Multivariate analysis of the Fugl-Meyer outcome measures assessing the effectiveness of GENTLE/S robot-mediated stroke therapy

Background: Robot-mediated therapies offer entirely new approaches to neurorehabilitation. In this paper we present the results obtained from trialling the GENTLE/S neurorehabilitation system assessed using the upper limb section of the Fugl-Meyer ( FM) outcome measure. Methods: We demonstrate the design of our clinical trial and its results analysed using a novel statistical approach based on a multivariate analytical model. This paper provides the rational for using multivariate models in robot-mediated clinical trials and draws conclusions from the clinical data gathered during the GENTLE/S study. Results: The FM outcome measures recorded during the baseline ( 8 sessions), robot-mediated therapy ( 9 sessions) and sling-suspension ( 9 sessions) was analysed using a multiple regression model. The results indicate positive but modest recovery trends favouring both interventions used in GENTLE/S clinical trial. The modest recovery shown occurred at a time late after stroke when changes are not clinically anticipated. Conclusion: This study has applied a new method for analysing clinical data obtained from rehabilitation robotics studies. While the data obtained during the clinical trial is of multivariate nature, having multipoint and progressive nature, the multiple regression model used showed great potential for drawing conclusions from this study. An important conclusion to draw from this paper is that this study has shown that the intervention and control phase both caused changes over a period of 9 sessions in comparison to the baseline. This might indicate that use of new challenging and motivational therapies can influence the outcome of therapies at a point when clinical changes are not expected. Further work is required to investigate the effects arising from early intervention, longer exposure and intensity of the therapies. Finally, more function-oriented robot-mediated therapies or sling-suspension therapies are needed to clarify the effects resulting from each intervention for stroke recovery.

Challenges and opportunities for robot-mediated neurorehabilitation

Robot-mediated neurorehabilitation is a rapidly advancing field that seeks to use advances in robotics, virtual realities, and haptic interfaces, coupled with theories in neuroscience and rehabilitation to define new methods for treating neurological injuries such as stroke, spinal cord injury, and traumatic brain injury. The field is nascent and much work is needed to identify efficient hardware, software, and control system designs alongside the most effective methods for delivering treatment in home and hospital settings. This paper identifies the need for robots in neurorehabilitation and identifies important goals that will allow this field to advance.

Upper limb robot mediated stroke therapy - GENTLE/s approach

Stroke is a leading cause of disability in particular affecting older people. Although the causes of stroke are well known and it is possible to reduce these risks, there is still a need to improve rehabilitation techniques. Early studies in the literature suggest that early intensive therapies can enhance a patient's recovery. According to physiotherapy literature, attention and motivation are key factors for motor relearning following stroke. Machine mediated therapy offers the potential to improve the outcome of stroke patients engaged on rehabilitation for upper limb motor impairment. Haptic interfaces are a particular group of robots that are attractive due to their ability to safely interact with humans. They can enhance traditional therapy tools, provide therapy "on demand" and can present accurate objective measurements of a patient's progression. Our recent studies suggest the use of tele-presence and VR-based systems can potentially motivate patients to exercise for longer periods of time. The creation of human-like trajectories is essential for retraining upper limb movements of people that have lost manipulation functions following stroke. By coupling models for human arm movement with haptic interfaces and VR technology it is possible to create a new class of robot mediated neuro rehabilitation tools. This paper provides an overview on different approaches to robot mediated therapy and describes a system based on haptics and virtual reality visualisation techniques, where particular emphasis is given to different control strategies for interaction derived from minimum jerk theory and the aid of virtual and mixed reality based exercises.

Adult skeletal muscle stem cell migration is mediated by a blebbing/amoeboid mechanism

Adult skeletal muscle possesses a resident stem cell population called satellite cells which are responsible for tissue repair following damage. Satellite cell migration is crucial in promoting rapid tissue regeneration but is a poorly understood process. Furthermore, the mechanisms facilitating satellite cell movement have yet to be elucidated. Here the process of satellite cell migration has been investigated revealing that they undergo two distinct phases of movement; firstly under the basal lamina and then rapidly increasing their velocity when on the myofibre surface. Most significantly we show that satellite cells move using a highly dynamic blebbing based mechanism and not via lamellopodia mediated propulsion. We show that nitric oxide and non-canonical Wnt signalling pathways are necessary for regulating the formation of blebs and the migration of satellite cells. In summary, we propose that the formation of blebs and their necessity for satellite cell migration has significant implications in the future development of therapeutic regimes aimed at promoting skeletal muscle regeneration.

