Qing Mao

Rationale, methodology, and implementation of a nationwide multicenter randomized controlled trial of long-term mild hypothermia for severe traumatic brain injury (the LTH-1 trial).

BACKGROUND Traumatic brain injury (TBI) is a major public health problem recently, however, no intervention showing convincing efficacy. Therapeutic hypothermia with a relatively long duration (more than 48 h), as a promising treatment measure, might improve the patient outcome following severe TBI. METHODS/DESIGN The LTH-1 trial is a prospective, nationwide multicenter, randomized, controlled clinical trial to examine the efficacy and safety of long-term mild hypothermia in adult patients after severe traumatic brain injury. A total of 300 consecutive patients will be recruited from 15 large neurosurgical centers in China. The eligible patient will be randomized to receive either long-term mild hypothermia (34-35 °C) for 5 days, or normothermia (36-37 °C). Additionally, a standardized management protocol will be used in all patients. The primary end point is the neurological outcome 6 months post-injury on the Glasgow Outcome Scale. The secondary outcomes include GOS score at one month post-injury, mortality during six months after injury, length of ICU and hospital stay, intracranial pressure control and Glasgow Coma Scale score during the hospital stay and frequency of complications during the six-month follow-up period. DISCUSSION Long-term hypothermia is recommended by most recent studies and its efficacy urgently needs to be established in randomized controlled settings. The LTH-1 trial, together with other ongoing studies, will present more evidence for optimal use of hypothermia in severe TBI patients.

Expression of Voltage-Gated Sodium Channel Nav1.3 Is Associated with Severity of Traumatic Brain Injury in Adult Rats

During the secondary injury period after traumatic brain injury (TBI), depolarization of neurons mediated by voltage-gated sodium channels (VGSCs) leads to cellular abnormalities and neurological dysfunction. Alterations in expression of different α subunits of VGSCs can affect early brain pathology following TBI. This study detected the expression of Nav1.3 mRNA and protein in the rat cortex post-TBI. Adult male Sprague-Dawley rats were randomly assigned to sham-TBI, mild-TBI (mTBI), or severe-TBI (sTBI) groups. TBI was induced using a fluid percussion device at magnitudes of 1.5-1.6 atm (mTBI) and 2.9-3.0 atm (sTBI). Nav1.3 mRNA and protein levels in the ipsilateral-injured cortex were examined at 2 h, 12 h, 24 h, and 72 h post-TBI by real-time reverse transcriptase quantitative polymerase chain reaction and Western blot. Brains were collected at 24 h, 72 h, and 7 days post-TBI for TUNEL staining and cell count analysis. Immunofluorescence was performed to localize expression of Nav1.3 protein in the ipsilateral-injured cortex. Expression of Nav1.3 mRNA and protein were significantly upregulated in mTBI and sTBI groups when compared with the sham-TBI group at 2 h and 12 h post-TBI. Nav1.3 mRNA and protein levels in the sTBI group were much higher than in the mTBI group at 12 h post-TBI. TUNEL-positive cell numbers were significantly higher in the sTBI group than in the mTBI at 24 h, 72 h, and 7 days post-TBI. Expression of Nav1.3 was observed predominantly in neurons of the cortex. These findings indicated significant upregulation in the expression of Nav1.3 mRNA and protein in the rat ipsilateral-injured cortex at the very early stage post-TBI, and were also correlated with TBI severity.

Alteration of microRNA expression in cerebrospinal fluid of unconscious patients after traumatic brain injury and a bioinformatic analysis of related single nucleotide polymorphisms

Purpose It is becoming increasingly clear that genetic factors play a role in traumatic brain injury (TBI), whether in modifying clinical outcome after TBI or determining susceptibility to it. MicroRNAs are small RNA molecules involved in various pathophysiological processes by repressing target genes at the post-transcriptional level, and TBI alters microRNA expression levels in the hippocampus and cortex. This study was designed to detect differentially expressed microRNAs in the cerebrospinal fluid (CSF) of TBI patients remaining unconscious two weeks after initial injury and to explore related single nucleotide polymorphisms (SNPs). Methods We used a microarray platform to detect differential microRNA expression levels in CSF samples from patients with post-traumatic coma compared with samples from controls. A bioinformatic scan was performed covering microRNA gene promoter regions to identify potential functional SNPs. Results Totally 26 coma patients and 21 controls were included in this study, with similar distribution of age and gender between the two groups. Microarray showed that fourteen microRNAs were differentially expressed, ten at higher and four at lower expression levels in CSF of traumatic coma patients compared with controls (p < 0.05). One SNP (rs11851174 allele: C/T) was identified in the motif area of the microRNA hsa-miR-431-3P gene promoter region. Conclusion The altered microRNA expression levels in CSF after brain injury together with SNP identified within the microRNA gene promoter area provide a new perspective on the mechanism of impaired consciousness after TBI. Further studies are needed to explore the association between the specific microRNAs and their related SNPs with post-traumatic unconsciousness.

