The Role of Metals in the Neuroregenerative Action of BDNF, GDNF, NGF and Other Neurotrophic Factors.

Mature neurotrophic factors and their propeptides play key roles ranging from the regulation of neuronal growth and differentiation to prominent participation in neuronal survival and recovery after injury. Their signaling pathways sculpture neuronal circuits during brain development and regulate adaptive neuroplasticity. In addition, neurotrophic factors provide trophic support for damaged neurons, giving them a greater capacity to survive and maintain their potential to regenerate their axons. Therefore, the modulation of these factors can be a valuable target for treating or preventing neurologic disorders and age-dependent cognitive decline. Neuroregenerative medicine can take great advantage by the deepening of our knowledge on the molecular mechanisms underlying the properties of neurotrophic factors. It is indeed an intriguing topic that a significant interplay between neurotrophic factors and various metals can modulate the outcome of neuronal recovery. This review is particularly focused on the roles of GDNF, BDNF and NGF in motoneuron survival and recovery from injuries and evaluates the therapeutic potential of various neurotrophic factors in neuronal regeneration. The key role of metal homeostasis/dyshomeostasis and metal interaction with neurotrophic factors on neuronal pathophysiology is also highlighted as a novel mechanism and potential target for neuronal recovery. The progress in mechanistic studies in the field of neurotrophic factor-mediated neuroprotection and neural regeneration, aiming at a complete understanding of integrated pathways, offers possibilities for the development of novel neuroregenerative therapeutic approaches.

Surgical treatment of pathological fractures of the shaft of the humerus.

BACKGROUND: This report deals with the advantages and disadvantages associated with the most commonly used methods of stabilization after a pathologic fracture of the humerus shaft. PATIENTS: A total of 39 patients with 41 metastatic lesions and pathologic fractures of the humerus, treated surgically between 1992 and 2007, were retrospectively analyzed. RESULTS: The rate of local complications was 14.6% (6 of 41). Radial nerve injury was the only local complication and was exclusively observed in patients who underwent open reduction and plate fixation. The overall rate of osteosynthesis failure was 12.2% (5 of 41). Two failures were observed in 21 patients with open reductions and plate fixations, compared with three failures in 20 procedures involving closed reductions and intramedullary stabilization. The 1- and 2-year survival rates were 0.35 and 0.2 in ORIF and 0.07 and 0 in patients with IM fixation retrospectively. CONCLUSION: Intramedullary stabilization is a reliable method for fixation of pathologic fractures of the humerus diaphysis for patients in the advanced stage of metastatic disease. ORIF are preferable to IM fixations for the treatment of metaphyseal fractures and for those patients with a solitary metastasis in the humerus or those with a better prognosis.

Classification of Osteoporotic Thoracolumbar Spine Fractures: Recommendations of the Spine Section of the German Society for Orthopaedics and Trauma (DGOU).

STUDY DESIGN: Expert opinion. OBJECTIVES: Osteoporotic vertebral fractures are of increasing medical importance. For an adequate treatment strategy, an easy and reliable classification is needed. METHODS: The working group "Osteoporotic Fractures" of the Spine Section of the German Society for Orthopaedics and Trauma (DGOU) has developed a classification system (OF classification) for osteoporotic thoracolumbar fractures. The consensus decision followed an established pathway including review of the current literature. RESULTS: The OF classification consists of 5 groups: OF 1, no vertebral deformation (vertebral edema); OF 2, deformation with no or minor (<1/5) involvement of the posterior wall; OF 3, deformation with distinct involvement (>1/5) of the posterior wall; OF 4, loss of integrity of the vertebral frame or vertebral body collapse or pincer-type fracture; OF 5, injuries with distraction or rotation. The interobserver reliability was substantial (κ = .63). CONCLUSIONS: The proposed OF classification is easy to use and provides superior clinical differentiation of the typical osteoporotic fracture morphologies.

Analysis of S100 calcium binding protein B serum levels in different types of traumatic intracranial lesions.

