Intravenous tolerance effectively overcomes enhanced pro-inflammatory responses and EAE severity in the absence of IL-12 receptor signaling

Intravenous (i.v.) administration of autoantigen effectively induces Ag-specific tolerance against experimental autoimmune encephalomyelitis (EAE). We and others have shown enhanced EAE severity in mice lacking IL-12 or its receptor, strongly suggesting an immunoregulatory effect of IL-12 signaling. To examine the role of IL-12 responsiveness in autoantigen-induced tolerance in EAE, we administered autoantigen i.v. in two distinct treatment regimes to wildtype and IL-12Rβ2(-/-) mice, immunized to develop EAE. Administration at the induction phase suppressed EAE in wildtype and IL-12Rβ2(-/-) mice however the effect was somewhat less potent in the absence of IL-12Rβ2. Expression of pro-inflammatory cytokines such as IFN-γ, IL-17 and IL-2, was inhibited in wild-type tolerized mice but less so in IL-12Rβ2(-/-) mice. I.v. antigen was also effective in suppressing disease in both genotypes when given during the clinical phase of disease with similar CNS inflammation, demyelination and peripheral inflammatory cytokine profiles observed in both genotypes. There was however a mild impact of a lack of IL-12 signaling on Treg induction during tolerance induction compared to WT mice in this treatment regime. These findings show that the enhanced severity of EAE that occurs in the absence of IL-12 signaling can be effectively overcome by i.v. autoantigen, indicating that this therapeutic effect is not primarily mediated by IL-12 and that i.v. tolerance could be a powerful approach in suppressing severe and aggressive MS.

Management of long-term sickness absence: a systematic realist review

Purpose
The increasing impact and costs of long term sickness absence have been well documented. However, the diversity and complexity of interventions and of the contexts in which these take place makes a traditional review problematic. Therefore, we undertook a systematic realist review to identify the dominant programme theories underlying best practice, to assess the evidence for these theories, and to throw light on important enabling or disabling contextual factors.

Method
A search of the scholarly literature from 1950 to 2011 identified 5,576 articles, of which 269 formed the basis of the review.

Results
We found that the dominant programme theories in relation to effective management related to: early intervention or referral by employers; having proactive organisational procedures; good communication and cooperation between stakeholders; and workplace-based occupational rehabilitation. Significant contextual factors were identified as the level of support for interventions from top management, the size and structure of the organisation, the level of financial and organisational investment in the management of long-term sickness absence, and the quality of relationships between managers and staff.

Conclusions
Consequently, those with responsibility for managing absence should bear in mind the contextual factors that are likely to have an impact on interventions, and do what they can to ensure stakeholders have at least a mutual understanding (if not a common purpose) in relation to their perceptions of interventions, goals, culture and practice in the management of long term sickness absence.

The effects of ibuprofen and indomethacin on renal function in the presence and absence of frusemide in healthy volunteers on a restricted sodium diet

1. Since salt depletion stimulates the renal prostaglandin system to maintain renal function, the effects of indomethacin and ibuprofen upon renal haemodynamics, electrolyte excretion and renin release were examined in eight healthy male volunteers on a salt restricted diet, before and after frusemide administration. 2. Neither indomethacin (50 mg) nor ibuprofen (400 mg and 800 mg) affected renal blood flow, glomerular filtration rate or electrolyte excretion before frusemide. 3. Renal blood flow and glomerular filtration rate were significantly increased in the first 20 min after frusemide. These changes were significantly attenuated by indomethacin compared with placebo and ibuprofen 400 mg. Frusemide-induced diuresis but not natriuresis was inhibited by all treatments. 4. Both nonsteroidal agents inhibited equally the rise in renin activity seen after frusemide. 5. In this group of healthy volunteers on a salt restricted diet, ibuprofen and indomethacin had no detrimental effects on renal function in the absence of frusemide. The changes in renal haemodynamics due to frusemide were suppressed more by indomethacin than by ibuprofen, probably reflecting the more potent nature of indomethacin as an inhibitor of prostaglandin synthesis.

