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Towards translating research to clinical practice: Novel Strategies for Discovery and Validation of Biomarkers for Brain Injury

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193912 Year: Pages: 178 DOI: 10.3389/978-2-88919-391-2 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Neurology
Added to DOAB on : 2015-12-03 13:02:24
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Traumatic brain injury (TBI) is a major cause of death and disability and one of the greatest unmet needs in medicine and public health. TBI not only has devastating effects on patients and their relatives but results in huge direct and indirect costs to society. Although guidelines for the management of patients have been developed and more than 200 clinical trials have been conducted, they have resulted in few improvements in clinical outcomes and no effective therapies approved for TBI. It is now apparent that the heterogeneity of clinical TBI is underlain by molecular phenotypes more complex and interactive than initially conceived and current approaches to the characterization, management and outcome prediction of TBI are antiquated, unidimensional and inadequate to capture the interindividual pathophysiological heterogeneity. Recent advances in proteomics and biomarker development provide unparalleled opportunities for unraveling substantial injury-specific and patient-specific variability and refining disease characterization. The identification of novel, sensitive, objective tools, referred to as biomarkers, can revolutionize pathophysiological insights, enable targeted therapies and personalized approaches to clinical management. In this Research Topic, we present novel approaches that provide an infrastructure for discovery and validation of new biomarkers of acute brain injury. These techniques include refined mass spectrometry technology and high throughput immunoblot techniques. Output from these approaches can identify potential candidate biomarkers employing systems biology and data mining methods. In this Research Topic, we present novel approaches that provide an infrastructure for discovery and validation of new biomarkers of acute brain injury. These techniques include refined mass spectrometry technology and high throughput immunoblot techniques. Output from these approaches can identify potential candidate biomarkers employing systems biology and data mining methods. Finally, suggestions are provided for the way forward, with an emphasis on need for a multidimensional approach that integrate a panel of pathobiologically diverse biomarkers with clinical variables and imaging-based assessments to improve diagnosis and classification of TBI and to develop best clinical practice guidelines.

Traumatic Brain Injury as a Systems Neuroscience Problem

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889450985 Year: Pages: 167 DOI: 10.3389/978-2-88945-098-5 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2017-07-06 13:27:36
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Traumatic brain injury (TBI) is traditionally viewed as an anatomic and neuropathological condition. Caring for TBI patients is a matter of defining the extent of an anatomical lesion, managing this lesion, and minimizing secondary brain injury. On the research side, the effects of TBI often are studied in the context of neuronal and axonal degeneration and the subsequent deposition of abnormal proteins such as tau. These approaches form the basis of our current understanding of TBI, but they pay less attention to the function of the affected organ, the brain. Much can be learned about TBI by studying this disorder on a systems neuroscience level and correlating changes in neural circuitry with neurological and cognitive function. There are several aspects of TBI that are a natural fit for this perspective, including post-traumatic epilepsy, consciousness, and cognitive sequelae. How individual neurons contribute to network activity and how network function responds to injury are key concepts in examining these areas. In recent years, the available tools for studying the role of neuronal assemblies in TBI have become increasingly sophisticated, ranging from optogenetic and electrophysiological techniques to advanced imaging modalities such as functional magnetic resonance imaging and magnetoencephalography. Further progress in understanding the disruption and subsequent reshaping of networks is likely to have substantial benefits in the treatment of patients with TBI-associated deficits. In this Frontiers Topic, we intend to highlight the systems neuroscience approach to studying TBI. In addition to analyzing the clinical sequelae of TBI in this context, this series of articles explores the pathophysiological mechanisms underlying network dysfunction, including alterations in synaptic activity, changes in neural oscillation patterns, and disruptions in functional connectivity. We also include articles on treatment options for TBI patients that modulate network function. It is our hope that this Frontiers Topic will increase the clinical and scientific communities’ awareness of this viable framework for deepening our knowledge of TBI and improving patient outcomes.

