Prevalence and clinical predictors of spasticity after intracerebral hemorrhage.

BACKGROUND: Spasticity is a common complication of intracerebral hemorrhage (ICH). However, no consensus exists on the relation between spasticity and initial clinical findings after ICH. METHODS: This retrospective study enrolled adult patients with a history of ICH between January 2012 and October 2020. The modified Ashworth scale was used to assess spasticity. A trained image analyst traced all ICH lesions. Multivariable logistic regression was used to examine the association between ICH lesion sites and spasticity. RESULTS: We finally analyzed 304 patients (mean age 54.86 ± 12.93 years; 72.04% men). The incidence of spasticity in patients with ICH was 30.92%. Higher National Institutes of Health stroke scale (NIHSS) scores were associated with an increased predicted probability for spasticity (odds ratio, OR = 1.153 [95% confidence interval, CI 1.093-1.216], p < .001). Logistic regression analysis revealed that lower age, higher NIHSS scores, and drinking were associated with an increased risk of moderate-to-severe spasticity (OR = 0.965 [95% CI 0.939-0.992], p = .013; OR = 1.068 [95% CI 1.008-1.130], p = .025; OR = 4.809 [95% CI 1.671-13.840], p = .004, respectively). However, smoking and ICH in the thalamus were associated with a reduced risk of moderate-to-severe spasticity (OR = 0.200 [95% CI 0.071-0.563], p = .002; OR = 0.405 [95% CI 0.140-1.174], p = .046, respectively) compared with ICH in the basal ganglia. CONCLUSIONS: Our results suggest that ICH lesion locations are at least partly associated with post-stroke spasticity rather than the latter simply being a physiological reaction to ICH itself. The predictors for spasticity after ICH were age, NIHSS scores, past medical history, and ICH lesion sites.

Rehabilitation Therapy for Vocal Fold Paralysis Caused by Lung Cancer: A Case Report.

OBJECTIVE: Unilateral vocal fold paralysis (UVFP) can be caused by iatrogenic injury or tumor-induced damage to the recurrent laryngeal nerve. Studies of comprehensive rehabilitation therapies for patients suffering from severe UVFP are limited. The purpose of this case report is to describe an improvement in complete aphonia after comprehensive rehabilitation therapies in a patient with severe UVFP due to a lung tumor. METHODS: An 81-year-old woman with a history of bronchial adenoma had complete aphonia due to compression of the left recurrent laryngeal nerve by the tumor. Dynamic fibrolaryngoscope revealed paralysis of the left vocal fold. The patient was treated with interferential current therapy, vocal training, and kinesiology taping. Indicators of voice recovery were scored according to the grade, roughness, breathiness, asthenia, strain scale, and the voice handicap index. RESULTS: After 10 days of comprehensive rehabilitation treatment, the patient recovered from complete aphonia to normal communication. The hoarseness and breathiness of patient were significantly improved. In addition, the grade, roughness, breathiness, asthenia, strain, and the voice handicap index scores changed from severe to mild or absent. CONCLUSION: This case provided a novel comprehensive treatment for a patient with UVFP, which was safe, cost-effective, and easy to implement in clinic.

The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau.

Tau pathology is characterized as a form of frontotemporal lobar degeneration (FTLD) known as FTLD-tau. The underlying pathogenic mechanisms are not known and no therapeutic interventions are currently available. Here, we report that the neurotrophin receptor p75NTR plays a critical role in the pathogenesis of FTLD-tau. The expression of p75NTR and the precursor of nerve growth factor (proNGF) were increased in the brains of FTLD-tau patients and mice (P301L transgenic). ProNGF-induced tau phosphorylation via p75NTR in vitro, which was associated with the AKT/glycogen synthase kinase (GSK)3ß pathway. Genetic reduction of p75NTR in P301L mice rescued the memory deficits, alleviated tau hyperphosphorylation and restored the activity of the AKT/GSK3ß pathway. Treatment of the P301L mice with the soluble p75NTR extracellular domain (p75ECD-Fc), which can antagonize neurotoxic ligands of p75NTR, effectively improved memory behavior and suppressed tau pathology. This suggests that p75NTR plays a crucial role in tau paGSKthology and represents a potential druggable target for FTLD-tau and related tauopathies.

Cysteine-Rich Repeat Domains 2 and 4 are Amyloid-ß Binding Domains of Neurotrophin Receptor p75NTR and Potential Targets to Block Amyloid-ß Neurotoxicity.

