Health-related quality of life in Huntington’s Disease patients: a comparison of proxy assessment and patient self-rating using the disease-specific Huntington’s Disease health-related quality of life questionnaire (HDQoL)

Huntington’s disease (HD) is a fatal, neurodegenerative disease for which there is no known cure. Proxy evaluation is relevant for HD as its manifestation might limit the ability of persons to report their health-related quality of life (HrQoL). This study explored patient–proxy ratings of HrQoL of persons at different stages of HD, and examined factors that may affect proxy ratings. A total of 105 patient–proxy pairs completed the Huntington’s disease health-related quality of life questionnaire (HDQoL) and other established HrQoL measures (EQ-5D and SF-12v2). Proxy–patient agreement was assessed in terms of absolute level (mean ratings) and intraclass correlation. Proxies’ ratings were at a similar level to patients’ self-ratings on an overall Summary Score and on most of the six Specific Scales of the HDQoL. On the Specific Hopes and Worries Scale, proxies on average rated HrQoL as better than patients’ self-ratings, while on both the Specific Cognitive Scale and Specific Physical and Functional Scale proxies tended to rate HrQoL more poorly than patients themselves. The patient’s disease stage and mental wellbeing (SF-12 Mental Component scale) were the two factors that primarily affected proxy assessment. Proxy scores were strongly correlated with patients’ self-ratings of HrQoL, on the Summary Scale and all Specific Scales. The patient–proxy correlation was lower for patients at moderate stages of HD compared to patients at early and advanced stages. The proxy report version of the HDQoL is a useful complementary tool to self-assessment, and a promising alternative when individual patients with advanced HD are unable to self-report.

Ballet-Granite

Live Performance, Szuper Gallery + Curtain Razors Dur: 50 mins NTSC HD 2011 Direction/Conception - Susanne Clausen, Pavlo Kerestey, Michele Sereda Performance Installation - Susanne Clausen, Pavlo Kerestey Performers - Jason Cawood, Susanne Clausen, Blair Fornwald, Morgan Garneau, John Hampton, Pavlo Kerestey, Michele Sereda Cave Video - Susanne Clausen and Pavlo Kerestey Sound scape - Szuper Gallery Voice - Michele Sereda Ballet Band - Billy Hughes, Trent Mailander and Otis Young Music - Dance of the Spirits - Danilo Villalta Technical Direction - Kenneth Young Stage Management - Paul Crepeau Sound Support - Jeff Morton Structural Design Consultant - James Phillips and Caragana Production Design Inc Set Assistants - Rebbeca Donison and Shelby Lowe Headress - Alla Sidorenko Costume consultation - Dean Renwick Documentation, Still - Carey Shaw, Szuper Gallery Documentation, Moving - Gabriel Yahyahkeekoot Administration + PR - Carey Shaw and the Mackenzie Art Gallery Poster Design - Rio Saxon Design Produced by Curtain Razors and Szuper Gallery in collaboration with the Mackenzie Art Gallery with the support of the Canada Council for the Arts, the Saskatchewan Arts Board and the City of Regina Arts Advisory Committee.

The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington's disease

Huntingtin (Htt) protein interacts with many transcriptional regulators, with widespread disruption to the transcriptome in Huntington's disease (HD) brought about by altered interactions with the mutant Htt (muHtt) protein. Repressor Element-1 Silencing Transcription Factor (REST) is a repressor whose association with Htt in the cytoplasm is disrupted in HD, leading to increased nuclear REST and concomitant repression of several neuronal-specific genes, including brain-derived neurotrophic factor (Bdnf). Here, we explored a wide set of HD dysregulated genes to identify direct REST targets whose expression is altered in a cellular model of HD but that can be rescued by knock-down of REST activity. We found many direct REST target genes encoding proteins important for nervous system development, including a cohort involved in synaptic transmission, at least two of which can be rescued at the protein level by REST knock-down. We also identified several microRNAs (miRNAs) whose aberrant repression is directly mediated by REST, including miR-137, which has not previously been shown to be a direct REST target in mouse. These data provide evidence of the contribution of inappropriate REST-mediated transcriptional repression to the widespread changes in coding and non-coding gene expression in a cellular model of HD that may affect normal neuronal function and survival.

