The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

The megafossil and microfossil floras of the Curlew Formation, Queensland / by Andrew Ian Rowett

Includes amendments (8 p.) in pocketBibliography: leaves 306-331iv, 349 leaves, [34] leaves of plates : ill ; 30 cm.Thesis (Ph.D.)--University of Adelaide, Dept. of Botany, 198

Dispersed cuticular floras of South Australian Tertiary coalfields: Part 2. Lochiel

Volume: 116Start Page: 95End Page: 10

The Use of Cuticular Features in the Taxonomy of the Lauraceae

Volume: 83Start Page: 419End Page: 43

Advanced practice: a survey of current perspectives of Australian pharmacists

Background: An Advanced Pharmacy Practice Framework for Australia (the 'APPF') was published in October 2012. Further to the release of theAPPF, the Advanced Pharmacy Practice Framework Steering Committee planned to develop an advanced practice recognition model forAustralian pharmacists.Aim: To gauge the perspectives of the pharmacy profession relating to advanced practice, via an online survey, in order to inform the design of the model.Method: A survey was developed and administered to Australian pharmacists through SurveyMonkey. The survey content was based on findings from a review of national and international initiatives for recognition of advanced practice in pharmacy and other health disciplines, including medicine and nursing.Results: The results of the survey showed that a high proportion of respondents considered they were already working at, or working towards achieving, an advanced level of practice. The responses relating to the assessment methods showed a clear preference for 'sub-mission of a professional portfolio'.A'written examination' had a low level of support and in relation to an 'oral examination by a panel'there was a marked preference for a panel of multidisciplinary health professionals over a panel of pharmacists.Conclusion: The survey outcomes will inform the development of an advanced pharmacy practice recognition model for Australian pharmacists, particularly in relation to the assessment methods. Survey outcomes also demonstrated that there is scope to further enhance theapplication of the APPF in the development and recognition of advanced practitioners, and to build greater awareness of the breadth ofcompetencies encompassed by 'advanced practice'

Biochemical markers of bone metabolism in growing thoroughbreds: a longitudinal study

Repetitive processes are characterized by a~series of sweeps, termed passes, through a set of dynamics defined over a finite duration known as the pass length. On each pass an output, termed the pass profile, is produced which acts as a forcing function on, and hence contributes to, the dynamics of the next pass profile. This can lead to oscillations which increase in amplitude in the pass to pass direction and cannot be controlled by standard control laws. Here we give new results on the design of physically based control laws for the sub-class of so-called discrete linear repetitive processes which arise in applications areas such as iterative learning control. The main contribution is to show how control law design can be undertaken within the framework of a general robust filtering problem with guaranteed levels of performance. In particular, we develop algorithms for the design of an and l 2–l 8 dynamic output feedback controller and filter which guarantees that the resulting controlled (filtering error) process, respectively, is stable along the pass and has prescribed disturbance attenuation performance as measured by and l 2–l 8 norms