Improvement in cognitive dysfunction following blast induced traumatic brain injury by thymosin α1 in rats: Involvement of inhibition of tau phosphorylation at the Thr205 epitope.

Cognitive impairment is a significant sequela of traumatic brain injury (TBI) especially blast induced traumatic brain injury (bTBI), which is characterized by rapid impairments of learning and memory ability. Although several neuroprotective agents have been postulated as promising drugs for bTBI in animal studies, very few ideal therapeutic options exist to improve cognitive impairment following bTBI. Thymosin α1(Tα1), a 28-amino-acid protein that possesses immunomodulatory functions, has exhibited beneficial effects in the treatment of infectious diseases, immunodeficiency diseases and cancers. However, it remains unclear whether Tα1 has a therapeutic role in bTBI. Thus, we hypothesized that Tα1 administration could reverse the outcomes of bTBI. The blast induced TBI (bTBI) rat model was established with the compressed gas driven blast injury model system. A consecutive Tα1 therapy (in 1 ml saline, twice a day) at a dose of 200 µg/kg or normal saline (NS) (1 ml, twice a day) for 3 days or 2 weeks was performed. Utilizing our newly designed bTBI model, we investigated the beneficial effects of Tα1 therapy on rats exposed to bTBI including: cognitive functions, general histology, regulatory T (Treg) cells, edema, inflammation reactions and the expression and phosphorylation level of tau via Morris Water Maze test (MWM test), HE staining, flow cytometry, brain water content (BWC) calculation, IL-6 assay and Western blotting, respectively. Tα1 treatment seemed to reduce the 24-hour mortality, albeit with no statistical significance. Moreover, Tα1 treatment markedly improved cognitive dysfunction by decreasing the escape latency in the acquisition phase, and increasing the crossing numbers in the probe phase of MWM test. More interestingly, Tα1 significantly inhibited tau phosphorylation at the Thr205 epitope, but not at the Ser404 and Ser262 epitopes. Tα1 increased the percentage of Treg cells and inhibited plasma IL-6 production on 3d post bTBI. Moreover, Tα1 suppressed brain edema as demonstrated by decrease of BWC. However, there was a lack of obvious change in histopathology in the brain upon Tα1 treatment. This is the first study showing that Tα1 improves neurological deficits after bTBI in rats, which is potentially related to the inhibition of tau phosphorylation at the Thr205 epitope, increased Treg cells and decreased inflammatory reactions and brain edema.

A novel model of blast induced traumatic brain injury caused by compressed gas produced sustained cognitive deficits in rats: involvement of phosphorylation of tau at the Thr205 epitope.

Improvised explosive devices (IEDs) represent the leading causes for casualties among civilians and soldiers in the present war (including counter-terrorism). Traumatic brain injury (TBI) caused by IEDs results in different degrees of impairment of cognition and behavior, but the exact brain pathophysiological mechanism following exposure to blast has not been clearly investigated. Here, we sought to establish a rat model of closed-head blast injury using compressed gas to deliver a single blast only to the brain without systemic injuries. The cognitive functions of these bTBI models were assessed by Morris Water Maze test (MWM test). The HE staining, flow cytometry, ELISA and Western Blotting were used to measure the effects of shock wave on general histology, regulatory T (Treg) cells percentage, inflammatory reactions, the expression and phosphorylation level of tau, respectively. In addition, the brain water content and 24 -h mortality were also assessed. As the distance from the blast source increased, the input pressure did not change, the overpressure decreased, and the mortality decreased. Receiver operating characteristic (ROC) curves for predicting 24 -h mortality using peak overpressure fits with the following areas under ROC curves: 0.833. In 2 weeks after blast injury, cognitive tests revealed significantly decreased performance at 20 cm distance from the blast (about 136.44 kPa) as demonstrated by increased escape latency in the acquisition phase, and decreased crossing numbers in the probe phase of MWM test. Interestingly, a single blast exposure (at 20 cm) lead to significantly increased tau phosphorylation at the Thr205 epitope but not at the Ser404 and Ser262 epitopes at 12 h, 24 h, 3d, and 7d after blast injury. Blast decreased the percentage of CD4+T cells, CD8+T cells, Treg cells and lymphocytes at different time points after blast injury, and blast increased the percentage of neutrophils at 12 h after blast injury and significantly increased IL-6 production at 12 h, 24 h and 3d after blast injury. In addition, blast lead to an increase of brain edema at 24 h and 3d after blast injury. However, no obvious alterations in brain gross pathology were found acutely in the blast-exposed rats. In conclusion, we established a rat model of simple craniocerebral blast injury characterized by impairment of cognitive function, Thr205 phosphorylation of tau, decreased Treg cells and increased inflammatory reactions and brain edema. We expect this model may help clarify the underlying mechanism after blast injury and possibly serve as a useful animal model in the development of novel therapeutic and diagnostic approaches.

