898 research outputs found
Clinical decision-making on spinal cord injury-associated pneumonia: a nationwide survey in Germany
Study design: Survey study.
Objectives: Spinal cord injury (SCI)-associated pneumonia (SCI-AP) is associated with poor functional recovery and a major cause of death after SCI. Better tackling SCI-AP requires a common understanding on how SCI-AP is defined. This survey examines clinical algorithms relevant for diagnosis and treatment of SCI-AP.
Setting: All departments for SCI-care in Germany.
Methods: The clinical decision-making on SCI-AP and the utility of the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of ‘clinically defined pneumonia’ were assessed by means of a standardized questionnaire including eight case vignettes of suspected SCI-AP. The diagnostic decisions based on the case information were analysed using classification and regression trees (CART).
Results: The majority of responding departments were aware of the CDC-criteria (88%). In the clinical vignettes, 38–81% of the departments diagnosed SCI-AP in accordance with the CDC-criteria and 7–41% diagnosed SCI-AP in deviation from the CDC-criteria. The diagnostic agreement was not associated with the availability of standard operating procedures for SCI-AP management in the departments. CART analysis identified radiological findings, fever, and worsened gas exchange as most important for the decision on SCI-AP. Frequently requested supplementary diagnostics were microbiological analyses, C-reactive protein, and procalcitonin. For empirical antibiotic therapy, the departments used (acyl-)aminopenicillins/β-lactamase inhibitors, cephalosporins, or combinations of (acyl-)aminopenicillins/β-lactamase inhibitors with fluoroquinolones or carbapenems.
Conclusions: This survey reveals a diagnostic ambiguity regarding SCI-AP despite the awareness of CDC-criteria and established SOPs. Heterogeneous clinical practice is encouraging the development of disease-specific guidelines for diagnosis and management of SCI-AP
Association of age with the timing of acute spine surgery–effects on neurological outcome after traumatic spinal cord injury
Purpose: To investigate the association of age with delay in spine surgery and the effects on neurological outcome after traumatic spinal cord injury (SCI).
Methods: Ambispective cohort study (2011-2017) in n = 213 patients consecutively enrolled in a Level I trauma center with SCI care in a metropolitan region in Germany. Age-related differences in the injury to surgery interval and conditions associated with its delay (> 12 h after SCI) were explored using age categories or continuous variables and natural cubic splines. Effects of delayed surgery or age with outcome were analyzed using multiple logistic regression.
Results: The median age of the study population was 58.8 years (42.0-74.6 IQR). Older age (>= 75y) was associated with a prolonged injury to surgery interval of 22.8 h (7.2-121.3) compared to 6.6 h (4.4-47.9) in younger patients ( 60 h = 40y 5-20% probability).
Conclusion: Older patient age complexifies surgical SCI care and research. Tackling secondary referral to Level I trauma centers and delayed spine surgery imposes as tangible opportunity to improve the outcome of older SCI patients
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, ‘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
Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury
Resolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodeling and leads to functional deficits. Effective pharmacological treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized proresolving mediator (SPM) hosting potent anti-inflammatory and proresolving properties with potent tissue regenerative actions. Here, we provide evidence that the inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of inflammation and leads to deleterious consequences on neurological outcome in adult female mice. We report that, after spinal cord contusion injury in adult female mice, the biosynthesis of SPM is not induced in the lesion site up to 2 weeks after injury. Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory resolution after SCI, as revealed by accelerated clearance of neutrophils and a reduction in macrophage accumulation at the lesion site. In the search of mechanisms underlying the proresolving actions of MaR1 in SCI, we found that this SPM facilitated several hallmarks of resolution of inflammation, including reduction of proinflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, and CSF3), silencing of major inflammatory intracellular signaling cascades (STAT1, STAT3, STAT5, p38, and ERK1/2), redirection of macrophage activation toward a prorepair phenotype, and increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, MaR1 administration improved locomotor recovery significantly and mitigated secondary injury progression in a clinical relevant model of SCI. These findings suggest that proresolution, immunoresolvent therapies constitute a novel approach to improving neurological recovery after acute SCI.SIGNIFICANCE STATEMENT Inflammation is a protective response to injury or infection. To result in tissue homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution leads to detrimental effects, including propagated tissue damage and impaired wound healing, as occurs after spinal cord injury (SCI). We report that inflammation after SCI is dysregulated in part due to inappropriate synthesis of proresolving lipid mediators. We demonstrate that the administration of the resolution agonist referred to as maresin 1 (MaR1) after SCI actively propagates resolution processes at the lesion site and improves neurological outcome. MaR1 is identified as an interventional candidate to attenuate dysregulated lesional inflammation and to restore functional recovery after SCI
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
(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
Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury
BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines emerging autoantibody synthesis after SCI with binding to conformational spinal cord epitopes and surface peptides located on the intact neuronal membrane.
