The efficacy of SMART Arm training early after stroke for stroke survivors with severe upper limb disability:a protocol for a randomised controlled trial

Recovery of upper limb function after stroke is poor. The acute to subacute phase after stroke is the optimal time window to promote the recovery of upper limb function. The dose and content of training provided conventionally during this phase is however, unlikely to be adequate to drive functional recovery, especially in the presence of severe motor disability. The current study concerns an approach to address this shortcoming, through evaluation of the SMART Arm, a non-robotic device that enables intensive and repetitive practice of reaching by stroke survivors with severe upper limb disability, with the aim of improving upper limb function. The outcomes of SMART Arm training with or without outcome-triggered electrical stimulation (OT-stim) to augment movement and usual therapy will be compared to usual therapy alone.

Regulation of apoptotic protease activating factor-1 oligomerization and apoptosis by the WD-40 repeat region

Apoptotic protease activating factor-1 (Apaf-1) has been identified as a proximal activator of caspase-9 in cell death pathways that trigger mitochondrial damage and cytochrome c release. The mechanism of Apaf-1 action is unclear but has been proposed to involve the clustering of caspase-9 molecules, thereby facilitating autoprocessing of adjacent zymogens. Here we show that Apaf-1 can dimerize via the CED-4 homologous and linker domains of the molecule providing a means by which Apaf-1 can promote the clustering of caspase-9 and facilitate its activation. Apaf-1 dimerization was repressed by the C-terminal half of the molecule, which contains multiple WD-40 repeats, but this repression was overcome in the presence of cytochrome c and dATP. Removal of the WD-40 repeat region resulted in a constitutively active Apaf-1 that exhibited greater cytotoxicity in transient transfection assays when compared with full-length Apaf-1. These data suggest a mechanism for Apaf-1 function and reveal an important regulatory role for the WD-40 repeat region.

Women Speaking of National Security: The Case of Checkpoint Watch

The production of reports and the distribution of information have become integral to the operation of many non-governmental organizations. In this regard, the fact that the all-women organization of Checkpoint Watch publishes reports about the Israeli checkpoints in the occupied West Bank seems to comply with current trends. However, the reports—most of which are short repetitive descriptions of the banality and everydayness of the military checkpoints, counting the number of people and cars waiting, commenting on the manner in which the checks are performed and meticulously documenting what mostly amounts to minor incidents of humiliation and distress—do not seem to abide by any convention of reporting. This work analyzes the reporting praxis of the organization and claims that it should be understood as a form of activism in and of itself. Tracking the ways in which the reports address the Israeli public through the concept of parrhesia, the work suggests that this form of reporting enables the women activists to use their gendered marginality to make their way into the highly masculinized and militarized Israeli security discourse.

The relationship between specific cognitive impairment and behaviour in Prader-Willi syndrome

Background

Individuals with Prader-Willi syndrome (PWS) have been shown to demonstrate a particular cognitive deficit in attention switching and high levels of preference for routine and temper outbursts. This study assesses whether a specific pathway between a cognitive deficit and behaviour via environmental interaction can exist in individuals with PWS.

Methods

Four individuals with PWS participated in a series of three single-case experiments including laboratory-based and natural environment designs. Cognitive (computer-based) challenges placed varying demands on attention switching or controlled for the cognitive demands of the tasks while placing no demands on switching. Unexpected changes to routines or expectations were presented in controlled games, or imposed on participants' natural environments and compared with control conditions during which no unexpected changes occurred. Behaviour was observed and heart rate was measured.

Results

Participants showed significantly increased temper outburst related behaviours during cognitive challenges that placed demands on attention switching, relative to the control cognitive challenges. Participants showed significantly increased temper outburst related behaviours when unexpected changes occurred in an experimental or the natural environment compared with when no changes occurred.

Conclusions

Difficult behaviours that could be triggered reliably in an individual by a specific cognitive demand could also be triggered via manipulation of the environment. Results suggest that a directional relationship between a specific cognitive deficit and behaviour, via environmental interaction, can exist in individuals with PWS.

