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The adequate distribution of STI-571 (Gleevec) to the central nervous system (CNS) is critical for its effective use in CNS tumors. P-glycoprotein-mediated efflux in the blood-brain barrier may play a role in the CNS delivery of this drug. Whether STI-571 is a substrate of P-glycoprotein was determined by examining the directional flux of [(14)C]STI-571 in parental and MDR1-transfected Madin-Darby canine kidney (MDCK) II epithelial cell monolayers. The basolateral-to-apical flux of STI-571 was 39-fold greater than the apical-to-basolateral flux in the MDR1-transfected cells and 8-fold greater in the parental cell monolayers. This difference in directional flux was significantly reduced by a specific P-glycoprotein inhibitor (2R)-anti-5-[3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy]quinoline trihydrochloride (LY335979). The role of P-glycoprotein in the CNS distribution of STI-571 was examined in vivo, using wild-type and mdr1a/b (-/-) knockout mice that were orally administered 25 mg/kg [(14)C]STI-571. In the wild-type mice, the brain-to-plasma STI-571 concentration ratio at all time points was low (1-3%); however, there was an 11-fold greater brain partitioning of STI-571 at 1 h postdose in the mdr1a/b (-/-) mice compared with the wild-type mice. When 12.5 mg/kg STI-571 was given intravenously, the brain-to-plasma ratio of STI-571 in the mdr1a/b (-/-) mice was approximately 7-fold greater than that of wild-type mice up to 120 min postdose. These data indicate that STI-571 is a substrate of P-glycoprotein, and that the inhibition of P-glycoprotein affects the transport of STI-571 across MDCKII monolayers. Moreover, P-glycoprotein plays an important role in limiting the distribution of STI-571 to the CNS.

We describe 8 patients who presented with continuous, irregular movements occurring independently in individual fingers and, in some cases, toes, in the setting of mild dystonia present since early childhood and not associated with major disability. The finger movements varied from low-amplitude quivering or wriggling to larger amplitude movements in the plane of abduction-adduction as well as flexion-extension; they were asymmetrical but not unilateral. Quivering or working of the facial muscles was seen in 5 patients. Most patients reported worsening of the movements over the years, but there was no other evidence of a progressive neurological disease. We classify the movement disorder as athetosis as described by Hammond and Shaw and the syndrome as mild athetoid cerebral palsy.

Signal Transduction Inhibitor 571 (STI571, formerly known as CGP 57148B) or Gleevec™ received fast track approval by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia (CML). STI571 (Gleevec™) is a revolutionary and promising new oral therapy for CML, which functions at the molecular level with high specificity. The dramatic improvement in efficacy compared with existing treatments prompted an equally profound increase in the pace of development of Gleevec™. The duration from first dose in man to completion of the New Drug Application (NDA) filing was less than 3 years. In addition, recently, FDA approved Gleevec™ for the treatment of gastrointestinal stromal tumor (GIST). In order to support all toxicokinetic (TK) studies with sufficient speed to meet various target dates, a semi-automated procedure using solid phase extraction (SPE) was developed and validated. A Packard Multi-Probe I and a SPE step in a 96-well plate format were utilized. A 3M Empore octyl (C 8 )-standard density 96-well plate was used for plasma sample extraction. A Sciex API 3000 triple quadrupole mass spectrometer with an atmospheric pressure chemical ionization (APCI) interface operated in positive ion mode was used for detection. Lower limits of quantification of 1.00 and 2.00 ng/ml were attained for STI571 and its metabolite, CGP 74588, respectively. The method proved to be rugged and allowed the simultaneous quantification of STI571 and CGP 74588 in monkey plasma. Herein, assay development, validation, and representative concentration–time profiles obtained from TK studies are presented.

This study statistically evaluated a set of commonly measured tremor parameters to determine their individual and combined ability to discriminate between essential tremor (ET) and Parkinsonian tremor (PT). Accelerometer and surface electromyographic (EMG) records of moderate to severe upper limb tremor in 20 patients with ET and 22 patients with PT were used to quantitatively compare tremor amplitude, frequency and pattern of muscle bursting in two resting and three non resting postures. The group statistics showed significant differences between ET and PT with respect to tremor frequency in all five postures, tremor amplitude at rest and muscle bursting patterns. Discriminant function analysis showed that no single parameter or combination of parameters was able to correctly classify all patients. Frequency was much more discriminating than amplitude or muscle bursting patterns in all limb postures. The best amplitude discrimination was obtained when the hand and forearm were both fully supported. Muscle bursting patterns were poorly discriminating and did not assist in correct classification of single patients. Group statistics confirmed a highly significant biological difference between the two tremor types. Optimal classification of single PT (86% correct) and ET (95% correct) patients was obtained using frequency and two selected amplitude parameters from the resting limb. Limb posture was an important variable in optimising the discriminative ability of tremor studies. The implications for routine tremor studies are summarised.

