Angiopoietin-1/Tie-2 signal after focal traumatic brain injury is potentiated by BQ788, an ETB receptor antagonist, in the mouse cerebrum: Involvement in recovery of blood-brain barrier function.

Angiopoietin-1, an angiogenic factor, stabilizes brain microvessels through Tie-2 receptor tyrosine kinase. In traumatic brain injury, blood-brain barrier (BBB) disruption is an aggravating factor that induces brain edema and neuroinflammation. We previously showed that BQ788, an endothelin ETB receptor antagonist, promoted recovery of BBB function after lateral fluid percussion injury (FPI) in mice. To clarify the mechanisms underlying BBB recovery mediated by BQ788, we examined the involvements of the angiopoietin-1/Tie-2 signal. When angiopoietin-1 production and Tie-2 phosphorylation were assayed by quantitative reverse transcription polymerase chain reaction and western blotting, increased angiopoietin-1 production and Tie-2 phosphorylation were observed in 7-10 days after FPI in the mouse cerebrum, whereas no significant effects were obtained at 5 days. When BQ788 (15 nmol/day, i.c.v.) were administered in 2-5 days after FPI, increased angiopoietin-1 production and Tie-2 phosphorylation were observed. Immunohistochemical observations showed that brain microvessels and astrocytes contained angiopoietin-1 after FPI, and brain microvessels also contained phosphorylated Tie-2. Treatment with endothelin-1 (100 nM) decreased angiopoietin-1 production in cultured astrocytes and the effect was inhibited by BQ788 (1 µM). Five days after FPI, increased extravasation of Evans blue dye accompanied by reduction in claudin-5, occludin, and zonula occludens-1 proteins were observed in mouse cerebrum while these effects of FPI were reduced by BQ788 and exogenous angiopoietin-1 (1 µg/day, i.c.v.). The effects of BQ788 were inhibited by co-administration of a Tie-2 kinase inhibitor (40 nmol/day, i.c.v.). These results suggest that BQ788 administration after traumatic brain injury promotes recovery of BBB function through activation of the angiopoietin-1/Tie-2 signal.

LncRNA FIRRE/NF-kB feedback loop contributes to OGD/R injury of cerebral microglial cells.

Stroke is one of the leading causes for serious long-term neurological disability. LncRNAs have been investigated to be dysregulated in ischemic stroke. However, the underlying mechanisms of some specific lncRNAs have not been clearly clarified. To determine lncRNA-mediated regulatory mechanism in ischemic stroke, we constructed OGD/R injury model of cerebral microglial cells. Microarray analysis was carried out and analyzed that lncRNA functional intergenic repeating RNA element (FIRRE) was associated with OGD/R injury. Based on the molecular biotechnology, we demonstrated that FIRRE could activate NF-kB signal pathway. Meanwhile, the activated NF-kB promoted FIRRE expression in OGD/R-treated cerebral microglial cells. Therefore, FIRRE and NF-kB formed a positive feedback loop to promote the transcription of NLRP3 inflammasome, thus contributed to the OGD/R injury of cerebral microglial cells. All findings in this study may help to explore novel and specific therapeutic target for ischemic stroke.

Autopsy Case of a Penetrating Wound to the Left Cerebral Hemisphere Caused by an Accidental Shooting With a Crossbow.

A crossbow is a bow that shoots an arrow when a gun-like trigger is pulled. Deaths caused by accidental crossbow shootings are extremely rare. Here we describe an autopsy case of a penetrating wound to the left cerebral hemisphere caused by an accidental shooting with a crossbow. A man in his early 60s who lived with his wife and had used crossbows for 20 years as his hobby was found one early morning in the shed of his house, collapsed and bleeding from the head and neck. He was taken to a hospital and died after approximately 3 days of conservative treatment. At autopsy, a penetrating wound between the upper part of the left anterior neck and the left frontoparietal region was evident. Traumatic intracerebral hematoma was observed in the left frontal lobe, and severe traumatic subarachnoid hemorrhage was present throughout the brain. Cerebral contusion and hematoma without any organization were noted around the penetration. The cause of death was determined to be cerebral contusion and intracerebral hematoma due to the penetrating wound by the crossbow arrow. He was probably trying to load an arrow into the crossbow by placing it on the floor, pointing upward, and made a mistake in its operation that resulted in the shooting of the arrow. This case is unique because it was a rare accidental death caused by a crossbow arrow, and a detailed histopathological examination was performed.

