SPINAL STUDIES RESEARCH GROUP
Scientific Research Team: Professor Sally Roberts, Dr Sharon Owen, Dr Karina Wright, Dr Charlotte Hulme, Mrs Annie Kerr
Clinical Team: Mr Sarfraz Ahmad, Mr Birender Balain, Mr Shashank Chitgopkar, Mr Joy Chowdhury, Mr Neil Davison, Mr David C Jaffray, Mr Naveen Kumar, Mr Matthew Ockendon, Mr Aheed Osman, Mr Jayesh Trivedi, Professor Wagih El Masry, and Professor Stephen Eisenstein
PRIMARY CILIA: PRIMARY CILIA – DO THEY PLAY A ROLE IN DEGENERATION OF THE INTERVERTEBRAL DISC AND BACK PAIN?
Scientific Research Team:
Dr Sharon Owen and Professor Sally Roberts
Mr Birender Balain, Mr Shashank Chitgopkar, Mr Neil Davidson, Mr Sarfraz Ahmad, Mr Matthew Ockendon and Mr Jayesh Trivedi
Funded by the Orthopaedic Institute Ltd
Primary cilia are structures found on almost all vertebrate cells. Their function is not clear but they have thousands of proteins and receptors on them and appear to be important in acting as sensors for the cell receiving signals about its chemical and mechanical environment. They are increasingly being found to be abnormal in many diseases, including arthritis. Primary cilia consist of a microtubule-based ‘axoneme’ surrounded by a membrane, which is different to the plasma membrane, and a base which can be detected via staining for the protein pericentrin (Figure 1).
This base links the primary cilia to the cell’s centrosome, which both controls the microtubules (cytoskeleton) of the cell and when it divides. Signalling proteins are transported along the cilium and involve important signalling pathways such as Hedgehog, Wnt and TGF, with any alterations to this transport system impairing the primary cilia’s structure and function.
Figure 1: Microscopic images of primary cilia (stained GREEN, using an antibody to acetlyated α-tubulin) in human intervertebral disc cells cultured in monolayer and the base (pericentrin (RED)). Cell nuclei are stained BLUE (with DAPI). Cells with visible primary cilia are highlighted by an asterix when viewed at a lower magnification in (A);the presence of a break in the axoneme (arrow) may lead to impaired function of the primary cilia (B). Antibodies kindly provided by Dr Martin Knight (QMUL).
Previous research into the role of primary cilia in cartilage and osteoarthritis has been carried out, but at present, there are no current findings as to its presence and role in the human intervertebral disc. However, we hope to change this! In conjunction with Professor Martin Knight’s group based at Queen Mary’s University. London, we have been able to identify primary cilia in both human (Figure 1) and bovine intervertebral disc cells. We have recently been awarded a Travelling Fellowship from Keele University’s Institute of Liberal Arts and Science Fellowship Scheme which will enable Dr Sue McGlashan, an expert in the primary cilia field, to visit our laboratory for approximately 6 weeks at the end of 2017 to study these features further in human disc tissue. As always, are ultimate aim is to understand the processes which lead to degeneration of the intervertebral disc and the causes of back pain.
MCSI (The Midland Centre for Spinal Injuries) Research Report
Clinical Lead: Mr Joy Roy Chowdhury
Members of the Research Team: Dr K Wright, Dr S Owen, Dr Charlotte Hulme, Dr Heidi Fuller, Jayne Edwards (Research Nurse) and Emma Fosbrook (Physiotherapist)
Clinical Support: Mr Aheed Osman and Mr Naveen Kumar
2016-2017 year has been a very busy and productive year for the MCSI (The Midland Centre for Spinal Injuries) research group, establishing new collaborations and moving research forward for Spinal Cord Injury.
We have been very fortunate to receive funding from external sponsors and the Orthopaedic Institute.
2016-17 has seen further integration of clinical activity in the hospital and laboratory research programmes within the Centre the majority of which are national or international collaborative projects.
The completed projects have been presented at various national and international meetings including International Spinal Cord Society Annual Meetings. The majority of these projects have been published in peer reviewed journals.