An analysis is presented of stretching, shearing and spin of material line elements in a continuous medium. It is shown how to determine all pairs of material line elements at a point x, at time t, which instantaneously are not subject to shearing. For a given pair not subject to shearing, a formula is presented for the determination of a third material line element such that all three form a triad not subject to shearing, instantaneously. It is seen that there is an infinity of such triads not subject to shearing. A new decomposition of the velocity gradient L is introduced. In place of the classical decomposition of Cauchy and Stokes, L=d+w, where d is the stretching tensor and w is the spin tensor, the new decomposition is L=?+ℳ, where ?, called the ldquo;modified” stretching tensor, is not symmetric, and ℳ, called the “modified” spin tensor, is skew-symmetric – the tensor ? being chosen so that it has three linearly independent real right (and left) eigenvectors. The physical interpretation of this decomposition is that the material line elements along the three linearly independent right eigenvectors of ? instantaneously form a triad not subject to shearing. They spin as a rigid body with angular velocity μ (say) associated with ℳ. Also, for each decomposition L=?+ℳ, there is a decomposition L=? T + \widetilde{\pmb{\mathcal M}} , where \widetilde{\pmb{\mathcal M}} is also skew-symmetric. The triad of material line elements along the right eigenvectors of ? T (the set reciprocal to the right eigenvectors of ?) is also instantaneously not subject to shearing and rotates with angular velocity \widetilde{\boldsymbol{\mu}} (say) associated with \widetilde{\pmb{\mathcal M}} . It is seen that the vorticity vector ω is the mean of the two angular velocities μ and \widetilde{\boldsymbol{\mu}} , ω =(μ+ \widetilde{\boldsymbol{\mu}} )/2. For irrotational motion, ω =0, so that μ=- \widetilde{\boldsymbol{\mu}} ; any triad of material line elements suffering no shearing rotates with angular velocity equal and opposite to that of the reciprocal triad of material line elements. It is proved that provided d is not spherical, there is an infinity of choices for ? and ℳ in the decomposition L=?+ℳ. Two special types of decompositions are introduced. The first type is called “CCS-decomposition” (where CCS is an abbreviation for Central Circular Section). It is associated with the infinite family of triads (not subject to shearing) with a common edge along the normal to one plane of central circular section of an ellipsoid ? associated with the stretching tensor, and the two other edges arbitrary in the other plane of central circular section of ?. There are two such CCS-decompositions. The second type is called “triangular decomposition”, because, in a rectangular cartesian coordinate system, ? has three off-diagonal zero elements. There are six such decompositions.

The problem of the determination at any point P in a body of that pair of infinitesimal material line elements which suffers the maximum shear in a deformation has been solved [1]. Here that problem is revisited and a short proof, of geometrical type, of the result is presented.

Suppose the principal stretches are all different at a point P in a deformed body. In this case, it has been shown [1] that generally there is an infinity of non coplanar infinitesimal material line elements at P which remain unsheared following the deformation – that is, the angle between the arms of each pair of material line elements forming the triad remains unchanged. Here it is shown that in this case when all three principal stretches at P are different, there is no set of four infinitesimal material line elements, no three of which are coplanar, and such that the angle between each pair of the six pairs of material line elements is unchanged following the deformation. It is only when all three principal stretches at P are equal to each other, that there are unsheared tetrads at P, and in that case all tetrads are unsheared.

Performing predictive modelling, such as anomaly detection, in Big Data is a difficult task. This problem is compounded as more and more sources of Big Data are generated from environmental sensors, logging applications, and the Internet of Things. Further, most current techniques for anomaly detection only consider the content of the data source, i.e. the data itself, without concern for the context of the data. As data becomes more complex it is increasingly important to bias anomaly detection techniques for the context, whether it is spatial, temporal, or semantic. The work proposed in this paper outlines a contextual anomaly detection technique for use in streaming sensor networks. The technique uses a well-defined content anomaly detection algorithm for real-time point anomaly detection. Additionally, we present a post-processing context aware anomaly detection algorithm based on sensor profiles, which are groups of contextually similar sensors generated by a multivariate clustering algorithm. Our proposed research has been implemented and evaluated with real-world data provided by Powersmiths, located in Brampton, Ontario, Canada.

Background The UK has one of the highest rates for deaths from fire and flames in children aged 0-14 years compared to other high income countries. Evidence shows that smoke alarms can reduce the risk of fire-related injury but little exists on their cost-effectiveness. We aimed to compare the cost effectiveness of different interventions for the uptake of 'functioning' smoke alarms and consequently for the prevention of fire-related injuries in children in the UK. Methods We carried out a decision model-based probabilistic cost-effectiveness analysis. We used a hypothetical population of newborns and evaluated the impact of living in a household with or without a functioning smoke alarm during the first 5 years of their life on overall lifetime costs and quality of life from a public health perspective. We compared seven interventions, ranging from usual care to more complex interventions comprising of education, free/low cost equipment giveaway, equipment fitting and/or home safety inspection. Results Education and free/low cost equipment was the most cost-effective intervention with an estimated incremental cost-effectiveness ratio of [pound sign]34,200 per QALY gained compared to usual care. This was reduced to approximately £4,500 per QALY gained when 1.8 children under the age of 5 were assumed per household. Conclusions Assessing cost-effectiveness, as well as effectiveness, is important in a public sector system operating under a fixed budget restraint. As highlighted in this study, the more effective interventions (in this case the more complex interventions) may not necessarily be the ones considered the most cost-effective.

Highlights • We performed an overview of published systematic reviews and a systematic review of primary studies evaluating the effectiveness of interventions to prevent scalds in childhood. • There is little evidence that interventions are effective in reducing the incidence of scalds in children. • There is no consistent evidence on the effectiveness of interventions on the safe handling of hot food or drinks nor improving kitchen safety practices. • Education, home safety checks along with thermometers or thermostatic mixing valves is effective in reducing hot water temperature., Objective To synthesise and evaluate the evidence of the effectiveness of interventions to prevent scalds in children. Methods An overview of systematic reviews (SR) and a SR of primary studies were performed evaluating interventions to prevent scalds in children. A comprehensive literature search was conducted covering various resources up to October 2012. Experimental and controlled observational studies reporting scald injuries, safety practices and safety equipment use were included. Results Fourteen systematic reviews and 39 primary studies were included. There is little evidence that interventions are effective in reducing the incidence of scalds in children. More evidence was found that inventions are effective in promoting safe hot tap water temperature, especially when home safety education, home safety checks and discounted or free safety equipment including thermometers and thermostatic mixing valves were provided. No consistent evidence was found for the effectiveness of interventions on the safe handling of hot food or drinks nor improving kitchen safety practices. Conclusion Education, home safety checks along with thermometers or thermostatic mixing valves should be promoted to reduce tap water scalds. Further research is needed to evaluate the effectiveness of interventions on scald injuries and to disentangle the effects of multifaceted interventions on scald injuries and safety practices.

