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Here we aimed to investigate the effects of atorvastatin on accelerated reendothelialization after carotid balloon injury. A mouse model of carotid arterial injury was established, followed by intragastric administration of atorvastatin at a dose of 0.6 mg x [(kg body mass).sup.-1] x [d.sup.-1]. Pathological sections of carotid artery stained with hematoxylin and eosin were observed under light microscopy. Expression levels of eNOS mRNA and protein were detected with real-time quantitative PCR and Western blot analysis, respectively. Proliferation and differentiation of endothelial progenitor cells (EPCs) were observed after treatment, in vitro. Reendothelialization appeared on the neovascular surface, while intimal hyperplasia was inhibited after treatment with atorvastatin. Numbers of CD31-positive cells increased after atorvastatin treatment, as did the number of leucocyte antigen positive cells. The expression of cell markers, such as CD34, eNOS, and VEGF-R, were higher in the atorvastatin-treated group of mononuclear cells. EPC numbers increased with the concentration of atorvastatin. The expression of eNOS mRNA was reduced in the mice with carotid artery injury that were treated with normal saline. The expression levels of eNOS protein were increased in atorvastatin treatment group. In conclusion, atorvastatin stimulates EPCs to differentiate into endothelial cells and promotes the repair of carotid arterial injury. Key words: atorvastatin, endothelial progenitor cells, carotid arterial injury, reendothelialization. Nous avions pour but d'etudier les effets de l'atorvastatine sur l'acceleration de la re-endothelialisation apres un dommage a la carotide induit par ballon. Un modele de dommage arteriel carotidien chez la souris a ete etabli, suivi de l'administration intragastrique d'atorvastatine a une dose de 0,6 mg x [(kg de masse corporelle).sup.-1] x [jour.sup.- 1]. Des sections d'artere carotide colorees a l'HE ont ete soumises a un examen en pathologie par microscopie optique. Les niveaux d'expression de eNOS et de son ARNm ont detectes par buvardage Western et par PCR quantitative, respectivement. La proliferation et la differenciation des cellules souches endotheliales (CSE) ont ete observees apres le traitement medicamenteux in vitro.La re-endothelialisation etait apparente a la surface neovasculaire alors que l'hyperplasie de l'intima etait inhibee par le traitement a l'atorvastatine. Le nombre de cellules positives au CD31 de meme que le nombre de cellules positives a l'antigene leucocytaire etait accru a la suite du traitement a l'atorvastatine. L'expression de marqueurs cellulaires tels le CD34, eNOS et le VEGF-R etait plus elevee chez les cellules provenant du groupe traite a l'atorvastatine. Le nombre de CSE augmentait en fonction de la concentration d'atorvastatine. L'expression de l'ARNm d'eNOS etait reduite dans l'artere carotide endommagee des souris traitees a la saline normale. Les niveaux d'expression de la proteine eNOS etaient augmentes dans le groupe traite a l'atorvastatine. En conclusion, l'atorvastatine stimule les CSE a se differencier en cellules endotheliales et favorise la reparation du dommage de l'artere carotide. [Traduit par la Redaction] Mots-cles: atorvastatine, cellules souches endotheliales, dommage a l'artere carotide, re-endothelialisation., Introduction Endothelial progenitor cells (EPCs) isolated from human blood from the peripheral circulation can differentiate into endothelial cells (ECs) (Asahara et al. 1997). Recently, it has been shown that EPCs [...]

