Association between internal carotid artery kinking and ischemic stroke: A population-based cross-sectional study.

AIM: Evidence for an association between Internal carotid artery (ICA) kinking and ischemic stroke has been controversial. We aimed to examine the association between ICA tortuosity and risk of ischemic stroke and specific ischemic stroke subtypes (large artery atherosclerosis, LAA; small artery occlusion, SAO). METHODS: A total of 419 outpatients were included in this cross-sectional study. ICA kinking was objectively assessed by head and neck computed tomography angiography (CTA). The risk of ischemic stroke for each patient was evaluated according to the Essen Stroke Risk Score (ESRS). Ischemic stroke subtypes (LAA and SAO) were measure with head magnetic resonance imaging (MRI). RESULTS: The average age of patients was 59.1 years (SD = 13.25) and 264 (63.0 %) were males. The prevalence of ICA kinking in this sample was 31.5 % (132 out of 419). Individuals with ICA kinking was associated with 0.55-points increase in ESRS score than those without ICA kinking (95 % CI, 0.28-0.81, p < 0.001) among patients over 50 years. In addition, right ICA kinking or left ICA kinking were associated with 0.35-points (95 % CI, 0.08-0.63) and 0.49-points (95 % CI, 0.23-0.76) increase in ESRS score, respectively. For specific ischemic stroke subtypes, individuals with ICA kinking had a 10.34-fold increased risk of SAO compared to those without ICA kinking (95 % CI, 6.22-20.68). Individuals with right ICA kinking had a 4.51-fold risk of SAO than those without kinking (95 % CI, 2.64-7.71), and had an 8.86-fold risk of SAO than those without kinking in the left ICA kinking (95 % CI, 4.97-15.79). CONCLUSION: Our findings support the role of ICA kinking on ischemic stroke. Early screening and proper treatment of carotid artery tortuosity could be a potential intervention strategy for the prevention of ischemic stroke later on.

Blood cell-produced amyloid-ß induces cerebral Alzheimer-type pathologies and behavioral deficits.

It is traditionally believed that cerebral amyloid-beta (Aß) deposits are derived from the brain itself in Alzheimer's disease (AD). Peripheral cells such as blood cells also produce Aß. The role of peripherally produced Aß in the pathogenesis of AD remains unknown. In this study, we established a bone marrow transplantation model to investigate the contribution of blood cell-produced Aß to AD pathogenesis. We found that bone marrow cells (BMCs) transplanted from APPswe/PS1dE9 transgenic mice into wild-type (Wt) mice at 3 months of age continuously expressed human Aß in the blood, and caused AD phenotypes including Aß plaques, cerebral amyloid angiopathy (CAA), tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits in the Wt recipient mice at 12 months after transplantation. Bone marrow reconstitution in APPswe/PS1dE9 mice with Wt-BMCs at 3 months of age reduced blood Aß levels, and alleviated brain Aß burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the AD model mice at 12 months after transplantation. Our study demonstrated that blood cell-produced Aß plays a significant role in AD pathogenesis, and the elimination of peripheral production of Aß can decrease brain Aß deposition and represents a novel therapeutic approach for AD.

Exercise-induced muscle damage: multi-parametric MRI quantitative assessment.

BACKGROUND: To explore the value of magnetic resonance quantitative analysis using diffusion tensor imaging, T2 mapping, and intravoxel incoherent motion in the evaluation of eccentric exercise-induced muscle damage and to compare the effects of various eccentric exercise modes at different time points in rats. METHODS: A total of 174 Sprague-Dawley male rats were randomly divided into five groups: control, once-only exercise, continuous exercise, intermittent exercise, and once-fatigue exercise groups. Each experimental group was divided into seven time-subgroups: 0.5 h, 24 h, 48 h, 72 h, 96 h, 120 h and 168 h after exercise. The quadriceps femoris muscles were then scanned using magnetic resonance imaging. The apparent diffusion coefficient and fractional anisotropy values of diffusion tensor imaging, T2 values of T2 mapping, D and D* values of intravoxel incoherent motion and optical density values of desmin were measured. Associations among different eccentric exercise programmes, magnetic resonance imaging findings, and histopathological results were evaluated. Dunnett's test, two-way repeated measures analysis of variance, and Pearson correlation analysis were used for statistical analysis. RESULTS: Diffusion tensor imaging showed that the number of muscle fibre bundles decreased to varying degrees with different time points and eccentric exercises. Apparent diffusion coefficient values of the exercise groups showed a trend that first increased and then decreased, the opposite of fractional anisotropy. The specimens in all eccentric exercise programmes showed high signal T2 values after exercise, the highest among which was in the once-fatigue exercise group. D and D* in the experimental groups were significantly higher than those in the control group at 0.5-48 h after exercise. The apparent diffusion coefficient, fractional anisotropy, T2, D and D* values correlated with the optical density values of desmin. CONCLUSIONS: Diffusion tensor imaging, T2 mapping, and intravoxel incoherent motion technology accurately reflect the degree of skeletal muscle damage and recovery associated with eccentric exercise. The degree of muscle damage was the lowest in the continuous exercise group and the highest in the once-fatigue exercise group, which may provide more information and guidance for the formulation of physical and athletic training programmes.

