Naoxintong Capsule for Secondary Prevention of Ischemic Stroke: A Multicenter, Randomized, and Placebo-Controlled Trial.

OBJECTIVE: To examine whether the combination of Naoxintong Capsule with standard care could further reduce the recurrence of ischemic stroke without increasing the risk of severe bleeding. METHODS: A total of 23 Chinese medical centers participated in this trial. Adult patients with a history of ischemic stroke were randomly assigned in a 1:1 ratio using a block design to receive either Naoxintong Capsule (1.2 g orally, twice a day) or placebo in addition to standard care. The primary endpoint was recurrence of ischemic stroke within 2 years. Secondary outcomes included myocardial infarction, death due to recurrent ischemic stroke, and all-cause mortality. The safety of drugs was monitored. Results were analyzed using the intention-to-treat principle. RESULTS: A total of 2,200 patients were enrolled from March 2015 to March 2016, of whom 143 and 158 in the Naoxintong and placebo groups were lost to follow-up, respectively. Compared with the placebo group, the recurrence rate of ischemic stroke within 2 years was significantly lower in the Naoxintong group [6.5% vs. 9.5%, hazard ratio (HR): 0.665, 95% confidence interval (CI): 0.492-0.899, P=0.008]. The two groups showed no significant differences in the secondary outcomes and safety, including rates of severe hemorrhage, cerebral hemorrhage and subarachnoid hemorrhage (P>0.05). CONCLUSION: The combination of Naoxintong Capsule with standard care reduced the 2-year stroke recurrence rate in patients with ischemic stroke without increasing the risk of severe hemorrhage in high-risk patients. (Trial registration No. NCT02334969).

Clinical scoring model based on age, NIHSS, and stroke-history predicts outcome 3 months after acute ischemic stroke.

Background: The clinical nomogram is a popular decision-making tool that can be used to predict patient outcomes, bringing benefits to clinicians and patients in clinical decision-making. This study established a simple and effective clinical prediction model to predict the 3-month prognosis of acute ischemic stroke (AIS), and based on the predicted results, improved clinical decision-making and improved patient outcomes. Methods: From 18 December 2021 to 8 January 2022, a total of 146 hospitalized patients with AIS confirmed by brain MR were collected, of which 132 eligible participants constituted a prospective study cohort. The least absolute shrinkage and selection operator (LASSO) regression was applied to a nomogram model development dataset to select features associated with poor prognosis in AIS for inclusion in the logistic regression of our risk scoring system. On this basis, the nomogram was drawn, evaluated for discriminative power, calibration, and clinical benefit, and validated internally by bootstrap. Finally, the optimal cutoff point for each independent risk factor and nomogram was calculated using the Youden index. Results: A total of 132 patients were included in this study, including 85 men and 47 women. Good outcome was found in 94 (71.212%) patients and bad outcome in 38 (28.788%) patients during the follow-up period. A total of eight (6.061%) deaths were reported over this period, of whom five (3.788%) died during hospitalization. Five factors affecting the 3-month prognosis of AIS were screened by LASSO regression, namely, age, hospital stay, previous stroke, atrial fibrillation, and NIHSS. Further multivariate logistic regression revealed three independent risk factors affecting patient outcomes, namely, age, previous stroke, and NIHSS. The area under the curve of the nomogram was 0.880, and the 95% confidence interval was 0.818-0.943, suggesting that the nomogram model has good discriminative power. The p-value for the calibration curve is 0.925, indicating that the nomogram model is well-calibrated. According to the decision curve analysis results, when the threshold probability is >0.01, the net benefit obtained by the nomogram is the largest. The concordance index for 1,000 bootstrapping calculations is 0.869. The age cutoff for predicting poor patient outcomes using the Youden index was 76.5 years (specificity 0.777 and sensitivity 0.684), the cutoff for the NIHSS was 7.5 (specificity 0.936, sensitivity 0.421), and the cutoff for total nomogram score was 68.8 (sensitivity 81.6% and specificity 79.8%). Conclusion: The nomogram model established in this study had good discrimination, calibration, and clinical benefits. A nomogram composed of age, previous stroke, and NIHSS might predict the prognosis of stroke after AIS. It might intuitively and individually predict the risk of poor prognosis in 3 months of AIS and provide a reference basis for screening the treatment plan of patients.

Dynamic muscle paralytic effects of a novel botulinum toxin A free of neurotoxin-associated proteins.