Rescue of gene expression by modified REST decoy oligonucleotides in a cellular model of Huntington's disease

Transcriptional dysfunction is a prominent hallmark of Huntington's disease (HD). Several transcription factors have been implicated in the aetiology of HD progression and one of the most prominent is repressor element 1 (RE1) silencing transcription factor (REST). REST is a global repressor of neuronal gene expression and in the presence of mutant Huntingtin increased nuclear REST levels lead to elevated RE1 occupancy and a concomitant increase in target gene repression, including brain-derived neurotrophic factor. It is of great interest to devise strategies to reverse transcriptional dysregulation caused by increased nuclear REST and determine the consequences in HD. Thus far, such strategies have involved RNAi or mutant REST constructs. Decoys are double-stranded oligodeoxynucleotides corresponding to the DNA-binding element of a transcription factor and act to sequester it, thereby abrogating its transcriptional activity. Here, we report the use of a novel decoy strategy to rescue REST target gene expression in a cellular model of HD. We show that delivery of the decoy in cells expressing mutant Huntingtin leads to its specific interaction with REST, a reduction in REST occupancy of RE1s and rescue of target gene expression, including Bdnf. These data point to an alternative strategy for rebalancing the transcriptional dysregulation in HD.

The role of REST in transcriptional and epigenetic dysregulation in Huntington's disease

Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation. Although many transcriptional regulatory molecules have been implicated in the pathogenesis of HD, a growing body of evidence points to the pivotal role of RE1 Silencing Transcription Factor (REST). In HD, REST, translocates from the cytoplasm to the nucleus in neurons resulting in repression of key target genes such as BDNF. Since these original observations, several thousand direct target genes of REST have been identified, including numerous non-coding RNAs including both microRNAs and long non-coding RNAs, several of which are dysregulated in HD. More recently, evidence is emerging that hints at epigenetic abnormalities in HD brain. This in turn, promotes the notion that targeting the epigenetic machinery may be a useful strategy for treatment of some aspects of HD. REST also recruits a host of histone and chromatin modifying activities that can regulate the local epigenetic signature at REST target genes. Collectively, these observations present REST as a hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in HD. We identify several spokes emanating from this REST hub that may represent useful sites to redress REST dysfunction in HD.

Transcriptional dysregulation of coding and non-coding genes in cellular models of Huntington's disease

HD (Huntington's disease) is a late onset heritable neurodegenerative disorder that is characterized by neuronal dysfunction and death, particularly in the cerebral cortex and medium spiny neurons of the striatum. This is followed by progressive chorea, dementia and emotional dysfunction, eventually resulting in death. HD is caused by an expanded CAG repeat in the first exon of the HD gene that results in an abnormally elongated polyQ (polyglutamine) tract in its protein product, Htt (Huntingtin). Wild-type Htt is largely cytoplasmic; however, in HD, proteolytic N-terminal fragments of Htt form insoluble deposits in both the cytoplasm and nucleus, provoking the idea that mutHtt (mutant Htt) causes transcriptional dysfunction. While a number of specific transcription factors and co-factors have been proposed as mediators of mutHtt toxicity, the causal relationship between these Htt/transcription factor interactions and HD pathology remains unknown. Previous work has highlighted REST [RE1 (repressor element 1)-silencing transcription factor] as one such transcription factor. REST is a master regulator of neuronal genes, repressing their expression. Many of its direct target genes are known or suspected to have a role in HD pathogenesis, including BDNF (brain-derived neurotrophic factor). Recent evidence has also shown that REST regulates transcription of regulatory miRNAs (microRNAs), many of which are known to regulate neuronal gene expression and are dysregulated in HD. Thus repression of miRNAs constitutes a second, indirect mechanism by which REST can alter the neuronal transcriptome in HD. We will describe the evidence that disruption to the REST regulon brought about by a loss of interaction between REST and mutHtt may be a key contributory factor in the widespread dysregulation of gene expression in HD.