Background Childhood unintentional and suspected poisonings are a serious public health problem. Evidence from systematic reviews demonstrates that home safety education in combination with safety equipment provision increases the safe storage of medicines and other products. There is lack of evidence that poisoning prevention practices reduce poisoning rates. Objectives To estimate ORs for medically attended poisonings in children aged 0–4 years for items of safety equipment, home hazards and parental safety practices aimed at preventing poisoning, and to explore differential effects by child and family factors. Design Multicentre case-control study in UK hospitals with validation of parent-reported exposures using home observations. Cases are aged 0–4 years with a medically attended poisoning occurring at home, matched on age and sex with community controls. Children attending hospital for other types of injury will serve as unmatched hospital controls. Matched analyses will use conditional logistic regression; unmatched analyses will use unconditional logistic regression to adjust for confounding variables. The study requires 266 poisoning cases and 1064 matched controls to detect an OR of 0.64 for safe storage of medicinal products and of 0.65 for non-medicinal products, with 80% power, a 5% significance level and a correlation between exposures in cases and controls of 0.1. Main outcome measures Unintentional childhood poisoning. Discussion This will be the largest study to date exploring modifiable risk factors for poisoning in young children. Findings will inform: policy makers developing poison prevention strategies, practitioners delivering poison prevention interventions, parents to reduce the risk of poisoning in their homes.

Children's centres were established across England to provide a range of services including early education, social care and health to pre-school children and their families. We surveyed children's centres to ascertain the activities they were undertaking to prevent unintentional injuries in the under fives. A postal questionnaire was sent to a sample of children's centre managers (n = 694). It included questions on current activities, knowledge and attitudes to injury prevention, health priorities and partnership working. Responses were received from 384 (56%) children's centres. Overall, 58% considered unintentional injury prevention to be one of the three main child health priorities for their centre. Over half the respondents (59%) did not know if there was an injury prevention group in their area, and 21% did not know if there was a home safety equipment scheme. Knowledge of how child injury deaths occur in the home was poor. Only 11% knew the major cause of injury deaths in children under five. Lack of both staff time and funding were seen as important barriers by children's centre staff to undertake injury prevention activities. Nearly all stated that training (97%) and assistance with planning injury prevention (94%) would be helpful to their centres. Children's centres need further support if they are to effectively tackle this important public health area.

Over the past several years there has been significant development in low power wearable wireless electronics which can be powered from energy harvesting systems rather than from batteries. In this paper we present a thermoelectric energy harvesting system using human body heat to power wearable electronics. The main focus of this paper is to present a power management system suitable for this application. The voltage produced from the human body is small in quantity (~100mV). Ultra- low voltage boost converters and output voltage regulators have been designed for low power wearable electronics. This work considers the human arm/wrist as a source of heat, placing a thermoelectric generator (TEG) with a heat sink on a wrist using a watch like prototype. The TEG was tested with a body to room temperature difference ΔT=5°C producing 1.54 mW. The harvested and regulated power is 0.278 mW sufficient for a wearable wireless sensor (WSN) node [1].The proposed power management and dc-dc converter circuit operates with an input voltage as low as 30mV. 24% efficiency is achieved from the boost converter stage whilst the dc-dc converter stage gives approximately 75% efficiency. The average end-to-end efficiency is 18%.

This chapter introduced power management circuits and energy storage unit designs for sub-1 mW low power energy harvesting technologies, including indoor light energy harvesting, thermoelectric energy harvesting and vibration energy harvesting. The solutions address several of the problems associated with energy harvesting, power management and storage issues including low voltage operation, self-start, efficiency (conversion efficiency as well as impact of power consumption of the power management circuit itself), energy density and leakage current levels. Additionally, efforts to miniaturize and integrate magnetic parts as well as integrate discrete circuits onto silicon are outlined to offer improvements in cost, size and efficiency. Finally initial results from efforts to improve energy density of storage devices using nanomaterials are introduced.

This paper presents a design study of a new topology for miniaturized bondwire transformers fabricated and assembled with standard IC bonding wires and toroidal ferrite (Fair-Rite 5975000801) as a magnetic core. The microtransformer realized on a PCB substrate, enables the build of magnetics on-top-of-chip, thus leading to the design of high power density components. Impedance measurements in a frequency range between 100 kHz to 5 MHz, show that the secondary self-inductance is enhanced from 0.3 ?H with an epoxy core to 315 ?H with the ferrite core. Moreover, the micro-machined ferrite improves the coupling coefficient from 0.1 to 0.9 and increases the effective turns ratio from 0.5 to 35. Finally, a low-voltage IC DC-DC converter solution, with the transformer mounted on-top, is proposed for energy harvesting applications. © 2014 EDAA.

In the Big Data community, MapReduce has been seen as one of the key enabling approaches for meeting continuously increasing demands on computing resources imposed by massive data sets. The reason for this is the high scalability of the MapReduce paradigm which allows for massively parallel and distributed execution over a large number of computing nodes. This paper identifies MapReduce issues and challenges in handling Big Data with the objective of providing an overview of the field, facilitating better planning and management of Big Data projects, and identifying opportunities for future research in this field. The identified challenges are grouped into four main categories corresponding to Big Data tasks types: data storage (relational databases and NoSQL stores), Big Data analytics (machine learning and interactive analytics), online processing, and security and privacy. Moreover, current efforts aimed at improving and extending MapReduce to address identified challenges are presented. Consequently, by identifying issues and challenges MapReduce faces when handling Big Data, this study encourages future Big Data research.

Thomson and Tait pointed out that the deformation gradient F at a point X in a continuous medium has at least one real positive eigenvalue and showed that material line elements along N, the corresponding right eigenvector of F, retain their direction in the deformation. Here, we consider the case when the two remaining eigenvalues of F are complex conjugate, with corresponding right eigenvectors c ± id (say). It is seen that the "directional ellipse" corresponding to the bivector c + id is preserved in the deformation, the ellipse associated with the bivector c + id being transformed into a similar and similarly situated ellipse. Any two material line elements at X along a pair of conjugate radii of the directional ellipse are deformed into material line elements along another pair of conjugate radii of this ellipse. They are stretched by the same amount which is the modulus of the complex eigenvalue. Key Words: continuum kinematics, deformation, material line element, bivector

In this paper, the concept of unsheared triads of material line elements at a point X is introduced. We find that there is an infinity of unsheared triads. More precisely, it is shown that, in general, for any given unsheared pair at X , a unique third material line element at X may be found such that the three material line elements form an unsheared triad. Special cases are analyzed in detail. A link between unsheared triads and new decompositions of the deformation gradient, is exhibited. These decompositions generalize the classical polar decomposition F = RU = VR of the deformation gradient F , in which R is a proper orthogonal tensor and U , V are positive-definite symmetric. Associated with any unsheared (oblique) triad is a new decomposition F = QG = HQ , in which Q is a proper orthogonal tensor, but G and H are no longer symmetric, but have three positive eigenvalues and three linearly independent right eigenvectors. Because there is an infinity of unsheared triads, there is an infinity of such decompositions. We call them “extended polar decompositions”. Several examples of unsheared triads and extended polar decompositions are presented.

