the study treatment for 52 weeks. The coprimary outcomes were scores on the SMMSE and on the Bristol Activities of Daily Living Scale (BADLS, on which scores range from 0 to 60, with higher scores indicating greater impairment). The minimum clinically important differences were 1.4 points on the SMMSE and 3.5 points on the BADLS.
Results: Patients assigned to continue donepezil, as compared with those assigned to discontinue donepezil, had a score on the SMMSE that was higher by an average of 1.9 points (95% confidence interval [CI], 1.3 to 2.5) and a score on the BADLS that was lower (indicating less impairment) by 3.0 points (95% CI, 1.8 to 4.3) (P<0.001 for both comparisons). Patients assigned to receive memantine, as compared with those assigned to receive memantine placebo, had a score on the SMMSE that was an average of 1.2 points higher (95% CI, 0.6 to 1.8; P<0.001) and a score on the BADLS that was 1.5 points lower (95% CI, 0.3 to 2.8; P = 0.02). The efficacy of donepezil and of memantine did not differ significantly in the presence or absence of the other. There were no significant benefits of the combination of donepezil and memantine over donepezil alone.
Conclusions: In patients with moderate or severe Alzheimer's disease, continued treatment with donepezil was associated with cognitive benefits that exceeded the minimum clinically important difference and with significant functional benefits over the course of 12 months. (Funded by the U.K. Medical Research Council and the U.K. Alzheimer's Society; Current Controlled Trials number, ISRCTN49545035).

Functional study of elafin cleaved by Pseudomonas aeruginosa metalloproteinases

Elafin is a 6-kDa innate immune protein present at several epithelial surfaces including the pulmonary epithelium. It is a canonical protease inhibitor of two neutrophil serine proteases [neutrophil elastase (NE) and proteinase 3] with the capacity to covalently bind extracellular matrix proteins by transglutamination. In addition to these properties, elafin also possesses antimicrobial and immunomodulatory activities. The aim of the present study was to investigate the effect of Pseudomonas aeruginosa proteases on elafin function. We found that P aeruginosa PAO1-conditioned medium and two purified Pseudomonas metalloproteases, pseudolysin (elastase) and aeruginolysin (alkaline protease), are able to cleave recombinant elafin. Pseudolysin was shown to inactivate the anti-NE activity of elafin by cleaving its protease-binding loop. Interestingly, antibacterial properties of elafin against PAO1 were found to be unaffected after pseudolysin treatment. In contrast to pseudolysin, aeruginolysin failed to inactivate the inhibitory properties of elafin against NE. Aeruginolysin cleaves elafin at the amino-terminal Lys6-Gly7 peptide bond, resulting in a decreased ability to covalently bind purified fibronectin following transglutaminase activity. In conclusion, this study provides evidence that elafin is susceptible to proteolytic cleavage at alternative sites by P aeruginosa metalloproteinases, which can affect different biological functions of elafin.

Acoustic Interculturalism: Listening to Performance

Acoustic Interculturalism is a study of the soundscapes of intercultural performance through the examination of sound's performativity. Employing an interdisciplinary approach, the book examines an akoumenological reception of sound to postulate the need for an acoustic knowing – an awareness of how sound shapes the intercultural experience.

Every Situation has its Rhythm: Acoustic Mimesis and Sonic Exoticism in Tambours Sur La Digue.

This article examines the soundscapes of Ariane Mnouchkine’s Tambours Sur La Digue and explores the concept of acoustic mimesis located in the performance as a dramaturgical strategy to create, aurally, an imagined Far East. In Tambours, mimesis is the performative principle exemplified by the presentation of the mise en scène, and most distinctly Mnouckine’s decision to adapt the Japanese performance tradition of Bunraku through a process of 'reversed' mimicry (in which human bodies simulate the wooden marionettes of the Japanese style). Mimesis pervades the acoustemologies of the performance as it is heard in the extracted sounds, styles, and rhythms of Asian musical modes and movements that consequently become dislocated from context; the sounds become imitated, iconicised and exoticised as sonic signatures as they reify the Orientalist spectacle. The 'oriental' soundscape, reverberating with exotic overtones, becomes the means by which the production creates an imaginary Orient – one in which the Orient Other is silenced, and is resounded only through the musical sensibilities of the Occidental Self.

