Potentiation of triclabendazole action in vivo against a triclabendazole-resistant isolate of Fasciola hepatica following its co-administration with the metabolic inhibitor, ketoconazole

An in vivo study in the laboratory rat model has been carried out to monitor morphological changes in adult Fasciola hepatica over a 4-day period resulting from co-treatment with triclabendazole (TCBZ) and ketoconazole (KTZ), a cytochrome P450 inhibitor. Rats were infected with the triclabendazole-resistant Oberon isolate of F. hepatica, dosed orally with triclabendazole at a dosage of 10mg/kg live weight and ketoconazole at a dosage of 10mg/kg live weight. Flukes were recovered at 24, 48, 72 and 96 h post-treatment (p.t.) and changes to fluke ultrastructure were assessed using transmission electron microscopy (TEM). Results showed an increase in the severity of changes to the fluke ultrastructure with time p.t. Swelling of the basal infolds and the associated mucopolysaccharide masses became more severe with time. Golgi complexes, if present, were greatly reduced in size and number by 96 h p.t., and sub-tegumental flooding was seen from the 72 h time-period onwards. Some sloughing of the tegumental covering over the spines was observed at 96 h p.t. The results demonstrated that the Oberon isolate is more sensitive to TCBZ action in the presence of KTZ than to TCBZ alone, reinforcing the idea that altered drug metabolism is involved in the resistance mechanism. Moreover, they support the concept that TCBZ+inhibitor combinations (aimed at altering drug pharmacokinetics and potentiating the action of TCBZ) could be used in the treatment of TCBZ-R populations of F. hepatica.

A silicone elastomer vaginal ring for HIV prevention containing two microbicides with different mechanisms of action

Vaginal rings are currently being developed for the long-term (at least 30 days) continuous delivery of microbicides against human immunodeficiency virus (HIV). Research to date has mostly focused on devices containing a single antiretroviral compound, exemplified by the 25 mg dapivirine ring currently being evaluated in a Phase III clinical study. However, there is a strong clinical rationale for combining antiretrovirals with different mechanisms of action in a bid to increase breadth of protection and limit the emergence of resistant strains. Here we report the development of a combination antiretroviral silicone elastomer matrix-type vaginal ring for simultaneous controlled release of dapivirine, a non-nucleoside reverse transcriptase inhibitor, and maraviroc, a CCR5-targeted HIV-1 entry inhibitor. Vaginal rings loaded with 25 mg dapivirine and various quantities of maraviroc (50– 400 mg) were manufactured and in vitro release assessed. The 25 mg dapivirine and 100 mg maraviroc formulation was selected for further study. A 24-month pharmaceutical stability evaluation was conducted, indicating good product stability in terms of in vitro release, content assay, mechanical properties and related substances. This combination ring product has now progressed to Phase I clinical testing.

Monochloroacetic acid and 60% salicylic acid as a treatment for simple plantar warts:effectiveness and mode of action

Monochloroacetic acid crystals and 60% salicylic acid ointment was found to be more effective than placebo as a treatment for simple plantar warts in a double blind study on 57 patients. Nineteen (66%) patients in the active treatment group compared with five (18%) patients in the placebo group were cured after 6 weeks (P = 0.002). The active treatment was associated with a significantly higher cure rate 6 months after entry (P = 0.04). Treatments were well tolerated. IgG or IgM antibodies or both to human papilloma virus (HPV) types 1 or 2 or both were detected significantly more frequently in the actively treated group 6 weeks after entry (P = 0.0005). Twelve (50%) patients considered to be cured had no detectable secondary immune response. Our results suggest that cure does not depend primarily on the humoral system but rather on mechanical destruction of wart tissue, or occurs as a result of cell mediated immunity.

Assessing the sensitivity and specificity of fish community indicators to management action

We assessed ten trophodynamic indicators of ecosystem status for their sensitivity and specificity to fishing management using a size-resolved multispecies fish community model. The responses of indicators to fishing depended on effort and the size selectivity (sigmoid or Gaussian) of fishing mortality. The highest specificity against sigmoid (trawl-like) size selection was seen from inverse fishing pressure and the large fish indicator, but for Gaussian size selection, the large species indicator was most specific. Biomass, mean trophic level of the community and of the catch, and fishing in balance had the lowest specificity against both size selectivities. Length-based indicators weighted by biomass, rather than abundance, were more sensitive and specific to fishing pressure. Most indicators showed a greater response to sigmoid than Gaussian size selection. Indicators were generally more sensitive at low levels of effort because of nonlinear sensitivity in trophic cascades to fishing mortality. No single indicator emerged as superior in all respects, so given available data, multiple complementary indicators are recommended for community monitoring in the ecosystem approach to fisheries management.

'Sometimes I wish I was an "ex" ex-prisoner': identity processes in the collective action participation of former prisoners in Northern Ireland

Since the signing of the Northern Ireland peace agreement a plethora of community based prisoner self-help organisations have been established wherein former prisoners staff, manage and deliver services to colleagues. By forging and maintaining their collective identities through community based mutual aid, members of these self-help organisations have progressed to create not only individual change/assistance but have also developed and evolved to tackle serious wider social issues which impact on the members of their organisations. This article critically analyses how the conditions of a post conflict society can influence both the development and evolution of these organisations and also how members situate their claims about the self in the organisation and beyond. Using the social movement framework it is argued that the work of these self-help organisations have given rise to a new politics of identity … that is the ‘politically motivated’ ex-prisoner. ©2013 Taylor & Francis

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 comparison of stress intensity factors through crack closure integral and other approaches using eXtended element-free Galerkin method

In this paper, a new approach for extracting stress intensity factors (SIFs) by the extended element-free Galerkin method, through a crack closure integral (CCI) scheme, is proposed. The CCI calculation is used in conjunction with a local smoothing technique to improve the accuracy of the computed SIFs in a number of case studies of linear elastic fracture mechanics. The cases involve problems of mixed-mode, curved crack and thermo-mechanical loading. The SIFs by CCI, displacement and stress methods are compared with those based on the M-integral technique reported in the literature. The proposed CCI method involves very simple relations, and still gives good accuracy. The convergence of the results is also examined.