Abnormal substantia nigra morphology in healthy individuals, viewed with transcranial ultrasound, is a significant risk factor for Parkinson's disease. However, little is known about the functional consequences of this abnormality (termed 'hyperechogenicity') on movement. The aim of the current study was to investigate hand function in healthy older adults with (SN?) and without (SN-) substantia nigra hyperechogenicity during object manipulation. We hypothesised that SN? subjects would exhibit increased grip force and a slower rate of force application compared to SN- subjects. Twenty-six healthy older adults (8 SN? aged 58 ± 8 years, 18 SN- aged 57 ± 6 years) were asked to grip and lift a light-weight object with the dominant hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus EMG were recorded during three trials. During the first trial, SN? subjects exhibited a longer period between grip onset and lift onset (i.e. preload duration; 0.27 ± 0.25 s) than SN- subjects (0.13 ± 0.08 s; P = 0.046). They also exerted a greater downward force prior to lift off (-0.54 ± 0.42 N vs. -0.21 ± 0.12 N; P = 0.005) and used a greater grip force to lift the object (19.5 ± 7.0 N vs. 14.0 ± 4.3 N; P = 0.022) than SNsubjects. No between group differences were observed in subsequent trials. SN? subjects exhibit impaired planning for manipulation of new objects. SN? individuals overestimate the grip force required, despite a longer contact period prior to lifting the object. The pattern of impairment observed in SN? subjects shares similarities with de novo Parkinson's disease patients. Refereed/Peer-reviewed

Background:- The UK has one of the highest fatality rates for deaths from fire-related injuries in children aged 0–14 years; these injuries have the steepest social gradient of all injuries in the UK. Children’s centres provide children under five years old and their families with a range of services and information, including home safety, but their effectiveness in promoting injury prevention has yet to be evaluated. We developed a fire prevention intervention for use in children’s centres comprising an Injury Prevention Briefing (IPB) which provides evidence on what works and best practice from those running injury prevention programmes, and a facilitation package to support implementation of the IPB. This protocol describes the design and methods of a trial evaluating the effectiveness and cost-effectiveness of the IPB and facilitation package in promoting fire prevention. Methods/Design:- Pragmatic, multicentre cluster randomised controlled trial, with a nested qualitative study, in four study centres in England. Children’s centres in the most disadvantaged areas will be eligible to participate and will be randomised to one of three treatment arms comprising: IPB with facilitation package; IPB with no facilitation package; usual care (control). The primary outcome measure will be the proportion of families who have a fire escape plan at follow-up. Eleven children’s centres per arm are required to detect an absolute difference in the percentage of families with a fire escape plan of 20% in either of the two intervention arms compared with the control arm, with 80% power and a 5% significance level (2-sided), an intraclass correlation coefficient of 0.05 and assuming outcomes are assessed on 20 families per children’s centre. Secondary outcomes include the assessment of the cost-effectiveness of the intervention, other fire safety behaviours and factors associated with degree of implementation of the IPB. Discussion:- This will be the first trial to develop and evaluate a fire prevention intervention for use in children’s centres in the UK. Its findings will be generalisable to children’s centres in the most disadvantaged areas of the UK and may also be generalisable to similar interventions to prevent other types of injury. Trial registration:- http://NCT01452191 webcite (date of registration: 13/10/2011).

This working paper introduces a multi-source energy harvesting powered acoustic emissions (AE) monitoring system for the applications of rotating machine fault detections. This wireless sensor prototype records the AE signal at approximately 200KHz frequency. It performs fast Fourier transform (FFT) and compares the results with known fault patterns. An energy harvesting solution utilizes vibrational, thermal and light energy as the power supply for the AE wireless sensor node. The multiple-source energy harvester proposed in this work generates 1.56mW from 25--48mg vibration energy and 3.37mW from thermoelectric energy when deployed on the 62°C metal surface of air compressor. This AE wireless sensor prototype combines with the batteryless energy harvesting power supply in order to provide a self-powered health monitoring solution for wide range of rotating machinery.

The purpose of this paper is to present new special explicit inhomogeneous plane wave solutions of the linearized equations of motion for elastic cubic crystals. It is based upon the “directional-ellipse” method which leads to an eigenvalue problem for the complex symmetric acoustical tensor. The solutions are obtained by considering a special case for which the determination of the three complex eigenvalues of this tensor reduces to finding the three complex cubic roots of a real positive number. Explicit simple expressions are presented for the slowness and amplitude bivectors.

If a pair of material line elements, passing through a typical particle P in a body, subtend an angle Θ before deformation, and Θ+γ after deformation, the pair of material elements is said to be sheared by the amount γ. Here all pairs of material elements at P are considered for arbitrary deformations. Two main problems are addressed and solved. The first is the determination of all pairs of material line elements at P which are unsheared. The second is the determination of that pair of material line elements at P which suffers the maximum shear.

The Cauchy stress tensor, T_ij, is considered for an elastic material which is subject to any internal isotropic constraint, apart from the constraint of incompressibility. For a given strain, it is seen that if in a given basis one of the eigenvectors of the stress tensor has a zero component, say the αth component, and if the arbitrary scalar term in the stress may be chosen so that T_αβ(α≠β) shear stress component is zero, then the stress tensor has a double eigenvalue. This means that there is a great simplification in the stress field. The given strain may be maintained experimentally by a simple tension superimposed upon a hydrostatic stress field. Examples are presented for Bell-constrained and Ericksen-constrained materials.

