Stroke incidence and cognitive outcomes of intracranial atherosclerotic stenosis: study protocol for a multicenter, prospective, observational cohort study.

Background: Intracranial atherosclerotic stenosis (ICAS) is one of the leading causes of stroke worldwide. Current diagnostic evaluations and treatments remain insufficient to assess the vulnerability of intracranial plaques and reduce the recurrence of stroke in symptomatic ICAS. On the other hand, asymptomatic ICAS is associated with an increased risk of cognitive impairment. The pathogenesis of ICAS related cognitive decline is largely unknown. The aim of SICO-ICAS study (stroke incidence and cognitive outcomes of ICAS) is to elucidate the pathophysiology of stroke and cognitive impairment in ICAS population, comprehensively evaluating the complex interactions among life-course exposure, genomic variation, vascular risk factors, cerebrovascular burden and coexisting neurodegeneration. Methods: SICO-ICAS is a multicenter, prospective, observational cohort study. We aim to recruit 3,000 patients with symptomatic or asymptomatic ICAS (>50% or occlusion) who will be followed up for ≥12 months. All participants will undergo pre-designed magnetic resonance imaging packages, blood biomarkers testing, as well as detailed cognitive domains assessment. All participants will undergo clinical visits every 6 months and telephone interviews every 3 months. The primary outcome measurement is ischemic stroke or cognitive impairment within 12 months after enrollment. Discussion: This study will establish a large prospective ICAS cohort, hopefully discover new biomarkers associated with vulnerable intracranial plaques, identify subjects at high risk for incident ischemic stroke or cognitive impairment, and eventually propose a precise diagnostic and treatment strategy for ICAS population. Trial Registration: Chinese Clinical Trials Register ChiCTR2200061938.

Comparison of the effects of different doses of Glucocorticoids on distinct subtypes of Guillain-Barré syndrome in Southern China.

BACKGROUND: The effect of Glucocorticoids (GCs) on the treatment of Guillain-Barré syndrome (GBS) has been controversial. There is no information on whether specific subtypes of GBS respond differently to GCs. In this setting, we aimed to discuss whether GCs treating yield different effects in the distinct subtypes (acute inflammatory demyelinating polyneuropathy, AIDP; acute motor axonal neuropathy, AMAN). And further, we analyzed the impact of different doses on the outcome. METHODS: Medical records of 448 patients with a diagnosis of classic GBS admitted to 31 tertiary hospitals, located in 14 provinces of Southern China, from 1 January 2013 to 30 September 2016, were retrospectively collected. And 251 patients treated with GCs alone (AIDP=189, AMAN=62) were reviewed and analyzed. RESULTS: After GCs treatment, the Hughes score of AIDP patients was significantly lower than that of AMAN patients at discharge (P=0.005) and 3 months after onset (P<0.001). Further analysis revealed that among AIDP patients, the high-dose group had significantly shorter hospital stay (P=0.023), lower Hughes score at nadir (P<0.001), at discharge (P=0.005), and 3 months after onset (P<0.001), compared with the low-dose group. However, for AMAN patients, the outcome difference between groups was nonsignificant. CONCLUSION: Our data suggest that the high doses of GCs may result, at least in part, from the side of the duration of hospital stay and short-term outcome, favorable outcomes in AIDP patients. Therefore, we cannot completely deny the priority of GCs in the treatment of GBS, because the effect of different doses of GCs varies in treating different subtypes. More studies are needed in the future to further validate this issue. TRIAL REGISTRATION: ChiCTR-RRC-17014152 . Registered 26 December 2017- Retrospectively registered.

Guillain-Barré syndrome in southern China: retrospective analysis of hospitalised patients from 14 provinces in the area south of the Huaihe River.