BIOMARKER DISCOVERY AND USE IN SPINAL CORD INJURY PATIENTS: IDENTIFYING NEW TREATMENT TARGETS AND MARKERS FOR PREDICTING CLINICAL OUTCOME
Sharon Owen, Charlotte Hulme, Heidi Fuller, Naveen Kumar, Joy Chowdhury, Aheed Osman, Sally Roberts, and Karina Wright.
Funded by the Orthopaedic Institute Ltd and the Midland Centre for Spinal Injuries (MCSI), Oswestry
Our main aim is to identify biomarkers from bloods of spinal cord injury (SCI) patients that will predict their outcome neurology. Any such biomarker could then be used to enhance current treatments and rehabilitation regimes to ensure that these patients achieve their best potential clinical outcome.
Routine bloods taken from 82 acutely injured patients within 2 weeks of their injury have been collated and assessed in relation to the severity of their initial injury and their most recent neurological scores. These bloods provided information regarding the patient’s general health such as full blood counts, bone profile measures, liver function, and levels of C-reactive protein, urea and electrolytes. In addition, 45 of these patients were recruited into a study specifically assessing the levels of neurological markers within their bloods. Of these patients, 38 have had blood collected at the sub-acute phase of injury (3 months post-injury) and 30 at 12 months post-injury (chronic injury). At present information regarding neurology scores, both motor and sensory, for 63 patients on admission and at 3 months and 1 year post-injury have also been collected.
Certain routine measures, such as red blood count and albumin levels, appear to correlate with both initial and outcome neurology scores with lower values being associated with reduced neurology. This may reflect the greater likelihood of a more traumatic event having occurred in patients with a more severe SCI, such as, greater blood loss and shock and malnutrition. Of the specific neurology biomarkers assessed so far, S100 calcium binding protein β (S100β) (which is a protein secreted by cells of the central nervous system) appears to be the most promising, with some degree of correlation with long-term motor function in these patients. It is hoped that more patients can be recruited to provide a clearer picture of the predictive potential of these biomarkers.
Alongside this work, we are also using complex analytical techniques to try and identify new biomarkers that have not previously been investigated in relation to SCI. Compared to other medical fields, identification of biomarkers for SCI is relatively limited, therefore there is a possibility that new candidate biomarkers can be found to ensure that the most appropriate and effective biomarkers are being considered. To date, we have examined two different models of SCI, mild ‘contusion’ injury and severe ‘complete’ injury. From these investigations we have identified a large number of proteins that are altered over time following a SCI, several of which are being further studied for their potential as biomarkers of SCI. Assessment of these proteins that change following SCI has also highlighted some of the biological mechanisms that might be altered in response to SCI, including ‘acute phase response signalling’, which may be targets for new therapies to dampen the bodies response to a SCI.
The team are kindly supported by the Midlands Centre for Spinal Injuries (Dr Sharon Owen) and the Orthopaedic Institute (Dr Charlotte Hulme) and would like to thank MCSI staff for all their assistance in obtaining the blood samples.
PEPSCI (PAN-EUROPEAN PAEDIATRIC SPINAL CORD INJURY) - RESEARCH PRIORITIES FOR SPINAL CORD INJURY IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS: AN INTERNATIONAL SERVICE USER SURVEY. MULTI -CENTRE STUDY
Naveen Kumar (Principle Investigator), Joy Chowdhury, Aheed Osman, Jayne Edwards (Research Nurse) and Emma Fosbrook (Physiotherapist)
MCSI have joined an initiative (Dr Julian Taylor - Chief Investigator, Buckinghamshire Healthcare NHS Trust) to establish a Pan-European Paediatric Spinal Cord Injury network of specialists to investigate and standardise the management and care of children and adolescents with Spinal Cord Injury. The PEPSCI collaboration’s mission is to improve the overall management of a rare condition: spinal cord injury in children and adolescents.
This collaboration aims to:
•Standardize acute management, rehabilitation and outpatient care across Europe.
