Tianzhu Wang

Down-regulation of Nogo receptor promotes functional recovery by enhancing axonal connectivity after experimental stroke in rats

The inability of axons in central nervous system (CNS) to regenerate after injury is related partly to multiple endogenous axon growth inhibitors including Nogo receptor (NgR). This study tested the hypothesis that silencing NgR expression by adenovirus-mediated RNA interference (RNAi) (AD-NgR) may permit axonal connectivity after focal cerebral ischemia in rats. Male Sprague-Dawley rats (250-280g, n=97) were assigned into seven groups: sham, MCAO (24h and 2 weeks), MCAO plus AD-NgR (24h and 2 weeks), and MCAO plus AD-HK (control oligonucleotides) (24h and 2 weeks). After cerebral ischemia, NgR mRNA and protein in the cortex and hippocampus were significantly increased at 24h and 2 weeks. However, in AD-NgR treated rats, NgR mRNA and protein were reduced by 40-60% in the cortex and hippocampus at both time points as compared to controls. Although there was no significant difference in the infarct volume between the two groups, the number of midline-crossing fibers projecting to the contralateral red nucleus and corticostriatal fibers in the dorsolateral striatum were increased in AD-NgR injected rats, accompanied by improved behavioral outcomes. Taken together, these results suggest that NgR knockdown may promote CNS axonal regeneration and functional recovery after ischemic cerebral injury.

RNA interference against repulsive guidance molecule A improves axon sprout and neural function recovery of rats after MCAO/reperfusion

Repulsive guidance molecule a (RGMa) is a neurite growth inhibitor that is of great interest in the study of CNS neuronal regeneration. We adopted RNA interference (RNAi) as a means of suppressing the expression of RGMa and observed the improvement in axonal regeneration and neurological function of rats after cerebral ischemic injury. Recombinant adenovirus rAd5-shRNA-RGMa was constructed and prepared for animal experimentation. RGMa and neurofilament protein 200 (NF200) in the ischemic cortex and ipsilateral hippocampus were detected by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The ischemic regions were examined by triphenyltetrazolium chloride (TTC) staining and the newborn neurite branches by Biotinylated Dextran Amine (BDA) neuronal tracing. Behavior tests were adopted to evaluate neurologic function recovery. Results showed RGMa was down-regulated and axonal growth was improved in the RNAi treated group (P<0.01). The number of axonal sprouts of corticospinal tract from the uninjured side to the ischemic side in the RNAi treated group was increased (P<0.01). Behavior test scores in the RNAi treated group were significantly better than other groups after 6 weeks (P<0.01). RGMa in rat brains after middle cerebral artery occlusion (MCAO) can be down-regulated by RNAi successfully, which may lead to improved axonal growth and neural anatomy plasticity, as well as neuron functional recovery.

CRMP-2 Is Involved in Axon Growth Inhibition Induced by RGMa In Vitro and In Vivo

Repulsive guidance molecule-a (RGMa) is associated with axon growth inhibition in different central nervous system (CNS) injuries, but its signaling pathways remain unclear. We examined the involvement of collapsin response mediator protein-2 (CRMP-2), a common downstream target of Rho-kinase and GSK-3β, in vitro by culturing neonatal rat primary cortical neurons with RGMa protein, Rho-kinase inhibitor (Y-27632), and GSK-3β inhibitor. We examined CRMP-2 in vivo by suppressing RGMa expression using recombinant adenovirus (rAd-shRGMa) in a rat MCAO/reperfusion model. RGMa induced neurite retraction and CRMP-2 phosphorylation in vitro, which were reversed by either Rho-kinase or GSK-3β inhibitors. After MCAO/reperfusion in rats, pCRMP-2 protein was greatly increased in the ischemic cortex, axons were damaged severely, Neurofilament-200 (NF-200) expression was significantly decreased, and neurological deficits were significant, which were all improved by down-regulating RGMa. We concluded RGMa inhibits axon growth by phosphorylating CRMP-2 via both Rho-kinase and GSK-3β signaling pathways.