The objective of this study was to determine whether the type of intracranial traumatic lesions, the number of simultaneous traumatic lesions, and the occurrence of skull and facial bone fractures have an influence on S100 calcium binding protein B (S100B) serum levels. Patients with blunt traumatic brain injury were prospectively enrolled into this cohort study over a period of 13 months. Venous blood samples were obtained prior to emergency cranial CT scan in all patients within 3 h after injury. The patients were then assigned into six groups: 1) concussion, 2) epidural hematoma, 3) subdural hematoma, 4) subarachnoid hemorrhage, 5) brain contusions, and 6) brain edema. The study included 1696 head trauma patients with a mean age of 57.7 ± 25.3 years, and 126 patients (8%) had 182 traumatic lesions on CT. Significant differences in S100B serum levels were found between cerebral edema and the other four bleeding groups: epidural p = 0.0002, subdural p < 0.0001, subarachnoid p = 0.0001, brain contusions p = 0.0003, and concussion p < 0.0001. Significant differences in S100B values between patients with one or two intracranial lesions (p = 0.014) or with three (p < 0.0001) simultaneous intracranial lesions were found. In patients with intracranial traumatic lesions, skull fractures, as well as skull and facial bone fractures occurring together, were identified as significant additional factors for the increase in serum S100B levels (p < 0.0001). Older age was also associated with elevated S100B serum levels (p < 0.0001). Our data show that peak S100B serum levels were found in patients with cerebral edema and brain contusions.

Grafted murine induced pluripotent stem cells prevent death of injured rat motoneurons otherwise destined to die.

Human plexus injuries often include the avulsion of one or more ventral roots, resulting in debilitating conditions. In this study the effects of undifferentiated murine iPSCs on damaged motoneurons were investigated following avulsion of the lumbar 4 (L4) ventral root, an injury known to induce the death of the majority of the affected motoneurons. Avulsion and reimplantation of the L4 ventral root (AR procedure) were accompanied by the transplantation of murine iPSCs into the injured spinal cord segment in rats. Control animals underwent ventral root avulsion and reimplantation, but did not receive iPSCs. The grafted iPSCs induced an improved reinnervation of the reimplanted ventral root by the host motoneurons as compared with the controls (number of retrogradely labeled motoneurons: 503 ± 38 [AR+iPSCs group] vs 48 ± 6 [controls, AR group]). Morphological reinnervation resulted in a functional recovery, i.e. the grafted animals exhibited more motor units in their reinnervated hind limb muscles, which produced a greater force than that in the controls (50 ± 2.1% vs 11.9 ± 4.2% maximal tetanic tension [% ratio of operated/intact side]). Grafting of undifferentiated iPSCs downregulated the astroglial activation within the L4 segment. The grafted cells differentiated into neurons and astrocytes in the injured cord. The grafted iPSCs, host neurons and glia were found to produce the cytokines and neurotrophic factors MIP-1a, IL-10, GDNF and NT-4. These findings suggest that, following ventral root avulsion injury, iPSCs are able to induce motoneuron survival and regeneration through combined neurotrophic and cytokine modulatory effects.

Alterations of the biomarker S-100B and NSE in patients with acute vertebral spine fractures.

BACKGROUND CONTEXT: Although several publications concerning the use of the biomarkers S100B and neuron-specific enolase (NSE) in vertebral spine fractures in animal experimental studies have proven their usefulness as early indicators of injury severity, there are no clinical reports on their effectiveness as indicators in patients with spinal injuries. As these biomarkers have been examined, with promising results, in patients with traumatic brain injury, there is a potential for their implementation in patients with vertebral spine fractures. PURPOSE: To investigate the early serum measurement of S100B and NSE in patients with vertebral spine fractures compared with those in patients with acute fractures of the proximal femur. STUDY DESIGN: Prospective longitudinal cohort study. PATIENT SAMPLE: A cohort of 34 patients admitted over an 18-month period to a single medical center for suspected vertebral spine trauma. Twenty-nine patients were included in the control group. OUTCOME MEASURES: S100B and NSE serum levels were assessed in different types of vertebral spine fractures. METHODS: We included patients older than 16 years with vertebral spine fractures whose injuries were sustained within 24 hours before admission to the emergency room and who had undergone a brief neurologic examination. Spinal cord injuries (SCIs) were classified as being paresthesias, incomplete paraplegias, or complete paraplegias. Blood serum was obtained from all patients within 24 hours after the time of injury. Serum levels of S100B and NSE were statistically analyzed using Wilcoxon signed-rank test. RESULTS: S100B serum levels were significantly higher in patients with vertebral spine fractures (p=.01). In these patients, the mean S100B serum level was 0.75 µg/L (standard deviation [SD] 1.44, 95% confidence interval [CI] 0.24, 1.25). The mean S100B serum level in control group patients was 0.14 µg/L (SD 0.11, 95% CI 0.10, 0.19). The 10 patients with neurologic deficits had significantly higher S100B serum levels compared with the patients with vertebral fractures but without neurologic deficits (p=.02). The mean S100B serum level in these patients was 1.18 µg/L (SD 1.96). In the 26 patients with vertebral spine fractures but without neurologic injury, the mean S100B serum level was 0.42 µg/L (SD 0.91, 95% CI 0.08, 0.76). The analysis revealed no significant difference in NSE levels. CONCLUSIONS: We observed a significant correlation not only between S100B serum levels and vertebral spine fractures but also between S100B serum levels and SCIs with neurologic deficit. These results may be meaningful in clinical practice and to future studies.