Establishment of a novel rat model of blast-related diffuse axonal injury.

Although studies concerning blast-related traumatic brain injury (bTBI) have demonstrated the significance of diffuse axonal injury (DAI), no standard models for this type of injury have been widely accepted. The present study investigated a mechanism of inducing DAI through real blast injury, which was achieved by performing instantaneous high-speed swinging of the rat head, thus establishing a stable animal model of blast DAI. Adult Sprague-Dawley rats weighing 150±10 g were randomly divided into experimental (n=16), control (n=10) and sham control (n=6) groups. The frontal, parietal and occipital cortex of the rats in the experimental group were exposed, whereas those of the control group were unexposed; the sham control group rats were anesthetized and attached to the craniocerebral blast device without experiencing a blast. The rats were subjected to craniocerebral blast injury through a blast equivalent to 400 mg of trinitrotoluene using an electric detonator. Biomechanical parameters, and physical and behavioural changes of the sagittal head swing were measured using a high-speed camera. Magnetic resonance imaging (MRI) scans were conducted at 2, 12, 24 and 48 h after craniocerebral injury, only the experimental group indicated brain stem injury. The rats were sacrificed immediately following the MRI at 48 h for pathological examination of the brain stem using haematoxylin and eosin staining. The results indicated that 14 rats (87.5%) in the experimental group exhibited blast DAI, while no DAI was observed in the control and sham control groups, and the difference between the groups was significant (P<0.05). The present results indicated that this experimental design may serve to provide a stable model of blast DAI in rats.

Small-worldness of brain networks after brachial plexus injury: A resting-state functional magnetic resonance imaging study.

Research on brain function after brachial plexus injury focuses on local cortical functional reorganization, and few studies have focused on brain networks after brachial plexus injury. Changes in brain networks may help understanding of brain plasticity at the global level. We hypothesized that topology of the global cerebral resting-state functional network changes after unilateral brachial plexus injury. Thus, in this cross-sectional study, we recruited eight male patients with unilateral brachial plexus injury (right handedness, mean age of 27.9 ± 5.4 years old) and eight male healthy controls (right handedness, mean age of 28.6 ± 3.2). After acquiring and preprocessing resting-state magnetic resonance imaging data, the cerebrum was divided into 90 regions and Pearson's correlation coefficient calculated between regions. These correlation matrices were then converted into a binary matrix with affixed sparsity values of 0.1-0.46. Under sparsity conditions, both groups satisfied this small-world property. The clustering coefficient was markedly lower, while average shortest path remarkably higher in patients compared with healthy controls. These findings confirm that cerebral functional networks in patients still show small-world characteristics, which are highly effective in information transmission in the brain, as well as normal controls. Alternatively, varied small-worldness suggests that capacity of information transmission and integration in different brain regions in brachial plexus injury patients is damaged.

Surgical management of 142 cases of split cord malformations associated with osseous divide.

OBJECTIVES: To investigate the key surgical points in treating split cord malformations associated with osseous divide and scoliosis (SCM-OD-S). MATERIALS AND METHODS: The surgical options and methods of a total of 142 SCM-OD-S cases were retrospectively analyzed, and the surgical precautions and imaging diagnosis were also discussed. RESULTS: The 142 patients were performed osseous divide resection plus dural sac molding, which achieved good results and no serious complication such as spinal cord and nerve injury occurred; certain symptoms such as urination-defecation disorders, muscle strength subsidence, Pes Cavus, and toe movement disorder in partial patients achieved various degrees of relief, and it also created good conditions for next-step treatment against scoliosis. CONCLUSIONS: The diagnosis of SCM-OD mainly depended on imaging inspection, routine magnetic resonance imaging (MRI) combined with computed tomography (CT) 3D reconstruction, which can comprehensively evaluate the types and features of diastematomyelia as well as other concomitant diseases. SCM alone needed no treatment, but surgery will be the only means of treating SCM-OD. Intraoperatively removing osseous divide step-by-step, as well as carefully freeing the spinal cord and remodeling the dural sac, can lay good foundations for relieving tethered cord, improving neurological symptoms, and further scoliosis orthomorphia, thus particularly exhibiting importance for the growth and development of adolescents.

Acupuncture treatment of chronic low back pain reverses an abnormal brain default mode network in correlation with clinical pain relief.

