Showing papers in "Journal of Neurotrauma in 2004"
TL;DR: A novel survey was performed in which subjects were asked to rank seven functions in order of importance to their quality of life, and regained arm and hand function was most important to quadriplegics, while regaining sexual function was the highest priority for paraplegics.
Abstract: In the United States alone, there are more than 200,000 individuals living with a chronic spinal cord injury (SCI). Healthcare for these individuals creates a significant economic burden for the country, not to mention the physiological, psychological, and social suffering these people endure everyday. Regaining partial function can lead to greater independence, thereby improving quality of life. To ascertain what functions are most important to the SCI population, in regard to enhancing quality of life, a novel survey was performed in which subjects were asked to rank seven functions in order of importance to their quality of life. The survey was distributed via email, postal mail, the internet, interview, and word of mouth to the SCI community at large. A total of 681 responses were completed. Regaining arm and hand function was most important to quadriplegics, while regaining sexual function was the highest priority for paraplegics. Improving bladder and bowel function was of shared importance to both injury groups. A longitudinal analysis revealed only slight differences between individuals injured 3 years. The majority of participants indicated that exercise was important to functional recovery, yet more than half either did not have access to exercise or did not have access to a trained therapist to oversee that exercise. In order to improve the relevance of research in this area, the concerns of the SCI population must be better known and taken into account. This approach is consistent with and emphasized by the new NIH roadmap to discovery.
1,714 citations
TL;DR: The pathology of human spinal cord injury is reviewed, focusing on potential differences between humans and experimental animals, as well as on aspects that may have mechanistic or therapeutic relevance.
Abstract: This article reviews the pathology of human spinal cord injury (SCI), focusing on potential differences between humans and experimental animals, as well as on aspects that may have mechanistic or therapeutic relevance. Importance is placed on astrocyte and microglial reactions. These cells carry out a myriad of functions and we review the evidence that supports their beneficial or detrimental effects. Likewise, vascular responses and the role of inflammation and demyelination in the mechanism of SCI are reviewed. Lastly, schwannosis is discussed, highlighting its high frequency and potential role when designing therapeutic interventions. We anticipate that a better understanding of the pathological responses in the human will be useful to investigators in their studies on the pathogenesis and therapy of SCI.
606 citations
TL;DR: In this paper, a review examines mechanisms of secondary white matter injury after spinal cord injury with particular emphasis on glutamate excitotoxicity and the potential link of this mechanism to apoptosis.
Abstract: Following an initial impact after spinal cord injury (SCI), there is a cascade of downstream events termed 'secondary injury', which culminate in progressive degenerative events in the spinal cord. These secondary injury mechanisms include, but are not limited to, ischemia, inflammation, free radical-induced cell death, glutamate excitotoxicity, cytoskeletal degradation and induction of extrinsic and intrinsic apoptotic pathways. There is emerging evidence that glutamate excitotoxicity plays a key role not only in neuronal cell death but also in delayed posttraumatic spinal cord white matter degeneration. Importantly however, the differences in cellular composition and expression of specific types of glutamate receptors in grey versus white matter require a compartmentalized approach to understand the mechanisms of secondary injury after SCI. This review examines mechanisms of secondary white matter injury with particular emphasis on glutamate excitotoxicity and the potential link of this mechanism to apoptosis. Recent studies have provided new insights into the mechanisms of glutamate release and its potential targets, as well as the downstream pathways associated with glutamate receptor activation in specific types of cells. Evidence from molecular and functional expression of glutamatergic AMPA receptors in white matter glia (and possibly axons), the protective effects of AMPA/kainate antagonists in posttraumatic white matter axonal function, and the vulnerability of oligodendrocytes to excitotoxic cell death suggest that glutamate excitotoxicity is associated with oligodendrocyte apoptosis. The latter mechanism appears key to glutamatergic white matter degeneration after SCI and may represent an attractive therapeutic target.
540 citations
TL;DR: The results imply that omega-3 enriched dietary supplements can provide protection against reduced plasticity and impaired learning ability after traumatic brain injury.
Abstract: Omega-3 fatty acids (i.e., docosahexaenoic acid; DHA) regulate signal transduction and gene expression, and protect neurons from death. In this study we examined the capacity of dietary omega- 3 fatty acids supplementation to help the brain to cope with the effects of traumatic injury. Rats were fed a regular diet or an experimental diet supplemented with omega-3 fatty acids, for 4 weeks before a mild fluid percussion injury (FPI) was performed. FPI increased oxidative stress, and impaired learning ability in the Morris water maze. This type of lesion also reduced levels of brainderived neurotrophic factor (BDNF), synapsin I, and cAMP responsive element-binding protein (CREB). It is known that BDNF facilitates synaptic transmission and learning ability by modulating synapsin I and CREB. Supplementation of omega-3 fatty acids in the diet counteracted all of the studied effects of FPI, that is, normalized levels of BDNF and associated synapsin I and CREB, reduced oxidative damage, and counteracted learning ...