A comparison of the effects of ibuprofen and indomethacin upon renal haemodynamics and electrolyte excretion in the presence and absence of frusemide

1. This study has compared the effects of ibuprofen and indomethacin upon renal haemodynamics, electrolyte excretion and renin release in the presence and absence of frusemide under sodium replete conditions in eight healthy volunteers. 2. Neither ibuprofen (400 mg and 800 mg) nor indomethacin (50 mg) affected renal blood flow, glomerular filtration rate or electrolyte excretion in the basal state. 3. Frusemide had no effect on renal blood flow, but significantly increased glomerular filtration rate. This latter change was suppressed significantly only by ibuprofen 400 mg. Frusemide-induced diuresis was inhibited by all treatments, while natriuresis following frusemide was inhibited by indomethacin only. 4. Significant increments in plasma renin activity, which were suppressed by all treatments, were observed after frusemide. The degree of inhibition of the renin responses was significantly greater in the presence of indomethacin than with either dose of ibuprofen. 5. In a sodium replete setting in healthy volunteers, indomethacin and ibuprofen had no detrimental effects on basal renal function. In the presence of frusemide, indomethacin had more anti-natriuretic and renin-suppressing effect than ibuprofen. There was no evidence for a dose-related effect of ibuprofen.

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.

Lipopolysaccharide O antigen status of Yersinia enterocolitica O:8 is essential for virulence and absence of O antigen affects the expression of other Yersinia virulence factors

Lipopolysaccharide (LPS) is the major component of the outer membrane of Gram-negative bacteria. Although much attention has been given to the biological effects of its lipid A portion, a great body of evidence indicates that its O chain polysaccharide (O antigen) portion plays an important role in the bacterium-host interplay. In this work we have studied in-depth the role of the O antigen in Yersinia enterocolitica serotype O:8 pathogenesis. We made a detailed virulence analysis of three mutants having different O antigen phenotypes: (i) LPS with no O antigen (rough mutant); (ii) LPS with one O unit (semirough mutant) and (iii) LPS with random distribution of O antigen chain lengths. We demonstrated that these LPS O antigen mutants were attenuated in virulence regardless of the infection route used. Co-infection experiments revealed that the rough and semirough mutants were severely impaired in their ability to colonize the Peyer's patches and in contrast to the wild-type strain they did not colonize spleen and liver. The mutant with random distribution of O antigen chain lengths, however, survived better but started to be cleared from mouse organs after 8 days. As an explanation to this attenuation we present here evidence that other Yersinia virulence factors depend on the presence of O antigen for their proper function and/or expression. We demonstrated that in the rough mutant: (i) the YadA function but not its expression was altered; (ii) Ail was not expressed and (iii) inv expression was downregulated. On the other hand, expression of flhDC, the flagellar master regulatory operon, was upregulated in this mutant with a concomitant increase in the production of flagellins. Finally, expression of yplA, encoding for the Yersinia phospholipase A, was also upregulated accompanied by an increased flagellar type III secretion system mediated secretion of YplA to culture medium. Together these findings suggest that the absence of O antigen in the outer membrane of Yersinia either directly or indirectly, for example through a cellular or membrane stress, could act as a regulatory signal.

Cathelicidin-like Helminth Defence Molecules (HDMs):Absence of Cytotoxic, Anti-microbial and Anti-protozoan Activities Imply a Specific Adaptation to Immune Modulation

Host defence peptides (HDPs) are expressed throughout the animal and plant kingdoms. They have multifunctional roles in the defence against infectious agents of mammals, possessing both bactericidal and immune-modulatory activities. We have identified a novel family of molecules secreted by helminth parasites (helminth defence molecules; HDMs) that exhibit similar structural and biochemical characteristics to the HDPs. Here, we have analyzed the functional activities of four HDMs derived from Schistosoma mansoni and Fasciola hepatica and compared them to human, mouse, bovine and sheep HDPs. Unlike the mammalian HDPs the helminth-derived HDMs show no antimicrobial activity and are non-cytotoxic to mammalian cells (macrophages and red blood cells). However, both the mammalian- and helminth-derived peptides suppress the activation of macrophages by microbial stimuli and alter the response of B cells to cytokine stimulation. Therefore, we hypothesise that HDMs represent a novel family of HDPs that evolved to regulate the immune responses of their mammalian hosts by retaining potent immune modulatory properties without causing deleterious cytotoxic effects.

