Contusion Volume Research Articles

Early Head Computed Tomography Abnormalities Associated with Elevated Intracranial Pressure in Severe Traumatic Brain Injury.

Intracranial pressure (ICP) monitoring is recommended in severe traumatic brain injury (sTBI), yet invasive monitoring has risks, and many patients do not develop elevated ICP. Tools to identify patients at risk for ICP elevation are limited. We aimed to identify early radiologic biomarkers of ICP elevation. In this retrospective study, we analyzed a prospectively enrolled cohort of patients with a sTBI at an academic level 1 trauma center. Inclusion criteria were nonpenetrating TBI, age ≥16 years, Glasgow Coma Scale (GCS) score ≤8, and presence of an ICP monitor. Two independent reviewers manually evaluated 30 prespecified features on serial head computed tomography (CTs). Patient characteristics and radiologic features were correlated with elevated ICP. The primary outcome was clinically relevant ICP elevation, defined as ICP ≥ 20 mm Hg on at least 5 or more hourly recordings during postinjury days 0-7 with concurrent administration of an ICP-lowering treatment. Among 111 sTBI patients, the median GCS was 6 (interquartile range 3-8), and 45% had elevated ICP. Features associated with elevated ICP were younger age (every 10-year decrease, odds ratio [OR] 1.4), modified Fisher scale (mFS) score at 0-4 hours postinjury (every 1 point, OR 1.8), and combined volume of contusional hemorrhage and peri-hematoma edema (10 ml, OR 1.2) at 4-18 hours postinjury. Younger age, mFS score, and volume of contusion are associated with ICP elevation in patients with a sTBI. Imaging features may stratify patients by their risk of subsequent ICP elevation.

P.263 Outcome of treatment in clinical practice compared to a clinical trial in treatment-resistant depression: a matched adjusted indirect comparison

For patients with TBI, traditional methods such as clinical examination and imaging data are the primary references used for deciding whether to operate or not. Intracranial pressure (ICP) monitoring based on lateral ventricles or parenchymal pressure is a more direct reflection of ICP. However, the research on whether the outcome results of ICP monitoring are better than results based on clinical signs and imaging is sparse. Therefore, we compared treatment results for patients with TBI based on ICP monitoring and traditional methods.This retrospective study included patients with TBI admitted to our collaborative hospitals between January 1, 2012, and December 31, 2013. All patients enrolled were divided into a traditional methods group and ICP monitoring group. Follow-up treatment was determined by ICP monitoring value or traditional methods in the 2 groups. Propensity matching scores were used to ensure that baseline characteristics of patients in the 2 groups were consistent.A significant association was found between the initial ICP value and neurologic deterioration (odds ratio 1.24; P < 0.001), and nonlinear correlation achieved the best fit (R2 = 0.547). Both 6-month good recovery rate and favorable outcome rate were higher in the ICP monitoring group than the traditional methods group by propensity score analysis (P < 0.05).For patients with TBI with cerebral contusion volume >20 mL, both 6-month good recovery rate and favorable outcome rate were significantly higher in the ICP monitoring group than the traditional methods group.

CPCGI Reduces Gray and White Matter Injury by Upregulating Nrf2 Signaling and Suppressing Calpain Overactivation in a Rat Model of Controlled Cortical Impact.

BackgroundCompound porcine cerebroside and ganglioside injection (CPCGI), which involves injection of a neurotrophic drug, has been widely used to treat certain brain disorders in the clinic; however, the detailed mechanism is unknown. This study investigated whether CPCGI protects the brain from trauma by stimulating antioxidative nuclear factor erythroid-2-related factor 2 (Nrf2) signaling and suppressing calpain overactivation in a rat model of controlled cortical impact (CCI).Materials and MethodsThe rat model of CCI was used. Neurological deficits, contusion, and white matter damage were evaluated 3 days after CCI. Calpain activation, Nrf2 signaling and oxidative stress were determined 24 h after CCI.ResultsCPCGI dose-dependently reduced neurological deficits, attenuated axonal and myelin sheath injury, and decreased contusion volume 3 days post-CCI. Moreover, CPCGI reduced calpain activity, and enhanced the cytosolic levels of calpastatin, αII-spectrin, microtubule-associated protein 2 (MAP2), neurofilament heavy chain (NF-H) and myelin basic protein (MBP) in traumatic tissues 24 h post-CCI. Furthermore, CPCGI reduced the levels of nuclear Kelch-like ECH-associated protein 1 (Keap1) and thioredoxin interacting protein (TXNIP); increased the levels of cytosolic Nrf2 and thioredoxin 1 (Trx 1) and nuclear Nrf2; increased the cytosolic and nuclear Nrf2/Keap1 and Trx 1/TXNIP ratios; enhanced the levels of heme oxygenase 1 (HO-1), glutathione (GSH), superoxide dismutase activity, and total antioxidative capacity; and reduced the levels of malondialdehyde in TBI tissues.ConclusionThese data confirm the neuroprotective effect of CPCGI against gray and white matter damage due to CCI and suggest that activating Nrf2 signaling and alleviating oxidative stress-mediated calpain activation could be one mechanism by which CPCGI protects against brain trauma.