•Improve the understanding of neurological and functional recovery profiles.
•Map psychosocial processes and coping after the spinal cord injury.
•Evaluate cross-cultural differences in physical and psychosocial outcomes.
This is a cross-sectional quantitative survey. The survey which includes three questionnaires will be distributed among children, adolescents and young adults with SCI treated at investigative sites and their parents/caregivers. A fourth questionnaire, the Neurology Form, will be completed by the health care professional. Centres from Europe, North America, South America and Australasia are involved and centres from other parts of the world are encouraged to participate.
Primary aim and objective
The principal aim of this survey is to identify the most important research topics for SCI in children, adolescents and young adults that will enable SCI researchers to scope their future research activities
Secondary aims and objectives
- To assess the quality of life of participating children, adolescents and their caregivers using a validated questionnaire (PedsQL™).
- To evaluate whether research priorities primarily comprise ‘health domains’ or ‘social domains’.
- To examine the relation between quality of life outcomes, life satisfaction scores and advocated research priorities.
- To examine the similarities and differences of advocated research priorities between children and caregivers.
- To compare findings between children, adolescents and young adults with congenital versus acquired spinal cord lesions.
The Robert Jones and Agnes Hunt Orthopaedic Hospital (RJAH) receives no funding from its participation.
MCSI at RJAH was the first to recruit to this PEPSCI cross-sectional quantitative survey. To date (May 12th 2017) the target of 14 (out of 20) has been achieved. Anticipated end date of this multicentre international study is January 2018.
Through this survey child, adolescents and their parents are invited to suggest topics of research and healthcare where researchers and clinicians should focus on. The results of this survey will be used to select future topics for research projects and guidelines.
(European Multicenter Study about Spinal Cord Injury)
MULTICENTRE RESEARCH COLLABORATION FOR SPINAL CORD INJURY
Naveen Kumar (Principle Investigator), Joy Chowdhury, Aheed Osman and Jayne Edwards (Research Nurse)
Midland Centre for Spinal Injuries (MCSI), Oswestry
MCSI have joined an internationally recognized and scientifically successful clinical spinal cord injury network.
European Multicenter Study About Spinal Cord Injury Network.
Patients with acute traumatic spinal cord injury are tested and documented within a fixed time schedule (acute, 4, 12, 24 and 48 weeks) after spinal cord injury and must comply with clearly defined inclusion criteria. The examinations consist of a standard set of neurological and functional assessments. The collected data from each centre is sent to the coordinating centre (Zurich) at regular time intervals to be joined into a central database.
The establishment of combined clinical and functional measures for a qualitative and quantitative assessment of spinal cord function in patients with SCI at different stages during rehabilitation represents a basic requirement to monitor any significant effect of a new treatment. Therefore, several European paraplegic centres involved in the rehabilitation of acute traumatic SCI patients build up a close collaboration for standardised assessment. The aim is to get knowledge about the natural recorder after spinal cord lesion in a larger population of patients in the sense of a historical control group.
MCSI has successfully established a collaboration with the 3 other UK spinal centres for European Multicenter Study About Spinal Cord Injury Network.
Currently we are waiting start date, pending approval of an amended REC. Anticipated end date of this multicentre international study is 04/06/2021.
ECLISP – (EFFICACY OF CONSUMING LCS (LACTOBACILLUS CASEI SHIRTTA) IN SPINAL CORD INJURY PATIENTS)
Naveen Kumar (Principle Investigator), Joy Chowdhury, Aheed Osman, Theresa Garrett (Research Nurse) and Jayne Edwards (Research Nurse)
Midland Centre for Spinal Injuries (MCSI), Oswestry
Funding / Sponsor: Yakult Honsha Co Ltd (YHL)
UK multicentre, randomised, controlled study evaluating efficacy of LCS in prevention of antibiotic acquired diarrhoea (AAD) in spinal cord injury patients. MCSI joined this research (ISRCTN 13119162, MREC N°14/SC/1101,UKCRN ID 17618) in 2014.