A semi-automated solid-phase extraction (SPE) liquid chromatography/mass spectrometry (LC/MS) procedure was validated for the simultaneous determination of everolimus (RAD001) and cyclosporin A (CsA) in human blood. Whole blood samples (350microL) were pretreated with acetonitrile/zinc sulfate mixture to precipitate the sample proteins. The samples were centrifuged and the resulting supernatants were manually transferred to a 96-well plate format. All subsequent sample transfer and solid phase extraction was automated using a Tomtec Quadra 96 workstation. Samples were analyzed by LC/MS using an atmospheric pressure chemical ionization (APcI) interface. In order to enhance sensitivity, the MS method used negative ion mode for RAD001 ([M]-) and its internal standard and positive ion mode for CsA ([M + H]+) and its internal standard. The lower limit of quantitation was 0.375 ng.ml(-1) for RAD001 and 6.95 ng.ml(-1) for CsA. The reproducibility of the method was evaluated by analyzing six replicates at five or more quality control (QC) levels over the nominal concentration range 0.375 to 253 ng.ml(-1) for RAD001 and 6.95 to 1,530 ng.ml(-1) for CsA. The inter- and intra-day accuracy was found to range from 89.7 to 114% with precision (% CV) of less than 12% for both compounds. The sensitivity, small sample volume needed and high sample throughput of this method make it an attractive option for pharmacokinetic studies in pediatric patients.

Vancomycin, a macrocyclic antibiotic, is an amphoteric glycopeptide produced by Streptomyces orientalis which has proven to be a viable chiral selector for high performance liquid chromatograph (HPLC) (D. W. Armstrong, Y. Tang, S. Chen, Y. Zhou, C. Bagwill and J-R. Chen, Anal. Chem. (1994; 66: 1473). While it is related to other glycopeptide antibiotics, vancomycin has a number of unique structural features, including 18 stereogenic centers, five aromatic rings, and two side chains one of which is a carbohydrate dimer. Therefore, a vancomycin-based stationary phase appears to be multimodal in that it can be utilized in both normal-phase and reversed-phase liquid chromatography. Consequently, the enantiomeric separation may be operative via several mechanisms, including π–π complexation, dipole stacking, inclusion, hydrogen bonding, or combinations of these interactions. LC/MS/MS is a powerful tool for quantitative analysis when evaluated on the basis of speed, specificity, reliability and sensitivity. For these reasons, the present paper explored the feasibility of bonded macrocyclic glycopeptide phases for chiral LC/MS/MS quantitative analysis. Methylphenidate was used as a model compound. A rapid chiral bioanalytical method (

OBJECTIVES—To describe the clinical and neuroradiological features of basilar impression in patients with osteogenesis imperfecta type IV. METHODS—Four patients with basilar impression were ascertained in a population study of osteogenesis imperfecta. All four had detailed clinical and neuroradiological examination with both CT and MRI of the craniocervical junction andposterior fossa structures. RESULTS—All four showed significant compression of the posterior fossa structures and surgical decompression was performed with relief of symptoms. CONCLUSION—Symptoms of cough headache and trigeminal neuralgia occurring in patients with osteogenesis imperfecta are indications for detailed clinical and neuroradiological investigation to document basilar impression.

A 1996 World Health Organisation report, Investing in Health Research and Development , warns that worldwide, “the epidemic of injuries may be among the most neglected health problems of the late 20th century” .1 We see evidence of this neglect in investment in injury research, and in the paucity of evaluated studies on injury prevention for children and young people. More neglected still, is a concerted attempt to implement established interventions at national and local levels throughout the UK. The path to implementation is broken too often. In this chapter we explore the barriers and opportunities in the UK for implementing injury prevention for this age group in a more widespread and systematic manner. We first examine the picture of injury prevention at national and local levels. This leads to the conclusion that there would be significant benefits from having national lead agencies for this problem along with improved local coordination. To this end we look at: Three examples are then presented. The first examines the scope for injury prevention in the primary health care setting. It focuses on an individual approach to children, young people and their families, and represents a possible opportunity for health promotion. The other examples both involve multiagency approaches. Example two is a multiagency programme to promote cycle helmet use. Example three documents the use of a Safe Community approach. In the UK, no single agency or profession “owns” the prevention of unintentional injuries to children and young people, either at national government or local levels. This can lead, at worst, to a failure to act, or at best to a lack of coordination or duplication of …

The propagation of plane waves is considered in the context of the linearized theory of elastic crystals (or anisotropic materials) which exhibit orthorhombic, tetragonal, hexagonal, or cubic symmetry (‘RTHC crystals’). Although not explicitly considered, the analysis is valid also for waves of infinitesimal amplitude superposed on finite static homogeneous deformations of isotropic elastic bodies. An extremely simple procedure is presented for finding a lower bound and an upper bound on the speeds of propagation of all possible plane waves which may propagate in a given crystal of these classes. There is a drawback, however, in that the procedure may fail to give a meaningful lower bound (negative lower bound for the squared wave speeds). Also, the bounds are not always attained, but the procedure immediately shows in which cases they are attained. Even so, because of its simplicity the procedure may be of value particularly when searching for crystals with desirable properties. The procedure is then applied in turn to each of the RTHC crystal systems. Numerical values of the bounds are presented for several specific crystals, illustrating the various possibilities arising in the theory.

The purpose of this paper is to present a simple and direct way of finding the number of acoustic axes and their locations for all crystals of orthorhombic, tetragonal, hexagonal or cubic symmetry (‘RTHC crystals’). The procedure is based upon a decomposition of the acoustical tensor due to Fedorov and Fedorov. Excepting cases for which there may be an infinity of acoustic axes (for instance, the case of hexagonal crystals), it is shown that RTHC crystals may have at most sixteen acoustic axes, four in each coordinate plane, and four out of coordinate planes. Very simple equations are presented for the explicit determination of these acoustic axes. Then, these results are applied in turn to each of the RTHC crystal systems. In each case the possible numbers of acoustic axes are easily obtained. Explicit numerical examples are presented for several specific crystals.