Neural correlates of task switching in paternal 15q11-q13 deletion Prader-Willi syndrome

We report a first study of brain activity linked to task switching in individuals with Prader-Willi syndrome (PWS) PWS individuals show a specific cognitive deficit in task switching which may be associated with the display of temper outbursts and repetitive questioning The performance of participants with PWS and typically developing controls was matched in a cued task switching procedure and brain activity was contrasted on switching and non switching blocks using SARI Individuals with PWS did not show the typical frontal-parietal pattern of neural activity associated with switching blocks, with significantly reduced activation in regions of the posterior parietal and ventromedial prefrontal cortices We suggest that this is linked to a difficulty in PWS in setting appropriate attentional weights to enable task set reconfiguration In addition to this, PWS individuals did not show the typical pattern of deactivation, with significantly less deactivation in an anterior region of the ventromedial prefrontal cortex One plausible explanation for this is that individuals with PWS show dysfunction within the default mode network which has been linked to attentional control The data point to functional changes in the neural circuitry supporting task switching in PWS even when behavioural performance is matched to controls and thus highlight neural mechanisms that may be involved in a specific pathway between genes cognition and behaviour (C) 2010 Elsevier B V All rights reserved

The Relationship between Components of the Behavioural Phenotype in Prader-Willi Syndrome

Background

Repetitive questions and temper outbursts form part of the behavioural phenotype of Prader-Willi syndrome (PWS). We investigated the phenomenology of temper outbursts in PWS and their relationship with other PWS behavioural characteristics.

Method

Four individuals with PWS were observed (5-10 h), during a number of experimental and natural environment challenges, some of which were expected to trigger temper outbursts. Individual behaviours including crying, ignoring, arguing, questioning, stereotypy, frowning and posture changes were recorded and subjected to lag sequential analysis.

Results

All participants were significantly more likely to show repetitive questioning before more challenging behaviours such as crying, arguing or ignoring requests. Precursor behaviours such as frowning and stereotypical behaviour were identified in three participants.

Conclusions

Temper outbursts in PWS may be associated with other PWS behavioural phenotypic characteristics such as repetitive questions and 'stubbornness'. A progression of behaviours may lead up to the most challenging temper outburst behaviours. This may have important implications for effective coping strategies.

A specific pathway can be identified between genetic characteristics and behaviour profiles in Prader-Willi syndrome via cognitive, environmental and physiological mechanisms

Behavioural phenotypes associated with genetic syndromes have been extensively investigated in order to generate rich descriptions of phenomenology, determine the degree of specificity of behaviours for a particular syndrome, and examine potential interactions between genetic predispositions for behaviour and environmental influences. However, relationships between different aspects of behavioural phenotypes have been less frequently researched and although recent interest in potential cognitive phenotypes or endophenotypes has increased, these are frequently studied independently of the behavioural phenotypes.

Taking Prader-Willi syndrome (PWS) as an example, we discuss evidence suggesting specific relationships between apparently distinct aspects of the PWS behavioural phenotype and relate these to specific endophenotypic characteristics.

The framework we describe progresses through biological, cognitive, physiological and behavioural levels to develop a pathway from genetic characteristics to behaviour with scope for interaction with the environment at any stage.

We propose this multilevel approach as useful in setting out hypotheses in order to structure research that can more rapidly advance theory.

Prospective clinical audit of chloral hydrate administration practices in a neonatal unit

Aim: Chloral hydrate is generally considered a safe and effective single dosing procedural sedative for neonates in the clinical setting. However, its safety profile as a repetitive dosing maintenance sedative is largely unknown. This study aimed to document current administration practices of chloral hydrate in the Neonatal Unit, Royal Children's Hospital, Melbourne, Australia, over a 6-month period.

Methods: Patients who had been prescribed chloral hydrate during the specified audit period were recruited into the study and prospectively followed for a period of 28 days, or until they were discharged from the unit. Demographic data were collected on recruitment, and daily documentation of chloral hydrate administration was recorded.

