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      Revisiting Traumatic Brain Injury: From Molecular Mechanisms to Therapeutic Interventions

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          Abstract

          Studying the complex molecular mechanisms involved in traumatic brain injury (TBI) is crucial for developing new therapies for TBI. Current treatments for TBI are primarily focused on patient stabilization and symptom mitigation. However, the field lacks defined therapies to prevent cell death, oxidative stress, and inflammatory cascades which lead to chronic pathology. Little can be done to treat the mechanical damage that occurs during the primary insult of a TBI; however, secondary injury mechanisms, such as inflammation, blood-brain barrier (BBB) breakdown, edema formation, excitotoxicity, oxidative stress, and cell death, can be targeted by therapeutic interventions. Elucidating the many mechanisms underlying secondary injury and studying targets of neuroprotective therapeutic agents is critical for developing new treatments. Therefore, we present a review on the molecular events following TBI from inflammation to programmed cell death and discuss current research and the latest therapeutic strategies to help understand TBI-mediated secondary injury.

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          Most cited references393

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          Structural and functional features of central nervous system lymphatics

          One of the characteristics of the CNS is the lack of a classical lymphatic drainage system. Although it is now accepted that the CNS undergoes constant immune surveillance that takes place within the meningeal compartment 1–3 , the mechanisms governing the entrance and exit of immune cells from the CNS remain poorly understood 4–6 . In searching for T cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the CSF, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the CNS. The discovery of the CNS lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
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            Assessment of coma and impaired consciousness. A practical scale.

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              Estimating the global incidence of traumatic brain injury

              Traumatic brain injury (TBI)—the “silent epidemic”—contributes to worldwide death and disability more than any other traumatic insult. Yet, TBI incidence and distribution across regions and socioeconomic divides remain unknown. In an effort to promote advocacy, understanding, and targeted intervention, the authors sought to quantify the case burden of TBI across World Health Organization (WHO) regions and World Bank (WB) income groups. Open-source epidemiological data on road traffic injuries (RTIs) were used to model the incidence of TBI using literature-derived ratios. First, a systematic review on the proportion of RTIs resulting in TBI was conducted, and a meta-analysis of study-derived proportions was performed. Next, a separate systematic review identified primary source studies describing mechanisms of injury contributing to TBI, and an additional meta-analysis yielded a proportion of TBI that is secondary to the mechanism of RTI. Then, the incidence of RTI as published by the Global Burden of Disease Study 2015 was applied to these two ratios to generate the incidence and estimated case volume of TBI for each WHO region and WB income group. Relevant articles and registries were identified via systematic review; study quality was higher in the high-income countries (HICs) than in the low- and middle-income countries (LMICs). Sixty-nine million (95% CI 64–74 million) individuals worldwide are estimated to sustain a TBI each year. The proportion of TBIs resulting from road traffic collisions was greatest in Africa and Southeast Asia (both 56%) and lowest in North America (25%). The incidence of RTI was similar in Southeast Asia (1.5% of the population per year) and Europe (1.2%). The overall incidence of TBI per 100,000 people was greatest in North America (1299 cases, 95% CI 650–1947) and Europe (1012 cases, 95% CI 911–1113) and least in Africa (801 cases, 95% CI 732–871) and the Eastern Mediterranean (897 cases, 95% CI 771–1023). The LMICs experience nearly 3 times more cases of TBI proportionally than HICs. Sixty-nine million (95% CI 64–74 million) individuals are estimated to suffer TBI from all causes each year, with the Southeast Asian and Western Pacific regions experiencing the greatest overall burden of disease. Head injury following road traffic collision is more common in LMICs, and the proportion of TBIs secondary to road traffic collision is likewise greatest in these countries. Meanwhile, the estimated incidence of TBI is highest in regions with higher-quality data, specifically in North America and Europe.
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                Author and article information

                Journal
                Biomedicines
                Biomedicines
                biomedicines
                Biomedicines
                MDPI
                2227-9059
                29 September 2020
                October 2020
                : 8
                : 10
                : 389
                Affiliations
                [1 ]Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; ajarrahi@ 123456augusta.edu (A.J.); mobraun@ 123456uw.edu (M.B.); Rgupta@ 123456augusta.edu (R.V.G.); wilsonma@ 123456evms.edu (M.W.); munie@ 123456musc.edu (S.M.); jvender@ 123456augusta.edu (J.R.V.); fvalediaz@ 123456augusta.edu (F.L.V.); kdhandapani@ 123456augusta.edu (K.M.D.)
                [2 ]Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA
                [3 ]VISN 20 Northwest Mental Illness Research, Education and Clinical Center (NW MIRECC), VA Puget Sound Health Care System, Seattle, WA 98108, USA
                [4 ]Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; mahluwalia@ 123456augusta.edu (M.A.); pahluwalia@ 123456augusta.edu (P.A.)
                [5 ]School of Medicine, Eastern Virginia Medical School, Norfolk, VA 23501, USA
                [6 ]College of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
                Author notes
                [* ]Correspondence: kvaibhav@ 123456augusta.edu ; Tel.: +1-(706)-721-4691
                [†]

                These authors contributed equally to this study.

                Author information
                https://orcid.org/0000-0002-0830-5445
                https://orcid.org/0000-0002-4206-3830
                Article
                biomedicines-08-00389
                10.3390/biomedicines8100389
                7601301
                33003373
                01a47540-4bbd-4837-aeb4-7e06e641352a
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 08 September 2020
                : 26 September 2020
                Categories
                Review

                neurotrauma,neuroinflammation,excitotoxicity,oxidative stress,apoptosis,edema,brain injury,therapeutic strategies

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