Chronic effects of blast injury on the microvasculature in a transgenic mouse model of Alzheimer's disease related Aß amyloidosis.

BACKGROUND: Altered cerebrovascular function and accumulation of amyloid-ß (Aß) after traumatic brain injury (TBI) can contribute to chronic neuropathology and increase the risk for Alzheimer's disease (AD). TBI due to a blast-induced shock wave (bTBI) adversely affects the neurovascular unit (NVU) during the acute period after injury. However, the chronic effects of bTBI and Aß on cellular components of the NVU and capillary network are not well understood. METHODS: We exposed young adult (age range: 76-106 days) female transgenic (Tg) APP/PS1 mice, a model of AD-like Aß amyloidosis, and wild type (Wt) mice to a single bTBI (~ 138 kPa or ~ 20 psi) or to a Sham procedure. At 3-months or 12-months survival after exposure, we quantified neocortical Aß load in Tg mice, and percent contact area between aquaporin-4 (AQP4)-immunoreactive astrocytic end-feet and brain capillaries, numbers of PDGFRß-immunoreactive pericytes, and capillary densities in both genotypes. RESULTS: The astroglia AQP4-capillary contact area in the Tg-bTBI group was significantly lower than in the Tg-Sham group at 3-months survival. No significant changes in the AQP4-capillary contact area were observed in the Tg-bTBI group at 12-months survival or in the Wt groups. Capillary density in the Tg-bTBI group at 12-months survival was significantly higher compared to the Tg-Sham control and to the Tg-bTBI 3-months survival group. The Wt-bTBI group had significantly lower capillary density and pericyte numbers at 12-months survival compared to 3-months survival. When pericytes were quantified relative to capillary density, no significant differences were detected among the experimental groups, for both genotypes. CONCLUSION: In conditions of high brain concentrations of human Aß, bTBI exposure results in reduced AQP4 expression at the astroglia-microvascular interface, and in chronic capillary proliferation like what has been reported in AD. Long term microvascular changes after bTBI may contribute to the risk for developing chronic neurodegenerative disease later in life.

Injury scoring systems for blast injuries: a narrative review.

Injury scoring systems can be used for triaging, predicting morbidity and mortality, and prognosis in mass casualty incidents. Recent conflicts and civilian incidents have highlighted the unique nature of blast injuries, exposing deficiencies in current scoring systems. Here, we classify and describe deficiencies with current systems used for blast injury. Although current scoring systems highlight survival trends for populations, there are several major limitations. The reliable prediction of mortality on an individual basis is inaccurate. Other limitations include the saturation effect (where scoring systems are unable to discriminate between high injury score individuals), the effect of the overall injury burden, lack of precision in discriminating between mechanisms of injury, and a lack of data underpinning scoring system coefficients. Other factors influence outcomes, including the level of healthcare and the delay between injury and presentation. We recommend that a new score incorporates the severity of injuries with the mechanism of blast injury. This may include refined or additional codes, severity scores, or both, being added to the Abbreviated Injury Scale for high-frequency, blast-specific injuries; weighting for body regions associated with a higher risk for death; and blast-specific trauma coefficients. Finally, the saturation effect (maximum value) should be removed, which would enable the classification of more severe constellations of injury. An early accurate assessment of blast injury may improve management of mass casualty incidents.

Longitudinal auditory pathophysiology following mild blast-induced trauma.

