Wen-Wei Gao

Predicting outcomes after traumatic brain injury: The development and validation of prognostic models based on admission characteristics

BACKGROUND Early estimation of prognosis for the patient with traumatic brain injury is an important factor in making treatment decisions, resource allocation, classify patients, or communicating with family. We aimed to develop and validate practical prognostic models for mortality at 30 days and for 6 months unfavorable outcome after moderate and severe traumatic brain injury. METHODS Retrospectively collected data from our department were used to develop prognostic models for outcome. We developed four prognostic models based on admission predictors with logistic regression analysis. The performance of models was assessed with respect to discrimination and calibration. Discriminative ability was evaluated with C statistic, equal to the area under the receiver operating characteristic curve. Calibrative ability was assessed with the Hosmer-Lemeshow test (H-L test). The internal validity of models was evaluated with the bootstrap re-sampling technique. We validated three of the models in an external series of 203 patients that collected from another research center. Discrimination and calibration were further assessed to indicate the performance of the models in external patients. RESULTS Logistic regression showed that age, pupillary reactivity, motor Glasgow Coma Score, computed tomography characters, glucose, hemoglobin, D-dimer, serum calcium, and intracranial pressure were independent prognostic factors of outcome. The models discriminated well in the development patients (C statistic 0.709–0.939). We extensively validate three of the models. Internal validation showed no overoptimism in any of the models’ predictive C statistics. External validity was much better (C statistic 0.844–0.902). Calibration was also good (H-L tests, p > 0.05). Computer-based calculator that based on prognostic models was developed for clinical use. CONCLUSION Our validated prognostic models have good performance and are generalizable to be used to predict outcome of new patients. We recommend the use of prognostic models to complement clinical decision making. (J Trauma Acute Care Surg. 2012;73: 137–145. Copyright

Clinical characterization of comatose patients with cervical spine injury and traumatic brain injury.

BACKGROUND Reports on the risk factors for combined craniocervical spine injury in comatose patients are rare. The incidence of concomitant cervical injury in comatose patients with traumatic brain injury (TBI) was determined herein. METHODS One thousand twenty-six comatose patients with TBI were examined. The clinical characteristics of combined craniocervical trauma were documented, including type and location of cervical injury, occurrence of hypotension, and dyspnea. RESULTS Seventy-one patients (6.92%) sustained cervical spine injury. The most common injury region included the upper cervical segments, demonstrated in 37 (52.11%) of 71 patients. Of the 71 patients who sustained combined craniocervical spine injury, 42 (59.15%) had hypotension, including 26 (36.62%) with dyspnea. With regard to the association between the severity of TBI and the incidence of the cervical injury, a significant difference was apparent between patients with an initial Glasgow Coma Scale (GCS) score of 3-5 and those with an initial GCS score of 9-12 (11.62% compared with 4.03%, p < 0.01). Regarding the relationship between the mechanism of injury and the occurrence of cervical spine injury, cervical spine injury was associated at a significantly higher incidence with motorcycle accident-related head trauma as compared with non motorcycle accident-related trauma (10.32% vs. 4.68%, p < 0.01). CONCLUSION Patients who sustained TBI as a result of motorcycle accidents and those exhibiting a lower GCS score are at the highest risk for concomitant cervical spine injury.

Predicting Progressive Hemorrhagic Injury after Traumatic Brain Injury: Derivation and Validation of a Risk Score Based on Admission Characteristics

Previous studies have demonstrated that patients with traumatic brain injury (TBI) who also have progressive hemorrhagic injury (PHI), have a higher risk of clinical deterioration and worse outcomes than do TBI patients without PHI. Therefore, the early prediction of PHI occurrence is useful to evaluate the status of patients with TBI and to improve outcomes. The objective of this study was to develop and validate a prognostic model that uses information available at admission to determine the likelihood of PHI after TBI. Retrospectively collected data were used to develop a PHI prognostic model with a logistic regression analysis. The prediction model was validated in 114 patients from a separate hospital. Eight independent prognostic factors were identified: age ≥ 57 years (5 points), intra-axial bleeding/brain contusion (4 points), midline shift ≥ 5 mm (6 points), platelet (PLT) count<100×10⁹/L (10 points), PLT count ≥ 100 but <150×10⁹/L (4 points), prothrombin time>14 sec (7 points), D-dimer ≥ 5 mg/L (12 points), and glucose ≥ 10 mmol/L (10 points). Each patient was assigned a number of points proportional to the regression coefficient. We calculated risk scores for each patient and defined three risk groups: low risk (0-13 points), intermediate risk (14-22 points), and high risk (23-54 points). In the development cohort, the PHI rates after TBI for these three groups were 10.3%, 47.3%, and 85.2%, respectively. In the validation cohort, the corresponding PHI rates were 10.9%, 47.3%, and 86.9%. The C-statistic for the point system was 0.864 (p=0.509 by the Hosmer-Lemeshow test) in the development cohort, and 0.862 (p=0.589 by the Hosmer-Lemeshow test) in the validation cohort. In conclusion, a relatively simple risk score using admission predictors accurately predicted the risk for PHI after TBI.

