Helen Palmer

INTRODUCTION: The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily, contributes to acute and chronic disease processes, including sepsis. METHODS: We studied the possible therapeutic role of RAGE inhibition in the cecal ligation and puncture (CLP) model of polymicrobial sepsis and a model of systemic listeriosis using mice genetically deficient in RAGE expression or mice injected with a rat anti-murine RAGE monoclonal antibody. RESULTS: The 7-day survival rates after CLP were 80% for RAGE-/- mice (n = 15) (P < 0.01 versus wild-type), 69% for RAGE+/- mice (n = 23), and 37% for wild-type mice (n = 27). Survival benefits were evident in BALB/c mice given anti-RAGE antibody (n = 15 per group) over serum-treated control animals (P < 0.05). Moreover, delayed treatment with anti-RAGE antibody up to 24 hours after CLP resulted in a significant survival benefit compared with control mice. There was no significant increase in tissue colony counts from enteric Gram-negative or Gram-positive bacteria in animals treated with anti-RAGE antibody. RAGE-/-, RAGE+/-, and anti-RAGE antibody-treated animals were resistant to lethality from Listeria monocytogenes by almost two orders of magnitude compared with wild-type mice. CONCLUSION: Further studies are warranted to determine the clinical utility of anti-RAGE antibody as a novel treatment for sepsis.

Short term toxicity studies are conducted in animals to provide information on major adverse effects typically at the maximum tolerated dose (MTD). Such studies are important from a scientific and ethical perspective as they are used to make decisions on progression of potential candidate drugs, and to set dose levels for subsequent regulatory studies. The MTD is usually determined by parameters such as clinical signs, reductions in body weight and food consumption. However, these assessments are often subjective and there are no published criteria to guide the selection of an appropriate MTD. Even where an objective measurement exists, such as body weight loss (BWL), there is no agreement on what level constitutes an MTD. A global initiative including 15 companies, led by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs), has shared data on BWL in toxicity studies to assess the impact on the animal and the study outcome. Information on 151 studies has been used to develop an alert/warning system for BWL in short term toxicity studies. The data analysis supports BWL limits for short term dosing (up to 7days) of 10% for rat and dog and 6% for non-human primates (NHPs).

The idea that physical activity differentially impacts upon performance of various cognitive tasks has recently gained increased interest. However, our current knowledge about how cognition is altered by acute physical activity is incomplete. To measure how different intensity levels of physical activity affect cognition during and after 1 bout of physical activity, 30 healthy, young participants were randomized to perform a not-X continuous performance test (CPT) during low (LI)- and moderate intensity (MI) running. The same participants were subsequently randomized to perform the not-X CPT post LI, MI, and high intensity (HI) running. In addition, exercise related mood changes were assessed through a self-report measure pre and post running at LI, MI, and HI. Results showed worsening of performance accuracy on the not-X CPT during one bout of moderate compared to low intensity running. Post running, there was a linear decrease in reaction time with increasing running intensity and no change in accuracy or mood. The decreased reaction times post HI running recovered back to baseline within 20 min. We conclude that accuracy is acutely deteriorated during the most straining physical activity while a transient intensity-dependent enhancement of cognitive control function is present following physical activity.

Background: There is increasing evidence for music-based interventions in neurorehabilitation, improving mood and functional outcomes. In response, there is growing interest from health-care providers in setting up Neurologic Music Therapy (NMT) services. This paper presents some preliminary data on the feasibility and acceptability of NMT in the acute stroke, multidisciplinary team setting, about which little is known.Objectives: To assess the feasibility and acceptability of a two-day per-week NMT service over 24 months.Methods: Data were collected on the number of referrals received, sessions attended, sessions declined and reasons why. Staff completed questionnaires, and collected them from patients and their relatives, rating interventions: 1. Not helpful, 2. Quite helpful, 3. Helpful, 4. Very helpful. Patients completed the Visual Analogue Mood Scale (VAMS) pre-/post- a single session.Results: Of 201 patients referred, 177 received treatment and 675 sessions were delivered. Twenty-four patients were discharged before sessions were scheduled and 28 sessions were declined, predominantly due to fatigue. Mean scores (SD) from questionnaire data were: patients (n = 99) 3.34 (0.825), relatives (n = 13) 3.83 (0.372), staff (n = 27) 3.85 (0.388). Mean, post-session VAMS data (n = 52) showed a non-significant reduction in ‘Sad’ (7.5, p = .007, CI = 2.1, 12.9) and an increase in ‘Happy’ (+ 6.2, p = .013, CI = −11.0, −1.4).Conclusions: Data suggest the service was feasible and helpful, particularly for patient mood, possibly improving engagement in rehabilitation. Research to determine generalizability in different stroke environments and treatment effects within them is warranted.