Therapeutic Trial of anle138b in Mouse Models of Genetic Prion Disease.

Phenotypic screening has yielded small-molecule inhibitors of prion replication that are effective in vivo against certain prion strains but not others. Here, we sought to test the small molecule anle138b in multiple mouse models of prion disease. In mice inoculated with the RML strain of prions, anle138b doubled survival and durably suppressed astrogliosis measured by live-animal bioluminescence imaging. In knock-in mouse models of the D178N and E200K mutations that cause genetic prion disease, however, we were unable to identify a clear, quantifiable disease endpoint against which to measure therapeutic efficacy. Among untreated animals, the mutations did not impact overall survival, and bioluminescence remained low out to >20 months of age. Vacuolization and PrP deposition were observed in some brain regions in a subset of mutant animals but appeared to be unable to carry the weight of a primary endpoint in a therapeutic study. We conclude that not all animal models of prion disease are suited to well-powered therapeutic efficacy studies, and care should be taken in choosing the models that will support drug development programs. IMPORTANCE There is an urgent need to develop drugs for prion disease, a currently untreatable neurodegenerative disease. In this effort, there is a debate over which animal models can best support a drug development program. While the study of prion disease benefits from excellent animal models because prions naturally afflict many different mammals, different models have different capabilities and limitations. Here, we conducted a therapeutic efficacy study of the drug candidate anle138b in mouse models with two of the most common mutations that cause genetic prion disease. In a more typical model where prions are injected directly into the brain, we found anle138b to be effective. In the genetic models, however, the animals never reached a clear, measurable point of disease onset. We conclude that not all prion disease animal models are ideally suited to drug efficacy studies, and well-defined, quantitative disease metrics should be a priority.

Improvement of ENU Mutagenesis Efficiency Using Serial Injection and Mismatch Repair Deficiency Mice.

ENU mutagenesis is a powerful method for generating novel lines of mice that are informative with respect to both fundamental biological processes and human disease. Rapid developments in genomic technology have made the task of identifying causal mutations by positional cloning remarkably efficient. One limitation of this approach remains the mutation frequency achievable using standard treatment protocols, which currently generate approximately 1-2 sequence changes per megabase when optimized. In this study we used two strategies to attempt to increase the number of mutations induced by ENU treatment. One approach employed mice carrying a mutation in the DNA repair enzyme Msh6. The second strategy involved injection of ENU to successive generations of mice. To evaluate the number of ENU-induced mutations, single mice or pooled samples were analyzed using whole exome sequencing. The results showed that there is considerable variability in the induced mutation frequency using these approaches, but an overall increase in ENU-induced variants from one generation to another was observed. The analysis of the mice deficient for Msh6 also showed an increase in the ENU-induced variants compared to the wild-type ENU-treated mice. However, in both cases the increase in ENU-induced mutation frequency was modest.

The struggle with employee engagement: Measures and construct clarification using five samples.

Among scholarly researchers, the Utrecht Work Engagement Scale (UWES) is a popular scale for assessing employee or work engagement. However, challenges to the scale's validity have raised major concerns about the measurement and conceptualization of engagement as a construct. Across 4 field samples, we examined 2 measures of engagement, the UWES and the Job Engagement Scale (JES), in both factor structure and patterns of relationships with theoretically hypothesized antecedents and consequences. In a fifth field sample, we examined the construct-level relationships between engagement and related variables, while controlling for sources of measurement error (i.e., item-specific factor, scale-specific factor, random response, and transient). By examining 2 measures, each derived from different theoretical bases, we provide unique insight into the measurement and construct of engagement. Our results show that, although correlated, the JES and UWES are not interchangeable. The UWES, more so than the JES, assesses engagement with overlap from other job attitudes, requiring improvement in the measurement of engagement. We offer guidance as to when to use each measure. Furthermore, by isolating the construct versus measurement of engagement relative to burnout, commitment, stress, and psychological meaningfulness and availability, we determined (a) the engagement construct is not the same as the opposite of burnout, warranting a reevaluation of the opposite-of-burnout conceptualization of engagement; and (b) psychological meaningfulness and engagement are highly correlated and likely reciprocally related, necessitating a modification to the self-role-expression conceptualization of engagement. (PsycINFO Database Record

International trends in health science librarianship Part 9: the UK - Scotland and Wales.

This is the 9th in a series of articles exploring international trends in health science librarianship. The previous article in this series looked at Northern Ireland and the Republic of Ireland. In this issue the focus is Scotland and Wales. There will be three or four more articles this year tracking trends in the Far East, Africa, South Asia and the Middle East. JM.

Follow-up results from a randomised controlled trial evaluating in- and outpatient pain management programmes.

This study reports a 9-18 month follow-up of a randomised controlled trial of pain management programmes for chronic, non-malignant pain. Twenty-two inpatients, 18 outpatients and 12 control subjects completed the follow-up assessments. Significant treatment effects were demonstrated by the inpatient group on pain ratings, the Pain Behaviour Checklist, and General Health Questionnaire, with similar effects demonstrated by the outpatient group on the former 2 measures. The findings were confounded by higher inpatient scores at pretreatment, in comparison with the 2 other conditions. There was a high drop-out rate of subjects, particularly from the control condition which illustrates the limitations of controlled group designs in this area. Analgesic use, activity levels and pain ratings were also evaluated using the criteria for 'success' described by Malec et al. (1981). Results indicated that 68% of inpatients, 61% of outpatients and 21% of control subjects met all 3 criteria. Both treatment programmes were effective in returning patients to paid employment, whilst 3 control group patients gave up work. The cost-benefit implications of these changes are discussed. We conclude that pain management programmes contribute substantially to the rehabilitation of chronic pain sufferers.

A randomised control trial evaluating in- and outpatient pain management programmes.

This study investigated the clinical efficacy of in- and outpatient pain management programmes in comparison with a control group. Following physical examination and psychosocial assessments, and after obtaining informed consent, patients were randomly assigned to 1 of 3 groups: (1) a 4 week multidisciplinary inpatient pain management programme; (2) a 9 week (2 h/week) multidisciplinary outpatient programme; or (3) a control group. Self-report, behavioural and physiological measures were taken pre and post treatment. Patients in the treatment groups demonstrated significant improvement at posttreatment on measures of psychological distress, pain behaviour, health-related disability and pain intensity (following physical exertion) when compared with the control group. Little difference was demonstrated on the remaining measures. Difficulties encountered in conducting clinical research with this population and utilising a control group design are discussed.