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OBJECTIVES: To evaluate how blast exposure impacts peripheral biomarkers.in military personnel enrolled in 10-day blast training. METHODS: On day 7, 21 military personnel experienced peak overpressure <2 pounds per square inch (psi); while 29 military personnel experienced peak overpressure ≥5 psi. Blood samples were collected each day to measure changes in amyloid beta (Aß), neurofilament light chain (NFL), and tau concentrations. RESULTS: Within 24 hours following exposure ≥5 psi, the ≥5 psi group had lower Aß42 (p = .004) and NFL (p < .001) compared to the <2 psi group and lower Aß42 (9.35%) and NFL (22.01%) compared to baseline. Twenty-four hours after ≥5 psi exposure, the ≥5 psi group had lower tau (p < .001) and NFL (p < .001) compared to the <2 psi group and baseline. Seventy-two hours after exposure ≥5 psi, tau increased in the ≥5 psi group compared to the <2 psi group (p = .02) and baseline. The tau:Aß42 ratio 24 hours after blast (p = .012), and the Aß40:Aß42 ratio 48 hours after blast (p = .04) differed in the ≥5 psi group compared to the <2 psi group. CONCLUSIONS: These findings provide an initial report of acute alterations in biomarker concentrations following blast exposure.
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Péptidos beta-Amiloides , Personal Militar , Biomarcadores , Humanos , Filamentos Intermedios , Proteínas de Neurofilamentos , Proteínas tauRESUMEN
OBJECTIVE: The aim of this study was to assess, in two experiments, the safety and efficacy of the PFC emulsion Oxycyte as an oxygen therapeutic for TBI to test the hypothesis that early administration of this oxygen-carrying fluid post-TBI would improve brain tissue oxygenation (Pbt O2 ). METHODS: The first experiment assessed the effects of Oxycyte on cerebral vasoactivity in healthy, uninjured rats using intravital microscopy. The second experiment investigated the effect of Oxycyte on cerebral Pbt O2 using the PQM in TBI model. Animals in the Oxycyte group received a single injection of Oxycyte (6 mL/kg) shortly after TBI, while NON animals received no treatment. RESULTS: Oxycyte did not cause vasoconstriction in small- (<50 µm) or medium- (50-100 µm) sized pial arterioles nor did it cause a significant change in blood pressure. Treatment with Oxycyte while breathing 100% O2 did not improve Pbt O2 . However, in rats ventilated with ~40% O2 , Pbt O2 improved to near pre-TBI values within 105 minutes after Oxycyte injection. CONCLUSIONS: Although Oxycyte did not cause cerebral vasoconstriction, its use at the dose tested while breathing 100% O2 did not improve Pbt O2 following TBI. However, Oxycyte treatment while breathing a lower enriched oxygen concentration may improve Pbt O2 after TBI.
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Lesiones Traumáticas del Encéfalo/terapia , Fluorocarburos/uso terapéutico , Oxígeno/sangre , Animales , Arteriolas/fisiología , Encéfalo/metabolismo , Circulación Cerebrovascular , Microscopía Intravital , Oxígeno/administración & dosificación , Ratas , Vasoconstricción/efectos de los fármacosRESUMEN
Sanguinate, a polyethylene glycol-conjugated carboxyhemoglobin, was investigated for cerebral vasoactivity in healthy male Sprague-Dawley rats (Study 1) and for its ability to increase brain tissue oxygen pressure (PbtO2) after controlled cortical impact (CCI) - traumatic brain injury (TBI) (Study 2). In both studies ketamine-acepromazine anesthetized rats were ventilated with 40% O2. In Study 1, a cranial window was used to measure the diameters of medium - (50-100µm) and small-sized (<50µm) pial arterioles before and after four serial infusions of Sanguinate (8mL/kg/h, cumulative 16mL/kg IV), volume-matched Hextend, or normal saline. In Study 2, PbtO2 was measured using a phosphorescence quenching method before TBI, 15min after TBI (T15) and then every 10min thereafter for 155min. At T15, rats received either 8mL/kg IV Sanguinate (40mL/kg/h) or no treatment (saline, 4mL/kg/h). Results showed: 1) in healthy rats, percentage changes in pial arteriole diameter were the same among the groups, 2) in TBI rats, PbtO2 decreased from 36.5±3.9mmHg to 19.8±3.0mmHg at T15 in both groups after TBI and did not recover in either group for the rest of the study, and 3) MAP increased 16±4mmHg and 36±5mmHg after Sanguinate in healthy and TBI rats, respectively, while MAP was unchanged in control groups. In conclusion, Sanguinate did not cause vasoconstriction in the cerebral pial arterioles of healthy rats but it also did not acutely increase PbtO2 when administered after TBI. Sanguinate was associated with an increase in MAP in both studies.