BACKGROUND: Acupuncture is gaining in popularity as a treatment for chronic low back pain (cLBP); however, its therapeutic mechanisms remain controversial, partly because of the absence of an objective way of measuring subjective pain. Resting-state functional MRI (rsfMRI) has demonstrated aberrant default mode network (DMN) connectivity in patients with chronic pain, and also shown that acupuncture increases DMN connectivity in pain-modulator and affective-emotional brain regions of healthy subjects. OBJECTIVE: This study sought to explore how cLBP influences the DMN and whether, and how, the altered DMN connectivity is reversed after acupuncture for clinical pain. METHODS: RsfMRI data from 20 patients with cLBP, before and after 4 weeks of treatment, and 10 age- and gender-matched healthy controls (without treatment) were analysed using independent components analyses to determine connectivity within the DMN, and combined with correlation analyses to compute covariance between changes in DMN connectivity and changes in clinical pain. Visual analogue scale data were assessed to rate clinical pain levels. RESULTS: Less connectivity within the DMN was found in patients with cLBP than in healthy controls, mainly in the dorsolateral prefrontal cortex, medial prefrontal cortex, anterior cingulate gyrus and precuneus. After acupuncture, patients' connectivities were restored almost to the levels seen in healthy controls. Furthermore, reductions in clinical pain were correlated with increases in DMN connectivity. CONCLUSIONS: This result suggests that modulation of the DMN by acupuncture is related to its therapeutic effects on cLBP. Imaging of the DMN provides an objective method for assessment of the effects of acupuncture-induced analgesia.

Protein-protein interaction network analysis and gene set enrichment analysis in epilepsy patients with brain cancer.

Many patients with brain cancer experience seizures or epilepsy and tumor-associated epilepsy (TAE) significantly decreases their quality of life. This study aimed to achieve a better understanding of the mechanisms of TAE. The differentially expressed genes (DEG) between epilepsy patients with or without brain tumor were firstly screened using the Linear Models for Microarray Data package using GSE4290 datasets from the USA National Center for Biotechnology Information Gene Expression Omnibus database. Then the protein-protein interaction (PPI) network, using data from the Human Protein Reference Database and the Biological General Repository for Interaction Datasets, was constructed. For further analysis, the PPI network structure and clusters in this PPI network were identified by ClusterOne. Meanwhile, gene set enrichment analysis was performed to illuminate the biological pathways and processes which generally affect patients with TAE. A total of 5113 DEG were identified and a PPI network, which contained 114 DEG and 21 normal genes, was established. Proteins, which mainly belonged to the mini chromosome maintenance and collagen families, were discovered to be enriched in the three identified clusters in the PPI network. Finally, several biological pathways (including cell cycle, DNA replication and transforming growth factor ß1 signaling pathways) and processes (such as nucleocytoplasmic transport, nuclear transport and regulation of phosphorylation) were identified. Proteins in these three clusters may become new targets for TAE treatment. Our results provide some potential underlying biomarkers for understanding the pathogenesis of epilepsy in patients with brain tumor.

Overexpression of MACC1 protein and its clinical implications in patients with glioma.

Metastasis associated in colon cancer 1 (MACC1) has been regarded as a novel potential therapeutic target for multiple cancers. However, the impact of MACC1 in glioma remains unclear. The aim of this study was to analyze the correlation of MACC1 expression with the clinicopathological features of glioma. MACC1 mRNA and protein expression levels in human glioma tissues were detected by quantitative real-time polymerase chain reaction and immunohistochemistry assays, respectively. MACC1 mRNA and protein expression were both significantly higher in glioma tissues than in corresponding noncancerous brain tissues (both P < 0.001). In addition, statistical analysis suggested that high MACC1 expression was significantly correlated with advanced pathological grade (P = 0.004) and that patients with high expression of MACC1 protein exhibited a poorer prognosis than those with low MACC1 expression. Furthermore, Cox multivariate analysis showed that MACC1 overexpression was an independent prognostic factor for predicting the overall survival of glioma patients. In conclusion, expression of MACC1 in glioma could be adopted as a candidate biomarker for the diagnosis of clinical stage and for assessing prognosis, indicating for the first time that MACC1 may play an important role in the tumor development and progression in glioma. MACC1 might be considered as a novel therapeutic target against this cancer.

Comparison of the safety and efficacy of propofol with midazolam for sedation of patients with severe traumatic brain injury: a meta-analysis.

