Mechanisms of vascular injury in neurotrauma: A critical review of the literature

One in every two individuals will experience a traumatic brain injury in their lifetime with significant impacts on the global economy and healthcare system each year.Neurovascular injury is a key aspect of neurotrauma to both the brain and the spinal cord and an important avenue of current and future research seeking innovative therapies.In this paper,we discuss primary and secondary neurotrauma,mechanisms of injury,the glymphatic system,repair and recovery.Each of these topics are directly connected to the vasculature of the central ner-vous system,affecting severity of injury and recovery.Consequently,neurova-scular injury in trauma represents a promising target for future therapeutics and innovation.

WJSC 6^(th) Anniversary Special Issues(2):Mesenchymal stem cells Neurotrauma and mesenchymal stem cells treatment:From experimental studies to clinical trials

Mesenchymal stem cell(MSC)therapy has attracted the attention of scientists and clinicians around the world.Basic and pre-clinical experimental studies have highlighted the positive effects of MSC treatment after spinal cord and peripheral nerve injury.These effects are believed to be due to their ability to differentiate into other cell lineages,modulate inflammatory and immunomodulatory responses,reduce cell apoptosis,secrete several neurotrophic factors and respond to tissue injury,among others.There are many pre-clinical studies on MSC treatment for spinal cord injury(SCI)and peripheral nerve injuries.However,the same is not true for clinical trials,particularly those concerned with nerve trauma,indicating the necessity of more well-constructed studies showing the benefits that cell therapy can provide for individuals suffering the consequences of nerve lesions.As for clinical trials for SCI treatment the results obtained so far are not as beneficial as those described in experimental studies.For these reasons basic and pre-clinical studies dealing with MSC therapy should emphasize the standardization of protocols that could be translated to the clinical set with consistent and positive outcomes.This review is based on pre-clinical studies and clinical trials available in the literature from 2010 until now.At the time of writing this article there were 43 and 36 pre-clinical and 19 and 1 clinical trials on injured spinal cord and peripheral nerves,respectively.

Altered physiology of gastrointestinal vagal afferents following neurotrauma

The adaptability of the central nervous system has been revealed in several model systems.Of particular interest to central nervous system-injured individuals is the ability for neural components to be modified for regain of function.In both types of neurotrauma,traumatic brain injury and spinal cord injury,the primary parasympathetic control to the gastrointestinal tract,the vagus nerve,remains anatomically intact.However,individuals with traumatic brain injury or spinal cord injury are highly susceptible to gastrointestinal dysfunctions.Such gastrointestinal dysfunctions attribute to higher morbidity and mortality following traumatic brain injury and spinal cord injury.While the vagal efferent output remains capable of eliciting motor responses following injury,evidence suggests impairment of the vagal afferents.Since sensory input drives motor output,this review will discuss the normal and altered anatomy and physiology of the gastrointestinal vagal afferents to better understand the contributions of vagal afferent plasticity following neurotrauma.

Epidemiology and Challenges of Neurotraumas Care in the Emergency Department of a Semi-Urban Hospital in Guinea, West Africa

Trauma is one of the most common surgical emergencies admitted in the acute care departments of hospitals in Guinea, West Africa. We carried a study to assess the epidemiological pattern and clinical care of neurotrauma in the emergency department of the Kindia regional hospital, a rural secondary hospital catering to the needs of western Guinea and nearby districts. Data were prospectively collected from December 2019 to March 2020 after receiving the required hospital authorization and informed consent from the patients or relatives. We recorded two hundred cases of neurotraumas (64.5% of traumatic brain injury cases and 14.5% of spinal cord injury). Neurotraumas represented 17.7% of all admitted patients in the department in the study period. The mean age was 25.34 ± 16.73, and the age range 16 to 30 was the most affected. The predominance was male, with a sex ratio of 3.43. Motor Vehicle Accident was the leading cause 68.5%, and 73.2% of them involved a motorcycle. Motorcycle-to-motorcycle collision was responsible for more than a third of neurotraumas. We classified the majority of the cases as mild and low risk neurotrauma representing 62.08%. All patients benefited from medical treatment, and 30.7% of patients received surgical treatment for associated abdominal, orthopedic, and minor procedures for scalp dilacerations. No patient was referred to a Neurosurgery department, and all living patients were discharged home during the study period with minimal disability. The mortality was 16.3%. Our results could be biased by the lack of interhospital networking and the fact that severe traumatic brain-injured patient dies before seeking medical attention.

