Xinyue Qin

Blend Sign on Computed Tomography Novel and Reliable Predictor for Early Hematoma Growth in Patients With Intracerebral Hemorrhage

Background and Purpose— Early hematoma growth is not uncommon in patients with intracerebral hemorrhage and is an independent predictor of poor functional outcome. The purpose of our study was to report and validate the use of our newly identified computed tomographic (CT) blend sign in predicting early hematoma growth. Methods— Patients with intracerebral hemorrhage who underwent baseline CT scan within 6 hours after onset of symptoms were included. The follow-up CT scan was performed within 24 hours after the baseline CT scan. Significant hematoma growth was defined as an increase in hematoma volume of >33% or an absolute increase of hematoma volume of >12.5 mL. The blend sign on admission nonenhanced CT was defined as blending of hypoattenuating area and hyperattenuating region with a well-defined margin. Univariate and multivariable logistic regression analyses were performed to assess the relationship between the presence of the blend sign on nonenhanced admission CT and early hematoma growth. Results— A total of 172 patients were included in our study. Blend sign was observed in 29 of 172 (16.9%) patients with intracerebral hemorrhage on baseline nonenhanced CT scan. Of the 61 patients with hematoma growth, 24 (39.3%) had blend sign on admission CT scan. Interobserver agreement for identifying blend sign was excellent between the 2 readers (&kgr;=0.957). The multivariate logistic regression analysis demonstrated that the time to baseline CT scan, initial hematoma volume, and presence of blend sign on baseline CT scan to be independent predictors of early hematoma growth. The sensitivity, specificity, positive and negative predictive values of blend sign for predicting hematoma growth were 39.3%, 95.5%, 82.7%, and 74.1%, respectively. Conclusions— The CT blend sign could be easily identified on regular nonenhanced CT and is highly specific for predicting hematoma growth.

Nrf2—a Promising Therapeutic Target for Defensing Against Oxidative Stress in Stroke

Stroke is one of the leading causes of death and disability in the world. Oxidative stress, which refers to an excessive generation of reactive oxygen species (ROS), plays a key role in the pathological process of stroke. Excessive ROS production contributes to brain ischemia/reperfusion injury through many mechanisms including BBB disruption, inflammation, apoptosis, and cellular necrosis. Nuclear factor-E2-related factor 2 (Nrf2) is one of the critical regulators of endogenous antioxidant defense, which promote the transcription of a wide variety of antioxidant genes. Emerging evidence has demonstrated that activation of Nrf2 and its target genes may protect the brain against ischemia/reperfusion injury, and therapies aimed at increasing Nrf2 activity appear to be beneficial to alleviate brain injury in stroke through the suppression of oxidative stress. The main purpose of this review is to discuss the current evidence for the role of Nrf2 in stroke and the potential interventions to enhance Nrf2 activation to attenuate stroke-induced injury.

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.

Minocycline promotes axonal regeneration through suppression of RGMa in rat MCAO/reperfusion model.

Minocycline has been recently implicated in protection against focal cerebral ischemia reperfusion (I/R), but the protective effects on neurobehavioral abnormalities remains contradictory. In the present study, we investigate whether minocycline improves axonal regeneration and neurological function recovery by inhibiting the expression of the repulsive guidance molecular A (RGMa) after focal cerebral ischemia reperfusion. Male Sprague‐Dawley (SD) rats were subjected to occlusion of the right middle cerebral artery (MCAO) for 2 h and 3 mg kg−1 minocycline was injected intravenously immediately after reperfusion twice a day for 14 days. The staircase test and modified neurological severity score (mNSS) were performed to evaluate functional outcome and blood‐brain barrier (BBB) permeability was assessed by Evans blue dye extravasation (EB) at the expected time point. The expression of RGMa in ischemic cortex was measured by immunohistochemical staining and Western blot 2 weeks after MCAO. Neurofilament protein 200 (NF‐200) immunohistochemical staining was used to assess axonal damage. Treatment with minocycline at a dose of 3 mg kg−1 via the caudal vein significantly reduced the extravasation of EB, elevated mNSS and improved forelimb motor function as assessed by the staircase test when compared to the I/R group (P < 0.05). Moreover, axonal regrowth was enhanced in the minocycline treatment group when compared to the I/R group (P < 0.05). In addition, minocycline significantly reduced the expression of RGMa protein 2 weeks after MCAO as assessed by both immunostaining and Western blot. Our studies suggest that early minocycline treatment promotes neurological functional recovery and axonal regeneration in rats after MCAO, which might be mediated by down‐regulating RGMa expression. Synapse, 2013.