Spatiotemporally limited BDNF and GDNF overexpression rescues motoneurons destined to die and induces elongative axon growth.

Axonal injury close to cell bodies of motoneurons induces the death of the vast majority of affected cells. Neurotrophic factors, such as brain derived neurotrophic factor (BDNF) and glial cell derived neurotrophic factor (GDNF), delivered close to the damaged motor pool in a non-regulated manner induce good survival of injured motoneurons and sprouting of their axons but fail to induce functional reinnervation. To avoid these drawbacks of high levels of neurotrophic expression, we devised an ex vivo gene therapy system to induce transient expression of BDNF/GDNF in transfected rat adipose tissue-derived stem cells (rASCs) which were grafted around the reimplanted ventral root, embedded in collagen gel. Strong BDNF/GDNF expression was induced in vitro in the first days after transfection with a significant decline in expression 10-14 days following transfection. Numerous axons of injured motoneurons were able to enter the reimplanted root following reimplantation and BDNF or GDNF treatment (192±17 SEM vs 187±12 SEM, respectively) and produce morphological and functional reinnervation. Treatment with a combined cell population (BDNF+GDNF-transfected rASCs) induced slightly improved reinnervation (247±24 SEM). In contrast, only few motoneurons regenerated their axons in control animals (63±4 SEM) which received untransfected cells. The axons of surviving motoneurons showed elongative growth typical of regenerative axons, without aberrant growth or coil formation of sprouting axons. These findings provide evidence that damaged motoneurons require limited and spatially directed amounts of BDNF and GDNF to support their survival and regeneration. Moreover, neurotrophic support appears to be needed only for a critical period of time not longer than for two weeks after injury.

Risk factors indicating the need for cranial CT scans in elderly patients with head trauma: an Austrian trial and comparison with the Canadian CT Head Rule.

OBJECT: This study presents newly defined risk factors for detecting clinically important brain injury requiring neurosurgical intervention and intensive care, and compares it with the Canadian CT Head Rule (CCHR). METHODS: This prospective cohort study was conducted in a single Austrian Level-I trauma center and enrolled a consecutive sample of mildly head-injured adults who presented to the emergency department with witnessed loss of consciousness, disorientation, or amnesia, and a Glasgow Coma Scale (GCS) score of 13-15. The studied population consisted of a large number of elderly patients living in Vienna. The aim of the study was to investigate risk factors that help to predict the need for immediate cranial CT in patients with mild head trauma. RESULTS: Among the 12,786 enrolled patients, 1307 received a cranial CT scan. Four hundred eighty-nine patients (37.4%) with a mean age of 63.9 ± 22.8 years had evidence of an acute traumatic intracranial lesion on CT. Three patients (< 0.1%) were admitted to the intensive care unit for neurological observation and received oropharyngeal intubation. Seventeen patients (0.1%) underwent neurosurgical intervention. In 818 patients (62.6%), no evidence of an acute trauma-related lesion was found on CT. Data analysis showed that the presence of at least 1 of the following factors can predict the necessity of cranial CT: amnesia, GCS score, age > 65 years, loss of consciousness, nausea or vomiting, hypocoagulation, dementia or a history of ischemic stroke, anisocoria, skull fracture, and development of a focal neurological deficit. Patients requiring neurosurgical intervention were detected with a sensitivity of 90% and a specificity of 67% by using the authors' analysis. In contrast, the use of the CCHR in these patients detected the need for neurosurgical intervention with a sensitivity of only 80% and a specificity of 72%. CONCLUSIONS: The use of the suggested parameters proved to be superior in the detection of high-risk patients who sustained a mild head trauma compared with the CCHR rules. Further validation of these results in a multicenter setting is needed. Clinical trial registration no.: NCT00451789 ( ClinicalTrials.gov .).