Blockage of the Upregulation of Voltage-Gated Sodium Channel Nav1.3 Improves Outcomes after Experimental Traumatic Brain Injury

Excessive active voltage-gated sodium channels are responsible for the cellular abnormalities associated with secondary brain injury following traumatic brain injury (TBI). We previously presented evidence that significant upregulation of Nav1.3 expression occurs in the rat cortex at 2 h and 12 h post-TBI and is correlated with TBI severity. In our current study, we tested the hypothesis that blocking upregulation of Nav1.3 expression in vivo in the acute stage post-TBI attenuates the secondary brain injury associated with TBI. We administered either antisense oligodeoxynucleotides (ODN) targeting Nav1.3 or artificial cerebrospinal fluid (aCSF) at 2 h, 4 h, 6 h, and 8 h following TBI. Control sham animals received aCSF administration at the same time points. At 12 h post-TBI, Nav1.3 messenger ribonucleic acid (mRNA) levels in bilateral hippocampi of the aCSF group were significantly elevated, compared with the sham and ODN groups (p<0.01). However, the Nav1.3 mRNA levels in the uninjured contralateral hippocampus of the ODN group were significantly lowered, compared with the sham group (p<0.01). Treatment with antisense ODN significantly decreased the number of degenerating neurons in the ipsilateral hippocampal CA3 and hilar region (p<0.01). A set of left-to-right ratio value analyzed by magnetic resonance imaging T2 image on one day, three days, and seven days post-TBI showed marked edema in the ipsilateral hemisphere of the aCSF group, compared with that of the ODN group (p<0.05). The Morris water maze memory retention test showed that both the aCSF and ODN groups took longer to find a hidden platform, compared with the sham group (p<0.01). However, latency in the aCSF group was significantly higher than in the ODN group (p<0.05). Our in vivo Nav1.3 inhibition studies suggest that therapeutic strategies to block upregulation of Nav1.3 expression in the brain may improve outcomes following TBI.

Mild Hypothermia Promotes Pericontusion Neuronal Sprouting via Suppressing Suppressor of Cytokine Signaling 3 Expression after Moderate Traumatic Brain Injury

Mild therapeutic hypothermia is a candidate for the treatment of traumatic brain injury (TBI). However, the role of mild hypothermia in neuronal sprouting after TBI remains obscure. We used a fluid percussion injury (FPI) model to assess the effect of mild hypothermia on pericontusion neuronal sprouting after TBI in rats. Male Sprague-Dawley rats underwent FPI or sham surgery, followed by mild hypothermia treatment (33°C) or normothermia treatment (37°C) for 3 h. All the rats were euthanized at 7 days after FPI. Neuronal sprouting that was confirmed by an increase in growth associated protein-43 (GAP-43) expression was evaluated using immunofluorescence and Western blot assays. The expression levels of several intrinsic and extrinsic sprouting-associated genes such as neurite outgrowth inhibitor A (NogoA), phosphatase and tensin homolog (PTEN), and suppressor of cytokine signaling 3 (SOCS3) were analyzed by quantitative real-time polymerase chain reaction (RT-PCR). Our results revealed that mild hypothermia significantly increased the expression level of GAP-43 and dramatically suppressed the expression level of interleukin-6 (IL-6) and SOCS3 at 7 days after FPI in the ipsilateral cortex compared with that of the normothermia TBI group. These data suggest that post-traumatic mild hypothermia promotes pericontusion neuronal sprouting after TBI. Moreover, the mechanism of hypothermia-induced neuronal sprouting might be partially associated with decreased levels of SOCS3.

Comprehensive Proteomic Profiling of Patients’ Tears Identifies Potential Biomarkers for the Traumatic Vegetative State

The vegetative state is a complex condition with unclear mechanisms and limited diagnostic, prognostic, and therapeutic methods. In this study, we aimed to explore the proteomic profile of tears from patients in a traumatic vegetative state and identify potential diagnostic markers using tears—a body fluid that can be collected non-invasively. Using iTRAQ quantitative proteomic technology, in the discovery phase, tear samples collected from 16 patients in a traumatic vegetative state and 16 normal individuals were analyzed. Among 1080 identified tear proteins, 57 were upregulated and 15 were downregulated in the patients compared to the controls. Bioinformatics analysis revealed that the differentially-expressed proteins were mainly involved in the wound response and immune response signaling pathways. Furthermore, we verified the levels of 7 differentially-expressed proteins in tears from 50 traumatic vegetative state patients and 50 normal controls (including the samples used in the discovery phase) using ELISA. The results showed that this 7-protein panel had a high discrimination ability for traumatic vegetative state (area under the curve = 0.999). In summary, the altered tear proteomic profile identified in this study provides a basis for potential tear protein markers for diagnosis and prognosis of the traumatic vegetative state and also provides novel insights into the mechanisms of traumatic vegetative state.