Structurally, botulinum toxin type A (BTX-A) is composed of neurotoxin and nontoxic complexing proteins (CPs), and the neurotoxin has the function of blocking acetylcholine release from the neuromuscular junction and therefore paralyzing muscles. Nowadays, a novel botulinum toxin A free of CPs (chinbotulinumtoxin A, A/Chin) is produced, and the present study comprehensively evaluated the dynamic paralytic effect of A/Chin on the gastrocnemius muscle of rats. Different doses (0.01, 0.1, 0.5, 1, 2, and 4 U) of A/Chin and other BTX-As with and without CPs were administered to the gastrocnemius muscles of rats and muscle strength was measured and compared at different postinjection timepoints (from day 0 to 84). With the dose increased, time-to-peak paralytic effect of other BTX-As varied from day 3 to day 14, while A/Chin groups showed rapid and steady time to peak on day 3. At the lowest dose of 0.01 U, A/Chin showed significantly better peak paralytic effect than the others on day 3. When the dose increased to 0.5 U and more, A/Chin group also showed significant paralytic effect when the paralytic effect of other BTX-As was worn off. Moreover, the paralytic effect of A/Chin was confirmed as muscle atrophy while hematoxylin-eosin staining was performed. In conclusion, compared with other BTX-As, A/Chin showed rapid and steady time-to-peak paralytic effect and long-term paralytic efficacy at the same dose level. And it might lay a solid foundation for further wide application of A/Chin in both clinical and cosmetic areas.

Neural Mechanism of Repeated Transcranial Magnetic Stimulation to Enhance Visual Working Memory in Elderly Individuals With Subjective Cognitive Decline.

Visual working memory (VWM), the core process inherent to many advanced cognitive processes, deteriorates with age. Elderly individuals usually experience defects in the processing of VWM. The dorsolateral prefrontal cortex is a key structure for the top-down control of working memory processes. Many studies have shown that repeated transcranial magnetic stimulation (rTMS) improves VWM by modulating the excitability of neurons in the target cortical region, though the underlying neural mechanism has not been clarified. Therefore, this study sought to assess the characteristics of brain memory function post-rTMS targeting the left dorsolateral prefrontal cortex. The study stimulated the left dorsolateral prefrontal cortex in elderly individuals by performing a high-frequency rTMS protocol and evaluated behavioral performance using cognitive tasks and a VWM task. Based on the simultaneously recorded electroencephalogram signals, event-related potential and event-related spectral perturbation analysis techniques were used to investigate the variation characteristics of event-related potential components' (N2PC and CDA) amplitudes and neural oscillations in elderly individuals to elucidate the effect of high-frequency rTMS. The results found that rTMS enhanced VWM performance and significantly improved attention and executive function in elderly individuals with subjective cognitive decline. We therefore speculate that rTMS enhances VWM by increasing the N2PC and CDA amplitude, alongside increasing ß oscillation activity. This would improve the attention and allocation of resources in elderly individuals such as to improve an individual's VWM.

Clinical and Molecular Features of POLG-Related Sensory Ataxic Neuropathy with Dysarthria and Ophthalmoparesis.

Sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) is a rare mitochondrial disorder associated with mutations in the POLG gene, which encodes the DNA polymerase gamma catalytic subunit. A few POLG-related SANDO cases have been reported, but the genotype-phenotype correlation remains unclear. Here, we report a patient with SANDO carrying two novel missense variants (c.2543G>C, p.G848A and c.452 T>C, p.L151P) in POLG. We also reviewed previously reported cases to systematically evaluate the clinical and genetic features of POLG-related SANDO. A total of 35 distinct variants in the coding region of POLG were identified in 63 patients with SANDO. The most frequent variant was the p.A467T variant, followed by the p.W748S variant. The clinical spectrum of SANDO is heterogeneous. No clear correlation has been observed between the mutation types and clinical phenotypes. Our findings expand the mutational spectrum of POLG and contribute to clinical management and genetic counseling for POLG-related SANDO.

Mutation screening of VPS16 gene in patients with isolated dystonia.

Mutations in VPS16 have been identified to be responsible for generalized dystonia. We screened VPS16 variants in 53 unrelated subjects with isolated dystonia via whole-exome sequencing. A novel pathogenic frameshift mutation p.R643fs* was found in a patient with early-onset multifocal dystonia with prominent oromandibular and bulbar involvement. Our findings expanded the spectrum of VPS16-related dystonia and suggested that mutations in VPS16 should be considered in patients with progressive early-onset dystonia.

Clinical characteristics of perivascular space and brain CT perfusion in stroke-free patients with intracranial and extracranial atherosclerosis of different extents.

