49 research outputs found
Study protocol - A systematic review and meta-analysis of hypothermia in experimental traumatic brain injury: Why have promising animal studies not been replicated in pragmatic clinical trials?
Traumatic brain injury (TBI) is a major cause of death and permanent disability. Systemic hypothermia, a treatment used in TBI for many decades, has recently been found to be associated with neutral or unfavourable clinical outcomes despite apparently promising preclinical research. Systematic review and metaâanalysis is a tool to summarize literature and observe trends in experimental design and quality that underpin its general conclusions. Here we aim to use these techniques to describe the use of hypothermia in animal TBI models, collating data relating to outcome and both study design and quality. From here we intend to observe correlations between features and attempt to explain any discrepancies found between animal and clinical data. This protocol describes the relevant methodology in detail
Inhibition of Neutrophil Recruitment Partially Explained by Impaired Mobilization from Bone Marrow and Reduced Chemokine Levels
Rapid activation of the innate immune system is critical for an efficient host
response to invading pathogens. However, the inflammatory reaction has to be
strictly controlled to minimize harmful immunopathology. A number of mediators
including the cytokine interleukin-27 (IL-27) appear to be responsible for
limitation and resolution of inflammation. Despite increasing knowledge of its
suppressive effects on T cells, the influence on neutrophils and macrophages
is poorly understood. To determine the role of IL-27 in innate immune
responses we analysed the effect of IL-27 in a T cell independent model of
zymosan-induced peritonitis. Early administration of recombinant IL-27
strongly reduced the number of neutrophils recruited to the peritoneal cavity
after zymosan application as well as the neutrophil frequency in the blood.
Simultaneously, IL-27 reduced the release of neutrophils from the bone marrow
upon inflammation. Although cytokine levels were not affected by IL-27
treatment, the levels of the chemokines KC, MCP-1 and MIP-1α in the peritoneal
fluid were strongly decreased. These findings demonstrate that IL-27 is able
to control mobilisation and recruitment of neutrophils into the peritoneal
cavity and identify a novel mechanism to limit inflammation caused by innate
immune cells
a clinical study protocol
Introduction The approved analgesic and anti-inflammatory drugs ibuprofen and
indometacin block the small GTPase RhoA, a key enzyme that impedes axonal
sprouting after axonal damage. Inhibition of the Rho pathway in a central
nervous system-effective manner requires higher dosages compared with orthodox
cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury
(SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho
inhibition. This has been reassessed by a meta-analysis of the underlying
experimental evidence, which indicates an overall effect size of 20.2%
regarding motor outcome achieved after ibuprofen/indometacin treatment
compared with vehicle controls. In addition, ibuprofen/indometacin may also
limit sickness behaviour, non-neurogenic systemic inflammatory response
syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI.
Consequently, âsmall moleculeâ-mediated Rho inhibition after acute SCI
warrants clinical investigation. Methods and analysis Protocol of an
investigator-initiated clinical open-label pilot trial on high-dose ibuprofen
treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients
will be enrolled in two cohorts treated with 2400â
mg/day ibuprofen for 4 or 12
weeks, respectively. The primary safety end point is an occurrence of serious
adverse events, primarily gastroduodenal bleedings. Secondary end points are
pharmacokinetics, feasibility and preliminary effects on neurological
recovery, neuropathic pain and heterotopic ossifications. The primary safety
analysis is based on the incidence of severe gastrointestinal bleedings.