495 citations
TL;DR: It is found that SCI varies in etiology, male-to-female ratios, age distributions, age distribution, and complications in different countries, and it is clear that the categorization and evaluation of SCI must be standardized.
Abstract: Spinal cord injury (SCI) is a devastating condition often affecting young and healthy individuals around the world. This debilitating condition not only creates enormous physical and emotional cost to individuals but also is a significant financial burden to society at large. This review was undertaken to understand the global impact of SCI on society. We also attempted to summarize the worldwide demographics and preventative strategies for SCI in varying economic and climatic environments and to evaluate how cultural and economic differences affect the etiology of SCI. A PUBMED database search was performed in order to identify clinical epidemiological studies of SCI within the last decade. In addition, World Bank and World Health Organization websites were used to obtain demographics, economics, and health statistics of countries of interest. A total of 20 manuscripts were selected from 17 countries. We found that SCI varies in etiology, male-to-female ratios, age distributions, and complications in different countries. Nations with similar economies tend to have similar features and incidences in all the above categories. However, diverse methods of classifying SCI were found, making comparisons difficult. Based upon these findings, it is clear that the categorization and evaluation of SCI must be standardized. The authors suggest improved methods of reporting in the areas of etiology, neurological classification, and incidence of SCI so that, in the future, more useful global comprehensive studies and comparisons can be undertaken. Unified injury prevention programs should be implemented through methods involving the Internet and international organizations, targeting the different etiologies of SCI found in different countries.
418 citations
TL;DR: It is shown that intravenous administration of MSCs after TBI increases the expression of growth factors (NGF, BDNF), which possibly contributes to the improvement in functional outcome seen in these rats.
Abstract: This study was designed to investigate the effects of intravenous administration of marrow stromal cells (MSCs) on the expression of growth factors in rat brain after traumatic brain injury (TBI). The fate of transplanted MSCs and expression of growth factors was examined by immunohistochemistry. In addition, the level of growth factors was measured quantitatively using enzyme linked immunosorbent assay (ELISA). Growth factors that were studied included nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and basic fibroblast growth factor (bFGF). For immunohistochemical studies, 12 male Wistar rats were subjected to TBI and then divided into three groups with the first group receiving no treatment, the second group receiving saline (placebo) and the third group receiving MSCs intravenously 1 day after TBI. The neurological function of rats was studied by using Rotarod motor test and modified neurological severity scores. The animals were sacrificed 15 days after TBI and brain sections stained by immunohistochemistry to study the distribution of MSCs as well as expression of growth factors NGF, BDNF, and bFGF. For quantitative analysis, a second set of male Wistar rats (n = 18) was subjected to TBI and then injected with either saline (n = 9) or MSCs (n = 9) 1 day after injury. These rats were sacrificed on days 2, 5, and 8 after TBI and brain extracts used to measure NGF, BDNF, and bFGF. We found that after transplantation, MSCs preferentially migrated into the injured hemisphere and there was a statistically significant improvement in the functional outcome of MSC-treated rats compared to control rats. NGF, BDNF, and bFGF were expressed in the injured brain of both treated as well as control rats; however, quantitative ELISA studies showed that expression of NGF and BDNF was significantly increased (p < 0.05) in the treated group. This study shows that intravenous administration of MSCs after TBI increases the expression of growth factors (NGF, BDNF), which possibly contributes to the improvement in functional outcome seen in these rats.
350 citations
TL;DR: Both measurement of GFAP and S100B is a useful non-invasive means of identifying brain damage with some differences based on the pattern of TBI and accompanying multiple trauma and/or shock.
Abstract: Research indicates that glial fibrillary acidic protein (GFAP), part of the astroglial skeleton, could be a marker of traumatic brain injury (TBI). S100B, an astroglial protein, is an acknowledged marker of TBI. Our goal was to analyze the relationship of GFAP/S100B to brain damage and outcome, and to compare the accuracy of GFAP/S100B for prediction of mortality after TBI. Our prospective study included 92 patients admitted 0.5 cm (p 25 mL (p 0.5 cm (p or = 25 (p or = 60 than CPP 70 than MAP < or = 70 mm Hg, and in GOS 4-5 than GOS 1 (p < 0.0005). Both measurement of GFAP and S100B is a useful non-invasive means of identifying brain damage with some differences based on the pattern of TBI and accompanying multiple trauma and/or shock.