Blast-induced hearing difficulties affect thousands of veterans and civilians. The long-term impact of even a mild blast exposure on the central auditory system is hypothesized to contribute to lasting behavioral complaints associated with mild blast traumatic brain injury (bTBI). Although recovery from mild blast has been studied separately over brief or long time windows, few, if any, studies have investigated recovery longitudinally over short-term and longer-term (months) time windows. Specifically, many peripheral measures of auditory function either recover or exhibit subclinical deficits, masking deficits in processing complex, real-world stimuli that may recover differently. Thus, examining the acute time course and pattern of neurophysiological impairment using appropriate stimuli is critical to better understanding and intervening in bTBI-induced auditory system impairments. Here, we compared auditory brainstem response, middle-latency auditory-evoked potentials, and envelope following responses. Stimuli were clicks, tone pips, amplitude-modulated tones in quiet and in noise, and speech-like stimuli (iterated rippled noise pitch contours) in adult male rats subjected to mild blast and sham exposure over the course of 2 mo. We found that blast animals demonstrated drastic threshold increases and auditory transmission deficits immediately after blast exposure, followed by substantial recovery during the window of 7-14 days postblast, although with some deficits remaining even after 2 mo. Challenging conditions and speech-like stimuli can better elucidate mild bTBI-induced auditory deficit during this period. Our results suggest multiphasic recovery and therefore potentially different time windows for treatment, and deficits can be best observed using a small battery of sound stimuli.NEW & NOTEWORTHY Few studies on blast-induced hearing deficits go beyond simple sounds and sparsely track postexposure. Therefore, the recovery arc for potential therapies and real-world listening is poorly understood. Evidence suggested multiple recovery phases over 2 mo postexposure. Hearing thresholds largely recovered within 14 days and partially explained recovery. However, midlatency responses, responses to amplitude modulation in noise, and speech-like pitch sweeps exhibited extended changes, implying persistent central auditory deficits and the importance of subclinical threshold shifts.

Mild blast wave exposure produces intensity-dependent changes in MMP2 expression patches in rat brains - Findings from different blast severities.

Matrix metalloproteinase 2 (MMP2) is a gelatinase with multiple functions at the neurovascular interface, including local modification of the glia limitans to facilitate access of immune cells into the brain and amyloid-beta degradation during responses to injury or disease. This study examines regional changes in immunoreactive MMP2 in the rat brain after a single mild (2.7-7.9 psi peak) or moderate (13-17.5 psi peak) blast overpressure (BOP) exposure. Immunopositive MMP2 expression was examined quantitatively in histological sections of decalcified rat heads as a marker at 2, 24, and 72 h after BOP. The MMP2 immunoreactivity was isolated to patchy deposits in brain parenchyma surrounding blood vessels. Separate analyses were conducted for the cerebellum, brain stem caudal to the thalamo-mesencephalic junction, and the cerebrum (including diencephalon). The deposits varied in number, size, staining homogeneity (standard deviation of immunopositive region), and a cumulative measure, the product of size, average intensity and number, as a function of blast intensity and time. The sequences of changes in MMP2 spots from sham control animals suggested that the mild BOP exposure differences normalized within 72 h. However, the responses to moderate exposure revealed a delayed response at 72 h in the subtentorial brain stem and the cerebrum, but not the cerebellum. Hence, local MMP2 responses may be a contextual biomarker for locally regulated responses to widely distributed brain injury foci.

POSTERIOR SEGMENT INJURIES IN OPERATION IRAQI FREEDOM AND OPERATION ENDURING FREEDOM: 2001 to 2011.

