From lab to clinic : towards a virtual reality platform for routine clinical rehabilitation

Background: Recent advances in technology have led to the widespread commercialisation of virtual reality (VR). Many researchers have investigated the use of VR for rehabilitation; however few have extended VR use into routine clinical practice. This is mainly due to systems being too complex and time consuming or too simple to provide necessary information regarding patient function. Aim: Develop a VR platform that can provide an objective measure of patient function and can be integrated into clinical practice with minimal disruption to routine care. Method: Motion analysis is currently the gold standard for non-invasive measurement of human movement and therefore was implemented in this study to provide an objective analysis of function. A bespoke, cluster based protocol was developed and used to create an avatar and three feedback scenarios for standard orthopaedic rehabilitation exercises (step up, sit to stand, weight transfer). A cohort study was carried out in a hospital clinic with 15 control and 15 intervention orthopaedic rehabilitation patients to assess the effectiveness of feedback and the integration of the system into routine practice. Results/Findings: Visual feedback was successfully delivered using motion capture with minimal disruption to routine practice. Further, provision of feedback may have a positive effect on knee sagittal RoM, although larger scale studies are required to confirm these findings. Discussion and Conclusion: Use of a motion analysis protocol which was designed for purpose allowed integration of the system into routine practice. There was minimal disruption to patient care and use of the system may improve functional outcome of orthopaedic rehabilitation patients

Development of a motion analysis protocol for use in routine clinical care

There is widespread agreement that motion analysis is currently the gold standard for measuring human movement in a non-invasive manner [1]. Current commercially available systems, such as Vicon Plug in Gait (PiG, Vicon Motion Systems, Oxford, UK) have been developed over a number of years and are capable of providing a biomechanical analysis which is robust enough to dictate complex treatment plans, such as multi-level surgery [1]. However, due to the vast capabilities of PiG, it is a time consuming and technically complex protocol to deliver. Additionally, there are currently limited options for delivering motion capture using other protocols which vastly limits the use of motion analysis in other aspects of clinical care, such as outpatient rehabilitation. Cluster based marker sets may provide a faster and less technically complex alternative to models such as PiG; however these are currently not commercially available and have thus far been restricted to research environments. Therefore, the aim of this study was to develop a bespoke cluster based motion analysis protocol (Strathclyde Cluster Model; SCM) capable of calculating lower limb kinematics which could be implemented in routine clinical care in order to expand the use of motion analysis beyond research and complex clinical cases. Further aims included an assessment of the kinematic output and reliability of SCM in comparison to PiG. SCM is a motion analysis protocol which has been developed for routine clinical use, such as outpatient rehabilitation and therefore application of markers and participant calibration is quicker and easier than current commercial alternatives. Further, kinematic output and reliability are comparable between SCM and the current clinical gold standard. Therefore, SCM is a suitable alternative for providing an objective assessment of function and outcome in routine clinical practice

Effects of visual feedback on orthopaedic rehabilitation

Currently, functional outcome following total knee arthroplasty (TKA) is not fully restored, with the majority of TKA patients exhibiting lower functional outcome scores than their healthy counterparts [1]. A contributing factor to limited functional outcome may be the nature of the rehabilitation provided as there is still some controversy regarding the most appropriate methods for rehabilitation delivery [2]. Providing patients with visual feedback during rehabilitation has had a positive effect in other patient populations such as stroke survivors [3] and therefore may also improve the efficacy of orthopaedic rehabilitation. The aim of this study was to develop a visual feedback tool based on real time data from 3D motion capture for routine clinical use. Further aims included determining if provision of augmented feedback was acceptable to patients and whether it had a positive effect on functional outcome. Visual feedback using motion analysis was successfully delivered in a routine clinical environment and was widely acceptable to patients. Further, provision of visual feedback appeared to lead to improved knee range of motion in the sagittal plane in comparison to control patients. However, larger scale studies are required to confirm these positive effects

Development of a bespoke movement analysis protocol for routine clinical use in orthopaedics