Background: After a traumatic brain injury (TBI), the cell environment is dramatically changed, which has various influences on grafted neural stem cells (NSCs). At present, these influences on NSCs have not been fully elucidated, which hinders the finding of an optimal timepoint for NSC transplantation. Methods: Brain extracts of TBI mice were used in vitro to simulate the different phase TBI influences on the differentiation of human NSCs. Protein profiles of brain extracts were analyzed. Neuronal differentiation and the activation of autophagy and the WNT/CTNNB pathway were detected after brain extract treatment. Results: Under subacute TBI brain extract conditions, the neuronal differentiation of hNSCs was significantly higher than that under acute brain extract conditions. The autophagy flux and WNT/CTNNB pathway were activated more highly within the subacute brain extract than in the acute brain extract. Autophagy activation by rapamycin could rescue the neuronal differentiation of hNSCs within acute TBI brain extract. Conclusions: The subacute phase around 7 days after TBI in mice could be a candidate timepoint to encourage more neuronal differentiation after transplantation. The autophagy flux played a critical role in regulating neuronal differentiation of hNSCs and could serve as a potential target to improve the efficacy of transplantation in the early phase. [ABSTRACT FROM AUTHOR]

Background: Isocitrate dehydrogenase wild-type (WT) glioblastoma (GBM) accounts for 90% of all GBMs, yet only 27% of isocitrate dehydrogenase WT-GBMs have p53 mutations. However, the tumor surveillance function of WT-p53 in GBM is subverted by mechanisms that are not fully understood.Methods: We investigated the proteolytic inactivation of WT-p53 by asparaginyl endopeptidase (AEP) and its effects on GBM progression in cancer cells, murine models, and patients' specimens using biochemical and functional assays. The sera of healthy donors (n = 48) and GBM patients (n = 20) were examined by enzyme-linked immunosorbent assay. Furthermore, effects of AEP inhibitors on GBM progression were evaluated in murine models (n = 6-8 per group). The statistical significance between groups was determined using two-tailed Student t tests.Results: We demonstrate that AEP binds to and directly cleaves WT-p53, resulting in the inhibition of WT-p53-mediated tumor suppressor function in both tumor cells and stromal cells via extracellular vesicle communication. High expression of uncleavable p53-N311A-mutant rescue AEP-induced tumorigenesis, proliferation, and anti-apoptotic abilities. Knock down or pharmacological inhibition of AEP reduced tumorigenesis and prolonged survival in murine models. However, overexpression of AEP promoted tumorigenesis and shortened the survival time. Moreover, high AEP levels in GBM tissues were associated with a poor prognosis of GBM patients (n = 83; hazard ratio = 3.94, 95% confidence interval = 1.87 to 8.28; P < .001). A correlation was found between high plasma AEP levels and a larger tumor size in GBM patients (r = 0.6, P = .03), which decreased dramatically after surgery.Conclusions: Our results indicate that AEP promotes GBM progression via inactivation of WT-p53 and may serve as a prognostic and therapeutic target for GBM. [ABSTRACT FROM AUTHOR]

Glioma initiating cells (GICs) function as the seed for the propagation and relapse of glioma. Designing a smart and efficient strategy to target the GICs and to suppress the multiple signaling pathways associated with stemness and chemoresistance is essential to achieving a cancer cure. Inspired by the metabolic difference in endocytosis between GICs, differentiated glioma cells, and normal cells, a tailored lipoprotein‐like nanostructure is developed to amplify their internalization into GICs through receptor‐stimulated macropinocytosis. As CXCR4 is highly expressed on GICs and glioma tumor sites, meanwhile, the activation of CXCR4 induces the receptor‐stimulated macropinocytosis pathway in GICs, this CXCR4 receptor‐stimulated lipoprotein‐like nanoparticle (SLNP) achieves efficient accumulation in GICs in vitro and in vivo. By carrying microRNA‐34a in the core, this tailored SLNP reduces sex‐determining region Y‐box 2 and Notch1 expression, powerfully inhibits GICs stemness and chemoresistance, and significantly prolongs the survival of GICs‐bearing mice. Taken together, a tailored lipoprotein‐based nanostructure realizes efficient GICs accumulation and therapeutic effect through receptor‐stimulated macropinocytosis, providing a powerful nanoplatform for RNA interference drugs to combat glioma. [ABSTRACT FROM AUTHOR]

Byline: Liemei. Guo, Chunlong. Zhong, Jiyao. Jiang, Yongming. Qiu Sir, A 74-year-old man presented with a 2-week history of decreased sensation and weakness of bilateral lower extremities along with urinary [...]