Rescue of injured motoneurones by grafted neuroectodermal stem cells: effect of the location of graft.

PURPOSE: Avulsion of one or more ventral roots from the spinal cord leads to the death of the majority of affected motoneurons. In this study we investigated whether immortalized clonal neuroectodermal stem cells applied to the injured cord in various ways impart neuroprotection on motoneurons otherwise destined to die. METHODS: The lumbar 4 (L4) ventral root of Sprague-Dawley rats was avulsed and reimplanted ventrolaterally into the injured cord. Clonal neuroectodermal murine stem cells (NE-GFP-4C) were placed in fibrin clot around the reimplanted root, were injected immediately following avulsion into the reimplanted ventral root or directly into the L4 segment. Three months after the primary surgery the L4 motoneuron pool was retrogradely labelled with Fast blue and the numbers of reinnervating motoneurons were determined. Functional recovery was tested biweekly through the use of the CatWalk automated gait analysis system. RESULTS: Transplantation of neuroectodermal stem cells into the reimplanted root or into the L4 spinal segment resulted in similarly extensive regeneration of the motoneurons (671 ± 26 and 711 ± 14 L4 motoneurons, respectively). In these groups significant functional recovery was achieved. The negative controls and animals with periradicular stem cell treatment showed poor motor recovery and reinnervation (42 ± 10 and 65 ± 2.5, respectively). CONCLUSION: This study provides evidence that neuroectodermal stem cell transplantation into the reimplanted ventral root induces as successful regeneration of injured motoneurons as stem cells grafted into the spinal cord.

Predictive value of neuromarkers supported by a set of clinical criteria in patients with mild traumatic brain injury: S100B protein and neuron-specific enolase on trial: clinical article.

OBJECT: The role of the neuromarkers S100B protein and neuron-specific enolase (NSE) in minor head injury is well established. Moreover, there are sensitive decision rules available in the literature to identify clinically important brain lesions. However, it is not clear if using the biomarkers has an influence on the predictability of the decision rule. The purpose of this study was to determine if a set of preclinical and clinical parameters combined with 2 neuromarker levels could serve as reliable guidance for accurate diagnosis. METHODS: Prospective evaluation of a cohort of head trauma patients with Glasgow Coma Scale scores of 13-15 was performed at an academic, Level I trauma center. Blood samples and cranial CT studies were obtained for all patients within 3 hours after injury. The hypothesis of the study was whether the combination of an increase of S100B and NSE levels in serum and other defined risk factors are associated with a pathological finding on CT. A forward stepwise logistic regression model was used. RESULTS: The study included 107 head trauma patients with a mean age of 59 ± 23 years. Twenty-five patients (23.4%) had traumatic lesions on CT. Eight patients underwent craniotomy. The analysis provided a model with good overall accuracy for discriminating cases with clinically important brain injury, including the 6 variables of S100B, NSE, nausea, amnesia, vomiting, and loss of consciousness. The area under the curve (AUC) was 0.88 (0.83-0.93). The receiver operating characteristic curve plots detecting clinically important brain injury for the single variables of S100B and NSE showed an AUC of 0.63 and 0.64, respectively. Conclusions The integration of the neuromarker panel as part of a diagnostic rule including the high-risk factors of nausea, vomiting, amnesia, and loss of consciousness is safe and reliable in determining a diagnosis, pending the availability of more brain-specific neuromarkers. CLINICAL TRIAL REGISTRATION NO.: NCT00622778 (ClinicalTrials.gov).