343 citations
TL;DR: Evaluation of pituitary hormone secretion, including GH, should be included in the long-term follow-up of all TBI patients so that adequate hormone replacement therapy may be administered.
Abstract: Traumatic brain injury (TBI) may be associated with impairment of pituitary hormone secretion, which may contribute to long-term physical, cognitive, and psychological disability. We studied the occurrence and risk factors of pituitary dysfunction, including growth hormone deficiency (GHD) in 50 patients (mean age 37.6 ± 2.4 years; 40 males, age 20–60 years; 10 females, age 23–87 years) with TBI over 5 years. Cranial or facial fractures were documented in 12 patients, and neurosurgery was performed in 14. According to the Glasgow Coma Scale (GCS), 16 patients had suffered from mild, 7 moderate, and 27 severe TBI. Glasgow Outcome Scale (GOS) indicated severe disability in 5, moderate disability in 11, and good recovery in 34 cases. Basal pituitary hormone evaluation, performed once at times variable from 12 to 64 months after TBI, showed hypogonadotrophic hypogonadism in 7 (14%), central hypothyroidism in 5 (10%), low prolactin (PRL) levels in 4 (8%), and high PRL levels in 4 (8%) cases. All subjects had n...
281 citations
TL;DR: Investigation of the role of the ROS, peroxynitrite (PON), in the acute pathophysiology of TBI and its temporal relationship to neurodegeneration in the context of the mouse model of diffuse head injury model indicates that optimal pharmacological inhibition of post-traumatic oxidative damage in TBI may need to combine two functionalities.
Abstract: The role of reactive oxygen-induced oxidative damage to lipids (i.e., lipid peroxidation, LP) and proteins has been strongly supported in previous work. Most notably, a number of free radical scavengers and lipid antioxidants have been demonstated to be neuroprotective in traumatic brain injury (TBI) models. However, the specific sources of reactive oxygen species (ROS), the time course of oxidative damage and its relationship to post-traumatic neurodegeneration in the injured brain have been incompletely defined. The present study was directed at an investigation of the role of the ROS, peroxynitrite (PON), in the acute pathophysiology of TBI and its temporal relationship to neurodegeneration in the context of the mouse model of diffuse head injury model. Male CF-1 mice were subjected to a moderately severe head injury and assessed at 1-, 3-, 6-, 12-, 24-, 48-, 72, 96- and 120-h post-injury for neurodegeneration using quantitative image analysis of silver staining and semi-quantitative analysis of PON-me...
227 citations
TL;DR: Atorvastatin administration after brain injury significantly reduced the neurological functional deficits, increased neuronal survival and synaptogenesis in the boundary zone of the lesion and in the CA3 regions of the hippocampus, and induced angiogenesis in these regions.
Abstract: Statins administered postischemia promote functional improvement in rats, independent of their capability to lower cholesterol. We therefore tested the effect of statin treatment on traumatic brain injury (TBI) in rats. Atorvastatin was orally administered (1 mg/kg/day) to Wistar rats starting 1 day after TBI for 7 consecutive days. Control animals received saline. Modified Neurological Severity Scores and Corner tests were utilized to evaluate functional response to treatment. Bromodeoxyuridine (BrdU, 100 mg/kg) was also intraperitoneally injected daily for 14 consecutive days to label the newly generated endothelial cells. Rats were sacrificed at day 14 after TBI, and the brain samples were processed for immunohistochemical staining. Atorvastatin administration after brain injury significantly reduced the neurological functional deficits, increased neuronal survival and synaptogenesis in the boundary zone of the lesion and in the CA3 regions of the hippocampus, and induced angiogenesis in these regions. The results suggest that atorvastatin may provide beneficial effects in experimental TBI.
198 citations
TL;DR: The employment of traditional methods of functional evaluation in conjunction with the modern techniques of computerized analysis of gait and histomorphometric analysis should be recommended for an overall assessment of recovery in the rat sciatic nerve crush model.