Strategies to limit dysmyelination during secondary degeneration following neurotrauma

Following trauma to the central nervous system （CNS）, cells in the lesion site die rapidly. In addition, neurons and glia be- yond the initial lesion are vulnerable. These cells can undergo delayed death due to metabolic events that follow the initial trauma, via mechanisms thought to he triggered by gluta- mate-induced excitotoxicity and Ca2＋ overload, leading to mitochondrial dysfunction, associated with increased oxida- tive stress （Camello-Almaraz et al., 2006; Peng and Jou, 2010）. The resultant death of areas of grey and white matter adjacent to the lesion site is termed secondary degeneration, and is a feature of brain and spinal cord injury （Park et al., 2004; Gi- aume et al., 2007）. Secondary degeneration contributes sub- stantially to functional loss following neurotrauma （Profyris et al., 2004; Farkas and Povlishock, 2007） and rescuing this intact, but vulnerable, tissue is considered critical to mini- mising adverse sequelae and improving long term functional outcomes after CNS trauma （Fehlings et al., 2012）. However, our understanding of many of the metabolic events thought to contribute to secondary degeneration is based largely on in vitro studies （Khodorov, 2004; Tretter et al., 2007; Peng and Jou, 2010） and there is a need to confirm the relevance of these mechanisms in vivo, as well as their structural and func- tional consequences.

Membrane resealing as a promising strategy for early treatment of neurotrauma

Traumatic injuries to the central nervous system （CNS）, in- cluding traumatic brain injury （TBI） and spinal cord injury （SCI）, often involve an immediate mechanical damage to plas- ma membrane that surrounds neuronal sornata and axons. This initial disruption of plasma membrane following injuries has been convincingly demonstrated by increased membrane permeability to large molecules and dyes that are normally inaccessible to cellular plasma （Farkas et al., 2006; Cho and Borgens, 2012）. Further evidence comes from experiments that showed ultra-structural changes of plasma membranes, axons, and organelles, and subsequent neuronal death and axotomy （Povlishock and Pettus, 1996; Whalen et al., 2008）.

“临床营养”团体标准在提高神经重症患者肠内营养治疗全流程管理达标率中的应用

目的提高神经重症患者肠内营养治疗全流程管理达标率。方法对照中国医院协会中国《医院质量安全管理》“第2-29部分患者服务临床营养”团体标准中肠内营养标准条款,对神经创伤重症科住院患者肠内营养治疗全流程管理达标情况进行调查,通过现状调查、原因解析,制订针对性方策,从组建肠内营养治疗全流程管理“医-护-营-康”多学科团队、构建基于“知-信-行”理论的肠内营养治疗培训闭环管理模式、建立以肠内营养治疗数据精准分析为基础的质量改进体系3方面予以改进。结果科室肠内营养治疗全流程管理达标率由改善前33.9%上升至改善后62.5%。结论开展“临床营养”团体标准实践可有效提高神经重症患者肠内营养治疗全流程管理达标率,规范肠内营养治疗操作流程,减少并发症,保障患者安全。

Neutrophil extracellular traps mediate neuro-immunothrombosis

Neutrophil extracellular traps are primarily composed of DNA and histones and are released by neutrophils to promote inflammation and thrombosis when stimulated by various inflammato ry reactions.Neutrophil extracellular trap formation occurs through lytic and non-lytic pathways that can be further classified by formation mechanisms.Histones,von Willebrand factor,fibrin,and many other factors participate in the interplay between inflammation and thrombosis.Neuroimmunothrombosis summarizes the intricate interplay between inflammation and thrombosis during neural development and the pathogenesis of neurological diseases,providing cutting-edge insights into post-neurotrauma thrombotic events.The blood-brain barrier defends the brain and spinal cord against external assaults,and neutrophil extracellular trap involvement in blood-brain barrier disruption and immunothrombosis contributes substantially to secondary injuries in neurological diseases.Further research is needed to understand how neutrophil extracellular traps promote blood-brain barrier disruption and immunothrombosis,but recent studies have demonstrated that neutrophil extracellular traps play a crucial role in immunothrombosis,and identified modulators of neuro-immunothrombosis.However,these neurological diseases occur in blood vessels,and the mechanisms are unclear by which neutrophil extracellular traps penetrate the blood-brain barrier to participate in immunothrombosis in traumatic brain injury.This review discusses the role of neutrophil extracellular traps in neuro-immunothrombosis and explores potential therapeutic interventions to modulate neutrophil extracellular traps that may reduce immunothrombosis and improve traumatic brain injury outcomes.