OBJECTIVES: The clinical and epidemiological profiles of Guillain-Barré syndrome (GBS) in southern China have yet to be fully recognised. We aimed to investigate the subtypes of GBS in southern China, compare the clinical features of demyelinating form with that of axonal form and test whether preceding infections and age have influence on the clinical phenotype, disease course and severity of GBS. METHODS: Medical records of patients with a diagnosis of GBS admitted to 31 tertiary hospitals, located in 14 provinces in southern China, from 1 January 2013 to 30 September 2016, were collected and retrospectively reviewed. RESULTS: Finally. 1056 patients, including 887 classic GBS and 169 variants, were enrolled. The 661 classic patients with available electromyographic data were grouped as having acute inflammatory demyelinating polyneuropathy (AIDP, 49.0%), acute motor axonal neuropathy (AMAN, 18.8%), inexcitable (0.9%) and equivocal (31.3%). In contrast to AIDP, patients with AMAN were characterised by earlier nadir (P=0.000), higher Hughes score at nadir (P=0.003) and at discharge (P=0.000). Preceding upper respiratory infections were identified in 369 (34.9%) patients, who were more inclined to develop AIDP (P=0.000) and Miller-Fisher syndrome (P=0.027), whereas gastrointestinal infection were found in 89 (8.4%) patients, who were more prone to develop AMAN (P=0.000), with more severe illness (P=0.001) and longer hospital stay (P=0.009). Children (≤15 years) and the elderly (≥56 years) were more severe at nadir, the elderly had the longest hospital stay (P=0.023). CONCLUSION: AIDP is the predominant form in southern China, which is different from data of northern China. The different subtypes, preceding infection and age of onset can partially determine the disease progression, severity and short-term recovery speed of GBS. CLINICAL TRIAL REGISTRATION: ChiCTR-RRC-17014152.

Effect of thrombin preconditioning on migration of subventricular zone-derived cells after intracerebral hemorrhage in rats.

OBJECTIVE: To investigate the effect of thrombin preconditioning (TPC) on the intracerebral hemorrhage (ICH)-induced proliferation, migration, and function of subventriclular zone (SVZ) cells and to find new strategies that enhance endogenous neurogenesis after ICH. METHODS: Male Sprague-Dawley rats were randomly divided into 3 groups (ICH, TPC, and control group). Rats of each group were randomly divided into 5 subgroups (3-d, 7-d, 14-d, 21-d, and 28-d subgroup). ICH was caused by intrastrial stereotactic administration of collagenase type IV. Brdu was used to label newborn SVZ cells. Organotypic brain slices were cultured to dynamically observe the migration of SVZ cells at living brain tissue. Migration of Dil-labeled SVZ cells in living brain slices was traced by time-lapse microscopy. To assess whether SVZ cells migrating to injured striatum had the ability to form synapses with other cells, brain slices from each group were double immunolabeled with Brdu and synapsin I. RESULTS: The number of Brdu-positive cells markedly increased in the ipsilateral SVZ and striatum 3 days after TPC, peaked at 14 days (P < 0.01), continued to 21 days, and then gradually decreased at 28 days with significant difference compared to the ICH group at each time point (P < 0.01). Migration of Dil-labeled SVZ cells in brain slices in each group was observed and imaged during a 12-h period. Dil-labeled SVZ cells in the TPC group were observed to migrate laterally toward striatum with time with a faster velocity compared to the ICH group (P < 0.01). Our study also demonstrated that TPC induced strong colocalization of Brdu and synapsin I in the ipsilateral striatum between 3 and 28 days after injury.TPC made colocalization of Brdu and synapsin I appear earlier and continue for a longer time compared to the ICH group. CONCLUSIONS: Our results demonstrated that TPC could promote proliferation, migration, and function of SVZ cells after ICH, which may provide a new idea for enhancing endogenous neurogenesis and developing new therapeutic strategies against ICH-induced brain injury.

The effect of captopril on the expression of MMP-9 and the prognosis of neurological function in herpes simplex encephalitis mice.

BACKGROUND AND PURPOSE: Early increased matrix metalloproteinase-9 (MMP-9) expression is involved in the evolution of herpes simplex encephalitis (HSE) by facilitating the development of cerebrovascular complications. However, the molecular mechanism underlying the detrimental effects of MMP-9 in HSE has not been elucidated. Recent research finds angiotensin II plays an important role in regulation of MMP-9 activity. The aim of this work was to identify the influence of angiotensin-converting enzyme inhibitor (ACEI) captopril on MMP-9 activation after herpes simplex virus 1 (HSV-1) infection. METHODS: Animal models of HSE were established by intracerebral inoculation of HSV-1 into mice. Brain tissue ROS levels were measured by staining with dihydroethidium. MMP-9 protein expression was detected by immunofluorescence and brain water content was measured with dry-wet weight method. Neurological function score was quantified 5 d after HSV-1 infection. Microglial cells were treated with various concentrations of captopril. MMP-9 gelatinolytic activity in the supematant of the cell cultures was assessed by zymography. RT-PCR was used to detect the mRNA expressions of p47phox and MMP-9. RESULTS: Immunofluorescence showed that expression of MMP-9 in brain tissue was mainly presented in OX-42 positive microglia. Quantification of gelatinolytic activity by densitometry showed that expression of MMP-9 in microglia was significantly increased after HSV-1 infection and inhibited by captopril treatment. NADPH oxidase subunit p47phox and MMP-9 mRNA expression were significantly increased 6 h after HSV-1 infection, and were seen reduced after captopril treatment in dose dependence. Captopril also downregulated ROS and MMP-9 protein expression following encephalitis in vivo, and attenuated brain edema, and improved neurological function. DISCUSSION: This compelling evidence suggests that MMP-9 is a key pathogenic factor within HSE. ACEI captopril could reduce the expression of MMP-9 mediated by ROS, then relieve cerebral edema and improve neurological function, which may lay a foundation for further basic research and clinical application.

