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Samuel S. Shin, C. Edward Dixon, David O. Okonkwo, and R. Mark Richardson

T here are multiple therapy modalities for attenuating neurological disabilities in traumatic brain injury (TBI) patients, including occupational, physical, and cognitive rehabilitation, but there is a critical need for more effective therapies, especially pharmacological or surgical treatments. The pathophysiology of TBI is complex and includes inflammation, oxidative stress, apoptosis, excitotoxicity, and mitochondrial dysfunction. After almost a century of translational science, there has yet to be a successful Phase III clinical trial investigating a

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Matthew T. Harting, James E. Baumgartner, Laura L. Worth, Linda Ewing-Cobbs, Adrian P. Gee, Mary-Clare Day, and Charles S. Cox Jr.

T raumatic brain injury directly affects an estimated 1.5 million Americans annually, although the resultant acute and/or chronic deficits in motor, cognitive, behavioral, and/or social functioning have equally devastating effects on friends, families, and society. 2 Of the TBIs suffered each year, ~50,000 deaths result, and nearly 100,000 injuries lead to life-long impairment with substantial loss of function. 2 Traumatic brain injury contributes to 50% of all trauma-related deaths. 25 The national economic impact is difficult to quantify, due to the

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Alexandra D. Beier and Peter B. Dirks

: 508 – 510 , 2000 5 Hashimoto T , Nakamura N , Richard KE , Frowein RA : Primary brain stem lesions caused by closed head injuries . Neurosurg Rev 16 : 291 – 298 , 1993 6 Jacob AT , Heuer GG , Grant R , Georgoff P , Danish SF , Storm PB , : Decompressive hemicraniectomy for pediatric traumatic brain injury: long-term outcome based on quality of life . Pediatr Neurosurg 47 : 81 – 86 , 2011 7 Jagannathan J , Okonkwo DO , Dumont AS , Ahmed H , Bahari A , Prevedello DM , : Outcome following decompressive

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Shirley I. Stiver and Geoffrey T. Manley

: Fluid replacement for hypotensive injury victims: how, when and what risks? . Curr Opin Anaesthesiol 11 : 177 – 180 , 1998 13 Bloch M : Cerebral effects of rewarming following prolonged hypothermia: significance for the management of severe cranio-cerebral injury and acute pyrexia . Brain 90 : 769 – 784 , 1967 14 Bochicchio GV , Ilahi O , Joshi M , Bochicchio K , Scalea TM : Endotracheal intubation in the field does not improve outcome in trauma patients who present without an acutely lethal traumatic brain injury . J Trauma 54 : 307

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Leonardo Rangel-Castilla, Jaime Gasco, Haring J. W. Nauta, DaviD O. Okonkwo, and Claudia S. Robertson

, Stringer WA , Choi SC , Fatouros P , Young HF : Ultra-early evaluation of regional cerebral blood flow in severely head-injured patients using xenon-enhanced computerized tomography . J Neurosurg 77 : 360 – 368 , 1992 6 Bratton SL , Chestnut RM , Ghajar J , McConnell Hammond FF , Harris OA , Hartl R , : Guidelines for the management of severe traumatic brain injury. II. Hyperosmolar therapy . J Neurotrauma 24 : 1 Suppl S14 – S20 , 2007 7 Bratton SL , Chestnut RM , Ghajar J , McConnell Hammond FF , Harris OA

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Adam Ross Befeler, William Gordon, Nickalus Khan, Julius Fernandez, Michael Scott Muhlbauer, and Jeffrey Marius Sorenson

management of traumatic brain injury? A prospective evaluation . J Trauma 57 : 939 – 943 , 2004 5 Brown CV , Zada G , Salim A , Inaba K , Kasotakis G , Hadjizacharia P , : Indications for routine repeat head computed tomography (CT) stratified by severity of traumatic brain injury . J Trauma 62 : 1339 – 1345 , 2007 6 Chao A , Pearl J , Perdue P , Wang D , Bridgeman A , Kennedy S , : Utility of routine serial computed tomography for blunt intracranial injury . J Trauma 51 : 870 – 876 , 2001 7 Fazel R , Krumholz HM

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Efthimios Dardiotis, Kostas N. Fountas, Maria Dardioti, Georgia Xiromerisiou, Eftychia Kapsalaki, Anastasia Tasiou, and Georgios M. Hadjigeorgiou

elevated, and this upregulation after injury was associated with better neurological outcome. 18 However, a polymorphism in the promoter of IL-6 was not found to have any effect on the outcome of patients with TBI. 88 Other Association Studies Clinical studies in patients who have sustained TBI have investigated the role of genetic variants in genes that modulate neurotransmitters such as dopamine 81 or serotonin. 16 Traumatic brain injury induces excessive neurotransmitter release, and this may affect motor function, behavior, mood, and cognition. Dopamine

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Brian Appavu, Stephen T. Foldes, and P. David Adelson

Adelson PD : Animal models of traumatic brain injury in the immature: a review . Exp Toxicol Pathol 51 : 130 – 136 , 1999 2 Adelson PD : Hypothermia following pediatric traumatic brain injury . J Neurotrauma 26 : 429 – 436 , 2009 3 Adelson PD , Bratton SL , Carney NA , Chestnut RM , du Coudray HE , Goldstein B , : Guidelines for the acute medical management of severe traumatic brain injury in infants, children and adolescents . Pediatr Crit Care Med 4 ( 3 Suppl ): S38 – S39 , 2003 4 Adelson PD , Ragheb J , Kanev P

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Fatima Khalid, George L. Yang, Jennifer L. McGuire, Matthew J. Robson, Brandon Foreman, Laura B. Ngwenya, and John N. Lorenz

an association with improved survival, without information regarding functional or quality-of-life outcomes. 31 The ongoing double-blind randomized clinical trial Decreasing Adrenergic or Sympathetic Hyperactivity after Traumatic Brain Injury (or DASH after TBI) is comparing combination propranolol and clonidine therapy with a placebo in ICU patients. 48 The results of this trial will add additional evidence regarding the efficacy of these drugs in PSH management and shed light on the interplay between TBI and organ function. In this paper, we will review the

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Luke G. F. Smith, Eric Milliron, Mai-Lan Ho, Houchun H. Hu, Jerome Rusin, Jeffrey Leonard, and Eric A. Sribnick

I n the United States, traumatic brain injury (TBI) accounts for more than 280,000 hospitalizations and 50,000 deaths annually. 52 The most common causes of TBI include falls, impact against an object or with an object, and motor vehicle collisions. 67 It is estimated that more than 3 million people in the United States are living with a long-term disability from a TBI. 82 Despite advances in our understanding regarding the pathophysiology of TBI, there has not been a significant improvement in patient outcomes over the past 2 decades. 64 A recent study