A novel method for the study of repetitive mild traumatic brain injury (rmTBI) that models the most common form of head injury in humans is presented. Existing animal models of TBI impart focal, severe damage unlike that seen in repeated and mild concussive injuries, and few are configured for repetitive application. Our model is a modification of the Marmarou weight drop method and allows repeated head impacts to lightly anesthetized mice. A key facet of this method is the delivery of an impact to the cranium of an unrestrained subject allowing rapid acceleration of the free-moving head and torso, an essential characteristic known to be important for concussive injury in humans, and a factor that is missing from existing animal models of TBI. Our method does not require scalp incision, emplacement of protective skull helmets or surgery and the procedure can be completed in 1-2 minutes. Mice spontaneously recover the righting reflex and show no evidence of seizures, paralysis or impaired behavior. Skull fractures and intracranial bleeding are very rare. Minor deficits in motor coordination and locomotor hyperactivity recover over time. Histological analyses reveal mild astrocytic reactivity (increased expression of GFAP) and increased phospho-tau but a lack of blood-brain-barrier disruption, edema and microglial activation. This new animal model is simple and cost-effective and will facilitate characterization of the neurobiological and behavioral consequences of rmTBI. It is also ideal for high throughput screening of potential new therapies for mild concussive injuries as experienced by athletes and military personnel.

The data support the notion that HIF-1α plays a role in brain edema formation and BBB disruption via a molecular pathway cascade involving AQP-4 and MMP-9. Pharmacological blockade of this pathway in patients with TBI may provide a novel therapeutic strategy.

INTRODUCTION: While surgical resection has been shown to improve short-term local disease control, it remains debated whether surgical resection is associated with improved overall survival in patients with malignant primary osseous spinal neoplasms. We reviewed survival data from a US cancer registry spanning 30 years to determine if surgical resection was independently associated with overall survival.METHODS: The SEER registry was queried to identify cases of histologically confirmed primary spinal chordoma, chondrosarcoma, osteosarcoma, or Ewing's sarcoma of the mobile spine and pelvis via ICD-O-2 coding. Patients with systemic metastasis were excluded. Age, sex, race, tumor location, and primary treatments were identified. Extent of local tumor invasion was classified as confined within periosteum vs extension beyond periosteum to surrounding tissues. The association of surgical resection with overall survival was assessed via Cox proportional-hazards regression analysis adjusting for age, radiotherapy, and tumor invasiveness.RESULTS: Eight-hundred, twenty-seven patients were identified with non-metastatic primary osseous spinal neoplasms (215 chordoma, 282 chondrosarcoma, 158 osteosarcoma, 172 Ewing's sarcoma). Overall median survival was histology specific (chordoma: 96 months, Ewing's sarcoma: 90 months, chondrosarcoma: 88 months, osteosarcoma: 18 months). Adjusting for age, radiation therapy, and extent of local tumor invasion in patients with isolated (non-metastatic) spine tumors, surgical resection was independently associated with significantly improved survival for chordoma (Hazard Ratio [95% confidence interval (CI); 0.617 (0.25-0.98)], chondrosarcoma (HR [95%CI]; 0.153 [0.07-0.36]), osteosarcoma (HR [95%CI]; 0.382 [0.21-0.69]), and Ewing's sarcoma (HR [95%CI]; 0.494 [0.26-0.96]).CONCLUSION: In our analysis of a 30-year US population based cancer registry (SEER), patients undergoing surgical resection of primary spinal chordoma, chondrosarcoma, Ewing's sarcoma, or osteosarcoma demonstrated prolonged overall survival independent of patient age, extent of local invasion, or location. Surgical resection may play a role in prolonging survival in the multi-modality treatment of patients with these malignant primary osseous spinal neoplasms.