Systematic Review of Clinical Practice Guidelines Related to Multiple Sclerosis

Background High quality clinical practice guidelines (CPGs) can provide clinicians with explicit recommendations on how to manage health conditions and bridge the gap between research and clinical practice. Unfortunately, the quality of CPGs for multiple sclerosis (MS) has not been evaluated. Objective To evaluate the methodological quality of CPGs on MS using the AGREE II instrument. Methods According to the inclusion and exclusion criteria, we searched four databases and two websites related to CPGs, including the Cochrane library, PubMed, EMBASE, DynaMed, the National Guideline Clearinghouse (NGC), and Chinese Biomedical Literature database (CBM). The searches were performed on September 20th 2013. All CPGs on MS were evaluated by the AGREE II instrument. The software used for analysis was SPSS 17.0. Results A total of 27 CPGs on MS met inclusion criteria. The overall agreement among reviews was good or substantial (ICC was above 0.70). The mean scores for each of all six domains were presented as follows: scope and purpose (mean ± SD: 59.05±16.13), stakeholder involvement (mean ± SD: 29.53±17.67), rigor of development (mean ± SD: 31.52±21.50), clarity of presentation (mean ± SD: 60.39±13.73), applicability (mean ± SD: 27.08±17.66), editorial independence (mean ± SD: 28.70±22.03). Conclusions The methodological quality of CPGs for MS was acceptable for scope, purpose and clarity of presentation. The developers of CPGs need to pay more attention to editorial independence, applicability, rigor of development and stakeholder involvement during the development process. The AGREE II instrument should be adopted by guideline developers.

Serum Levels of IL-1β, IL-6, TGF-β, and MMP-9 in Patients Undergoing Carotid Artery Stenting and Regulation of MMP-9 in a New In Vitro Model of THP-1 Cells Activated by Stenting

Inflammation plays an important role in the pathophysiological process after carotid artery stenting (CAS). Monocyte is a significant source of inflammatory cytokines in vascular remodeling. Telmisartan could reduce inflammation. In our study, we first found that, after CAS, the serum IL-1β, IL-6, TGF-β, and MMP-9 levels were significantly increased, but only MMP-9 level was elevated no less than 3 months. Second, we established a new in vitro model, where THP-1 monocytes were treated with the supernatants of human umbilical vein endothelial cells (HUVECs) that were scratched by pipette tips, which mimics monocytes activated by mechanical injury of stenting. The treatment enhanced THP-1 cell adhesion, migration and invasion ability, and the phosphorylation of ERK1/2 and Elk-1 and MMP-9 expression were significantly increased. THP-1 cells pretreated with PD98095 (ERK1/2 inhibitor) attenuated the phosphorylation of ERK1/2 and Elk-1 and upregulation of MMP-9, while pretreatment with telmisartan merely decreased the phosphorylation of Elk-1 and MMP-9 expression. These results suggested that IL-1β, IL-6, TGF-β, and MMP-9 participate in the pathophysiological process after CAS. Our new in vitro model mimics monocytes activated by stenting. MMP-9 expression could be regulated through ERK1/2/Elk-1 pathway, and the protective effects of telmisartan after stenting are partly attributed to its MMP-9 inhibition effects via suppression of Elk-1.

Effects of Early Serum Glucose Levels on Prognosis of Patients with Acute Intracerebral Hemorrhage

Studies have indicated that hyperglycemia might cause cerebral damage to patients after acute intracerebral hemorrhage (ICH). But systematic studies on the effects of diabetes, stress hyperglycemia and normal serum glucose level on the prognosis of ICH patients are insufficient. It is essential to explore the prognosis among them. According to their serum glucose level within 24 h, 189 patients with ICH were divided into three groups: diabetes (group A), stress hyperglycemia (group B) and normal serum glucose (group C). The activity of daily living ability of patients was evaluated by Barthel index at 30 days after admission. The data analysis was done using cumulative logit model and rank sum test. Significant differences were observed in prognosis between group A and group C (OR: 0.056; CI: 0.022-0.143; p<0.0001), B and C (OR: 0.081; CI: 0.039-0.167; p<0.0001), respectively; there was no significant difference between A and B (p>0.05). No difference was found between A and B in the early serum glucose level, but significant differences were observed between A and C, and between B and C. Early hyperglycemia may worsen the prognosis of ICH patients, though patients with diabetes or stress hyperglycemia after ICH may have similar outcomes when early serum glucose levels fluctuate within the same range.

Subarachnoid Hemorrhage in Old Patients in Chongqing China

BACKGROUND Subarachnoid hemorrhage (SAH) is a disorder with high mortality in central nervous system, especially in old population. Misdiagnosis and poor outcome frequently occur in old patients with SAH. This research is to investigate the demographic characteristics, clinical features, neuroimaging data, and the outcome of the old patients (≥60 of age) with SAH. METHODS The data was from both neurosurgical and neurology departments of two hospitals in Chongqing, China, from October 2007 to March 2009. One hundred and seventy eight patients were enrolled and divided into two groups: the elderly group (≥60 of age) and the non-elderly group (≥18 but <60 of age). The condition on admission was assessed by Hunt-Hess grade (H-H) and the Glasgow scales of coma (GCS). Findings on computerized tomography (CT) were measured by Fisher grades. The outcome after 3 months was evaluated by the modified Rankin Scale (mRS). Statistic analysis was managed by Chi-square test and t-test. FINDINGS Compared to the non-elderly group, the clinical conditions on admission in the elderly group was worse, with lower average scores of GCS, higher Fisher grades, systolic blood pressure, and percentage of the H-H IV and V. Some preexisting medical conditions with the old such as arterial hypertension, pulmonary diseases, and diabetes mellitus were worsening. During the clinical course, the elderly group had the following characteristics: the incidence of rebleeding, asymptomatic vasospasm, hydrocephalus, and other severe medical complications were all higher, while the percentage of early surgery was lower. The outcome after 3 months was poorer in the elderly. CONCLUSIONS It is indicated that the elderly patients with SAH have poorer clinical conditions, much lower ratio of early surgery and higher incidence of rebleeding. Together, these factors contribute to a poorer short-term outcome after SAH.