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Arteriolas/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Carboxihemoglobina/farmacología , Circulación Cerebrovascular/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Oxígeno/metabolismo , Piamadre/irrigación sanguínea , Sustitutos del Plasma/farmacología , Polietilenglicoles/farmacología , Animales , Presión Arterial/efectos de los fármacos , Arteriolas/metabolismo , Arteriolas/fisiopatología , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/fisiopatología , Carboxihemoglobina/análogos & derivados , Carboxihemoglobina/toxicidad , Modelos Animales de Enfermedad , Derivados de Hidroxietil Almidón/farmacología , Masculino , Microcirculación/efectos de los fármacos , Sustitutos del Plasma/toxicidad , Polietilenglicoles/toxicidad , Ratas Sprague-Dawley , Factores de Tiempo , Vasoconstricción/efectos de los fármacosRESUMEN
BACKGROUND: White matter hyperintensities (WMHs) are foci of abnormal signal intensity in white matter regions seen with magnetic resonance imaging (MRI). WMHs are associated with normal ageing and have shown prognostic value in neurological conditions such as traumatic brain injury (TBI). The impracticality of manually quantifying these lesions limits their clinical utility and motivates the utilization of machine learning techniques for automated segmentation workflows. METHODS: This study develops a concatenated random forest framework with image features for segmenting WMHs in a TBI cohort. The framework is built upon the Advanced Normalization Tools (ANTs) and ANTsR toolkits. MR (3D FLAIR, T2- and T1-weighted) images from 24 service members and veterans scanned in the Chronic Effects of Neurotrauma Consortium's (CENC) observational study were acquired. Manual annotations were employed for both training and evaluation using a leave-one-out strategy. Performance measures include sensitivity, positive predictive value, [Formula: see text] score and relative volume difference. RESULTS: Final average results were: sensitivity = 0.68 ± 0.38, positive predictive value = 0.51 ± 0.40, [Formula: see text] = 0.52 ± 0.36, relative volume difference = 43 ± 26%. In addition, three lesion size ranges are selected to illustrate the variation in performance with lesion size. CONCLUSION: Paired with correlative outcome data, supervised learning methods may allow for identification of imaging features predictive of diagnosis and prognosis in individual TBI patients.
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Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Procesamiento Automatizado de Datos , Aprendizaje Automático Supervisado , Sustancia Blanca/diagnóstico por imagen , Adolescente , Adulto , Mapeo Encefálico , Estudios de Cohortes , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Core proteins of mitochondrial protein import are found in all mitochondria, suggesting a common origin of this import machinery. Despite the presence of a universal core import mechanism, there are specific proteins found only in a few groups of organisms. One of these proteins is the translocase of outer membrane 70 (Tom70), a protein that is essential for the import of preproteins with internal targeting sequences into the mitochondrion. Until now, Tom70 has only been found in animals and Fungi. We have identified a tom70 gene in the human parasitic anaerobic stramenopile Blastocystis sp. that is neither an animal nor a fungus. Using a combination of bioinformatics, genetic complementation, and immunofluorescence microscopy analyses, we demonstrate that this protein functions as a typical Tom70 in Blastocystis mitochondrion-related organelles. Additionally, we identified putative tom70 genes in the genomes of other stramenopiles and a haptophyte, that, in phylogenies, form a monophyletic group distinct from the animal and the fungal homologues. The presence of Tom70 in these lineages significantly expands the evolutionary spectrum of eukaryotes that contain this protein and suggests that it may have been part of the core mitochondrial protein import apparatus of the last common ancestral eukaryote.
