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Study design Systematic review and meta-analysis of preclinical literature. Objectives To assess the effects of biomaterial-based combination (BMC) strategies for the treatment of Spinal Cord Injury (SCI), the effects of individual biomaterials in the context of BMC strategies, and the factors influencing their efficacy. To assess the effects of different preclinical testing paradigms in BMC strategies. Methods We performed a systematic literature search of Embase, Web of Science and PubMed. All controlled preclinical studies describing an in vivo or in vitro model of SCI that tested a biomaterial in combination with at least one other regenerative strategy (cells, drugs, or both) were included. Two review authors conducted the study selection independently, extracted study characteristics independently and assessed study quality using a modified CAMARADES checklist. Effect size measures were combined using random-effects models and heterogeneity was explored using meta-regression with tau2, I2 and R2 statistics. We tested for small-study effects using funnel plot–based methods. Results 134 publications were included, testing over 100 different BMC strategies. Overall, treatment with BMC therapies improved locomotor recovery by 25.3% (95% CI, 20.3–30.3; n = 102) and in vivo axonal regeneration by 1.6 SD (95% CI 1.2–2 SD; n = 117) in comparison with injury only controls. Conclusion BMC strategies improve locomotor outcomes after experimental SCI. Our comprehensive study highlights gaps in current knowledge and provides a foundation for the design of future experiments.

Study Design: Prospective cohort study. Objectives: The purpose of this prospective study was to evaluate a protocol for radiation-sparing kyphoplasty by assessing dosemetrically recorded radiation exposures to both patient and surgeon. Methods: This prospective clinical study examines the radiation exposure to patient and surgeon during single-level kyphoplasty in 32 thoracolumbar osteoporotic vertebral body fractures (12 OF 2, 9 OF 3, 11 OF 4 types) using a radiation aware surgical protocol between May 2017 and November 2019. The radiation exposure was measured at different locations using film, eye lens and ring dosemeters. Dose values are reported under consideration of lower detection limits of each dosemeter type. Results: A high proportion of dosemeter readings was below the lower detection limits, especially for the surgeon (>90%). Radiation exposure to the surgeon was highest at the unprotected thyroid gland (0.053 ± 0.047 mSv), however only slightly above the lower detection limit of dosemeters (0.044 mSv). Radiation exposure to the patient was highest at the chest (0.349 ± 0.414 mSv) and the gonad (0.186 ± 0.262 mSv). Fluoroscopy time, dose area product and number of fluoroscopic images were 46.0 ± 17.9 sec, 124 ± 109 cGy×cm2, and 35 ± 13 per kyphoplasty, respectively. Back pain significantly improved from 6.8 ± 1.6 to 2.5 ± 1.7 on the numeric rating scale on the first postoperative day ( P < 0.0001). Conclusions: The implementation of a strict intraoperative radiation protection protocol allows for safely performed kyphoplasty with ultra-low radiation exposure for the patient and surgeon without exceeding the annual occupational dose limits. Trial registration: The study was registered in the German Clinical Trials Register (DRKS00011908, registration date 16/05/2017).

Background Deep surgical site infections (dSSIs) after instrumented spinal surgery pose major therapeutic challenges. Standard treatment involves surgical debridement, wound drainage, and long-term antibiotic administration. Autologous platelet-rich fibrin (PRF) constitutes a biomaterial obtained from patients’ own blood that contains leukocytes, chemokines and growth factors boosting cicatrization. Due to favorable results reported from other surgical disciplines such as dentistry, orthopedics, maxillofacial and plastic surgery using PRF, the authors hypothesized that PRF augmentation will promote wound healing in dSSIs. Objective To report our preliminary results on the safety and efficacy of autologous-PRF as an add-on therapy on a pilot case series of persistent dSSI after instrumented spinal surgery. Methods Among the 293 patients who underwent dorsal decompression and stabilization of the cervical, thoracic, and lumbar spine due to degenerative diseases in our department, 12 patients (4%) presented persisting dSSI after standard wound debridement and antibiotic treatment. PRF augmentation was used during a second surgical revision as an add-on therapy to standard debridement. In all cases, the wound was primarily closed without drains. Results Wound healing was completed between 14 and 21 days after the second surgical revision in all patients. At a median follow-up of 8 months (range: 6 to 18 months), no recurrence of dSSI nor complications were encountered in any case. Conclusions Our preliminary results suggest that PRF augmentation in persistent dSSI after instrumented spinal surgery appears to be a safe and effective strategy to promote wound healing. Prospective controlled studies are required to define the efficiency of PRF more clearly in both treating and preventing dSSI.