OBJECTIVE: To perform a meta-analysis to compare the safety and efficacy of propofol with midazolam for sedation of patients with severe traumatic brain injury. MATERIALS AND METHODS: Studies were included in the meta-analysis if they met the following criteria: randomized controlled trial of sedative-hypnotic agents including propofol and midazolam; patients had severe traumatic brain injury; the primary outcome was the Glasgow Outcome Scale score; secondary outcomes included mortality, therapeutic failure, intracranial pressure, and cerebral perfusion pressure. The data were analyzed using software for meta-analysis. RESULTS: Seven relevant studies were identified. Three of these studies were excluded: one was a single-arm study, one compared morphine and propofol, and for one the full text article could not be obtained. The remaining 4 studies were included in the meta-analysis. The results of the meta-analysis showed that propofol and midazolam have similar effects on the Glasgow Outcome Scale score, mortality, intracranial pressure, and cerebral perfusion pressure. CONCLUSION: Our meta-analysis of 4 studies showed that there are no important differences between propofol and midazolam when administered to provide sedation for patients with severe traumatic brain injury. Further randomized, controlled trials comparing propofol with midazolam for sedation of such patients are needed.

Can electroacupuncture affect the sympathetic activity, estimated by skin temperature measurement? A functional MRI study on the effect of needling at GB 34 and GB 39 on patients with pain in the lower extremity.

The Purpose of this study was to investigate the possible needling effect on sympathetic activity by using functional MRI (fMRI). Twelve patients with left lower extremity pain were enrolled in our study. Each was given deep needling at left GB34 (yanglingquan) and GB39 (xuanzhong) points simultaneously. All patients got the strong DeQi sensation by manipulating the needles, and then electroacupucture (EA) was given and lasted for thirty minutes before fMRI scan. Then the fMRI scan was performed by scanning the whole brain with five blocks lasting 2 minutes each. The patients' palm skin temperatures were tested every five minutes as indication of the sympathetic activity from the beginning of EA to the end of our fMRI scan. Functional images were processed by using FEAT software at different levels including the simple single subject analysis, multi-subjects group mean analysis, and multi-subjects unpaired two difference analysis. Finally, 9 of 12 patients' palm temperatures increased gradually but the other three decreased. In comparison of two different palm skin temperature change groups, more significant activation over bilateral caudate head, right lentiform and periaqueductal gray (PAG) were found in the temperature-increased group, but palm temperature-decreased patients revealed more significant activation over bilateral anterior cingulated cortex (ACC), insula, primary somatosensory gyrus (SI), orbitofrontal cortex, occipital cortex, hippocampus and amygdala formation. Our study suggested that needling at analgesic points may modulate the sympathetic activity and such evident difference on brain responses may correlate with the clinical analgesia effects.

Neuronal specificity of needling acupoints at same meridian: a control functional magnetic resonance imaging study with electroacupuncture.

The purpose of this study was to investigate the neuronal specificity of needling acupoints at same meridian by functional Magnetic Resonance Imaging (fMRI). The selected acupoints GB34 (Yanglinquan) and GB39 (Xuanzhong) were at the same gallbladder meridian based on traditional Chinese medicine. In our study we devise three distinct EA (electroacupuncture) manipulations: real EA (deep needling at acupoints), sham EA (deep needling at no-meridian points) and shallow EA (subcutaneous needling at acupoints). Twelve healthy volunteers with right-handiness were enrolled and received three different EA manipulations in counter-balanced orders. DeQi scores were used to evaluate the degree of needling sensation. We found real EA can induce significant stronger needling sensation than sham EA and shallow EA. Multisubjects group mean analysis showed that pain-related cortex including primary and secondary somatosensory cortex (SI and S II), anterior cingulated cortex (ACC), insula were involved in three EA stimulation. Bilateral activation of prefrontal gyrus and occipital cortex were exclusively found in real EA. Deactivation over the rostral segment of ACC was also shown in real and shallow EA. Further paired two difference analysis indicated that real EA induced higher activation than sham EA over bilateral prefrontal gyrus, right-side occipital gyrus and deactivation over the rostral segment of ACC. In the comparing with real EA versus shallow EA, there was right-side activation over the SI, S II, motor cortex, ACC, insula, thalamus, hippocampus, occipital cortex, and cerebellum; also activation over bilateral prefrontal gyrus, caudate and pons. Although no significant activation was found over periaqueductal gray (PAG), further analysis showed the mean and maximal signal changes were different under three EA manipulations. We concluded that EA at analgesic acupoints of same meridian maybe involved the pain-related neuromatrix especially the hypothalamus-limbic system; deep EA at meridian points could elicit stronger needling sensation and modulate the pain-related neuromatrix more effectively than EA at nonmeridian points or shallow EA at meridian points.