Behavioral, biophysical, and pharmacological studies have implicated the hippocampus in the formation and storage of spatial memory. Traumatic brain injury (TBI) often causes spatial memory deficits, which are thought to arise from the death as well as the dysfunction of hippocampal neurons. Cell death and dysfunction are commonly associated with and often caused by altered expression of specific genes. The identification of the genes involved in these processes, as well as those participating in postinjury cellular repair and plasticity, is important for the development of mechanism-based therapies. To monitor the expression levels of a large number of genes and to identify genes not previously implicated in TBI pathophysiology, a high-density oligonucleotide array containing 8,800 genes was interrogated. RNA samples were prepared from ipsilateral hippocampi 3 hr and 24 hr following lateral cortical impact injury and compared to samples from sham-operated controls. Cluster analysis was employed using statistical algorithms to arrange the genes according to similarity in patterns of expression. The study indicates that the genomic response to TBI is complex, affecting approximately 6% (at the time points examined) of the total number of genes examined. The identity of the genes revealed that TBI affects many aspects of cell physiology, including oxidative stress, metabolism, inflammation, structural changes, and cellular signaling. The analysis revealed genes whose expression levels have been reported to be altered in response to injury as well as several genes not previously implicated in TBI pathophysiology.
These results suggest that the novel hemostatic devices perform at least as well as the current Committee on Tactical Combat Casualty Care standard for point-of-injury hemorrhage control. Despite their different compositions and sizes, the lack of clear superiority of any agent suggests that contemporary hemostatic dressing technology has potentially reached a plateau for efficacy.
BackgroundSurvival rates remain low after hemorrhage-induced traumatic cardiac arrest (TCA). Noncompressible torso hemorrhage (NCTH) is a major cause of potentially survivable trauma death. Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) at the thoracic aorta (Zone 1) can limit subdiaphragmatic blood loss and allow for IV fluid resuscitation when intrinsic cardiac activity is still present. Selective Aortic Arch Perfusion (SAAP) combines thoracic aortic balloon hemorrhage control with intra-aortic oxygenated perfusion to achieve return of spontaneous circulation (ROSC) when cardiac arrest has occurred.Methods and findingsMale Yorkshire Landrace cross swine (80.0 ± 6.0 kg) underwent anesthesia, instrumentation for monitoring, and splenectomy. TCA was induced by laparoscopic liver lobe resection combined with arterial catheter blood withdrawal to achieve a sustained systolic blood pressure <10 mmHg, cardiac arrest. After 3 min of arrest, swine were allocated to one of three interventions: (1) REBOA plus 4 units of IV fresh whole blood (FWB), (2) SAAP with oxygenated lactated Ringer’s (LR), 1,600 mL/2 min, or (3) SAAP with oxygenated FWB 1,600 mL/2 min. Primary endpoint was survival to the end of 60 min of resuscitation, a simulated prehospital phase. Thirty animals were allocated to 3 groups (10 per group)—5 protocol exclusions resulted in a total of 35 animals being used. Baseline measurements and time to cardiac arrest were not different amongst groups. ROSC was achieved in 0/10 (0%, 95% CI 0.00–30.9) REBOA, 6/10 (60%, 95% CI 26.2–87.8) SAAP-LR and 10/10 (100%, 95% CI 69.2–100.0) SAAP-FWB animals, p < 0.001. Survival to end of simulated 60-minute prehospital resuscitation was 0/10 (0%, 95% CI 0.00–30.9) for REBOA, 1/10 (10%, 95% CI 0.25–44.5) for SAAP-LR and 9/10 (90%, 95% CI 55.5–99.7) for SAAP-FWB, p < 0.001. Total FWB infusion volume was similar for REBOA (2,452 ± 0 mL) and SAAP-FWB (2,250 ± 594 mL). This study was undertaken in laboratory conditions, and as such may have practical limitations when applied clinically. Cardiac arrest in this study was defined by intra-aortic pressure monitoring that is not feasible in clinical practice, and as such limits the generalizability of findings. Clinical trials are needed to determine if the beneficial effects of SAAP-FWB observed in this laboratory study will translate into improved survival in clinical practice.ConclusionsSAAP conferred a superior short-term survival over REBOA in this large animal model of hemorrhage-induced traumatic cardiac arrest with NCTH. SAAP using an oxygen-carrying perfusate was more effective in this study than non-oxygen carrying solutions in TCA. SAAP can effect ROSC from hemorrhage-induced electrocardiographic asystole in large swine.
Damage to the frontal cortex and to the hippocampus, both in terms of cell loss and neuronal dysfunction, is thought to underlie many of the neurological and behavioural consequences of traumatic brain injury (TBI). Several studies have indicated that the hippocampus is particularly susceptible to central nervous system insults, whereas the frontal cortex possesses relatively higher capacities for regeneration and plasticity. It has been postulated that dissimilarities in the gene expression profiles in these structures, both in the normal and the postinjury states, may underlie these differences. In order to explore this issue, mRNA samples taken from the frontal cortex and the hippocampus of uninjured animals were subjected to high-density microarray analysis. The analysis indicated that the mRNA levels of 65 genes were differentially expressed between these two brain regions. Among these, genes involved in intracellular signalling, neurotransmitter release, and genes encoding for channels and receptors were identified. Samples taken from animals injured using controlled cortical impact (a model of TBI) showed altered mRNA levels for 341 frontal cortex genes 24 h following injury. These genes can be broadly classified into one of 12 functional classes: cell cycle, metabolism, reactive oxygen metabolism, inflammation, receptors, channels and transporters, signal transduction, cytoskeleton, membrane proteins, neuropeptides, growth factors, and proteins involved in transcription/translation. The expression profile of these genes is compared to the expression profile of 241 genes in the hippocampus 24 h following cortical impact injury as previously reported by our laboratory. In addition to genes previously reported in the literature, this study found several genes that have not been associated with TBI. The functional implications of changes in the expression of some of these genes are discussed.
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