Analysis of risk factors for depression in Alzheimer's disease patients.

Purpose: Depression, which affects about 52% of Alzheimer's disease (AD) patients, can worsen cognitive impairment and increase mortality and suicide rates. We hope to provide clinical evidence for the prevention and treatment of depression in AD patients by investigating related risk factors of depression in AD patients.Methods: 158 AD inpatients of the Department of Neurology, Daping Hospital from September 2017 to March 2019 were enrolled. General information, laboratory tests, cognitive and emotional function assessments of the inpatients were collected. Logistic regression was used to analyze the risk factors of depression in AD patients, and the relationship between 17 Hamilton depression scale scores and HbA1c levels in AD patients was further analyzed.Results: The prevalence of age, gender, hypertension, hyperlipidemia, Type 2 diabetes mellitus (T2DM), and white matter lesions (WML) in the AD with depression group was significantly different from without depression group. Hypertension, T2DM, and WML are independent risk factors for depression in AD patients. The depression scores of AD patients with HbA1c>6.5% were significantly higher than AD patients with HbA1c ≤ 6.5%, and there were significant difference in depression scale scores between using anti-diabetes drugs group and not using anti-diabetes drugs group whose HbA1c level is >6.5%, while no difference in depression scores between using anti-diabetes drugs group and not using anti-diabetes drugs group whose HbA1c level is ≤6.5%.Conclusion: T2DM is an independent risk factor for AD patients with depression. Increased HbA1c levels aggravate depression in AD patients, and controlling HbA1c levels and anti-diabetes drugs can reduce the severity of depression in AD patients.

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.

Effects of Metabolic Syndrome on Cognitive Impairment with White Matter Lesions.

OBJECTIVE: To explore the relationship between metabolic syndrome (MetS) and cognitive impairment in elderly patients with white matter lesions (WML). METHODS: From -January 2016 to June 2017, a cross-sectional study was conducted on the clinical data of 358 WML patients over 65 years old in the Department of Neurology of the Daping Hospital. Mini-mental state examination scales were used to evaluate the cognitive function of the patients, and the cognitive impairment was diagnosed and grouped according to the scoring and diagnostic criteria. All WML patients were divided into the cognitive impairment group and normal cognition group. Clinical data of age, sex, education level, body mass index, abdominal circumference, smoking and alcohol consumption, blood pressure, fasting blood glucose, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) were collected. Multivariate logistic regression analyses were performed to examine the relationship between MetS and cognitive impairment in WML patients. RESULTS: Compared with the normal cognition group, the proportion of MetS in the cognitive impairment group was significantly higher (χ2 = 11.211, p < 0.01), the proportion of MetS components such as elevated blood pressure, elevated blood glucose, elevated TG, decreased HDL-C and abdominal obesity in the cognitive impairment group was also higher (p < 0.01 or p < 0.05). After adjustment for age, sex, low education level, current smoking, daily drinking, severity of WML, MetS, and its components, multivariate logistic regression analysis showed that MetS was an independent risk factor for cognitive impairment in WML patients (OR 3.32, 95% CI 1.31-5.19). In addition, The greater the number of MetS components, the higher the risk of cognitive impairment in WML patients (ptrend < 0.01). CONCLUSION: MetS is an independent risk factor for cognitive impairment in patients with WML.

Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies.