Abstract: Peripheral nerve researchers frequently use the rat sciatic nerve crush as a model for axonotmesis. Unfortunately, studies from various research groups report results from different crush techniques and by using a variety of evaluation tools, making comparisons between studies difficult. The purpose of this investigation was to determine the sequence of functional and morphologic changes after an acute sciatic nerve crush injury with a non-serrated clamp, giving a final standardized pressure of p = 9 MPa. Functional recovery was evaluated using the sciatic functional index (SFI), the extensor postural thrust (EPT) and the withdrawal reflex latency (WRL), before injury, and then at weekly intervals until week 8 postoperatively. The rats were also evaluated preoperatively and at weeks 2, 4, and 8 by ankle kinematics, toe out angle (TOA), and gait-stance duration. In addition, the motor nerve conduction velocity (MNCV) and the gastrocnemius-soleus weight parameters were measured just before euthanasia. Finally, structural, ultrastructural and histomorphometric analyses were carried out on regenerated nerve fibers. At 8 weeks after the crush injury, a full functional recovery was predicted by SFI, EPT, TOA, and gait-stance duration, while all the other parameters were still recovering their original values. On the other hand, only two of the histomorphometric parameters of regenerated nerve fibers, namely myelin thickness/axon diameter ratio and fiber/axon diameter ratio, returned to normal values while all other parameters were significantly different from normal values. The employment of traditional methods of functional evaluation in conjunction with the modern techniques of computerized analysis of gait and histomorphometric analysis should thus be recommended for an overall assessment of recovery in the rat sciatic nerve crush model.
TL;DR: The present study is the first to show that axons from brainstem motor nuclei regenerated in unfilled synthetic hydrogel guidance channels after complete spinal cord transection.
Abstract: Synthetic guidance channels or tubes have been shown to promote axonal regeneration within the spinal cord from brainstem motor nuclei with the inclusion of agents such as matrices, cells, or growth factors to the tube. We examined the biocompatibility and regenerative capacity of synthetic hydrogel tubular devices that were composed of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) (PHEMA-MMA). Two PHEMA-MMA channels, having a mean elastic modulus of either 177 or 311 kPa were implanted into T8-transected spinal cords of adult Sprague Dawley rats. The cord stumps were inserted into the channels and fibrin glue was applied to the cord-channel interface. An expanded polytetrafluoroethylene (ePTFE) membrane was used for duraplasty. Controls underwent cord transection alone. Gross and microscopic examination of the spinal cords showed continuity of tissue within the synthetic guidance channels between the cord stumps at 4 and 8 weeks. There was a trend towards an increased area and width of bridging neural tissue in the 311-kPa guidance channels compared to the 177-kPa channels. Neurofilament stained axons were visualized within the bridging tissue, and serotonergic axons were found to enter the 311-kPa channel. Retrograde axonal tracing revealed regeneration of axons from reticular, vestibular, and raphe brainstem motor nuclei. For both channels, there was minimal scarring at the channel-cord interface, and less scarring at the channel-dura interface compared to that observed next to the ePTFE. The present study is the first to show that axons from brainstem motor nuclei regenerated in unfilled synthetic hydrogel guidance channels after complete spinal cord transection.
TL;DR: The first study showing gender differences in lipid peroxidation after clinical TBI in humans was evaluated, establishing that gender is an important consideration in clinical trial design, particularly in the case of antioxidant strategies.
Abstract: Striking gender differences have been reported in the pathophysiology and outcome of acute neurological injury. Greater neuroprotection in females versus males may be due, in part, to direct and indirect sex hormone-mediated antioxidant mechanisms. Progesterone administration decreases brain levels of F2-isoprostane, a marker of lipid peroxidation, after experimental traumatic brain injury (TBI) in male rats, and estrogen is neuroprotective in experimental neurological injury. In this study, we evaluated the effect of gender on lipid peroxidation, as assessed by cerebrospinal fluid (CSF) levels of F2-isoprostane, after severe TBI in humans. Lipid peroxidation was assessed in CSF from 68 adults enrolled in two randomized controlled trials evaluating the effect of therapeutic hypothermia after severe TBI (Glasgow coma scale [GCS] score ≤ 8). Patients treated with hypothermia (n = 41, 12 females, 29 males) were cooled to 32-33°C (within ~6 h) for either 24 or 48 h and then re-warmed. F2-isoprostane levels we...
TL;DR: The main features distinguishing MS from truly severe cases were younger age, higher Glasgow Coma Scale score at all time points, Marshall classification of Computerized Tomographic scan mostly Diffuse Injury I and II, fewer pupillary abnormalities, and a lower frequency of hypoxia, hypotension, and extra-cranial injuries.