No abstract

■ AbstractEncephalopathy is an increasingly recognized complication of type 1 diabetes. The underlying mechanisms are not well understood, although insulin deficiency has been implicated. The spontaneously diabetic BB/Wor-rat develops neurobehavioral deficits and neuronal cell death in hippocampus and frontal cortex, which can be prevented by insulinomimetic C-peptide. Here we examined whether contributing factors such as activation of innate immune mediators are responsive to C-peptide replacement. Seven-month diabetic BB/Wor-rats and those treated with full C-peptide replacement were compared to age-matched control rats. Hippocampi of diabetic rats showed upregulation of RAGE and NF-κB, the former being localized to proliferating astrocytes. These changes were associated with increased expression of TNF-α, IL-1β, IL-2 and IL-6 in hippocampi of diabetic rats. Full C-peptide replacement, which did not induce hyperglycemia, resulted in significant prevention of upregulation of RAGE expression, activation of NF-κB and activation of pro-inflammatory factors. In conclusion, impaired insulin activity is associated with upregulation of RAGE and pro-inflammatory factors, and these are likely to contribute to previously described oxidative and apoptotic neuronal cell death. Replacement of insulinomimetic C-peptide significantly prevents this cascade of events.

Our results indicated that following TBI, there is a substantial increase in angiogenesis and based on morphologic characterization of BrdU-positive nuclei within the endothelium, we provide evidence for vasculogenesis following injury.

Previous studies have demonstrated that traumatic brain injury (TBI) causes brain edema via aquaporins (AQPs), the water transporting proteins. In the present study, we determined the role of hypoxia inducible factor-1α (HIF-1α), which is a transcription factor in response to physiological hypoxia, in regulating expression of AQP4 and AQP9.Adult male Sprague-Dawley rats (400-425g) received a closed head injury using the Marmarou weight drop model with a 450 g weight and survived for 1, 4, 24 and 48 hours. Some animals were administered 30 minutes after injury with 2-Methoxyestradiol (2ME2), a naturally occurring metabolite of estradiol which is known to post-transcriptionally down-regulate HIF-1α expression, and sacrificed 4 hours after injury. Real-time PCR and Western blot were used, respectively, to detect gene and protein expressions of manganese superoxide dismutase (MnSOD, showing hypoxic stress), HIF-1α, AQP4, and AQP9.ANOVA analysis demonstrated a significant (p<0.05) increase in gene expression of MnSOD, HIF-1α, AQP4, and AQP9, starting at 1 hour after injury through 48 hours. Western blot analysis further indicated a significant (p<0.05) increase in protein expression of these molecules at the same time points. Pharmacological inhibition of HIF-1α by 2ME2 reduced the up-regulated levels of AQP4 and AQP9 after TBI.The present study suggests that hypoxic conditions determined by MnSOD expression after closed head injury contribute to HIF-1α expression. HIF-1α, in turn, up-regulates expression of AQP4 and AQP9. These results characterize the pathophysiological mechanisms, and suggest possible therapeutic targets for TBI patients.

Diabetic encephalopathy is a recently recognized complication in type 1 diabetes. In this review, we summarize a series of experimental results obtained longitudinally in the spontaneously type 1 diabetic BB/Wor-rat, and bringing out the beneficial effects of C-peptide replacement. It is increasingly clear that lack of insulin and C-peptide, and perturbations of their signaling cascades in type 1 diabetes are detrimental to the regulation of neurotrophic factors and their receptors. Other consequences of such deficits and perturbations are innate inflammatory responses with effects on synaptogenesis, neurite degeneration, and early behavioral abnormalities. Replacement of C-peptide, which does not effect hyperglycemia, has beneficial effects on a variety of pro-apoptotic stressors, oxidative stressors, and finally on apoptosis. Eventually, this cascade of events leads to neuronal loss and decreased densities of white matter myelinating cells, with more profound deficits in behavioral and cognitive function. Such changes are likely to underlie gray and white matter atrophy in type 1 diabetes, and are significantly prevented by full C-peptide replacement. Present data demonstrate that C-peptide replacement has beneficial effects on numerous sequential and partly interrelated pathogenetic mechanisms, resulting in prevention of neuronal and oligodendroglial cell loss, with significant prevention of neurobehavioral and cognitive functions.