The look: style, technology and televisuality in the New Who

This chapter explores the distinctive qualities of the Matt Smith era Doctor Who, focusing on how dramatic emphases are connected with emphases on visual style, and how this depends on the programme's production methods and technologies. Doctor Who was first made in the 1960s era of live, studio-based, multi-camera television with monochrome pictures. However, as technical innovations like colour filming, stereo sound, CGI and post-production effects technology have been routinely introduced into the programme, and now High Definition (HD) cameras, they have given Doctor Who’s creators new ways of making visually distinctive narratives. Indeed, it has been argued that since the 1980s television drama has become increasingly like cinema in its production methods and aesthetic aims. Viewers’ ability to view the programme on high-specification TV sets, and to record and repeat episodes using digital media, also encourage attention to visual style in television as much as in cinema. The chapter evaluates how these new circumstances affect what Doctor Who has become and engages with arguments that visual style has been allowed to override characterisation and story in the current Doctor Who. The chapter refers to specific episodes, and frames the analysis with reference to earlier years in Doctor Who’s long history. For example, visual spectacle using green-screen and CGI can function as a set-piece (at the opening or ending of an episode) but can also work ‘invisibly’ to render a setting realistically. Shooting on location using HD cameras provides a rich and detailed image texture, but also highlights mistakes and especially problems of lighting. The reduction of Doctor Who’s budget has led to Steven Moffat’s episodes relying less on visual extravagance, connecting back both to Russell T. Davies’s concern to show off the BBC’s investment in the series but also to reference British traditions of gritty and intimate social drama. Pressures to capitalise on Doctor Who as a branded product are the final aspect of the chapter’s analysis, where the role of Moffat as ‘showrunner’ links him to an American (not British) style of television production where the preservation of format and brand values give him unusual power over the look of the series.

Using lexical diversity measures to operationalise language dominance in bilinguals

Treffers-Daller and Korybski propose to operationalize language dominance on the basis of measures of lexical diversity, as computed, in this particular study, on transcripts of stories told by Polish-English bilinguals in each of their languages They compute four different Indices of Language Dominance (ILD) on the basis of two different measures of lexical diversity, the Index of Guiraud (Guiraud, 1954) and HD-D (McCarthy & Jarvis, 2007). They compare simple indices, which are based on subtracting scores from one language from scores for another language, to more complex indices based on the formula Birdsong borrowed from the field of handedness, namely the ratio of (Difference in Scores) / (Sum of Scores). Positive scores on each of these Indices of Language Dominance mean that informants are more English-dominant and negative scores that they are more Polish-dominant. The authors address the difficulty of comparing scores across languages by carefully lemmatizing the data. Following Flege, Mackay and Piske (2002) they also look into the validity of these indices by investigating to what extent they can predict scores on other, independently measured variables. They use correlations and regression analysis for this, which has the advantage that the dominance indices are used as continuous variables and arbitrary cut-off points between balanced and dominant bilinguals need not be chosen. However, they also show how the computation of z-scores can help facilitate a discussion about the appropriateness of different cut-off points across different data sets and measurement scales in those cases where researchers consider it necessary to make categorial distinctions between balanced and dominant bilinguals. Treffers-Daller and Korybski correlate the ILD scores with four other variables, namely Length of Residence in the UK, attitudes towards English and life in the UK, frequency of usage of English at home and frequency of code-switching. They found that the indices correlated significantly with most of these variables, but there were clear differences between the Guiraud-based indices and the HDD-based indices. In a regression analysis three of the measures were also found to be a significant predictor of English language usage at home. They conclude that the correlations and the regression analyses lend strong support to the validity of their approach to language dominance.