Assessment of progress and outcome of orthopaedic interventions are often carried out using subjective observational methods. These may not be the most accurate or sensitive way to assess patient progress (Ong et al. 2008). In contrast, motion capture is currently the gold-standard for measuring human movement (Gage 1993; Cook et al. 2003) and the equipment cost is decreasing, making routine clinical use a possibility. However, current movement analysis protocols and setups are not suited for routine clinical use as they are time consuming and complex. Therefore, the aim of this study was to develop a protocol which could be easily adopted by the orthopaedic community and provide more sensitive outcome measures in routine clinical practice. A bespoke, cluster based marker model (CM) was developed. Kinematics were calculated using the Grood and Suntay (1983) method and the kinematic output was compared to the current clinical gold-standard (Vicon Plug in Gait; PiG). Ten healthy volunteers wore a comprehensive marker set comprised of CM and PiG and performed 10 over-ground walking trials. Hip and knee flexion, abduction and rotation were compared along with ankle dorsi/plantar flexion. T-tests determined any significant difference between models. The cluster based marker set was quick and easy to apply. When comparing the kinematic output between CM and PiG, there were some small but statistically significant differences. Differences were more likely to occur in rotations out with the sagittal plane. CM provides a kinematic output comparable to that of the current clinical gold-standard. Differences in output may be due to different methods for estimating joint centres and calculating kinematics. In conclusion, CM is tailored for clinical use and should be considered the preferred option in routine clinical practice. Using the methods described, a gait test can be conducted in 10 minutes in the clinic by a physiotherapist or nurse

Characterization of Histone Modifications in Late-Stage Rotator Cuff Tendinopathy

The development and progression of rotator cuff tendinopathy (RCT) is multifactorial and likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in RCT, including the role of histone modification, is not well established. Using chromatin immunoprecipitation sequencing, differences in the trimethylation status of H3K4 and H3K27 histones in late-stage RCT compared to control were investigated in this study. For H3K4, 24 genomic loci were found to be significantly more trimethylated in RCT compared to control (p < 0.05), implicating genes such as DKK2, JAG2, and SMOC2 in RCT. For H3K27, 31 loci were shown to be more trimethylated (p < 0.05) in RCT compared to control, inferring a role for EPHA3, ROCK1, and DEFβ115. Furthermore, 14 loci were significantly less trimethylated (p < 0.05) in control compared to RCT, implicating EFNA5, GDF6, and GDF7. Finally, the TGFβ signaling, axon guidance, and regulation of focal adhesion assembly pathways were found to be enriched in RCT. These findings suggest that the development and progression of RCT is, at least in part, under epigenetic control, highlighting the influence of histone modifications in this disorder and paving the way to further understand the role of epigenome in RCT

Hypertension in mice lacking 11beta-hydroxysteroid dehydrogenase type 2

Deficiency of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in humans leads to the syndrome of apparent mineralocorticoid excess (SAME), in which cortisol illicitly occupies mineralocorticoid receptors, causing sodium retention, hypokalemia, and hypertension. However, the disorder is usually incompletely corrected by suppression of cortisol, suggesting additional and irreversible changes, perhaps in the kidney. To examine this further, we produced mice with targeted disruption of the 11β-HSD2 gene. Homozygous mutant mice (11β-HSD2(–/–)) appear normal at birth, but ∼50% show motor weakness and die within 48 hours. Both male and female survivors are fertile but exhibit hypokalemia, hypotonic polyuria, and apparent mineralocorticoid activity of corticosterone. Young adult 11β-HSD2(–/–) mice are markedly hypertensive, with a mean arterial blood pressure of 146 ± 2 mmHg, compared with 121 ± 2 mmHg in wild-type controls and 114 ± 4 mmHg in heterozygotes. The epithelium of the distal tubule of the nephron shows striking hypertrophy and hyperplasia. These histological changes do not readily reverse with mineralocorticoid receptor antagonism in adulthood. Thus, 11β-HSD2(–/–) mice demonstrate the major features of SAME, providing a unique rodent model to study the molecular mechanisms of kidney resetting leading to hypertension. J. Clin. Invest. 103:683–689 (1999

Bifidobacterium castoris strains isolated from wild mice show evidence of frequent host switching and diverse carbohydrate metabolism potential

Members of the gut microbiota genus Bifidobacterium are widely distributed human and animal symbionts believed to exert beneficial effects on their hosts. However, in-depth genomic analyses of animal-associated species and strains are somewhat lacking, particularly in wild animal populations. Here, to examine patterns of host specificity and carbohydrate metabolism capacity, we sequenced whole genomes of Bifidobacterium isolated from wild-caught small mammals from two European countries (UK and Lithuania). Members of Bifidobacterium castoris, Bifidobacterium animalis and Bifodobacterium pseudolongum were detected in wild mice (Apodemus sylvaticus, Apodemus agrarius and Apodemus flavicollis), but not voles or shrews. B. castoris constituted the most commonly recovered Bifidobacterium (78% of all isolates), with the majority of strains only detected in a single population, although populations frequently harboured multiple co-circulating strains. Phylogenetic analysis revealed that the mouse-associated B. castoris clades were not specific to a particular location or host species, and their distribution across the host phylogeny was consistent with regular host shifts rather than host-microbe codiversification. Functional analysis, including in vitro growth assays, suggested that mouse-derived B. castoris strains encoded an extensive arsenal of carbohydrate-active enzymes, including putative novel glycosyl hydrolases such as chitosanases, along with genes encoding putative exopolysaccharides, some of which may have been acquired via horizontal gene transfer. Overall, these results provide a rare genome-level analysis of host specificity and genomic capacity among important gut symbionts of wild animals, and reveal that Bifidobacterium has a labile relationship with its host over evolutionary time scales

