Extracellular cold-inducible RNA-binding protein mediated neuroinflammation and neuronal apoptosis after traumatic brain injury.

Background: Extracellular cold-inducible RNA-binding protein (eCIRP) plays a vital role in the inflammatory response during cerebral ischaemia. However, the potential role and regulatory mechanism of eCIRP in traumatic brain injury (TBI) remain unclear. Here, we explored the effect of eCIRP on the development of TBI using a neural-specific CIRP knockout (KO) mouse model to determine the contribution of eCIRP to TBI-induced neuronal injury and to discover novel therapeutic targets for TBI. Methods: TBI animal models were generated in mice using the fluid percussion injury method. Microglia or neuron lines were subjected to different drug interventions. Histological and functional changes were observed by immunofluorescence and neurobehavioural testing. Apoptosis was examined by a TdT-mediated dUTP nick end labelling assay in vivo or by an annexin-V assay in vitro. Ultrastructural alterations in the cells were examined via electron microscopy. Tissue acetylation alterations were identified by non-labelled quantitative acetylation via proteomics. Protein or mRNA expression in cells and tissues was determined by western blot analysis or real-time quantitative polymerase chain reaction. The levels of inflammatory cytokines and mediators in the serum and supernatants were measured via enzyme-linked immunoassay. Results: There were closely positive correlations between eCIRP and inflammatory mediators, and between eCIRP and TBI markers in human and mouse serum. Neural-specific eCIRP KO decreased hemispheric volume loss and neuronal apoptosis and alleviated glial cell activation and neurological function damage after TBI. In contrast, eCIRP treatment resulted in endoplasmic reticulum disruption and ER stress (ERS)-related death of neurons and enhanced inflammatory mediators by glial cells. Mechanistically, we noted that eCIRP-induced neural apoptosis was associated with the activation of the protein kinase RNA-like ER kinase-activating transcription factor 4 (ATF4)-C/EBP homologous protein signalling pathway, and that eCIRP-induced microglial inflammation was associated with histone H3 acetylation and the α7 nicotinic acetylcholine receptor. Conclusions: These results suggest that TBI obviously enhances the secretion of eCIRP, thereby resulting in neural damage and inflammation in TBI. eCIRP may be a biomarker of TBI that can mediate the apoptosis of neuronal cells through the ERS apoptotic pathway and regulate the inflammatory response of microglia via histone modification.

Neuroimmune Regulation in Sepsis-Associated Encephalopathy: The Interaction Between the Brain and Peripheral Immunity.

Sepsis-associated encephalopathy (SAE), the most popular cause of coma in the intensive care unit (ICU), is the diffuse cerebral damage caused by the septic challenge. SAE is closely related to high mortality and extended cognitive impairment in patients in septic shock. At present, many studies have demonstrated that SAE might be mainly associated with blood-brain barrier damage, abnormal neurotransmitter secretion, oxidative stress, and neuroimmune dysfunction. Nevertheless, the precise mechanism which initiates SAE and contributes to the long-term cognitive impairment remains largely unknown. Recently, a growing body of evidence has indicated that there is close crosstalk between SAE and peripheral immunity. The excessive migration of peripheral immune cells to the brain, the activation of glia, and resulting dysfunction of the central immune system are the main causes of septic nerve damage. This study reviews the update on the pathogenesis of septic encephalopathy, focusing on the over-activation of immune cells in the central nervous system (CNS) and the "neurocentral-endocrine-immune" networks in the development of SAE, aiming to further understand the potential mechanism of SAE and provide new targets for diagnosis and management of septic complications.

[Establishment of a Wistar rat model bearing brain glioma C6 cells and its experimental application].

OBJECTIVE: To establish a rat model bearing brain glioma and investigate the optimal conditions for its experimental application. METHODS: C6 cells were implanted into the unilateral brain hemisphere of 20 Wistar rats. The growth behaviors of the brain tumor and behavioral changes of the rats were observed at different time points after the implantation. RESULTS: On day 3 after the implantation, only a slight increase of signal intensity was observed on T2-weighted images. By day 5, the tumor became visible in 15/18 of the rats in at least two sections. By day 11, 16/18 of the rats showed space-occupying effect in the brain, and by day 14, the tumor occupied over 1/2 of the hemisphere in 14/18 of the rats. By day 20, 14/18 of the rats showed a tumor mass occupying over 2/3 of the hemisphere, and some tumor cells had migrated into the contralateral hemisphere. CONCLUSION: In this model of brain glioma, the optimal time widow for experiment is between 14 and 18 days after the cell implantation. The cell density and viability for implantation and the site of implantation may also affect the experimental time widow.

[Ocular manifestations of brainstem tumor].

OBJECTIVE: To investigate the ocular manifestations of brainstem tumors and to avoid misdiagnosis and missed diagnosis. METHODS: This is a retrospective case series study. The clinical data of 57 brainstem tumor in-patients were collected from 1993 to 2007. The clinical manifestations and the results of related examinations were analyzed. RESULTS: The present series included 51 cases of brainstem germinoma, 4 cases of cavernous hemangioma, 1 case of hemangioblastoma and 1 case of metastatic tumor. In 51 cases of brainstem germinoma, there were 37 males and 14 females. The first attack age varied from 5 to 55 years old and the median age was 23 years old. The high incident ages of brainstem germinoma were 10 - 35 years. Patients were presented with diplopia, ocular motility disturbance, nystagmus, anisocoria, and facial palsy. In 57 patients, diplopia was the initial symptom in 12.3% (7/57) cases. The incidence of oculomotor nerve paralysis was 17.5% (10/57); trochlear paralysis, 1.8% (1/57); trigeminal nerve paralysis, 5.3% (3/57); abducens nerve paralysis, 35.1% (20/57); facial palsy, 14.0% (8/57); optic disc edema, 19.3% (11/57); nystagmus, 21.1% (12/57) and anisocoria, 10.5% (6/57). CONCLUSIONS: Ocular manifestations occur frequently in brainstem tumor. Nuclear ophthalmoplegia, nystagmus and other neuro-ophthalmic signs provide helpful clues for the diagnosis of brainstem tumor.