The p75 neurotrophin receptor (p75NTR) is an amyloid-ß (Aß) receptor that both mediates Aß neurotoxicity and regulates Aß production and deposition, thus playing an important role in the pathogenesis of Alzheimer's disease (AD). The extracellular domain of p75NTR (p75ECD), consisting of four cysteine-rich repeat domains (CRDs), was recently reported to be an endogenous anti-Aß scavenger to block p75NTR-mediated neuronal death and neurite degeneration signaling of Aß and pro-neurotrophins. Identification of the specific Aß binding domains of p75NTR is crucial for illuminating their interactions and the etiology of AD. CRDs of p75ECD were obtained by expression of recombinant plasmids or direct synthesis. Aß aggregation inhibiting test and immunoprecipitation assay were applied to locate the specific binding domains of Aß to p75ECD. The Aß neurotoxicity antagonistic effects of different CRDs were examined by cytotoxicity experiments including neurite outgrowth assay, propidium iodide (PI) staining, and MTT assay. In the Aß aggregation inhibiting test, the fluorescence intensity in the CRD2 and CRD4 treatment groups was significantly lower than that in the CRD1 and CRD3 treatment groups. Immunoprecipitation assay and western blot confirmed that Aß could bind to CRD2 and CRD4. Besides, CRD2 and CRD4 antagonized Aß neurotoxicity suggested by longer neurite length, less PI labelled cells, and higher cell viability than the control group. Our results indicate that CRD2 and CRD4 are Aß binding domains of p75NTR and capable of antagonizing Aß neurotoxicity, and therefore are potential therapeutic targets to block the interaction of Aß and p75NTR in the pathogenesis of AD.

Influence of interleukin-6 gene -174G>C polymorphism on development of atherosclerosis: a meta-analysis of 50 studies involving 33,514 subjects.

Increasing epidemiological studies have focused on the associations between interleukin-6 (IL-6) gene -174G>C polymorphism and atherosclerotic diseases, but the results are still controversial. This meta-analysis was designed to identify whether this association exists. PubMed, Embase, Web of Science, Cochrane database, Clinicaltrials.gov and Current Controlled Trials, Chinese Clinical Trial Registry, CBMdisc, CNKI and Google Scholar were searched to get the genetic association studies. The crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were used to estimate the association between the IL-6 gene -174G>C polymorphism and atherosclerosis ( AS ) risk. The subgroup analyses were made on the following: ethnicity, atherosclerotic diseases and source of controls. Finally, 50 studies (15,029 cases and 18,485 controls) were included in this meta-analysis. Overall, no significant association was found between the IL-6 gene -174G>C polymorphism and AS risk (for C allele vs. G allele: OR=1.02, 95% CI=0.94-1.11, p=0.64; for C/C vs. G/G: OR=1.01, 95% CI=0.85-1.21, p=0.88; for C/C vs. C/G+G/G: OR=0.97, 95% CI=0.84-1.12, p=0.68; for C/C+C/G vs. G/G: OR=1.07, 95% CI=0.97-1.17, p=0.18). In the subgroup analyses, significant associations were found between the IL-6 gene -174G>C polymorphism and AS in non-Caucasian group (for CC+CG vs. GG: OR=1.22, 95% CI=1.06-1.41, p=0.005), other atherosclerotic diseases group (for C allele vs. G allele: OR =0.75, 95% CI=0.61-0.93, p=0.008; for C/C vs. G/G: OR=0.56, 95% CI=0.38-0.81, p=0.002; for C/C vs. C/G+G/G: OR=0.60, 95% CI=0.45-0.79, p=0.0004) and population-based group (for C allele vs. G allele: OR=1.09, 95% CI=1.00-1.18, p=0.04; for CC+CG vs. GG: OR=1.15, 95% CI=1.04-1.27, p=0.005). In summary, the present meta-analysis suggests that the IL-6 gene -174G C polymorphism is associated with the susceptibility to AS. However, due to the high heterogeneity in the meta-analysis, the results should be interpreted with caution.

Inhibition of reactive oxygen species generation attenuates TLR4-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells.