BACKGROUND/PURPOSE: To characterize the nature of posterior segment ocular injuries in combat trauma. METHODS: Eyes in the Walter Reed Ocular Trauma Database were evaluated for the presence of posterior segment injury. Final visual outcomes in open-globe versus closed-globe injuries and by zone of injury and the types of posterior segment injuries in open-globe versus closed-globe injuries were assessed. RESULTS: Four hundred fifty-two of 890 eyes (50.8%) had at least one posterior segment injury. The mechanism of injury was most commonly an improvised explosive device in 280 (62.0%) eyes. Sixty-one patients (13.5%) had a Zone I injury, 50 (11.1%) a Zone II injury, and 341 (75.4%) a Zone III injury. Patients with Zone I injuries were more likely to have a final visual acuity of 20/200 or better compared with patients with either a Zone II (P < 0.001) or Zone III injury (P = 0.007). Eyes with a closed-globe injury were more likely to have a final visual acuity of 20/200 or better compared with those with an open-globe injury (P < 0.001). Furthermore, closed-globe injury compared with open-globe injury had a lower risk of vitreous hemorrhage (odds ratio 0.32, P < 0.001), proliferative vitreoretinopathy (odds ratio 0.14, P < 0.001), and retinal detachment (odds ratio 0.18, P < 0.001) but a higher risk of chorioretinal rupture (odds ratio 2.82, P < 0.001) and macular hole (odds ratio 3.46, P = 0.004). CONCLUSION: Patients with combat ophthalmic trauma had similar posterior segment injury patterns to civilian trauma in open-globe versus closed-globe injuries. Zone II and III injuries were associated with a worse visual prognosis.

Proteomic Analysis Revealed the Characteristics of Key Proteins Involved in the Regulation of Inflammatory Response, Leukocyte Transendothelial Migration, Phagocytosis, and Immune Process during Early Lung Blast Injury.

Previous studies found that blast injury caused a significant increased expression of interleukin-1, IL-6, and tumor necrosis factor, a significant decrease in the expression of IL-10, an increase in Evans blue leakage, and a significant increase in inflammatory cell infiltration in the lungs. However, the molecular characteristics of lung injury at different time points after blast exposure have not yet been reported. Therefore, in this study, tandem mass spectrometry (TMT) quantitative proteomics and bioinformatics analysis were used for the first time to gain a deeper understanding of the molecular mechanism of lung blast injury at different time points. Forty-eight male C57BL/6 mice were randomly divided into six groups: control, 12 h, 24 h, 48 h, 72 h, and 1 w after low-intensity blast exposure. TMT quantitative proteomics and bioinformatics analysis were performed to analyze protein expression profiling in the lungs from control and blast-exposed mice, and differential protein expression was verified by Western blotting. The results demonstrated that blast exposure induced severe lung injury, leukocyte infiltration, and the production of inflammatory factors in mice. After analyzing the expression changes in global proteins and inflammation-related proteomes after blast exposure, the results showed that a total of 6861 global proteins and 608 differentially expressed proteins were identified, of which 215, 128, 187, 232, and 65 proteins were identified at 12 h, 24 h, 48 h, 72 h, and 1 week after blast exposure, respectively. Moreover, blast exposure-induced 177 differentially expressed proteins were associated with inflammatory responses, which were enriched in the inflammatory response regulation, leukocyte transendothelial migration, phagocytosis, and immune response. Therefore, blast exposure may induce early inflammatory response of lung tissue by regulating the expression of key proteins in the inflammatory process, suggesting that early inflammatory response may be the initiating factor of lung blast injury. These data can provide potential therapeutic candidates or approaches for the development of future treatment of lung blast injury.

Information Transfer and Multifractal Analysis of EEG in Mild Blast-Induced TBI.

Mild, blast-induced traumatic brain injury (mbTBI) is a common combat brain injury characterized by typically normal neuroimaging findings, with unpredictable future cognitive recovery. Traditional methods of electroencephalography (EEG) analysis (e.g., spectral analysis) have not been successful in detecting the degree of cognitive and functional impairment in mbTBI. We therefore collected resting state EEG (5 minutes, 64 leads) from twelve patients with a history of mbTBI, along with repeat neuropsychological testing (D-KEFS Tower test) to compare two new methods for analyzing EEG (multifractal detrended fluctuation analysis (MF-DFA) and information transfer modeling (ITM)) with spectral analysis. For MF-DFA, we extracted relevant parameters from the resultant multifractal spectrum from all leads and compared with traditional power by frequency band for spectral analysis. For ITM, because the number of parameters from each lead far exceeded the number of subjects, we utilized a reduced set of 10 leads which were compared with spectral analysis. We utilized separate 30 second EEG segments for training and testing statistical models based upon regression tree analysis. ITM and MF-DFA models both generally had improved accuracy at correlating with relevant measures of cognitive performance as compared to spectral analytic models ITM and MF-DFA both merit additional research as analytic tools for EEG and cognition in TBI.

