Quantitative genetics of trauma induced mortality in Drosophila melanogaster.

Traumatic brain injury is a major cause of chronic neurological impairment worldwide, and there is evidence that both genetic and environmental variation contribute to the likelihood of recovery. Using an insect model of traumatic brain injury, we examined variation in the risk of mortality using quantitative genetic approaches applied previously for life history traits in Drosophila melanogaster. We quantified additive genetic variance for mortality risk using a controlled breeding design and found levels of variation consistent with existing data on major fitness components. We found no evidence for inbreeding effects on mortality risk, suggesting that dominance genetic variance makes little contribution to this trait. To explain the high level of standing genetic variation, we considered whether mortality risk depends on the metabolic resources available to an individual, also known as “condition”. We manipulated condition by inducing random mutations and by restricting calories during larval development. We found that reduced condition due to both random mutations and resource limitation significantly increased the risk of mortality following trauma. Among inbred lines, greater mortality risk was associated with lower viability, fecundity and longevity, consistent with an effect of genome-wide genetic quality. Our results suggest that further consideration of individual condition would be valuable for understanding and predicting variation in the outcomes of traumatic brain injury.

The aim of this investigation was to compare cognitive and affective functions in men and women who had suffered comparable brain injuries. In a prospective matched cohort design, 150 community-dwelling patients were individually matched on the basis of age, severity of injury, premorbid IQ, and time since injury. Women were significantly more impaired in verbal and visual memory compared with men. The degree of cognitive decline was significantly positively correlated with age in women, but not in men. Women had marginally higher scores compared with men on measures of anxiety and depression. It is concluded that gender is a moderator of cognitive and affective outcome after brain injury

Social Determinants of Health and Traumatic Brain Injury: Implications for Rehabilitation Service Delivery and Outcomes.

Workshop on animal models of traumatic brain injury.

Background Traumatic brain injury in pediatrics is one of the commonest causes of morbidity, disability and mortality worldwide. In low- and middle-income countries Study showed that death of pediatrics from traumatic brain injury was 7.3%. However, there is limited data towards the outcome of traumatic brain injury and its associated factors in Ethiopia. Objective To assess the outcome of traumatic brain injury and associated factors among pediatrics patients in Amhara National Regional State Comprehensive Specialized Hospitals, Ethiopia. Methods An institution based retrospective cross-sectional study was conducted among 423 pediatrics patients from January 1, 2019 to December 30, 2021, and data extraction period was from May 16 to June15, 2022. Systematic random sampling technique was employed to select the study participants. Data were collected from patient charts and registry books by using a data extraction tool. Data were entered into the Epi-info version 7 and analysis was done by SPSS Version 25. Both Bi-variable and multi-variable analyses were employed to identify factors associated with outcome of traumatic brain injury. Result From 423 sampled study participant charts 404 of them had complete information with response rate of 95.5% and included in the final analysis. The overall unfavorable outcome of traumatic brain injury at discharge was found that 12.13% (95% CI: 9.1% - 15.7 %). Sever traumatic brain injury (AOR: 5.11(CI :1.8-14.48), moderate traumatic brain injury (AOR:2.44(CI:1.07-5.58), Hyperglycemia (AOR: 3.01 (CI:1.1-8.04), sign of increased intracranial pressure (AOR:7.4(CI:3.5-15.26), and medical comorbidity (AOR: 2.65(CI:1.19-5.91) were predicted of unfavorable outcome of traumatic brain injury pediatrics patient. Conclusion and recommendations twelve present of traumatic brain injury results unfavorable outcome. Sever and moderate form of traumatic brain injury, hyperglycemia, signs of increased intracranial pressure, and medical comorbidity were factors associated with unfavorable outcome of traumatic brain injury in children. Therefore, it is preferable to improve accesses to acute and post-acute care services to lower the unfavorable outcome of traumatic brain injury in children.