Improvement of cold injury-induced mouse brain edema by endothelin ETB antagonists is accompanied by decreases in matrixmetalloproteinase 9 and vascular endothelial growth factor-A.

Brain edema is a potentially fatal pathological state that often occurs after brain injuries such as ischemia and trauma. However, therapeutic agents that fundamentally treat brain edema have not yet been established. We previously found that endothelin ETB receptor antagonists attenuate the formation and maintenance of vasogenic brain edema after cold injury in mice. In this study, the effects of ETB antagonists on matrixmetalloproteinase (MMP)9 and vascular endothelial growth factor (VEGF)-A expression were examined in the cold injury model. Cold injury was performed in the left brain of male ddY mice (5-6 weeks old) for the induction of vasogenic edema. Expression of MMP9 and VEGF-A mRNA in the mouse cerebrum was increased by cold injury. Immunohistochemical observations showed that the MMP9 and VEGF-A were mainly produced in reactive astrocytes in the damaged cerebrum. Intracerebroventricular administration of BQ788 (10 µg) or IRL-2500 (10 µg) (selective ETB antagonists) attenuated brain edema and disruption of the blood-brain barrier after cold injury. BQ788 and IRL-2500 reversed the cold injury-induced increases in MMP9 and VEGF-A expression. The induction of reactive astrocytes producing MMP9 and VEGF-A in the damaged cerebrum was attenuated by BQ788 and IRL-2500. These results suggest that attenuations of astrocytic MMP9 and VEGF-A expression by ETB antagonists may be involved in the amelioration of vasogenic brain edema.

Contextual Constraint Treatment for coarse coding deficit in adults with right hemisphere brain damage: generalisation to narrative discourse comprehension.

Coarse coding is the activation of broad semantic fields that can include multiple word meanings and a variety of features, including those peripheral to a word's core meaning. It is a partially domain-general process related to general discourse comprehension and contributes to both literal and non-literal language processing. Adults with damage to the right cerebral hemisphere (RHD) and a coarse coding deficit are particularly slow to activate features of words that are relatively distant or peripheral. This manuscript reports a pre-efficacy study of Contextual Constraint Treatment (CCT), a novel, implicit treatment designed to increase the efficiency of coarse coding with the goal of improving narrative comprehension and other language performance that relies on coarse coding. Participants were four adults with RHD. The study used a single-subject controlled experimental design across subjects and behaviours. The treatment involved pre-stimulation, using a hierarchy of strong and moderately biased contexts, to prime the intended distantly related features of critical stimulus words. Three of the four participants exhibited gains in auditory narrative discourse comprehension, the primary outcome measure. All participants exhibited generalisation to untreated items. No strong generalisation to processing non-literal language was evident. The results indicate that CCT yields both improved efficiency of the coarse coding process and generalisation to narrative comprehension.

The complementary role of the cerebral hemispheres in recovery from aphasia after stroke: a critical review of literature.