BACKGROUND: This study aimed to investigate the clinical characteristics of perivascular space (PVS) and cerebral blood flow (CBF) in stroke-free patients with intracranial and extracranial atherosclerosis of different extents. METHODS: Two hundred and twenty-two patients received carotid artery ultrasonography, magnetic resonance imaging (MRI), cranial computed tomography angiography (CTA) and computed tomography perfusion (CTP). PVS was scored. The extents of intracranial and extracranial arteriosclerosis were evaluated based on the scores of intracranial and extracranial arteriosclerosis. CTP was done to determine the CBF in the region of interest (ROI). The risk factors of vascular disease were assessed in patients with and without PVS. The relationship between PVS and CBF was evaluated among patients with different scores of intracranial and extracranial atherosclerosis. RESULTS: The incidences of intracranial atherosclerosis and extracranial carotid plaque were higher in PVS patients. Subjects with intracranial and/or extracranial arteriosclerosis also had a higher incidence of PVS as compared to controls. The score of intracranial and/or extracranial arteriosclerosis was positively related to the score of basal ganglia PVS. Patients with intracranial and/or extracranial arteriosclerosis had lower CBF as compared to controls. The CBF was negatively associated with the intracranial and/or extracranial arteriosclerosis and the PVS score. CONCLUSIONS: The incidence of PVS in patients with intracranial and extracranial arteriosclerosis is higher than in patients without arteriosclerosis. The extent of intracranial and extracranial atherosclerosis is related to PVS, especially the basal ganglia PVS. The decreased CBF may be associated with the occurrence of PVS.

Controlled growth of single-crystalline metal nanowires via thermomigration across a nanoscale junction.

Mass transport driven by temperature gradient is commonly seen in fluids. However, here we demonstrate that when drawing a cold nano-tip off a hot solid substrate, thermomigration can be so rampant that it can be exploited for producing single-crystalline aluminum, copper, silver and tin nanowires. This demonstrates that in nanoscale objects, solids can mimic liquids in rapid morphological changes, by virtue of fast surface diffusion across short distances. During uniform growth, a thin neck-shaped ligament containing a grain boundary (GB) usually forms between the hot and the cold ends, sustaining an extremely high temperature gradient that should have driven even larger mass flux, if not counteracted by the relative sluggishness of plating into the GB and the resulting back stress. This GB-containing ligament is quite robust and can adapt to varying drawing directions and velocities, imparting good controllability to the nanowire growth in a manner akin to Czochralski crystal growth.

Analysis of correlation between cerebral perfusion and KIM score of white matter lesions in patients with Alzheimer's disease.

PURPOSE: This study aimed to characterize white matter lesions (WMLs) and regional cerebral perfusion, and evaluate their correlations with cognitive deficits in Alzheimer's disease (AD) patients. PATIENT AND METHODS: One hundred and twenty-eight patients with AD (AD group) and 75 subjects without AD (control group) were recruited. The medical information was collected from each subject. Montreal cognitive assessment (MoCA) was employed for the assessment of cognition. Cranial MRI was performed, and the KIM scoring system was used to evaluate the white matter hyperintensity. The CT perfusion (CTP) imaging was employed to assess the whole cerebral perfusion, and the region of interest (ROI) was selected to determine the blood perfusion at different parts. RESULTS: The education level and MoCA score in AD group were significantly lower than in control group (P<0.001). The KIM score of juxtaventricular WML (JVWMLs) was significantly different between two groups (P<0.05) and AD group showed a higher incidence of severe JVWML and periventricular WML (PVWMLs); in AD group, the total KIM score and KIM scores of JVWMLs, PVWMLs and deep WML (DWMLs) showed negative relationships with the MoCA score (P<0.001). As compared to control group, the blood perfusion of either whole brain or different parts in the AD group reduced significantly (P<0.05). In the AD group, there was a negative correlations of blood perfusion at JVWM and PVWM with corresponding KIM scores (P<0.05 or 0.01). In the AD group, the blood perfusions of the whole brain, JVWMLs, PVWMLs and deep WML were negatively related to MoCA score (P<0.05). CONCLUSION: In conclusion, the cognitive deficits in the AD patients are associated with the degree of WMLs, especially the JVWML, PVWML and DWML as well as with the reduced perfusion of JVWM, PVWM and deep WM.

Correlation of Brain Perfusion with White Matter Hyperintensity, Brain Atrophy, and Cognition in Patients with Posterior Cerebral Artery Stenosis and Subjective Cognitive Decline.

