Genetic and pharmacological intervention of the p75NTR pathway alters morphological and behavioural recovery following traumatic brain injury in mice.

PRIMARY OBJECTIVE: Neurotrophin levels are elevated after TBI, yet there is minimal regeneration. It was hypothesized that the pro-neurotrophin/p75NTR pathway is induced more than the mature neurotrophin/Trk pathway and that interfering with p75 signalling improves recovery following TBI. RESEARCH DESIGN: Lateral Fluid Percussion (LFP) injury was performed on wildtype and p75 mutant mice. In addition, TrkB agonist 7,8 Dihydroxyflavone or p75 antagonist TAT-Pep5 were tested. Western blot and immunohistochemistry revealed biochemical and cellular changes. Morris Water Maze and Rotarod tests demonstrated cognitive and vestibulomotor function. MAIN OUTCOMES AND RESULTS: p75 was up-regulated and TrkB was down-regulated 1 day post-LFP. p75 mutant mice as well as mice treated with the p75 antagonist or the TrkB agonist exhibited reduced neuronal death and degeneration and less astrocytosis. The cells undergoing apoptosis appear to be neurons rather than glia. There was improved motor function and spatial learning in p75 mutant mice and mice treated with the p75 antagonist. CONCLUSIONS: Many of the pathological and behavioural consequences of TBI might be due to activation of the pro-neurotrophin/p75 toxic pathway overriding the protective mechanisms of the mature neurotrophin/Trk pathway. Targeting p75 can be a novel strategy to counteract the damaging effects of TBI.

Infectious complications following serial transverse enteroplasty in infants and children with short bowel syndrome.

BACKGROUND: Serial transverse enteroplasty (STEP) lengthens and tapers dilated small bowel in patients with short bowel syndrome (SBS). Previous reports document encouraging outcomes with regard to tolerance for enteral nutrition (EN) and complications appear related to the re-operative nature of many cases and to the presence of multiple staple lines. However, infectious complications following STEP have not been examined. Since infections, especially catheter-related blood stream infections (CRBSI), are considered detrimental in infants and children with SBS, we sought to define the frequency and outcomes of peri-operative infections associated with STEP. METHODS: All children with SBS who underwent a STEP between 2004 and 2012 were indentified and their medical records were reviewed. Patients were considered candidates for a STEP if they had dilated small bowel and failure to advance enteral nutrition. For the purpose of this study, infections occurring within a 14-day period after STEP were considered procedure-related and were the focus of the study. RESULTS: A total of 18 patients underwent 23 STEP procedures. Primary diagnoses included intestinal atresia, gastroschisis, necrotizing enterocolitis, and midgut volvulus. After the STEP, eight patients (35%) developed CRBSI, three developed wound infections, and two had urinary tract infections. Organisms isolated from either blood, wound or urine cultures included gram-positive cocci, gram-negative rods, and yeast. Perioperative antibiotics were administered in all cases with cefoxitin (43%) and piperacillin/tazobactam (30%) being most common. Neither antibiotic appeared superior in reducing the incidence of CRBSI. In three patients with persistent bacteremia despite adequate antibiotic therapy, a 74% ethanol lock resulted in negative blood cultures in all cases. Only one central venous catheter required replacement acutely for persistent fungemia. CONCLUSION: STEP can improve enteral tolerance. In this fragile patient population, however, STEP carries a documented infectious burden. The optimal antibiotic prophylaxis and the role of ethanol locking in patients undergoing STEP require further study.

Lateral fluid percussion: model of traumatic brain injury in mice.

Traumatic brain injury (TBI) research has attained renewed momentum due to the increasing awareness of head injuries, which result in morbidity and mortality. Based on the nature of primary injury following TBI, complex and heterogeneous secondary consequences result, which are followed by regenerative processes (1,2). Primary injury can be induced by a direct contusion to the brain from skull fracture or from shearing and stretching of tissue causing displacement of brain due to movement (3,4). The resulting hematomas and lacerations cause a vascular response (3,5), and the morphological and functional damage of the white matter leads to diffuse axonal injury (6-8). Additional secondary changes commonly seen in the brain are edema and increased intracranial pressure (9). Following TBI there are microscopic alterations in biochemical and physiological pathways involving the release of excitotoxic neurotransmitters, immune mediators and oxygen radicals (10-12), which ultimately result in long-term neurological disabilities (13,14). Thus choosing appropriate animal models of TBI that present similar cellular and molecular events in human and rodent TBI is critical for studying the mechanisms underlying injury and repair. Various experimental models of TBI have been developed to reproduce aspects of TBI observed in humans, among them three specific models are widely adapted for rodents: fluid percussion, cortical impact and weight drop/impact acceleration (1). The fluid percussion device produces an injury through a craniectomy by applying a brief fluid pressure pulse on to the intact dura. The pulse is created by a pendulum striking the piston of a reservoir of fluid. The percussion produces brief displacement and deformation of neural tissue (1,15). Conversely, cortical impact injury delivers mechanical energy to the intact dura via a rigid impactor under pneumatic pressure (16,17). The weight drop/impact model is characterized by the fall of a rod with a specific mass on the closed skull (18). Among the TBI models, LFP is the most established and commonly used model to evaluate mixed focal and diffuse brain injury (19). It is reproducible and is standardized to allow for the manipulation of injury parameters. LFP recapitulates injuries observed in humans, thus rendering it clinically relevant, and allows for exploration of novel therapeutics for clinical translation (20). We describe the detailed protocol to perform LFP procedure in mice. The injury inflicted is mild to moderate, with brain regions such as cortex, hippocampus and corpus callosum being most vulnerable. Hippocampal and motor learning tasks are explored following LFP.