Regionally coupled atmosphere-ocean-sea ice-marine biogeochemistry model ROM: 1. Description and validation

The general circulation models used to simulate global climate typically feature resolution too coarse to reproduce many smaller-scale processes, which are crucial to determining the regional responses to climate change. A novel approach to downscale climate change scenarios is presented which includes the interactions between the North Atlantic Ocean and the European shelves as well as their impact on the North Atlantic and European climate. The goal of this paper is to introduce the global ocean-regional atmosphere coupling concept and to show the potential benefits of this model system to simulate present-day climate. A global ocean-sea ice-marine biogeochemistry model (MPIOM/HAMOCC) with regionally high horizontal resolution is coupled to an atmospheric regional model (REMO) and global terrestrial hydrology model (HD) via the OASIS coupler. Moreover, results obtained with ROM using NCEP/NCAR reanalysis and ECHAM5/MPIOM CMIP3 historical simulations as boundary conditions are presented and discussed for the North Atlantic and North European region. The validation of all the model components, i.e., ocean, atmosphere, terrestrial hydrology, and ocean biogeochemistry is performed and discussed. The careful and detailed validation of ROM provides evidence that the proposed model system improves the simulation of many aspects of the regional climate, remarkably the ocean, even though some biases persist in other model components, thus leaving potential for future improvement. We conclude that ROM is a powerful tool to estimate possible impacts of climate change on the regional scale.

Back to basics: how measures of lexical diversity can help discriminate between CEFR levels

This study contributes to ongoing discussions on how measures of lexical diversity (LD) can help discriminate between essays from second language learners of English, whose work has been assessed as belonging to levels B1 to C2 of the Common European Framework of Reference (CEFR). The focus is in particular on how different operationalisations of what constitutes a “different word” (type) impact on the LD measures themselves and on their ability to discriminate between CEFR levels. The results show that basic measures of LD, such as the number of different words, the TTR (Templin 1957) and the Index of Guiraud (Guiraud 1954) explain more variance in the CEFR levels than sophisticated measures, such as D (Malvern et al. 2004), HD-D (McCarthy and Jarvis 2007) and MTLD (McCarthy 2005) provided text length is kept constant across texts. A simple count of different words (defined as lemma’s and not as word families) was the best predictor of CEFR levels and explained 22 percent of the variance in overall scores on the Pearson Test of English Academic in essays written by 176 test takers.

Epstein-Barr virus: clinical and epidemiological revisits and genetic basis of oncogenesis

Epstein-Barr virus (EBV) is classified as a member in the order herpesvirales, family herpesviridae, subfamily gammaherpesvirinae and the genus lymphocytovirus. The virus is an exclusively human pathogen and thus also termed as human herpesvirus 4 (HHV4). It was the first oncogenic virus recognized and has been incriminated in the causation of tumors of both lymphatic and epithelial nature. It was reported in some previous studies that 95% of the population worldwide are serologically positive to the virus. Clinically, EBV primary infection is almost silent, persisting as a life-long asymptomatic latent infection in B cells although it may be responsible for a transient clinical syndrome called infectious mononucleosis. Following reactivation of the virus from latency due to immunocompromised status, EBV was found to be associated with several tumors. EBV linked to oncogenesis as detected in lymphoid tumors such as Burkitt's lymphoma (BL), Hodgkin's disease (HD), post-transplant lymphoproliferative disorders (PTLD) and T-cell lymphomas (e.g. Peripheral T-cell lymphomas; PTCL and Anaplastic large cell lymphomas; ALCL). It is also linked to epithelial tumors such as nasopharyngeal carcinoma (NPC), gastric carcinomas and oral hairy leukoplakia (OHL). In vitro, EBV many studies have demonstrated its ability to transform B cells into lymphoblastoid cell lines (LCLs). Despite these malignancies showing different clinical and epidemiological patterns when studied, genetic studies have suggested that these EBV- associated transformations were characterized generally by low level of virus gene expression with only the latent virus proteins (LVPs) upregulated in both tumors and LCLs. In this review, we summarize some clinical and epidemiological features of EBV- associated tumors. We also discuss how EBV latent genes may lead to oncogenesis in the different clinical malignancies

