Targeted Modulation of the Neuroinflammatory Response after Spinal Cord Injury : The Ongoing Quest for the ��Holy Grail��

This Commentary discusses the role of inflammation after spinal cord injury.Healing of the injured spinal cord represents one of the remaining challenging frontiers in medicine. The posttraumatic neuroinflammatory response has been shown to contribute, at least in part, to the development of secondary neuronal cell death.¹ Research strategies to prevent these pathological sequelae after spinal cord injury (SCI) have largely failed in translation from the “bench to beside.”² A classic example related to our lack of understanding the basic immunological mechanisms that lead to delayed neuronal cell death is the failure to administer high-dose methylprednisolone to improve neurological outcome after SCI.³ While considered a standard of care incorporated in clinical guidelines for many years, based on promising data from the NASCIS trials, high-dose steroids recently were recognized to be harmful, rather than beneficial, in the management of acute SCI, and their application in the field of neurotrauma is now considered obsolete.^4,5,6Current research strategies in neurotrauma are therefore aimed at targeting more specific pathways of inflammation, such as the pharmacological inhibition of the complement cascade, which represents the major effector arm of the innate immune system.⁷ Interestingly, the first studies investigating complement activation in patients with SCI were published more than three decades ago. In 1980, Rebhuhn and Botvin⁸ showed that about two-thirds of all patients with SCI had elevated complement levels, and the authors postulated that complement activation may propagate a “self-feeding” immunological response responsible for the failure of regeneration of the injured spinal cord. The recent availability of higher quality complement reagents, including genetically engineered mice and tissue-targeted chimeric complement inhibitors, currently allows for the more detailed elucidation of specific pathways of complement activation involved in the pathophysiology of neuroinflammation after SCI^7,9 (Figure 1).Open in a separate windowFigure 1Simplified depiction of the three traditional complement activation pathways and the potential pharmacological interventions designed to ameliorate the extent of neuroinflammation and neuropathology after spinal cord injury. See text for details.The recent study by Qiao and colleagues¹⁰ published in this issue of The American Journal of Pathology was designed to analyze the role of the alternative activation pathway (factor B) and terminal lytic pathway (C5b-9) in contributing to the secondary neuropathological sequelae after traumatic SCI in adult C57BL/6 mice.¹⁰ In the first part of the study, a traumatic spinal cord contusion was applied to mice with a genetic deficiency for factor B (fB^−/−). These mice therefore lacked a functional alternative pathway of complement activation.¹¹ Impressively, fB^−/− mice showed significantly improved locomotor function scores for up to 21 days after trauma, compared to wild-type controls. The neurological improvement was substantiated by significantly reduced neutrophil infiltration, complement deposition, and tissue damage in the injured spinal cord of fB^−/− mice, compared to that of wild-type littermates. These data imply a crucial role of complement activation, via the alternative pathway, in the development of posttraumatic neuroinflammation and propagation of delayed neuronal injury. In the second part of the study, these positive insights derived from gene knockout mice were translated to a pharmacological approach using a neutralizing monoclonal anti-factor B antibody (mAb1379), which is a potent inhibitor of the alternative complement activation pathway.^12,13 Using a clinically relevant paradigm of systemic (intravenous) compound administration at 1 and 12 hours after trauma, the authors were able to replicate the neuroprotective effects seen in fB^−/− mice, to the pharmacological mAb1379-treatment model in wild-type mice, using vehicle-injected animals as appropriate controls. Finally, the third part of the study was designed to determine the role of the membrane attack complex (C5b-9), as the terminal downstream event of complement activation, in the neuropathophysiology after SCI. For this purpose, mice lacking the gene for the membrane-bound complement regulatory molecule CD59a (CD59a^−/−) were subjected to traumatic spinal cord injury and analyzed by the same outcome parameters as for the fB^−/− mice. One of the putative mechanisms of complement-mediated neuronal death after spinal cord injury is represented by posttraumatic activation of phosphatidyl inositol-specific phospholipase C (PI-PLC), which renders neurons vulnerable to membrane attack complex-mediated lysis by shedding of the glycosyl phosphatidyl inositol-anchored glycoprotein CD59a from neuronal membranes.^14,15 In contrast with data from fB^−/− mice and mAb1379-treated animals, CD59a^−/− mice showed a significant deterioration of neurological scores from 11 to 21 days after SCI, compared to wild-type littermates. In addition, deposition of complement C9, as a surrogate marker for the membrane attack complex (C5b-9), was significantly increased in the spinal cord of CD59a^−/− mice and associated with exacerbated tissue damage and local neutrophil infiltration.¹⁰The exact cellular and molecular mechanisms of complement-mediated neuropathology after spinal cord injury remain far from fully understood. The present study¹⁰ sheds further light toward our understanding of the immunological pathophysiology of SCI, as it offers novel insights into the impact of the different complement activation pathways (classical, alternative, lectin, and terminal pathway) and their involvement in posttraumatic neuroinflammation and neurodegeneration^16,17 (Figure 1).Recent experimental studies have provided initial evidence of involvement of the classical pathway of complement activation in the pathogenesis of neuronal tissue damage and adverse neurological outcome after SCI.¹⁸ In contrast, data from multiple studies on inflammatory conditions in and outside the CNS have revealed that the selective inhibition of the alternative complement pathway may represent a promising new immunomodulatory approach for multiple neuroinflammatory disorders.^{7,11,13,19,20,21} The current experimental study¹⁰ implies that the therapeutic inhibition of the alternative pathway (factor B) during a clinically relevant time window within 1 to 12 hours after trauma may represent a promising new avenue in the search for a pharmacological remedy to host-mediated progressive inflammation and neurodegeneration within the injured spinal cord. In this regard, it is notable that the monoclonal anti-factor B antibody used in the present study has cross-reactivity across species and was originally designed as an anti-human antibody.^12,13 Thus, this specific compound has potential for promising “bench-to-bedside” translation in the future. Similarly, the therapeutic blockade of membrane attack complex assembly, by the use of anti-C9 antibodies, or stimulation/up-regulation of CD59 expression (eg, through gene therapy), may represent a new strategy to avoid “innocent bystander” complement-mediated neuronal lysis after spinal cord injury.Future experimental studies must be designed to titrate the optimal dosage, time window of administration, and time intervals for repeated injections of these new generation complement inhibitory and regulatory molecules. One shortcoming of these therapeutic approaches is the potential for a limited extent of complement inhibition related to the half-life of these compounds and peak concentration at the site of the injured tissue. In this regard, repeated injections at closer time intervals and the use of newly available chimeric compounds consisting of complement inhibitors fused to complement receptors that bind at the site of complement activation, such as CR2-factor H and CR2-Crry molecules,^9,22 may represent the future “golden bullet” for amelioration of complement-mediated exacerbation of SCI.     