OBJECTIVES: To review the literature on the specific role of the right cerebral hemisphere during recovery from aphasia in order to address the lack of consensus among authors. To derive a theoretical model reconciling the controversial findings in the literature. METHODS: Initial PubMed, MEDLINE (1946 to 5 May 2012) and PsycINFO (1806 to first week June 2012) searches on recovery mechanisms from aphasia, whether treatment-related or not, retrieved a total of 35 English language articles. Articles, cross-referenced in this initial set were also reviewed if they met the inclusion criteria, thus resulting in a total of 42 articles included in this review. MAIN OUTCOMES: Recruitment of the right hemisphere during recovery from aphasia can be effective if it occurs during a critical time window post-stroke. The recruitment's effectiveness will depend on the lesion's location, extent and permanence. Preservation of core language processing areas will generate minimal right hemisphere recruitment and vice versa. Some experimental studies seem to suggest that the improvement linked to a particular hemisphere can be modulated by specific therapy methods. CONCLUSION: The specific conditions in which effective right recruitment takes place may have important implications for rehabilitation treatment. These findings could lead to improved recovery in people suffering from aphasia. However, more research with non-invasive brain stimulation is needed.

Differentiating hemispheric contributions to syntax and semantics in patients with left-hemisphere lesions.

Understanding the relationship between brain and cognition critically depends on data from brain-damaged patients since these provide major constraints on identifying the essential components of brain-behavior systems. Here we relate structural and functional fMRI data with behavioral data in 21 human patients with chronic left hemisphere (LH) lesions and a range of language impairments to investigate the controversial issue of the role of the hemispheres in different language functions. We address this issue within a dual neurocognitive model of spoken language comprehension in which core linguistic functions, e.g., syntax, depend critically upon an intact left frontotemporal system, whereas more general communicative abilities, e.g., semantics, are supported by a bilateral frontotemporal system and may recover from LH damage through normal or enhanced activity in the intact right hemisphere. The fMRI study used a word-monitoring task that differentiated syntactic and semantic aspects of sentence comprehension. We distinguished overlapping interactions between structure, neural activity, and performance using joint independent components analysis, identifying two structural-functional networks, each with a distinct relationship with performance. Syntactic performance correlated with tissue integrity and activity in a left frontotemporal network. Semantic performance correlated with activity in right superior/middle temporal gyri regardless of tissue integrity. Right temporal activity did not differ between patients and controls, suggesting that the semantic network is degenerately organized, with regions in both hemispheres able to perform similar computations. Our findings support the dual neurocognitive model of spoken language comprehension and emphasize the importance of linguistic specificity in investigations of language recovery in patients.

Right hemisphere brain damage impairs strategy updating.

Our behavior is predicated on mental models of the environment that must be updated to accommodate incoming information. We had 13 right-brain-damaged (RBD) patients and 10 left-brain-damaged (LBD) patients play the children's game "rock, paper, scissors" against a computer opponent that covertly altered its strategy. Healthy age-matched controls and LBD patients quickly detected extreme departures from uniform play ("paper" chosen on 80% of trials), but the RBD patient group did not. Seven RBD patients presented with neglect and although this was associated with greater impairment in strategy updating, there were exceptions: 2 of 7 neglect patients performed above the median of the patient group and 1 of the 6 nonneglect participants was severely impaired. Although speculative, lesion analyses contrasting high and low performing patients showed that severe impairments were associated with insula and putamen lesions. Interestingly, relative to the controls, the LBD group tended to "maximize" choices in the strongly biased condition (i.e., optimal strategy chosen on 100% of the trials), whereas controls "matched" the computer's strategy (i.e., optimal strategy chosen on 80% of the trials). We conclude that RBD leads to impaired updating of mental models to exploit environmental changes.

Doxycycline treatment in a neonatal rat model of hypoxia-ischemia reduces cerebral tissue and white matter injury: a longitudinal magnetic resonance imaging study.