Accumulation of pathological tau is the hallmark of Alzheimer's disease and other tauopathies and is closely correlated with cognitive decline. Clearance of pathological tau from the brain is a major therapeutic strategy for tauopathies. The physiological capacity of the periphery to clear brain-derived tau and its therapeutic potential remain largely unknown. Here, we found that cisterna magna injected 131I-labelled synthetic tau dynamically effluxed from the brain and was mainly cleared from the kidney, blood, and liver in mice; we also found that plasma tau levels in inferior vena cava were lower than those in femoral artery in humans. These findings suggest that tau proteins can efflux out of the brain and be cleared in the periphery under physiological conditions. Next, we showed that lowering blood tau levels via peritoneal dialysis could reduce interstitial fluid (ISF) tau levels in the brain, and tau levels in the blood and ISF were dynamically correlated; furthermore, tau efflux from the brain was accelerated after the addition of another set of peripheral system in a parabiosis model. Finally, we established parabiosis mouse models using tau transgenic mice and their wild-type littermates and found that brain tau levels and related pathologies in parabiotic transgenic mice were significantly reduced after parabiosis, suggesting that chronic enhancement of peripheral tau clearance alleviates pathological tau accumulation and neurodegeneration in the brain. Our study provides the first evidence of physiological clearance of brain-derived pathological tau in the periphery, suggesting that enhancing peripheral tau clearance is a potential therapeutic strategy for tauopathies.

Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits.

Alzheimer's disease (AD) is one of most devastating diseases affecting elderly people. Amyloid-ß (Aß) accumulation and the downstream pathological events such as oxidative stress play critical roles in pathogenesis of AD. Lessons from failures of current clinical trials suggest that targeting multiple key pathways of the AD pathogenesis is necessary to halt the disease progression. Here we show that Edaravone, a free radical scavenger that is marketed for acute ischemic stroke, has a potent capacity of inhibiting Aß aggregation and attenuating Aß-induced oxidation in vitro. When given before or after the onset of Aß deposition via i.p. injection, Edaravone substantially reduces Aß deposition, alleviates oxidative stress, attenuates the downstream pathologies including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, synaptic dysfunction, and rescues the behavioral deficits of APPswe/PS1 mice. Oral administration of Edaravone also ameliorates the AD-like pathologies and memory deficits of the mice. These findings suggest that Edaravone holds a promise as a therapeutic agent for AD by targeting multiple key pathways of the disease pathogenesis.

Concomitant Asymptomatic Intracranial Atherosclerotic Stenosis Increase the 30-Day Risk of Stroke in Patients Undergoing Symptomatic Intracranial Atherosclerotic Stenosis Stenting.

BACKGROUND: In the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, 19.1% of ischemic strokes occurred out of the territory of previously symptomatic stenosis during the mean follow-up period of 23.4 months. However, it is unknown how many ischemic strokes were due to a previously asymptomatic intracranial atherosclerotic stenosis (ICAS). The objective of this study was to investigate whether the concomitant asymptomatic ICAS influences the outcome of patients undergoing symptomatic ICAS stenting. METHODS: We retrospectively reviewed 576 consecutive patients with nondisabling ischemic stroke (modified Rankin scale score of ≤3) who were treated with symptomatic ICAS (≥70% stenosis) stenting with or without concomitant asymptomatic ICAS. The baseline characteristics and the 30-day primary end points (stroke or death after stenting) were compared by bivariate and multivariable logistic analyses. RESULTS: The 30-day rate of primary end points was 5.2%, which was higher in patients with concomitant asymptomatic ICAS (≥50% stenosis) than in those without asymptomatic ICAS (no stenosis or <50% stenosis) (8.9% versus 3.8%, P = .014). In patients with concomitant asymptomatic ICAS, 25% of ischemic strokes occurred out of the territory of the stented artery, whereas in patients without asymptomatic ICAS, no ischemic stroke occurred out of the territory of the stented artery. Multivariable analysis showed that concomitant asymptomatic ICAS was an independent risk factor for 30-day stroke (odds ratio = 2.37, 95% confidence interval, 1.14-5.63; P = .023). CONCLUSIONS: Concomitant asymptomatic ICAS (≥50% stenosis) might increase the 30-day risk of stroke in patients undergoing symptomatic ICAS stenting.

Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model.

