Structure-based design and confirmation of peptide ligands for neuronal polo-like kinase to promote neuroregeneration.

Neuronal polo-like kinase (nPLK) is an essential regular of cell cycle and differentiation in nervous system, and targeting nPLK has been established as a promising therapeutic strategy to treat neurological disorders and to promote neuroregeneration. The protein contains an N-terminal kinase domain (KD) and a C-terminal Polo-box domain (PBD) that are mutually inhibited by each other. Here, the intramolecular KD-PBD complex in nPLK was investigated at structural level via bioinformatics analysis, molecular dynamics (MD) simulation and binding affinity scoring. From the complex interface two regions representing separately two continuous peptide fragments in PBD domain were identified as the hot spots of KD-PBD interaction. Structural and energetic analysis suggested that one (PBD peptide 1) of the two peptides can bind tightly to a pocket nearby the active site of KD domain, which is thus potential as self-inhibitory peptide to target and suppress nPLK kinase activity. The knowledge harvesting from computational studies were then used to guide the structural optimization and mutation of PBD peptide 1. Consequently, two of three peptide mutants separately exhibited moderately and considerably increased affinity as compared to the native peptide. The computationally modeled complex structures of KD domain with these self-inhibitory peptides were also examined in detail to unravel the structural basis and energetic property of nPLK-peptide recognition and interaction.

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

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.

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.

The influence of hemocoagulation disorders on the development of posttraumatic cerebral infarction and outcome in patients with moderate or severe head trauma.

Posttraumatic cerebral infarction (PTCI) is a severe secondary insult of head injury and often leads to a poor prognosis. Hemocoagulation disorder is recognized to have important effects on hemorrhagic or ischemic damages. We sought to assess if posttraumatic hemocoagulation disorders were associated with cerebral infarction, and evaluate their influence on outcome among patients with moderate or severe head trauma. In this study, PTCI was observed in 28 (10.57%) of the 265 patients within the first week after injury. In multivariate analysis, the thrombocytopenia (odds ratio (OR) 2.210, 95% confidence interval (CI) 1.065-4.674), abnormal prothrombin time (PT) (OR 3.241, 95% CI 1.090-7.648), D-dimer (>2 mg/L) (OR 7.260, 95% CI 1.822-28.076), or disseminated intravascular coagulation (DIC) scores (≥ 5) (OR 4.717, 95% CI 1.778-12.517) were each independently associated with an increased risk of PTCI. Admission Glasgow Coma Scale (GCS) score, abnormal activated partial thromboplastin time (APTT) and fibrinogen, and D-dimer (>2 mg/L) and DIC scores (≥ 5) showed an independent predictive effect on poor outcome. In conclusion, recognition of this important treatable cause of PTCI and the associated risk factors may help identify the group at risk and tailor management of patients with TBI.

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

We investigated whether IFN-ß inhibits the growth of human malignant glioma and induces glioma cell apoptosis using the human IFN-ß gene transfected into glioma cells. A eukaryonic expression vector (pSV2IFNß) for IFN-ß was transfected into the glioma cell line SHG44 using liposome transfection. Stable transfection and IFN-ß 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-ß 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-ß 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-ß gene induces apoptosis in glioma cells, possibly through upregulation of Fas. The IFN-ß gene modulation in the Fas pathway and apoptosis in glioma cells may be important for the treatment of gliomas.

A prospective clinical study of routine repeat computed tomography (CT) after traumatic brain injury (TBI).

PURPOSE: To discuss the repeated CT scanning in patients with traumatic brain injury (TBI) and to identify the conditions under which this approach is necessary. METHODS: One hundred and seventy-one patients who suffered TBI but were not surgically treated were divided into two groups: the routine-repeat CT group (n = 89) and the non-routine-repeat CT group (n = 82). The patients' clinical characteristics were compared. T-tests and stepwise logistic regression were used for analysis. Patients in the routine-repeat CT group were divided into three groups according to GCS scores to determine the need for routinely repeated CT scans. RESULTS: The results revealed statistically significant differences between the two groups in terms of neuro-ICU-LOS and LOS (p < 0.01). No significant differences emerged with respect to hospital charges and GCS scores at discharge (p > 0.05). AGE, international normalized ratio (INR), D-dimer concentration (DD), GCS scores and number of hours between the first CT scan and the injury (HCT1) were influential factors of developing progressive haemorrhage. CONCLUSION: The routine-repeat CT group fared better than did the non-routine-repeat CT group. Routinely repeated CTs were minimally effective among those with mild TBI, whereas this procedure demonstrated a significant effect on patients with moderate and severe TBI.

Progressive epidural hematoma in patients with head trauma: incidence, outcome, and risk factors.