Perimesencephalic Subarachnoid Hemorrhage: Risk Factors, Clinical Presentations, and Outcome

BACKGROUND Perimesencephalic nonaneurysmal subarachnoid hemorrhage (PNSH) appears to have an origin and natural history distinct from aneurysm rupture. However, the risk factors and complications of this pattern are still in debate. We performed a study with goals of comparing PNSH risk factors and clinical presentations with other sorts of spontaneous subarachnoid hemorrhages (SAH) and exhibit the PNSH outcome and prognosis. METHODS Retrospective review of patients who experienced SAH between May 2006 and July 2008 in the First Affiliated Hospital of Chongqing Medical University was undertaken. Patients were categorized as perimesencephalic nonaneurysmal subarachnoid hemorrhage (PNSH), nonperimesencephalic nonaneurysmal subarachnoid hemorrhage (NPNSH), aneurismal subarachnoid hemorrhage (ASH), and uncertain SAH of which the patterns were not clear. The possible risk factors and clinical presentations within the three groups were used to proceed for statistical analysis. RESULTS A total of 159 residents were identified. Among of them, 12 patients had the perimesencephalic pattern. Patients with PNSH showed less likelihood with the female (P=0.029), alcohol consumption (P=0.033), hypertensive (P=0.005), diabetes (P=0.013) or hyperlipidemia (P=0.034) when compared with aneurismal SAH. The clinical presentations of this pattern showed less conscious disturbance (P=0.004), vomiting (P=0.005), or poor Hunt & Hess Grade (P=0.003). There was one death among PNSH patients during 12 months mean follow-up. CONCLUSIONS Patients with PNSH present better clinical course than other forms of SAH, which could assist the diagnosis of this pattern. The moderate clinical course may suggest clinician apt to exclude aneurysm rupture. However, similar presents in remaining nonaneurysmal subarachnoid hemorrhage might suggest benign entities in other forms of nonaneurysmal subarachnoid hemorrhage.

Electrical stimulation of olfactory bulb downregulates RGMa expression after ischemia/reperfusion injury in rats

Repulsive guidance molecule A (RGMa) is associated with limited axonal growth after cerebral ischemia. This study focused on the effects of electrical stimulation of olfactory bulb (OB) on the expression of RGMa and axonal regeneration after focal cerebral ischemia/reperfusion injury. Sprague-Dawley (SD) rats were randomly divided into sham-operated group, ischemia/reperfusion (I/R) group (48h, 1 w), stimulation group (48h, 1 w), and sham-stimulated group (48h, 1 w). Focal cerebral ischemia/reperfusion was induced by intraluminal middle cerebral artery occlusion. Electrical stimulation was performed via a bipolar electrode implanted in the right OB. The changes in the expression of RGMa were analyzed by reverse transcription polymerase chain reaction (RT-PCR), Western-blot and immunohistochemistry, respectively. Neurofilament protein 200 (NF-200) immunohistochemical staining was used to assess axonal regeneration. Another group of rats were divided into sham-operated group, I/R group, sham-stimulated group and stimulation group. The behavioral test was conducted using the modified neurological severity score (mNSS). The infarct volume was determined by triphenyltetrazolium chloride (TTC) staining. The levels of RGMa were significantly elevated after ischemia/reperfusion injury. Stimulation treatment downregulated the expression of RGMa, reduced infarct volume and improved neurological function. These observations demonstrated that electrical stimulation of OB might promote axonal regeneration and function recovery after ischemic cerebral injury.

Proton Pump Inhibitor Prophylaxis Increases the Risk of Nosocomial Pneumonia in Patients with an Intracerebral Hemorrhagic Stroke