Clearance of amyloid-beta (Aß) from the brain is an important therapeutic strategy for Alzheimer's disease (AD). Current studies mainly focus on the central approach of Aß clearance by introducing therapeutic agents into the brain. In a previous study, we found that peripheral tissues and organs play important roles in clearing brain-derived Aß, suggesting that the peripheral approach of removing Aß from the blood may also be effective for AD therapy. Here, we investigated whether peritoneal dialysis, a clinically available therapeutic method for chronic kidney disease (CKD), reduces brain Aß burden and attenuates AD-type pathologies and cognitive impairments. Thirty patients with newly diagnosed CKD were enrolled. The plasma Aß concentrations of the patients were measured before and after peritoneal dialysis. APP/PS1 mice were subjected to peritoneal dialysis once a day for 1 month from 6 months of age (prevention study) or 9 months of age (treatment study). The Aß in the interstitial fluid (ISF) was collected using microdialysis. Behavioural performance, long-term potentiation (LTP), Aß burden and other AD-type pathologies were measured after 1 month of peritoneal dialysis. Peritoneal dialysis significantly reduced plasma Aß levels in both CKD patients and APP/PS1 mice. Aß levels in the brain ISF of APP/PS1 mice immediately decreased after reduction of Aß in the blood during peritoneal dialysis. In both prevention and treatment studies, peritoneal dialysis substantially reduced Aß deposition, attenuated other AD-type pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, and synaptic dysfunction, and rescued the behavioural deficits of APPswe/PS1 mice. Importantly, the Aß phagocytosis function of microglia was enhanced in APP/PS1 mice after peritoneal dialysis. Our study suggests that peritoneal dialysis is a promising therapeutic method for AD, and Aß clearance using a peripheral approach could be a desirable therapeutic strategy for AD.

Metabolic syndrome is associated with increased risk of short-term post-procedural complications after carotid artery stenting.

The risk factors for post-procedural events after carotid artery stenting (CAS) have not been well established. The aim of this study was to investigate the association between metabolic syndrome (MetS) and the risk of post-CAS complications. A total of 358 consecutive patients who underwent CAS were enrolled in this prospective study. Patients' demographic data, clinical characteristics, and complications after CAS within 30 days were recorded. Logistic regression analysis was performed to identify possible risk factors for post-procedural complications after CAS. The incidence of complications after CAS within 30 days was 7.0%. Logistic regression analysis identified the following as independent risk factors for 30-day transient ischemic attacks, stroke, myocardial infarction, and death after CAS: metabolic syndrome (OR = 2.31, 95% CI 1.91-3.01, P = 0.004), diabetes (OR = 2.24, 95% CI 1.74-2.76, P = 0.026), symptomatic patient (OR = 1.73, 95% CI 1.23-3.05, P = 0.011), and age (OR = 1.87, 95% CI 1.35-2.57, P = 0.042). Among the components of MetS, central obesity (OR = 2.21, 95% CI 1.24-2.63, P = 0.006), low high-density lipoprotein cholesterol (HDL-C) (OR = 1.66, 95% CI 1.34-2.27, P = 0.022), and high fasting plasma glucose (OR = 2.32, 95% CI 1.85-2.74, P = 0.003) were associated with increased risk of 30-day complications after CAS. This present study suggests that patients with metabolic syndrome have significantly increased risk of complications after CAS within 30 days. Moreover, MetS patients with central obesity, high fasting plasma glucose, or low HDL-C have significantly increased risk of complications after CAS within 30 days.

Association of ADIPOQ single nucleotide polymorphisms with the risk of intracranial atherosclerosis.

BACKGROUND: The genetic mechanism of the racial distribution difference of intracranial atherosclerosis (ICAS) is unclear. The single nucleotide polymorphisms (SNPs) may be associated with different genetic susceptibility to ICAS. At present, the correlation between ADIPOQ gene SNPs and the risk of ICAS remains unknown. METHODS: Continuous inpatients were selected and divided into ICAS group and control group. Computed tomography angiography was performed to observe intracranial arteries. ADIPOQ SNPs were detected using the ligase detection reaction-PCR. The correlation between the identified SNPs and ICAS was determined using the binary logistic regression analysis. RESULTS: This study contained 602 patients in total, including 199 ICAS and 403 control cases. The binary logistic regression analysis showed that the AG/AA genotype of the rs2241767 (OR = 2.242, 95% CI: 1.037-4.878, P = 0.040) and the AG/GG genotype of the rs182052 (OR = 1.822, 95% CI: 1.111-2.987, P = 0.017) were closely related to the risk of ICAS after adjusting for conventional cardiovascular risk factors. The haploid analysis results indicated that the incidence of the A-G haplotype of the rs2241767 and rs182052 was higher in the ICAS group than in the control group (P = 0.026). CONCLUSIONS: The SNPs of the ADIPOQ gene are closely related to increased risk of ICAS in Chinese Han population.