This short paper discusses teaching western Cultural Studies, in particular Australian Cultural Studies, in Thailand. By contextualising pedagogical issues, such as classroom practices and course contents, with the surrounding economic, institutional, and national educational agendas, this paper outlines some of the tensions between western and Asian tertiary education systems. Specifically, examining the development and place of cultural studies in the western university highlights the inability for cultural studies to articulate its specific view of culture.

It is known that all transverse plane acceleration waves that propagate through a homogeneously deformed Mooney Rivlin material do so without a change in amplitude. Here it is shown that the MooneyRivlin material is the only incompressible isotropic hyperelastic material that permits transverse plane acceleration waves to propagate in any direction without a change in amplitude, regardless of the homogeneous prestrain.

The speeds of propagation and polarization amplitudes are presented for finite amplitude plane shear waves propagating in rubber which is maintained in a state of static finite simple shear. The Mooney-Rivlin form of the stored-energy function is used to model the mechanical behaviour of the material. General relations are obtained between the speed of propagation of the fastest and slowest waves and the speed of propagation of the finite amplitude circularly polarized waves which may propagate along the acoustic axes. The slowness and ray surfaces are also presented.

The isolation of embryonic stem cells (ESCs) has furthered our understanding of normal embryonic development and fueled the progression of stem cell derived therapies. However, the generation of ESCs requires the destruction of an embryo, making the use of these cells ethically controversial. In 2006 the Yamanaka group overcame this ethical controversy when they described a protocol whereby somatic cells could be dedifferentiated into a pluripotent state following the transduction of a four transcription factor cocktail. Following this initial study numerous groups have described protocols to generate induced pluripotent stem cells (iPSCs). These protocols have simplified the reprogramming strategy by employing polycistronic reprogramming cassettes and flanking such polycistronic cassettes with loxP or piggyBac recognition sequences. Thus, these strategies allow for excision of the entire transgene cassette, limiting the potential for the integration of exogenous transgenes to have detrimental effect. Others have prevented the potentially deleterious effects of integrative reprogramming strategies by using non-integrating adenoviral vectors, traditional recombinant DNA transfection, transfection of minicircle DNA, or transfection of episomally maintained EBNA1/OriP plasmids. Interestingly, transfection of mRNA or miRNA has also been shown to be capable of reprogramming cells, and multiple groups have developed protocols using cell penetrating peptide tagged reprogramming factors to de-differentiate somatic cells in the absence of exogenous nucleic acid. Despite the numerous different reprogramming strategies that have been developed, the reprogramming process remains extremely inefficient. To overcome this inefficiency multiple groups have successfully used small molecules such as valproic acid, sodium butyrate, PD0325901, and others to generate iPSCs.The fast paced field of cellular reprogramming has recently produced protocols to generate iPSCs using non integrative techniques with an ever improving efficiency. These recent developments have brought us one step closer to developing a safe and efficient method to reprogram cells for clinical use. However, a lot of work is still needed before iPSCs can be implemented in a clinical setting.

The isolation of embryonic stem cells (ESCs) has furthered our understanding of normal embryonic development and fueled the progression of stem cell derived therapies. However, the generation of ESCs requires the destruction of an embryo, making the use of these cells ethically controversial. In 2006 the Yamanaka group overcame this ethical controversy when they described a protocol whereby somatic cells could be dedifferentiated into a pluripotent state following the transduction of a four transcription factor cocktail. Following this initial study numerous groups have described protocols to generate induced pluripotent stem cells (iPSCs). These protocols have simplified the reprogramming strategy by employing polycistronic reprogramming cassettes and flanking such polycistronic cassettes with loxP or piggyBac recognition sequences. Thus, these strategies allow for excision of the entire transgene cassette, limiting the potential for the integration of exogenous transgenes to have detrimental effect. Others have prevented the potentially deleterious effects of integrative reprogramming strategies by using non-integrating adenoviral vectors, traditional recombinant DNA transfection, transfection of minicircle DNA, or transfection of episomally maintained EBNA1/OriP plasmids. Interestingly, transfection of mRNA or miRNA has also been shown to be capable of reprogramming cells, and multiple groups have developed protocols using cell penetrating peptide tagged reprogramming factors to de-differentiate somatic cells in the absence of exogenous nucleic acid. Despite the numerous different reprogramming strategies that have been developed, the reprogramming process remains extremely inefficient. To overcome this inefficiency multiple groups have successfully used small molecules such as valproic acid, sodium butyrate, PD0325901, and others to generate iPSCs.The fast paced field of cellular reprogramming has recently produced protocols to generate iPSCs using non integrative techniques with an ever improving efficiency. These recent developments have brought us one step closer to developing a safe and efficient method to reprogram cells for clinical use. However, a lot of work is still needed before iPSCs can be implemented in a clinical setting.

OBJECTIVE: To determine whether advocacy targeted at local politicians leads to action to reduce the risk of pedestrian injury in deprived areas. DESIGN: Cluster randomised controlled trial. SETTING: 239 electoral wards in 57 local authorities in England and Wales. PARTICIPANTS: 617 elected local politicians. INTERVENTIONS: Intervention group politicians were provided with tailored information packs, including maps of casualty sites, numbers injured and a synopsis of effective interventions. MAIN OUTCOME MEASURES: 25-30 months post intervention, primary outcomes included: electoral ward level: percentage of road traffic calmed; proportion with new interventions; school level: percentage with 20 mph zones, Safe Routes to School, pedestrian training or road safety education; politician level: percentage lobbying for safety measures. Secondary outcomes included politicians' interest and involvement in injury prevention, and facilitators and barriers to implementation. RESULTS: PRIMARY OUTCOMES DID NOT SIGNIFICANTLY DIFFER: % difference in traffic calming (0.07, 95%CI: -0.07 to 0.20); proportion of schools with 20 mph zones (RR 1.47, 95%CI: 0.93 to 2.32), Safe Routes to School (RR 1.34, 95%CI: 0.83 to 2.17), pedestrian training (RR 1.23, 95%CI: 0.95 to 1.61) or other safety education (RR 1.16, 95%CI: 0.97 to 1.39). Intervention group politicians reported greater interest in child injury prevention (RR 1.09, 95%CI 1.03 to 1.16), belief in potential to help prevent injuries (RR 1.36, 95%CI 1.16 to 1.61), particularly pedestrian safety (RR 1.55, 95%CI 1.19 to 2.03). 63% of intervention politicians reported supporting new pedestrian safety schemes. The majority found the advocacy information surprising, interesting, effectively presented, and could identify suitable local interventions. CONCLUSIONS: This study demonstrates the feasibility of an innovative approach to translational public health by targeting local politicians in a randomised controlled trial. The intervention package was positively viewed and raised interest but changes in interventions were not statistically significance. Longer term supported advocacy may be needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN91381117. Language: en