Reactive oxygen species (ROS) are associated with inflammation and vasculature dysfunction. This study aimed to investigate the potential role of the ROS on vascular Toll-like receptor 4 (TLR4)-mediated proinflammatory and proliferative phenotype of vascular smooth muscle cells (VSMCs). A wire-induced carotid injury model was used in male TLR4-deficient (TLR4(-/-)) and wild-type C57BL/6J mice to induce neointima formation. In the presence or absence of the ROS scavenger apocynin for 14 days, increased TLR4 and proinflammatory cytokines were observed in wire injury-induced carotid neointima and in platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMCs. The TLR4(-/-) protected the injured carotid from neointimal formation and impaired the cellular proliferation and migration in response to PDGF-BB. Apocynin attenuated intimal hyperplasia. Pre-treatment with apocynin significantly inhibited intracellular ROS generation, accompanied by a significant suppression of TLR4 and proinflammatory cytokines expression, and VSMC proliferation and migration. However, the results were not obvious in TLR4(-/-) condition. These findings highlight the importance of ROS inhibition in TLR4-mediated proinflammatory and proliferative phenotype of VSMCs, and suggest ROS as an essential therapeutic target for TLR4-associated vascular inflammation and vascular diseases.

Association between estrogen receptor alpha c.454-397T>C and c.454-351A>G and ischemic stroke risk: a systematic review and meta-analysis.

The association between estrogen receptor alpha (ESR1) c.454-397T>C and c.454-351A>G polymorphism and ischemic stroke remains controversial. The aim of this study was to perform a meta-analysis to investigate a more authentic association between c.454-397T>C and c.454-351A>G mutation and ischemic stroke. Systematic searches of electronic databases Embase, PubMed, Web of Science as well as hand-searching of the references of identified articles and the meeting abstracts were performed. Study selection, data abstraction and study quality evaluation were independently conducted in duplicate. Statistical analyses were performed using software Stata 11.0. The pooled odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were performed. Different effect models were used according to the difference in heterogeneity. Publication bias was tested by Begg's funnel plot and Egger's regression test. For c.454-397T>C mutation, five studies were combined. Significant association was found in allelic model (OR = 1.12, 95 % CI = 1.01-1.25, p = 0.03), additive model (OR = 1.25, 95 % CI = 1.01-1.54, p = 0.04), and recessive model (OR = 1.23, 95 % CI = 1.02-1.49, p = 0.03), whereas no evidence of association was found for dominant model (OR = 1.10, 95 % CI = 0.85-1.42, p = 0.47). For c.454-351A>G mutation, no evidence of association was found for all genetic models. Our meta-analysis suggests that ESR1 c.454-397T>C mutation is significantly associated with increased risk of ischemic stroke, whereas no evidence of association was found for ESR1 c.454-351A>G mutation.

[Clinical characteristics and risk factors of hemodynamic depression after carotid angioplasty and stenting].

OBJECTIVE: To investigate the carotid angioplasty and stenting (CAS)-induced hemodynamic depression (HD) and its impact on postprocedural complications so as to identify its risk factors. METHODS: The incidence, onset time, duration and severity of HD were observed in 196 CAS patients. The influences of clinical baseline and vascular angiographic characteristics on HD were recorded and the relationship between HD and postprocedural complications was analyzed. Logistic regression analysis was used to identify the independent risk factors of HD. RESULTS: The incidence of HD was 53.1%. Most cases of HD (67.3%) developed within 1 - 16 hours postprocedural. And 55.8% HD lasted for over 24 hours and became relieved within 3 - 16 days post-operation. And 78.9% HD patients required medications for the controls of blood pressure and heart rate. Diabetes, hypertension, smoking, plaque involving carotid bulb, ulcerated plaque and calcified plaque were shown to be associated with HD. Further analysis of logistic regression suggested that diabetes and smoking were two protective factors for HD while plaque involving carotid bulb and calcified plaque two independent risk factors for HD. The HD patients were at an increased risk of neurological and cardiopulmonary complications. CONCLUSION: With a high post-CAS incidence after CAS, HD is associated with postprocedural complications. Lesions involving carotid bulb and calcified plaque are two independent risk factors for HD.

p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain.

Accumulation of toxic amyloid-ß (Aß) in the cerebral cortex and hippocampus is a major pathological feature of Alzheimer's disease (AD). The neurotrophin receptor p75NTR has been proposed to mediate Aß-induced neurotoxicity; however, its role in the development of AD remains to be clarified. The p75NTR/ExonIII-/- mice and APPSwe/PS1dE9 mice were crossed to generate transgenic AD mice with deletion of p75NTR gene. In APPSwe/PS1dE9 transgenic mice, p75NTR expression was localized in the basal forebrain neurons and degenerative neurites in neocortex, increased with aging, and further activated by Aß accumulation. Deletion of the p75NTR gene in APPSwe/PS1dE9 mice reduced soluble Aß levels in the brain and serum, but increased the accumulation of insoluble Aß and Aß plaque formation. There was no change in the levels of amyloid precursor protein (APP) and its proteolytic derivatives, or α-, ß-, and γ-secretase activities, or in levels of BACE1, neprilysin (NEP), and insulin-degrading enzyme (IDE) proteins. Aß production by cortical neurons of APPSwe/PS1dE9 mice was reduced by deletion of p75NTR gene in vitro. Recombinant extracellular domain of p75NTR attenuated the oligomerization and fibrillation of synthetic Aß(42) peptide in vitro, and reduced local Aß plaques after hippocampus injection in vivo. In addition, deletion of p75NTR attenuated microgliosis but increased the microhemorrhage profiles in the brain. The deletion of p75NTR did not significantly change the cognitive function of the mice up to the age of 9 months. Our data suggest that p75NTR plays a critical role in regulating Aß levels by both increasing Aß production and attenuating its aggregation, and they caution that a therapeutic intervention simply reducing p75NTR may exacerbate AD pathology.