Early predictors of mortality in hemodynamically unstable pelvis fractures

OBJECTIVES: To determine reliable, early indicators of mortality and causes of death in hemodynamically unstable patients with pelvic ring injuries. DESIGN: This was a retrospective review of a prospective pelvic database. METHODS: In all, 187 hemodynamically unstable patients with pelvic fractures (persistent systolic blood pressure <90 mm Hg after receiving 2 L of intravenous crystalloid) admitted from April 1998 to November 2004 were included. Intervention was Level 1 Trauma Center-Pelvis Fracture standardized protocol. Main outcome measurements were: Injury Severity Score (ISS), Revised Trauma Score (RTS), age, blood transfusion, mortality, and multisystem organ failure (MOF). RESULTS: Group 1 (39 patients) did not survive their injury. Group 2 (148 patients) survived their injury. Fracture pattern (chi(2) = 9.1, P = 0.33), and treatment with angiography/embolization (chi(2) = 0.054, P = 0.84) were not predictive of death. Patients requiring more blood had a statistically significant higher mortality rate. The ISS (t = -5.62, P < 0.001), RTS (t = 6.10, P < 0.001), age >60 years old (chi(2) = 5.4, P = 0.03), and transfusion (t = -2.70, P = 0.010) were statistically significant independent predictors of mortality. A logistic regression analysis and receiver operating characteristic curves indicated that of these variables, RTS was the most predictive independent variable. However, a model including all four variables was superior at predicting mortality. Most deaths were attributed to exsanguination (74.4%) or MOF (17.9%). CONCLUSIONS: Predictors of mortality in pelvis fracture patients should be available early in the course of treatment in order to be useful. Death within 24 hours was most often a result of acute blood loss while death after 24 hours was most often caused by MOF. Improved survival will depend upon the evolution of early hemorrhage control and resuscitative strategies in patients at high mortality risk.     

Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections

Mutations in the gene encoding smooth muscle cell alpha actin (ACTA2) have recently been shown to cause familial thoracic aortic aneurysms leading to type A dissections (TAAD) and predispose to premature stroke and coronary artery disease. In order to further explore the role of ACTA2 variations in the pathogenesis of TAAD, we sequenced the coding regions of this gene in 40 unrelated German patients with TAAD (with (n=21) or without (n=19) clinical features suggestive of Marfan syndrome). All patients had previously tested negative for mutations in the FBN1 and TGFBR2 genes. We identified three novel ACTA2 mutations and mapped them on a three-dimensional model of actin. Two mutations affect residues within (M49V) or adjacent to (R39C), the DNAse-I-binding loop within subdomain 2 of alpha actin. They were observed in families with recurrent aortic aneurysm (R39C) or aortic dissection (M49V). The third mutation causes an exchange in the vicinity of the ATP-binding site (G304R) in a patient thought to have isolated TAAD. None of the affected individuals had clinical features typical for Marfan syndrome, and no case of premature stroke or coronary artery disease was reported from the affected families. In conclusion, we underscore the role of ACTA2 mutations in nonsyndromic TAAD and suggest that ACTA2 should be included in the genes routinely investigated for syndromic and nonsyndromic TAAD. Detailed clinical investigations of additional families are warranted to further explore the full range of phenotypic signs associated with the three novel mutations described here.     

Taurolidine and povidone-iodine induce different types of cell death in malignant pleural mesothelioma

Taurolidine and povidone-iodine (PVP-I) are used in every day clinical practice, taurolidine as a broad spectrum antibiotic, and PVP-I as an antiseptic. The type of cell death induced in malignant pleural mesothelioma (MPM) cell lines by these agents was compared, and their ability to sensitize to chemotherapy assessed. Both taurolidine and PVP-I inhibited MPM cell growth after 7.5min incubation, but taurolidine was more effective at later time points and was more specific towards tumour cells than PVP-I. Taurolidine induced death by caspase-dependent and independent mechanisms, whereas in contrast, PVP-I induced a necrotic phenotype that was not caspase-dependent. Interestingly, both taurolidine and PVP-I induced the production of reactive oxygen intermediates and decreased mitochondrial membrane permeability, and cell death was inhibited by the oxygen scavenger N-acetyl cysteine. Taurolidine but not PVP-I treatment resulted in p53 activation in 2/3 MPM cell lines and a decrease in the protein levels of survivin, Bcl-2 and Mcl-1. Survivin also decreased in response to PVP-I whereas Bcl-xL remained unaffected by both treatments. Targeting of Bcl-xL with siRNA sensitized MPM cells to taurolidine and taurolidine treatment sensitized MPM cells to cisplatin-induced apoptosis. In conclusion, taurolidine and PVP-I are both cytotoxic to human MPM cells at early and late time points and induce reactive oxygen intermediate production. Taurolidine induces apoptosis and necrosis, activates p53 and sensitizes cells to cisplatin, whereas PVP-I inhibits cell growth via necrosis. Both agents are promising candidates for use in local treatment within multimodality concepts for MPM.     

Bias towards publishing positive results in orthopedic and general surgery: a patient safety issue?

Background  

Research articles reporting positive findings in the fields of orthopedic and general surgery appear to be represented at a considerably higher prevalence in the peer-reviewed literature, compared to published studies on negative or neutral data. This "publication bias" may alter the balance of the available evidence-based literature and may affect patient safety in surgery by depriving important information from unpublished negative studies.     

Das Sjögrensche Syndrom Eine A-Hypo-Vitaminose

Ohne Zusammenfassung