Study of some physical properties of biodegradable films based on blends of gelatin and poly(vinyl alcohol) using a response-surface methodology

The aim of this work was to study the effect of the hydrolysis degree (HD) and the concentration (C(PVA)) Of two types of poly(vinyl alcohol) (PVA) and of the type (glycerol and sorbitol) and the concentration (C(P)) of plasticizers on some physical properties of biodegradable films based on blends of gelatin and PVA Using a response-surface methodology. The films were prepared with a film forming solutions (FFS) with 2 g of macromolecules (gelatin+PVA)/100 g de FFS. The responses analyzed were the mechanical properties, the solubility, the moisture Content. the color difference and the opacity. The linear model was statistically significant and predictive for puncture force and deformation. elongation at break, solubility in water, Moisture content and opacity. The CPVA affected strongly the elongation at break of the films. The interaction of the HD and the C(P) affected this property. Moreover. the puncture force was affected slightly by the C(PVA). Concerning the Solubility in water, the reduction of the HD increased it and this effect was greater for high CPVA Values. In general. the most important effect observed in the physical properties of the films was that of the plasticizer type and concentration. The PVA hydrolysis degree and concentration have an important effect only for the elongation at break, puncture deformation and solubility in water. (C) 2008 Elsevier B.V. All rights reserved.

Reliability of orbital fits for resonant extrasolar planetary systems: the case of HD82943

We perform a statistical study of the process of orbital determination of the HD82943 extrasolar planetary system, using the current observational data set of N = 165 radial velocity (RV) measurements. Our aim is to analyse the dispersion of possible orbital fits leading to residuals compatible with the best solution, and to discuss the sensitivity of the results with respect to both the data set and the error distribution around the best fit. Although some orbital parameters (e.g. semimajor axis) appear well constrained, we show that the best fits for the HD82943 system are not robust, and at present it is not possible to estimate reliable solutions for these bodies. Finally, we discuss the possibility of a third planet, with a mass of 0.35M(Jup) and an orbital period of 900 d. Stability analysis and simulations of planetary migration indicate that such a hypothetical three-planet system could be locked in a double 2/1 mean-motion resonance, similar to the so-called Laplace resonance of the three inner Galilean satellites of Jupiter.

Exoplanet discoveries with the CoRoT space observatory

The CoRoT space observatory is a project which is led by the French space agency CNES and leading space research institutes in Austria, Brazil, Belgium, Germany and Spain and also the European Space Agency ESA. CoRoT observed since its launch in December 27, 2006 about 100 000 stars for the exoplanet channel, during 150 days uninterrupted high-precision photometry. Since the The CoRoT-team has several exoplanet candidates which are currently analyzed under its study, we report here the discoveries of nine exoplanets which were observed by CoRoT. Discovered exoplanets such as CoRoT-3b populate the brown dwarf desert and close the gap of measured physical properties between usual gas giants and very low mass stars. CoRoT discoveries extended the known range of planet masses down to about 4.8 Earth-masses (CoRoT-7b) and up to 21 Jupiter masses (CoRoT-3b), the radii to about 1.68 x 0.09 R (Earth) (CoRoT-7b) and up to the most inflated hot Jupiter with 1.49 x 0.09 R (Earth) found so far (CoRoT-1b), and the transiting exoplanet with the longest period of 95.274 days (CoRoT-9b). Giant exoplanets have been detected at low metallicity, rapidly rotating and active, spotted stars. Two CoRoT planets have host stars with the lowest content of heavy elements known to show a transit hinting towards a different planethost-star-metallicity relation then the one found by radial-velocity search programs. Finally the properties of the CoRoT-7b prove that rocky planets with a density close to Earth exist outside the Solar System. Finally the detection of the secondary transit of CoRoT-1b at a sensitivity level of 10(-5) and the very clear detection of the ""super-Earth"" CoRoT-7b at 3.5 x 10(-4) relative flux are promising evidence that the space observatory is being able to detect even smaller exoplanets with the size of the Earth.