Intramuscular delivery of p75NTR ectodomain by an AAV vector attenuates cognitive deficits and Alzheimer's disease-like pathologies in APP/PS1 transgenic mice.

The neurotrophin receptor p75 (p75NTR) is a receptor for amyloid-beta (Aß) and mediates Aß-induced neurodegenerative signals. The ectodomain of p75NTR (p75ECD) is a physiological protective factor against Aß in Alzheimer's disease (AD). We have previously demonstrated that the shedding of p75ECD from the cell surface is down-regulated in AD brains and restoration of the p75ECD level in the brain, through intracranial administration of p75ECD by adeno-associated virus vectors, attenuates AD-like pathologies in an AD mouse model. In this study, we further investigated the feasibility and efficacy of peripheral administration of AAV-p75ECD on brain amyloid burden and associated pathogenesis. We found that intramuscular delivery of AAV-p75ECD increased the level of p75ECD in the blood, significantly improved the behavioral phenotype of amyloid precursor protein/PS1 transgenic mice, and reduced brain amyloid burden, attenuated Tau hyperphosphorylation, and neuroinflammation. Furthermore, intramuscular delivery of AAV-p75ECD was well tolerated. Our results indicate that peripheral delivery of p75ECD represents a safe and effective therapeutic strategy for AD. The ectodomain of p75NTR (p75ECD) is a physiological protective factor against amyloid-beta (Aß) in Alzheimer's disease (AD). Intramuscular delivery of AAV-p75ECD increased the p75ECD levels in the blood, reduced brain amyloid burden through a 'peripheral sink' mechanism and alleviates AD-type pathologies. Peripheral delivery of p75ECD represents a promising therapeutic strategy for AD.

Association of post stroke depression with social factors, insomnia, and neurological status in Chinese elderly population.

The purpose of this study was to investigate the association of post stroke depression (PSD) with social factors, insomnia, and neurological status among elderly Chinese patients with ischemic stroke. Six hundred and eight patients over 60 years of age, who had suffered from a first episode of ischemic stroke within 7 days, were enrolled into the study. They were divided into PSD and non-PSD groups according to the Self-rating Depression Scale (SDS) scores. The association of PSD with social factors, insomnia, and neurological status was analyzed using multivariable logistic regression analysis. Compared with the patients who did not develop PSD, those with PSD reported adverse life events more frequently, and more subjects with PSD lived alone, had left carotid artery infarction and cortical infarction (P < 0.05), history of insomnia, and high National Institute of Health Stroke Scale (NIHSS) scores and low Barthel Index (BI) scores (P < 0.01). The multivariable logistic regression analysis showed that the occurrence of PSD was associated with a history of insomnia (HR = 1.59, 95 % CI 1.12-2.36, P < 0.01), NIHSS scores (HR = 2.45, 95 % CI 1.42-3.91, P < 0.01) and BI scores (HR = 2.56, 95 % CI 1.39-4.25, P < 0.01). Insomnia and the degree of neurological deficit were associated with PSD in an elderly population of Chinese people.

An N-terminal antibody promotes the transformation of amyloid fibrils into oligomers and enhances the neurotoxicity of amyloid-beta: the dust-raising effect.

BACKGROUND: Senile plaques consisting of amyloid-beta (Aß) are the major pathological hallmark of Alzheimer's disease (AD) and have been the primary therapeutic target. Immunotherapies, which are designed to remove brain Aß deposits, increased levels of soluble Aß and accelerated brain atrophy in some clinical trials, suggesting that the solubilization of Aß deposition might facilitate the formation of more toxic Aß oligomers and enhance neurotoxicity. METHODS: The capacity of antibodies against different epitopes of Aß to disaggregate preformed Aß fibrils was investigated. The co-incubation of antibodies and Aß fibrils was then tested for neurotoxicity both in vitro and in vivo. RESULTS: After the incubation of preformed Aß fibrils with the N-terminal antibody 6E10, the fibrils were decreased, while the oligomers, mostly dimers and trimers, were significantly increased. However, no such effects were observed for antibodies targeting the middle domain (4G8) and C-terminus of Aß (8G7). The co-incubates of preformed Aß fibrils with 6E10 were more neurotoxic, both in vitro and in vivo, than the co-incubates with 4G8 and 8G7. CONCLUSIONS: Our results indicate that the antibody targeting the N-terminus of Aß promoted the transformation of Aß from fibrils into oligomers and increased neurotoxicity. Immunotherapies should take into consideration the enhanced neurotoxicity associated with the solubilization of Aß deposits by antibodies against the Nterminus of Aß.

Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer's disease.

Amyloid-beta (Aß) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). The physiological capacity of peripheral tissues and organs in clearing brain-derived Aß and its therapeutic potential for AD remains largely unknown. Here, we measured blood Aß levels in different locations of the circulation in humans and mice, and used a parabiosis model to investigate the effect of peripheral Aß catabolism on AD pathogenesis. We found that blood Aß levels in the inferior/posterior vena cava were lower than that in the superior vena cava in both humans and mice. In addition, injected (125)I labeled Aß40 was located mostly in the liver, kidney, gastrointestinal tract, and skin but very little in the brain; suggesting that Aß derived from the brain can be cleared in the periphery. Parabiosis before and after Aß deposition in the brain significantly reduced brain Aß burden without alterations in the expression of amyloid precursor protein, Aß generating and degrading enzymes, Aß transport receptors, and AD-type pathologies including hyperphosphorylated tau, neuroinflammation, as well as neuronal degeneration and loss in the brains of parabiotic AD mice. Our study revealed that the peripheral system is potent in clearing brain Aß and preventing AD pathogenesis. The present work suggests that peripheral Aß clearance is a valid therapeutic approach for AD, and implies that deficits in the Aß clearance in the periphery might also contribute to AD pathogenesis.

Correlation of single nucleotide polymorphisms in the pregnancy-associated plasma protein-A gene with carotid plaques.

BACKGROUND: Pregnancy-associated plasma protein A (PAPP-A) is abundantly expressed in carotid plaques. This study investigated the association between single nucleotide polymorphisms (SNPs) of PAPP-A and the presence of carotid plaques. METHODS: A total of 408 patients with carotid plaques and 493 controls were included in the study. All subjects were Southern Chinese Han. Carotid plaques were analyzed by computer tomography angiography. PAPP-A SNPs were identified by ligase detection reaction-polymerase chain reaction analysis. The PAPP-A genotypes rs3747823, rs7020782, and rs13290387 were analyzed. RESULTS: The rs7020782 C allele genotype correlated with an increased risk of developing carotid plaques under the dominant, recessive, and additive models (adjusted odds ratios: 2.60, 2.36, and 3.48, respectively; P ≤ 0.001). Only C allele-carrying genotypes correlated with a significantly increased risk of carotid plaque based on studies stratified by age and sex under the dominant model. rs7020782 remained significantly associated with the risk of carotid plaque calcification after adjusting for age and potential confounders (adjusted odds ratio, 1.89; 95 % confidence interval, 1.17-3.08; P = 0.010). CONCLUSIONS: This study found, for the first time, that the A˃C variation of rs7020782 might be an independent risk factor for carotid plaque development and calcification. The determination of such genotypes could provide a new tool for identifying individuals at high risk for carotid atherosclerosis.

Significant Association between Carotid Artery Kinking and Leukoaraiosis in Middle-Aged and Elderly Chinese Patients.

BACKGROUND: Leukoaraiosis (LA) and carotid artery morphologic variations are 2 common imaging manifestations. The purpose of this study was to determine whether carotid artery morphologic variations are correlated with LA. METHODS: A total of 702 patients, aged 50 years or older, admitted to our hospital from November 1, 2013, to January 30, 2014, were prospectively enrolled in this study. All participants underwent magnetic resonance imaging to assess the presence and severity of LA. Carotid artery morphologic variations were classified into tortuosity, kinking, and coiling by computed tomography angiography. Logistic regression analyses were performed to examine the relationship between carotid artery morphologic variations, its components, and LA. RESULTS: The frequency of hemisphere with LA and carotid artery with carotid artery morphologic variations was 49.9% and 70.3% in the cohort, respectively. Carotid kinking was associated with an increased risk of ipsilateral LA after multivariable adjustment (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.57-3.36 for left side; OR, 2.51; 95% CI: 1.68-3.74 for right side), whereas carotid tortuosity and coiling were not related to LA. Moreover, the prevalence of carotid kinking gradually increased with advancing grades of ipsilateral LA. CONCLUSIONS: The present study demonstrated that carotid artery kinking may be associated with an increased risk of LA in middle-aged and elderly Chinese patients. Further prospective studies are needed to confirm these findings.