Pre-clinical vertebrate models of traumatic brain injury (TBI) routinely use anesthetics for animal welfare; however, humans experience TBI without anesthetics. Therefore, translation of findings from vertebrate models to humans hinges on understanding how anesthetics influence cellular and molecular events that lead to secondary injuries following TBI. To investigate the effects of anesthetics on TBI outcomes, we used an invertebrate Drosophila melanogaster model to compare outcomes between animals exposed or not exposed to anesthetics prior to the same primary injury. Using a common laboratory fly line, w1118, we found that exposure to the volatile anesthetics isoflurane or sevoflurane, but not ether, prior to TBI produced a dose-dependent reduction in mortality within 24 h following TBI. Thus, isoflurane and sevoflurane precondition w1118 flies to deleterious effects of TBI. To examine the effects of genetic differences on anesthetic preconditioning of TBI, we repeated the experiment with the Drosophila Genetic Reference Panel (DGRP) collection of genetically diverse, inbred fly lines. Pre-exposure to either isoflurane or sevoflurane revealed a wide range of preconditioning levels among 171 and 144 DGRP lines, respectively, suggesting a genetic component for variation in anesthetic preconditioning of mortality following TBI. Finally, genome-wide association study analyses identified single-nucleotide polymorphisms in genes associated with isoflurane or sevoflurane preconditioning of TBI. Several of the genes, including the fly ortholog of mammalian Calcium Voltage-Gated Subunit Alpha1 D (CACNA1D), are highly expressed in neurons and are functionally linked to both anesthetics and TBI. These data indicate that anesthetic dose and genetic background should be considered when investigating effects of anesthetics in vertebrate TBI models, and they support use of the fly model for elucidating the mechanisms underlying anesthetic preconditioning of TBI.

Studies on murine models show that Toxoplasma gondii infection reduces cerebral microvascular perfusion and induces neuroinflammation by activating cerebral endothelial cells, which could affect traumatic brain injury (TBI) outcomes. Whether TBI inflammatory profile and outcomes differ in persons with concurrent latent infection with Toxoplasma gondii has not yet been elucidated in TBI patients, constituting the core of this study. Understanding the impact of chronic T. gondii infection on neuroinflammation after TBI may ensure better management and prognosis of TBI. This study aimed to investigate the inflammatory profile in TBI patients and investigate the influence of concurrent T. gondii infection on inflammatory markers and TBI outcomes. The level of inflammatory markers [interleukin (IL)-1β, IL-6, IL-10, interferon-gamma (INF-ɣ), Tumour necrosis factor-alpha (TNF-α)], and Toxoplasma gondii infection were detected in serum obtained < 24h post-injury. Glasgow Outcome Scale-Extended (GOSE) was used to evaluate the 6-month outcome post-discharge. The Wilcoxon and Kruskal-Wallis's rank sum tests were used to compare concentrations of inflammatory markers to T. gondii infection and TBI outcome. T. gondii infection was detected in 33% (52/160) of TBI cases. There was a significant increase (p < 0.001) in the concentrations of all inflammatory markers (IM) in TBI patients compared with the healthy controls. Higher levels of IL-6, INF-ɣ, and TNF-α were associated with mortality. Findings from this study show an increase in IM levels for all the T. gondii-positive TBI cases, which were significant for IL-1β (P < 0.001) and TNF-α (P < 0.001). IL-1β and TNF-α, had significantly greater density values, above 30pg/mL and 90pg/mL, respectively, in TBI patients infected with T. gondii, compared to greater density values, below 30 pg/mL and 90 pg/mL, respectively, for TBI patients seronegative to T. gondii. Concurrent T. gondii infection in TBI significantly influenced the inflammation profile of patients. Further multicenter studies with larger sample sizes will provide more insights into T. gondii induced neuropathology and prognostication in TBI care.