This paper presents the design of hybrid energy storage unit (HESU) for energy harvesting applications using super-capacitor and thin film battery (TFB). The power management circuits of this hybrid energy storage unit are proposed to perform "smart" charge/discharge control in order to optimize the HESU from the perspectives of energy loss due to leakage current and equivalent series resistance (ESR). This paper shows the characterizations of ESUs for energy harvesting powered wireless sensor networks (WSN) applications. A new design of power management circuits is proposed in order to utilize the low ESR characteristics of super-capacitor and the low leakage current characteristics of the TFB in the hybrid energy storage. The average power loss due to leakage current is measured at 38μW in the proposed system. When Compared to the super-capacitor energy storage with the similar capacity, the proposed hybrid energy storage unit reduces the leakage power by approximately 45% whilst maintains a similar (

Journal article Small-amplitude inhomogeneous plane waves propagating in any direction in a homogeneously deformed Hadamard material are considered. Conditions for circular polarization are established. The analysis relies on the use of complex vectors (or bivectors) to describe the slowness and the polarization of the waves. Generally, homogeneous circularly polarized plane waves may propagate in only two directions, the directions of the acoustic axes, in a homogeneously deformed Hadamard material. For inhomogeneous circularly polarized plane waves, the number of possibilities is far greater. They include an infinity of 'transverse waves', as well as 'longitudinal waves', and the superposition of transverse waves and longitudinal waves, where 'transverse' and 'longitudinal' are used in the bivector sense. Each and every possibility of circular polarization is examined in turn, and explicit examples of solutions are given in every case. EU (TMR programme) contract FMBICT983468 peer-reviewed

Advanced monitoring systems of smart grids (SG) present significant growth potential for renewable energy generation whilst low-cost and miniaturized wireless sensor nodes bring opportunities to replace large and expensive monitoring equipment. Renewable power systems required complicated monitoring and control. For example, a concentrated photovoltaic (CPV) power plant requires temperature, electric current and component faults monitoring. All of these can be provided by wireless sensor networks (WSN). However, the practical implementation of WSN solutions for CPV application remains largely unexploited. A gap exists in the research of SG WSN monitoring system. Power system researchers lack understanding of the capability of state-of-the-art WSN systems, whilst the WSN researcher lack on understanding of the detailed application area of SG. This paper addresses the practical issues encountered during the design of a SG WSN and an insight how this knowledge gap can be bridged. It starts with introduction of WSN system with the concept of constrained resources in wireless communication, energy and data processing capability. Then, it presents the CPV WSN design architecture and issues ranging from network scalability, topology, sampling rate to sensor selection based on the constrained resources in WSN. The target application scenario is 1MW scale CPV power plant with 40 CPV panels. Overall, this paper presents valuable design considerations along with an analysis of trade-offs for power plant level CPV monitoring system implementation based on IEEE 802.15.4 wireless sensor platforms.

During pubertal maturation, there is an increase in the number of androgen receptor-immunoreactive (AR-IR) cells in the preoptic area (POA), arcuate nucleus (ARC), medial amygdala (mAMY), and ventromedial hypothalamic nucleus (VMH) of the male ferret brain. In contrast, the number of AR-IR cells in the bed nucleus of the stria terminalis (BNST) or lateral septum (ISEP) does not change with pubertal development. This experiment tested the hypothesis that the pubertal increase in AR-IR cells in certain brain regions is the result of the pubertal increase in circulating androgens. Prepubertal male ferrets were left intact or were castrated and treated daily (10 days) with s.c. injections of either oil, testosterone (T; 5 mg/kg), dihydrotestosterone (DHT; 5 mg/kg), or estradiol (E; 10 hg/kg). Brains were processed for AR immunocytochemistry, and the number of immunopositive cells was quantified in POA, ARC, mAMY, VMH, BNST, and ISEP. Overall, castration reduced the number of AR-IR cells below that seen in intact animals, and E administration did not restore AR-IR cell number. Treatment of castrates with androgens restored numbers of AR-IR cells to those of intact animals in the BNST, ISEP, and VMH. However, AR-IR cell numbers were significantly greater in androgen-treated castrates than in intact animals in POA, mAMY, and ARC. These data show that AR-IR cells in prepubertal male ferrets are sensitive to circulating levels of androgens, supporting the hypothesis that the pubertal rise in T is responsible for the pubertal increase in the number of AR-IR cells in the POA, mAMY, and ARC.