NEUROTRAUMA: From Emergency Room to Back to Day-by-Day Life

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889457243 Year: Pages: 96 DOI: 10.3389/978-2-88945-724-3 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Neurology
Added to DOAB on : 2019-01-23 14:53:43
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Traumatic brain injury (TBI) is a nondegenerative, noncongenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impairment of cognitive, physical, and psychosocial functions, with an associated diminished or altered state of consciousness. The definition of TBI has not been consistent and tends to vary according to specialties and circumstances. The term brain injury is often used synonymously with head injury, which may not be associated with neurological deficits. The definition has also been problematic due to variations in inclusion criteria. Both American and Brazilian data indicate that more than 700,000 people suffer TBI annually, with 20% afflicted with moderate or severe TBI. According to this data, 80% of people who suffered mild TBI can return to work, whist only 20% of moderate, and 10% of victims of severe TBI can return to their daily routine. Cognitive rehabilitation, a clinical area encompassing interdisciplinary action aimed at recovery as well as compensation of cognitive functions, altered as a result of cerebral injury, is extremely important for these individuals. The aim of a cognitive and motor rehabilitation program is to recover an individual's ability to process, interpret and respond appropriately to environmental inputs, as well as to create strategies and procedures to compensate for lost functions that are necessary in familial, social, educational and occupational relationships. In general, the cognitive rehabilitation programs tend to focus on specific cognitive domains, such as memory, motor, language and executive functions. By contrast, the focus of compensatory training procedures is generally on making environmental adaptations and changes to provide grater autonomy for patients. Successful cognitive rehabilitation programs are those whose aim is both recovery and compensation based on an integrated and interdisciplinary approach. The purpose of this Research Topic is to review the basic concepts related to TBI, including mechanisms of injury, severity levels of TBI, the most common findings in mild, moderate and severe TBI survivors, and the most cognitive and motor impairments following TBI, and also to discuss the strategies used to handle patients post-TBI. Within this context, the importance of an interdisciplinary rehabilitation for TBI is underlined.

Glycolysis at 75: Is it time to tweak the first elucidated metabolic pathway in history?

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195862 Year: Pages: 126 DOI: 10.3389/978-2-88919-586-2 Language: English
Publisher: Frontiers Media SA
Subject: Nutrition and Food Sciences --- Medicine (General) --- Neurology --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
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Glycolysis, the pathway of enzymatic reactions responsible for the breakdown of glucose into two trioses and further into pyruvate or lactate, was elucidated in 1940. For more than seven decades, it has been taught precisely the way its sequence was proposed by Embden, Meyerhof and Parnas. Accordingly, two outcomes of this pathway were proposed, an aerobic glycolysis, with pyruvate as its final product, and an anaerobic glycolysis, identical to the aerobic one, except for an additional reaction, where pyruvate is reduced to lactate. Several studies in the 1980s have shown that both muscle and brain tissues can oxidize and utilize lactate as an energy substrate, challenging this monocarboxylate’s reputation as a useless end-product of anaerobic glycolysis. These findings were met with great skepticism about the idea that lactate could be playing a role in bioenergetics. In the past quarter of a century monocarboxylate transporters (MCTs) were identified and localized in both cellular and mitochondrial membranes. A lactate receptor has been identified. Direct and indirect evidence now indicate that the enzyme lactate dehydrogenase (LDH) resides not only in the cytosol, as part of the glycolytic pathway machinery, but also in the mitochondrial outer membrane. The mitochondrial form of the enzyme oxidizes lactate to pyruvate and concomitantly produces the reducing agent NADH. These findings have shed light on a major drawback of the originally proposed aerobic version of the glycolytic pathway i.e., its inability to regenerate NAD+, as opposed to anaerobic glycolysis that features the cyclical ability of regenerating NAD+ upon pyruvate reduction to lactate by the cytosolic form of LDH. The malate-aspartate shuttle (MAS), a major redox shuttle in the brain, was proposed as an alternative pathway for NAD+ generation for aerobic glycolysis. Nonetheless, would MAS really be necessary for that function if glycolysis always proceeds to the end-products, lactate and NAD+? An additional dilemma the originally proposed aerobic glycolysis presents has to do with the glycolytic pathway of erythrocytes, which despite its highly aerobic environment, always produces lactate as its end-product. It is time to reexamine the original, dogmatic separation of glycolysis into two distinct pathways and put to test the hypothesis of a unified, singular pathway, the end-product of which is lactate, the real substrate of the mitochondrial TCA cycle.

Mechanisms of neuroinflammation and inflammatory neurodegeneration in acute brain injury