Circular RNA Expression Profiles Alter Significantly after Traumatic Brain Injury in Rats

Circular RNAs (circRNAs) are involved in a variety of diseases. However, the roles of circRNAs in traumatic brain injury (TBI) remain unknown. In this study, circRNA microarray was used to profile the altered circRNAs in the rat hippocampus following TBI. A total of 192 circRNAs were observed to be differentially expressed (fold change [FC] ≥1.5 and p < 0.05) after TBI, including 98 upregulated and 94 downregulated. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that many messenger RNAs (mRNAs) transcribed from the host genes of altered circRNAs were implicated in brain damage and neural regeneration. CircRNA/microRNA (miRNA) interaction was predicted using Arraystars homemade miRNA target prediction software based on TargetScan and miRanda. Thus, our studies have demonstrated altered circRNA expression pattern in the rat hippocampus after TBI, which may play important roles in post-TBI physiological and pathological processes. These findings may provide not only a new direction for studying the molecular mechanisms underlying TBI but also a new possibility for the treatment of TBI by modulating circRNAs.

The preventive effect of dexmedetomidine on paroxysmal sympathetic hyperactivity in severe traumatic brain injury patients who have undergone surgery: a retrospective study

Background Paroxysmal sympathetic hyperactivity (PSH) results and aggravates in secondary brain injury, which seriously affects the prognosis of severe traumatic brain injury patients. Although several studies have focused on the treatment of PSH, few have concentrated on its prevention. Methods Ninety post-operation (post-op) severe traumatic brain injury (sTBI) patients admitted from October 2014 to April 2016 were chosen to participate in this study. Fifty of the post-op sTBI patients were sedated with dexmedetomidine and were referred as the “dexmedetomidine group” (admitted from May 2015 to April 2016). The other 40 patients (admitted from October 2014 to May 2015) received other sedations and were referred as the “control group.” The two groups were then compared based on their PSH scores and the scores and ratios of those patients who met the criteria of “probable,” “possible” and “unlikely” using the PSH assessment measure (PSH-AM) designed by Baguley et al. (2014). The durations of the neurosurgery intensive care unit (NICU) and hospital stays and the Glasgow outcome scale (GOS) values for the two groups were also compared to evaluate the therapeutic effects and the patients’ prognosis. Results The overall PSH score for the dexmedetomidine group was 5.26 ± 4.66, compared with 8.58 ± 8.09 for the control group. The difference between the two groups’ PSH scores was significant (P = 0.017). The score of the patients who met the criterion of “probable” was 18.33 ± 1.53 in the dexmedetomidine group and 22.63 ± 2.97 in the control group, and the difference was statistically significant (P = 0.045). The ratio of patients who were classified as “unlikely” between the two groups was statistically significant (P = 0.028); that is, 42 (84%) in the dexmedetomidine group and 25 (62.5%) in the control group. The differences in NICU, hospital stays and GOS values between the two groups were not significant. Conclusion Dexmedetomidine has a preventive effect on PSH in sTBI patients who have undergone surgery.

Amplitude-Integrated Electroencephalography Predicts Outcome in Patients with Coma After Acute Brain Injury

AbstractPrognostication of coma patients after brain injury is important, yet challenging. In this study, we evaluated the predictive value of amplitude-integrated electroencephalography (aEEG) for neurological outcomes in coma patients. From January 2013 to January 2016, 128 coma patients after acute brain injury were prospectively enrolled and monitored with aEEG. The 6-month neurological outcome was evaluated using the Cerebral Performance Category Scale. aEEG monitoring commenced at a median of 7.5 days after coma onset. Continuous normal voltage predicted a good 6-month neurological outcome with a sensitivity of 93.6% and specificity of 85.2%. In contrast, continuous extremely low voltage, burst-suppression, or a flat tracing was correlated with poor 6-month neurological outcome with a sensitivity of 76.5% and specificity of 100%. In conclusion, aEEG is a promising predictor of 6-month neurological outcome for coma patients after acute brain injury.

Prevalence of persistent vegetative state in patients with severe traumatic brain injury and its trend during the past four decades: A meta-analysis

BACKGROUND Estimating the prevalence of persistent vegetative state (PVS) following severe traumatic brain injury (sTBI) and its change over time is important for the study of the disease. OBJECTIVE To estimate the prevalence of PVS at six months after sTBI and its trend over the past four decades, and to explore the effect of demographic data, such as age and sex, on the prevalence of PVS. METHOD Observational studies presenting the prevalence of PVS or the number of patients with PVS at six months after sTBI were included in the analysis. The overall prevalence and prevalence within pre-defined time intervals were calculated and meta-regression analysis was performed to assess the effect of age, gender, and time on the prevalence. RESULTS Twenty articles reporting 21 cohort studies were included. The overall prevalence of PVS at six months after injury was 2.77% (95% CI 0.0204-0.0375). There was no statistically significant trend towards time (P = 0.77). And we found no differences in prevalence according to age (P = 0.68) and gender (P = 0.57). CONCLUSIONS Prevalence of PVS at six months after sTBI has no significant change over the past four decades. Age and gender do not seem to have a significant effect on the prevalence.