Proline-rich tyrosine kinase 2 mediates gonadotropin-releasing hormone signaling to a specific extracellularly regulated kinase-sensitive transcriptional locus in the luteinizing hormone beta-subunit gene

G protein-coupled receptor regulation of gene transcription primarily occurs through the phosphorylation of transcription factors by MAPKs. This requires transduction of an activating signal via scaffold proteins that can ultimately determine the outcome by binding signaling kinases and adapter proteins with effects on the target transcription factor and locus of activation. By investigating these mechanisms, we have elucidated how pituitary gonadotrope cells decode an input GnRH signal into coherent transcriptional output from the LH β-subunit gene promoter. We show that GnRH activates c-Src and multiple members of the MAPK family, c-Jun NH(2)-terminal kinase 1/2, p38MAPK, and ERK1/2. Using dominant-negative point mutations and chemical inhibitors, we identified that calcium-dependent proline-rich tyrosine kinase 2 specifically acts as a scaffold for a focal adhesion/cytoskeleton-dependent complex comprised of c-Src, Grb2, and mSos that translocates an ERK-activating signal to the nucleus. The locus of action of ERK was specifically mapped to early growth response-1 (Egr-1) DNA binding sites within the LH β-subunit gene proximal promoter, which was also activated by p38MAPK, but not c-Jun NH(2)-terminal kinase 1/2. Egr-1 was confirmed as the transcription factor target of ERK and p38MAPK by blockade of protein expression, transcriptional activity, and DNA binding. We have identified a novel GnRH-activated proline-rich tyrosine kinase 2-dependent ERK-mediated signal transduction pathway that specifically regulates Egr-1 activation of the LH β-subunit proximal gene promoter, and thus provide insight into the molecular mechanisms required for differential regulation of gonadotropin gene expression

The effect of exercise on cytokines: implications for musculoskeletal health: a narrative review

The physiological effects of physical exercise are ubiquitously reported as beneficial to the cardiovascular and musculoskeletal systems. Exercise is widely promoted by medical professionals to aid both physical and emotional wellbeing; however, mechanisms through which this is achieved are less well understood. Despite numerous beneficial attributes, certain types of exercise can inflict significant significant physiological stress. Several studies document a key relationship between exercise and immune activation. Activation of the innate immune system occurs in response to exercise and it is proposed this is largely mediated by cytokine signalling. Cytokines are typically classified according to their inflammatory properties and evidence has shown that cytokines expressed in response to exercise are diverse and may act to propagate, modulate or mitigate inflammation in musculoskeletal health. The review summarizes the existing literature on the relationship between exercise and the immune system with emphasis on how exercise-induced cytokine expression modulates inflammation and the immune response

S100A8 & S100A9: alarmin mediated inflammation in tendinopathy

Alarmins S100A8 and S100A9 are endogenous molecules released in response to environmental triggers and cellular damage. They are constitutively expressed in immune cells such as monocytes and neutrophils and their expression is upregulated under inflammatory conditions. The molecular mechanisms that regulate inflammatory pathways in tendinopathy are largely unknown therefore identifying early immune effectors is essential to understanding the pathology. Based on our previous investigations highlighting tendinopathy as an alarmin mediated pathology we sought evidence of S100A8 & A9 expression in a human model of tendinopathy and thereafter, to explore mechanisms whereby S100 proteins may regulate release of inflammatory mediators and matrix synthesis in human tenocytes. Immunohistochemistry and quantitative RT-PCR showed S100A8 & A9 expression was significantly upregulated in tendinopathic tissue compared with control. Furthermore, treating primary human tenocytes with exogenous S100A8 & A9 significantly increased protein release of IL-6, IL-8, CCL2, CCL20 and CXCL10; however, no alterations in genes associated with matrix remodelling were observed at a transcript level. We propose S100A8 & A9 participate in early pathology by modulating the stromal microenvironment and influencing the inflammatory profile observed in tendinopathy. S100A8 and S100A9 may participate in a positive feedback mechanism involving enhanced leukocyte recruitment and release of pro-inflammatory cytokines from tenocytes that perpetuates the inflammatory response within the tendon in the early stages of disease