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196913 Year: Pages: 284 DOI: 10.3389/978-2-88919-691-3 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2016-04-07 11:22:02
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Mechanisms of brain-immune interactions became a cutting-edge topic in systemic neurosciences over the past years. Acute lesions of the brain parenchyma, particularly, induce a profound and highly complex neuroinflammatory reaction with similar mechanistic properties between differing disease paradigms like ischemic stroke, intracerebral hemorrhage (ICH) and traumatic brain injury (TBI). Resident microglial cells sense tissue damage and initiate inflammation, activation of the endothelial brain-immune interface promotes recruitment of systemic immune cells to the brain and systemic humoral immune mediators (e.g. complements and cytokines) enter the brain through the damaged blood-brain barrier. These cellular and humoral constituents of the neuroinflammatory reaction to brain injury contribute substantially to secondary brain damage and neurodegeneration. Diverse inflammatory cascades such as pro-inflammatory cytokine secretion of invading leukocytes and direct cell-cell-contact cytotoxicity between lymphocytes and neurons have been demonstrated to mediate the inflammatory ‘collateral damage’ in models of acute brain injury. Besides mediating neuronal cell loss and degeneration, secondary inflammatory mechanisms also contribute to functional modulation of neurons and the impact of post-lesional neuroinflammation can even be detected on the behavioral level. The contribution of several specific immune cell subpopulations to the complex orchestration of secondary neuroinflammation has been revealed just recently. However, the differential vulnerability of specific neuronal cell types and the molecular mechanisms of inflammatory neurodegeneration are still elusive. Furthermore, we are only on the verge of characterizing the control of long-term recovery and neuronal plasticity after brain damage by inflammatory pathways. Yet, a more detailed but also comprehensive understanding of the multifaceted interaction of these two supersystems is of direct translational relevance. Immunotherapeutic strategies currently shift to the center of translational research in acute CNS lesion since all clinical trials investigating direct neuroprotective therapies failed. To advance our knowledge on brain-immune communications after brain damage an interdisciplinary approach covered by cellular neuroscience as well as neuroimmunology, brain imaging and behavioral sciences is crucial to thoroughly depict the intricate mechanisms.

The Role of the Plasminogen Activating System in Neurobiology

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889450633 Year: Pages: 132 DOI: 10.3389/978-2-88945-063-3 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2017-07-06 13:27:36
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This ebook contains a series of original publications, reviews and mini-reviews by leaders in the field that address the growing importance of the plasminogen activating system in neurobiology. The articles included cover the role of the plasminogen activating system as a key modulator of blood brain barrier permeability, and the implications of this in traumatic brain injury and in ischemic stroke. State-of-the-Art manuscripts are also included that address the regulatory mechanisms that control this important process.This ebook contains a series of original publications, reviews and mini-reviews by leaders in the field that address the growing importance of the plasminogen activating system in neurobiology. The articles included cover the role of the plasminogen activating system as a key modulator of blood brain barrier permeability, and the implications of this in traumatic brain injury and in ischemic stroke. State-of-the-Art manuscripts are also included that address the regulatory mechanisms that control this important process.

Neuroimmune Interface in Health and Diseases

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889453788 Year: Pages: 174 DOI: 10.3389/978-2-88945-378-8 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology --- Neurology
Added to DOAB on : 2018-11-16 17:17:57
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It is now well appreciated that the immune system, in addition to its traditional role in defending the organism against pathogens, communicate in a well-organized fashion with the brain to maintain homeostasis and regulate a set of neural functions. Perturbation in this brain-immune interactions due to inflammatory responses may lead to psychiatric and neurological disorders. Microglia are one of the essential cells involved in the brain-immune interactions. Microglial cells are now not simply regarded as resident tissue macrophages in the brain. These cells are derived from myeloid progenitor cells in the yolk sac in early gestation, travel to the brain parenchyma and interact actively with neurons during the critical period of neurogenesis. Microglia provide a trophic support to developing neurons and take part in the neural wiring through the activity-dependent synapse elimination via direct neuron-microglia interactions. Altered microglial functions including changes in the gene expression due to early life inflammatory events or psychological and environmental stressors can be causally related to neurodevelopmental diseases and mental health disorders. This type of alterations in the neural functions can occur in the absence of infiltration of inflammatory cells in the brain parenchyma or leptomeninges. In this sense, the pathogenetic state underlying a significant part of psychiatric and neurological diseases may be similar to “para-inflammation”, an intermediate state between homeostatic and classical inflammatory states as defined by Ruslan Medzhitov (Nature 454:428-35, 2008). Therefore, it is important to study how systemic inflammation affects brain health and how local peripheral inflammation induces changes in the brain microenvironment. Chronic pain is also induced by disturbance in otherwise well-organized multisystem interplay comprising of reciprocal neural, endocrine and immune interactions. Especially, early-life insults including exposure to immune challenges can alter the neuroanatomical components of nociception, which induces altered pain response later in life. Recently the discrete roles of microglia and blood monocyte-derived macrophages are being defined. The distinction may be further highlighted by disorders in which the brain parenchymal tissue is damaged. Therefore, studies investigating the dynamics of immune cells in traumatic brain injury and neurotropic viral infections including human immunodeficiency virus, etc. as well as neurodegenerative diseases such as amyotrophic lateral sclerosis are promising to clarify the interplay between the central nervous and immune systems. The understanding of the histological architecture providing the infrastructure of such neuro-immune interplay is also essential. This Frontiers research topic brings together fourteen articles and aims to create a platform for researchers in the field of psychoneuroimmunology to share the recent theories, hypotheses and future perspectives regarding open questions on the mechanisms of cell-cell interactions with chemical mediators among the nervous, immune and endocrine systems. We hope that this platform would reveal the relevance of the studies on multisystem interactions to enhance the understanding of the mechanisms underlying a wide variety of neurological and psychiatric disorders.