If Music Be the Food of Love:An Acoustic ‘Fourth World’ in Ong Keng Sen’s Awaking”

Staged as an attempt to ‘bring together Shakespeare’s plays and Tang Xian Zu’s classical Kunqu opera, The Peony Pavilion,’ (Ong, Programme Notes) Awaking stands as Singapore Director Ong Keng Sen’s most recent and prominent attempt at engaging issues of the intercultural through music and sound. While Ong’s previous intercultural projects sought to explore the politics of intercultural performance through the exchange, layering, confrontation and inter-mixing of Asian performance modes as visual aesthetics, Awaking is a performance at the borders of theatrical and musical conventions, as it features the music and musicians as central performative devices of staging the intercultural. Northern Kunqu opera, Chinese classical music and Elizabethan folk tunes from Shakespeare’s plays were re-moved, re-contextualised, and juxtaposed to explore ‘differing yet connected philosophies on love, death, and the afterlife’ (Awaking, Publicity). These humanist and ‘universal’ themes found expression in the ‘universal’ language of music. Through a study of the musicalities and sonic expressions of Awaking, the paper seeks to explore the implications of such cultural-musical juxtapositions. The paper engages, specifically, with the problematics and possibilities of music as a ‘universal language’ as implied by Ong’s concordance of Eastern and Western sounds in the final act. It further considers the politics of an intercultural soundscape and the acoustemologies of such an intercultural approach.

Between Sound and Sight: Framing the Exotic in Roysten Abel's The Manganiyar Seduction

Roysten Abel’s The Manganiyar Seduction is perhaps the most popular performance of Indian folk music on the global festival market today. This performance of Rajasthani folk music is an apt exemplification of an auto-exoticism framed as cultural commodity. Its mise en scéne of musicians framed, literally, by illuminated red square boxes ‘theatricalises’ Rajasthan’s folk culture of orality and renders such a tradition the quality of strangeness that borders on theatre and music, contemporary and traditional. The ‘dazzling’ union of the Manganiyar’s music and scenography of Amsterdam’s red light district engendered an exotic seduction that garnered raving reviews on its global tour. This paper then examines the production’s performative interstices: the in betweenness of sound and sight where aural tradition is ‘spectacularised’, and the shifting convergences of tradition and cultural consumption. It further interrogates the role of reception in the construction of such ‘exotic’ spectacles.

Zeros and Os:Silence, Absence and Erasure in an Intercultural O-thello

The performative function of sound and music has received little attention in performance theory and criticism and certainly much less so in studies of intercultural theatre. Such an absence is noteworthy particularly since interculturalism is an appropriative Western theatrical form that absorbs Eastern sources to re-create the targeted Western mise en scene. Consequently, a careful consideration of the employment of sound and music are imperative for sound and music form the vertebrae of Asian traditional performance practices. In acoustemological and ethnomusicological studies, sound and music demarcate cultural boundaries and locate cultures by an auditory (dis)recognition. In the light of this need for a more considered understanding of the performative function of sound and music in intercultural performance, this paper seeks to examine the soundscapes of an intercultural production of Shakespeare’s Othello – Desdemona. Directed by Singaporean Ong Keng Sen, Desdemona was a re-scripting of Shakespeare’s text and a self-conscious performance an identity politics. Staged with a multi-ethnic, multi-national cast, Desdemona employed various Asian performance traditions such as Sanskrit Kutiyattam, Myanmarese puppetry, and Korean p’ansori to create the intercultural spectacle. The spectacle was not only a visual aesthetic but an aural one as well. By examining the soundscapes of fractured silences and eruptive cultural sounds the paper hopes to establish the ways in which Desdemona performs absences and erasures of ‘Asia’ in a simultaneous act of performing an Asian Shakespeare.

A Document in Madness:Ophelia's Music of Insanity

This paper considers the musicological aspects of the songs performed by Ophelia in Shakespeare's Hamlet. It proposes a reconsideration of the concept of madness and insanity by an attentive, attuned and learned listening to the songs sung by Ophelia and the ways in which they are performed and received.

Dis)Harmony in Illyria: Music, Order, and Time in Twelfth Night:Music, Order, and Time in Twelfth Night

This paper considers the integral aspect of music as performed in Shakespeare's Twelfth Night. It posits that music is that which orders and structures time in its interplay throughout the play.

Here I am yet cannot hold this visible shape:The Music of Gender in Shakespeare’s Twelfth Night

Music has always been used as an important dramaturgical strategy in Western theatre to create a holistic theatrical experience. In Shakespeare’s plays, music was employed as a unique dramaturgical device for various purposes. Twelfth Night distinguishes itself from among the many plays that employ music because it begins, ends and progresses with music. Music pervades Twelfth Night and is tightly interwoven into the thematic concerns of the play such as love and gender. Because of music’s elusive nature and the difficulty of discussing a musical aesthetics, Shakespearean music critics have approached music in the play as a theme or an idea. This paper hopes to develop upon older scholarship by introducing an alternate framework of considering music’s musicality through a musicological analysis of the songs in Twelfth Night. In so doing, the paper hopes to show how and why music can modulate our responses to the play and in particular, to the theme of gender, a problematic issue that produces the elusive and darker nature of this festive comedy.

