Intrabody Gene Therapy Ameliorates Motor, Cognitive, and Neuropathological Symptoms in Multiple Mouse Models of Huntington's Disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease resulting from the expansion of a glutamine repeat in the huntingtin (Htt) protein. Current therapies are directed at managing symptoms such as chorea and psychiatric disturbances. In an effort to develop a therapy directed at disease prevention we investigated the utility of highly specific, anti-Htt intracellular antibodies (intrabodies). We previously showed that V_(L)12.3, an intrabody recognizing the N terminus of Htt, and Happ1, an intrabody recognizing the proline-rich domain of Htt, both reduce mHtt-induced toxicity and aggregation in cell culture and brain slice models of HD. Due to the different mechanisms of action of these two intrabodies, we then tested both in the brains of five mouse models of HD using a chimeric adeno-associated virus 2/1 (AAV2/1) vector with a modified CMV enhancer/chicken β-actin promoter. V_(L)12.3 treatment, while beneficial in a lentiviral model of HD, has no effect on the YAC128 HD model and actually increases severity of phenotype and mortality in the R6/2 HD model. In contrast, Happ1 treatment confers significant beneficial effects in a variety of assays of motor and cognitive deficits. Happ1 also strongly ameliorates the neuropathology found in the lentiviral, R6/2, N171-82Q, YAC128, and BACHD models of HD. Moreover, Happ1 significantly prolongs the life span of N171-82Q mice. These results indicate that increasing the turnover of mHtt using AAV-Happ1 gene therapy represents a highly specific and effective treatment in diverse mouse models of HD

Widening access in selection using situational judgement tests: evidence from the UKCAT

CONTEXT Widening access promotes student diversity and the appropriate representation of all demographic groups. This study aims to examine diversity-related benefits of the use of situational judgement tests (SJTs) in the UK Clinical Aptitude Test (UKCAT) in terms of three demographic variables: (i) socioeconomic status (SES); (ii) ethnicity, and (iii) gender. METHODS Outcomes in medical and dental school applicant cohorts for the years 2012 (n = 15 581) and 2013 (n = 15 454) were studied. Applicants' scores on cognitive tests and an SJT were linked to SES (parents' occupational status), ethnicity (White versus Black and other minority ethnic candidates), and gender. RESULTS Firstly, the effect size for SES was lower for the SJT (d = 0.13-0.20 in favour of the higher SES group) than it was for the cognitive tests (d = 0.38-0.35). Secondly, effect sizes for ethnicity of the SJT and cognitive tests were similar (d = similar to 0.50 in favour of White candidates). Thirdly, males outperformed females on cognitive tests, whereas the reverse was true for SJTs. When equal weight was given to the SJT and the cognitive tests in the admission decision and when the selection ratio was stringent, simulated scenarios showed that using an SJT in addition to cognitive tests might enable admissions boards to select more students from lower SES backgrounds and more female students. CONCLUSIONS The SJT has the potential to appropriately complement cognitive tests in the selection of doctors and dentists. It may also put candidates of lower SES backgrounds at less of a disadvantage and may potentially diversify the student intake. However, use of the SJT applied in this study did not diminish the role of ethnicity. Future research should examine these findings with other SJTs and other tests internationally and scrutinise the causes underlying the role of ethnicity

IKKα and IKKβ Regulation of DNA Damage-Induced Cleavage of Huntingtin

Background: Proteolysis of huntingtin (Htt) plays a key role in the pathogenesis of Huntington's disease (HD). However, the environmental cues and signaling pathways that regulate Htt proteolysis are poorly understood. One stimulus may be the DNA damage that accumulates in neurons over time, and the subsequent activation of signaling pathways such as those regulated by IκB kinase (IKK), which can influence neurodegeneration in HD. Methodology/Principal Findings: We asked whether DNA damage induces the proteolysis of Htt and if activation of IKK plays a role. We report that treatment of neurons with the DNA damaging agent etoposide or γ-irradiation promotes cleavage of wild type (WT) and mutant Htt, generating N-terminal fragments of 80–90 kDa. This event requires IKKβ and is suppressed by IKKα. Elevated levels of IKKα, or inhibition of IKKβ expression by a specific small hairpin RNA (shRNA) or its activity by sodium salicylate, prevents Htt proteolysis and increases neuronal resistance to DNA damage. Moreover, IKKβ phosphorylates the anti-apoptotic protein Bcl-xL, a modification known to reduce Bcl-xL levels, and activates caspases that can cleave Htt. When IKKβ expression is blocked, etoposide treatment does not decrease Bcl-xL and activation of caspases is diminished. Similar to silencing of IKKβ, increasing the level of Bcl-xL in neurons prevents etoposide-induced caspase activation and Htt proteolysis. Conclusions/Significance: These results indicate that DNA damage triggers cleavage of Htt and identify IKKβ as a prominent regulator. Moreover, IKKβ-dependent reduction of Bcl-xL is important in this process. Thus, inhibition of IKKβ may promote neuronal survival in HD as well as other DNA damage-induced neurodegenerative disorders