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. Electronic supplementary material The online version of this article (10.1007/s00401-020-02179-x) contains supplementary material, which is available to authorized users.

OBJECTIVEIntraoperative 3D imaging and navigation is increasingly used for minimally invasive spine surgery. A novel, noninvasive patient tracker that is adhered as a mask on the skin for 3D navigation necessitates a larger intraoperative 3D image set for appropriate referencing. This enlarged 3D image data set can be acquired by a state-of-the-art 3D C-arm device that is equipped with a large flat-panel detector. However, the presumably associated higher radiation exposure to the patient has essentially not yet been investigated and is therefore the objective of this study.METHODSPatients were retrospectively included if a thoracolumbar 3D scan was performed intraoperatively between 2016 and 2019 using a 3D C-arm with a large 30 × 30–cm flat-panel detector (3D scan volume 4096 cm3) or a 3D C-arm with a smaller 20 × 20–cm flat-panel detector (3D scan volume 2097 cm3), and the dose area product was available for the 3D scan. Additionally, the fluoroscopy time and the number of fluoroscopic images per 3D scan, as well as the BMI of the patients, were recorded.RESULTSThe authors compared 62 intraoperative thoracolumbar 3D scans using the 3D C-arm with a large flat-panel detector and 12 3D scans using the 3D C-arm with a small flat-panel detector. Overall, the 3D C-arm with a large flat-panel detector required more fluoroscopic images per scan (mean 389.0 ± 8.4 vs 117.0 ± 4.6, p < 0.0001), leading to a significantly higher dose area product (mean 1028.6 ± 767.9 vs 457.1 ± 118.9 cGy × cm2, p = 0.0044).CONCLUSIONSThe novel, noninvasive patient tracker mask facilitates intraoperative 3D navigation while eliminating the need for an additional skin incision with detachment of the autochthonous muscles. However, the use of this patient tracker mask requires a larger intraoperative 3D image data set for accurate registration, resulting in a 2.25 times higher radiation exposure to the patient. The use of the patient tracker mask should thus be based on an individual decision, especially taking into considering the radiation exposure and extent of instrumentation.

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults with peak incidence in patients older than 65 years. These patients are mostly underrepresented in clinical trials and often undertreated due to concomitant diseases. Recently, different therapeutic approaches for elderly patients with GBM were discussed. To date, there is no defined standard treatment. The aim of the present study is to evaluate the functional and oncological outcome in surgical treatment of elderly patients. A total of 342 elderly patients aged ≥ 65 years were retrospectively analyzed in our neurosurgical center. Surgical therapy, adjuvant treatment, overall survival (OS) and functional outcome using Karnofsky performance scale (KPS) and Neurological assessment of neuro-oncology-score were analyzed. The median age at GBM diagnosis was 73.4 (IQR 9.28) years. Median overall survival was 7.5 (CI 95% 6.0–9.1) months and median preoperative or postoperative KPS was 80 (IQR 20). Surgical resection was performed in 216 (63.2%) patients, in 125 patients (36.5%) patients a stereotactic biopsy was performed. The median OS was significantly higher in patients with gross total resection (GTR) compared to partial resection and biopsy (10.8 months; CI 95% 9.5–12.3). Patients with combined radio- and chemo-therapy (RCT) showed significant longer OS, particularly MGMT-negative GBM. Higher preoperative KPS was found to be associated with improved overall survival. GTR and adjuvant combined RCT provides benefits for overall survival in elderly patients. Therapy decision should be made in regard to preoperative functional status instead of biological age.