Vision and Virtuality:The Construction of Narrative Space in Film and Computer Games

This paper seeks to explore the construction of narrative space in 3D PC computer games. With reference to Stephen Heath’s theory of filmic narrative space, the paper will examine how computer games, based on the rendition of a continuous 3D, real-time interactive environment, construct a distinct mode of narrativisation. The dynamic imbrication of the manipulation of 3D objects in a virtual world and the (re)presentation of this virtual mise-en-scene constitute an interaction that affects the concept of narrative in computer games. This leads to several questions that the paper seeks to investigate: How does the construction of space in PC games contribute to the meaning-making process or the gamer’s experience of narrative? How then is this experience of narrative game-space different from that of film?

Thou art a strange fellow:Dissonance and Discordance in Intercultural Shakespeares

Any performance of the intercultural necessarily, and always, advances the question of the cultural since it involves the inter-action and interplay of unique and particular cultural performance styles and modes. Intercultural theatre, according to Pavis, is a hybrid theatrical form “drawing upon performance traditions traceable to distinct cultural areas. The hybridization is very often such that the original forms can no longer be distinguished.” The result of this collaboration of forms is, however, often not a ‘hybrid’ where cultural texts work cohesively and in unison to produce a harmonious mise en scene. Instead, intercultural performances are performances at the interstices and at the intersections of cultures. They raise problems of authorship, authority and performance unities and expose a sense of cultural foreignness. Consequently, intercultural performance can be said to be meta-theatre that queries the construction of culture since it places alongside performance traditions that confront.

Music, as performative unit, is a significant line of action by which the intercultural spectacle is constructed. Integral to Western theatre, and certainly more so in traditional Asian performance forms, the deliberate ‘fusion’ and ‘blending’ of musical styles in intercultural performances underscore not a harmony of diverse sounds but the possible dissonance and discordance already performed by the visual and verbal texts. The paper thus seeks to examine, in particular, the musical elements in intercultural performances such as Ong Keng Sen’s Lear (Theatreworks, 1999) and explore the ways in which music could possibly intensify the confrontation of performative texts resulting in a disruption of performance unities. When watching and listening to Lear, the question of the ‘local’ thus arises not merely with identification and alienation from what is seen but also what is familiar and foreign to one’s ears.

A revised age for the Kawakawa/Oruanui tephra, a key marker for the Last Glacial Maximum in New Zealand

The Kawakawa/Oruanui tephra (KOT) is a key chronostratigraphic marker in terrestrial and marine deposits of the New Zealand (NZ) sector of the southwest Pacific. Erupted early during the Last Glacial Maximum (LGM), the wide distribution of the KOT enables inter-regional alignment of proxy records and facilitates comparison between NZ climatic variations and those from well-dated records elsewhere. We present 22 new radiocarbon ages for the KOT from sites and materials considered optimal for dating, and apply Bayesian statistical methods via OxCal4.1.7 that incorporate stratigraphic information to develop a new age probability model for KOT. The revised calibrated age, ±2 standard deviations, for the eruption of the KOT is 25,360 ± 160 cal yr BP. The age revision provides a basis for refining marine reservoir ages for the LGM in the southwest Pacific.

K-Contagion: Sound, Space and Speed in Psy's 'Gangnam Style'

Park Jae-Sang’s (otherwise known as PSY) bewilderingly successful pop contagion ‘Gangnam Style’ needs no introduction. As of January 2013, it has become the most watched video in YouTube’s history and has garnered over 1.23 billion hits since. ‘Gangnam Style’ has also become a rapid global pop phenomenon with multiple parodic reproductions, imitations and adaptations; Rapper PSY himself has become an international name and styled as the ‘anti-hero’ of the glamour-driven K-pop scene. His fame has transcended the social sphere and permeated the political stratosphere with politicians such as Barrack Obama and David Cameron being among the many whom PSY has exchanged pleasantries with. Apart from breaking ground and creating social and media history in many ways, ‘Gangnam Style’ has even been purported by UN Secretary-General Ban Ki Moon to be a “force for world peace” – cultural barriers are demolished as the world dances. Underlying this sentiment is the video’s almost universal appeal that assumes a supracultural yet equally paradoxical translatability: Korea’s neoteric ‘K-Wave’ phenomenon is at once local yet global, and where the latter is predicated on the former quality. The paper’s concern is thus two-fold. It will consider the dromological aspects of this musical contagion as it exemplifies and performs quite literally Paul Virilio’s thesis that the modern condition is driven by speed yet arrested to a dictatorship of movement. While many theories have been put forward for this astounding pop peculiarity, this paper would also examine the intercultural currents that advocate such a global (pop) cultural response. Through an analysis of sonic qualities – digital techno-beat rhythms, synth-based musicality, cyclical lyrics, horse-galloping movements – and acoustic receptions, it will consider the simultaneous and dichotomous currents of glocalisation and globalisation as it relates to the ways in which sonic ‘hyper-links’ establish new concepts of global-cultural identities even as these seem to be interrogated in the borderless worlds of hyper-mediatised realities and cultural technologies.