[Associated risk factors of ischemic events for spontaneous cervical artery dissection].

OBJECTIVE: This study sought to identify risk factors of ischemic events and predictors of outcome for spontaneous cervical artery dissection (sCAD). METHODS: One hundred and sixty one patients diagnosed as sCAD were classified as patients with (n=77) and without (n=84) cerebral ischemia. Demographics, vascular risk factors and imaging features were compared between the two groups. Multivariate Cox regression analysis was performed to identify predictors of primary end-point events (all cause stroke and death) at follow-up. RESULTS: Patients with cerebral ischemia had a higher prevelence of hypertension and diabetes mellitus (62.3% vs 41.7%, 14.3% vs 6.2%, P<0.05). Patients with cerebral ischemia were more likely to present with stenosis (61.0% vs 23.8%, P<0.001) and less likely to present with aneurysmal dilatation (19.5% vs 44.0%, P<0.001) and double lumen (22.1% vs 38.1%, P<0.05). There was significant positive association of diabetes mellitus (odds ratio 3.095; 95% confidence interval, 1.273 to 7.524, P=0.013) and stenosis (odds ratio 4.335, 95% confidence interval, 2.123 to 8.854, P<0.001), and an inverse association of aneurysmal dilatation (odds ratio 0.429, 95% confidence interval, 0.198 to 0.930, P=0.032) with occurrence of ischemic events in patients with sCAD. At a mean follow-up of 16.0 months, overall incidence of primary end-point was 9.3% (n=15). Cox regression analysis showed cerebral ischemia at onset, arterial occlusion, obesity or overweightness were significant predictors of the primary endpoint. CONCLUSIONS: This study confirms that diabetes mellitus and arterial stenosis are risk factors of ischemic events for sCAD patients. Cerebral ischemia at onset, arterial occlusion, obesity or overweightness are predictors of primary endpoint at follow-up.

Exploring the mechanism of bioactive components of Prunella vulgaris L. in treating hepatocellular carcinoma based on network pharmacology.

In traditional Chinese Medicine, Prunella vulgaris L. (PVL) is potentially effective in the treatment of some human malignancies including hepatocellular carcinoma (HCC). However, the detailed mechanism of action remains unclear. The purpose of this study was to decipher the constitutes of the bioactive ingredients of PVL, and its mechanism against HCC using network pharmacology and in vitro experiments. The bioactive components of PVL were obtained by Traditional Chinese Medicine System Pharmacology Database and Analysis platform database, and the targets of bioactive components of PVL was investigated by Swiss Target Prediction database. HCC related targets were obtained from GEO database, GeneCards database and DisGeNET database, and the gene ontology function annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted for annotating the biological function of gene targets. A protein-protein interaction network was constructed using STRING database. Molecular docking of key bioactive ingredients was performed using AutoDock Vina. Cell proliferation and apoptosis were detected by cell counting kit-8 and flow cytometry, respectively. The expression level of the target genes of PI3K/Akt pathway were detected by qPCR. In the present work, 11 bioactive components of PVL were screened out, which acted on 177 potential targets. In addition, 13,517 genes were strongly associated with HCC pathogenesis, of which 158 targets are overlapped with PVL's targets. KEGG results identified 39 signaling pathways closely associated with the 158 targets. Molecular docking showed that the main bioactive components of PVL, kaempferol, morin, quercetin, luteolin, and spinasterol, had good binding activity with the core proteins in cancer biology such as AKT1, EGFR, SRC, ESR1, and PPARG. In vitro assays showed that quercetin, one of the main components of PVL extracts effectively inhibited HCC cell proliferation, and promoted apoptosis, which may be associated with PI3K/AKT signaling pathway. In summary, PVL may regulate HCC progression by regulating core targets such as AKT1, EGFR, SRC, ESR1, and PPARG, and acting on PI3K-Akt signaling pathway.