Abstract: Intubation, which requires sedation and myorelaxants, may lead to inaccurate neurological evaluation of severely head-injured patients. Aims of this study were to describe the early clinical evolution of traumatic brain injured (TBI) patients admitted to intensive care unit (ICU), to identify cases of over-estimated neurological severity, and to quantify the risk factors for this over-estimation. A total of 753 TBI patients consecutively admitted to ICU of three academic neurosurgical hospitals (NSH) were assessed. Cases whose severity was potentially over-estimated were identified by four criteria and indicated as "mistakenly severe" (MS): (1) no surgical intracranial masses; (2) could not follow commands at neurological assessment; (3) were dismissed from the ICU in < or =3 days to a regular ward; and (4) had regained the ability to obey commands. A total of 675 patients were intubated and/or sedated-paralyzed at the post-stabilization evaluation. In all, 304 patients had surgically treated intracranial masses. Among the 449 non-surgical cases, 58 patients fulfilling the criteria for MS were identified. The main features distinguishing MS from truly severe cases were younger age, higher Glasgow Coma Scale (GCS) score at all time points, Marshall classification of Computerized Tomographic (CT) scan mostly Diffuse Injury I and II, fewer pupillary abnormalities, and a lower frequency of hypoxia, hypotension, and extra-cranial injuries. In a certain proportion of non-surgical TBI patients, mostly intubated and sedated, neurological examination is difficult and severity can be over-estimated. Risk factors for this inaccurate evaluation can be identified, and clinical decisions should be based on further examination.
TL;DR: The behavioral and histological effects of the lateral fluid percussion (LFP) brain injury model were compared with the weight drop impact-acceleration model with 10 min of secondary hypoxia (WDIA + H).
Abstract: The behavioral and histological effects of the lateral fluid percussion (LFP) brain injury model were compared with the weight drop impact-acceleration model with 10 min of secondary hypoxia (WDIA + H). LFP injury resulted in significant motor deficits on the beam walk and inclined plane, and memory deficits on the radial arm maze and Morris water maze. Motor deficits following LFP remained throughout 6 weeks of behavioral testing. WDIA + H injury produced significant motor deficits on the beam walk and inclined plane immediately following injury, but these effects were transient and recovered by 14 days post-injury. In contrast to the LFP injury, the WDIA + H injured animals showed no memory deficits on the radial arm maze and Morris water maze. In order to determine if the differences in behavioral outcome between models were due to differences in injury mechanism or injury severity, 10 LFP-injured animals were matched with 10 WDIA-injured animals based on injury severity (i.e., time to regain righting ...
TL;DR: Data from anesthetized 3-5-day-old piglets subjected to rapid, non-impact, axial rotations are indicative of the graded response of the immature brain to rotational load magnitude, and importantly, the vulnerability to repeated, mild,non-impact loading conditions.
Abstract: Inflicted brain injury is associated with widespread traumatic axonal injury (TAI) and subdural hematoma and is the leading cause of death in infants and children. Anesthetized 3-5-day-old piglets ...
TL;DR: Although changes in the PbtO2 provided the earliest sign of hypoxia/ischemia, the microdialysis assays provided additional information about the consequences that the reduced tissue pO2 has on brain metabolism, which may be helpful in managing these critically ill patients.
Abstract: The purpose of this study was to examine the patterns of change in microdialysate concentrations of glucose, lactate, pyruvate, and glutamate in the brain during periods of hypoxia/ischemia identified by monitoring brain tissue pO2 (PbtO2). Of particular interest was a better understanding of what additional information could be obtained by the microdialysis parameters that was not available from the PbtO2. Fifty-seven patients admitted with severe traumatic brain injury who had placement of both a brain tissue pO2 (PbtO2) and microdialysis probe were studied. The microdialysis probe was perfused with Ringer's solution at 0.3 μL/min and dialysate was collected at 1-h intervals. The concentration of glucose, pyruvate, lactate, and glutamate were measured in each dialysate sample. Changes in the microdialysis parameters were examined during episodes where the PbtO2 decreased to below 10 mm Hg. Ten episodes of tissue hypoxia/ischemia identified by a decrease in PbtO2 below 10 mm Hg were observed during the p...
TL;DR: Morphological analysis showed that lesion sizes increased progressively in either vehicle-treated or 17β-estradiol-treated spinal cords, however, in response to treatment with 17 β-ESTradiol, the lesion size was significantly reduced 18-28 days after SCI when compared to vehicle-treatment.