The effect of cyclin-dependent kinases inhibitor treatment on experimental herpes simplex encephalitis mice.

Herpes simplex encephalitis(HSE) is the most common and serious viral encephalitis in humans. There is a lack of effective medication to date for HSE. A better understanding of the mediators of tissue damage is essential for finding new targets for therapeutic intervention. In this project, we explored the effect of cyclin-dependent kinases inhibitor olomoucine treatment on experimental HSE mice. The following results were obtained: (1) olomoucine increased survival in HSE mice; (2) olomoucine inhibited microglial activation and reduced HSV-1-induced cytokines release; (3) olomoucine prevented neural cells apoptosis and attenuated brain tissue pathological changes following HSV-1 infection; (4) olomoucine reduced brain edema and improved neurological function in HSE. Overall, olomoucine can induce a blunted inflammatory response, maintain the blood vessel wall intact, improve neurological function and increase survival in HSE mice.

The diagnostic accuracy of TCD for intracranial arterial stenosis/occlusion in patients with acute ischemic stroke: the importance of time interval between detection of TCD and CTA.

OBJECTIVE: To evaluate prospectively the diagnostic accuracy of transcranial doppler (TCD) as an additional screening tool for intracranial arterial steno-occlusive disease against computed tomography angiography (CTA) in patients with acute ischemic stroke (AIS) if both are performed in a short time interval. METHODS: Between July 2011 and May 2012, 128 patients who were hospitalized within 24 hours of symptom onset and fulfilled the criteria for the clinical diagnosis of AIS were enrolled. Bedside detection of TCD was accomplished immediately after admission. High-resolution brain CTA was performed within 3 hours after the completion of TCD and the images were interpreted by a neuroradiologist blinded to TCD findings. The accuracy parameters of TCD against CTA were calculated after computation of true-positive, false-positive, true negative, and false-negative values. RESULTS: Among the 128 patients, there were 68 males and 60 females, aged 61.4 ± 17.5 years. The mean time interval between the detection of TCD and CTA was 89.7 (77.8) minutes. In 65% of patients, both examinations were performed with less than a half-hour interval between them. The diagnostic accuracy of TCD for different arteries showed slight distinction. Transcranial doppler demonstrated the most accurate diagnosis for middle cerebral artery (MCA), where TCD showed 35 true-positive, 0 false-negative, 1 false-positive, and 92 true-negative studies compared with CTA. Furthermore, elevated MCA velocities on TCD correlated well with the severity of intracranial stenosis detected on CTA. Vertebral artery (VA) is one of the arteries with the lowest sensitivity for TCD diagnosis (sensitivity 63.4%, specificity 96.5%, positive predictive value (PPV) 89.6%, negative predictive value (NPV) 84.8%, and accuracy 85.9%). In 20 cases (15.6%), TCD showed findings complementary to CTA (real-time embolization, collateral flow patterns, and steal phenomenon). CONCLUSIONS: Transcranial doppler shows high diagnostic accuracy against CTA if both are performed in a short time interval in evaluating intracranial arterial stenosis/occlusion in patients with AIS, especially for MCA obstruction. Transcranial doppler can also provide additional real-time dynamic findings complementary to the information provided by CTA. This can result in changes in the management in some of these patients.

Usefulness of transcranial Doppler ultrasound in evaluating cervical-cranial collateral circulations.

Transcranial Doppler (TCD) ultrasound is a noninvasive, safe and cost-effective bedside test for evaluating cerebrovascular circulation in real time. It has been rapidly evolving from a simple noninvasive diagnostic tool to an imaging model with a broad spectrum of clinical applications. TCD can show the spectral flow waveforms, blood flow direction, velocities and intensity in the intracerebral vessels, adding physiologic information to other imaging models. TCD can also detect collateral channels through the anterior communicating artery, posterior communicating arteries, reversed ophthalmic artery, leptomeningeal collaterals, reversed basilar artery and reversed vertebral artery caused by hemodynamically significant carotid or intracranial stenosis. This article gives a brief overview of its use in evaluation of collateral circulation in carotid and intracranial steno-occlusive disease.