Intramuscular delivery of a single chain antibody gene prevents brain Aß deposition and cognitive impairment in a mouse model of Alzheimer's disease.

Anti-beta-amyloid (Aß) immunotherapy is effective in removing brain Aß, but has shown to be associated with detrimental effects. We have demonstrated that Adeno-associated virus (AAV)-mediated delivery of an anti-Aß single chain antibody (scFv) gene was effective in clearing brain Aß without eliciting any inflammatory side effects in old APP(Swe)/PS1dE9 transgenic mice. In the present study, we tested the efficacy and safety of intramuscular delivery of the scFv gene in preventing brain Aß deposition. The scFv gene was intramuscularly delivered to APP(Swe)/PS1dE9 transgenic mice at 3 months of age, prior to Aß deposition in the brain. Six months later, we found that the transgenes were expressed in a stable form at the delivered sites, with a small amount of ectopic expression in the liver and olfactory bulb. Brain Aß plaque formation, Aß accumulation, AD-type pathologies and cognitive impairment were significantly attenuated in scFv-treated APP(Swe)/PS1dE9 transgenic mice relative to EGFP-treated mice. Intramuscular delivery of scFv gene was well tolerated by the animals, did not cause inflammation or microhemorrhage at the gene expression site and in the brain, and did not induce neutralizing antibodies in the animals. These findings suggest that peripheral application of scFv is effective and safe in preventing the development of Alzheimer's disease (AD), and would be a promising non-inflammatory immunological modality for prevention and treatment of AD.

Nicotine exacerbates tau phosphorylation and cognitive impairment induced by amyloid-beta 25-35 in rats.

Nicotine was reported to reduce the plaque burden and could be used as a possible anti-Alzheimer's disease agent. However, the effect of nicotine on memory and tau pathology in Alzheimer's disease has been less studied. The present study investigated the effect of nicotine on tau phosphorylation and cognitive impairment induced by hippocampus injections of amyloid-beta (Abeta) 25-35. Rats were treated with nicotine hydrogen tartrate salt dissolved in normal saline by subcutaneous injection twice per day for 14 days. The age and gender matched rats treated with same amount of normal saline were used as the control. Morris water maze was used to detect the cognitive impairment induced by Abeta25-35. Compared to the sham-operated rats, Abeta25-35 injection significantly prolonged the mean escape latency in vehicle-treated rats in the Morris water maze test and increased the number of tau(pS202) and tau(pT231) immunoreactive cells. The data show that nicotine (1mg/kg in base weight) treatment significantly exacerbates cognitive impairment and tau phosphorylation at Ser-202 and Thr-231 in the hippocampus compared with Abeta25-35 injection groups in the Abeta rat model of Alzheimer's disease. The use of nicotine for treatment of Alzheimer's disease should be reassessed.

Effects of proNGF on neuronal viability, neurite growth and amyloid-beta metabolism.

Alzheimer's disease (AD) is characterized pathologically by the deposition of amyloid-beta peptides (Abeta), neurofibrillary tangles, distinctive neuronal loss and neurite dystrophy. Nerve growth factor (NGF) has been suggested to be involved in the pathogenesis of AD, however, the role of its precursor (proNGF) in AD remains unknown. In this study, we investigated the effect of proNGF on neuron death, neurite growth and Abeta production, in vitro and in vivo. We found that proNGF promotes the death of different cell lines and primary neurons in culture, likely dependent on the expression of p75(NTR). We for the first time found that proNGF has an opposite role in neurite growth to that of mature NGF, retarding neurite growth in both cell lines and primary neurons. proNGF is localized to the Abeta plaques in AD mice brain, however, it had no significant effect on Abeta production in vitro and in vivo. Our findings suggest that proNGF is an important factor involving AD pathogenesis.