Pulmonary contusions in patients with rib fractures: The need to better classify a common injury

BackgroundPulmonary contusions are common injuries. Computed tomography reveals vast contused lung volume spectrum, yet pulmonary contusions are defined dichotomously (unilateral vs bilateral). We assessed whether there is stepwise increased risk of pulmonary complications among patients without, with unilateral, and with bilateral pulmonary contusion. MethodsWe identified adults admitted with rib fractures using the largest US inpatient database. After propensity-score-matching patients without vs with unilateral vs bilateral pulmonary contusions and adjusting for residual confounders, we compared risk for pneumonia, ventilator-associated pneumonia (VAP), respiratory failure, intubation, and mortality. ResultsAmong 148,140 encounters of adults with multiple rib fractures, 19% had concomitant pulmonary contusions. Matched patients with pulmonary contusions had increased risk of pneumonia 19% [95%CI:16–33%], respiratory failure 40% [95%CI: 31–50%], and intubation 46% [95%CI: 33–61%]. Delineation showed bilateral contusions, not unilateral contusions, attributed to increased risk of complications. ConclusionsThere is likely a correlation between contused lung volume and risk of pulmonary complications; dichotomously classifying pulmonary contusions is insufficient. Better understanding this correlation requires establishing the clinically significant contusion volume and a correspondingly refined classification system.

3,6'-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation.

Traumatic brain injury (TBI) causes mortality and disability worldwide. It can initiate acute cell death followed by secondary injury induced by microglial activation, oxidative stress, inflammation and autophagy in brain tissue, resulting in cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom) analog, 3,6'-dithioPom (DP), and Pom as immunomodulatory agents to mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral impairments in rats challenged with controlled cortical impact TBI. Both agents significantly reduced the injury contusion volume and degenerating neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with a therapeutic window of 5 hr post-injury. TBI-induced upregulated markers of microglial activation, astrogliosis and the expression of pro-inflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater efficacy. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and α-synuclein-induced toxicity.

HEMORRHAGIC PROGRESSION OF CONTUSION IN PATIENTS WITH MILD TRAUMATIC BRAIN INJURY ON THE ROUTINE REPEAT HEAD COMPUTED TOMOGRAPHY

Computed tomography (CT) scan is a standard for the diagnosis of intracranial pathology after traumatic brain injury (TBI). Hemorrhagic progression of contusion (HPC) is frequently seen on repeat CT, but its clinical and radiological significance in case of mild TBI is not well define. The aim of the study: to evaluate the result of routine repeat head CT in patients with mild TBI and brain contusions. Materials and methods: retrospective analysis of management of patients with mild TBI (Glasgow Coma Scale (GCS) score – 13 to 15) and cerebral contusion. All patients were treated at the Kyiv City Clinical Emergency Hospital between 2016 and 2017. Results: within 202 patients with mild TBI, 87 (43.1 %) met the inclusion criteria and were selected for detailed analysis. There were 69 (79.3 %) men and 18 (20.7 %) women. The mean age of the patients was 43.8±12.7 years (17–82 years). The average time between trauma and CT was 3.3 hours. The average volume of contusion on the initial CT was 1.9±0.6 cm3 (0.2–9.6 cm3). The average time of routine CT was 6.8 hours (range 4–24 hours) after the initial scans. HPC was found in 24 (30.7 %) of 87 cases. The average volume of brain contusion on the repeat CT was 2.3±0.5 cm3 (0.2-17.1 cm3). In 3 (3.4 %) patients the size of the hematoma increased. Clinical deterioration occurred in 10 (11.5 %) patients. Six (6.9 %) patients were operated after a CT scan due to HPC with midline shift in 4 cases and increasing of subdural hematoma – 2 cases. Four of these patients had clinical deterioration, and 2 patients were neurological stable. Patients with HPC at admission had lower points of GCS, fractures of the skull (both p &lt;0.001), subdural blood collection (p=0.002), a higher average duration of treatment 8.1±4.2 vs 14.3±5.2 days (p=0.0001), and mortality rate 0 vs. 3 (12.5 %) (p=0.02). Conclusions: Routine repeat CT in patients with mild TBI with brain contusions is aimed to find a patients with s high risk for clinical deterioration. One third of patients with mild TBI and brain contusion experienced HPC. Patients with HPC often have unfavorable clinical course with higher average duration of treatment, delay surgical treatment and mortality rate.