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Evolución Biológica , Blastocystis/genética , Blastocystis/metabolismo , Mitocondrias/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Blastocystis/ultraestructura , Técnicas de Silenciamiento del Gen , Prueba de Complementación Genética , Humanos , Mitocondrias/genética , Proteínas de Transporte de Membrana Mitocondrial/química , Proteínas de Transporte de Membrana Mitocondrial/clasificación , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas del Complejo de Importación de Proteínas Precursoras Mitocondriales , Modelos Moleculares , Filogenia , Conformación Proteica , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
Background: Blast exposure is a potential hazard in modern military operations and training, especially for some military occupations. Helmets, peripheral armor, hearing protection, and eye protection worn by military personnel provide some acute protection from blast effects but may not fully protect personnel against cumulative effects of repeated blast overpressure waves experienced over a career. The current study aimed to characterize the long-term outcomes of repeated exposure to primary blast overpressure in experienced career operators with an emphasis on the assessment of hearing and vestibular outcomes. Methods: Participants included experienced "breachers" (military and law enforcement explosives professionals who gain entry into structures through controlled detonation of charges) and similarly aged and experienced "non-breachers" (non-breaching military and law enforcement personnel). Responses to a clinical interview and performance on audiological and vestibular testing were compared. Results: Hearing loss, ringing in the ears, irritability, and sensitivity to light or noise were more common among breachers than non-breachers. Breachers reported more combat exposure than non-breachers, and subsequently, memory loss and difficulty concentrating were associated with both breaching and combat exposure. Vestibular and ocular motor outcomes were not different between breachers and non-breachers. Conclusion: Hearing-related, irritability, and sensitivity outcomes are associated with a career in breaching. Future studies examining long-term effects of blast exposure should take measures to control for combat exposure.
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Mild traumatic brain injury is a common outcome of blast exposure, and current literature indicates high rates of comorbid posttraumatic stress disorder (PTSD) in military personnel. Blast-exposed rats display PTSD-like behavior, suggesting relationships may exist between PTSD and blast exposure. Other studies demonstrate the roles of stathmin and corticosterone associated with fear- and anxiety-like behaviors in rodent models. Furthermore, studies have observed ranges of responses to both physical and psychological trauma in animal populations (Elder 2012, Ritov 2016). This study exposed rodents to repeated blast overpressure (BOP) and analyzed behavioral responses and molecular variables at 3 weeks and 6 months after exposure. We applied a modified version of a previously reported behavioral profiling approach that separates "affected" and "unaffected" rats based on the presence of anxiety-like behaviors (Ritov, 2016). We report that "affected" 3 week animals showed higher plasma corticosterone and amygdalar stathmin levels, while "affected" 6 month animals had lower prefrontal cortex stathmin. Higher corticosterone also paralleled anxiety behavior in "affected" 3 week animals, which was not observed in 6 month animals, indicating possible negative feedback loop mechanisms. Elevated levels of amygdalar stathmin correlated with anxiety behaviors in "affected" 3 week and 6 month animals, indicating sustained molecular changes. We conclude that this unique analysis may provide more information about response to blast. This type of analysis should also be considered when treating clinical populations, since individual differences may affect behavioral and long-term outcomes. Future studies should elucidate relationships of stress and fear responses in the context of BOP.
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Ansiedad/fisiopatología , Conmoción Encefálica/metabolismo , Conmoción Encefálica/psicología , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/psicología , Traumatismos por Explosión/psicología , Lesiones Encefálicas/psicología , Comorbilidad , Corticosterona/análisis , Corticosterona/sangre , Modelos Animales de Enfermedad , Miedo/fisiología , Masculino , Corteza Prefrontal/metabolismo , Ratas , Ratas Long-Evans , Estatmina/análisis , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/psicologíaRESUMEN
Objective: The purpose of this study is to utilize a natural history approach to describe and understand symptom recovery in personnel diagnosed with a blast-related mild traumatic brain injury (mTBI) resulting from an improvised explosive device blast. Participants and Design: The population included military personnel who experienced a blast mTBI while mounted (vehicle; n = 176) or dismounted (on foot; n = 37) (N = 213). Patients had no co-morbid psychiatric or muscle-skeletal issues and were treated within 72 h of injury. Prevalence and duration of self-reported symptoms were separately analyzed by injury context (mounted vs dismounted). Results: Headache was prominently reported in both mounted (85%) and dismounted (75%) populations. The mean time from injury to return to full duty was between 7.8 d (mounted) and 8.5 d (dismounted). The dismounted population reported visual changes that lasted 0.74 d longer. Conclusion: Our analysis implicates that headache is a common and acutely persistent symptom in mTBI regardless of injury context. Additionally, patients in mounted vs dismounted injury did not report significant differences in symptom prevalence. Although knowing the injury context (i.e., dismounted vs mounted) may be beneficial for providers to understand symptom presentations and deliver accurate anticipatory guidance for patients with blast-related mTBI, no significant differences were observed in this population. This may be due to the population characteristic as the trajectory of recovery may vary for patients who were not able to return to full duty within 30 d or required higher levels of care.