BACKGROUND Stress-related mucosal damage is an erosive process of the gastric lining resulting from abnormally high physiologic demands. To avoid the morbidity and mortality associated with significant bleeding from the damage, prophylaxis with an acid suppression medication is given. This is especially common in stroke victims. Recent studies have suggested a link between acid suppression therapy and nosocomial pneumonia, specifically implicating proton pump inhibitors (PPI), a potent acid suppression medication, as the culprit. In this retrospective study, we reviewed the medical records of admitted intracerebral hemorrhage (ICH) patients and determined if there is a link between PPI prophylaxis and nosocomial pneumonia in our ICH population. MATERIALS AND METHODS Medical records of 200 ICH patients admitted to the First Affiliated Hospital of Chongqing Medical University were reviewed from January 1, 2008 to October 31, 2009. PPIs were the only accepted form of acid suppression therapy. In all, 95 patients were given PPI prophylaxis, whereas 105 patients did not receive any form of acid suppression. RESULTS The unadjusted incidence rate of pneumonia in the PPI prophylactic group was 23.2%, and 10.5% in patients not having received prophylaxis. Additionally, patients treated with PPI prophylaxis were more likely to be critically ill, defined by an increase in conscious disturbance and dependency on mechanical ventilation and/or a nasogastric tube. CONCLUSION The use of a PPI as a prophylactic treatment against stress-related mucosal damage was associated with a higher occurrence of nosocomial pneumonia in our ICH population. This study suggests the need for further research investigating the use of PPI prophylaxis in ICH patients and the possibility of using alternate acid suppression therapeutic modalities.

Overexpression of Fibulin-5 Attenuates Ischemia/Reperfusion Injury After Middle Cerebral Artery Occlusion in Rats.

Ischemia/reperfusion (I/R) injury after middle cerebral artery occlusion (MCAO) induces detrimental processes such as oxidative stress, inflammation, and apoptosis. All parts of the neurovascular unit are involved in these pathological processes. Fibulin-5 is a 66-kD glycoprotein secreted by various vascular cells, including vascular smooth muscle cells (SMCs), fibroblasts, and endothelial cells. As an extracellular matrix protein involved in cell adhesion, fibulin-5 has been widely studied in tumor growth and invasion. However, the effects of fibulin-5 on brain injury following ischemia/reperfusion have not been reported. In this study, we examined the effect of overexpressed fibulin-5 on reactive oxygen species (ROS) production. Fibulin-5 overexpression attenuated ROS expression, which in turn decreased apoptosis and blood–brain barrier (BBB) permeability following MCAO and reperfusion. Fibulin-5 also improved neurological deficits but had no effect on infarction volume. T2-weighted MRI and electron microscopy further confirmed brain edema reduction and decreased BBB disruption in fibulin-5 overexpression recombinant adenovirus (Ad-FBLN) treated rats. In addition, tight junction protein occludin was significantly degraded and matrix metalloproteinase 9 (MMP-9) immunoreactivity was significantly increased. Fibulin-5-mediated ROS decrease was not due to increased total superoxide dismutase levels but was instead correlated with the activation of Rac-1 pathway. The findings highlight the importance of antioxidant mechanism underlying cerebral ischemia/reperfusion.

Subtypes and Prognosis of Guillain-Barré Syndrome in Southwest China.

The proportion of different subtypes of Guillain-Barré syndrome (GBS) and their prognosis varied significantly among different regions. This study attempts to investigate the clinical subtypes and outcome of GBS in southwest China. Patients with GBS admitted to The First Affiliated Hospital of Chongqing Medical University from January 2006 to March 2013 were included in our study. Patients were classified into acute inflammatory demyelinating polyneuropathy (AIDP) group, acute motor axonal neuropathy (AMAN) group, Miller-Fisher syndrome (MFS) group, cranial nerve variants(CNV), Bickerstaffs brainstem encephalitis overlaps with GBS (BBE-GBS) group and unclassifiable group based on clinical features and electrophysiological findings. Hughes function grade score (HFGS) was used to assess the prognosis at 3 and 6 months. The prognosis of different subtypes and outcome predictors were analyzed. The most common subtype of GBS was AIDP (57%), followed by AMAN (22%) and MFS (7%). The prognosis of AMAN and BBE-GBS is similar at 3 month(P = 0.0704)and 6 month (P = 0.1614) follow-up. The prognosis of AMAN group was poorer than that of AIDP group at 3 month and 6 month follow-up (P<0.001). Outcome of MFS group and that of CNV group at 6 months were both good(Hughes≤1). Hughes≥3(P<0.0001,OR = 6.650,95%CI = 2.865 to 15.023))and dysautonomia (P = 0.043,OR = 2.820,95%CI = 1.031 to 7.715)) were associated with poor outcome at 6 month follow-up. AIDP is the most common subtype of GBS. Prognosis of AMAN group and BBE-GBS group is poorer than that of AIDP group at 3 month and 6 month follow-up. Hughes≥3 at nadir and dysautonomia are predictors of poor prognosis at 6 month follow-up.