Characteristics of Pulse Pressure Parameters in Acute Intracerebral Hemorrhage Patients

We explored the features of changes in pulse pressure (PP) in patients with intracerebral hemorrhage (ICH). Two hundred one patients with ICH were admitted to our hospital from January 2008 to August 2009. Meanwhile, another 201 people matching in age and gender with these patients were assigned as controls. Blood Pressures (BP) were collected within the first 24 h after admission. PP was calculated from the BP readings. The mean of PPs was compared via T-test. The distributed frequency of the PP level was analyzed using the chi-square test. PPs in the ICH group were higher than those of the controls (P<0.001). Chi-square test showed a significant difference in distribution ratios of PP (P<0.01) between the ICH and control group. The largest PP range in the ICH group was from 80 to 99 mmHg, which accounted for 33.3%; PP of the control group was from 40 to 49 mmHg (30.3%). The PP level in the 40-89-year-old case group was higher than that in the 40-89-year-old control group. PP increased with age. Our investigation indicates that higher PP is correlated with acute ICH and that PP is important in predicting the risk of ICH.

Analysis on Death-Associated Factors of Patients with Subarachnoid Hemorrhage During Hospitalization

OBJECTIVE The prognosis of patients with high-clinical-score subarachnoid hemorrhage remains poor, with early high mortality rate. Therefore, to predict the early outcome of patients after subarachnoid hemorrhage, several clinical factors were hypothesized to be related to death during hospitalization. METHODS Eighty-nine cases after subarachnoid hemorrhage, divided into two groups (① death group; ② survival group) according to their clinical situations during hospitalization, were studied. Twelve factors, including gender, hypertension, intracranial aneurysm, cerebral vascular spasm, hydrocephalus and conscious disturbance during hospitalization, smoking, age, WFNS (World Federation of Neurological Surgeons) scale, Fisher grade, white blood cell count and blood glucose level at admission, were analyzed by using Chi-square test, t test, and Logistic multiple regression analysis. RESULTS The results of single-factor analysis indicated that ruptured intracranial aneurysm, conscious disturbance, increasing age, high WFNS scale, high Fisher grade, increasing white blood cell count and blood glucose level were statistically significant different between the two groups.The logistic analysis results showed that ruptured intracranial aneurysm (odds ratio [OR], 9.253; 95% confidence interval [CI], 0.617-98.263), high WFNS score (OR, 2.105; 95% CI, 1.275-5.204) and increasing white blood cell count (OR, 1.397; 95% CI 1.062-2.013) were the independent risk factors associated with death during hospitalization for patients with subarachnoid hemorrhage. CONCLUSIONS Increased white blood cell count may indicate poor outcomes for patients during hospitalization, even early death.

Clinical Analysis of Electrolyte Imbalance in Thalamic Hemorrhage Patients Within 24 H After Admission

We have observed that patients with thalamic hemorrhage are more likely to have electrolyte disturbances than those with non-thalamic hemorrhage. Here, we are attempting to provide some comprehensive information on electrolyte disturbances in patients with thalamic hemorrhage. Retrospectively, 67 patients with thalamic hemorrhage (TH group) and 256 with non-thalamic hemorrhage (N-TH group) were found from computer tomography images. Electrolytes of these patients were tested within 24 h after hospitalization. Chi-square test was used to compare the incidence of electrolyte imbalance. Serum K+ levels were found to be abnormal in 37.31% of the patients in the TH group and 24.21% in the N-TH group, and the difference was significant (p<0.05). Such a difference was also observed for the levels of serum Na+ and Cl+. Incidences of abnormal serum K+ (p<0.05), Na+ (p<0.01) and Cl(-) (p<0.01) levels were different among thalamic hemorrhage, basal ganglia area hemorrhage and lobar hemorrhage patients. In the TH group, the mortality of patients with electrolyte disturbances (42.50%) was higher than that of patients with normal electrolyte levels (14.81%, p<0.05). The incidence of electrolyte imbalance is higher in patients with thalamic hemorrhage than in those with non-thalamic hemorrhage. The reason may be partly related to the location of the hemorrhage. Electrolyte disturbance may contribute to the higher mortality of patients with thalamic hemorrhage.