肺冲击伤对大鼠学习、记忆能力的影响及其机制

目的:探讨胸部局部冲击伤后大鼠神经行为功能改变，及肺冲击伤对中枢神经系统的影响。方法:致伤前，动物均在一计算机控制的双向穿梭箱内连续训练6d，每天连续训练20次，以获得主动回避反射（AAR）。在最后2d的训练中，AAR≥80％的大鼠被选用于冲击伤实验。采用BST-Ⅲ生物激波管致大鼠单纯脑冲击伤。脑组织内NO2／NO3、cGMP含量分别采用比色测定试剂盒和酶免疫测定试剂盒进行测定。结果:①肺冲击伤后，大鼠AAR和ER明显下降.主动回避反应潜伏期（AARL）明显延长。②肺冲击伤后3、24h和5d，海马和脑子组织内NO2／NO3、cGMP含量明显升高。③海马和脑干组织内NO2／NO3水平变化分别与肺冲击伤伤情、AAR、ER和AARL值呈显著相关性。结论:单纯肺冲击伤可引起远隔器官-中枢神经系统功能损害，其机制可能与海马和脑于组织内NO释放增多有关。

创伤性脑损伤动物模型及其实验治疗学应用

创伤性脑损伤(traumatic brain injury,TBI),亦称颅脑损伤或头部外伤,专指由外伤引起的脑组织损害。TBI发生机制以及神经损伤后的修复治疗是当前脑研究的热点问题。动物模型的复制对开展TBI的实验治疗学研究起了巨大的推动作用。该文就国内外已经建立的撞击脑损伤、非撞击加速脑损伤和爆炸冲击波致脑外伤三类动物模型的进展作系统综述,同时列举这些模型在实验治疗学上的应用,为神经保护药物的药效学筛选提供科学指导。

人脑挫裂伤组织的超微病理观察和损伤机理及临床探讨

对１７例人脑挫裂伤的神经组织进行了超微病理及钙细胞化学的形态学观察，研究结果显示星形细胞高度肿胀、细胞器崩解，神经细胞内脂褐素增多，血脑屏障破坏，微循环障碍，兴奋性神经递质明显增多，小胶质细胞增生并迁移至神经元周围；损伤的神经组织内有多量钙离子沉积。文中结合外伤脑组织的超微形态学变化，讨论了脑损伤机制并提出了药物治疗的可能途径。

Fast-tracking regenerative medicine for traumatic brain injury

Traumatic brain injury remains a global health crisis that spans all demographics,yet there exist limited treatment options that may effectively curtail its lingering symptoms.Traumatic brain injury pathology entails a progression from primary injury to inflammation-mediated secondary cell death.Sequestering this inflammation as a means of ameliorating the greater symptomology of traumatic brain injury has emerged as an attractive treatment prospect.In this review,we recapitulate and evaluate the important developments relating to regulating traumatic brain injury-induced neuroinflammation,edema,and blood-brain barrier disintegration through pharmacotherapy and stem cell transplants.Although these studies of stand-alone treatments have yielded some positive results,more therapeutic outcomes have been documented from the promising area of combined drug and stem cell therapy.Harnessing the facilitatory properties of certain pharmaceuticals with the anti-inflammatory and regenerative effects of stem cell transplants creates a synergistic effect greater than the sum of its parts.The burgeoning evidence in favor of combined drug and stem cell therapies warrants more elaborate preclinical studies on this topic in order to pave the way for later clinical trials.

Restoring nervous system structure and function using tissue engineered living scaffolds

Neural tissue engineering is premised on the integration of engineered living tissue with the host nervous system to directly restore lost function or to augment regenerative capacity following ner- vous system injury or neurodegenerative disease. Disconnection of axon pathways - the long-distance fibers connecting specialized regions of the central nervous system or relaying peripheral signals - is a common feature of many neurological disorders and injury. However, functional axonal regenera- tion rarely occurs due to extreme distances to targets, absence of directed guidance, and the presence of inhibitory factors in the central nervous system, resulting in devastating effects on cognitive and sensorimotor function. To address this need, we are pursuing multiple strategies using tissue engi- neered ＂living scaffolds＂, which are preformed three-dimensional constructs consisting of living neural cells in a defined, often anisotropic architecture. Living scaffolds are designed to restore function by serving as a living labeled pathway for targeted axonal regeneration - mimicking key developmental mechanisms- or by restoring lost neural circuitry via direct replacement of neurons and axonal tracts. We are currently utilizing preformed living scaffolds consisting of neuronal dusters spanned by long axonal tracts as regenerative bridges to facilitate long-distance axonal regeneration and for targeted neurosurgical reconstruction of local circuits in the brain. Although there are formidable challenges in predinical and clinical advancement, these living tissue engineered constructs represent a promising strategy to facilitate nervous system repair and functional recovery.