Purpose The violation of the cranial adjacent facet is a frequent complication in lumbar instrumentations and can induce local pain and adjacent segment disease. Minimally invasive screw implantation is often stated as risk factor in comparison with open approaches. Percutaneous pedicle screw placement (PPSP) can be performed using single X-ray images (fluoroscopy) or intraoperative 3D navigation. The study compares top-level screws in percutaneous lumbar instrumentations regarding facet violations and screw pedicle position using navigation or fluoroscopy. Methods Patients after lumbar PPSP were retrospectively separated according to the intraoperative technique: navigation (NAV) or fluoroscopy (FLUORO). Two blinded investigators graded the top-level screws regarding facet violations and pedicle breach in postoperative CT scans. Subsequent matched cohort analysis was performed for comparable groups. Results Evaluating 768 screws, we assessed 70 (9.1%) facet violations. Overall, 186 (24.2%) screws were implanted using navigation. There was no significant difference in the rate of facet violations between both imaging groups (NAV 19/186, 10.2%, FLUORO 51/582, 8.8%, p = 0.55). Totally, 728 (94.8%) of all screws showed a correct pedicle position. Most of the 40 unfavorable pedicle positions were placed by fluoroscopy (NAV 4/186, 2.2%, FLUORO 36/582, 6.6%, p = 0.03). The matched cohorts verified these results (facet violations: NAV 19/186, 10.2%, FLUORO 18/186, 9.7%, p = 0.55; pedicle penetrations: NAV 4/186, 2.2%, FLUORO 12/186, 6.9%, p = 0.04). Conclusions Both intraoperative imaging techniques allow lumbar PPSP with low rates of cranial facet violations if the surgeon intends to preserve facet integrity. Navigation was superior concerning accurate pedicle screw position, but could not significantly prevent facet violations.

ObjectiveTo determine whether and to what degree bias and underestimated variability undermine the predictive value of preclinical research for clinical translation.MethodsWe investigated experimental spinal cord injury (SCI) studies for outcome heterogeneity and the impact of bias. Data from 549 preclinical SCI studies including 9,535 animals were analyzed with meta-regression to assess the effect of various study characteristics and the quality of neurologic recovery.ResultsOverall, the included interventions reported a neurobehavioral outcome improvement of 26.3% (95% confidence interval 24.3–28.4). Response to treatment was dependent on experimental modeling paradigms (neurobehavioral score, site of injury, and animal species). Applying multiple outcome measures was consistently associated with smaller effect sizes compared with studies applying only 1 outcome measure. More than half of the studies (51.2%) did not report blinded assessment, constituting a likely source of evaluation bias, with an overstated effect size of 7.2%. Assessment of publication bias, which extrapolates to identify likely missing data, suggested that between 2% and 41% of experiments remain unpublished. Inclusion of these theoretical missing studies suggested an overestimation of efficacy, reducing the effect sizes by between 0.9% and 14.3%.ConclusionsWe provide empirical evidence of prevalent bias in the design and reporting of experimental SCI studies, resulting in overestimation of the effectiveness. Bias compromises the internal validity and jeopardizes the successful translation of SCI therapies from the bench to bedside.

Observational studies investigating large real-life datasets are a valuable resource in clinical research. Understanding the imperfect nature of clinical data, statistical approaches factoring in known confounders are instrumental for rigorously addressing bias.1 Our recent work identifying pneumonia and postoperative wound infections (Pn/Wi) as risk markers for impaired long-term functional recovery and survival after spinal cord injury (SCI)2 was considered as a strong statistical analysis.3 However, some unexplored putative confounders in terms of nonrandom loss to follow-up, temporal changes in clinical practice, and exclusion criteria were discussed.3 In order to evaluate and objectivize for the probability of attrition and temporal and selection bias, we apply and discuss an array of analytical tools extending beyond the format of the original publication.2

Objective:To investigate whether prevalent hospital-acquired pneumonia and wound infection affect the clinical long-term outcome after acute traumatic spinal cord injury (SCI).Methods:This was a longitudinal cohort study within the prospective multicenter National Spinal Cord Injury Database (Birmingham, Alabama). We screened datasets of 3,834 patients enrolled in 20 trial centers from 1995 to 2005 followed up until 2016. Eligibility criteria were cervical SCI and American Spinal Cord Injury Association impairment scale A, B, and C. Pneumonia or postoperative wound infections (Pn/Wi) acquired during acute medical care/inpatient rehabilitation were analyzed for their association with changes in the motor items of the Functional Independence Measure (FIMmotor) using regression models (primary endpoint 5-year follow-up). Pn/Wi-related mortality was assessed as a secondary endpoint (10-year follow-up).Results:A total of 1,203 patients met the eligibility criteria. During hospitalization, 564 patients (47%) developed Pn/Wi (pneumonia n = 540; postoperative wound infection n = 11; pneumonia and postoperative wound infection n = 13). Adjusted linear mixed models after multiple imputation revealed that Pn/Wi are significantly associated with lower gain in FIMmotorup to 5 years after SCI (−7.4 points, 95% confidence interval [CI] −11.5 to −3.3). Adjusted Cox regression identified Pn/Wi as a highly significant risk factor for death up to 10 years after SCI (hazard ratio 1.65, 95% CI 1.26 to 2.16).Conclusion:Hospital-acquired Pn/Wi are predictive of propagated disability and mortality after SCI. Pn/Wi qualify as a potent and targetable outcome-modifying factor. Pn/Wi prevention constitutes a viable strategy to protect functional recovery and reduce mortality. Pn/Wi can be considered as rehabilitation confounders in clinical trials.