A Comparison between Endoscopic Transsphenoidal Surgery and Traditional Trans-Sphenoidal Microsurgery for Functioning Pituitary Adenomas

This retrospective study reviewed and compared the efficacy and safety outcomes following trans-sphenoidal endoscopy or microsurgery approaches in patients with functioning pituitary adenomas: 68 patients underwent endoscopic transsphenoidal resections and 59 patients had microsurgical resections. Tumours were classified according to diameter and clinical outcomes were evaluated. Overall disease control rates were 70.6% following endoscopy and 49.2% following microsurgery. The most obvious between-group difference was observed in macroadenomas: disease control rates were 63.9% following endoscopy and 27.3% following microsurgery. Cerebrospinal fluid leaks, diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion were observed postoperatively in both groups. The complication rate was lower following endoscopy compared with microsurgery (this difference was not statistically significant). Trans-sphenoidal endoscopy resection achieved good results in pituitary tumours, particularly for the complete removal of macroadenomas, and was an effective alternative to microsurgery.

Proteomic Analysis of the Cerebrospinal Fluid of Parkinson's Disease Patients Pre- and Post-Deep Brain Stimulation

Aims: To investigate alterations in protein expression associated with deep brain stimulation (DBS) in an attempt to elucidate possible mechanisms of action. Methods: Cerebrospinal fluid (CSF), obtained from six Parkinsons disease (PD) patients (pre- and post-DBS) and from six normal healthy controls, was studied for differentially expressed proteins. 2-D DIGE, in combination with MALDI-TOF and TOF-TOF Mass Spectrometry (MS) or ESI-MS, was used to identify the changed proteins (3 PD patients and 3 controls). Selected proteins were further studied using western blotting (6 PD patients and 6 controls). Results: Twenty-one proteins were identified after MS and protein database interrogation. Apart from apolipoprotein A-I (apoA-I), the expression levels of complement C4 (C4), IgA, tetranectin, and extracellular superoxide dismutase (EC-SOD), detected by western blotting, correlated well with the 2-D DIGE results. In the follow-up period, the expression levels of C4, apoA-I and IgA were stable whereas EC-SOD and tetranectin were significantly elevated. In addition, when DBS was ceased in one patient due to a suicide attempt, the levels of EC-SOD and tetranectin significantly decreased. Conclusion: Our preliminary results suggest that variations in the expression levels of EC-SOD and tetranectin in CSF is related to DBS.

Tetranectin knockout mice develop features of Parkinson disease.

Background/Aims: Aggregation of insoluble α-synuclein to form Lewy bodies (LBs) may contribute to the selective loss of midbrain dopaminergic neurons in Parkinson disease (PD). Lack of robust animal models has impeded elucidation of the molecular mechanisms of LB formation and other critical aspects of PD pathogenesis. Methods: We established a mouse model with targeted deletion of the plasminogen-binding protein tetranectin (TN) gene (TN-/-) and measured the behavioral and histopathological features of PD. Results: Aged (15-to 20-month-old) TN-/- mice displayed motor deficits resembling PD symptoms, including limb rigidity and both slower ambulation (bradykinesia) and reduced rearing activity in the open field. In addition, these mice exhibited more numerous α-synuclein-positive LB-like inclusions within the substantia nigra pars compacta (SNc) and reduced numbers of SNc dopaminergic neurons than age-matched wild type (WT) mice. These pathological changes were also accompanied by loss of dopamine terminals in the dorsal striatum. Conclusion: The TN-/- mouse exhibits several key features of PD and so may be a valuable model for studying LB formation and testing candidate neuroprotective therapies for PD and other synucleinopathies.

Endostatin/Collagen XVIII Is Increased in Cerebrospinal Fluid after Severe Traumatic Brain Injury