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Traumatismos por Explosión/rehabilitación , Conmoción Encefálica/rehabilitación , Personal Militar/psicología , Adulto , Campaña Afgana 2001- , Traumatismos por Explosión/epidemiología , Traumatismos por Explosión/psicología , Conmoción Encefálica/epidemiología , Conmoción Encefálica/psicología , Distribución de Chi-Cuadrado , Comorbilidad , Explosiones/estadística & datos numéricos , Femenino , Humanos , Masculino , Personal Militar/estadística & datos numéricos , Autoinforme , Estados Unidos/epidemiologíaRESUMEN
Traumatic brain injury (TBI) is one of the most common forms of neurotrauma that has affected more than 250,000 military service members over the last decade alone. While in battle, service members who experience TBI are at significant risk for the development of normal TBI symptoms, as well as risk for the development of psychological disorders such as Post-Traumatic Stress Disorder (PTSD). As such, these service members often require intense bouts of medication and therapy in order to resume full return-to-duty status. The primary aim of this study is to identify the relationship between the administration of specific medications and reductions in symptomology such as headaches, dizziness, or light-headedness. Service members diagnosed with mTBI and seen at the Concussion Restoration Care Center (CRCC) in Afghanistan were analyzed according to prescribed medications and symptomology. Here, we demonstrate that in such situations with sparse labels and small feature sets, classic analytic techniques such as logistic regression, support vector machines, naïve Bayes, random forest, decision trees, and k-nearest neighbor are not well suited for the prediction of outcomes. We attribute our findings to several issues inherent to this problem setting and discuss several advantages of spectral graph methods.
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Algoritmos , Conmoción Encefálica/clasificación , Lesiones Traumáticas del Encéfalo/clasificación , Biología Computacional/métodos , Pruebas de Estado Mental y Demencia , Adulto , Teorema de Bayes , Análisis por Conglomerados , Bases de Datos Factuales , Humanos , Personal Militar , Adulto JovenRESUMEN
BACKGROUND: Hypoxia is a critical secondary injury mechanism in traumatic brain injury (TBI), and early intervention to alleviate post-TBI hypoxia may be beneficial. NVX-108, a dodecafluoropentane perfluorocarbon, was screened for its ability to increase brain tissue oxygen tension (PbtO2) when administered soon after TBI. METHODS: Ketamine-acepromazine anesthetized rats ventilated with 40% oxygen underwent moderate controlled cortical impact (CCI)-TBI at time 0 (T0). Rats received either no treatment (NON, n=8) or 0.5 ml/kg intravenous (IV) NVX-108 (NVX, n=9) at T15 (15 min after TBI) and T75. RESULTS: Baseline cortical PbtO2 was 28±3 mm Hg and CCI-TBI resulted in a 46±6% reduction in PbtO2 at T15 (P<0.001). Significant differences in time-group interactions (P=0.013) were found when comparing either absolute or percentage change of PbtO2 to post-injury (mixed-model ANOVA) suggesting that administration of NVX-108 increased PbtO2 above injury levels while it remained depressed in the NON group. Specifically in the NVX group, PbtO2 increased to a peak 143% of T15 (P=0.02) 60 min after completion of NVX-108 injection (T135). Systemic blood pressure was not different between the groups. CONCLUSION: NVX-108 caused an increase in PbtO2 following CCI-TBI in rats and should be evaluated further as a possible immediate treatment for TBI.
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Lesiones Traumáticas del Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Fluorocarburos/administración & dosificación , Hipoxia/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Lesiones Traumáticas del Encéfalo/complicaciones , Corteza Cerebral/lesiones , Frecuencia Cardíaca/efectos de los fármacos , Hipoxia/etiología , Hipoxia/prevención & control , Masculino , Presión Parcial , Ratas , Ratas Sprague-DawleyRESUMEN
We examined unconscious priming in a stem-completion task with both identity and form-related primes. Participants were given exclusion instructions to avoid completing a stem (e.g., ca---) with a briefly flashed masked word (e.g., candy). In Experiment 1, priming of around 7% occurred for both identity (e.g., candy) and form-based (e.g., windy) primes at a 33 ms exposure duration. When examining only trials in which the participants failed to identify the prime, this effect increased to 12% for identity primes, but remained the same for form-based primes. In Experiment 2, priming without prime identification was 9% for identity primes, 4% for homophone primes, and 3% for orthographic control primes. Although identity priming was greater than form priming in both experiments, regression analyses revealed that orthographic and phonological overlap alone between the flashed primes and targets could completely account for unconscious identity priming. Hence, we conclude that masked words may only activate their sublexical orthographic and phonological representations and not their lexical representations.