Performance validity and symptom validity tests: Are they measuring different constructs?

OBJECTIVE: To evaluate the relationships among performance validity, symptom validity, symptom self-report, and objective cognitive testing. METHOD: Combat Veterans (N = 338) completed a neurocognitive assessment battery and several self-report symptom measures assessing depression, posttraumatic stress disorder (PTSD) symptoms, sleep quality, pain interference, and neurobehavioral complaints. All participants also completed two performance validity tests (PVTs) and one stand-alone symptom validity test (SVT) along with two embedded SVTs. RESULTS: Results of an exploratory factor analysis revealed a three-factor solution: performance validity, cognitive performance, and symptom report (SVTs loaded on the third factor). Results of t tests demonstrated that participants who failed PVTs displayed significantly more severe symptoms and significantly worse performance on most measures of neurocognitive functioning compared to those who passed. Participants who failed a stand-alone SVT also reported significantly more severe symptomatology on all symptom report measures, but the pattern of cognitive performance differed based on the selected SVT cutoff. Multiple linear regressions revealed that both SVT and PVT failure explained unique variance in symptom report, but only PVT failure significantly predicted cognitive performance. CONCLUSIONS: Performance and symptom validity tests measure distinct but related constructs. SVTs and PVTs are significantly related to both cognitive performance and symptom report; however, the relationship between symptom validity and symptom report is strongest. SVTs are also differentially related to cognitive performance and symptom report based on the utilized cutoff score. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Craniocerebral Dynamic Response and Cumulative Effect of Damage Under Repetitive Blast.

Soldiers suffer from multiple explosions in complex battlefield environment resulting in aggravated brain injuries. At present, researches mostly focus on the damage to human body caused by single explosion. In the repetitive impact study, small animals are mainly used for related experiments to study brain nerve damage. No in-depth research has been conducted on the dynamic response and damage of human brain under repetitive explosion shock waves. Therefore, this study use the Euler-Lagrange coupling method to construct an explosion shock wave-head fluid-structure coupling model, and numerically simulated the brain dynamic response subjected to single and repetitive blast waves, obtained flow field pressure, skull stress, skull displacement, intracranial pressure to analyze the brain damage. The simulation results of 100 g equivalent of TNT exploding at 1 m in front of the craniocerebral show that repetitive blast increase skull stress, intracranial pressure, skull displacement, and the damage of brain tissue changes from moderate to severe. Repetitive blasts show a certain cumulative damage effect, the severity of damage caused by double blast is 122.5% of single shock, and the severity of damage caused by triple blast is 105.9% of double blast and 131.5% of single blast. The data above shows that it is necessary to reduce soldiers' exposure from repetitive blast waves.

Repetitive blast mild traumatic brain injury increases ethanol sensitivity in male mice and risky drinking behavior in male combat veterans.