Comparison of two different doses of citicoline in patients with traumatic brain injury

Introduction: The ever-increasing and common occurrence of head traumas highlight the importance of adopting therapeutic measures for the reduction of the associated morbidity and mortality. Citicoline, as a safe medicine with positive effects on improving traumatic injuries, has been proven to be useful in various studies. However, there are still no data on the specific standard method and dosage of citicoline for the treatment of patients with traumatic head injuries. Regarding this, the present study was performed to determine the effective therapeutic dosage of citicoline and its impact on patients with traumatic head injuries. Methods: This double-blind clinical trial was performed on 30 patients with traumatic concussion (a Glasgow coma scale [GCS] of ≤8) admitted to the intensive care unit and neurosurgery department. The patients were randomly divided into three groups of A (control), B (citicoline with a dosage of 0.5 g/twice a day), and C (citicoline with a dosage of 1.5 g/twice a day). The GCS, degree of muscle strength, Glasgow outcome score (GOS), contusion volume, and cerebral edema (based on brain CT scans) were calculated at specific times and intervals. In addition, the patients' dependency on a ventilator and their length of ICU stay were registered. Results: Mean GCS on the first day of stay, GCS changes on the third and fourth days of stay, first and seventh days of stay, seventh and fourteenth days of stay, and first and fourteenth days of stay in the three study groups showed the significant statistical difference (P&lt;0.05). Significant statistical differences were seen between the GOS of the 30th day of stay in the three study groups (P&lt;0.05). The contusion volume difference was only significant between the first and seventh days of stay in groups A and C (P&lt;0.05). No significant difference was observed in the mean length of stay in ICU and duration of dependency on a ventilator in the three study groups (P&lt;0.05). The mean degree of muscle strength was only significantly different on the first day of stay between groups B and C (P=0.008). Conclusions: In contrary to similar studies, the results of the current study revealed that citicoline had no positive effect on patient healing. This result may be due to the small sample size and the inconsistent first-day GCSs of the patients in all three groups. Therefore, given the confirmation of the effectiveness of citicoline even at higher dosages in other studies in future studies, it is recommended to use populations with a larger number of patients.

Novel neuroprotection using antioxidant nanoparticles in a mouse model of head trauma.

Free radicals and reactive oxygen species are related to deteriorating pathological conditions after head trauma because of their secondary effects. 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO) scavenges free radicals; however, this molecule is also toxic. Here, we have evaluated the neuroprotective effect of antioxidant nanoparticles, which consisted of a novel core-shell type nanoparticle containing 4-amino-TEMPO, that is, redox-active nitroxide radical-containing nanoparticles (RNPs). Institute of Cancer Research mice were subjected to a head-impact procedure, randomly divided into four groups and intravenously (3 mg/kg) administered phosphate-buffered saline, TEMPO, micelle (a self-assembling block copolymer micelle without a TEMPO moiety), or RNP through the tail vein immediately thereafter and intraperitoneally at days 1, 3, and 5 after traumatic brain injury (TBI). The RNP distribution was detected by rhodamine labeling. Cognitive behavior was assessed using the neurological severity score and a rotarod test at days 1, 3, and 7 following TBI, and contusion volume was measured at day 7 after TBI. Free radical-scavenging capacity was analyzed by electron paramagnetic resonance on day 1 after TBI, and immunostaining was used to observe mobilization of microglia (Iba-1) and rescued neuronal cells (NeuN). Redox-active nitroxide radical-containing nanoparticle was detected in the microvessels around the injured area in the brain. Cognitive behavior assessment was significantly better, and contusion volume was significantly smaller in the RNP group compared with the other groups. Superoxide anion scavenging capacity was significantly higher in the RNP group, and neuronal loss was significantly suppressed around the injured area at day 7 after TBI. Furthermore, in the RNP group, neurodegenerative microglia production was suppressed at days 3 and 7 after TBI, whereas neuroprotective microglia production was higher at day 7 after TBI. The RNP administration after TBI improved cognitive behavior and reduced contusion volume by improving reactive oxygen species scavenging capacity. Therefore, RNP may have a neuroprotective effect after TBI. Therapeutic test.