INTRODUCTION: The International Mission on Prognosis and Analysis of Clinical Trials in Traumatic Brain Injury (IMPACT) and Corticosteroid Randomisation After Significant Head Injury (CRASH) prognostic models for mortality and functional outcome in traumatic brain injury (TBI) were developed using historical data from 1984-2004. METHODS: The prospective, 18-center Transforming Research and Clinical Knowledge in Traumatic Brain Injury study enrolled participants aged = 17-years who presented to Level 1 trauma center and received head computed tomography (CT) scan &lt;24-hours of TBI. Data was extracted from participants meeting IMPACT (Glasgow Coma Scale (GCS) 3-12; completed 6-month Glasgow Outcome Scale-Extended (GOSE); N = 441) and CRASH criteria (GCS 3-14; completed 2-week and 6-month GOSE; N = 831). Original model coefficients were applied, and performances were assessed using discrimination (area under the receiver-operating characteristic curve (AUC)) and calibration (intercept; slope; [95% confidence interval]). RESULTS: IMPACT and CRASH models discriminated mortality (AUC = 0.77-0.81, 0.90-0.91, respectively) and unfavorable outcome (0.77-0.81; 0.83, respectively). The IMPACT Lab model overestimated mortality (intercept = -0.79 [-1.05, -0.53]; slope = 1.37 [1.05-1.69]) and acceptably estimated unfavorable outcome (intercept = 0.07 [-0.14, 0.29]; slope = 1.19 [0.96-1.42]). The CRASH CT model overestimated mortality (intercept = -1.06 [-1.36, -0.75]; slope = 0.96 [0.79-1.14]) and unfavorable outcome (intercept = -0.60 [-0.78, -0.41]; slope = 1.20 [1.03-1.37]). Calibration performance differences were observed across the 5 leading enrollment centers (IMPACT Lab model: intercept -1.66 to -0.35, slope 1.07-1.86; CRASH CT model: intercept -1.81 to -0.67, slope 0.67-1.56) and unfavorable outcome (IMPACT Lab model: intercept -0.57 to 0.34, slope 1.28-2.89; CRASH CT model: intercept -1.15 to -0.10, slope 1.02-1.44). CONCLUSIONS: IMPACT and CRASH models discriminated mortality and unfavorable outcome. Observed overestimations of mortality and unfavorable outcome underscore the need to develop prognostic models that incorporate contemporary changes in TBI casemix. Investigations to elucidate the relationships between increased survival, functional outcome, treatment intensity, and center-specific practices will be highly relevant.

Astragaloside (AST) is traditionally prescribed for the prevention and treatment of cerebrovascular diseases. We directly tested the therapeutic effects of AST in a rat model of traumatic brain injury (TBI). One hour after the onset of TBI rats were given Saline (1 ml/kg) or AST (20-80 mg/kg) via i.p. injection. AST causes the attenuation of TBI-induced cerebral contusion, neuronal apoptosis, and neurological motor dysfunction. TBI-induced microglial activation evidenced by the morphological transformation of microglia (or ameboid microglia) and the microglial overexpression of tumor necrosis factor-alpha was reduced by AST. Our results indicate that AST may protect against brain contusion and neuronal apoptosis after TBI by attenuating microglia activation in male rats.

Traumatic brain injury (TBI) outcomes vary greatly among individuals, but most of the variation remains unexplained. Using a Drosophila melanogaster TBI model and 178 genetically diverse lines from the Drosophila Genetic Reference Panel (DGRP), we investigated the role that genetic variation plays in determining TBI outcomes. Following injury at 20-27 days old, DGRP lines varied considerably in mortality within 24 h ("early mortality"). Additionally, the disparity in early mortality resulting from injury at 20-27 vs 0-7 days old differed among DGRP lines. These data support a polygenic basis for differences in TBI outcomes, where some gene variants elicit their effects by acting on aging-related processes. Our genome-wide association study of DGRP lines identified associations between single nucleotide polymorphisms in Lissencephaly-1 (Lis-1) and Patronin and early mortality following injury at 20-27 days old. Lis-1 regulates dynein, a microtubule motor required for retrograde transport of many cargoes, and Patronin protects microtubule minus ends against depolymerization. While Patronin mutants did not affect early mortality, Lis-1 compound heterozygotes (Lis-1x/Lis-1y) had increased early mortality following injury at 20-27 or 0-7 days old compared with Lis-1 heterozygotes (Lis-1x/+), and flies that survived 24 h after injury had increased neurodegeneration but an unaltered lifespan, indicating that Lis-1 affects TBI outcomes independently of effects on aging. These data suggest that Lis-1 activity is required in the brain to ameliorate TBI outcomes through effects on axonal transport, microtubule stability, and other microtubule proteins, such as tau, implicated in chronic traumatic encephalopathy, a TBI-associated neurodegenerative disease in humans.