Results: A total of 238 doses of chloral hydrate were administered to a cohort of 32 patients during the study period. The majority of the audited doses (84%) were ordered as repeating doses. Doses were more likely to be given at night than during the day, and the median dosage for repetitive dosing was found to be above the study site's recommended dosing range. Pre-dose and/or post-dose assessment of distress/agitation accompanied dosage approximately half of the time. The audit did not reveal any recognisable pattern of sedation maintenance or weaning process for patients who received multiple doses.

Conclusions: Health-care professionals caring for hospitalised infants should be made aware of the potential risks of chloral hydrate as a repetitive dosing sedative, and of the importance of systematically evaluating the appropriateness and effectiveness of utilising such pharmacological intervention for managing and treating distress.

Defining Simulation Intent

Defining Simulation Intent involves capturing high level modelling and idealisation decisions in order to create an efficient and fit-for-purpose analysis. These decisions are recorded as attributes of the decomposed design space.

An approach to defining Simulation Intent is described utilising three known technologies: Cellular Modelling, the subdivision of space into volumes of simulation significance (structures, gas paths, internal and external airflows etc.); Equivalencing, maintaining a consistent and coherent description
of the equivalent representations of the spatial cells in different analysis models; and Virtual Topology, which offers tools for partitioning and de-partitioning the model without disturbing the manufacturing oriented design geometry. The end result is a convenient framework to which high level analysis attributes can be applied, and from which detailed analysis models can be generated
with a high degree of controllability, repeatability and automation. There are multiple novel aspects to the approach, including its reusability, robustness to changes in model topology and the inherent links created between analysis models at different levels of fidelity and physics.

By utilising Simulation Intent, CAD modelling for simulation can be fully exploited and simulation work-flows can be more readily automated, reducing many repetitive manual tasks (e.g. the definition of appropriate coupling between elements of different types and the application of boundary conditions). The approach has been implemented and tested with practical examples, and
significant benefits are demonstrated.

Evidence-based management and intervention for autism spectrum disorders

Autism Spectrum Disorder (ASD) is diagnosed along a continuum of behavioural variants in social communication and repetitive behaviours [96]. Most individuals on the autism spectrum also experience differences in sensory perception. Some individuals on the spectrum are ‘high-functioning’ and able to cope in every day environments, while others are severely affected, non-verbal, and may have co-occurring diagnoses, such as intellectual disability, epilepsy, and/or obsessional, conduct, or mental health disorders. These individuals require substantial support, caring and careful management, and evidence-based, effective interventions.

A conserved spider silk domain acts as a molecular switch that controls fibre assembly

A huge variety of proteins are able to form fibrillar structures(1), especially at high protein concentrations. Hence, it is surprising that spider silk proteins can be stored in a soluble form at high concentrations and transformed into extremely stable fibres on demand(2,3). Silk proteins are reminiscent of amphiphilic block copolymers containing stretches of polyalanine and glycine-rich polar elements forming a repetitive core flanked by highly conserved non-repetitive amino-terminal(4,5) and carboxy-terminal(6) domains. The N-terminal domain comprises a secretion signal, but further functions remain unassigned. The C-terminal domain was implicated in the control of solubility and fibre formation(7) initiated by changes in ionic composition(8,9) and mechanical stimuli known to align the repetitive sequence elements and promote beta-sheet formation(10-14). However, despite recent structural data(15), little is known about this remarkable behaviour in molecular detail. Here we present the solution structure of the C-terminal domain of a spider dragline silk protein and provide evidence that the structural state of this domain is essential for controlled switching between the storage and assembly forms of silk proteins. In addition, the C-terminal domain also has a role in the alignment of secondary structural features formed by the repetitive elements in the backbone of spider silk proteins, which is known to be important for the mechanical properties of the fibre.