Diffuse Intracranial Injury Patterns Are Associated with Impaired Cerebrovascular Reactivity in Adult Traumatic Brain Injury: A CENTER-TBI Validation Study.

Recent single-center retrospective analysis displayed the association between admission computed tomography (CT) markers of diffuse intracranial injury and worse cerebrovascular reactivity. The goal of this study was to further explore these associations using the prospective multi-center Collaborative European Neurotrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) high-resolution intensive care unit (HR ICU) data set. Using the CENTER-TBI HR ICU sub-study cohort, we evaluated those patients with both archived high-frequency digital physiology (100 Hz or higher) and the presence of a digital admission CT scan. Physiological signals were processed for pressure reactivity index (PRx) and both the percent (%) time above defined PRx thresholds and mean hourly dose above threshold. Admission CT injury scores were obtained from the database. Quantitative contusion, edema, intraventricular hemorrhage (IVH), and extra-axial lesion volumes were obtained via semi-automated segmentation. Comparison between admission CT characteristics and PRx metrics was conducted using Mann-U, Jonckheere-Terpstra testing, with a combination of univariate linear and logistic regression techniques. A total of 165 patients were included. Cisternal compression and high admission Rotterdam and Helsinki CT scores, and Marshall CT diffuse injury sub-scores were associated with increased percent (%) time and hourly dose above PRx threshold of 0, +0.25, and +0.35 (p < 0.02 for all). Logistic regression analysis displayed an association between deep peri-contusional edema and mean PRx above a threshold of +0.25. These results suggest that diffuse injury patterns, consistent with acceleration/deceleration forces, are associated with impaired cerebrovascular reactivity. Diffuse admission intracranial injury patterns appear to be consistently associated with impaired cerebrovascular reactivity, as measured through PRx. This is in keeping with the previous single-center retrospective literature on the topic. This study provides multi-center validation for those results, and provides preliminary data to support potential risk stratification for impaired cerebrovascular reactivity based on injury pattern.

Role of Intracellular Toll Like Receptors (TLRs) in the Secondary Events of Traumatic Brain Injury

The mechanisms underlying secondary brain damage following traumatic brain injury (TBI) is still unclear. Many studies demonstrated that inflammatory cascades contribute to brain damage through the activation of immune/inflammatory responses, including the increased release of cytokines and chemokines as well as the recruitment of leukocytes. The cells and tissues damaged by primary mechanical injury released a number of endogenous factors acting as damage‐associated molecular patterns (DAMPs), which initiate and perpetuate noninfectious inflammatory responses through transduction signaling pathways. Toll‐like receptors (TLRs) are a transmembrane receptor family that can recognize the specific DAMPs released from damaged cells and recruit a set of adaptors leading to the activation of downstream kinases and nuclear factors which regulate the expression of inflammatory genes. The activation of inflammatory responses mediated by TLR signaling is closely associated with brain tissue damage and neurological dysfunction following TBI. Since the role of intracellular TLRs such as 7, 8 and 9 after TBI is still unclear, we decided to evaluate the outcome and the secondary brain damage after TBI in TLR 7/8−/−and TLR 7/9−/−double KO mice. We performed a TBI, using a validate experimental model of controlled cortical impact injury (CCI), both TLR 7/8−/−and TLR 7/9−/−and in wild type (WT) mice. 24h thereafter we evaluated the contusion volume, the brain edema formation, the expression of pro‐inflammatory cytokines as well as the activation of immune response.Thus the obtained results demonstrated that modulation of intracellular TLR‐mediated signaling may attenuate brain damage and improve TBI outcome. Therefore, the intracellular TLRs and their downstream protein kinases may be potential targets for the treatment of TBI.