Doxycycline may potentially be a neuroprotective treatment for neonatal hypoxic-ischemic brain injury through its anti-inflammatory effects. The aim of this study was to examine any long-term neuroprotection by doxycycline treatment on cerebral gray and white matter. Hypoxic-ischemic brain injury was induced in 7-day-old rats. Pups were treated with either doxycycline (HI+doxy) or saline (HI+vehicle) by intraperitoneal injection at 1 h after hypoxia-ischemia (HI). At 6 h after HI, MnCl(2) was injected intraperitoneally for later manganese-enhanced magnetic resonance imaging (MRI). MRI was performed with diffusion-weighted imaging on day 1 and T(1) -weighted imaging and diffusion tensor imaging at 7, 21 and 42 days after HI. Animals were killed after MRI on day 42 and histological examinations of the brains were performed. There was a tendency towards lower lesion volumes on diffusion maps among HI+doxy than HI+vehicle rats at 1 day after HI. Volumetric MRI showed increasing differences between groups with time after HI, with less cyst formation and less cerebral tissue loss among HI+doxy than HI+vehicle pups. HI+doxy pups had less manganese enhancement on day 7 after HI, indicating reduced inflammation. HI+doxy pups had higher fractional anisotropy on diffusion tensor imaging in major white matter tracts in the injured hemisphere than HI+vehicle pups, indicating less injury to white matter and better myelination. Histological examinations supported the MRI results. Lesion size on early MRI was highly correlated with final injury measures. In conclusion, a single dose of doxycycline reduced long-term cerebral tissue loss and white matter injury after neonatal HI, with an increasing effect of treatment with time after injury.

Morphological changes in rat hippocampus after brain injury.

We performed morphological analysis of the structure of rat hippocampus after ablation of the left sensorimotor cortex. Four experimental groups were formed: two control groups (intravenous and intracerebral injections of the culture medium) and two experimental groups (intravenous and intracerebral transplantation of MSC). Ten weeks after surgery, disturbed cytoarchitectonics and great number of dead neurons were found in all zones of the hippocampus in animals of the control groups. In animals receiving cell therapy, no pathological changes in the structure of the hippocampus were found: hyperchromatic neurons were absent and the cells had regular shape and closely adjoined to each other.

Brain MRI signal abnormalities and right-to-left shunting in asymptomatic military divers.

INTRODUCTION: We conducted a controlled study to assess the prevalence of brain MRI hyperintense signals and their correlation with right-to-left shunting (RLS) in military divers. METHODS: We prospectively enrolled 32 asymptomatic military divers under 41 yr of age and 32 non-diving healthy subjects matched with respect to age and vascular disease risk factors. We examined both groups with a 3-Tesla brain MRI; RLS was detected using transcranial pulsed Doppler in divers only. RESULTS: Hyperintense spots were observed in 43.7% of the divers and 21.8% of the control subjects. In particular, divers with significant shunting exhibited a higher prevalence of hyperintensities compared to those with slight or no RLS (75% vs. 25%, respectively). Linear trend analysis also revealed a positive correlation between focal white matter changes, determined using a validated visual rating scale and the RLS grade. CONCLUSION: Healthy military divers with a hemodynamically relevant RLS have an increased likelihood of cerebral hyperintense spots compared to age-matched normal subjects. The clinical relevance of these MRI signal abnormalities and their causal relationship with diving remain unclear.

An Integrative Review of Cerebral Salt Wasting Syndrome.

BACKGROUND: Although cerebral salt wasting syndrome (CSWS) is widely recognized, its clinical characteristics, diagnostic criteria, and management have not been clearly defined. This study was undertaken to comprehensively review current literature and provide a more complete picture of CSWS. This review also aimed to provide information for nurses on how to differentiate cerebral salt wasting syndrome from syndrome of inappropriate antidiuretic hormone secretion. METHODS: An integrative review was performed. Searches were conducted between May and July 2018. The primary information sources were CINAHL, Google Scholar, MEDLINE, PubMed, Scopus, and Web of Science. Included articles were published from 1954 to July 2018. RESULTS: The essential features of CSWS are hyponatremia, hypovolemia, and increased urine output. Treatment regimens may be determined based on the acuity and severity of hyponatremia and hypovolemia as well as evident symptoms and signs. CONCLUSION: This review may help neuroscience nurses become knowledgeable about CSWS for the drafting of appropriate nursing care plans and also be able to differentiate CSWS from syndrome of inappropriate antidiuretic hormone secretion as early as possible for timely and proper management.

