Articles: traumatic-brain-injuries.
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Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. Despite extensive preclinical research supporting the effectiveness of neuroprotective therapies for brain trauma, there have been no successful randomized controlled clinical trials to date. TBI results in delayed secondary tissue injury due to neurochemical, metabolic and cellular changes; modulating such effects has provided the basis for neuroprotective interventions. ⋯ We discuss the concept of utilizing multipotential drugs that target multiple secondary injury pathways, rather than more specific "laser"-targeted strategies that have uniformly failed in clinical trials. Moreover, we assess data supporting use of neuroprotective drugs that are currently being evaluated in human clinical trials for TBI, as well as promising emerging experimental multipotential drug treatment strategies. Finally, we describe key challenges and provide suggestions to improve the likelihood of successful clinical translation.
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Frontiers in neurology · Jan 2015
The Temporal Pattern of Changes in Serum Biomarker Levels Reveals Complex and Dynamically Changing Pathologies after Exposure to a Single Low-Intensity Blast in Mice.
Time-dependent changes in blood-based protein biomarkers can help identify the -pathological processes in blast-induced traumatic brain injury (bTBI), assess injury severity, and monitor disease progression. We obtained blood from control and injured mice (exposed to a single, low-intensity blast) at 2-h, 1-day, 1-week, and 1-month post-injury. We then determined the serum levels of biomarkers related to metabolism (4-HNE, HIF-1α, ceruloplasmin), vascular function (AQP1, AQP4, VEGF, vWF, Flk-1), inflammation (OPN, CINC1, fibrinogen, MIP-1a, OX-44, p38, MMP-8, MCP-1 CCR5, CRP, galectin-1), cell adhesion and the extracellular matrix (integrin α6, TIMP1, TIMP4, Ncad, connexin-43), and axonal (NF-H, Tau), neuronal (NSE, CK-BB) and glial damage (GFAP, S100β, MBP) at various post-injury time points. ⋯ Conversely, serum levels of the majority of biomarkers related to metabolic and vascular functions, cell adhesion, as well as neuronal and axonal damage remained elevated at the termination of the experiment (1 month), indicating long-term systemic and cerebral alterations due to blast. Our findings show that the exposure to a single, low-intensity blast induces complex pathological processes with distinct temporal profiles. Hence, monitoring serum biomarker levels at various post-injury time points may provide enhanced diagnostics in blast-related neurological and multi-system deficits.
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Brain injury : [BI] · Jan 2015
ReviewEmbracing failure: What the Phase III progesterone studies can teach about TBI clinical trials.
Despite positive preclinical studies and two positive Phase II clinical trials, two large Phase III clinical trials of progesterone treatment of acute traumatic brain injury (TBI) recently ended with negative results, so a 100% failure rate continues to plague the field of TBI trials. ⋯ Better definitions of injury and healing and better outcome measures are essential to change the embrace of failure that has dominated the field for over 30 years. This review offers suggestions to improve the situation.
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Frontiers in neurology · Jan 2015
Effects of blast overpressure on neurons and glial cells in rat organotypic hippocampal slice cultures.
Due to recent involvement in military conflicts, and an increase in the use of explosives, there has been an escalation in the incidence of blast-induced traumatic brain injury (bTBI) among US military personnel. Having a better understanding of the cellular and molecular cascade of events in bTBI is prerequisite for the development of an effective therapy that currently is unavailable. The present study utilized organotypic hippocampal slice cultures (OHCs) exposed to blast overpressures of 150 kPa (low) and 280 kPa (high) as an in vitro bTBI model. ⋯ Labeling OHCs with PI, neuronal, and glial markers revealed that the blast-evoked extensive neuronal death and to a lesser extent loss of glial cells. Furthermore, our data demonstrated activation of astrocytes and microglial cells in low- and high-blasted OHCs, which reached a statistically significant difference in the high-blast group. These data confirmed that our in vitro bTBI model is a useful tool for studying cellular and molecular changes after blast exposure.
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Traumatic brain injury (TBI) is an important cause of death and disability, particularly in younger populations. The prehospital evaluation and management of TBI is a vital link between insult and definitive care and can have dramatic implications for subsequent morbidity. Following a TBI the brain is at high risk for further ischemic injury, with prehospital interventions targeted at reducing this secondary injury while optimizing cerebral physiology. ⋯ We evaluate patient management strategies including indications for advanced airway management, oxygenation, ventilation, and fluid resuscitation, as well as prehospital strategies for the management of suspected or impending cerebral herniation including hyperventilation and brain-directed hyperosmolar therapy. Transport decisions including the role of triage models and trauma centers are discussed. Finally, future directions in the prehospital management of traumatic brain injury are explored.