BACKGROUND: Mild traumatic brain injury (mTBI) is common in civilians and highly prevalent among military service members. mTBI can increase health risk behaviors (e.g., sensation seeking, impulsivity) and addiction risk (e.g., for alcohol use disorder (AUD)), but how mTBI and substance use might interact to promote addiction risk remains poorly understood. Likewise, potential differences in single vs. repetitive mTBI in relation to alcohol use/abuse have not been previously examined. METHODS: Here, we examined how a history of single (1×) or repetitive (3×) blast exposure (blast-mTBI) affects ethanol (EtOH)-induced behavioral and physiological outcomes using an established mouse model of blast-mTBI. To investigate potential translational relevance, we also examined self-report responses to the Alcohol Use Disorders Identification Test-Consumption questions (AUDIT-C), a widely used measure to identify potential hazardous drinking and AUD, and used a novel unsupervised machine learning approach to investigate whether a history of blast-mTBI affected drinking behaviors in Iraq/Afghanistan Veterans. RESULTS: Both single and repetitive blast-mTBI in mice increased the sedative properties of EtOH (with no change in tolerance or metabolism), but only repetitive blast potentiated EtOH-induced locomotor stimulation and shifted EtOH intake patterns. Specifically, mice exposed to repetitive blasts showed increased consumption "front-loading" (e.g., a higher rate of consumption during an initial 2-h acute phase of a 24-h alcohol access period and decreased total daily intake) during an intermittent 2-bottle choice condition. Examination of AUDIT-C scores in Iraq/Afghanistan Veterans revealed an optimal 3-cluster solution: "low" (low intake and low frequency), "frequent" (low intake and high frequency), and "risky" (high intake and high frequency), where Veterans with a history of blast-mTBI displayed a shift in cluster assignment from "frequent" to "risky," as compared to Veterans who were deployed to Iraq/Afghanistan but had no lifetime history of TBI. CONCLUSIONS: Together, these results offer new insight into how blast-mTBI may give increase AUD risk and highlight the increased potential for adverse health risk behaviors following repetitive blast-mTBI.

Different Responses to Identical Trauma Between BALB/C and C57BL/6 Mice.

BACKGROUND Different responses to identical trauma may be related to the genetic background of individuals, but the molecular mechanism is unclear. In this study we investigated the heterogeneity of trauma in mice and the potential biological explanations for the differences. MATERIAL AND METHODS Compared with other organs, the pathological response of the lung after injury is the earliest and most serious. We used C57BL/6 and BALB/C mice to explore the genetic background of different responses to trauma in the lung. We measured mortality rate, pulmonary microvascular permeability, and Cxcl15 gene expression in BALB/C and C57BL/6 mice before and after blast-wave injury. Microvascular permeability was measured using a fluorescent tracer, and Cxcl15 gene expression level and expression distribution were measured using fluorogenic probe quantitative polymerase chain reaction and northern blot. RESULTS C57BL/6 mice showed lower mortality rates and pulmonary microvascular permeability than BALB/C mice after blast-wave injury; there was no significant difference in the permeability before blast-wave injury. The Cxcl15 gene was expressed specifically in the lung tissue of mice. The level of Cxcl15 expression in BALB/C mice was higher than in C57BL/6 mice before and after injury, and the variation trend of Cxcl15 expression level after injury was significantly different between BALB/C and C57BL/6 mice. CONCLUSIONS Our results indicated that BALB/C and C57BL/6 mice had significant heterogeneity in posttraumatic response in terms of mortality and degree of lung damage. The differences in genetic factors such as Cxcl15 may have played a role in this heterogeneity.

Axonal damage and behavioral deficits in rats with repetitive exposure of the brain to laser-induced shock waves: Effects of inter-exposure time.

Much attention has been given to effects of repeated exposure to a shock wave as a possible factor causing severe higher brain dysfunction and post-traumatic stress disorder (PTSD)-like symptoms in patients with mild to moderate blast-induced traumatic brain injury (bTBI). However, it is unclear how the repeated exposure and the inter-exposure time affect the brain. In this study, we topically applied low-impulse (∼54 Pa·s) laser-induced shock waves (LISWs; peak pressure, ∼75.7 MPa) to the rat brain once or twice with the different inter-exposure times (15 min, 1 h, 3 h, 24 h and 7 days) and examined anxiety-related behavior and motor dysfunction in the rats as well as expression of ß-amyloid precursor protein (APP) as an axonal damage marker in the brains of the rats. The averaged APP expression scores for the rat brains doubly-exposed to LISWs with inter-exposure times from 15 min to 24 h were significantly higher than those for rats with a single exposure (P < 0.0001). The rats with double exposure to LISWs showed significantly more frequent anxiety-related behavior (P < 0.05) and poorer motor function (P < 0.01) than those of rats with a single exposure. When the inter-exposure time was extended to 7 days, however, the rats showed no significant differences either in axonal damage score or level of motor dysfunction. The results suggest that the cumulative effects of shock wave-related brain injury can be avoided with an appropriate inter-exposure time. However, clinical bTBI occurs in much more complex environments than those in our model. Further study considering other factors, such as the effects of acceleration, is needed to know the clinically-relevant, necessary inter-exposure time.