The Short-Term Effects of Isolated Traumatic Brain Injury on the Heart in Experimental Healthy Rats.

To date, cardiac dysfunction after traumatic brain injury (TBI) has not been consistent. In this study, we hypothesized that TBI may play a role in the development of new-onset cardiac dysfunction in healthy experimental rats. Anesthetized healthy male Sprague-Dawley rats were divided into two groups: a sham-operated control group and a TBI group. The brain was injured with 2.4atm percussion via a fluid percussion injury model. During the 120min after TBI, we continuously measured brain parameters, including intracranial pressure (ICP) and cerebral perfusion pressure (CPP), and cardiac parameters, such as heart rate (HR), inter-ventricular septum dimension (IVSD), left ventricular internal dimension diastole (LVIDd), end-diastolic volume (EDV), ejection fraction (EF), fractional shortening (FS), and LV mass diastole (LVd mass) by cardiac echo. On days 1, 3, 7, and 14 after TBI, the brain damage volume was evaluated with triphenyltetrazolium chloride; the physiological parameters of the heart, including HR, IVSd, LVIDd, EDV, EF, FS, and LVd mass, were evaluated with cardiac echo; the morphology of cardiomyocytes was examined by hematoxylin and eosin (HE) and Masson trichrome staining; and the biomarkers of cardiac injury troponin I and B-type natriuretic peptide (BNP) were also examined. Compared to sham-operated controls, the TBI groups had higher ICP, lower CPP, and higher brain neuronal apoptosis and infarction contusion volume. The impact of TBI on heart function showed hyperdynamic response trends in IVSd, LVIDd, EDV, EF, FS, and LVd mass within 30min after TBI; however, EF and FS exhibited eventual decreasing trends. Simultaneously, the values of the biomarkers troponin I and BNP were within normal limits, and HE and Mass trichrome staining revealed no significant differences between the sham-operated control group and the TBI group. Our results suggest that TBI due to 2.4atm fluid percussion injury in healthy experimental rats may cause significant damage to the brain and affect the heart function as investigated by cardiac echo but not as investigated by HE and Masson trichrome stainings or troponin I and BNP evaluation.

Influence of Organic Solvents on Secondary Brain Damage after Experimental Traumatic Brain Injury.

Many compounds tested for a possible neuroprotective effect after traumatic brain injury (TBI) are not readily soluble and therefore organic solvents need to be used as a vehicle. It is, however, unclear whether these organic solvents have intrinsic pharmacological effects on secondary brain damage and may therefore interfere with experimental results. Thus, the aim of the current study was to evaluate the effect of four widely used organic solvents, dimethylsulfoxide (DMSO), Miglyol 812 (Miglyol®), polyethyleneglycol 40 (PEG 40), and N-2-methyl-pyrrolidone (NMP) on outcome after TBI in mice. A total of 143 male C57Bl/6 mice were subjected to controlled cortical impact (CCI). Contusion volume, brain edema formation, and neurological function were assessed 24 h after TBI. Test substances or saline were injected intraperitoneally (i.p.) 10 min before CCI. DMSO, Miglyol, and PEG 40 had no effect on post-traumatic contusion volume after CCI; NMP, however, significantly reduced contusion volume and brain edema formation at different concentrations. The use of DMSO, Miglyol, and PEG 40 is unproblematic for studies investigating neuroprotective treatment strategies as they do not influence post-traumatic brain damage. NMP seems to have an intrinsic neuroprotective effect that should be considered when using this agent in pharmacological experiments; further, a putative therapeutic effect of NMP needs to be elucidated in future studies.

The Potassium SK Channel Activator NS309 Protects Against Experimental Traumatic Brain Injury Through Anti-Inflammatory and Immunomodulatory Mechanisms.