Regulation of neuroimmune processes by damage-and resolution-associated molecular patterns

Sterile inflammatory processes are essential for the maintenance of central nervous system homeostasis,but they also contribute to various neurological disorders,including neurotrauma,stroke,and demyelinating or neurodegenerative diseases.Immune mechanisms in the central nervous system and periphery are regulated by a diverse group of endogenous proteins,which can be broadly divided into the pro-inflammatory damageassociated molecular patterns(DAMPs)and anti-inflammatory resolution-associated molecular patterns(RAMPs),even though there is notable overlap between the DAMPand RAMP-like activities for some of these molecules.Both groups of molecular patterns were initially described in peripheral immune processes and pathologies;however,it is now evident that at least some,if not all,of these immunomodulators also regulate neuroimmune processes and contribute to neuroinflammation in diverse central nervous system disorders.The review of recent literature demonstrates that studies on DAMPs and RAMPs of the central nervous system still lag behind the much broader research effort focused on their peripheral counterparts.Nevertheless,this review also reveals that over the last five years,significant advances have been made in our understanding of the neuroimmune functions of several well-established DAMPs,including high-mobility group box 1 protein and interleukin 33.Novel neuroimmune functions have been demonstrated for other DAMPs that previously were considered almost exclusively as peripheral immune regulators;they include mitochondrial transcription factor A and cytochrome C.RAMPs of the central nervous system are an emerging area of neuroimmunology with very high translational potential since some of these molecules have already been used in preclinical and clinical studies as candidate therapeutic agents for inflammatory conditions,such as multiple sclerosis and rheumatoid arthritis.The therapeutic potential of DAMP antagonists and neutralizing antibodies in central nervous system neuroinflammatory diseases is also supported by several of the identified studies.It can be concluded that further studies of DAMPs and RAMPs of the central nervous system will continue to be an important and productive field of neuroimmunology.

Autonomic responses to blast overpressure can be elicited by exclusively exposing the ear in rats

Blast overpressure has become an increasing cause of brain injuries in both military and civilian populations. Though blast＇s direct effects on the cochlea and vestibular organs are active areas of study, little attention has been given to the ear＇s contribution to the overall spectrum of blast injury. Acute auto- nomic responses to blast exposure, including bradycardia and hypotension, can cause hypoxia and contribute to blast-induced neurotrauma. Existing literature suggests that these autonomic responses are elicited through blast impacting the thorax and lungs. We hypothesize that the unprotected ear also provides a vulnerable locus for blast to cause autonomic responses. We designed a blast generator that delivers controlled overpressure waves into the ear canal without impacting surrounding tissues in order to study the ear＇s specific contribution to blast injury. Anesthetized adult rats＇ left ears were exposed to a single blast wave ranging from 0 to 110 PSI （0-758 kPa）. Blast exposed rats exhibited decreased heart rates and blood pressures with increased blast intensity, similar to results gathered using shock tubes and whole-body exposure in the literature. While rats exposed to blasts below 50 PSI （345 kPa） exhibited increased respiratory rate with increased blast intensity, some rats exposed to blasts higher than 50 PSI （345 kPa） stopped breathing immediately and ultimately died. These autonomic responses were significantly reduced in vagally denervated rats, again similar to whole-body exposure literature. These results support the hypothesis that the unprotected ear contributes to the autonomic responses to blast.

Rapid GFAP and Iba1 expression changes in the female rat brain following spinal cord injury

Evidence suggests that rapid changes to supporting glia may predispose individuals with spinal cord injury(SCI) to such comorbidities. Here, we interrogated the expression of astrocyte-and microglial-specific markers glial fibrillary acidic protein(GFAP) and ionized calcium binding adaptor molecule 1(Iba1) in the rat brain in the first 24 hours following SCI. Female Sprague-Dawley rats underwent thoracic laminectomy;half of the rats received a mild contusion injury at the level of the T10 vertebral body(SCI group), the other half did not(Sham group). Twenty-four hours post-surgery the amygdala, periaqueductal grey, prefrontal cortex, hypothalamus, lateral thalamus, hippocampus(dorsal and ventral) in rats were collected. GFAP and Iba1 m RNA and protein levels were measured by real-time quantitative polymerase chain reaction and Western blot. In SCI rats, GFAP m RNA and protein expression increased in the amygdala and hypothalamus. In contrast, gene and protein expression decreased in the thalamus and dorsal hippocampus. Interestingly, Iba1 transcripts and proteins were significantly diminished only in the dorsal and ventral hippocampus, where gene expression diminished. These findings demonstrate that as early as 24 hours post-SCI there are region-specific disruptions of GFAP and Iba1 transcript and protein levels in higher brain regions. All procedures were approved by the University of Technology Sydney Institutional Animal Care and Ethics Committee(UTS ACEC13-0069).

