RESUMEN
BACKGROUND: Existing evidence suggests that clinician and organisation engagement in research can improve healthcare performance. With the increase in allied health professional (AHP) research activity, it is imperative for healthcare organisations, clinicians, managers, and leaders to understand research engagement specifically within allied health fields. This systematic review aims to examine the value of research engagement by allied health professionals and organisations on healthcare performance. METHODS: This systematic review had a two-stage search strategy. Firstly, the papers from a previous systematic review examining the effect of research engagement in healthcare were screened to identify papers published pre-2012. Secondly, a multi-database search was used to conduct a re-focused update of the previous review, focusing specifically on allied health to identify publications from 2012-2021. Studies which examined the value of allied health research engagement on healthcare performance were included. All stages of the review were conducted by two reviewers independently. Each study was assessed using the appropriate Joanna Briggs Institute critical appraisal tool. A narrative synthesis was completed to analyse the similarities and differences between and within the different study types. RESULTS: Twenty-two studies were included, comprising of mixed research designs, of which six were ranked as high importance. The findings indicated that AHP research engagement appears related to positive findings in improvements to processes of care. The review also identified the most common mechanisms which may link research engagement with these improvements. DISCUSSION: This landmark systematic review and narrative synthesis suggests value in AHP research engagement in terms of both processes of care and more tentatively, of healthcare outcomes. While caution is required because of the lack of robust research studies, overall the findings support the agenda for growing AHP research. Recommendations are made to improve transparent reporting of AHP research engagement and to contribute essential evidence of the value of AHP research engagement. TRIAL REGISTRATION: This systematic review protocol was registered with the international prospective register of systematic reviews, PROSPERO (registration number CRD42021253461 ).
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Técnicos Medios en Salud , Atención a la Salud , Humanos , Instituciones de Salud , OrganizacionesRESUMEN
Cytoplasmic ubiquitin-positive inclusions containing TAR-DNA-binding protein-43 (TDP-43) within motor neurons are the hallmark pathology of sporadic amyotrophic lateral sclerosis (ALS). TDP-43 is a nuclear protein and the mechanisms by which it becomes mislocalized and aggregated in ALS are not properly understood. A mutation in the vesicle-associated membrane protein-associated protein-B (VAPB) involving a proline to serine substitution at position 56 (VAPBP56S) is the cause of familial ALS type-8. To gain insight into the molecular mechanisms by which VAPBP56S induces disease, we created transgenic mice that express either wild-type VAPB (VAPBwt) or VAPBP56S in the nervous system. Analyses of both sets of mice revealed no overt motor phenotype nor alterations in survival. However, VAPBP56S but not VAPBwt transgenic mice develop cytoplasmic TDP-43 accumulations within spinal cord motor neurons that were first detected at 18 months of age. Our results suggest a link between abnormal VAPBP56S function and TDP-43 mislocalization.
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Esclerosis Amiotrófica Lateral/metabolismo , Proteínas de Unión al ADN/metabolismo , Predisposición Genética a la Enfermedad/genética , Proteínas de la Membrana/metabolismo , Sustitución de Aminoácidos/genética , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/patología , Animales , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Cuerpos de Inclusión/genética , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos , Neuronas Motoras/metabolismo , Neuronas Motoras/patología , Mutación Puntual/genética , Transporte de Proteínas/genética , Médula Espinal/metabolismo , Médula Espinal/patología , Médula Espinal/fisiopatología , Proteínas de Transporte VesicularRESUMEN
Neurofilaments are among the most abundant organelles in neurones. They are synthesised in cell bodies and then transported into and through axons by a process termed 'slow axonal transport' at a rate that is distinct from that driven by conventional fast motors. Several recent studies have now demonstrated that this slow rate of transport is actually the consequence of conventional fast rates of movement that are interrupted by extended pausing. At any one time, most neurofilaments are thus stationary. Accumulations of neurofilaments are a pathological feature of several human neurodegenerative diseases suggesting that neurofilament transport is disrupted in disease states. Here, we review recent advances in our understanding of neurofilament transport in both normal and disease states. Increasing evidence suggests that phosphorylation of neurofilaments is a mechanism for regulating their transport properties, possibly by promoting their detachment from the motor(s). In some neurodegenerative diseases, signal transduction mechanisms involving neurofilament kinases and phosphatases may be perturbed leading to disruption of transport.