Loss of guidewire and its sequelae after central venous catheterization: A case report.

RATIONALE: Central venous catheterization is a common tool used to monitor central venous pressure and administer fluid medications in patients undergoing surgery. The loss of a broken guide wire into the circulation is a rare and preventable complication. Here, we report a peculiar case of a missed guidewire puncturing the aortic arch and cerebrum. PATIENT CONCERNS: A 53-year-old man with complaints of an intermittent headache and right swollen ankle following central venous catheterization. DIAGNOSES: Using computed tomography; the patient was diagnosed with the loss of a guide wire in his body. The guide wire had migrated to the brain and punctured the vascular wall of the aortic arch. INTERVENTIONS: Due to the risks of surgery, the patient was advised to have a follow-up visit once every 3 months. OUTCOMES: At present, the patient could live like a normal person, although he suffers from intermittent headaches. LESSONS: The loss of a guide wire is a completely preventable complication, provided that a hold on the tip of the wire is maintained during placement, and the correct safety measurements and protocols are followed.

Recovery of learning ability after the ablation of the procerebrum in the terrestrial slug, Limax valentianus.

The procerebrum (PC) is indispensable for odor-aversion learning in Limax. On the other hand, the central nervous system (CNS) of some Pulmonata shows robustness against injury, recovering from nerve injury both at the histological and functional levels. To investigate whether the PC of Limax also shows robustness against nerve injury, we tested whether or not the slugs can acquire and retrieve odor-aversion memory after a long recovery period from PC ablation. When the recovery period is short (7 days), the PC-ablated slugs failed to avoid the conditioned odor. But when the recovery period is long (1 month), the PC-ablated slugs successfully avoided the conditioned odor. These results indicate that the CNS including the PC can recover from injury at least at the functional level.

Routine cervical spine immobilisation is unnecessary in patients with isolated cerebral gunshot wounds: A South African experience.

OBJECTIVE: Routine immobilisation of the cervical spine in trauma has been a long established practice. Very little is known in regard to its appropriateness in the specific setting of isolated traumatic brain injury secondary to gunshot wounds (GSWs). METHODS: A retrospective study was conducted over a 5 year period (January 2010 to December 2014) at the Pietermaritzburg Metropolitan Trauma Service, Pietermaritzburg, South Africa in order to determine the actual incidence of concomitant cervical spine injury (CSI) in the setting of isolated cerebral GSWs. RESULTS: During the 5 year study period, 102 patients were included. Ninety-two per cent (94/102) were male and the mean age was 29 years. Ninety-eight per cent of the injuries were secondary to low velocity GSWs. Twenty-seven (26%) patients had cervical collar placed by the Emergency Medical Service. The remaining 75 patients had their cervical collar placed in the resuscitation room. Fifty-five (54%) patients had a Glasgow Coma Scale (GCS) of 15 and underwent plain radiography, all of which were normal. Clearance of cervical spine based on normal radiography combined with clinical assessment was achieved in all 55 (100%) patients. The remaining 47 patients whose GCS was <15 all underwent a computed tomography (CT) scan of their cervical spine and brain. All 47 CT scans of the cervical spine were normal and there was no detectable bone or soft tissue injury noted. CONCLUSION: Patients who sustain an isolated low velocity cerebral GSW are highly unlikely to have concomitant CSI. Routine cervical spine immobilisation is unnecessary, and efforts should be directed at management strategies aiming to prevent secondary brain injury. Further studies are required to address the issue in the setting of high velocity GSWs.

Navigational memory functional magnetic resonance imaging: a test for concussion in children.