High-throughput single-nucleotide polymorphism-based typing of shared Pseudomonas aeruginosa strains in cystic fibrosis patients using the Sequenom iPLEX platform

Shared strains of Pseudomonas aeruginosa are now well recognized in people with cystic fibrosis (CF), and suitable P. aeruginosa laboratory typing tools are pivotal to understanding their clinical significance and guiding infection control policies in CF clinics. We therefore compared a single-nucleotide polymorphism (SNP)-based typing method using Sequenom iPLEX matrix-assisted laser desorption ionization with time-of-flight mass spectrometry (MALDI-TOF MS) with typing methods used routinely by our laboratory. We analysed 617 P. aeruginosa isolates that included 561 isolates from CF patients collected between 2001 and 2009 in two Brisbane CF clinics and typed previously by enterobacterial repetitive intergenic consensus (ERIC)-PCR, as well as 56 isolates from non-CF patients analysed previously by multilocus sequence typing (MLST). The isolates were tested using a P. aeruginosa Sequenom iPLEX MALDI-TOF (PA iPLEX) method comprising two multiplex reactions, a 13-plex and an 8-plex, to characterize 20 SNPs from the P. aeruginosa housekeeping genes acsA, aroE, guaA, mutL, nuoD, ppsA and trpE. These 20 SNPs were employed previously in a real-time format involving 20 separate assays in our laboratory. The SNP analysis revealed 121 different SNP profiles for the 561 CF isolates. Overall, there was at least 96% agreement between the ERIC-PCR and SNP analyses for all predominant shared strains among patients attending our CF clinics: AUST-01, AUST-02 and AUST-06. For the less frequently encountered shared strain AUST-07, 6/25 (24%) ERIC-PCR profiles were misidentified initially as AUST-02 or as unique, illustrating the difficulty of gel-based analyses. SNP results for the 56 non-CF isolates were consistent with previous MLST data. Thus, the PA iPLEX format provides an attractive high-throughput alternative to ERIC-PCR for large-scale investigations of shared P. aeruginosa strains.

Shared Pseudomonas aeruginosa genotypes are common in Australian cystic fibrosis centres

Recent molecular-typing studies suggest cross-infection as one of the potential acquisition pathways for Pseudomonas aeruginosa in patients with cystic fibrosis (CF). In Australia, there is only limited evidence of unrelated patients sharing indistinguishable P. aeruginosa strains. We therefore examined the point-prevalence, distribution, diversity and clinical impact of P. aeruginosa strains in Australian CF patients nationally. 983 patients attending 18 Australian CF centres provided 2887 sputum P. aeruginosa isolates for genotyping by enterobacterial repetitive intergenic consensus-PCR assays with confirmation by multilocus sequence typing. Demographic and clinical details were recorded for each participant. Overall, 610 (62%) patients harboured at least one of 38 shared genotypes. Most shared strains were in small patient clusters from a limited number of centres. However, the two predominant genotypes, AUST-01 and AUST-02, were widely dispersed, being detected in 220 (22%) and 173 (18%) patients attending 17 and 16 centres, respectively. AUST-01 was associated with significantly greater treatment requirements than unique P. aeruginosa strains. Multiple clusters of shared P. aeruginosa strains are common in Australian CF centres. At least one of the predominant and widespread genotypes is associated with increased healthcare utilisation. Longitudinal studies are now needed to determine the infection control implications of these findings.

Clonal complex Pseudomonas aeruginosa in horses

Pseudomonas aeruginosa is associated with infectious endometritis in horses. Although infectious endometritis is often considered a venereal infection, there is relatively limited genotypic-based evidence to support this mode of transmission. The study sought to determine the relatedness between genital P. aeruginosa isolates collected from a limited geographical region using molecular strain typing. Enterobacterial repetitive intergenic consensus PCR typing was performed on 93 isolates collected between 2005 and 2009 from 2058 thoroughbred horses (including 18 stallions) at 66 studs. While P. aeruginosa was not detected in the stallions, 53/93 (57%) mares harbouring P. aeruginosa had clonally related strains, which included a single dominant genotype detected in 42 (45%) mares from 13 different studs. These novel findings suggest that most equine genital P. aeruginosa infections in this region may have been acquired from mechanisms other than direct horse to horse transmission. Instead, other potential acquisition pathways, as well as strain specific adaptation to the equine genital tract, should be investigated.