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, ‘small molecule’-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 2400 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.

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., This meta-analysis study examines the effects of transplanting olfactory ensheathing cells in rodents with experimental spinal cord injury, finding evidence for significant recovery and identifying aspects of the procedure that influence the effect size., Author Summary Spinal cord injury converts into a debilitating disease affecting millions of chronic patients worldwide. Despite increased molecular knowledge over the last decades, no causal pharmacological or cellular therapy has proven effective so far. Due to their unique regenerative capabilities and their autologous origin, olfactory ensheathing cells (OECs) constitute an appealing candidate for topical cell transplantation. In contrast to few and heterogeneous experimental reports of OEC transplantation after spinal cord injury in humans, a considerable number of preclinical studies have been conducted applying OEC transplantation in rodent models. We set out to conduct a systematic review and meta-analysis to assess preclinical efficacy of OEC transplantation. We detected a significant overall increase of functional neurological recovery in animals after OEC transplantation compared to the control group. This effect was not distorted by publication bias. We identified several specific hallmarks of the cell transplantation procedure that determine the effect size of the transplantation. Our findings delineate conditions for optimized OEC transplantation into lesioned spinal cords and its relevance for effective translation to human 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 meta‐analysis 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.

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.

Importance Blockade of small GTPase-RhoA signaling pathway is considered a candidate translational strategy to improve functional outcome after spinal cord injury (SCI) in humans. Pooling preclinical evidence by orthodox meta-analysis is confounded by missing data (publication bias). Objective To conduct a systematic review and meta-analysis of RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) blocking approaches to (1) analyze the impact of bias that may lead to inflated effect sizes and (2) determine the normalized effect size of functional locomotor recovery after experimental thoracic SCI. Evidence Review We conducted a systematic search of PubMed, EMBASE, and Web of Science and hand searched related references. Studies were selected if they reported the effect of RhoA/ROCK inhibitors (C3-exoenzmye, fasudil, Y-27632, ibuprofen, siRhoA, and p21) in experimental spinal cord hemisection, contusion, or transection on locomotor recovery measured by the Basso, Beattie, and Bresnahan score or the Basso Mouse Scale for Locomotion. Two investigators independently assessed the identified studies. Details of individual study characteristics from each publication were extracted and effect sizes pooled using a random effects model. We assessed risk for bias using a 9-point-item quality checklist and calculated publication bias with Egger regression and the trim and fill method. A stratified meta-analysis was used to assess the impact of study characteristics on locomotor recovery. Findings Thirty studies (725 animals) were identified. RhoA/ROCK inhibition was found to improve locomotor outcome by 21% (95% CI, 16.0-26.6). Assessment of publication bias by the trim and fill method suggested that 30% of experiments remain unpublished. Inclusion of these theoretical missing studies suggested a 27% overestimation of efficacy, reducing the overall efficacy to a 15% improvement in locomotor recovery. Low study quality was associated with larger estimates of neurobehavioral outcome. Conclusions and Relevance Taking into account publication bias, RhoA/ROCK inhibition improves functional outcome in experimental SCI by 15%. This is a plausible strategy for the pharmacological augmentation of neurorehabilitation after human SCI. These findings support the necessity of a systematic analysis to identify preclinical bias before embarking on a clinical trial.