Does tympanic membrane perforation have a protective effect on the inner ear in blast-injured patients?

BACKGROUND: Blast-induced hearing loss is an acoustic trauma commonly caused by high-energy explosions of improvised explosive devices, and the auditory system may be affected by blast damage. This study aims to evaluate the protective effect of tympanic membrane perforation (TMP) on the inner ear against blast injury. METHODS: In this study, 43 adult patients who had suffered blast injury were divided into three subgroups: intact tympanic membranes in both ears, unilateral TMP, and bilateral TMP. Each patient underwent a comprehensive audiogram, including bone conduction, in the audiology department. RESULTS: Evaluation was performed on 43 (100%) males with a mean age of 31.44±8.01 years (range, 18-52 years). When the type of hearing loss was evaluated separately for each ear, sensorineural hearing loss (SNHL) was observed in 31 (36%), high-frequency SNHL in 26 (30.2%), conductive hearing loss in eight (9.3%), and mixed type hearing loss in 21 (24.4%) ears. TMP was detected in 21 (48.8%) of 43 blast-injured patients, on the right side in four (9.3%) patients, on the left side in seven (16.3%), and bilateral in 10 (23.3%). When the type of acoustic trauma was evaluated, 15 (34.9%) patients were observed to have suffered from the explosion of an IED, 12 (30.2%) from weapon explosion, six (14%) were a vehicle bomb explosion, three (7%) were projectile missile explosion, three (7%) were mortar explosion, two (4.7%) were mine explosion, and two (4.7%) were exposed to the explosion in an armored vehicle (Table 1). CONCLUSION: No significant difference was observed in the majority of the frequencies whether the tympanic membrane was perforated or not in the blast-injured patients and it was concluded that tympanic membrane perforation caused by blast injury had no protective effect on the inner ear.

Cerebral perfusion is associated with blast exposure in military personnel without moderate or severe TBI.

Due to the use of improvised explosive devices, blast exposure and mild traumatic brain injury (mTBI) have become hallmark injuries of the Iraq and Afghanistan wars. Although the mechanisms of the effects of blast on human neurobiology remain active areas of investigation, research suggests that the cerebrovasculature may be particularly vulnerable to blast via molecular processes that impact cerebral blood flow. Given that recent work suggests that blast exposure, even without a subsequent TBI, may have negative consequences on brain structure and function, the current study sought to further understand the effects of blast exposure on perfusion. One hundred and eighty military personnel underwent pseudo-continuous arterial spin labeling (pCASL) imaging and completed diagnostic and clinical interviews. Whole-brain analyses revealed that with an increasing number of total blast exposures, there was significantly increased perfusion in the right middle/superior frontal gyri, supramarginal gyrus, lateral occipital cortex, and posterior cingulate cortex as well as bilateral anterior cingulate cortex, insulae, middle/superior temporal gyri and occipital poles. Examination of other neurotrauma and clinical variables such as close-range blast exposures, mTBI, and PTSD yielded no significant effects. These results raise the possibility that perfusion may be an important neural marker of brain health in blast exposure.

Neuropsychological, Neurocognitive, Vestibular, and Neuroimaging Correlates of Exposure to Repetitive Low-Level Blast Waves: Evidence From Four Nonoverlapping Samples of Canadian Breachers.

