Development of a framework to define the functional goals and outcomes of botulinum toxin A spasticity treatment relevant to the child and family living with cerebral palsy using the International Classification of Functioning, Disability and Health for Children and Youth

Objective: To define a sub-set of functional goals and outcomes relevant to children and families living with cerebral palsy following treatment with botulinum toxin type A using the International Classification of Functioning, Disability and Health for Children and Youth. Methods: We identified treatment goals and treatment outcomes from medical case records in 2102 assessments of 239 children with cerebral palsy treated with botulinum toxin between 1994 and 2009. Goals were set through assessment and discussion by experienced clinicians, therapists, parents and children. Results: There were 61 separate goals, mapping to 40 categories, falling mostly within Body Functions: b710 Mobility of joint functions (414 times); b770 Gait pattern functions (374 times); b7351 Tone of muscles of one limb (117 times). A total of 93 separate treatment outcomes were identified, mapping to 51 categories. Two of the 3 most common outcomes correspond to the 2 most common goals (gait pattern and mobility of joint functions). Conclusion: The International Classification of Functioning, Disability and Health for Children and Youth provides a useful framework to categorize the reasons for using botulinum toxin in children and focuses the clinical consultation not only on impairments but also functional outcomes

Transcription activator like effector (TALE)-directed piggyBac transposition in human cells.

Insertional therapies have shown great potential for combating genetic disease and safer methods would undoubtedly broaden the variety of possible illness that can be treated. A major challenge that remains is reducing the risk of insertional mutagenesis due to random insertion by both viral and non-viral vectors. Targetable nucleases are capable of inducing double-stranded breaks to enhance homologous recombination for the introduction of transgenes at specific sequences. However, off-target DNA cleavages at unknown sites can lead to mutations that are difficult to detect. Alternatively, the piggyBac transposase is able perform all of the steps required for integration; therefore, cells confirmed to contain a single copy of a targeted transposon, for which its location is known, are likely to be devoid of aberrant genomic modifications. We aimed to retarget transposon insertions by comparing a series of novel hyperactive piggyBac constructs tethered to a custom transcription activator like effector DNA-binding domain designed to bind the first intron of the human CCR5 gene. Multiple targeting strategies were evaluated using combinations of both plasmid-DNA and transposase-protein relocalization to the target sequence. We demonstrated user-defined directed transposition to the CCR5 genomic safe harbor and isolated single-copy clones harboring targeted integrations

Antitubercular specific activity of ibuprofen and the other 2-arylpropanoic acids using the HT-SPOTi whole-cell phenotypic assay

Objectives: Lead antituberculosis (anti-TB) molecules with novel mechanisms of action are urgently required to fuel the anti-TB drug discovery pipeline. The aim of this study was to validate the use of the high-throughput spot culture growth inhibition (HT-SPOTi) assay for screening libraries of compounds against Mycobacterium tuberculosis and to study the inhibitory effect of ibuprofen (IBP) and the other 2-arylpropanoic acids on the growth inhibition of M tuberculosis and other mycobacterial species. Methods: The HT-SPOTi method was validated not only with known drugs but also with a library of 47 confirmed anti-TB active compounds published in the ChEMBL database. Three over-the-counter non-steroidal anti-inflammatory drugs were also included in the screening. The 2-arylpropanoic acids, including IBP, were comprehensively evaluated against phenotypically and physiologically different strains of mycobacteria, and their cytotoxicity was determined against murine RAW264.7 macrophages. Furthermore, a comparative bioinformatic analysis was employed to propose a potential mycobacterial target. Results: IBP showed antitubercular properties while carprofen was the most potent among the 2-arylpropanoic class. A 3,5-dinitro-IBP derivative was found to be more potent than IBP but equally selective. Other synthetic derivatives of IBP were less active, and the free carboxylic acid of IBP seems to be essential for its anti-TB activity. IBP, carprofen and the 3,5-dinitro-IBP derivative exhibited activity against multidrug-resistant isolates and stationary phase bacilli. On the basis of the human targets of the 2-arylpropanoic analgesics, the protein initiation factor infB (Rv2839c) of M tuberculosis was proposed as a potential molecular target. Conclusions: The HT-SPOTi method can be employed reliably and reproducibly to screen the antimicrobial potency of different compounds. IBP demonstrated specific antitubercular activity, while carprofen was the most selective agent among the 2-arylpropanoic class. Activity against stationary phase bacilli and multidrug-resistant isolates permits us to speculate a novel mechanism of antimycobacterial action. Further medicinal chemistry and target elucidation studies could potentially lead to new therapies against TB