Abstract: Recent evidence indicates that estrogen exerts neuroprotective effects in both brain injury and neurodegenerative diseases We examined the protective effect of estrogen on functional recovery after spinal cord injury (SCI) in rats 17β-estradiol (3, 100, or 300 μg/kg) was administered intravenously 1-2 h prior to injury (pre-treatment), and animals were then subjected to a mild, weight-drop spinal cord contusion injury Estradiol treatment significantly improved hind limb motor function as determined by the Basso-Beattie-Bresnahan (BBB) locomotor open field behavioral rating test Fifteen to 30 days after SCI, BBB scores were significantly higher in estradiol-treated (100 μg/kg) rats when compared to vehicle-treated rats Morphological analysis showed that lesion sizes increased progressively in either vehicle-treated or 17β-estradiol-treated spinal cords However, in response to treatment with 17β-estradiol, the lesion size was significantly reduced 18-28 days after SCI when compared to vehicle-treated
TL;DR: It is suggested that females have smaller oxidative damage loads than males for a given excitotoxic or ischemic insult and female gonadal hormones may play a role in mediating this neuroprotective effect.
Abstract: Excitotoxicity and ischemia can result in oxidative stress after TBI. Female sex hormones are hypothesized to be neuroprotective after TBI by affecting multiple mechanisms of secondary injury, including oxidative damage, excitotoxicity and ischemia. Ca2+ mediated oxidative stress increases with age, and hypothermia is known to attenuate secondary injury. The purpose of this study was to determine if the relationship between cerebral spinal fluid (CSF) markers of excitotoxicity, ischemia, and oxidative damage are gender and age specific and the role of hypothermia in affecting these relationships. F2-isoprostane, glutamate, and lactate/pyruvate, were assessed in CSF from adults (n = 68) with severe TBI (Glasgow coma scale [GCS] score
TL;DR: How tissue protective agents may transform the milieu of the injured spinal cord to the benefit or detriment of later transplanted cells and whether neuroprotectants need to be re-administered at the time of cell grafting or less invasive transplantation techniques employed to reduce damage to tissue spared by an earlier protection strategy are understood.
Abstract: Methylprednisolone (MP) and interleukin-10 (IL-10) are tissue protective acutely after spinal cord injury (SCI); their combination offers additive protection (Takami et al., 2002a). Our study exami...
TL;DR: A framework by which behavioral testing can be standardized within and across spinal cord injury labs is provided to provide a framework for selecting the most sensitive behavioral tests.
Abstract: Selection and implementation of behavioral tests in spinal cord injury research is an important process, and yet few papers have focused on these issues. The critical component of any behavioral experiment is the ability to produce reliable, reproducible, and worthwhile data. Unfortunately, the difference between worthwhile and worthless data is often subtle. This paper describes factors that must be considered in order to select the most sensitive behavioral tests to match the hypothesis of the experiment and apply any test in a standardized, consistent manner. Classifications of behavioral tests, their strengths and limitations, as well as methods to overcome these limitations are discussed. Recent work in translating behavioral tests from rats to mice is also provided. The purpose of this article is to provide a framework by which behavioral testing can be standardized within and across spinal cord injury labs.
TL;DR: It is found that glutamate/glutamine (Glx) and choline (Cho) were significantly elevated in occipital gray and parietal white matter early after injury in patients with poor long-term outcomes.
Abstract: Proton magnetic resonance spectroscopy (MRS) is being used to evaluate individuals with acute traumatic brain injury and several studies have shown that changes in certain brain metabolites (N-acetylaspartate, choline) are associated with poor neurologic outcomes. The majority of previous MRS studies have been obtained relatively late after injury and none have examined the role of glutamate/ glutamine (Glx). We conducted a prospective MRS study of 42 severely injured adults to measure quantitative metabolite changes early (7 days) after injury in normal appearing brain. We used these findings to predict long-term neurologic outcome and to determine if MRS data alone or in combination with clinical outcome variables provided better prediction of long-term outcomes. We found that glutamate/glutamine (Glx) and choline (Cho) were significantly elevated in occipital gray and parietal white matter early after injury in patients with poor long-term (6-12-month) outcomes. Glx and Cho ratios predicted long-term outcome with 94% accuracy and when combined with the motor Glasgow Coma Scale score provided the highest predictive accuracy (97%). Somatosensory evoked potentials were not as accurate as MRS data in predicting outcome. Elevated Glx and Cho are more sensitive indicators of injury and predictors of poor outcome when spectroscopy is done early after injury. This may be a reflection of early excitotoxic injury (i.e., elevated Glx) and of injury associated with membrane disruption (i.e., increased Cho) secondary to diffuse axonal injury.
TL;DR: A classification and regression tree (CART) technique was employed in the analysis of data from 345 patients with isolated severe brain injury who were admitted to Asclepeion General Hospital of Athens, and indicated that Glasgow Coma Scale was the best predictor of outcome.