Neural and Immune Consequences of Traumatic Brain Injury

There is a growing literature on the impact of genetic variation on outcome in traumatic brain injury (TBI). Whereas a substantial proportion of these publications have focused on the apolipoprotein E (APOE) gene, several have explored the influence of other polymorphisms. We undertook a systematic review of the impact of single-nucleotide polymorphisms (SNPs) in non–apolipoprotein E (non-APOE) genes associated with patient outcomes in adult TBI). We searched EMBASE, MEDLINE, CINAHL, and gray literature from inception to the beginning of August 2017 for studies of genetic variance in relation to patient outcomes in adult TBI. Sixty-eight articles were deemed eligible for inclusion into the systematic review. The SNPs described were in the following categories: neurotransmitter (NT) in 23, cytokine in nine, brain-derived neurotrophic factor (BDNF) in 12, mitochondrial genes in three, and miscellaneous SNPs in 21. All studies were based on small patient cohorts and suffered from potential bias. A range of SNPs associated with genes coding for monoamine NTs, BDNF, cytokines, and mitochondrial proteins have been reported to be associated with variation in global, neuropsychiatric, and behavioral outcomes. An analysis of the tissue, cellular, and subcellular location of the genes that harbored the SNPs studied showed that they could be clustered into blood–brain barrier associated, neuroprotective/regulatory, and neuropsychiatric/degenerative groups. Several small studies report that various NT, cytokine, and BDNF-related SNPs are associated with variations in global outcome at 6–12 months post-TBI. The association of these SNPs with neuropsychiatric and behavioral outcomes is less clear. A definitive assessment of role and effect size of genetic variation in these genes on outcome remains uncertain, but could be clarified by an adequately powered genome-wide association study with appropriate recording of outcomes.

IntroductionRecently, it has been shown in several experimental settings that the noble gases xenon and helium have neuroprotective properties. In this study we tested the hypothesis that the noble gas argon has a neuroprotective potential as well. Since traumatic brain injury and stroke are widespread and generate an enormous economic and social burden, we investigated the possible neuroprotective effect in in vitro models of traumatic brain injury and cerebral ischemia.MethodsOrganotypic hippocampal slice cultures from mice pups were subjected to either oxygen-glucose deprivation or to a focal mechanical trauma and subsequently treated with three different concentrations (25, 50 and 74%) of argon immediately after trauma or with a two-or-three-hour delay. After 72 hours of incubation tissue injury assessment was performed using propidium iodide, a staining agent that becomes fluorescent when it diffuses into damaged cells via disintegrated cell membranes.ResultsWe could show argon's neuroprotective effects at different concentrations when applied directly after oxygen-glucose deprivation or trauma. Even three hours after application, argon was still neuroprotective.ConclusionsArgon showed a neuroprotective effect in both in vitro models of oxygen-glucose deprivation and traumatic brain injury. Our promising results justify further in vivo animal research.

Regenerative approaches towards neuronal loss following traumatic brain or spinal cord injury have long been considered a dogma in neuroscience and remain a cutting-edge area of research. This is reflected in a large disparity between the number of studies investigating primary and secondary injury as therapeutic targets in spinal cord and traumatic brain injuries. Significant advances in biotechnology may have the potential to reshape the current state-of-the-art and bring focus to primary injury neurotrauma research. Recent studies using neural-glial factor/antigen 2 (NG2) cells indicate that they may differentiate into neurons even in the developed brain. As these cells show great potential to play a regenerative role, studies have been conducted to test various manipulations in neurotrauma models aimed at eliciting a neurogenic response from them. In the present study, we systematically reviewed the experimental protocols and findings described in the scientific literature, which were peer-reviewed original research articles (1) describing preclinical experimental studies, (2) investigating NG2 cells, (3) associated with neurogenesis and neurotrauma, and (4) in vitro and/or in vivo, available in PubMed/MEDLINE, Web of Science or SCOPUS, from 1998 to 2022. Here, we have reviewed a total of 1504 papers, and summarized findings that ultimately suggest that NG2 cells possess an inducible neurogenic potential in animal models and in vitro. We also discriminate findings of NG2 neurogenesis promoted by different pharmacological and genetic approaches over functional and biochemical outcomes of traumatic brain injury and spinal cord injury models, and provide mounting evidence for the potential benefits of manipulated NG2 cell ex vivo transplantation in primary injury treatment. These findings indicate the feasibility of NG2 cell neurogenesis strategies and add new players in the development of therapeutic alternatives for neurotrauma.

Neuroglobin overexpression improves sensorimotor outcomes in a mouse model of traumatic brain injury