INTRODUCTION: We assessed the utility of a battery of neuropsychological, neurocognitive, physiological (balance, ataxia, postural tremor), and neuroimaging measures for studying the effects of blast waves in breachers-a population repeatedly exposed to low-level blast during military training and operations. MATERIALS AND METHODS: Data were collected from four nonoverlapping samples, in the course of similarly structured 4-day breacher training exercises in successive years involving a combination of indoor and outdoor blast events. In all cases, self-report and neuropsychological measures were administered once at baseline (i.e., 1 day before the start of training). In years 1-2, neurocognitive and physiological measures were administered daily before and after training. In years 3-4, neurocognitive data were collected once at baseline. In Year 4, we introduced 3 modifications to our design. First, in addition to breachers, we also collected data from sex-and age-matched military controls at the same time points. Second, we assessed balance, ataxia, and postural tremor immediately following blast exposure "in the field," enabling us to quantify its acute effects. Third, structural magnetic resonance imaging (MRI) scans were acquired before and after the 4-day training exercise to explore differences between breachers and controls at baseline, as well as possible training-related changes using voxel-based morphometry. These design modifications were made to enable us to test additional hypotheses in the context of the same training exercise. RESULTS: At baseline, scores on the "Rivermead Post Concussion Symptoms Questionnaire," "RAND SF-36" (physical functioning, role limitation due to physical health, social functioning, energy/fatigue, general health), and "Short Musculoskeletal Function Questionnaire" distinguished breachers from controls. Also at baseline, the MRI data revealed that there was greater regional gray matter volume in controls compared to breachers in the right superior frontal gyrus. Balance, ataxia, and postural tremor did not exhibit sensitivity to the acute effects of blast in the field, nor did neurocognitive measures to its cumulative or daily effects. CONCLUSION: Our exploratory results suggest that self-report neuropsychological measures and structural MRI hold promise as sensitive measures for quantifying the long-term, cumulative effects of blast exposure in breachers. We discuss the limitations of our study and the need for prospective longitudinal data for drawing causal inferences regarding the impact of blast exposure on breachers' health and performance.

Sex Does Not Influence Visual Outcomes After Blast-Mediated Traumatic Brain Injury but IL-1 Pathway Mutations Confer Partial Rescue.

Purpose: In a mouse model of blast-mediated traumatic brain injury (bTBI), interleukin-1 (IL-1)-pathway components were tested as potential therapeutic targets for bTBI-mediated retinal ganglion cell (RGC) dysfunction. Sex was also evaluated as a variable for RGC outcomes post-bTBI. Methods: Male and female mice with null mutations in genes encoding IL-1α, IL-1ß, or IL-1RI were compared to C57BL/6J wild-type (WT) mice after exposure to three 20-psi blast waves given at an interblast interval of 1 hour or to mice receiving sham injury. To determine if genetic blockade of IL-1α, IL-1ß, or IL-1RI could prevent damage to RGCs, the function and structure of these cells were evaluated by pattern electroretinogram and optical coherence tomography, respectively, 5 weeks following blast or sham exposure. RGC survival was also quantitatively assessed via immunohistochemical staining of BRN3A at the completion of the study. Results: Our results showed that male and female WT mice had a similar response to blast-induced retinal injury. Generally, constitutive deletion of IL-1α, IL-1ß, or IL-1RI did not provide full protection from the effects of bTBI on visual outcomes; however, injured WT mice had significantly worse visual outcomes compared to the injured genetic knockout mice. Conclusions: Sex does not affect RGC outcomes after bTBI. The genetic studies suggest that deletion of these IL-1 pathway components confers some protection, but global deletion from birth did not result in a complete rescue.

Altered monoaminergic levels, spasticity, and balance disability following repetitive blast-induced traumatic brain injury in rats.