Nano-formulation of Ethambutol with multifunctional Graphene Oxide and magnetic nanoparticles retains Its anti-tubercular activity with prospects of improving chemotherapeutic efficacy

Tuberculosis (TB) is a dreadful bacterial disease, infecting millions of human and cattle every year worldwide. More than 50 years after its discovery, ethambutol continues to be an effective part of the World Health Organization’s recommended frontline chemotherapy against TB. However, the lengthy treatment regimens consisting of a cocktail of antibiotics affect patient compliance. There is an urgent need to improve the current therapy so as to reduce treatment duration and dosing frequency. In this study, we have designed a novel anti-TB multifunctional formulation by fabricating graphene oxide with iron oxide magnetite nanoparticles serving as a nano-carrier on to which ethambutol was successfully loaded. The designed nanoformulation was characterised using various analytical techniques. The release of ethambutol from anti-TB multifunctional nanoparticles formulation was found to be sustained over a significantly longer period of time in phosphate buffer saline solution at two physiological pH (7.4 and 4.8). Furthermore, the nano-formulation showed potent anti-tubercular activity while remaining non-toxic to the eukaryotic cells tested. The results of this in vitro evaluation of the newly designed nano-formulation endorse its further development in vivo

A System in the Wild: Deploying a Two Player Arm Rehabilitation System for Children With Cerebral Palsy in a School Environment

This paper outlines a system for arm rehabilitation for children with upper-limb hemiplegia resulting from cerebral palsy. Our research team designed a two-player, interactive (competitive or collaborative) computer play therapy system that provided powered assistance to children while they played specially designed games that promoted arm exercises. We designed the system for a school environment. To assess the feasibility of deploying the system in a school environment, the research team enlisted the help of teachers and staff in nine schools. Once the system was set up, it was used to deliver therapy without supervision from the research team. Ultimately, the system was found to be suitable for use in schools. However, the overriding need for schools to focus on academic activities meant that children could not use the system enough to achieve the amount of use desired for therapeutic benefit. In this paper, we identify the key challenges encountered during this study. For example, there was a marked reluctance to report system issues (which could have been fixed) that prevented children from using the system. We also discuss future implications of deploying similar studies with this type of system

An Instrumented Walking-Aid to Assess and Retrain Gait

An instrumented walking-aid, the iWA system, has been developed to measure kinematic and kinetic properties of walking aid (WA) use and deliver feedback to improve gait. The clinical requirements, technical specification and design of the system are developed through clinical collaboration. The development of the system is described, including hardware components and data analysis used to process the measured data for assessment. The system measurements are validated under controlled laboratory conditions. The iWA system is evaluated in a typical UK clinical environment by a participant in a rehabilitation session. The resultant data successfully capture the quality of the participant’s walking aid use and agree with clinical opinion, supporting the efficacy of this approach

New Spirometry Indices for Detecting Mild Airflow Obstruction.

The diagnosis of chronic obstructive pulmonary disease (COPD) relies on demonstration of airflow obstruction. Traditional spirometric indices miss a number of subjects with respiratory symptoms or structural lung disease on imaging. We hypothesized that utilizing all data points on the expiratory spirometry curves to assess their shape will improve detection of mild airflow obstruction and structural lung disease. We analyzed spirometry data of 8307 participants enrolled in the COPDGene study, and derived metrics of airflow obstruction based on the shape on the volume-time (Parameter D), and flow-volume curves (Transition Point and Transition Distance). We tested associations of these parameters with CT measures of lung disease, respiratory morbidity, and mortality using regression analyses. There were significant correlations between FEV1/FVC with Parameter D (r = -0.83; p < 0.001), Transition Point (r = 0.69; p < 0.001), and Transition Distance (r = 0.50; p < 0.001). All metrics had significant associations with emphysema, small airway disease, dyspnea, and respiratory-quality of life (p < 0.001). The highest quartile for Parameter D was independently associated with all-cause mortality (adjusted HR 3.22,95% CI 2.42-4.27; p < 0.001) but a substantial number of participants in the highest quartile were categorized as GOLD 0 and 1 by traditional criteria (1.8% and 33.7%). Parameter D identified an additional 9.5% of participants with mild or non-recognized disease as abnormal with greater burden of structural lung disease compared with controls. The data points on the flow-volume and volume-time curves can be used to derive indices of airflow obstruction that identify additional subjects with disease who are deemed to be normal by traditional criteria