Neuroinflammation plays important roles in neuronal cell death and functional deficits after TBI. Small conductance Ca2+-activated K+ channels (SK) have been shown to be potential therapeutic targets for treatment of neurological disorders, such as stroke and Parkinson’s disease (PD). The aim of the present study was to investigate the role of SK channels in an animal model of TBI induced by controlled cortical impact (CCI). The SK channels activator NS309 at a concentration of 2 mg/kg was administered by intraperitoneal injection, and no obviously organ-related toxicity of NS309 was found in Sprague-Dawley (SD) rats. Treatment with NS309 significantly reduced brain edema after TBI, but had no effect on contusion volume. This protection can be observed even when the administration was delayed by 4 h after injury. NS309 attenuated the TBI-induced deficits in neurological function, which was accompanied by the reduced neuronal apoptosis. The results of immunohistochemistry showed that NS309 decreased the number of neutrophils, lymphocytes, and microglia cells, with no effect on astrocytes. In addition, NS309 markedly decreased the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and chemokines (MCP-1, MIP-2, and RANTES), but increased the levels of anti-inflammatory cytokines (IL-4, IL-10, and TGF-β1) after TBI. The results of RT-PCR and western blot showed that NS309 increased TSG-6 expression and inhibited NF-κB activation. Furthermore, knockdown of TSG-6 using in vivo transfection with TSG-6 specific shRNA partially reversed the protective and anti-inflammatory effects of NS309 against TBI. In summary, our results indicate that the SK channel activator NS309 could modulate inflammation-associated immune cells and cytokines via regulating the TSG-6/NF-κB pathway after TBI. The present study offers a new sight into the mechanisms responsible for SK channels activation with implications for the treatment of TBI.

The p53 inactivators pifithrin-μ and pifithrin-α mitigate TBI-induced neuronal damage through regulation of oxidative stress, neuroinflammation, autophagy and mitophagy

Traumatic brain injury (TBI) is one of the most common causes of death and disability worldwide. We investigated whether inhibition of p53 using pifithrin (PFT)-α or PFT-μ provides neuroprotective effects via p53 transcriptional dependent or -independent mechanisms, respectively. Sprague Dawley rats were subjected to controlled cortical impact TBI followed by the administration of PFTα or PFT-μ (2 mg/kg, i.v.) at 5 h after TBI. Brain contusion volume, as well as sensory and motor functions were evaluated at 24 h after TBI. TBI-induced impairments were mitigated by both PFT-α and PFT-μ. Fluoro-Jade C staining was used to label degenerating neurons within the TBI-induced cortical contusion region that, together with Annexin V positive neurons, were reduced by PFT-μ. Double immunofluorescence staining similarly demonstrated that PFT-μ significantly increased HO-1 positive neurons and mRNA expression in the cortical contusion region as well as decreased numbers of 4-hydroxynonenal (4HNE)-positive cells. Levels of mRNA encoding for p53, autophagy, mitophagy, anti-oxidant, anti-inflammatory related genes and proteins were measured by RT-qPCR and immunohistochemical staining, respectively. PFT-α, but not PFT-μ, significantly lowered p53 mRNA expression. Both PFT-α and PFT-μ lowered TBI-induced pro-inflammatory cytokines (IL-1β and IL-6) mRNA levels as well as TBI-induced autophagic marker localization (LC3 and p62). Finally, treatment with PFT-μ mitigated TBI-induced declines in mRNA levels of PINK-1 and SOD2. Our data suggest that both PFT-μ and PFT-α provide neuroprotective actions through regulation of oxidative stress, neuroinflammation, autophagy, and mitophagy mechanisms, and that PFT-μ, in particular, holds promise as a TBI treatment strategy.

Complement C3 participates in the function and mechanism of traumatic brain injury at simulated high altitude

BackgroundTraumatic brain injury (TBI) leads to severe mortality and disability, in which secondary injury induced by complement activation plays an important role. TBI tends to be associated with more severe cerebral edema and worse neurological functional recovery if it occurs in high-altitude areas than in low-altitude areas. However, the underlying mechanism of this difference is unknown. Thus, we used cobra venom factor (CVF) to deplete complement C3 in simulated high-altitude areas to explore whether the differences in outcome at different altitudes are related to secondary injury caused by complement C3. MethodsThe weight-drop model was adopted to induce TBI in rats. Rats were randomly divided into the following groups: sham + saline (sham), high altitude + TBI + saline (HAT), high altitude + TBI + CVF (H-CVF), low altitude + TBI + saline (LAT), and low altitude + TBI + CVF (L-CVF). Brain contusion and edema volumes, brain water content, myelin basic protein (MBP) expression, tumor necrosis factor alpha (TNF-a) expression, interleukin 1 beta (IL1B) expression, mortality rate, neurological function, and complement component 3 (C3) mRNA expression were measured by techniques such as Evans blue fluorescence, Perls staining, TUNEL staining, ELISA, immunohistochemistry and Western blotting to evaluate correlations between complement activation and secondary injury. ResultsThe activation of complement after TBI was significantly higher at high altitude than at low altitude. High-altitude TBI resulted in a leakier blood-brain barrier, more severe cerebral edema and higher mortality than low-altitude TBI did. In addition, high-altitude TBI tended to be associated with more MBP degradation, ferric iron deposition, neuronal apoptosis, and inflammatory factor deposition than low-altitude TBI. All of these effects of TBI were partially reversed by inhibiting complement activation using CVF. ConclusionOur study provided evidence that TBI at high altitude leads to severe edema and high mortality and disability rates. Complement C3 activation is one of the important factors contributing to secondary brain injury.