Critical role of mitochondrial aldehyde dehydrogenase 2 in acrolein sequestering in rat spinal cord injury

Lipid peroxidation-derived aldehydes,such as acrolein,the most reactive aldehyde,have emerged as key culprits in sustaining post-spinal cord injury(SCI)secondary pathologies leading to functional loss.Strong evidence suggests that mitochondrial aldehyde dehydrogenase-2(ALDH2),a key oxidoreductase and powerful endogenous anti-aldehyde machinery,is likely important for protecting neurons from aldehydesmediated degeneration.Using a rat model of spinal cord contusion injury and recently discovered ALDH2 activator(Alda-1),we planned to validate the aldehyde-clearing and neuroprotective role of ALDH2.Over an acute 2 day period post injury,we found that ALDH2 expression was significantly lowered post-SCI,but not so in rats given Alda-1.This lower enzymatic expression may be linked to heightened acrolein-ALDH2 adduction,which was revealed in co-immunoprecipitation experiments.We have also found that administration of Alda-1 to SCI rats significantly lowered acrolein in the spinal cord,and reduced cyst pathology.In addition,Alda-1 treatment also resulted in significant improvement of motor function and attenuated post-SCI mechanical hypersensitivity up to 28 days post-SCI.Finally,ALDH2 was found to play a critical role in in vitro protection of PC12 cells from acrolein exposure.It is expected that the outcome of this study will broaden and enhance anti-aldehyde strategies in combating post-SCI neurodegeneration and potentially bring treatment to millions of SCI victims.All animal work was approved by Purdue Animal Care and Use Committee(approval No.1111000095)on January 1,2021.

Hyponatremia in the acute phase of spinal cord trauma: Review

Hyponatremia is a common electrolyte disturbance usually observed in neurosurgical patients undergoing surgical management of traumatic, as well as, nontraumatic intracranial pathology. The spinal cord trauma is also associated with occasional development of such hyponatremia;it usually occurs within the first two-weeks of the injury. Hyponatremia can lead to alterations of consciousness, convulsions, coma, cardiac arrhythmias and on rare occasions, death. Authors present a practical oriented review of the literature.

神经创伤救治的转化医学思考

近年来，转化医学（translational medicine）已成为研究的热点。实际上，医学自始至终都是在小断地将经验、理论和研究成果向实际应用转化的过程中发展的。本述评将从理解当前提倡的转化医学的概念、定义和范畴出发，结合我国医学发展的实际情况，分析转化医学在神经创伤救治中的应用。

c-Jun N-terminal kinase 3 deficiency protects axotomized retinal ganglion cells via affecting mitochondria involved apoptosis pathway

AIM: To illustrate the isoform-specific role and mechanism of c-Jun N-terminal kinases(JNKs) in mouse optic nerve axotomy induced neurotrauma. METHODS: We firstly investigated the expression of JNK1, JNK2, and JNK3 in the retinal ganglion cells(RGCs) by double-immunofluorescent staining. Then we created optic nerve axotomy model in wild type as well as JNK1, JNK2, JNK3, isoform specific gene deficiency mice. With that, we checked the protein expression profile of JNKs and its active form, and quantified the survival RGCs number by immunofluorescence staining. We further explored the molecules underlying isoform specific protective effect by real-time polymerase chain reaction(PCR) and Western blotting assay. RESULTS: We found that all the three isoforms of JNKs were expressed in the RGCs. Deficiency of JNK3, but not JNK1 or JNK2, significantly alleviated optic nerve axotomyinduced RGCs apoptosis. We further established that expression of Noxa, a pro-apoptotic member of BH3 family, was significantly suppressed only in JNK3 gene deficiency mice. But tumor necrosis factor receptor 1(TNFR1) and Fas, two key modulators of death receptor mediated apoptosis pathway, did not display obvious change in the expression. CONCLUSION: It is suggested that mitochondria mediated apoptosis, but not death receptor mediated apoptosis got involved in the JNK3 gene deficiency induced RGCs protection. Our study provides a novel insight into the isoform-specific role of JNKs in neurotrauma and indicates some cues for its therapeutics.