The Management of Long-Term Sickness Absence in Large Public Sector Healthcare Organisations: A Realist Evaluation Using Mixed Methods

Purpose The success of measures to reduce long-term sickness absence (LTSA) in public sector organisations is contingent on organisational context. This realist evaluation investigates how interventions interact with context to influence successful management of LTSA. Methods Multi-method case study in three Health and Social Care Trusts in Northern Ireland comprising realist literature review, semi-structured interviews (61 participants), Process-Mapping and feedback meetings (59 participants), observation of training, analysis of documents. Results Important activities included early intervention; workplace-based occupational rehabilitation; robust sickness absence policies with clear trigger points for action. Used appropriately, in a context of good interpersonal and interdepartmental communication and shared goals, these are able to increase the motivation of staff to return to work. Line managers are encouraged to take a proactive approach when senior managers provide support and accountability. Hindering factors: delayed intervention; inconsistent implementation of policy and procedure; lack of resources; organisational complexity; stakeholders misunderstanding each other’s goals and motives. Conclusions Different mechanisms have the potential to encourage common motivations for earlier return from LTSA, such as employees feeling that they have the support of their line manager to return to work and having the confidence to do so. Line managers’ proactively engage when they have confidence in the support of seniors and in their own ability to address LTSA. Fostering these motivations calls for a thoughtful, diagnostic process, taking into account the contextual factors (and whether they can be modified) and considering how a given intervention can be used to trigger the appropriate mechanisms.

Measuring beta diversity for presence-absence data

1. Little consensus has been reached as to general features of spatial variation in beta diversity, a fundamental component of species diversity. This could reflect a genuine lack of simple gradients in beta diversity, or a lack of agreement as to just what constitutes beta diversity. Unfortunately, a large number of approaches have been applied to the investigation of variation in beta diversity, which potentially makes comparisons of the findings difficult.

2. We review 24 measures of beta diversity for presence/absence data (the most frequent form of data to which such measures are applied) that have been employed in the literature, express many of them for the first time in common terms, and compare some of their basic properties.

3. Four groups of measures are distinguished, with a fundamental distinction arising between 'broad sense' measures incorporating differences in composition attributable to species richness gradients, and 'narrow sense' measures that focus on compositional differences independent of such gradients. On a number of occasions on which the former have been employed in the literature the latter may have been more appropriate, and there are many situations in which consideration of both kinds of measures would be valuable.

4. We particularly recommend (i) considering beta diversity measures in terms of matching/mismatching components (usually denoted a , b and c) and thereby identifying the contribution of different sources of variation in species composition, and (ii) the use of ternary plots to express the relationship between the values of these measures and of the components, and as a way of understanding patterns in beta diversity.

Chronic PEGylated obestatin treatment prevents the onset of high fat diet-induced hypertension and endothelial dysfunction in the absence of metabolic actions

Background: Obestatin is a gastrointestinal peptide with established metabolic actions and emerging vascular effects which involve activation of NO signalling. The aim of this study was to investigate effects of a recently-characterised stable analogue, PEGylated obestatin (PEG-OB), in the setting of diet-induced obesity which is associated with both metabolic and vascular dysfunction. Methods: Male Sprague Dawley rats (6 weeks; n=8) were maintained on standard (SD) or high fat (HF) diet (60% fat) for 8 weeks with once-daily injection of either PEG-OB (50nmol/kg/day) or saline from 2 weeks. Results: HF feeding for 8 weeks resulted in marked body weight gain which was not affected by chronic PEG-OB treatment (HF saline, 175.0±12.2; HF PEG-OB, 190.4±6.4g; P=NS). Similarly, blood glucose, as indicated by HbA1c (HF saline, 6.30±0.15; HF PEG-OB, 6.13±0.36%; P=NS) and insulin tolerance (HF saline, 105.2±52.5; HF PEG-OB, 90.3±45.4mmol/L.min; P=NS), were unaltered by PEG-OB. Despite the apparent lack of metabolic effects, chronic PEG-OB treatment markedly attenuated development of HF-induced hypertension (HF saline, 146.5±4.9mmHg; HF PEG-OB, 123.0±9.7mmHg; P<0.01), assessed by tail-cuff plethysmography. Furthermore, organ bath pharmacology in isolated aortic rings, indicated that HF diet-induced endothelial dysfunction was completely prevented by PEG-OB (acetylcholine, EC50: SD saline, 335±113; HF saline, 758±164; HF PEG-OB, 277±85nmol/L; P<0.05). However, contraction to phenylephrine and relaxation to the NO donor, sodium nitroprusside, were unaltered between groups. Conclusions: PEG-OB exerts beneficial effects on hypertension and endothelial function in diabetes independently of metabolic actions suggesting that obestatin signalling may represent a novel therapeutic target to reduce the risk of associated cardiovascular complications.