BACKGROUND This study aimed to investigate the correlation of brain perfusion with white matter hyperintensity (WMH), brain atrophy, and cognition in patients with moderate to severe posterior cerebral artery stenosis (PCAS). MATERIAL AND METHODS 65 patients with memory decline as the main complaint and no history of brain infarction were recruited from the Department of Neurology of Tongji Hospital. Patients with moderate to severe PCAS were included in case group, and subjects with normal intracranial blood vessels served as controls. The demographics and vascular risk factors were recorded. Montreal Cognitive Assessment (MoCA) was used to evaluate the cognition. CT perfusion imaging was performed, and WASID was employed for the assessment of intracranial artery stenosis. The region of interest (ROI) was analyzed based on the whole brain perfusion. Cranial MRI was performed, and Scheltens scoring system was used for the assessment of WMH on FLAIR. T1 weighed images were obtained, and global cortical atrophy (GCA) scale was employed for the assessment of brain atrophy. The detections of brain perfusion, WMH and brain atrophy were done at centrum ovale, parietal lateral ventricle and basal ganglia layers. RESULTS In PCAS patients we found low perfusion in the antecornu and postcornu blood supply areas at the lateral ventricle, the blood supply area of the anterior cerebral artery, the blood supply area of the posterior cerebral artery, and the blood supply area at the hippocampus as compared with control subjects (p<0.05). As compared with control subjects, the incidence of WMH in the blood supply areas at the deep brain and lateral ventricle was significantly higher in PCAS patients (p<0.05). When compared with controls, the incidence of brain atrophy increased significantly in PCAS patients (p<0.01). Correlation analysis showed the brain perfusion at the blood supply area of the posterior cerebral artery was positively correlated to the total MoCA score and negatively correlated to the severity of WMH at the blood supply area of the posterior cerebral artery (p<0.05). Further analysis showed the brain perfusion at the blood supply area of the posterior cerebral artery was negatively associated with cortex supplied by the posterior cerebral artery, posterior cingulate, and hippocampus (p<0.01). CONCLUSIONS PCAS patients have a higher incidence of brain atrophy, and the perfusion at the area supplied by the posterior cerebral artery is correlated to the severity of brain atrophy and of WMH, as well as to cognition decline.

Endovascular isolation of intracranial blood blister-like aneurysms with Willis covered stent.

OBJECTIVE: Intracranial blood blister-like aneurysm (BBA) is a rare type of aneurysm that lacks all layers of the arterial wall. These fragile aneurysms have the propensity to rupture with minimal manipulation, which makes them hazardous and difficult to treat. The present study evaluated the safety and feasibility of endovascular treatment of BBAs with the Willis covered stent. MATERIALS: Thirteen patients (7 men and 6 women, age range 28-68 years) who presented with ruptured BBAs and were treated with the Willis covered stent were retrospectively reviewed. Results of the procedures and treatment-related complications were recorded. Angiographic and clinical follow-ups were performed 4-6 months after the procedure. RESULTS: Placement of the covered stent was successful in all patients. Immediate angiography showed complete aneurysm occlusion in 12 patients while one patient showed a mild endoleak. This high rate of aneurysm exclusion ensured the security of postoperative antiplatelet treatment. Occlusion of the ophthalmic artery occurred in two patients and occlusion of the anterior choroidal artery occurred in one patient; however, none of them showed acute or delayed clinical symptoms. Thrombosis, aneurysm rupture, and other complications did not develop in any case. Angiographic follow-up showed complete aneurysm exclusion without aneurysm recurrence in any patients. Only two patients showed asymptomatic mild to moderate in-stent stenosis. All patients had satisfactory clinical outcomes (modified Rankin Scale score ≤1). CONCLUSIONS: Willis covered stent implementation may be safe and feasible for BBAs. This strategy might be a promising option for this high-risk type of aneurysm.

Effects of Tai Chi and Multimodal Exercise Training on Movement and Balance Function in Mild to Moderate Idiopathic Parkinson Disease.

OBJECTIVE: The primary aim of this study was to investigate the effects of two different patterns of rehabilitation training on movement and balance function in patients with idiopathic Parkinson disease. DESIGN: Forty patients with Parkinson disease were randomized into the tai chi group (n = 20) or the multimodal exercise training group (n = 20). Outcome measures were assessed at baseline and after 12 wks of exercise. Balance was assessed using the Berg Balance Scale, and movement was assessed by the Unified Parkinson's Disease Rating Scale-Motor Examination, stride length, gait velocity, and Timed Up and Go Test. RESULTS: The multimodal exercise training group improved significantly in movement from baseline, and a reduction in balance impairment was observed for the multimodal exercise training group. The questionnaire results after training showed that the multimodal exercise training is easy to learn and adhere to. No major adverse events were noted in both groups. CONCLUSIONS: This multimodal exercise training could improve motion function and benefit balance function in patients with Parkinson disease. The multimodal exercise training is easy to learn and practice.