Sonographic and electrophysiological detection in patients with carpal tunnel syndrome.

OBJECTIVES: To assess prospectively the significance of sonographic measurements of the median nerve in the diagnosis of carpal tunnel syndrome (CTS), to look for proper parameters and cutoff values for the sonographic diagnosis, and to correlate with the electrophysiological findings. MATERIALS AND METHODS: This study involved 30 patients, who were clinically diagnosed as CTS merely based on their symptoms and signs; and 30 healthy volunteers were served as controls. Eligible subjects underwent sonographic and electromyographic detection. RESULTS: In the CTS patient group, the cross-sectional area (CSA) at the pisiform bone level (CSA2) and the diameter (D) of the median nerve increased. When the cutoff values of CSA2 and D were 0.105 cm(2) and 0.195 cm, the sensitivity, specificity and accuracy of the diagnosis were 91.5, 94.5, 94.1%, and 90.7, 80.4, 86.5%, respectively. Both CSA and D were negatively related to sensory conduction velocity, while CSA was positively related to distal motor latency. CONCLUSION: There is a good association of sonographic with electrophysiologic detection for the diagnosis of CTS.

Effect of thrombin on blood brain barrier permeability and its mechanism.

BACKGROUND: Previous studies have indicated that thrombin (TM) may play a major role in brain edema after intracerebral hemorrhages (ICHs). However, the mechanism of TM-induced brain edema is poorly understood. In this study, we explored the effect of TM on the permeability of the blood brain barrier (BBB) and investigated its possible mechanism, aiming at providing a potential target for brain edema therapy after ICHs. METHODS: TM or TM + cathepsin G (CATG) was stereotaxically injected into the right caudate nucleus of Sprague-Dawley rats in vivo. BBB permeability was measured by Evans-Blue extravasation. Brain water content was determined by the dry-wet weight method. Brain microvascular endothelial cells were then cultured in vitro. After TM or TM + CATG was added to the endothelial cell medium, changes in the morphology of cells were dynamically observed by phase-contrast light microscopy, and the expression of matrix metalloproteinase-2 (MMP-2) protein was measured by immunohistochemical method. RESULTS: BBB permeability increased at 6 hours after a TM injection into the ipsilateral caudate nucleus (P < 0.05), peaked between 24 hours (P < 0.01) and 48 hours (P < 0.05) after the injection, and then declined. Brain water content changed in parallel with the changes in BBB permeability. However, at all time points, BBB permeability and brain water content after a TM + CATG injection were not significantly different from the respective parameters in the control group (P > 0.05). TM induced endothelial cell contraction in vitro in a time-dependent manner and enhanced the expression of MMP-2 protein. After incubation with TM + CATG, cell morphology and MMP-2 expression did not change significantly as compared to the control group (P > 0.05). CONCLUSIONS: Increased BBB permeability may be one of the mechanisms behind TM-induced cerebral edema. TM induces endothelial cell contraction and promotes MMP-2 expression by activating protease activated receptor-1 (PAR-1), possibly leading to the opening of the BBB.

Experimental study on the PAR-1 expression around hemotoma following intracerebral hemorrhage in rats.

In order to explore the PAR-1 mRNA and protein expression around hemotoma following intracerebral hemorrhage and the relation between the PAR-1 expression and thrombin, collagenase VII was stereotaxically injected into right caudate nucleus in rats. The PAR-1 mRNA expression was detected by RT-PCR method and the PAR-1 protein expression by immunohistochemical method respectively. It was found that the PAR-1 mRNA and protein expression around hemotoma was increased at 6 h after intracerebral hemorrhage (P<0.05), peaked at 2 days (P<0.01), and then declined. The change pattern of the PAR-1 mRNA and protein expression was similar to that of intracerebral hemorrhage after thrombin intracerebral injection. The PAR-1 mRNA and protein expression in hirudin group showed no significant difference with control group. These results indicated that the PAR-1 mRNA and protein expression were markedly increased after intracerebral hemorrhage, which may be closely related to thrombin. Upregulation of the PAR-1 expression may involve in neurotoxic injury induced by thrombin.