Infection with influenza virus can result in massive pulmonary infiltration and potentially fatal immunopathology. Understanding the endogenous mechanisms that control immunopathology could provide a key to novel adjunct therapies for this disease. Here we show that the cytokine IL-27 plays a crucial role in protection from exaggerated inflammation during influenza virus infection. Using Il-27ra −/− mice, IL-27 was found to limit immunopathology, neutrophil accumulation, and dampened TH1 or TH17 responses via IL-10–dependent and -independent pathways. Accordingly, the absence of IL-27 signals resulted in a more severe disease course and in diminished survival without impacting viral loads. Consistent with the delayed expression of endogenous Il-27p28 during influenza, systemic treatment with recombinant IL-27 starting at the peak of virus load resulted in a major amelioration of lung pathology, strongly reduced leukocyte infiltration and improved survival without affecting viral clearance. In contrast, early application of IL-27 impaired virus clearance and worsened disease. These findings demonstrate the importance of IL-27 for the physiological control of immunopathology and the potential value of well-timed IL-27 application to treat life-threatening inflammation during lung infection., Author Summary Annual epidemics of influenza result in 3 to 5 million cases of severe illness and approximately 300,000 deaths around the world. Although most patients infected with normal circulating influenza A viruses recover from the illness, complications arise during infections with highly pathogenic strains of the virus, resulting in increased mortality associated with severe immunopathology and acute respiratory distress. Previous studies suggested a major contribution of the vigorous immune response to lung damage. How the immune system constrains the negative impact of inflammation might therefore be of significant importance for future therapies. Our study in a mouse model of influenza shows that the cytokine IL-27 plays a crucial role in survival by protecting against lung damage. Its actions include regulation of innate (neutrophil influx) and adaptive (inflammatory cytokine production of T cells) arms of immunity during the acute respiratory infection. The data also suggest a therapeutic potential of IL-27, as mice treated with recombinant cytokine at later stages of infection exhibited decreased immunopathology and showed improved survival. The findings uncover an important role of IL-27 in limiting the collateral damages of anti-viral immunity and provide initial evidence that these mechanisms might be exploited for the management of severe immunopathology after infection.

Background There is currently only one clinically approved drug, tissue plasminogen activator (tPA), for the treatment of acute ischaemic stroke. The RhoA pathway, including RhoA and its downstream effector Rho kinase (ROCK), has been identified as a possible therapeutic target. Our aim was to assess the impact of study design characteristics and study quality on reported measures of efficacy and to assess for the presence and impact of publication bias. Methods We conducted a systematic review and meta-analysis on publications describing the efficacy of RhoA and ROCK inhibitors in animal models of focal cerebral ischaemia where outcome was assessed as a change in lesion size or neurobehavioural score, or both. Results We identified 25 published papers which met our inclusion criteria. RhoA and ROCK inhibitors reduced lesion size by 37.3% in models of focal cerebral ischaemia (95% CI, 28.6% to 46.0%, 41 comparisons), and reduced neurobehavioural data by 40.5% (33.4% to 47.7%, 30 comparisons). Overall study quality was low (median=4, interquartile range 3–5) and measures to reduce bias were seldom reported. Publication bias was prevalent and associated with a substantial overstatement of efficacy for lesion size. Conclusions RhoA and ROCK inhibitors appear to be effective in animal models of stroke. However the low quality score, publication bias and limited number of studies are areas which need attention prior to conducting clinical trials.

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 (5–9) days, 14 days (11–28) days, and 10 (8–12) 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) 8–12 weeks following SCI. Secondary endpoints are the NK cell’s TNF-α and IFN-γ production by the NK cells 8–12 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.

Background Infections are the leading cause of death in the acute phase following spinal cord injury and qualify as independent risk factor for poor neurological outcome (“disease modifying factor”). The enhanced susceptibility for infections is not stringently explained by the increased risk of aspiration in tetraplegic patients, neurogenic bladder dysfunction, or by high-dose methylprednisolone treatment. Experimental and clinical pilot data suggest that spinal cord injury disrupts the balanced interplay between the central nervous system and the immune system. The primary hypothesis is that the Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS) is 'neurogenic’ including deactivation of adaptive and innate immunity with decreased HLA-DR expression on monocytes as a key surrogate parameter. Secondary hypotheses are that the Immune Depression Syndrome is i) injury level- and ii) severity-dependent, iii) triggers transient lymphopenia, and iv) causes qualitative functional leukocyte deficits, which may endure the post-acute phase after spinal cord injury. Methods/Design SCIentinel is a prospective, international, multicenter study aiming to recruit about 118 patients with acute spinal cord injury or control patients with acute vertebral fracture without neurological deficits scheduled for spinal surgery. The assessment points are: i)