Gene expression profile and functional analysis of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder with largely unknown genetic mechanisms. Identifying altered neuronal gene expression in brain regions differentially affected by AD may provide the diagnostic or therapeutic targets of AD. METHODS: The gene expression profile of AD was analyzed with bioinformatics. Function analysis was performed with Database for Annotation, Visualization and Integrated Discovery (DAVID), and TransFind was used to predict the possible transcriptional regulators in AD. Finally, connectivity map (cMap) database was used to explore small molecules targeted for AD. RESULTS: The AD gene signatures associated with 6 different brain regions were identified. Functional analysis revealed that biological processes involved with metabolism, protein ubiquitination, and vasculature development were found dysregulated, and synaptic signaling pathways were found perturbated in AD. The WT1 was identified as an important transcriptional regulator in AD, and cMap database predicted that small molecules, such as histone deacetylase (HDAC) inhibitor, may be candidate drugs in the treatment of AD. CONCLUSION: According to our in silico analysis, Wilms' tumor suppressor may play regulatory roles in AD development and progress. The HDAC inhibitor could possibly be used to treat AD.

Screening for Parkinson syndrome in a Chinese rural population: re-examination of a historic questionnaire.

BACKGROUND: Standardized screening tools for Parkinson syndrome have not been developed for non-western populations. This study aimed to validate the Copiah County questionnaire (CCQ) as a screening instrument in a Chinese rural population. METHODS: All participants of a previously reported prevalent study were interviewed using CCQ. The participants who answered yes to at least one item on CCQ were defined as positive. The Parkinson's disease (PD) diagnosis was established using United Kingdom Parkinson's disease Brain Bank Clinical diagnosis criteria (UKPDBBC) and served as a gold standard to determine the sensitivity, specificity, and positive and negative predictive values (PPV, NPV) for the questionnaire. RESULTS: Among 16 130 participants, 2872 (17.8%) were screened positive for CCQ and 13 258 negative (82.2%). Among the 697 participants diagnosed as having Parkinson syndrome, 605 were positive for CCQ, and 92 were negative, leading to a sensitivity of 86.8%. Out of the 15 433 non-Parkinson syndrome participants, 13 166 were negative to CCQ, giving a specificity of 85.3%. Among the 2872 participants screened positive, 605 were diagnosed with Parkinson syndrome, and their PPV was 21.1%. For the 13 258 participants screened negative on CCQ, 92 were diagnosed with Parkinson syndrome and 13 166 did not have Parkinson syndrome, leading to a NPV of 99.3%. CONCLUSIONS: CCQ appeared to have satisfactory statistical parameters to serve as a screening instrument for Parkinson syndrome in this rural Chinese population. Further studies may prove the utility of this short questionnaire in Parkinson syndrome screening among Chinese populations including those residing in rural areas.

The two different effects of the potential neuroprotective compound minocycline on AMPA-type glutamate receptors.

BACKGROUND: Minocycline has demonstrated neuroprotective effects in experimental neurodegenerative diseases. The aim of this study was to investigate if there is any direct interaction between minocycline and the AMPA-type receptor channels, and to elucidate the underlying molecular pharmacological mechanisms. METHODS: The patch-clamp technique was used combined with an ultrafast solution exchange system to investigate the interaction of minocycline with recombinant AMPA-type glutamate receptor channels (homomeric GluR2flipGQ or nondesensitizing GluR2L504Y). RESULTS: Dose-dependent decreases in the relative peak current amplitude (rAmp) and the relative steady-state current (rC(des)) were found in coapplication experiments with GluR2L504Y receptors, but not in preincubation experiments. Furthermore, coapplication of 1 or 3 mmol/l minocycline showed a decrease in the fast time constant of current decay, and reopening currents were observed. But in the test with GluR2flipGQ receptors, rAmp, relative area under the curve and rC(des) increased with increasing concentrations of minocycline, and the steady-state time constant also increased when 3 µmol/l glutamate were used as agonist. CONCLUSION: Minocycline modulates AMPA-type receptor channels in a combination of a weaker open-channel block effect and a stronger potentiation effect, and the latter effect arises mainly from attenuating the extent of receptor desensitization.