[Effect of intensive insulin therapy on serum proinflammatory cytokine levels in patients with severe trauma].

OBJECTIVE: To investigate the effect of intensive insulin therapy on serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and C reaction protein (CRP), all of which reflected the inflammatory status in patients with severe trauma. METHODS: Forty patients with severe trauma [injury severity score (ISS)>or=20] were randomly divided into intensive insulin therapy group and control group. Enzyme-linked immunoadsorbent assay (ELISA) method was used to determine the TNF-alpha and IL-6 levels within 72 hours after admission. RESULTS: Serum levels of TNF-alpha, IL-6 and CRP in patients received intensive insulin therapy were significantly lower than those in patients without the therapy (P<0.05 or P<0.01). CONCLUSION: Intensive insulin therapy can attenuate the systemic inflammatory response to trauma. The anti-inflammatory actions of insulin, as well as its glycemia controlling effects, might contribute to the improved outcomes of patients with severe trauma.

Localization and distribution of magnetic chemotherapeutic drugs with magnetic targeting in rat brain.

BACKGROUND: Magnetic targeting therapy may be a new method for the treatment of malignent tumors. The purpose of this study was to investigate the localization and distribution of ferrofluid microsphere of human serum albumin methotrexate (FM-HSA-MTX) carriers in the brain and to explore the magnetic targeting chemotherapy for malignant brain tumor. METHODS: Ninety SD rats were divided into three groups: targeting group, non-magnetic targeting group, and control group. Synthesized FM-HSA-MTX carriers (MTX 25 mg/kg) were injected into the systemic circulation via the caudal vein (magnetic targeting group, n = 30). A 0.6 T magnetic field was placed around the right hemisphere. The non-magnetic targeting group (n = 30) was administered with FM-HSA-MTX without external magnetic field, meanwhile the control group (n = 30) was treated with MTX and a magnetic field. Random serial sacrifices (n = 10) were conducted at 15, 30 and 45 minutes after drug administration. Bilateral hemispheres were collected respectively, and analyzed for total MTX content. RESULTS: MTX content in the right hemisphere of the magnetic targeting group was significantly higher than that in the other two groups at 15, 30 and 45 minutes after drug administration (P < 0.05) No difference was seen between the non-targeting group and control group. In the magnetic targeting group, MTX returned to the peak level [(0.564 +/- 0.018) mg/g, q15-45 = 32.252, P < 0.05] 45 minutes after the injection but it deceased in the other two groups [non-magnetic targeting group: (0.060 +/- 0.015) mg/g, q15-45 = 9.245, P < 0.05, control group: (0.074 +/- 0.045) mg/g, q15-45 = 6.299, P < 0.05]. In the magnetic targeting group, the concentration of MTX in the right hemisphere was significantly higher than that in the left hemisphere (t45min = 21.135, P = 0.000) but no difference was observed between bilateral hemispheres in the other two groups (non-magnetic targeting group: t45min = 0.434, P = 0.670; control group: t45min = 0.533, P = 0.600). CONCLUSION: In the presence of the external magnetic field, FM-HSA-MTX can distribute successfully in the targeting areas of the brain.

[A study on detecting specific antibodies of hemorrhagic fever with renal syndrome and treatment with integrated traditional Chinese and western medicine].

OBJECTIVE: To explore a simple speedy specific and sensitive method to detect specific IgM (sIgM) and IgG (sIgG) antibodies of hemorrhagic fever with renal syndrome (HFRS),and to study the therapeutic effects of integrated traditional Chinese and western medicine on HFRS. METHODS: The serum of 559 patients with HFRS were tested with colloidal gold immuno-dot assay (CGIDA) for sIgM and sIgG antibodies and compared with enzyme linked immunosorbent assay (ELISA) or indirect fluorescent antibody test (IFAT). One hundred and one patients with HFRS were randomized into treatment group (n=50),treated with Kuhuang Injection, Shenmai Injection and Huangqi Liquid) and control group (n=51),treated with Ribarvirin and Ganlixin Injection). RESULTS: The positive rate of sIgM detected with CGIDA was 70.8% and the positive rate of sIgG detected with CGIDA was 87.5%. The days for fever decline, symptoms alleviation and sign relief between the treatment group and control group were similar (P>0.05). The days for recovery of kidney function in the control group was less than that in the treatment group (P<0.01). The rate of crossing shock stage in the treatment group was higher than that of the control group (P<0.01). CONCLUSION: CGIDA was more simple, speedy, specific and sensitive than ELISA or IFAT in detecting the sIgM or sIgG antibodies in serum of patients with HFRS. Although the sensitivity of CGIDA was lower than that of ELISA the CGIDA had no false positive reaction the sensitivity of CGIDA was higher than that of IFAT on detecting IgG. The effect of the treatment group was similar to that of the control group. But the crossing shock stage rate in the treatment group was higher than that of the control group while the control group was better than the treatment group in recovering the kidney function.