Background: Traumatic brain injury (TBI) has become the most common cause of death and disability in persons between 15 and 30 years of age, and about 10-15% of patients affected by TBI will end up in a coma. Coma caused by TBI presents a significant challenge to neuroscientists. Right median nerve electrical stimulation has been reported as a simple, inexpensive, non-invasive technique to speed recovery and improve outcomes for traumatic comatose patients.Methods/design: This multicentre, prospective, randomised (1:1) controlled trial aims to demonstrate the efficacy and safety of electrical right median nerve stimulation (RMNS) in both accelerating emergence from coma and promoting long-term outcomes. This trial aims to enrol 380 TBI comatose patients to partake in either an electrical stimulation group or a non-stimulation group. Patients assigned to the stimulation group will receive RMNS in addition to standard treatment at an amplitude of 15-20 mA with a pulse width of 300 μs at 40 Hz ON for 20 s and OFF for 40 s. The electrical treatment will last for 8 h per day for 2 weeks. The primary endpoint will be the percentage of patients regaining consciousness 6 months after injury. The secondary endpoints will be Extended Glasgow Outcome Scale, Coma Recovery Scale-Revised and Disability Rating Scale scores at 28 days, 3 months and 6 months after injury; Glasgow Coma Scale, Glasgow Coma Scale Motor Part and Full Outline of Unresponsiveness scale scores on day 1 and day 7 after enrolment and 28 days, 3 months and 6 months after injury; duration of unconsciousness and mechanical ventilation; length of intensive care unit and hospital stays; and incidence of adverse events.Discussion: Right median nerve electrical stimulation has been used as a safe, inexpensive, non-invasive therapy for neuroresuscitation of coma patients for more than two decades, yet no trial has robustly proven the efficacy and safety of this treatment. The Asia Coma Electrical Stimulation (ACES) trial has the following novel features compared with other major RMNS trials: (1) the ACES trial is an Asian multicentre randomised controlled trial; (2) RMNS therapy starts at an early stage 7-14 days after the injury; and (3) various assessment scales are used to evaluate the condition of patients. We hope the ACES trial will lead to optimal use of right median nerve electrical treatment.Trial Registration: ClinicalTrials.gov, NCT02645578 . Registered on 23 December 2015. [ABSTRACT FROM AUTHOR]

Background: Glutamate carboxypeptidase II (GCPII) inactivates the peptide co-transmitter N-acetylaspartylglutamate following synaptic release. Inhibition of GCPII elevates extracellular levels of the peptide, inhibits glutamate release and is neuroprotective in an animal model of traumatic brain injury. GCPII gene knockout mice were used to examine the cellular mechanisms underlying the neuroprotective efficacy of this transmitter system.Results: Following controlled cortical impact injury, GCPII knockout (KO) mice exhibited reduced TUNEL-positive nuclei in the contusion margin of the cerebral cortex relative to wild type mice. Impact injury reduced glutathione levels and superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde. Each of these effects was moderated in KO mice relative to wild type. Similarly, the injury-induced increases in cleaved caspase-3, cytosolic cytochrome c levels and Bcl-2/Bax ratio observed in wild type mice were attenuated in the knockout mice.Conclusions: These data support the hypothesis that the neuroprotective efficacy of GCPII KO in traumatic brain injury is mediated via a reduction in oxidative stress. [ABSTRACT FROM AUTHOR]