Acute Kahweol Treatment Attenuates Traumatic Brain Injury Neuroinflammation and Functional Deficits.

Traumatic brain injury (TBI) affects millions worldwide with devastating long-term effects on health and cognition. Emerging data suggest that targeting the immune response may offer promising strategies to alleviate TBI outcomes; kahweol, an anti-inflammatory diterpene that remains in unfiltered coffee, has been shown to be beneficial in neuronal recovery. Here, we examined whether kahweol could alleviate brain trauma-induced injury in a mouse model of TBI and its underlying mechanisms. TBI was induced by controlled cortical impact (CCI) and various doses of kahweol were intraperitoneally administered following injury. Contusion volume, brain edema, neurobehavioral deficits, and protein expression and activity were evaluated in both short-term and long-term recovery. We found that kahweol treatments significantly reduced secondary brain injury and improved neurobehavioral outcomes in TBI mice. These changes were accompanied by the attenuation of proinflammatory cytokine secretion, decreased microglia/macrophage activation, and reduction of neutrophil and leukocyte infiltration. In addition, continuous kahweol treatment further improved short-term TBI outcomes compared to single-dosage. Collectively, our data showed that kahweol protects against TBI by reducing immune responses and may serve as a potential therapeutic intervention for TBI patients.

First Intracranial Pressure Monitoring or First Operation: Which One Is Better?

For patients with TBI, traditional methods such as clinical examination and imaging data are the primary references used for deciding whether to operate or not. Intracranial pressure (ICP) monitoring based on lateral ventricles or parenchymal pressure is a more direct reflection of ICP. However, the research on whether the outcome results of ICP monitoring are better than results based on clinical signs and imaging is sparse. Therefore, we compared treatment results for patients with TBI based on ICP monitoring and traditional methods. This retrospective study included patients with TBI admitted to our collaborative hospitals between January 1, 2012, and December 31, 2013. All patients enrolled were divided into a traditional methods group and ICP monitoring group. Follow-up treatment was determined by ICP monitoring value or traditional methods in the 2 groups. Propensity matching scores were used to ensure that baseline characteristics of patients in the 2 groups were consistent. A significant association was found between the initial ICP value and neurologic deterioration (odds ratio 1.24; P < 0.001), and nonlinear correlation achieved the best fit (R2= 0.547). Both 6-month good recovery rate and favorable outcome rate were higher in the ICP monitoring group than the traditional methods group by propensity score analysis (P < 0.05). For patients with TBI with cerebral contusion volume >20 mL, both 6-month good recovery rateand favorable outcome rate were significantly higher in the ICP monitoring group than the traditional methods group.

PDIA3-regulted inflammation and oxidative stress contribute to the traumatic brain injury (TBI) in mice

Traumatic brain injury (TBI) is a leading cause of death and disability throughout the world. However, the molecular mechanism contributing to TBI still remains unclear. Protein disulfide isomerases (PDI) are a family of redox chaperones, which catalyze formation or isomerization of disulfide bonds in proteins. PDIA3, a critical member of PDI family, is a multi-functional protein, playing critical roles in modulating inflammation, apoptosis and oxidative stress under various kinds of disease conditions. Nevertheless, its regulatory effects on TBI have far from to be known. In the present study, we attempted to explore the modulation of neuroinflammatory responses by PDIA3 and its contribution to oxidative stress and cell death after TBI in the wild type (PDIA+/+) and PDIA3 knockout (PDIA3+/+) C57BL/6 mice. Results here suggested that PDIA3 expression was markedly up-regulated in the late trauma human brain tissues, which was verified in the PDIA3+/+ mice at 24 h after TBI. PDIA−/- provided significant improvements in cognitive impairments and contusion volume induced by TBI. Apoptosis in brain samples was also alleviated in TBI mice with PDIA3 deficiency. Significantly, PDIA3−/− mitigated neuroinflammation after TBI in mice, as evidenced by the reduced expression of pro-inflammatory factors interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and IL-1β, while the enhanced anti-inflammatory regulator IL-10. These anti-inflammatory activities by PDIA3−/− were associated with the decrease in phosphorylated nuclear factor kappa B (NF-κB)/p65. PDIA3−/− mice following TBI showed attenuated oxidative stress, as proved by the restored superoxide dismutase (SOD) and glutathione (GSH) activities, and the down-regulated malondialdehyde (MDA) levels in brain samples. These effects regulated by PDIA3 were confirmed in OGDR-treated astrocytes. Collectively, these data demonstrated a detrimental role of PDIA3 in regulating TBI, providing an effective therapeutic target for TBI treatment in future.