Abstract: Many previous studies have constructed several predictive models for outcome after severe head injury, but these have often used expensive, time consuming, or highly specialized measurements. The goal of this study was to develop a simple, easy to use a model involving only variables that are rapidly and easily achievable in daily routine practice. To this end, a classification and regression tree (CART) technique was employed in the analysis of data from 345 patients with isolated severe brain injury who were admitted to Asclepeion General Hospital of Athens from January, 1993, to December, 2000. A total of 16 prognostic indicators were examined to predict neurological outcome at 6 months after head injury. Our results indicated that Glasgow Coma Scale was the best predictor of outcome. With regard to the other data, not only the most widely examined variables such as age, pupillary reactivity, or computed tomographic findings proved again to be strong predictors, but less commonly applied parameters, indirectly associated with brain damage, such as hyperglycemia and leukocytosis, were found to correlate significantly with prognosis too. The overall cross-validated predictive accuracy of CART model for these data was 86.84%, with a cross-validated relative error of 0.308. All variables included in this tree have been shown previously to be related to outcome. Methodologically, however, CART is quite different from the more commonly used statistical methods, with the primary benefit of illustrating the important prognostic variables as related to outcome. This technique may prove useful in developing new therapeutic strategies and approaches for patients with severe brain injury.
TL;DR: Calpain cleaves alphaII-spectrin into breakdown products (SBDP) after TBI and ischemia to determine the seriousness of injury or the extent of cellular pathology and evaluation of CSF SBDP levels as a biomarker of TBI is warranted in clinical studies.
Abstract: Currently, there is no definitive diagnostic test for traumatic brain injury (TBI) to help physicians determine the seriousness of injury or the extent of cellular pathology. Calpain cleaves αII-sp...
TL;DR: Results indicate that MMP-9 is elevated in patients with acute TBI, and may play an important role in traumatic brain damage, and a significant correlation was seen between levels of M MP-9 and IL-6 in internal jugular venous blood during the investigation period.
Abstract: Recent experimental data have shown that levels of matrix metalloproteinase-9 (MMP-9) increase after traumatic brain injury (TBI), degrading components of the basal lamina disrupting the blood–brain barrier. However, the post-traumatic secretion patterns of MMP-9 in humans are unknown. We measured the concentration of MMP-9 in plasma after TBI at the same time as the concentration of interleukin-6 (IL-6) in serum. Levels of MMP-9 and IL-6 in systemic arterial and jugular venous blood from seven patients with TBI were measured on days 0 and 1 post-injury. All patients underwent hypothermia at 32–35°C as soon as possible after admission. Before induction of hypothermia, levels of MMP-9 in arterial and internal jugular venous blood exceeded the normal range. Higher MMP-9 levels were detected in internal jugular venous blood than in arterial blood. After hypothermia had been induced, MMP-9 levels in arterial blood and internal jugular venous blood decreased significantly, to within the normal range. In additi...
TL;DR: It is determined that polymer injection is a safe adjunct to the conventional management of severe neurological injury in dogs and evidence consistent with the notion that the injection of inorganic polymers in acute neurotrauma may be a simple and useful intervention during the acute phase of the injury is provided.
Abstract: Hydrophilic polymers, both surfactants and triblock polymers, are known to seal defects in cell membranes. In previous experiments using laboratory animals, we have exploited this capability using polyethylene glycol (PEG) to repair spinal axons after severe, standardized spinal cord injury (SCI) in guinea pigs. Similar studies were conducted using a related co-polymer Poloxamer 188 (P 188). Here we carried out initial investigations of an intravenous application of PEG or P 188 (3500 Daltons, 30% w/w in saline; 2 mL/kg I.V. and 2 mL/kg body weight or 300 mL P 188 per kg, respectively) to neurologically complete cases of paraplegia in dogs. Our aim was to first determine if this is a clinically safe procedure in cases of severe naturally occurring SCI in dogs. Secondarily, we wanted to obtain preliminary evidence if this therapy could be of clinical benefit when compared to a larger number of similar, but historical, control cases. Strict entry criteria permitted recruitment of only neurologically complet...
TL;DR: Nerve repair with a silicone tube leaving a short gap does not increase accuracy of reinnervation in rat sciatic nerve.