Objective: To retrospectively analyse the surgical management and outcomes of non-missile open head injuries (NMOHI). Methods: Forty-four patients who suffered from NMOHI were included. The Glasgow outcome score (GOS), computed tomography (CT), aetiology and outcomes and complications at discharge and during a 6-month follow-up were analysed. All patients underwent debridement. Intracranial haematoma evacuation, decompressive craniectomy (DC) or replacement were performed. Results: Motor vehicle accident and struck by/against were the most common causes (43.2% each). At admission, 33 patients had Glasgow coma scores (GCS) > 8 and 27 of them had a GCS score of > 13. Mean follow-up was 8.7 ± 4.3 months. All patients underwent debridement, 20 underwent bone fracture replacement and 27 underwent haematoma evacuation; 11 patients underwent haematoma evacuation and DC and one had bilateral DC. Twenty-seven patients showed good recovery; 11 patients had moderate disability; three patients had severe disability; and three patients died. After 6 months, 32 patients had good recovery and the morbidity of severe disability had decreased to 13.6%. Thirteen patients developed intracranial infection. Post-traumatic epilepsy and hydrocephalus was detected in three patients. Cerebrospinal fluid fistula was found in five patients. Only one patient developed a brain abscess after 6 months. Conclusions: NMOHI yielded satisfactory recovery and achieved good outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Glial fibrillary acidic protein (GFAP) may serve as a serum marker of traumatic brain injury (TBI) that can be used to monitor biochemical changes in patients and gauge the response to treatment. However, the temporal profile of serum GFAP in the acute period of brain injury and the associated utility for outcome prediction has not been elucidated.Methods: We conducted a prospective longitudinal cohort study of consecutive severe TBI patients in a local tertiary neurotrauma center in Shanghai, China, between March 2011 and September 2014. All patients were monitored and managed with a standardized protocol with inclusion of hypothermia and other intensive care treatments. Serum specimens were collected on admission and then daily for the first 5 days. GFAP levels were measured using enzyme-linked immunosorbent assay techniques. Patient outcome was assessed at 6 months post injury with the Glasgow Outcome Scale and further grouped into death versus survival and unfavorable versus favorable.Results: A total of 67 patients were enrolled in the study. The mean time from injury to admission was 2.6 hours, and the median admission Glasgow Coma Scale score was 6. Compared with healthy subjects, patients with severe TBI had increased GFAP levels on admission and over the subsequent 5 days post injury. Serum GFAP levels showed a gradual reduction from admission to day 3, and then rebounded on day 4 when hypothermia was discontinued with slow rewarming. GFAP levels were significantly higher in patients who died or had an unfavorable outcome across all time points than in those who were alive or had a favorable outcome. Results of receiver operating characteristic curve analysis indicated that serum GFAP at each time point could predict neurological outcome at 6 months. The areas under the curve for GFAP on admission were 0.761 for death and 0.823 for unfavorable outcome, which were higher than those for clinical variables such as age, Glasgow Coma Scale score, and pupil reactions.Conclusions: Serum GFAP levels on admission and during the first 5 days of injury were increased in patients with severe TBI and were predictive of neurological outcome at 6 months. [ABSTRACT FROM AUTHOR]

The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress glutamate release mainly through selective activation of presynaptic Group II metabotropic glutamate receptor subtype 3 (mGluR3). Therefore, strategies of inhibition of NAAG peptidases and subsequent NAAG hydrolysis to elevate levels of NAAG could reduce glutamate release under pathological conditions and be neuroprotective by attenuating excitotoxic cell injury. A series of potent inhibitors of NAAG peptidases has been synthesized and demonstrated efficacy in experimental models of ischemic-hypoxic brain injury, traumatic brain injury, inflammatory pain, diabetic neuropathy, amyotrophic lateral sclerosis and phencyclidine-induced schizophrenia-like behaviors. The excessive glutamatergic transmission has been implicated in all of these neurological disorders. Thus, blockade of NAAG peptidases may augment an endogenous protective mechanism and afford neuroprotection in the brain. This review aims to summarize and provide insight into the current understanding of the novel neuroprotective strategy based on limiting glutamate excitotoxicity for a wide variety of brain injuries and neurological disorders. [ABSTRACT FROM AUTHOR]