(-)-Phenserine Ameliorates Contusion Volume, Neuroinflammation, and Behavioral Impairments Induced by Traumatic Brain Injury in Mice

Traumatic brain injury (TBI), a major cause of mortality and morbidity, affects 10 million people worldwide, with limited treatment options. We have previously shown that (-)-phenserine (Phen), an acetylcholinesterase inhibitor originally designed and tested in clinical phase III trials for Alzheimer’s disease, can reduce neurodegeneration after TBI and reduce cognitive impairments induced by mild TBI. In this study, we used a mouse model of moderate to severe TBI by controlled cortical impact to assess the effects of Phen on post-trauma histochemical and behavioral changes. Animals were treated with Phen (2.5 mg/kg, IP, BID) for 5 days started on the day of injury and the effects were evaluated by behavioral and histological examinations at 1 and 2 weeks after injury. Phen significantly attenuated TBI-induced contusion volume, enlargement of the lateral ventricle, and behavioral impairments in motor asymmetry, sensorimotor functions, motor coordination, and balance functions. The morphology of microglia was shifted to an active from a resting form after TBI, and Phen dramatically reduced the ratio of activated to resting microglia, suggesting that Phen also mitigates neuroinflammation after TBI. While Phen has potent anti-acetylcholinesterase activity, its (+) isomer Posiphen shares many neuroprotective properties but is almost completely devoid of anti-acetylcholinesterase activity. We evaluated Posiphen at a similar dose to Phen and found similar mitigation in lateral ventricular size increase, motor asymmetry, motor coordination, and balance function, suggesting the improvement of these histological and behavioral tests by Phen treatment occur via pathways other than anti-acetylcholinesterase inhibition. However, the reduction of lesion size and improvement of sensorimotor function by Posiphen were much smaller than with equivalent doses of Phen. Taken together, these results show that post-injury treatment with Phen over 5 days significantly ameliorates severity of TBI. These data suggest a potential development of this compound for clinical use in TBI therapy.

Elevated expression of miR-302 cluster improves traumatic brain injury by inhibiting phosphorylation of connexin43 via ERK signaling

We have previously found that connexin43 is phosphorylated by extracellular-signal-regulated kinase (ERK)1/2 in rats of cerebral ischemia. Here, we investigated the potential roles of microRNA (miR)-302 cluster in the regulation of ERK1/2 mediated connexin43 phosphorylation and protection from traumatic brain injury (TBI) induced brain damage. We examined apoptosis and ERK1/2 and connexin43 phosphorylation in SH-SY5Y cells undergoing pulsatile shear stress treatment. We assessed expression of miR-302 cluster members and exogenously expressed miR-302 cluster in stressed cells to determine its effect on ERK1/2 and connexin43 phosphorylation. Finally, we investigated the effects of elevated miR-302 expression on cognitive function and brain damage in TBI rats generated by the controlled cortical impact method. Pulsatile shear stress leads to increased apoptosis and upregulation of ERK1/2 and connexin43 phosphorylation in vitro. Additionally, pulsatile shear stress significantly suppressed miR-302 expression and exogenously expression of miR-302 cluster inhibited ERK1/2 and connexin43 phosphorylation. Finally, elevated expression of miR-302 cluster not only improved cognitive function of TBI rats but also attenuated brain damage by suppressing edema and reducing contusion volume. Our study suggests that miR-302 protects rats from TBI induced brain damage and cognitive impairment and may represent an effective therapeutic strategy for TBI.