Density Based Traffic Control

The project is aimed at designing a density based dynamic traffic signal system where the timing of signal will change automatically on sensing the traffic density at any junction. Traffic congestion is a severe problem in most cities across the world and therefore it is time to shift more manual mode or fixed timer mode to an automated system with decision making capabilities. Present day traffic signaling system is fixed time based which may render inefficient if one lane is operational than the others. To optimize this problem we have made a framework for an intelligent traffic control system. Sometimes higher traffic density at one side of the junction demands longer green time as compared to standard allotted time We, therefore propose here a mechanism in which the time period of green light and red light is assigned on the basis of the density of the traffic present at that time. This is achieved by using PIR(proximity Infrared sensors). Once the density is calculated, the glowing time of green light is assigned by the help of the microcontroller (Arduino). The sensors which are present on sides of the road will detect the presence of the vehicles and sends the information to the microcontroller where it will decide how long a flank will be open or when to change over the signal lights. In subsequent sections, we have elaborated the procedure of this framework

Clinical Significance of Bronchodilator Responsiveness Evaluated by Forced Vital Capacity in COPD: SPIROMICS Cohort Analysis.

ObjectiveBronchodilator responsiveness (BDR) is prevalent in COPD, but its clinical implications remain unclear. We explored the significance of BDR, defined by post-bronchodilator change in FEV1 (BDRFEV1) as a measure reflecting the change in flow and in FVC (BDRFVC) reflecting the change in volume.MethodsWe analyzed 2974 participants from a multicenter observational study designed to identify varying COPD phenotypes (SPIROMICS). We evaluated the association of BDR with baseline clinical characteristics, rate of prospective exacerbations and mortality using negative binomial regression and Cox proportional hazards models.ResultsA majority of COPD participants exhibited BDR (52.7%). BDRFEV1 occurred more often in earlier stages of COPD, while BDRFVC occurred more frequently in more advanced disease. When defined by increases in either FEV1 or FVC, BDR was associated with a self-reported history of asthma, but not with blood eosinophil counts. BDRFVC was more prevalent in subjects with greater emphysema and small airway disease on CT. In a univariate analysis, BDRFVC was associated with increased exacerbations and mortality, although no significance was found in a model adjusted for post-bronchodilator FEV1.ConclusionWith advanced airflow obstruction in COPD, BDRFVC is more prevalent in comparison to BDRFEV1 and correlates with the extent of emphysema and degree of small airway disease. Since these associations appear to be related to the impairment of FEV1, BDRFVC itself does not define a distinct phenotype nor can it be more predictive of outcomes, but it can offer additional insights into the pathophysiologic mechanism in advanced COPD.Clinical trials registrationClinicalTrials.gov: NCT01969344T4

The impact of negative selection on thymocyte migration in the medulla

Developing thymocytes are screened for self-reactivity before they exit the thymus, but how thymocytes scan the medulla for self antigens is unclear. Using two-photon microscopy, we observed that medullary thymocytes migrated rapidly and made frequent, transient contacts with dendritic cells. In the presence of a negative selecting ligand, thymocytes slowed, became confined to areas of approximately 30 mum in diameter and had increased contact with dendritic cells surrounding confinement zones. One third of polyclonal medullary thymocytes also showed confined, slower migration and may correspond to autoreactive thymocytes. Our data suggest that many autoreactive thymocytes do not undergo immediate arrest and death after encountering a negative selecting ligand but instead adopt an altered migration program while remaining in the medullary microenvironment