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Transporte Axonal , Filamentos Intermedios/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Humanos , Neuronas/metabolismo , Neuronas/ultraestructura , FosforilaciónRESUMEN
The neuronal cyclin-dependent kinase p35/cdk5 comprises a catalytic subunit (cdk5) and an activator subunit (p35). To identify novel p35/cdk5 substrates, we utilized the yeast two-hybrid system to screen for human p35 binding partners. From one such screen, we identified beta-catenin as an interacting protein. Confirmation that p35 binds to beta-catenin was obtained by using glutathione S-transferase (GST)-beta-catenin fusion proteins that interacted with both endogenous and transfected p35, and by showing that beta-catenin was present in p35 immunoprecipitates. p35 and beta-catenin also displayed overlapping subcellular distribution patterns in cells including neurons. Finally, we demonstrated that p35/cdk5 phosphorylates beta-catenin. beta-catenin also binds to presenilin-1 and altered beta-catenin/presenilin-1 interactions may be mechanistic in Alzheimer's disease (AD). Abnormal p35/cdk5 activity has also been suggested to contribute to AD. We therefore investigated how modulation of p35/cdk5 activity influenced beta-catenin/presenilin-1 interactions. Inhibition of p35/cdk5 with roscovitine did not alter the steady state levels of either beta-catenin or presenilin-1 but reduced the amount of presenilin-1 bound to beta-catenin. Thus, p35/cdk5 binds and phosphorylates beta-catenin and regulates its binding to presenilin-1. The findings reported here therefore provide a novel molecular framework to connect p35/cdk5 with beta-catenin and presenilin-1 in AD.
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Quinasas Ciclina-Dependientes/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Transactivadores , Enfermedad de Alzheimer/metabolismo , Animales , Células CHO , Calpaína/metabolismo , Corteza Cerebral/citología , Cricetinae , Quinasa 5 Dependiente de la Ciclina , Inhibidores Enzimáticos/farmacología , Humanos , Riñón/citología , Degeneración Nerviosa/metabolismo , Fosforilación , Presenilina-1 , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Purinas/farmacología , Ratas , Roscovitina , beta CateninaRESUMEN
The neuronal adaptor protein X11alpha participates in the formation of multiprotein complexes and intracellular trafficking. It contains a series of discrete protein-protein interaction domains including two contiguous C-terminal PDZ domains. We used the yeast two-hybrid system to screen for proteins that interact with the PDZ domains of human X11alpha, and we isolated a clone encoding domains II and III of the copper chaperone for Cu,Zn-superoxide dismutase-1 (CCS). The X11alpha/CCS interaction was confirmed in coimmunoprecipitation studies plus glutathione S-transferase fusion protein pull-down assays and was shown to be mediated via PDZ2 of X11alpha and a sequence within the carboxyl terminus of domain III of CCS. CCS delivers the copper cofactor to the antioxidant superoxide dismutase-1 (SOD1) enzyme and is required for its activity. Overexpression of X11alpha inhibited SOD1 activity in transfected Chinese hamster ovary cells which suggests that X11alpha binding to CCS is inhibitory to SOD1 activation. X11alpha also interacts with another copper-binding protein found in neurons, the Alzheimer's disease amyloid precursor protein. Thus, X11alpha may participate in copper homeostasis within neurons.
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Proteínas Adaptadoras Transductoras de Señales , Proteínas Portadoras/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Superóxido Dismutasa/metabolismo , Animales , Células CHO , Cricetinae , Humanos , Proteínas de la Membrana , Unión Proteica , Ratas , Superóxido Dismutasa/antagonistas & inhibidores , Transfección , Técnicas del Sistema de Dos HíbridosRESUMEN
Neurofilaments are transported through axons by slow axonal transport. Abnormal accumulations of neurofilaments are seen in several neurodegenerative diseases, and this suggests that neurofilament transport is defective. Excitotoxic mechanisms involving glutamate are believed to be part of the pathogenic process in some neurodegenerative diseases, but there is currently little evidence to link glutamate with neurofilament transport. We have used a novel technique involving transfection of the green fluorescent protein-tagged neurofilament middle chain to measure neurofilament transport in cultured neurons. Treatment of the cells with glutamate induces a slowing of neurofilament transport. Phosphorylation of the side-arm domains of neurofilaments has been associated with a slowing of neurofilament transport, and we show that glutamate causes increased phosphorylation of these domains in cell bodies. We also show that glutamate activates members of the mitogen-activated protein kinase family, and that these kinases will phosphorylate neurofilament side-arm domains. These results provide a molecular framework to link glutamate excitotoxicity with neurofilament accumulation seen in some neurodegenerative diseases.