Spasticity and balance disability are major complications following traumatic brain injury (TBI). Although monoaminergic inputs provide critical adaptive neuromodulations to the motor system, data are not available regarding the levels of monoamines in the brain regions related to motor functions following repetitive blast TBI (bTBI). The objective of this study was to determine if mild, repetitive bTBI results in spasticity/balance deficits and if these are correlated with altered levels of norepinephrine, dopamine, and serotonin in the brain regions related to the motor system. Repetitive bTBI was induced by a blast overpressure wave in male rats on days 1, 4, and 7. Following bTBI, physiological/behavioral tests were conducted and tissues in the central motor system (i.e., motor cortex, locus coeruleus, vestibular nuclei, and lumbar spinal cord) were collected for electrochemical detection of norepinephrine, dopamine, and serotonin by high-performance liquid chromatography. The results showed that norepinephrine was significantly increased in the locus coeruleus and decreased in the vestibular nuclei, while dopamine was significantly decreased in the vestibular nuclei. On the other hand, serotonin was significantly increased in the motor cortex and the lumbar spinal cord. Because these monoamines play important roles in regulating the excitability of neurons, these results suggest that mild, repetitive bTBI-induced dysregulation of monoaminergic inputs in the central motor system could contribute to spasticity and balance disability. This is the first study to report altered levels of multiple monoamines in the central motor system following acute mild, repetitive bTBI.

Nitric oxide synthase mediates cerebellar dysfunction in mice exposed to repetitive blast-induced mild traumatic brain injury.

We investigated the role of nitric oxide synthase (NOS) in mediating blood-brain barrier (BBB) disruption and peripheral immune cell infiltration in the cerebellum following blast exposure. Repetitive, but not single blast exposure, induced delayed-onset BBB disruption (72 hours post-blast) in cerebellum. The NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) administered after blast blocked BBB disruption and prevented CD4+ T-cell infiltration into cerebellum. L-NAME also blocked blast-induced increases in intercellular adhesion molecule-1 (ICAM-1), a molecule that plays a critical role in regulating blood-to-brain immune cell trafficking. Blocking NOS-mediated BBB dysfunction during this acute/subacute post-blast interval (24-71 hours after the last blast) also prevented sensorimotor impairment on a rotarod task 30 days later, long after L-NAME cleared the body. In postmortem brains from Veterans/military Servicemembers with blast-related TBI, we found marked Purkinje cell dendritic arbor structural abnormalities, which were comparable to neuropathologic findings in the blast-exposed mice. Taken collectively, these results indicate that blast provokes delayed-onset of NOS-dependent pathogenic cascades that can later emerge as behavioral dysfunction. These results also further implicate the cerebellum as a brain region vulnerable to blast-induced mTBI.

Fracture union rates across a century of war: a systematic review of the literature.

INTRODUCTION: Fractures have been a common denominator of the injury patterns observed over the past century of warfare. The fractures typified by the blast and ballistic injuries of war lead to high rates of bone loss, soft tissue injury and infection, greatly increasing the likelihood of non-union. Despite this, no reliable treatment strategy for non-union exists. This literature review aims to explore the rates of non-union across a century of conflict, in order to determine whether our ability to heal the fractures of war has improved. METHODS: A systematic review of the literature was conducted, evaluating the rates of union in fractures sustained in a combat environment over a 100-year period. Only those fractures sustained through a ballistic or blast mechanism were included. The review was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Quality and bias assessment was also undertaken. RESULTS: Thirty studies met the inclusion criteria, with a total of 3232 fractures described across 15 different conflicts from the period 1919-2019. Male subjects made up 96% of cases, and tibial fractures predominated (39%). The lowest fracture union rate observed in a series was 50%. Linear regression analysis demonstrated that increasing years had no statistically significant impact on union rate. CONCLUSIONS: Failure to improve fracture union rates is likely a result of numerous factors, including greater use of blast weaponry and better survivability of casualties. Finding novel strategies to promote fracture healing is a key defence research priority in order to improve the rates of fractures sustained in a combat environment.