Progressive epidural hematoma (PEDH) after head injury is often observed on serial computerized tomography (CT) scans. Recent advances in imaging modalities and treatment might affect its incidence and outcome. In this study, PEDH was observed in 9.2% of 412 head trauma patients in whom two CT scans were obtained within 24 hours of injury, and in a majority of cases, it developed within 3 days after injury. In multivariate logistic regression, patient gender, age, Glasgow Coma Scale (GCS) score at admission, and skull fracture were not associated with PEDH, whereas hypotension (odds ratio (OR) 0.38, 95% confidence interval (CI) 0.17-0.84), time interval of the first CT scanning (OR 0.42, 95% CI 0.19-0.83), coagulopathy (OR 0.36, 95% CI 0.15-0.85), or decompressive craniectomy (DC) (OR 0.46, 95% CI 0.21-0.97) was independently associated with an increased risk of PEDH. The 3-month postinjury outcome was similar in patients with PEDH and patients without PEDH (χ(2) = 0.07, P = 0.86). In conclusion, epidural hematoma has a greater tendency to progress early after injury, often in dramatic and rapid fashion. Recognition of this important treatable cause of secondary brain injury and the associated risk factors may help identify the group at risk and tailor management of patients with TBI.

D-dimer as a predictor of progressive hemorrhagic injury in patients with traumatic brain injury: analysis of 194 cases.

This study sought to describe and evaluate any relationship between D-dimer values and progressive hemorrhagic injury (PHI) after traumatic brain injury (TBI). In patients with TBI, plasma D-dimer was measured while a computed tomography (CT) scan was conducted as soon as the patient was admitted to the emergency department. A series of other clinical and laboratory parameters were also measured and recorded. A logistic multiple regression analysis was used to identify risk factors for PHI. A cohort of 194 patients with TBI was evaluated in this clinical study. Eighty-one (41.8%) patients suffered PHI as determined by a second CT scan. The plasma D-dimer level was higher in patients who demonstrated PHI compared with those who did not (P < 0.001. Using a receiver-operator characteristic curve to predict the possibility by measuring the D-dimer level, a value of 5.00 mg/L was considered the cutoff point, with a sensitivity of 72.8% and a specificity of 78.8%. Eight-four patients had D-dimer levels higher than the cut point value (5.0 mg/L); PHI was seen in 71.4% of these patients and in 19.1% of the other patients (P < 0.01). Factors with P < 0.2 on bivariate analysis were included in a stepwise logistic regression analysis to identify independent risk factors for TBI coagulopathy. Logistic regression analysis showed that the D-dimer value was a predictor of PHI, and the odds ratio (OR) was 1.341 with per milligram per liter (P = 0.020). The stepwise logistic regression also identified that time from injury to the first CT shorter than 2 h (OR = 2.118, P = 0.047), PLT counts lesser than 100 x 109/L (OR = 7.853, P = 0.018), and Fg lower than 2.0 g/L (OR = 3.001, P = 0.012) were risk factors for the development of PHI. When D-dimer values were dichotomized at 5 mg/L, time from injury to the first CT scan was no longer a risk factor statistically while the OR value of D-dimer to the occurrence of PHI elevated to 11.850(P < 0.001). The level of plasma D-dimer after TBI can be a useful prognostic factor for PHI and should be considered in the clinical management of patients in combination with neuroimaging and other data.

Risk factors for posttraumatic cerebral infarction in patients with moderate or severe head trauma.

We examined the incidence and timing of posttraumatic cerebral infarction (PTCI) and provide predictive factors for the development of PTCI in patients with moderate or severe traumatic brain injury. Three hundred and fifty-three consecutive patients with moderate or severe head trauma were retrospectively reviewed to determine the incidence and timing of PTCI and to evaluate the effects of age, gender, admission Glasgow Coma Scores (GCS), decompressive craniectomy, brain herniation, and low systolic blood pressure (BP) on the development of cerebral infarction. Risk factors for posttraumatic cerebral infarction were evaluated using logistic regression analysis. PTCI was observed in 36 (11.96%) of the 353 patients, and in a majority of cases, cerebral infarction developed within 2 weeks after injury. Poor admission GCS (P<0.01), low systolic BP (P<0.01), brain herniation (P<0.05), and decompression craniotomy (P<0.05) were significantly associated with the development of PTCI. No relationship was found between PTCI and gender or increased age. Posttraumatic cerebral infarction is a relatively common complication in patients with head trauma that develops early in the clinical course. Low GCS, low systolic BP, brain herniation, and decompression craniotomy may be risk factors for PTCI in patients with moderate or severe traumatic brain injury.