c-Jun N-terminal kinase (JNK)-mediated modulation of brain mitochondria function: new target proteins for JNK signalling in mitochondrion-dependent apoptosis

The molecular mechanisms underlying the initiation and control of the release of cytochrome c during mitochondrion-dependent apoptosis are thought to involve the phosphorylation of mitochondrial Bcl-2 and Bcl-x(L). Although the c-Jun N-terminal kinase (JNK) has been proposed to mediate the phosphorylation of Bcl-2/Bcl-x(L) the mechanisms linking the modification of these proteins and the release of cytochrome c remain to be elucidated. This study was aimed at establishing interdependency between JNK signalling and mitochondrial apoptosis. Using an experimental model consisting of isolated, bioenergetically competent rat brain mitochondria, these studies show that (i) JNK catalysed the phosphorylation of Bcl-2 and Bcl-x(L) as well as other mitochondrial proteins, as shown by two-dimensional isoelectric focusing/SDS/PAGE; (ii) JNK-induced cytochrome c release, in a process independent of the permeability transition of the inner mitochondrial membrane (imPT) and insensitive to cyclosporin A; (iii) JNK mediated a partial collapse of the mitochondrial inner-membrane potential (Deltapsim) in an imPT- and cyclosporin A-independent manner; and (iv) JNK was unable to induce imPT/swelling and did not act as a co-inducer, but as an inhibitor of Ca-induced imPT. The results are discussed with regard to the functional link between the Deltapsim and factors influencing the permeability transition of the inner and outer mitochondrial membranes. Taken together, JNK-dependent phosphorylation of mitochondrial proteins including, but not limited to, Bcl-2/Bcl-x(L) may represent a potential of the modulation of mitochondrial function during apoptosis.

Induction of the ferritin gene (ftnA) of Escherichia coli by Fe2+–Fur is mediated by reversal of H-NS silencing and is RyhB independent

FtnA is the major iron-storage protein of Escherichia coli accounting for < or = 50% of total cellular iron. The FtnA gene (ftnA) is induced by iron in an Fe(2+)-Fur-dependent fashion. This effect is reportedly mediated by RyhB, the Fe(2+)-Fur-repressed, small, regulatory RNA. However, results presented here show that ftnA iron induction is independent of RyhB and instead involves direct interaction of Fe(2+)-Fur with an 'extended' Fur binding site (containing five tandem Fur boxes) located upstream (-83) of the ftnA promoter. In addition, H-NS acts as a direct repressor of ftnA transcription by binding at multiple sites (I-VI) within, and upstream of, the ftnA promoter. Fur directly competes with H-NS binding at upstream sites (II-IV) and consequently displaces H-NS from the ftnA promoter (sites V-VI) which in turn leads to derepression of ftnA transcription. It is proposed that H-NS binding within the ftnA promoter is facilitated by H-NS occupation of the upstream sites through H-NS oligomerization-induced DNA looping. Consequently, Fur displacement of H-NS from the upstream sites prevents cooperative H-NS binding at the downstream sites within the promoter, thus allowing access to RNA polymerase. This direct activation of ftnA transcription by Fe(2+)-Fur through H-NS antisilencing represents a new mechanism for iron-induced gene expression.

Oxygen/Glucose deprivation induces a reduction in synaptic AMPA receptors on hippocampal CA3 neurons mediated by mGluR1 and adenosine A3 receptors

Hippocampal CA1 pyramidal neurons are highly sensitive to ischemic damage, whereas neighboring CA3 pyramidal neurons are less susceptible. It is proposed that switching of AMPA receptor (AMPAR) subunits on CA1 neurons during an in vitro model of ischemia, oxygen/glucose deprivation (OGD), leads to an enhanced permeability of AMPARs to Ca2+, resulting in delayed cell death. However, it is unclear whether the same mechanisms exist in CA3 neurons and whether this underlies the differential sensitivity to ischemia. Here, we investigated the consequences of OGD for AMPAR function in CA3 neurons using electrophysiological recordings in rat hippocampal slices. Following a 15 min OGD protocol, a substantial depression of AMPAR-mediated synaptic transmission was observed at CA3 associational/commissural and mossy fiber synapses but not CA1 Schaffer collateral synapses. The depression of synaptic transmission following OGD was prevented by metabotropic glutamate receptor 1 (mGluR1) or A3 receptor antagonists, indicating a role for both glutamate and adenosine release. Inhibition of PLC, PKC, or chelation of intracellular Ca2+ also prevented the depression of synaptic transmission. Inclusion of peptides to interrupt the interaction between GluA2 and PICK1 or dynamin and amphiphysin prevented the depression of transmission, suggesting a dynamin and PICK1-dependent internalization of AMPARs after OGD. We also show that a reduction in surface and total AMPAR protein levels after OGD was prevented by mGluR1 or A3 receptor antagonists, indicating that AMPARs are degraded following internalization. Thus, we describe a novel mechanism for the removal of AMPARs in CA3 pyramidal neurons following OGD that has the potential to reduce excitotoxicity and promote neuroprotection