The primary objective of this study is to assess the efficacy of a probiotic preparation (Yakult) containing a minimum of 6.5 x 109 Lactobacillus casei Shirota (LcS) compared to placebo for the prevention of AAD. Secondary objective is to analyse the effect of LcS on (i) occurrence of C. difficile diarrhoea; (ii) duration of diarrhoea; (iii) gastrointestinal microbiota and (iv) quality of life.
Participants are aged 18 years and over, any race or gender with a diagnosis of spinal cord injury are included in the research study.
Probiotic administration (all strains and dose information will be recorded) in the intervention group is given within 5 days of antibiotic commencement. The control group receive either placebo or routine clinical care.
The primary study end points include the incidence of diarrhoea associated with antibiotic use and Clostridium difficile infection. The definition of diarrhoea and occurrence of AAD/CDAD and its follow-up period will be recorded as per identified paper. The secondary end points include duration of diarrhoea, Intensive Care Unit (ICU) admission, hospital mortality, length of hospital stay and occurrence of adverse events.
First participant was recruited on 4/11/2014, to date (May 15th 2017) 50 participants have been recruited. The maximum agreed recruitment target from Oswestry was 104. Anticipated end date of this multicentre study is 31/10/2017.
PULSED MAGNETIC STIMULATION – MANAGING SPASTICITY IN SPINAL CORD INJURY (OSSTIM) STUDY – IN SET UP
Andrew Roberts, Sarah Turner, Aheed Osman, Naveen Kumar, Joy Chowdhury, Jan Herman Kuiper and Anand Pandyan (School of Health and Rehabilitation, Keele University)
A joint collaboration with ORLAU
Funding: The Orthopaedic Institute Ltd
Sponsor: The Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Foundation Trust
We plan, in this pilot study, to test whether firstly the application of pulsed magnetic stimulation of the spinal cord is achievable in patients with spinal cord injury (SCI) and secondly whether it has an effect on lower limb spasticity. These results will be used to help design a larger trial, to expand the numbers of participants and variety of pathologies treated.
Participants (in-patients at the Midland Centre for Spinal Injuries) with stable SCI will be randomised to receive either intermittent pulsed magnetic stimulation or no stimulation. Patients will be blinded as to whether they are receiving stimulation (the machine will be active up and placed in the same position for both groups, except the sham group will have the stimulation coil applied in an orientation that does not deliver the magnetic field to the spinal cord). Participants will receive stimulation treatment over the lumbar spine every day for 14 days. Spasticity will be measured both before the treatment (at day 0), at the end of the treatment (day 14).
Objective One: To identify the effect of sub threshold intermittent pulsed stimulation of the spinal cord to beneficially affect spasticity in the lower limbs
Objective Two: To identify the effect of sub threshold intermittent pulsed stimulation of the spinal cord to beneficially affect pain experienced in the lower limbs
Objective Three: To identify the effect of sub threshold intermittent pulsed stimulation of the spinal cord to beneficially affect autonomic dysreflexia in the lower limbs
Recruitment target: 30 patients
Study is awaiting REC and HRA approval before recruitment can commence.
SPINAL CORD INDEPENDENCE MEASURE (SCIM)- VERSION-4
Aheed Osman (Principle Investigator), Naveen Kumar, Joy Chowdhury
Midland Centre for Spinal Injuries (MCSI), Oswestry
The Spinal Cord Independence Measure (SCIM) version- 3, is a current disability scale developed and utilized specifically for patients with spinal cord lesions in order to make the functional assessments of patients with paraplegia or tetraplegia more sensitive to changes. The SCIM includes the following areas of function: self-care (subscore (0-20), respiration and sphincter management (0-40) and mobility (0-40). Each area is scored according to its proportional weight in these patients' general activity. The final score ranges from 0 to 100.
This study is aimed to evaluate the reliability of the SCIM -4 and its sensitivity to functional changes in spinal cord lesion patients compared with the SCIM -3.
Presently we are developing the protocol in order to obtain the relevant approvals.
The MCSI team are constantly contributing to research programmes; we are keen to maintain this pattern into the future.