Additional analyses will be mainly descriptive and casuistic. Ethics and
dissemination The clinical trial protocol was approved by the responsible
German state Ethics Board, and the Federal Institute for Drugs and Medical
Devices. The study complies with the Declaration of Helsinki, the principles
of Good Clinical Practice and all further applicable regulations. This safety
and pharmacokinetics trial informs the planning of a subsequent randomised
controlled trial. Regardless of the result of the primary and secondary
outcome assessments, the clinical trial will be reported as a publication in a
peer-reviewed journal. Trial registration number NCT02096913; Pre-results
Effectiveness of biomaterial-based combination strategies for spinal cord repair â a systematic review and meta-analysis of preclinical literature
Funding This work was supported by the Institute of Medical Sciences of the University of Aberdeen, International Spinal Research Trust, Scottish Rugby Union, RS McDonald Charitable Trust and The European Unionâs Horizon 2020 research and innovation programme (Marie SkĆodowska-Curie grant agreement no. 702213).Peer reviewedPublisher PD
protocol of a prospective, longitudinal study
Background Natural killer (NK) cells comprise the main components of
lymphocyte-mediated nonspecific immunity. Through their effector function they
play a crucial role combating bacterial and viral challenges. They are also
thought to be key contributors to the systemic spinal cord injury-induced
immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to
infection and extends to the post-acute and chronic phases after SCI. Methods
and design The prospective study of NK cell function after traumatic SCI was
carried out in two centers in Berlin, Germany. SCI patients and control
patients with neurologically silent vertebral fracture also undergoing
surgical stabilization were enrolled. Furthermore healthy controls were
included to provide reference data. The NK cell function was assessed at 7
(5â9) days, 14 days (11â28) days, and 10 (8â12) weeks post-trauma. Clinical
documentation included the American Spinal Injury Association (ASIA)
impairment scale (AIS), neurological level of injury, infection status,
concomitant injury, and medications. The primary endpoint of the study is
CD107a expression by NK cells (cytotoxicity marker) 8â12 weeks following SCI.
Secondary endpoints are the NK cellâs TNF-α and IFN-Îł production by the NK
cells 8â12 weeks following SCI. Discussion The protocol of this study was
developed to investigate the hypotheses whether i) SCI impairs NK cell
function throughout the post-acute and sub-acute phases after SCI and ii) the
degree of impairment relates to lesion height and severity. A deeper
understanding of the SCI-IDS is crucial to enable strategies for prevention of
infections, which are associated with poor neurological outcome and elevated
mortality. Trial registration DRKS00009855
The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study
Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84â
h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l Ă 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI
Enhanced axonal response of mitochondria to demyelination offers neuroprotection:implications for multiple sclerosis
Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.</p
Enhanced axonal response of mitochondria to demyelination offers neuroprotection:implications for multiple sclerosis
Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochromecoxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons,and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation.Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.</p
Olfactory Ensheathing Cell Transplantation in Experimental Spinal Cord Injury:Effect size and Reporting Bias of 62 Experimental Treatments: A Systematic Review and Meta-Analysis
Olfactory ensheathing cell (OEC) transplantation is a candidate cellular treatment approach for human spinal cord injury (SCI) due to their unique regenerative potential and autologous origin. The objective of this study was, through a meta-epidemiologic approach, (i) to assess the efficacy of OEC transplantation on locomotor recovery after traumatic experimental SCI and (ii) to estimate the likelihood of reporting bias and/or missing data. A study protocol was finalized before data collection. Embedded into a systematic review and meta-analysis, we conducted a literature research of databases including PubMed, EMBASE, and ISI Web of Science from 1949/01 to 2014/10 with no language restrictions, screened by two independent investigators. Studies were included if they assessed neurobehavioral improvement after traumatic experimental SCI, administrated no combined interventions, and reported the number of animals in the treatment and control group. Individual effect sizes were pooled using a random effects model. Details regarding the study design were extracted and impact of these on locomotor outcome was assessed by meta-regression. Missing data (reporting bias) was determined by Egger regression and Funnel-plotting. The primary study outcome assessed was improvement in locomotor function at the final time point of measurement. We included 49 studies (62 experiments, 1,164 animals) in the final analysis. The overall improvement in locomotor function after OEC transplantation, measured using the Basso, Beattie, and Bresnahan (BBB) score, was 20.3% (95% CI 17.8-29.5). One missing study was imputed by trim and fill analysis, suggesting only slight publication bias and reducing the overall effect to a 19.2% improvement of locomotor activity. Dose-response ratio supports neurobiological plausibility. Studies were assessed using a 9-point item quality score, resulting in a median score of 5 (interquartile range [IQR] 3-5). In conclusion, OEC transplantation exerts considerable beneficial effects on neurobehavioral recovery after traumatic experimental SCI. Publication bias was minimal and affirms the translational potential of efficacy, but safety cannot be adequately assessed. The data justify OECs as a cellular substrate to develop and optimize minimally invasive and safe cellular transplantation paradigms for the lesioned spinal cord embedded into state-of-the-art Phase I/II clinical trial design studies for human SCI