Adeno-associated virus-8-Mediated intravenous transfer of myostatin propeptide leads to systemic functional improvements of slow but not fast muscle

Myostatin is a member of the transformating growth factor-_ (TGF-_) superfamily of proteins and is produced almost exclusively in skeletal muscle tissue, where it is secreted and circulates as a serum protein. Myostatin acts as a negative regulator of muscle mass through the canonical SMAD2/3/4 signaling pathway. Naturally occurring myostatin mutants exhibit a ‘double muscling’ phenotype in which muscle mass is dramatically increased as a result of both hypertrophy and hyperplasia. Myostatin is naturally inhibited by its own propeptide; therefore, we assessed the impact of adeno associated virus-8 (AAV8) myostatin propeptide vectors when systemically introduced in MF-1 mice. We noted a significant systemic increase in muscle mass in both slow and fast muscle phenotypes, with no evidence of hyperplasia; however, the nuclei-to- cytoplasm ratio in all myofiber types was significantly reduced. An increase in muscle mass in slow (soleus) muscle led to an increase in force output; however, an increase in fast (extensor digitorum longus [EDL]) muscle mass did not increase force output. These results suggest that the use of gene therapeutic regimens of myostatin inhibition for age-related or disease-related muscle loss may have muscle-specific effects.

Professionalism in digitally-mediated project work

Fieldwork in a major construction programme is used to examine what is meant by professionalism where large integrated digital systems are used to design, deliver, and maintain buildings and infrastructure. The increasing ‘professionalization’ of the client is found to change other professional roles and interactions in project delivery. New technologies for approvals and workflow monitoring are associated with new occupational groups; new kinds of professional accountability; and a greater integration across professional roles. Further conflicts also arise, where occupational groups have different understandings of project deliverables and how they are competently achieved. The preliminary findings are important for an increasing policy focus on shareable data, in order for building owners and operators to improve the cost, value, handover and operation of complex buildings. However, it will also have an impact on wider public decision-making processes, professional autonomy, expertise and interdependence. These findings are considered in relation to extant literatures, which problematize the idea of professionalism; and the shift from drawings to shareable data as deliverables. The implications for ethics in established professions and other occupational groups are discussed; directions are suggested for further scholarship on professionalism in digitally mediated project work to improve practices which will better serve society.

Evidence for multiple-antibiotic resistance in Campylobacter jejuni not mediated by CmeB or CmeF

An efflux system, CmeABC, in Campylobacter jejuni was previously described, and a second efflux system, CmeDEF, has now been identified. The substrates of CmeDEF include ampicillin, ethidium bromide, acridine, sodium dodecyl sulfate (SDS), deoxycholate, triclosan, and cetrimide, but not ciprofloxacin or erythromycin. C. jejuni NCTC11168 and two efflux pump knockout strains, cmeB::Kan(r) and cmeF::Kan(r), were exposed to 0.5 to 1 mu g of ciprofloxacin/ml in agar plates. All mutants arising from NCTC11168 were resistant to ciprofloxacin but not to other agents and contained a mutation resulting in the replacement of threonine 86 with isoleucine in the quinolone resistance-determining region of GyrA. Mutants with two distinct phenotypes were selected from the efflux pump knockout strains. Mutants with the first phenotype were resistant to ciprofloxacin only and had the same substitution within GyrA as the NCTC11168-derived mutants. Irrespective of the parent strain, mutants with the second phenotype were resistant to ciprofloxacin, chloramphenicol, tetracycline, ethidium bromide, acridine orange, and SDS and had no mutation in gyrA. These mutants expressed levels of the efflux pump genes cmeB and cmeF and the major outer membrane protein gene porA similar to those expressed by the respective parent strains. No mutations were detected in cmeF or cmeB. Accumulation assays revealed that the mutants accumulated lower concentrations of drug. These data suggest the involvement of a non-CmeB or -CmeF efflux pump or reduced uptake conferring multiple-antibiotic resistance, which can be selected after exposure to a fluoroquinolone.