METHODS: This is a prospective longitudinal cohort study conducted in acute care and inpatient rehabilitation centers in conjunction with a neuropathologic case-control study in archival tissue samples ranging from acute injury (baseline) to several months thereafter (follow-up). In the cohort study, serum autoantibody binding was examined in a blinded manner using tissue-based assays (TBAs) and dorsal root ganglia (DRG) neuronal cultures. Groups with traumatic motor complete SCI vs motor incomplete SCI vs isolated vertebral fracture without SCI (controls) were compared. In the neuropathologic study, B cell infiltration and antibody synthesis at the spinal lesion site were examined by comparing SCI with neuropathologically unaltered cord tissue. In addition, the CSF in an individual patient was explored.
RESULTS: Emerging autoantibody binding in both TBA and DRG assessments was restricted to an SCI patient subpopulation only (16%, 9/55 sera) while being absent in vertebral fracture controls (0%, 0/19 sera). Autoantibody binding to the spinal cord characteristically detected the substantia gelatinosa, a less-myelinated region of high synaptic density involved in sensory-motor integration and pain processing. Autoantibody binding was most frequent after motor complete SCI (grade American Spinal Injury Association impairment scale A/B, 22%, 8/37 sera) and was associated with neuropathic pain medication. In conjunction, the neuropathologic study demonstrated lesional spinal infiltration of B cells (CD20, CD79a) in 27% (6/22) of patients with SCI, the presence of plasma cells (CD138) in 9% (2/22). IgG and IgM antibody syntheses colocalized to areas of activated complement (C9neo) deposition. Longitudinal CSF analysis of an additional single patient demonstrated de novo (IgM) intrathecal antibody synthesis emerging with late reopening of the blood-spinal cord barrier.
DISCUSSION: This study provides immunologic, neurobiological, and neuropathologic proof-of-principle for an antibody-mediated autoimmunity response emerging approximately 3 weeks after SCI in a patient subpopulation with a high demand of neuropathic pain medication. Emerging autoimmunity directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes
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 84 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 × 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
Daratumumab augments alloreactive natural killer cell cytotoxicity towards CD38+ multiple myeloma cell lines in a biochemical context mimicking tumour microenvironment conditions
Differences in the carcinogenic evaluation of glyphosate between the International Agency for Research on Cancer (IARC) and the European Food Safety Authority (EFSA)
The International Agency for Research on Cancer (IARC) Monographs Programme identifies chemicals, drugs, mixtures, occupational exposures, lifestyles and personal habits, and physical and biological agents that cause cancer in humans and has evaluated about 1000 agents since 1971. Monographs are written by ad hoc Working Groups (WGs) of international scientific experts over a period of about 12 months ending in an eight-day meeting. The WG evaluates all of the publicly available scientific information on each substance and, through a transparent and rigorous process,1 decides on the degree to which the scientific evidence supports that substance's potential to cause or not cause cancer in humans. For Monograph 112,2 17 expert scientists evaluated the carcinogenic hazard for four insecticides and the herbicide glyphosate.3 The WG concluded that the data for glyphosate meet the criteria for classification as a probable human carcinogen. The European Food Safety Authority (EFSA) is the primary agency of the European Union for risk assessments regarding food safety. In October 2015, EFSA reported4 on their evaluation of the Renewal Assessment Report5 (RAR) for glyphosate that was prepared by the Rapporteur Member State, the German Federal Institute for Risk Assessment (BfR). EFSA concluded that ?glyphosate is unlikely to pose a carcinogenic hazard to humans and the evidence does not support classification with regard to its carcinogenic potential?. Addendum 1 (the BfR Addendum) of the RAR5 discusses the scientific rationale for differing from the IARC WG conclusion. Serious flaws in the scientific evaluation in the RAR incorrectly characterise the potential for a carcinogenic hazard from exposure to glyphosate. Since the RAR is the basis for the European Food Safety Agency (EFSA) conclusion,4 it is critical that these shortcomings are corrected
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