Recent studies have suggested that endogenous angiogenesis inhibitor endostatin/collagen XVIII might play an important role in the secondary brain injury following traumatic brain injury (TBI). In this study, we measured endostatin/collagen XVIII concentrations serially for 1 week after hospitalization by using the enzyme-linked immunosorbent assay method in the cerebrospinal fluid (CSF) of 30 patients with TBI and a Glasgow Coma Scale (GCS) score of 8 or less on admission. There was a significant trend toward increased CSF levels of endostatin after TBI versus control from 72 h after injury. In patients with GCS score of 3–5, CSF endostatin concentration was substantially higher at 72 h after injury than that in patients with GCS score of 6–8 (P < 0.05) and peaked rapidly at day 5 after injury, but decreased thereafter. The CSF endostatin concentration in 12 patients with an unfavorable outcome was significantly higher than that in 18 patients with a favorable outcome at day 5 (P = 0.043) and day 7 (P = 0.005) after trauma. Receiver operating characteristic curve analysis suggested a reliable operating point for the 7-day CSF endostatin concentration predicting poor prognosis to be 67.29 pg/mL. Our preliminary findings provide new evidence that endostatin/collagen XVIII concentration in the CSF increases substantially in patients with sTBI. Its dynamic change may have some clinical significance on the judgment of brain injury severity and the assessment of prognosis. This trial is registered with the ClinicalTrials.gov Identifier: NCT01846546.

Induction of apoptosis in glioma cells and upregulation of Fas expression using the human interferon-β gene.

We investigated whether IFN-β inhibits the growth of human malignant glioma and induces glioma cell apoptosis using the human IFN-β gene transfected into glioma cells. A eukaryonic expression vector (pSV2IFNβ) for IFN-β was transfected into the glioma cell line SHG44 using liposome transfection. Stable transfection and IFN-β expression were confirmed using an enzyme-linked immunosorbent assay (ELISA). Cell apoptosis was also assessed by Hoechst staining and electron microscopy. In vivo experiments were used to establish a SHG44 glioma model in nude mice. Liposomes containing the human IFN-β gene were injected into the SHG44 glioma of nude mice to observe glioma growth and calculate tumor size. Fas expression was evaluated using immunohistochemistry. The IFN-β gene was successfully transfected and expressed in the SHG44 glioma cells in vitro. A significant difference in the number of apoptotic cells was observed between transfected and non- transfected cells. Glioma growth in nude mice was inhibited in vivo, with significant induction of apoptosis. Fas expression was also elevated. The IFN-β gene induces apoptosis in glioma cells, possibly through upregulation of Fas. The IFN-β gene modulation in the Fas pathway and apoptosis in glioma cells may be important for the treatment of gliomas.

Neuroglobin and Nogo-a as biomarkers for the severity and prognosis of traumatic brain injury

Abstract Objective: To identify the early changes of serum neuroglobin and Nogo-A concentrations and the relations to traumatic brain injury (TBI) severity and prognosis. Methods: Serum samples were obtained and analyzed from 34 patients with TBI within the first 96 h after injury. Comparative analysis combined with Glasgow Coma Scale (GCS) scores and the 6-month prognosis of these patients was performed. Results: Significant correlations were found between peak serum neuroglobin and Nogo-A concentrations and a patient’s GCS score on admission (p < 0.001). The mean peak serum neuroglobin and Nogo-A concentrations were both significantly higher in patients with an unfavorable outcome at 6 months after injury (p < 0.05). Conclusions: Serum neuroglobin and Nogo-A levels could be suggested as biomarkers for predicting TBI severity and prognosis. Trial registration: ClinicalTrials.gov identifier: NCT02229643.

Effect of Electro-Acupuncture on Neuroplasticity of Spinal Cord-Transected Rats

Background This study aimed to evaluate the effects of electro-acupuncture (EA) on neuroplasticity associated with the expressions of neurotrophic factors (NTFs) and their receptors in rats subjected to spinal cord transection (SCT). Material/Methods A total of 144 rats were randomly divided into 3 groups (n=48 per group): sham-operated group, SCT group, and EA (electro-acupuncture) group. Rats in SCT and EA groups received spinal cord transection at T10–T11 vertebral levels. Then, EA group rats received EA treatment. Reverse transcription polymerase chain reaction was used to detect NTFs and receptors at the mRNA level. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to detect the expression of NTFs and their receptors. Basso, Beattie, Bresnahan (BBB) scores and cortical somato-sensory evoked potentials (CSEP) were evaluated to assess the recovery of motor and sensory functions. We also measured BDA (Biotinylated dextran amine) axonal tracing, CGRP (Calcitonin gene-related peptide), GAP-43 (Growth-associated protein), and synaptophysin immunohistochemistry (IHC). Results EA treatment led to obvious improvement in hindlimb locomotor and sensory functions. CNTF, FGF-2, and TrkB mRNA were significantly upregulated, while NGF, PDGF, TGF-β1, IGF-1, TrkA, and TrkC mRNA were concomitantly downregulated in the caudal spinal segment (CSS) following EA. Immunohistochemistry demonstrated an increased number of CGRP fibers, GAP-43, and synaptophysin profiles in the CSS in the EA rats. Conclusions EA may promote the recovery of neuroplasticity in rats subjected to SCT. This could be attributed to the systematic regulation of NTFs and their receptors after EA.