Enhanced hepatitis C virus genome replication and lipid accumulation mediated by inhibition of AMP-activated protein kinase

Hepatitis C virus (HCV) infection is associated with dysregulation of both lipid and glucose metabolism. As well as contributing to viral replication, these perturbations influence the pathogenesis associated with the virus, including steatosis, insulin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) plays a key role in regulation of both lipid and glucose metabolism. We show here that, in cells either infected with HCV or harboring an HCV subgenomic replicon, phosphorylation of AMPK at threonine 172 and concomitant AMPK activity are dramatically reduced. We demonstrate that this effect is mediated by activation of the serine/threonine kinase, protein kinase B, which inhibits AMPK by phosphorylating serine 485. The physiological significance of this inhibition is demonstrated by the observation that pharmacological restoration of AMPK activity not only abrogates the lipid accumulation observed in virus-infected and subgenomic replicon-harboring cells but also efficiently inhibits viral replication. These data demonstrate that inhibition of AMPK is required for HCV replication and that the restoration of AMPK activity may present a target for much needed anti-HCV therapies.

Ruthenium mediated C–H activation of benzaldehyde thiosemicarbazones: Synthesis, structure and, spectral and electrochemical properties of the resulting complexes

Reaction of five 4R-benzaldehyde thiosemicarbazones (R = OCH3, CH3, H, Cl and NO2) with [ Ru(PPh3)(3)(-CO)(H) Cl] in refluxing methanol in the presence of a base (NEt3) affords complexes of two different types, viz. 1-R and 2-R. In the 1-R complexes the thiosemicarbazone is coordinated to ruthenium as a dianionic tridentate C,N,S-donor via C-H bond activation. Two triphenylphosphines and a carbonyl are also coordinated to ruthenium. The tricoordinated thiosemicarbazone ligand is sharing the same equatorial plane with ruthenium and the carbonyl, and the PPh3 ligands are mutually trans. In the 2-R complexes the thiosemicarbazone ligand is coordinated to ruthenium as a monoanionic bidentate N, S-donor forming a four-membered chelate ring with a bite angle of 63.91(11)degrees. Two triphenylphosphines, a carbonyl and a hydride are also coordinated to ruthenium. The coordinated thiosemicarbazone ligand, carbonyl and hydride constitute one equatorial plane with the metal at the center, where the carbonyl is trans to the coordinated nitrogen of the thiosemicarbazone and the hydride is trans to the sulfur. The two triphenylphosphines are trans. Structures of the 1-CH3 and 2-CH3 complexes have been determined by X-ray crystallography. All the complexes show intense transitions in the visible region, which are assigned, based on DFT calculations, to transitions within orbitals of the thiosemicarbazone ligand. Cyclic voltammetry on the complexes shows two oxidations of the coordinated thiosemicarbazone on the positive side of SCE and a reduction of the same ligand on the negative side.

Globalization and technology-mediated distance education: developing countries’ perspective

The contemporary global economy places great value on highly educated workers but devalues workers in repetitive or low skill jobs. In order to thrive in this new economy, countries must ensure sufficient higher education opportunities for their population. However, a lack of resources is a major barrier faced by many developing countries in expanding their higher education systems. Technology-mediated distance education has the potential to be an invaluable tool in offering educational opportunities to people, if the other necessary conditions for participation are met. Although technology-mediated education was first considered to be a medium to bridge the learning divide across space, today it is feared that it could well become an inequality intensifier. Drawing on examples from developing countries, this paper considers factors regarding implementing technology-mediated distance education, including failure to address contextual issues and possible consequences. Challenges and policy implications are also discussed.

Intramolecular Diels-Alder furan-mediated synthesis of 8-aryl-3, 4-di-hydroisoquinolin-1(2H)-ones, convenient precursors of indeno[1,2,3-ij]isoquinolines

We describe herein preliminary studies on the Intramolecular Diels-Alder Furan-Mediated Synthesis of 8-Aryl-3, 4-di-hydroisoquinolin-1(2H)-ones that constitutes a new, formal synthesis of Indeno[1,2,3-ij]isoquinolines.