The Effectiveness of Reciprocal Scaffolding Treatment in Anomic Aphasia

Reciprocal Scaffolding Treatment (RST) uses an apprenticeship model of learning that occurs between novices and a skilled partner. This project examined the effect of RST on improvement of word retrieval and conversational content for an individual with anomic aphasia. Novices were graduate student clinicians and the skilled partner was an individual with aphasia, who demonstrated facilitative communication techniques during conversational group treatment conducted by the novices. The individual with aphasia made positive changes in word fluency, correct information units and type-token ratio. Novice clinicians acquired training in facilitating conversational skills from a knowledgeable individual with aphasia

A rapid appraisal case study of South Australia's Social Inclusion Initiative

This Rapid Appraisal Case Study of South Australia’s Social Inclusion Initiative was undertaken to contribute to the work of the Social Exclusion Knowledge Network (SEKN) of the Commission on Social Determinants of Health (CSDH). The CSDH was established in 2005 by the World Health Organisation to investigate ways in which international, national, regional and local bodies could take action on the social determinants of health. The knowledge networks are one of the main mechanisms by which the CSDH is gathering evidence. This report provides a rapid assessment of the ways in which South Australia’s Social Inclusion Initiative has originated and operated. The report’s layout follows guidelines developed by the SEKN and draws on documentary and interview evidence. The project was conducted between March and June 2007 by researchers at Flinders University of South Australia, in conjunction with senior staff at South Australia’s Social Inclusion Unit, Department of the Premier and Cabinet. South Australia is a State within a federal system of government and has a population of 1.6 million. The population’s average health and well-being are high by world standards but the State continues to record significant levels of inequality for certain groups and areas, and particularly for its Aboriginal population

Partnership in knowledge creation: lessons learned from a researcher–policy actor partnership to co-produce a rapid appraisal case study of south australia’s social Inclusion Initiative

This paper describes a partnership between researchers and policy actors which was developed within a short time-frame to produce a rapid appraisal case study of a government policy initiative - South Australia’s Social Inclusion Initiative - for the Social Exclusion Knowledge Network of the international Commission on Social Determinants of Health. The paper does not focus on the case study findings or content, but rather on the researcher-policy actor partnership which developed in the process of producing the case study and its report. The paper is set against the broader literature on researcher-policy collaboration and is written to share lessons that may help others quickly establish or improve researcher-policy partnerships. It sets out six key elements for success in a framework for partnership which can meet policy rather than academic time frames and which can effectively co-produce knowledge that meets both research and policy objectives

Speech Melody Properties in English, Czech and Czech English: Reference and Interference

Two major objectives were set for the present study: to provide reference data for the description of Czech and English F0 contours, and to investigate the limits of the ‘interference hypothesis’ on Czech English data. Altogether, the production of 40 speakers in 2392 breath-group F0 contours was analyzed. The speech of 32 professional speakers of English and Czech provides reference values for various acoustic correlates of pitch level, pitch span and downtrend gradient. These values were subsequently used as a benchmark for a confirmation of the interference hypothesis through comparison with a further sample of 8 non-professional speakers of English and Czech-accented English. The native English speakers of both genders produced significantly higher pitch level indicators, wider pitch span and a steeper downtrend gradient than the reference native speakers of Czech. Although the pitch level of the Czech-accented material lies in between the two reference groups, the pitch span of this group is the narrowest, which indicates that factors of foreign-accentedness other than simply interference are in effect

Important features of home-based support services for older Australians and their informal carers

This author accepted manuscript (post print) is made available in accordance with the publisher copyright policy following 24 month embargo from the date of publication (8 February 2015) in accordance with publishers copyright policy.In Australia, newly initiated, publicly subsidised ‘Home-Care Packages’ designed to assist older people (≥65 years of age) living in their own home must now be offered on a ‘consumer-directed care’ (CDC) basis by service providers. However, CDC models have largely developed in the absence of evidence on users’ views and preferences. The aim of this study was to determine what features (attributes) of consumer-directed, home-based support services are important to older people and their informal carers to inform the design of a discrete choice experiment (DCE). Semi-structured, face-to-face interviews were conducted in December 2012–November 2013 with 17 older people receiving home-based support services and 10 informal carers from 5 providers located in South Australia and New South Wales. Salient service characteristics important to participants were determined using thematic and constant comparative analysis and formulated into attributes and attribute levels for presentation within a DCE. Initially, eight broad themes were identified: information and knowledge, choice and control, self-managed continuum, effective co-ordination, effective communication, responsiveness and flexibility, continuity and planning. Attributes were formulated for the DCE by combining overlapping themes such as effective communication and co-ordination, and the self-managed continuum and planning into single attributes. Six salient service features that characterise consumer preferences for the provision of home-based support service models were identified: choice of provider, choice of support worker, flexibility in care activities provided, contact with the service co-ordinator, managing the budget and saving unspent funds. Best practice indicates that qualitative research with individuals who represent the population of interest should guide attribute selection for a DCE and this is the first study to employ such methods in aged care service provision. Further development of services could incorporate methods of consumer engagement such as DCEs which facilitate the identification and quantification of users’ views and preferences on alternative models of delivery