Abstract: Functional recovery after peripheral nerve injury depends on the amount as well as on the accuracy of reinnervation by regenerative axons. In this study, the rat sciatic nerve was subjected to crush injury or complete transection repaired by either (1) straight nerve suture, (2) crossed nerve suture of tibial and peroneal fascicles, or (3) silicone tubulization leaving a gap of 4 mm. The compound muscle action potentials (CMAP) of gastrocnemius, tibialis anterior and plantar muscles were recorded 90 days post operation to assess functional reinnervation and Fast Blue, Fluoro Gold and DiI were applied to the nerve branches projecting into these muscles to quantify morphological reinnervation. The CMAP amplitude achieved in gastrocnemius, tibialis anterior and plantar muscles was higher after nerve crush (86%, 82%, 65% of control) than after any surgical nerve repair (straight suture: 49%, 53%, 32%; crossed suture: 56%, 50%, 31%; silicone tube: 42%, 44%, 25%). The total number of labeled motoneurons, however, did not significantly differ between groups (control: 1238 +/- 82, crush: 1048 +/- 49, straight suture: 1175 +/- 106, crossed suture: 1085 +/- 84, silicone tube: 1250 +/- 182). The volume occupied by labeled motoneurons within the spinal cord was larger after surgical nerve repair than in crush or normal control animals, and fewer neurons showed abnormal multiple projections after crush (2.5%) or straight suture (2.2%) than following crossed suture (5%) or silicone tube (6%). In conclusion, nerve repair with a silicone tube leaving a short gap does not increase accuracy of reinnervation.
TL;DR: Results indicate that in vivo, LiCl inhibits GSK-3beta and reinforces the regeneration-promoting function of ChABC through a Bcl-2-dependent mechanism, and combined use of LiCl together with ChABC could be a novel treatment for spinal cord injury.
Abstract: After spinal cord injury, enzymatic digestion of chondroitin sulfate proteoglycans promotes axonal regeneration of central nervous system neurons across the lesion scar. We examined whether chondroitinase ABC (ChABC) promotes the axonal regeneration of rubrospinal tract (RST) neurons following injury to the spinal cord. The effect of a GSK-3β inhibitor, lithium chloride (LiCl), on the regeneration of axotomized RST neurons was also assessed. Adult rats received a unilateral hemisection at the seventh cervical spinal cord segment (C7). Four weeks after different treatments, regeneration of RST axons across the lesion scar was examined by injection of Fluoro-Gold at spinal segment T2, and locomotor recovery was studied by a test of forelimb usage. Injured RST axons did not regenerate spontaneously after spinal cord injury, and intraperitoneal injection of LiCl alone did not promote the regeneration of RST axons. Administration of ChABC at the lesion site enhanced the regeneration of RST axons by 20%. Combin...
TL;DR: The results indicate that uncontrollable stimulation impairs recovery after spinal cord injury and suggest that reducing sources of uncontrolled afferent input (e.g., from peripheral tissue injury) could benefit patient recovery.
Abstract: Prior studies have shown that neurons within the spinal cord are sensitive to response-outcome relations, a form of instrumental learning Spinally transected rats that receive shock to one hind leg learn to maintain the leg in a flexed position that minimizes net shock exposure (controllable shock) Prior exposure to uncontrollable stimulation (intermittent shock) inhibits this spinally mediated learning Here it is shown that uncontrollable stimulation undermines the recovery of function after a spinal contusion injury Rats received a moderate injury (125 mm drop) and recovery was monitored for 6 weeks In Experiment 1, rats received varying amounts of intermittent tailshock 1–2 days after injury Just 6 min of intermittent shock impaired locomotor recovery In Experiment 2, rats were shocked 1, 4, or 14 days after injury Delaying the application of shock exposure reduced its negative effect on recovery In Experiment 3, rats received controllable or uncontrollable shock 24 and 48 h after injury Onl
TL;DR: Data support the hypothesis that complement activation plays a role in SCI, and suggest a potential role for the complement cascade in demyelination or axonal degeneration.
Abstract: Previous studies have shown that a cellular inflammatory response is initiated, and inflammatory cytokines are synthesized, following experimental spinal cord injury (SCI). In the present study, we tested the hypothesis that the complement cascade, a major component of both the innate and adaptive immune response, is also activated following experimental SCI. We investigated the pathways, cellular localization, timecourse, and degree of complement activation in rat spinal cord following acute contusion-induced SCI using the New York University (NYU) weight drop impactor. Mild and severe injuries (12.5 and 50 mm drop heights) at 1, 7, and 42 days post injury time points were evaluated. Classical (C1q and C4), alternative (Factor B) and terminal (C5b-9) complement pathways were strongly activated within 1 day of SCI. Complement protein immunoreactivity was predominantly found in cell types vulnerable to degeneration, neurons and oligodendrocytes, and was not generally observed in inflammatory or astroglial ...