The "Top 10" research and development priorities for battlefield surgical care: Results from the Committee on Surgical Combat Casualty Care research gap analysis.

BACKGROUND: The US Military has achieved the highest casualty survival rates in its history. However, there remain multiple areas in combat trauma that present challenges to the delivery of high-quality and effective trauma care. Previous work has identified research priorities for pre-hospital care, but there has been no similar analysis for forward surgical care. METHODS: A list of critical "focus areas" was developed by the Committee on Surgical Combat Casualty Care (CoSCCC). Individual topics were solicited and mapped to appropriate focus areas by group consensus and review of Eastern Association for the Surgery of Trauma (EAST) and Joint Trauma System guidelines. A web-based survey was distributed to the CoSCCC and the military committees of EAST and the American Association for the Surgery of Trauma. Topics were rated on a Likert scale from 1 (low) to 10 (high priority). Descriptives, univariate statistics, and inter-rater correlation analysis was performed. RESULTS: 13 research focus areas were identified (eight clinical and five adjunctive categories). Ninety individual topics were solicited. The survey received 64 responses. The majority of respondents were military (90%) versus civilians (10%). There was moderate to high agreement (inter-rater correlation coefficient = 0.93, p < 0.01) for 10 focus areas. The top five focus areas were Personnel/Staffing (mean, 8.03), Resuscitation and Hemorrhage Management (7.49), Pain/Sedation/Anxiety Management (6.96), Operative Interventions (6.9), and Initial Evaluation (6.9). The "Top 10" research priorities included four in Personnel/Staffing, four in Resuscitation/Hemorrhage Management, and three in Operative Interventions. A complete list of the topics/scores will be presented. CONCLUSIONS: This is the first objective ranking of research priorities for combat trauma care. The "Top 10" priorities were all from three focus areas, supporting prioritization of personnel/staffing of austere teams, resuscitation/hemorrhage control, and damage-control interventions. This data will help guide Department of Defense research programs and new areas for prioritized funding of both military and civilian researchers. LEVEL OF EVIDENCE: Study design, level IV.

Traumatic brain injury in the US military: epidemiology and key clinical and research programs.

Traumatic brain injury (TBI), and particularly concussion, is a major concern for the U.S. Military because of the associated short term disability, long term cognitive and pain symptoms suffered by some, and risk of prolonged or permanent neurologic injury if the Service member incurs a second TBI before full recovery from the first. Concussions were seen more often during the recent conflicts in Afghanistan and Iraq than in prior conflicts, such as the Vietnam War, because of the use of improvised explosive devices that typically caused non-penetrating closed head injury. Since 2000 more than 300,000 Service members were diagnosed with TBI, of which more than 80 % were concussions. Improved TBI screening tools also have identified a higher than expected incidence of concussions occurring in garrison. In this review we summarize current epidemiologic data for TBI in the Military, and describe contemporary Military procedures and strategies for TBI prevention, identification, evaluation, and acute and chronic care. Key TBI clinical research priorities and programs are described, and innovative organizational plans to address future TBI needs are summarized.

Identification of the rostral migratory stream in the canine and feline brain.

In the adult rodent brain, neural progenitor cells migrate from the subventricular zone of the lateral ventricle towards the olfactory bulb in a track known as the rostral migratory stream (RMS). To facilitate the study of neural progenitor cells and stem cell therapy in large animal models of CNS disease, we now report the location and characteristics of the normal canine and feline RMS. The RMS was found in Nissl-stained sagittal sections of adult canine and feline brains as a prominent, dense, continuous cellular track beginning at the base of the anterior horn of the lateral ventricle, curving around the head of the caudate nucleus and continuing laterally and ventrally to the olfactory peduncle before entering the olfactory tract and bulb. To determine if cells in the RMS were proliferating, the thymidine analog 5-bromo-2-deoxyuridine (BrdU) was administered and detected by immunostaining. BrdU-immunoreactive cells were present throughout this track. The RMS was also immunoreactive for markers of proliferating cells, progenitor cells and immature neurons (Ki-67 and doublecortin), but not for NeuN, a marker of mature neurons. Luxol fast blue and CNPase staining indicated that myelin is closely apposed to the RMS along much of its length and may provide guidance cues for the migrating cells. Identification and characterization of the RMS in canine and feline brain will facilitate studies of neural progenitor cell biology and migration in large animal models of neurologic disease.

The use of specific AAV serotypes to stably transduce primary CNS neuron cultures.

Although primary neuronal cell cultures are a valuable source of in vitro insight for many neurobiologists, all current gene expression technologies for these cells have significant drawbacks. Some of these limitations of current gene expression protocols include toxicity, transient expression, a requirement for postnatal neurons, and/or low efficiency. To date, many types of experiments were not possible because of these limitations. Here, we outline a methodology by which primary cultured neurons can be transduced at any age, after plating, with virtually no toxicity and continued gene expression for the lifetime of the culture. This method involves the use of adeno-associated viral vectors, which have the potential to be highly useful for either upregulation or downregulation of single or multiple genes, including neurotrophins, other neuroprotective genes, and neurotoxins.

Identification of potentially neuroprotective genes upregulated by neurotrophin treatment of CA3 neurons in the injured brain.

Specific neurotrophic factors mediate histological and/or functional improvement in animal models of traumatic brain injury (TBI). In previous work, several lines of evidence indicated that the mammalian neurotrophin NT-4/5 is neuroprotective for hippocampal CA3 pyramidal neurons after experimental TBI. We hypothesized that NT-4/5 neuroprotection is mediated by changes in the expression of specific sets of genes, and that NT-4/5-regulated genes are potential therapeutic targets for blocking delayed neuronal death after TBI. In this study, we performed transcription profiling analysis of CA3 neurons to identify genes regulated by lateral fluid percussion injury, or by treatment with the trkB ligands NT-4/5 or brain-derived neurotrophic factor (BDNF). The results indicate extensive overlap between genes upregulated by neurotrophins and genes upregulated by injury, suggesting that the mechanism behind neurotrophin neuroprotection may mimic the brain's endogenous protective response. A subset of genes selected for further study in vitro exhibited neuroprotection against glutamate excitotoxicity. The neuroprotective genes identified in this study were upregulated at 30 h post-injury, and are thus expected to act during a clinically useful time frame of hours to days after injury. Modulation of these factors and pathways by genetic manipulation or small molecules may confer hippocampal neuroprotection in vivo in preclinical models of TBI.

Role of monocyte chemoattractant protein-1 (MCP-1/CCL2) in migration of neural progenitor cells toward glial tumors.

Neural progenitor cells (NPCs) have been investigated as potential vehicles for brain tumor therapy because they have been shown to migrate toward central nervous system gliomas and can be genetically engineered to deliver cytotoxic agents to tumors. The mechanisms that regulate migration of NPCs to tumors are not fully understood. By means of microarray analysis, polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry, we found that monocyte chemoattractant protein-1 (MCP-1/CCL-2) was expressed in experimental brain tumor cells in vivo and in vitro. CCR2, the receptor for MCP-1, was expressed on C17.2 NPCs. We used a modified Boyden chamber assay and found increased migration of NPCs in vitro in response to MCP-1. By means of an in vivo model for NPC migration, we found evidence of NPC migration toward areas of MCP-1 infusion in rat brains. An understanding of NPC migration mechanisms may be used to enhance delivery of cytotoxic agents to brain tumor cells.