Monitoring Pathophysiology in the Injured Brain

Authors: --- --- ---
Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889454815 Year: Pages: 301 DOI: 10.3389/978-2-88945-481-5 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Neurology
Added to DOAB on : 2019-01-23 14:53:42
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Pathophysiological processes in brain-injured patients can be assessed with an array of methods, with a goal to identify potentially deleterious events, guide treatments and avoid further deterioration. This eBook provides an in-depth exploration into different aspects of neuro-critical care monitoring and how new tools and strategies may be utilized to improve patient outcomes.

All 3 Types of Glial Cells Are Important for Memory Formation

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889450251 Year: Pages: 150 DOI: 10.3389/978-2-88945-025-1 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Neurology
Added to DOAB on : 2018-02-27 16:16:44
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The vertebrate brain contains neurons and 3 classical types of glia cells, astrocytes, oligodendrocytes and microglia. Astrocytes and microglia have mainly been studied in gray matter, whereas oligodendrocytes myelinate white matter tracts. Until recently microglial effects were considered mainly during pathological conditions, but is now known that microglia plays important roles also in normal brain function. All these 3 glial cell types and their collaboration with neurons are important for learning. The concept that glia cells are important for cognitive function is not new. A glial-neuronal theory of brain function was proposed by Galambos in 1961. Hyden and Egyhazi demonstrated glial RNA changes in microdissected glia cells during learning in rats in 1963, and astrocytic and oligodendrocytic involvement of K+-mediated effects of learning has been suggested and/or demonstrated from the 1960’s and onwards as recently reviewed by Hertz and Chen (Neuroscience and Biobehavioural Reviews, 2016). In 1969 van den Berg et al. showed compartmentation of glutamate in brain and thus of production of the neurotransmitters glutamate and GABA, which are essential for learning. That glutamate is synthesized in astrocytes because they in contrast to neurons express the enzyme pyruvate carboxylase was demonstrated 10-15 years later by Yu et al. in cultured astrocytes and Shank et al. in intact brain tissue. However, the present e-book focuses on more recent developments. Most information is available about astrocytic roles in learning. The importance of astrocytes in the tripartite synapse and of microglia in the tetrapartite synapse is illustrated in the front-page figure, which emphasizes the role of gliotransmitters and of Ca2+ transport through gap junctions, coupling astrocytes into a functional syncytium. Astrocytes are important for establishments of brain rhythms, which may differ in different cognitive tasks, and although the exact reason why knock-out of the astrocytic water channel AQP4 impairs memory remains to be established, several possibilities are discussed. The importance of the two astrocyte specific processes glutamate and glutamine formation and glycogenolysis is discussed in considerable detail. Glycogenolysis is important not only for astrocytic processes involved in learning, but also for those in neurons because glycolytically derived lactate has signaling functions in the extracellular space and may be accumulated in minute quantities into very specific and small neuronal structures. Some neurotransmitters stimulating glycogenolysis are also involved in psychiatric disease. Noradrenaline, released from locus coeruleus exerts direct effects on both astrocytes and neurons and in addition promotes secretion of corticotropin-releasing hormone and adrenocorticotrophic hormone (ACTH) in brain, and of glucocorticoids from the adrenal cortex, all of which are responsible for stress effects on learning. Lead causes memory impairment by inhibition of glutamine formation due to oxidative stress and reduced effectiveness of the glutathione system. The many adverse effects of fetal alcohol exposure on behaviour and learning are caused by a multitude of effects on all three types of glia cells. Traumatic brain injury also exerts multifactorial effects, including microglia/astrocyte-induced secretion of neuroinflammatory molecules and axonal disruption and oligodendrocytic dysfunction. In normal brain oligodendrocytes respond to the depolarization caused by neuronal activity with accelerated conduction velocity and increased compound action potentials which facilitate learning.

Updates in Pediatric Sleep and Child Psychiatry

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ISBN: 9783038979388 / 9783038979395 Year: Pages: 160 DOI: 10.3390/books978-3-03897-939-5 Language: eng
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Medicine (General) --- Pediatrics
Added to DOAB on : 2019-06-26 08:44:06
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Sleep-related symptoms are common in the majority of psychiatric diagnostic categories. The overlap of sleep and psychiatric disorders have been demonstrated in numerous studies. The understanding of sleep and child psychiatry has progressively evolved in the last decade and newer insights have developed regarding the complex interaction between sleep and psychopathology. This collection of articles represents updates on sleep and psychiatric disorders with medical and neurological co-morbidities in children and adolescents.

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