In a previous paper, Currie and Hayes (J. Inst. Maths Applics 5 (1969) 140-161) showed that two linearly polarized finite-amplitude plane shear waves may propagate with constant speeds along any direction in a Mooney-Rivlin material which is maintained in a state of arbitrary static finite homogeneous deformation. Later, Boulanger and Hayes (Q. Jl Mech. appl. Math 45 (1992) 575-593), using special directions called 'acoustic axes', obtained explicit expressions for the polarization directions and the phase speeds of these waves in terms of the propagation direction.Here further properties of these waves are obtained. An energy-flux velocity vector is introduced and a duality between slowness and energy-flux velocity is exhibited. The slowness and ray surfaces are obtained and their singular points and singular tangent planes are studied. As in crystal optics and crystal acoustics, it follows that cones of internal and external conical refraction may be introduced.Also, it is shown that for a given direction of the energy-flux velocity ('ray direction'), two plane shear waves may propagate. Introducing new special directions called 'ray axes', explicit expressions are obtained for the various properties of these waves in terms of the ray direction. The duality between the results for a given propagation direction and for a given ray direction is clearly brought out.Finally, it is shown that a finite-amplitude plane shear wave is uniquely determined by its polarization direction, provided this direction is not along a principal axis of the basic static homogeneous deformation. Indeed all the properties of such a wave may be expressed in terms of its polarization direction. © 1995 Oxford University Press.

This work describes how a fine-grained filtering Web service is generated using an extended XACML architecture for Data Providing Web Services (DPWSs). A DPWS is a Web service tasked with the retrieval of data that is annotated using a domain ontology. This work extends XACML policies to reference filtering classes from a filtering ontology instead of directly referencing fine-grained XML elements. This paper then contributes a language to state relations between the filtering ontology and the DPWS's domain ontology. It also contributes an algorithm to interpret these relations to determine if a given XML element from a DPWS is a member of a filtering class. This algorithm is then used by the extended XACML architecture to infer how a DPWS shall be filtered. This approach provides a clear separation of concerns between a DPWS's data domain and the filtering domain.

This study evaluates the correlation between imatinib trough plasma concentrations (C(min)) and clinical response and safety in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in the Tyrosine Kinase Inhibitor OPtimization and Selectivity (TOPS) trial.Patients were randomized 1:2 to 400 mg/day or 800 mg/day imatinib. Imatinib C(min) levels were collected at pre-dose before treatment, and at the end of months 1 (day 29), 6, 9, and 12.Imatinib C(min) were stable over time in the 400 mg/day dose arm, but showed a slight decrease in the 800 mg/day arm due to dose adjustments between months 1-6. The overall median imatinib C(min) levels were 1040, 1200, 1935, and 2690 ng/mL for the actual 300, 400, 600, and 800 mg/day doses, respectively. The rates of major molecular response (MMR) at 3, 6, 9, and 12 months, and complete cytogenetic response (CCyR) at 6 and 12 months were significantly lower among patients with the lowest imatinib C(min) levels at Day 29 (1165 ng/mL, 25th percentile). There was an apparent association between high imatinib C(min) and the occurrence of grade 3/4 neutropenia and all-grade rash, diarrhea, arthralgia/myalgia, and all-cause edema. Conclusions Imatinib C(min) levels were relatively stable over time and proportional to the dose administered. Patients with an imatinib C(min) above 1165 ng/mL on Day 29 achieved MMR faster and had higher MMR and CCyR rates at 12 months. There appeared to be an association between imatinib C(min) and the frequency of some adverse events. This trial was registered at http://www.clinicaltrials.gov as NCT00124748.

Objective: To examine the safety and efficacy of onabotulinumtoxinA (Botox) for plantarflexor overactivity following stroke. Design: Double-blind randomized controlled trial, open-label extension phase. Setting: Neurology rehabilitation facilities. Subjects: Eighty-five subjects with lower limb hypertonia received 200 U ( n = 28) or 300 U ( n = 28) of onabotulinumtoxinA or saline ( n = 29) injection. Primary measures: Plantarflexor Ashworth scores at 12 weeks post injection and adverse events. Secondary measures: self-reported spasm frequency and pain, physician rating of hypertonia severity, gait quality and active dorsiflexion. Results: Differences were not seen between onabotulinumtoxinA groups; hence data were pooled. Incidence of adverse events was not different between groups ( P = 0.61). Reduction in hypertonia was not different between groups at 12 weeks ( P = 0.53); however for subjects with Ashworth scores of >3 at baseline, 14/31 in the onabotulinumtoxinA group demonstrated a reduction of >1 grade versus 1/17 receiving placebo injection ( P = 0.01). Overall, onabotulinumtoxinA-injected subjects demonstrated significantly greater improvement in spasm frequency (22/54 versus 4/29, P = 0.01), pain reduction (8/54 versus 1/29, P = 0.02), active dorsiflexion (8/54 versus 1/29 P = 0.03) and gait quality (17/54 versus 6/29, P = 0.02) than controls. In the open-label phase, a second onabotulinumtoxinA injection was associated with greater hypertonia reduction ( P = 0.005) and gait quality ( P = 0.002) compared with single injection. Conclusions: OnabotulinumtoxinA injection for ankle flexor overactivity after stroke was safe and well tolerated but did not alter local spasticity at 12 weeks; it did reduce spasms and improve gait quality. There were no detectable differences between higher and lower doses. A second injection may be associated with greater change.

Unintentional injuries are the second most common cause of child death, accounting for one in seven deaths between the ages of 1 and 14 years.1 These deaths represent just the tip of the iceberg. Every year, around 100 000 children are admitted to hospital2 and 2 million attend emergency departments.3 How many seek treatment only from their GP is not known. The impact of injuries on children, their families, and society can be considerable. The immediate effect of an injury is pain, followed by the psychological trauma of having to visit hospital, and loss of enjoyment of everyday activities such as play. But children can also be left disabled and disfigured, and lose education, potentially affecting the rest of their lives. Caring for an injured child can cause family breakdown and loss of employment, as well as having immediate economic consequences. Society has to bear the costs of treatment, rehabilitation, and long-term support. Unintentional injuries are often thought of as accidents, but they are not random, unpredictable events as the term accident implies. We can identify children at risk of injuries and the injuries they are likely to suffer. Those from disadvantaged families are at greatest risk.4 Not surprisingly, the types of injuries experienced are strongly related to a child's stage of development. For example, the more active children become, the more likely they are to run and trip, and climb and fall; the exploratory stage of child development results in children putting objects in their mouth leading to choking and poisoning. Copying adult tasks, such as food preparation, can lead to lacerations and burns. GPs and primary health care teams (PHCTs) have multiple opportunities to contribute to injury prevention and these are highlighted in three …