Concussions are high incidence injuries with potentially devastating consequences. Youths are at risk because of a higher threat of repeated injury, and cumulative effects of concussions exist, making accurate diagnosis and follow-up essential. This study examines a navigational memory functional magnetic resonance imaging (fMRI) task to determine whether activation differences exist between children with concussion and uninjured controls. Fifty adolescents were recruited-35 controls and 15 with concussion. All subjects underwent structural and fMRI testing using our navigational memory task, and a battery of neuropsychological testing. The activation patterns of the 15 subjects with concussion were compared with those of 15 age and sex-matched controls. Subtraction and regression analyses were performed using the matched controls along with scatter-plots using means and 95% quantiles of the 35 controls. While no differences were seen with neuropsychological testing or task performance, subjects with concussion had significantly diminished activation in the retrosplenial, thalamic, and parahippocampal areas bilaterally, along with the right dorsolateral prefrontal cortex and left precuneus. Interestingly, they had increased activation in the left hippocampus and right middle temporal gyrus. Regression analysis demonstrated negative correlations between activation and post-concussive symptoms in the left premotor cortex, superior and inferior parietal lobules, and parahippocampal gyrus. Subjects with concussion show both diminished and increased activation in specific cerebral regions, differentiating them from controls. This is one of the first studies to look at such a task using fMRI and its applicability in testing for concussion in children. These findings support navigational memory fMRI as a potential objective test for concussions.

Amelioration of cold injury-induced cortical brain edema formation by selective endothelin ETB receptor antagonists in mice.

Brain edema is a potentially fatal pathological condition that often occurs in stroke and head trauma. Following brain insults, endothelins (ETs) are increased and promote several pathophysiological responses. This study examined the effects of ETB antagonists on brain edema formation and disruption of the blood-brain barrier in a mouse cold injury model (Five- to six-week-old male ddY mice). Cold injury increased the water content of the injured cerebrum, and promoted extravasation of both Evans blue and endogenous albumin. In the injury area, expression of prepro-ET-1 mRNA and ET-1 peptide increased. Intracerebroventricular (ICV) administration of BQ788 (ETB antagonist), IRL-2500 (ETB antagonist), or FR139317 (ETA antagonist) prior to cold injury significantly attenuated the increase in brain water content. Bolus administration of BQ788, IRL-2500, or FR139317 also inhibited the cold injury-induced extravasation of Evans blue and albumin. Repeated administration of BQ788 and IRL-2500 beginning at 24 h after cold injury attenuated both the increase in brain water content and extravasation of markers. In contrast, FR139317 had no effect on edema formation when administrated after cold injury. Cold injury stimulated induction of glial fibrillary acidic protein-positive reactive astrocytes in the injured cerebrum. Induction of reactive astrocytes after cold injury was attenuated by ICV administration of BQ788 or IRL-2500. These results suggest that ETB receptor antagonists may be an effective approach to ameliorate brain edema formation following brain insults.

Ischemia preconditioning is neuroprotective in a rat cerebral ischemic injury model through autophagy activation and apoptosis inhibition.

Sublethal ischemic preconditioning (IPC) is a powerful inducer of ischemic brain tolerance. However, its underlying mechanisms are still not well understood. In this study, we chose four different IPC paradigms, namely 5 min (5 min duration), 5×5 min (5 min duration, 2 episodes, 15-min interval), 5×5×5 min (5 min duration, 3 episodes, 15-min intervals), and 15 min (15 min duration), and demonstrated that three episodes of 5 min IPC activated autophagy to the greatest extent 24 h after IPC, as evidenced by Beclin expression and LC3-I/II conversion. Autophagic activation was mediated by the tuberous sclerosis type 1 (TSC1)-mTor signal pathway as IPC increased TSC1 but decreased mTor phosphorylation. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and hematoxylin and eosin staining confirmed that IPC protected against cerebral ischemic/reperfusion (I/R) injury. Critically, 3-methyladenine, an inhibitor of autophagy, abolished the neuroprotection of IPC and, by contrast, rapamycin, an autophagy inducer, potentiated it. Cleaved caspase-3 expression, neurological scores, and infarct volume in different groups further confirmed the protection of IPC against I/R injury. Taken together, our data indicate that autophagy activation might underlie the protection of IPC against ischemic injury by inhibiting apoptosis.